CH2Cl2 (0.15 M) and oxalyl chloride (1.7 eq) and catalytic amounts of DMF were added. ...... and N-Methyl maleimide (53 mg, 0.48 mmol, 4.0 eq) was added.
SUPPLEMENTARY INFORMATION DOI: 10.1038/NCHEM.1729
A strategy for the diversity-oriented synthesis of A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling macrocyclic scaffolds using multidimensional coupling Henning S. G. Beckmann, Feilin Nie, Caroline E. Hagerman, Henrik Henning S. G. Beckmann, Feilin Nie, Caroline E. Hagerman, Henrik Johansson, Yaw Sing Tan, David Wilcke and David R. Spring* Johansson, Yaw Sing Tan, David Wilcke and David R. Spring*
Supplementary Supplementary Information Information
1 1 1 1
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Table of Contents SUPPLEMENTARY FIGURES ....................................................................................................3 GENERAL METHODS ................................................................................................................7 DIAZOTRANSFER REAGENT SI-11...........................................................................................8 GENERAL PROCEDURES .........................................................................................................8 GENERAL REMARKS REGARDING THE MACROCYCLIZATIONS ........................................ 12 SYNTHESIS OF THE COMMON PRECURSOR ....................................................................... 12 SYNTHESIS OF AZIDO ACIDS ................................................................................................ 13 SYNTHESIS OF AZIDO BUILDING BLOCKS ........................................................................... 19 PREPARATION OF LINEAR UREAS........................................................................................ 29 PREPARATION OF LINEAR OXALYL UREAS ......................................................................... 39 PREPARATION OF LINEAR HYDANTOINS............................................................................. 40 PREPARATION OF LINEAR DIHYDROURACILS .................................................................... 43 PREPARATION OF LINEAR GUANIDINES .............................................................................. 43 PREPARATION OF LINEAR AMIDES ...................................................................................... 45 PREPARATION OF LINEAR AMINES ...................................................................................... 52 PREPARATION OF LINEAR DIHYDROPYRIDINONES ........................................................... 53 CUAAC AND RUAAC MACROCYCLIZATIONS ........................................................................ 54 METATHESIS MACROCYCLIZATIONS.................................................................................... 81 DIELS-ALDER REACTION ....................................................................................................... 85 TRANSESTERIFICATIONS ...................................................................................................... 86 TRANSAMIDATION ................................................................................................................ 110 HYDROLYSIS ......................................................................................................................... 112 REDUCTION........................................................................................................................... 113 PRINCIPAL MOMENT OF INERTIA CALCULATIONS............................................................ 115 CRYSTAL STRUCTURE OF COMPOUND SI-106.................................................................. 120 REFERENCES........................................................................................................................ 121 NMR SPECTRA ...................................................................................................................... 122
2 2
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Supplementary Figures
Supplementary Figure S1: Synthesis of the starting unit 1
Supplementary Figure S2: Synthesis of azido building blocks
Supplementary Figure S3: Divergent cleavage of the fluorous tag, exemplified for compound 6
3 3
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Supplementary Figure S4: Overview final compounds N O
N
N
N O
HN
O
HN O O
N
SI-66 N
N
SI-79
SI-67
39
N
O N
O
O
O
N
NH O
SI-84
SI-85
SI-108
45
SI-117
SI-118
SI-120
8
SI-94
SI-95
40
SI-116
SI-119
46
SI-121
SI-122
SI-123
SI-124
42
SI-125
4 4
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SI-126
SI-128
SI-127
37 N N N O
N O
SI-129
43
SI-135
SI-139
SI-143
SI-130
NH
O N
O
O
SI-131
SI-132
SI-133
SI-134
38
SI-136
SI-137
SI-138
SI-141
SI-142
SI-140
SI-145
SI-144
SI-146
5 5
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N N N
O O
SI-147
SI-111
N
O
SI-148
44
N
SI-149
SI-150
O
SI-151
SI-153
SI-154
SI-156
SI-157
9
SI-158
SI-159
10
SI-160
41
11
12
SI-152
SI-155
6 6
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General Methods Except as otherwise indicated, reactions were carried out using oven-dried glassware under nitrogen with dry, freshly distilled solvents. Tetrahydrofuran was distilled from calcium hydride and LiAlH4 in the presence of triphenyl methane. Diethyl ether was distilled from calcium hydride and LiAlH4. CH2Cl2, MeOH, toluene, MeCN and hexane were distilled from calcium hydride. Petroleum ether refers to the 40-60 °C fractions. All other reagents were used as obtained from commercial sources. Reactions under microwave heating were performed in sealed vials using a CEM Discover SP microwave reactor. All reactions were monitored by thin layer chromatography (TLC) using glass plates precoated with Merck silica gel 60 F254. Visualization was by the quenching of UV fluorescence (λmax = 254 nm) or by staining with ceric ammonium molybdate or potassium permanganate. Retention factors (Rf) are quoted to 0.01. Flash column chromatography was carried out using slurry-packed Merck 9385 Kieselgel 60 silica gel under a positive pressure of air or nitrogen. Fluorous solid phase extraction (F-SPE) was carried out using dry-packed Fluorous Technologies Inc. FluoroFlash silica gel 40 µm (approx. 20 fold excess over sample weight) under a positive pressure of nitrogen. The sample mixture was loaded onto the column using DMSO (max. 1 mL per 1 g of fluorous silica) and MeOH/H2O (4:1) was used to elute nonfluorous compounds. The fluorous compounds were subsequently eluted using pure MeOH. The fluorous silica was regenerated by washing with acetone or THF and dried at room temperature. Preparative HPLC purification was performed on an Agilent 1260 Infinity system fitted with a Supelcosil ABZ+Plus column (250 mm x 21.2 mm, 5 µm) using linear gradient systems (solvent A: 0.1% (v/v) TFA in water, solvent B: 0.05% (v/v) TFA in acetonitrile) at a flow rate of 20 mL min-1. Analytical HPLC analysis was performed on an Agilent 1260 Infinity system fitted with a Supelcosil ABZ+Plus column (150 mm x 4.6 mm, 3 µm) using linear gradient systems (solvent A: 0.05% (v/v) TFA in water, solvent B: 0.05% (v/v) TFA in acetonitrile) over 15 min at a flow rate of 1 mL min-1. Retention times (tr) are reported to the nearest 0.01 min. Peak area percentages are calculated for the UV absorbance at 220 nm and reported to the nearest 1%. Melting points were obtained using a Büchi Melting Point B-545 melting point apparatus and are uncorrected. Optical rotations were recorded on a Perkin Elmer 343 polarimeter. [α]D values are reported in 10−1 deg cm2 g−1 at 589 nm, concentration (c) is given in g (100 mL)−1. Infrared (IR) spectra were recorded on a Perkin-Elmer Spectrum One FT-IR spectrometer with internal referencing as neat films. Selected absorption maxima (νmax) are reported in wavenumbers (cm-1) and the following abbreviations are used: w, weak; m, medium; s, strong; br, broad. 7 7
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Nuclear magnetic resonance (NMR) spectra were recorded using an internal deuterium lock on Bruker DPX 400 (400MHz), Bruker Avance 400 QNP Ultrashield (400 MHz), Bruker Avance 500 BB ATM (500 MHz) and Bruker Avance 500 Cryo Ultrashield (500 MHz) spectrometers. Chemical shifts (δ) are referenced to the solvent signal and are quoted in ppm to the nearest 0.01 ppm for δH and to the nearest 0.1 ppm for δC. Coupling constants (J) are reported in Hertz to the nearest 0.1 Hz. Assignments are supported by DEPT-135, 1H-1H COSY, HMQC, HMBC and NOESY spectra where necessary. Data are reported as follows: chemical shift, multiplicity (br, broad; s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet; or as a combination of these), coupling constant(s), integration and assignment. Diastereotopic protons are assigned as Ha and Hb, where Ha indicates the proton at higher chemical shift. The numbering schemes used on selected spectra do not follow the IUPAC naming system and are used for the clear assignment of 1H and 13C spectra. Carbons with fluorine atoms attached are not reported. Low resolution mass spectra (ESI) were recorded using an LCMS system (Agilent 1200 series LC with an ESCi Multi-Mode Ionization Waters ZQ spectrometer using MassLynx 4.0 software). High resolution mass spectrometry (HRMS) was carried out with a Micromass Q-TOF or a Waters LCT Premier Mass Spectrometer using electrospray ionisation [ESI] or electron ionisation [EI].
Diazotransfer Reagent SI-11 The diazo transfer reagent 1H-imidazole-1-sulfonyl azide hydrochloride SI-11 was prepared according to a published procedure.[1] In a recent publication, safety concerns regarding this diazo transfer reagent have been raised.[2] Though we never observed any incident using it, we would recommend considering the usage of alternative diazo transfer reagents introduced in that publication.
General Procedures GP1: Azido Building Block Formation Preparation of the acyl chloride: The azidoacid (1.3 eq) was dissolved or suspended in dry CH2Cl2 (0.15 M) and oxalyl chloride (1.7 eq) and catalytic amounts of DMF were added. After stirring until TLC indicated complete turnover (typically 0.5-3 h, small samples of the reaction mixture were quenched with MeOH for that purpose), the solvent was removed under reduced pressure and the acyl chloride was used without further purification. Amide formation: The amine (1.0 eq) was dissolved in dry CH2Cl2 or THF (0.1 M) and the freshly prepared acyl chloride (dissolved in a minimum amount of dry CH2Cl2 or THF) was added followed by the addition of saturated NaHCO3 (excess). After vigorous stirring for 0.5-2 h, the organic solvent was removed under reduced pressure. The residue was diluted with EtOAc, washed with 5% HCl, saturated NaHCO3, brine, dried over MgSO4, filtrated and the solvent was 8 8
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removed under reduced pressure. The crude product was purified by flash column chromatography.
GP2: Urea Formation The azido building block (1.00 eq) was dissolved in dry THF (0.05 M) under argon and PPh3 (1.00 eq) or P(n-Bu)3 (1.00 eq; in combination with 4 Å molecular sieves) was added. After TLC indicated complete consumption of the starting material (typically within 3 h for PPh3 and 0.5-3 h for P(n-Bu)3; if an incomplete turnover was observed, additional phosphine was added in portions of 0.05 eq), the hydrochloric salt of the amine (1.10-2.00 eq) and DIPEA (1.20-4.00 eq) were added and the reaction was put under a CO2 atmosphere. After stirring overnight, the solvent was removed under reduced pressure and the residue was purified using F-SPE.
GP3: Oxalylurea Formation The linear urea (1.0 eq) was dissolved in dry CH2Cl2 (0.05 M) and pyridine (3.0 eq) was added. The solution was cooled to 0 °C and oxalyl chloride (1.3-2.1 eq) was added. The reaction was stirred for 3 h or overnight. The reaction mixture was diluted with CH2Cl2, washed with 5% HCl, saturated NaHCO3 and brine, dried over MgSO4 and the solvent was removed under reduced pressure.
GP4: Hydantoin Formation The linear urea (1.0 eq) was dissolved in dry THF (0.02 M) and N,N'-diisopropylcarbodiimide (1.5 eq), N-hydroxysuccinimide (1.5 eq) and DMAP (1.5 eq) were added. After refluxing the reaction overnight, the solvent was removed and the residue was dissolved in EtOAc. The organic layer was washed with 5% HCl, saturated NaHCO3 and brine, dried over MgSO4 and the solvent was removed under reduced pressure.
GP5: Dihydrouracil Formation The linear urea (1.0 eq) was dissolved in dry THF (0.02 M) and N,N'-diisopropylcarbodiimide (1.6 eq), N-hydroxysuccinimide (1.6 eq) and DMAP (1.5 eq) were added. After refluxing the reaction for 19 h, the solvent was removed and the residue was purified by flash column chromatography.
GP6: Guanidine Formation The azido building block (1.00 eq) was dissolved in dry THF (0.04 M) under argon and molecular sieves (4 Å) and P(n-Bu)3 (1.15 eq) were added. After TLC indicated complete consumption of the starting material (typically within 0.5-3 h), the isocyanate (1.00-1.05 eq) was added. After stirring for 1-1.5 h, the hydrochloric salt of the amine (1.1 eq) and DIPEA (2.0 eq) were added and the reaction was stirred for 3-4 h. Subsequently, the solvent was removed under reduced pressure and the residue was purified as indicated.
9 9
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GP7: Amide Formation Preparation of the acyl chloride: The acid (1.3-1.6 eq) was dissolved in dry CH2Cl2 (0.2 M) and oxalyl chloride (1.6-2.4 eq) and catalytic amounts of DMF were added. After stirring until TLC indicated complete turnover (typically 0.5-3 h, small samples of the reaction mixture were quenched with MeOH for that purpose), the solvent was removed under reduced pressure and the acyl chloride was used without further purification. Amide formation: The azido building block (1.0 eq) was dissolved in dry THF (0.03 M) under argon and P(n-Bu)3 (1.0 eq) was added. After TLC indicated complete consumption of the starting material (typically after 0.5-3 h, further additions of P(n-Bu)3 in portions of 0.05 eq were made if no completion was observed), the freshly prepared acyl chloride (dissolved in a minimum amount of CH2Cl2) was added. After stirring overnight, the reaction was quenched by the addition of a small volume of MeOH and the solvent was removed followed by an optional aqueous workup, i.e. the residue was dissolved in EtOAc and washed with 5% HCl, saturated NaHCO3 and brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography.
GP8: Amine Formation The azido building block (1.0 eq) was dissolved in dry THF (0.1 M) under argon and molecular sieves (4 Å) and P(n-Bu)3 (1.0 eq) were added. After TLC indicated complete consumption of the starting material (typically after 0.5-3 h; further additions of P(n-Bu)3 (each 0.05 eq) were made if no completion was observed), the aldehyde (1.1-1.2 eq) in dry THF (0.1 M) was added and the reaction was stirred for 14-19 h. The solvent was removed in a stream of nitrogen and the residue was dissolved in dry MeOH (0.1 M). NaBH4 (2 eq) was added and the mixture was stirred until reduction and transesterification were completed (typically 2 h). The solvent was removed in a stream of nitrogen and the residue was dissolved in EtOAc, washed with saturated NaHCO3 and brine, dried over MgSO4, filtrated and the solvent was removed under reduced pressure. The crude product was purified as indicated.
GP9: CuAAC Macrocyclization The linear precursor (1.0 eq) was dissolved in dry THF (1 mM) and DIPEA (3 eq) was added. After bubbling argon through the solution for 20 min, CuI (2 eq) was added and the mixture was heated to reflux until HPLC indicated complete turnover. Subsequently, the solvent was removed and the residue was dissolved in CH2Cl2/MeOH 10:1, filtered through a pad of SiO2 and further purified as indicated.
GP10: RuAAC Macrocyclization The linear precursor (1.0 eq) was dissolved in dry THF (1 mM) and argon was bubbled through the solution for 20 min. [Cp*RuCl]4 (0.05-0.1 eq) was added and the mixture was heated to reflux until HPLC indicated complete turnover. Subsequently, the solvent was removed and the residue was dissolved in CH2Cl2/MeOH 10:1, filtered through a pad of SiO2 and further purified as indicated. 10 10
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GP11: Metathesis Macrocyclization The linear precursor (1.0 eq) was dissolved in dry CH2Cl2 (1 mM) and ethylene was bubbled through the solution for 10 min. Grubbs 2nd generation catalyst (0.2 eq) was added and the reaction was heated to reflux under an ethylene atmosphere. When HPLC indicated complete formation of the diene intermediate (typically after 4 h), the atmosphere was changed to argon. Refluxing was continued until HPLC indicated reaction completion; if an incomplete conversion was observed, additional catalyst was added in portions of 0.1 eq. The solvent was removed under reduced pressure and the crude product was purified as indicated.
GP12: Transesterification The fluorous-tagged macrocycle (1.0 eq) was dissolved in dry MeOH (15 mM) and MeONa (0.05 M in MeOH; 1.0-1.1 eq) was added. After stirring at room temperature until TLC indicated complete turnover (typically 30 min), the reaction was quenched by the addition of HCl in dioxane (4M; 1.05-1.2 eq) and the solvent was removed in a stream of nitrogen. Subsequently, the residue was purified as indicated.
GP13: Transamidation The fluorous-tagged macrocycle (1.0 eq) was dissolved in dry CH2Cl2 (20 mM) under argon. Molecular sieves (4 Å), the amine (10 eq), and DIPEA (20 eq) were added and the mixture was stirred for 10 min. A solution of Me2AlCl in hexane (1 M, 10 eq) was added dropwise over 5 min. The mixture was stirred in the microwave at 80 °C for 100 min. Saturated NH4Cl and MeOH were added and the solvents were removed under a flow of N2. The crude product was purified as indicated.
GP14: Hydrolysis The fluorous-tagged macrocycle (1.0 eq) was dissolved in THF (20 mM) and LiOH (2.0 eq) in water (half of the THF volume) was added at 0 °C. After stirring at room temperature until TLC indicated complete reaction (~2 h), the reaction was quenched by the addition of HCl in dioxane (4 M; 2.5 eq) and stirred for another 10 minutes. The solvent was removed under a stream of nitrogen and the residue was purified using preparative HPLC.
GP15: Reduction The fluorous-tagged macrocycle (1.0 eq) was dissolved in dry THF (20 mM) and LiCl (10 eq) and NaBH4 (15 eq) were added and the suspension was stirred at ambient temperature for 1-2 h. Dry EtOH (half the volume of THF) was added and the mixture was stirred overnight. The solvent was removed under a stream of N2. The residue was filtered through a short plug of silica (CH2Cl2/MeOH 10:1) and subsequently purified as indicated.
11 11
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General Remarks regarding the Macrocyclizations In general, the macrocyclization methods used in this study (CuAAC, RuAAC, enyne metathesis) delivered the desired macrocyclic products in moderate to good yields. However, there are two limitations we would like to report: 1. Due to the highly linear nature of the precursors derived from building block 16, dimer formation as a result of an intermolecular cyclization was mainly observed in this case with macrocycles SI-70 and SI-71 as the only succesful examples of an intramolecular cyclization with yields over 40%. 2. We observed that the RuAAC with precursors bearing an amine linker led to huge amounts of decomposed material and to a low yield of the desired macrocycle (e.g. see formation of 45). In another example, the RuAAC of the amine containing linear precursor SI-65 led to complete decomposition while the CuAAC of SI-65 (formation of 40) worked in 56% yield.
Synthesis of the Common Precursor Fluorous-tagged bromide SI-1
1H,1H,2H,2H-Perfluorodecan-1-ol (10 g, 22 mmol, 1.0 eq) was dissolved dry Et2O (50 mL) and bromoacetyl bromide (2.8 mL, 32 mmol, 1.5 eq) was added dropwise at 0 °C. After stirring at 0 °C for 2 h, the reaction was stirred overnight at room temperature. Subsequently, the reaction was quenched by the addition of water (5 mL). Saturated NaHCO3 was added, the layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure. Without need for further purification, title compound SI-1 (12.3 g, 21.0 mmol, 97%) was isolated as a yellow foam. TLC Rf = 0.31 (petroleum ether/EtOAc 5:1); IR (neat) νmax = 1743 (m, C=O), 1198 (s, C-F), 1145 (s, C-F), 1115 (s, C-F); 1H NMR (500 MHz, CDCl3, 27 °C) δ = 4.48 (t, J = 6.5, 2H; H-3), 3.85 (s, 2H; H-2), 2.52 (tt, J = 18.2, 6.5, 2H; H-4); 13C NMR (125 MHz, CDCl3, 27 °C) δ = 166.9 (C-1), 58.0 (C-3), 30.4 (C-4), 25.1 (C-2); LCMS (ESI+) m/z = 584.1 [M+H]+. An HRMS of this sample could not be obtained.
Fluorous-tagged amine 1
DIPEA (1.46 mL, 8.41 mmol, 1.00 eq) and bromide SI-1 (4.92 g, 8.41 mmol, 1.00 eq) were added to a solution of propargylamine (926 mg, 16.8 mmol, 2.00 eq) in dry CH2Cl2 (25 mL). After 12 12
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stirring for 20 h, the solvent was removed. After purification by flash column chromatography (petroleum ether/EtOAc 3:1 to 2:1), title compound 1 (3.91 g, 6.99 mmol, 83%) was isolated as a colorless foam. TLC Rf = 0.36 (petroleum ether/EtOAc 3:1); IR νmax (neat) = 3280 (w), 1744 (m, C=O), 1195 (s, C-F), 1116 (s, C-F); 1H NMR (500 MHz, CDCl3, 27 °C) δ = 4.45 (t, J = 6.5, 2H; H-6), 3.55 (s, 2H; H-2), 3.50 (d, J = 2.5 2H; H-3), 2.50 (tt, J = 18.3, 6.5, 2H; H-7), 2.23 (t, J = 2.5, 1H; H-5); 13C NMR (125 MHz, CDCl3, 27 °C) δ = 171.6 (C-1), 80.9 (C-4), 72.1 (C-5), 56.7 (C-6), 49.0 (C-2), 37.6 (C-3), 30.5 (C-7); HRMS (ESI+) m/z = 560.0506 [M+H]+ found, C15H11F17NO2+ required 560.0513.
Non-fluorous tagged amine SI-2[3]
The title compound SI-2 was prepared according to a published procedure.[3]
Synthesis of Azido Acids 3-Azidobenzoic acid SI-3[4]
3-Azidobenzoic acid (SI-3) was prepared according to a published procedure.[4]
4-Azidobenzoic acid SI-4[5]
4-Azidobenzoic acid (SI-4) was prepared according to a published procedure.[5]
13 13
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Figure S5: Synthesis of azido acids
Potassium 2-aminophenylacetate SI-5
2-Nitrophenylacetic acid (SI-4) (1.99 g, 11.0 mmol, 1.0 eq) was dissolved in dry MeOH (30 mL) and potassium carbonate (1.52 g, 11.0 mmol, 1.0 eq) was added. Pd/C (10%; 198 mg) was added and the mixture was stirred at room temperature under an atmosphere of H2 overnight. Subsequently, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and crude amine SI-5 was used in the next step without further purification 14 14
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2-Azidophenylacetic acid SI-6
Crude amine SI-5 (assuming 11 mmol, 1.0 eq) was dissolved in water (15 mL) and concentrated sulphuric acid (3 mL) was added at 0 °C. NaNO2 (797 mg, 11.6 mmol, 1.05 eq) in water (4 mL) was added to the reaction vessel and the reaction solution was stirred at 0 °C for 20 min. At 0°C, the reaction solution was added to NaN3 (751 mg, 11.6 mmol, 1.05 eq) in water (4 mL). After stirring for 10 min at 0°C, EtOAc was added, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure. Title compound SI-6[6] (1.6 g, 8.8 mmol, 80% over two steps) was isolated as a yellow solid. TLC Rf = 0.50 (CH2Cl2/MeOH/AcOH 10:1:0.1); HPLC tr = 8.72 min (20-70% B), peak area 99%; mp 154-157 °C (EtOAc); IR (neat) νmax = 2130 (m, N3), 2083 (m, N3), 1687 (s, C=O), 1584 (m), 1493 (m), 1457 (m), 1418 (m), 1407 (m) ,1342 (m), 1284 (s), 1237 (s), 1192 (m), 1167 (m), 952 (m), 754 (s); 1H NMR (400 MHz, DMSO-d6, 27 °C) δ = 12.34 (s, 1H; H-9), 7.36 (m, 1H; H-4), 7.28 (m, 2H; H-2 and H-5), 7.14 (m, 1H; H-3), 3.54 (s, 2H; H-7); 13C NMR (100 MHz, DMSO-d6, 27 °C) δ = 172.0 (C-8), 138.1 (C-6), 131.8 (C-5), 128.6 (C-4), 126.6 (C-1), 124.9 (C-3), 118.4 (C2), 36.2 (C-7); LCMS (ESI-) m/z = 176.1 [M-H]-. An HRMS of this sample could not be obtained.
3-(Azidomethyl)benzoic acid SI-7
3-(Chloromethyl)benzoic acid (3.00 g, 17.6 mmol, 1.00 eq) was dissolved in DMSO (60 mL), and sodium azide (1.37 g, 21.1 mmol, 1.20 eq) was added. After stirring at 30 °C for 5 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (4 × 30 mL). The combined organic layers were washed with water and brine and dried over NaSO4. The solvent was removed under reduced pressure to give the crude azide as yellow oil that solidified upon standing. Attempted recrystallization from n-hexane led to melting of the product giving a twophase mixture. Cooling under vigorous stirring afforded a precipitate, which was collected by filtration, washed with ice-cold Et2O and dried under vacuum. Title compound SI-7[7] (2.75 g, 15.5 mmol, 86%) was isolated as an off-white solid. TLC Rf = 0.23 (CH2Cl2/MeOH 20:1); mp 68-69°C (Et2O); IR (neat) νmax = 2815 (br, O-H), 2086 (s, N3), 1647 (s, C(=O)OH); 1H NMR (500 MHz, CDCl3, 27 °C) δ = 8.10 (dt, J = 7.7, 1.5, 1H; H-3 or H-5), 8.07 (s, 1H; H-7), 7.60 (dt, J = 7.7, 1.4, 1H; H-3 or H-5), 7.52 (t, J = 7.7, 1H; H-4), 4.44 15 15
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(s, 2H; H-8); 13C NMR (125 MHz, CDCl3, 27 °C) δ = 170.9 (C-1), 136.5 (C-6), 133.8 (C-3 or C5), 130.5 (C-7), 130.2 (C-4), 130.1 (C-2), 129.6 (C-3 or C-5) 54.7 (C-8). HRMS (ESI-) found m/z = 176.0465 [M-H]-, C8H6N3O2- required 176.0465.
Methyl 3-(2-azidoethyl)benzoate SI-12
Analogously to the diazo transfer protocol of Goddard-Borger and Stick,[1] to a solution of the hydrochloride salt of amine SI-10[8] (1.93 g, 8.98 mmol, 1.00 eq), CuSO4·5 H2O (27 mg, 0.090 mmol, 0.01 eq), and K2CO3 (4.06 g, 24.2 mmol, 2.70 eq) in dry MeOH (80 mL) was added diazotransfer reagent SI-11 (2.71 g, 10.8 mmol, 1.20 eq) in small portions. The reaction was stirred for 15 h. The solvent was removed under reduced pressure, diluted with H2O (150 mL) and acidified to pH 3 with 2 M aqueous HCl. The aqueous phase was extracted with EtOAc (3x50 mL) and the combined organic layers were washed with brine (50 mL), dried over MgSO4 and filtered. After purification by flash column chromatography (petroleum ether/EtOAc 6:1-5:1), title compound SI-12 (1.26 g, 6.17 mmol, 69%) was isolated as a clear oil. TLC Rf = 0.82 (petroleum ether/EtOAc 1:1); IR (neat) νmax = 2095 (s, N3), 1719 (s, (C=O)OR); 1H NMR (400 MHz, CDCl3, 27 °C) δ = 7.94 (dt, J = 7.0, 1.9, 1H; H-3 or H-5), 7.91 (s, 1H; H-7), 7.43 (dt, J = 7.5, 1.9, 1H; H-3 or H-5), 7.39 (t, J = 7.2, 1H; H-4), 3.92 (s, 3H; H-10), 3.54 (t, 2H; H-8), 2.94 (t, 2H; H-9); 13C NMR (100 MHz, CDCl3, 27 °C) δ = 167.3 (C-1), 138.8 (C-6), 133.8 (C-3 or C-5), 131.0 (C-2), 130.2 (C-7), 129.1 (C-4), 128.5 (C-3 or C-5), 52.6 (C-9), 52.5 (C-10), 35.5 (C8); HRMS (ESI+) m/z = 228.0754 [M+Na]+ found, C10H11N3O2Na+ required 228.0743.
3-(2-Azidoethyl)benzoic acid SI-13
Methyl ester SI-12 (1.07 g, 5.21 mmol, 1.00 eq) was dissolved in THF (21 mL) and H2O (14 mL) and NaOH (0.64 g, 16 mmol, 3.1 eq) was added portionwise. The reaction was stirred at 50°C for 15 h. The reaction was diluted with diethyl ether (50 mL) and water (50 mL), acidified to pH 3 with 1 M aqueous HCl. The layers were separated and aqueous layer was extracted with diethyl ether (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Title compound SI-13 (0.981 g, 5.13 mmol, 99%) was isolated as clear oil. TLC Rf = 0.30 (petroleum ether/EtOAc 1:1); IR (neat) νmax = 2941 (br, O-H), 2104 (s, N3), 1689 (s, C(=O)OH); 1H NMR (400 MHz, CDCl3, 27 °C) δ = 7.95 (dt, J = 7.4, 1.6, 1H; H-3 or H-5), 7.92 (s, 1H; H-7), 7.42 (dt, J = 7.7, 1.6, 1H; H-3 or H-5), 7.37 (t, J = 7.5, 1H; H-4), 3.49 (t, J = 7.1, 2H; H-8), 2.89 (t, J = 7.1, 2H; H-9); 13C NMR (100 MHz, CDCl3, 27 °C) δ = 172.4 (C-1), 139.0 (C-6), 16 16
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134.7 (C-3 or C-5), 130.8 (C-7), 130.1 (C-2), 129.3 (C-4), 129.1 (C-3 or C-5), 52.6 (C-9), 35.5 (C-8); HRMS (ESI+) m/z = 214.0594 [M+Na]+ found, C9H9N3O2Na+ required 214.0587.
5-(Azidomethyl)furan-2-carboxylic acid acid SI-15
Methyl 5-(azidomethyl)furan-2-carboxylate SI-14[9] (0.90 mg, 5.0 mmol, 1.0 eq) was dissolved in a mixture of THF (3 mL) and methanol (6 mL). NaOH (1.1 g, 28 mmol, 5.5 eq) dissolved in H2O (3 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and at room temperature for further 30 min. The organic solvent was removed under reduced pressure. The remaining aqueous solution was adjusted to pH 1-2 using 10% HCl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give SI-15 (0.72 g, 4.3 mmol, 86%) as a white solid. TLC Rf = 0.35 (CH2Cl2/MeOH/AcOH 5:0.2:0.1); HPLC tr = 9.40 min (5-60% B), peak area 99%; mp 105-106 °C (CH2Cl2); IR νmax (neat) = 2858 (br, OH), 2118 (m, N3), 2087 (m, N3), 1683 (s, C=O), 1596 (m), 1537 (m), 1420 (m), 1282 (s), 1206 (s), 1153 (m), 1018 (m), 965 (m), 942 (m), 876 (m), 822 (s), 760 (s); 1H NMR (400 MHz, CDCl3, 27 °C) δ = 10.71 (br s, 1H; H-7), 7.32 (d, J = 3.6, 1H; H-2), 6.51 (d, J = 3.6, 1H; H-3), 4.41 (s, 2H; H-5); 13C NMR (100 MHz, CDCl3, 27 °C) δ = 163.4 (C-6), 154.7 (C-4), 144.1 (C-1), 121.1 (C-2), 111.4 (C-3), 47.1 (C-5); HRMS (ESI+) m/z = 190.0217 [M+Na]+ found, C6H5N3O3Na+ required 190.0223.
5-Amino-1H-indole-3-carboxylic acid SI-16
5-Nitro-1H-indole-3-carboxylic acid[10] (3.40 g, 16.5 mmol) and Pd/C (684 mg, 10% Pd) were suspended in dry MeOH (120 mL) and stirred vigorously under an atmosphere of hydrogen at ambient temperature overnight. The catalyst was removed by filtration through a pad of Celite and the filtrate was evaporated to dryness affording 5-amino-1H-indole-3-carboxylic acid SI-16 (2.86 g, 16.2 mmol, 98%) as a dark brown solid. TLC Rf = 0.16 (CH2Cl2/MeOH 9:1); mp 155 °C; 1H NMR (400 MHz, DMSO-d6, 27 °C) δ = 11.30 (s, 1H; NHInd), 7.71 (s, 1H, H-2), 7.26 (d, J = 2.0, 1H; H-4), 7.10 (d, J = 8.5, 1H; H-7), 6.52 (dd, J = 8.5, 2.0, 1H; H-6), 4.63 (br s, 2H; NH2); 13C NMR (100 MHz, DMSO-d6, 27 °C) δ = 167.4 (CO2H), 143.0 (C-5), 131.0 (C-2), 129.9 (C-7’), 127.6 (C-4’), 112.1 (C-6 or C-7), 112.0 (C-6 or C7), 107.5 (C-3), 104.2 (C-4); HRMS (EI) m/z = 132.0685 [M-CO2]+ found, C8H8N2+ required 132.0682. 17 17
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5-Azido-1H-indole-3-carboxylic acid SI-17
5-Amino-1H-indole-3-carboxylic acid SI-16 (2.85 g, 16.2 mmol, 1.00 eq) was dissolved in 2 M HCl (50 mL) at −10 °C (ice/NaCl bath). Then NaNO2 (1.17 g, 17.0 mmol, 1.05 eq, dissolved in 50 mL of water) was added dropwise and the solution was stirred for 20 min at −10 °C. The mixture was added to a solution of NaN3 (1.10 g, 17.0 mmol, 1.05 eq) in ice water (50 mL). The reaction was warmed to ambient temperature and stirred for 2 h. Then conc. HCl (10 mL) was added and the mixture was filtered. The resulting solid was washed with water (100 mL) and petroleum ether (100 mL) and subsequently dried in vacuo affording 5-Azido-1H-indole-3-carboxylic acid SI-17 (2.00 g, 9.89 mmol, 61%) as a brown solid. TLC Rf = 0.34 (CH2Cl2/MeOH 9:1); mp 160 °C decomposition; 1H NMR (400 MHz, DMSO-d6, 27 °C) δ = 12.05 (br s, 1H; CO2H), 11.93 (br s, 1H; NH), 8.05 (d, J = 3.0, 1H; H-2), 7.69 (d, J = 2.3, 1H; H-4), 7.50 (d, J = 8.6, 1H; H-7), 6.93 (dd, J = 8.6, 2.3, 1H; H-6); 13C NMR (100 MHz, DMSO-d6, 27 °C) δ = 165.6 (CO2H), 134.1 (C-7’), 133.5 (C-2), 132.5 (C-5), 126.9 (C-4’), 114.2 (C-6), 113.7 (C-7), 109.7 (C-4), 107.0 (C-3); HRMS (EI) m/z = 174.0423 [M-N2]+ found, C9H6N2O2+ required 174.0424.
5-Azido-1-(tert-butoxycarbonyl)-1H-indole-3-carboxylic acid SI-18
5-Azido-1H-indole-3-carboxylic acid SI-17 (2.00 g, 9.89 mmol, 1.00 eq) and DMAP (604 mg, 4.95 mmol, 0.50 eq) were suspended in dry CH2Cl2 (55 mL) at ambient temperature under an atmosphere of nitrogen. Boc2O (2.27 g, 10.4 mmol, 1.05 eq) was added in one portion and the resulting solution was stirred at ambient temperature overnight. The mixture was evaporated to dryness and the residue was taken up in MeOH (60 mL). The resulting suspension was stored at 4 °C overnight and filtered. The filter cake was thoroughly washed with MeOH and dried in vacuo affording 5-azido-1-(tert-butoxycarbonyl)-1H-indole-3-carboxylic acid SI-18 (1.35 g, 4.47 mmol, 45%) as a pale brown solid. TLC Rf = 0.49 (CH2Cl2/MeOH 9:1); mp 163 °C decomposition; 1H NMR (400 MHz, CDCl3, 27 °C) δ = 8.37 (s, 1H; H-2), 8.16 (d, J = 8.9, 1H; H-7), 7.87 (d, J = 2.3, 1H; H-4), 7.05 (dd, J = 8.9, 2.3, 1H; H-6), 1.67 (s, 9H; C(CH3)3); 13C NMR (100 MHz, CDCl3, 27 °C) δ = 169.3 (CO2H), 148.5 (NCO2tBu), 136.5 (C-5), 134.5 (C-2), 133.0 (C-7’), 128.6 (C-4’), 117.0 (C-6), 116.5 (C-7), 111.4 (C-4), 110.9 (C-3), 85.7 (C(CH3)3), 28.1 (C(CH3)3); LCMS (ESI−) m/z = 301.2 [M-H]-. An HRMS of this sample could not be obtained. 18 18
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Synthesis of Azido Building Blocks Azido building block 17
Fluorous-tagged amine SI-2 (559 mg, 4.40 mmol, 1.0 eq) was reacted with azido acid SI-6 (1.01 g, 5.72 mmol, 1.30 eq) according to GP1 using saturated NaHCO3 as base. After purification by flash column chromatography (petroleum ether/EtOAc 2:1), title compound 17 (1.01 g, 3.53 mmol, 80%) was isolated as a yellow oil. TLC Rf = 0.55 (petroleum ether/EtOAc 1:1); HPLC tr = 10.60 min (20-70% B), peak area 99%; IR (neat) νmax = 3225 (m), 2129 (s, N3), 1725 (m, C=O), 1657 (m, C=O), 1588 (w), 1494 (w), 1451 (s), 1422 (s), 1287 (s), 1267 (s), 1205 (s), 1000 (s), 751 (s); 1H NMR (400 MHz, CDCl3, 27 °C) major rotamer signals only ⃰ δ = 7.34-7.24 (m, 2H; H-11 and H-9, coincides with solvent signal), 7.16-7.08 (m, 2H; H-10 and H-12), 4.26 (s, 2H; H-2), 4.22 (d, J = 2.4 Hz, 2H; H-3), 3.76 (s, 2H; H-7), 3.73 (s, 3H; H-14), 2.33 (t, J = 2.5 Hz, 1H; H-5); 13C NMR (100 MHz, CDCl3, 27 °C) major rotamer signals only ⃰ δ = 170.9 (C-6), 169.7 (C-1), 138.2 (C-13), 131.1 (C-9), 128.7 (C-11), 126.0 (C-8), 125.14 (C-10), 118.2 (C-12), 77.6 (C-4), 73.6 (C-5), 52.3 (C-14), 46.7 (C-2), 38.7 (C-3), 35.3 (C-7); HRMS (ESI+) m/z = 287.1132 [M+H]+ found, C14H15N4O3+ required 287.1139. ⃰ Higher temperatures led to intramolecular cyclization
Azido building block 3
Fluorous-tagged amine 1 (3.00 g, 5.36 mmol, 1.00 eq) was reacted with azido acid SI-3 (1.14 g, 6.97 mmol, 1.30 eq) according to GP1 using saturated NaHCO3 as base. After purification by flash column chromatography (petroleum ether/EtOAc 3:1), title compound 3 (3.22 g, 4.57 mmol, 85%) was isolated as a slightly yellow wax. TLC Rf = 0.46 (petroleum ether/EtOAc 3:1); HPLC tr = 11.98 min (50-100% B), peak area 100%; IR (neat) max = 2110 (m, N3), 1749 (m, C=O), 1650 (w), 1628 (w), 1582 (m), 1197 (s, C-F), 1145 (s, C-F); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.50 (t, J = 7.9, 1H; H-9), 7.26-7.21 (m, 2H; H-8 and H-9), 7.15 (br s, 1H; H-12), 4.42 (t, J = 6.0, 2H; H-13), 4.23 (s, 2H; H-2), 4.21 (br s, 2H; H-3), 3.16 (t, J = 2.5, 1H; H-5), 2.66 (tt, J = 19.1, 6.0, 2H ; H-14); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 169.1 (C=O), 167.8 (C=O), 139.6, 136.2 (both quat. Ar), 129.8, 122.8, 120.3, 116.8 19 19
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(each Ar), 78.0 (C-4), 74.9 (C-5), 56.4 (C-13), 29.6 (C-14); HRMS (ESI+) m/z = 705.0796 [M+H]+ found, C22H14F17N4O3+ required 705.0789.
Azido building block 16 5
4
O
11
F17C8 12
O
1
3
N 2
O
6 7
8 9 10
16
N3
Fluorous-tagged amine 1 (2.64 g, 4.72 mmol, 1.00 eq) was reacted with azido acid SI-4 (1.00 g, 6.13 mmol, 1.30 eq) according to GP1 using saturated NaHCO3 as base. After purification by flash column chromatography (petroleum ether/EtOAc 3:1), title compound 16 (2.85 g, 4.05 mmol, 86%) was isolated as an off-white foam. TLC Rf = 0.48 (petroleum ether/EtOAc 3:1); HPLC tr = 12.02 min (50-100% B), peak area 89%; mp 71-78 °C (CH2Cl2); IR (neat) νmax = 3258 (w), 2132 (m, N3), 2105 (m, N3), 1734 (m, C=O), 1634 (m, C=O), 1601 (m), 1504 (w), 1423 (m), 1405 (w), 1195 (s, C-F), 1144 (s, C-F), 848 (m); 1 H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.49 (d, J = 8.5, 2H; H-8), 7.18 (d, J = 8.5, 2H; H-9), 4.42 (t, J = 6.0, 2H; H-11), 4.23 (s, 2H; H-2), 4.22 (d, J = 2.0, 2H; H-3), 3.16 (t, J = 2.3, 1H; H-5), 2.66 (tt, J = 19.3, 6.0, 2H; H-12); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 170.2 (C-6), 168.7 (C-1), 141.9 (C-10), 131.9 (C-7), 129.0 (C-8), 119.5 (C-9), 78.9 (C-4), 75.5 (C-5), 57.1 (C-11), 48.5 (C-2), 38.6 (br, C-3), 30.4 (t, J = 21.5; C-12); HRMS (ESI+) m/z = 705.0798 [M+H]+ found, C22H14F17N4O3+ required 705.0789.
Azido building block 14
Fluorous-tagged amine 1 (313 mg, 0.560 mmol, 1.00 eq) was reacted with azido acid SI-7 (128 mg, 0.723 mmol, 1.30 eq) according to GP1. After purification by flash column chromatography (petroleum ether/EtOAc 4:1), title compound 14 (0.34 g, 0.47 mmol 84%) was isolated as as a colorless wax. TLC Rf = 0.23 (petroleum ether/EtOAc 4:1); HPLC tr = 9.72 min (60-100 % B), peak area 95%; IR (neat) νmax = 2103 (N3), 1753 ((C=O)O), 1648 ((C=O)N), 1146 (s, CF); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.49-7.48 (m, 2H; H-9 and H-10), 7.43-7.39 (m, 2H; H-12 and H-8), 4.51 (s, 2H; H-13), 4.42 (t, J = 6.5, 2H; H-14), 4.24 (s, 2H; H-2), 4.21 (s, 2H; H-3), 3.14 (t, J = 2.5, 1H; H-5), 2.72-2.62 (tt, J = 19.0, 6.5, 2H; H-15); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 169.7 (C6), 167.8 (C-1), 135.9 (C-11), 134.9 (C-7), 129.3 (C-10), 128.4 (C-9), 125.9 (C-12), 125.7 (C-8), 20 20
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78.0 (C-4), 74.8 (C-5), 56.3 (C-14), 53.0 (C-13), 47.5 (C-2), 29.6 (C-15); HRMS (ESI+) m/z = 719.0946 [M+H]+ found, C23H16F17N4O3+ required 719.0945.
Azido building block 15
Fluorous-tagged amine 1 (387 mg, 0.692 mmol, 1.00 eq) was reacted with azido acid SI-13 (170 g, 0.889 mmol, 1.30 eq) according to GP1. After purification by flash column chromatography (petroleum ether/EtOAc 4:1), title compound 15 (0.44 g, 0.60 mmol, 87%) was isolated as a colorless foam. TLC Rf = 0.24 (petroleum ether/EtOAc 4:1); HPLC tr = 10.02 min (60-100 % B), peak area 99%; IR (neat) νmax = 2095 (s, N3), 1776 (s, (C=O)O), 1636 ((C=O)N), 1196 (s, CF); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.41-7.38 (m, 2H; H-9 and H-10), 7.34 (s, 1H; H-12), 7.30-7.28 (m, 1H; H-8), 4.42 (t, J = 6.0, 2H; H-15), 4.23 (s, 2H; H-2), 4.20 (s, 2H; H-3), 3.59 (t, J = 7.0, 2H; H14), 3.14 (t, J = 2.5, 1H; H-5), 2.92 (t, J = 7.0, 2H; H-13), 2.71-2.61 (m, 2H; H-16); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 170.0 (C-6), 167.8 (C-1), 138.5 (C-11), 134.6 (C-7), 130.0 (C-10), 128.1 (C-9), 126.4 (C-12), 124.2 (C-8), 78.1 (C-4), 74.7 (C-5), 56.3 (C-15), 50.9 (C-14), 47.5 (C2), 33.8 (C-13), 29.6 (C-16); HRMS (ESI+) m/z = 733.1108 [M+H]+ found, C24H18F17N4O3+ required 733.1102.
Azido building block 2
Fluorous-tagged amine 1 (1.50 g, 2.68 mmol, 1.00 eq) was reacted with azido acid SI-15 (0.585 g, 3.53 mmol, 1.30 eq) according to GP1 using saturated NaHCO3 as base. After purification by flash column chromatography (petroleum ether/EtOAc 3:1), title compound 2 (1.72 g, 2.43 mmol, 91%) was isolated as as a colorless wax. TLC Rf = 0.24 (petroleum ether/EtOAc 3:1); HPLC tr = 11.19 min (50-100% B), peak area 100 %; IR (neat) νmax = 2100 (m, N3), 1754 (m, C=O), 1635 (s, C=O), 1532 (w), 1427 (m), 1368 (w), 1199 (s, C-F), 1147 (s, C-F), 703 (m); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.07 (d, J = 3.5, 1H; H-8), 6.62 (d, J = 3.5, 1H; H-9), 4.51 (s, 2H; H-11), 4.44-4.41 (m, 6H; H-2, H-3, H-12), 3.11 (t, J = 2.4, 1H; H-5), 2.66 (tt, J = 19.2, 6.1, 2H; H-13); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 167.9 (C-1), 158.4 (C-6), 151.3 (C-10), 146.3 (C-7), 116.8 (C-8), 110.3 (C-9), 78.2 (C-4), 74.5 (C-5), 56.4 (C-12), 48.0 (C-2), 45.8 (C-11), 37.4 (br, C-3), 29.6 (t, J = 21.4; C-13); HRMS (ESI+) m/z = 709.0712 [M+H] + found, C21H14F17N4O4+ required 709.0738. 21 21
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Azido building block 13
Fluorous-tagged amine 1 (108 mg, 0.19 mmol, 1.00 eq) was reacted with azido acid SI-18 (76 mg, 0.25 mmol, 1.3 eq) according to GP1 using DIPEA (99 µL, 0.58 mmol, 3.0 eq) as a base in dry CH2Cl2 (10 mL). After stirring for 1 h, the reaction was quenched with saturated aqueous NH4Cl (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2x10 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. After purification by flash column chromatography (petroleum ether/Et2O 2:1), title compound 13 (118 mg, 0.14 mmol, 72%) was isolated as a colorless oil. TLC Rf = 0.75 (petroleum ether/Et2O 1:3); NMR Appropriate NMR data could not be obtained for this compound due to the existence of rotamers at a temperature range of 25-90 °C and partial N-Boc-deprotection at higher temperatures; HRMS (ESI+) m/z = 844.1392 [M+H]+ found, C29H22F17N5O5+ required 844.1422.
22 22
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Figure S6: Preparation of azido amines
Boc-Lys(N3)-OH SI-19
Analogously to a published procedure,[1] Boc-Lys-OH (6.92 g, 28.1 mmol, 1.0 eq) was dissolved in dry MeOH (140 mL) and CuSO4·5 H2O (0.070 g, 0.28 mmol, 0.01 eq), K2CO3 (10.5 g, 75.9 mmol, 2.7 eq) were added followed by the addition of diazotransfer reagent SI-11 (7.07 g, 33.7 mmol, 1.2 eq) in small portions. The reaction was stirred for 15 h. The solvent was nearly removed under reduced pressure and the residue was diluted with H2O (300 mL) and acidified to pH 3 with 2 M aqueous HCl. The aqueous phase was extracted with EtOAc (3 x 100 mL). The organic phase was washed with brine (100 mL), dried over MgSO4 and filtered. After purification by flash column chromatography (CH2Cl2/MeOH 15:1-10:1), title compound SI-19[11] (8.66 g, not 23 23
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entirely pure) was isolated as pale yellow oil, which was used in the next steps without further purification. TLC Rf = 0.72 (CH2Cl2/MeOH 3:1); IR (neat) νmax = 3334 (br, N-H), 2936 (br, C-H), 2094 (s, N3), 1690 (m, C(=O)OH); 1H NMR (400 MHz, CD3OD, 27 °C) δ = 4.08 (dd, J = 9.1, 4.9, 1H; H-1), 3.30 (t, J = 6.5, 2H; H-5), 1.90 – 1.55 (m, 4H; H-2 and H-4), 1.52 – 1.40 (m, 11H; H-3 and H-11); 13 C NMR (100 MHz, CD3OD, 27 °C) δ = 176.2 (C-6), 158.1 (C-9), 80.5 (C-10), 56.4 (C-1), 52.2 (C-5), 32.4 (C-4), 29.4 (C-2), 28.7 (C-11), 24.1 (C-3).
Boc-Lys(N3)-NHMe SI-20
1-Hydroxy-7-azabenzotriazole (105 mg, 0.768 mmol, 1.10 eq), EDC x HCl (147 mg, 0.768 mmol, 1.10 eq), DIPEA (199 µl, 1.14 mmol, 1.60 eq) and MeNH2 x HCl (57 mg, 0.84 mmol, 1.2 eq) were added to acid SI-19 (200 mg, ~0.698 mmol, 1.00 eq) dissolved in CH2Cl2 (5 mL). Additional EDC x HCl (44 mg, 0.23 mmol, 0.33 eq), MeNH2 x HCl (14 mg, 0.21 mmol, 0.30 eq) and DIPEA (120 µl, 0.698 mmol, 1.00 eq) were added after 2.5 h. After stirring for additional 3 h, the reaction was diluted with diluted NaHCO3 solution. The layers were separated and the aqueous layer was once extracted with CH2Cl2. Combined organic layers were washed with 0.1 M HCl, dried over MgSO4, filtrated and the solvent was removed under reduced pressure. After purification by flash column chromatography (petroleum ether/EtOAc 2:3), title compound SI-20 (95 mg, 0.33 mmol, 48% over two steps from Boc-Lys-OH) was isolated as a colorless oil. 1
H NMR (500 MHz, CDCl3, 27 °C) δ = 6.39 (br s, 1H; H-7), 5.14 (d, J = 8.3, 1H; H-9), 4.08 (m 1H; H-1), 3.26 (t, J = 6.7, 2H; H-5), 2.79 (d, J = 4.8, 3H; H-8); 1.89-1.76 (m, 1H; H-2a); 1.69-1.52 (m, 3H; H-2b and H-4), 1.49-1.34 (m, 11H; H-3 and H-12); 13C NMR (125 MHz, CDCl3, 27 °C) δ = 172.5 (C-6), 155.7 (C-10), 80.1 (C-11), 54.3 (C-1), 51.2 (C-5), 32.2 (C-2), 28.5 (C-4), 28.3 (C12), 26.2 (C-8), 22.8 (C-3); HRMS (ESI+) m/z = 286.1874 [M+H]+ found, C12H24N5O3+ required 286.1874.
HCl x NH2-Lys(N3)-NHMe SI-21 N3 5
4 3
2 9
HCl x H2N
1
6
H N 7
8
O SI-21
Boc-protected amine SI-20 (816 mg, 2.86 mmol) was dissolved in CH2Cl2 (6 mL) and 4 M HCl in dioxane (2.1 mL) was added at 0 °C. After stirring overnight at room temperature, the solvent 24 24
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was removed in a stream of nitrogen. After co-evaporation with MeOH, title compound SI-21 was isolated as colorless foam. 1
H NMR (500 MHz, CD3OD, 27 °C) δ = 3.82 (t, 1H, J = 6.6; H-1), 3.35 (t, J = 6.6, 2H; H-5), 2.80 (s, 3H; H-8), 1.93-1.77 (m, 2H; H-2); 1.68-1.58 (m, 2H; H-4); 1.51-1.40 (m, 2H; H-3).
NH2-Lys(N3)-NHMe SI-22
Hydrochloric salt SI-21 was dissolved in water and saturated Na2CO3 solution was added. The aqueous layer was extracted with EtOAc. Combined organic layers were dried over MgSO4, filtrated and the solvent was removed under reduced pressure. Title compound SI-22 (448 mg, 2.42 mmol, 85%) was isolated as colorless oil. 1
H NMR (500 MHz, CDCl3, 27 °C) δ = 7.22 (br s, 1H; H-7), 3.30 (dd, J = 7.8, 4.3, 1H; H-1), 3.23 (t, J = 6.7, 2H; H-5), 2.75 (d, J = 5.0, 3H; H-8), 1.86-1.75 (m, 1H; H-2a); 1.61-1.34 (m, 7H; H-2b, H-3, H-4, H-9); 13C NMR (125 MHz, CDCl3, 27 °C) δ = 175.4 (C=O), 55.0 (C-1), 51.2 (C-5), 34.6 (C-2), 28.6 (C-4), 25.7 (C-8), 22.9 (C-3); HRMS (ESI+) m/z = 186.1360 [M+H]+ found, C7H16N5O+ required 186.1349.
Boc-Lys(N3)-NMe2 SI-23
To dry CH2Cl2 (40 mL) was added lysine derivative SI-19 (4.33 g, approx. 14 mmol, 1.0 eq), Me2NH x HCl (1.85 g, 22.7 mmol, 1.6 eq), HOBt x H2O (2.54 g, 16.6 mmol, 1.2 eq), and EDC x HCl (3.18 g, 16.6 mmol, 1.2 eq). DIPEA (3.96 mL, 22.7 mmol, 1.6 eq) was added dropwise. The reaction was stirred for 15 h. The reaction mixture was washed with 1 M aqueous HCl (2 x 100 mL), saturated aqueous NaHCO3 (100 mL), brine (100 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether/EtOAc 3:1-1:1) to yield amide SI-23 as colorless oil (3.03 g, 10.1 mmol, 72% over two steps from Boc-Lys-OH). TLC Rf = 0.65 (neat EtOAc); IR (neat) νmax = 2937 (br, alkyl C-H), 2093 (s, N3), 1702 (s, C(=O)OR), 1640 (s, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 6.08 (d, J = 3.4, 1H; H-9), 4.41 (dt, J = 8.2, 5.1, 1H; H-1), 3.30 (t, J = 6.8, 2H; H-5), 2.95 (s, 6H; H-8), 1.76 – 1.47 (m, 4H; H-2 and H-4), 1.47 – 1.31 (m, 11H; H-12 and H-3); 13C NMR (125 MHz, DMSO-d6, 120°C) δ 25 25
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= 172.1 (C-6), 155.5 (C-10), 78.8 (C-11), 51.4 (C-5), 50.8 (C-1), 36.3 (C-4), 28.7 (C-8), 28.5 (C2), 22.9 (C-3); HRMS (ESI+) m/z = 300.2020 [M+H]+ found, C13H26N5O3+ required 300.2030.
HCl x NH2-Lys(N3)-NMe2 SI-24 N3 5
4 3
2 9
HCl x H2N
1
N
6
7
8
O SI-24
A solution of Boc-protected amide SI-23 (3.10 g, 10.4 mmol) in dry CH2Cl2 (30 mL) was cooled to 0°C in an ice bath and 4M HCl in 1,4-dioxane (10 mL) was added. The reaction was stirred for 2 h, the solvent removed under a stream of N2, and the residue was co-evaporated with dry MeOH (2x50 mL) under reduced pressure to yield title compound SI-24 as yellow oil (2.24 g, 9.50 mmol, 91%). TLC Rf = 0.69 (CH2Cl2/MeOH 5:1); [α]D20 = +13.7 (c = 1 in MeOH); IR (neat) νmax = 2866 (br, alkyl C-H), 2090 (s, N3), 1650 (s, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 4.25 (t, J = 6.1, 1H; H-1), 3.32 (t, J = 7.0, 2H; H-5), 2.97 (br s, 6H; H-8), 1.85 – 1.79 (m, 2H; H-2), 1.64 – 1.50 (m, 2H; H-4), 1.50 – 1.40 (m, 2H; H-3); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 168.0 (C-7), 50.1 (C-5), 49.0 (C-8), 47.9 (C-1), 29.2 (C-4), 27.4 (C-2), 20.9 (C-3); HRMS (ESI+) found m/z = 200.1505 [M+H]+, C8H18 N5O+ required 200.1511.
HCl x NH2-Lys(N3)-OH SI-25 N3 5
4 3
2 8
HCl x H2N
1
6
OH 7
O SI-25
A solution of Boc-protected acid SI-19 (3.00 g, approx. 9.7 mmol) in dry CH2Cl2 (40 mL) was cooled to 0°C and 4M HCl in 1,4-dioxane (10 mL) was added. The reaction was stirred for 5 h. The solvent was partially removed under a stream of N2 until a white precipitate formed. The precipitate was collected by vacuum filtration and rinsed with diethyl ether to yield amine SI-25 as a white powder (1.47 g, 7.06 mmol, 72% over two steps from Boc-Lys-OH). IR (neat) νmax = 2972 (w, alkyl C-H), 2102 (m, N3), 1749 (m, C(=O)OH), 1642 (s, primary N-H); mp 192°C (CH2Cl2); [α]D20 = +18.9 (c = 1 in MeOH); 1H NMR (500 MHz, CD3OD, 27 °C) δ = 3.76 (t, J = 6.1, 1H; H-1), 3.35 (t, J = 6.6, 2H; H-5), 1.99-1.82 (m, 2H; H-2), 1.65 (tt, J = 7.1 & 6.8, 2H; H-4), 1.59-1.46 (m, 2H; H-3); 13C NMR (125 MHz, CD3OD, 27 °C) δ = 172.9 (C-6), 54.9 (C-1), 52.1 (C-5), 31.5 (C-2), 29.5 (C-4), 23.4 (C-3); HRMS (ESI+) found m/z = 173.1032 [M+H]+, C6H13 N4O2+ required 173.1033.
26 26
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Boc-β β-HLys(H)-OH SI-26
Boc-β-HLys(Cbz)-OH (1.00 g, 2.54 mmol) and Pd/C (10%; 20 mg) in dry MeOH were stirred overnight under an atmosphere of H2. Subsequently, the mixture was filtered through a pad of Celite and the solvent was removed under reduced pressure. After co-evaporation with CH2Cl2, title compound SI-26 (629 mg, 2.41 mmol, 95%) was isolated as an off-white solid. 1
H NMR (400 MHz, CD3OD, 27 °C) δ = 3.81 (m, 1H; H-1), 2.90 (m, 2H; H-5), 2.35 (dd, J = 14.4, 5.4, 1H; H-6a), 2.26 (dd, J = 14.4, 7.3, 1H; H-6b), 1.74-1.35 (m, 15H; H-2,H-3, H-4 and H-12); 13 C NMR (100 MHz, CD3OD, 27 °C) δ = 179.8, 157.8 (both C=O), 79.7 (C-11), 49.4 (C-1), 44.0, 40.5, 35.2 (each CH2), 28.8 (C-12), 28.4, 23.9 (both CH2); HRMS (ESI+) m/z = 261.1812 [M+H]+ found, C12H25N2O4+ required 261.1809.
Boc-β β-HLys(N3)-OH SI-27
Analogously to a published procedure,[1] Boc-β-HLys(H)-OH SI-26 (636 mg, 2.44 mmol, 1.00 eq) was dissolved in dry MeOH (15 mL) and CuSO4·5 H2O (6 mg, 0.02 mmol, 0.01 eq), K2CO3 (911 mg, 6.59 mmol, 2.70 eq) were added followed by the addition of diazotransfer reagent SI-11 (615 mg, 2.93 mmol, 1.20 eq) in small portions. After stirring overnight, the solvent was nearly removed under reduced pressure and the residue was dissolved in a mixture of CH2Cl2/H2O and acidified with 10% aqueous HCl. The layers were separated and the aqueous layer was extracted with CH2Cl2 (4x50 mL). The organic layers were combined, dried over MgSO4, filtered and the solvent was removed under reduced pressure. After purification by flash column chromatography (CH2Cl2 with 2% (v/v) AcOH), titel compound SI-27 (556 mg, not entirely pure, ~ 1.94 mmol, ~ 80%) was isolated as a white wax, which was used in the next step without further purification. 1
H NMR (400 MHz, DMSO-d6, 27 °C) δ = 12.10 (br s, 1H; H-8), 6.68 (d, J = 8.9, 1H; H-9), 3.783.65 (m, 1H; H-1), 3.29 (t, J = 6.8, 2H; H-5), 2.33 (dd, J = 15.2, 7.1, 1H; H-6a), 2.26 (dd, J = 15.2, 6.8, 1H; H-6b), 1.61-1.18 (m, 15H; H-2, H-3, H-4 and H-12); 13C NMR (100 MHz, DMSOd6, 27 °C) δ = 172.6, 155.1 (both C=O), 77.5 (C-11), 50.6 (CH2), 47.1 (C-1), 39.9 (CH2), 33.8 (CH2), 28.2 (C-12), 28.0 (CH2), 22.7 (CH2); HRMS (ESI+) m/z = 309.1529 [M+Na]+ found, C12H22N4O4Na+ required 309.1533. 27 27
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TFA x H-β β-HLys(N3)-OH SI-28
Boc-β-HLys(N3)-OH SI-27 (416 mg, 1.45 mmol) was dissolved in CH2Cl2 (8 mL) and TFA (3.7 mL) was added at 0 °C. After stirring at 0 °C for 2 h, the solvent was removed in a stream of N2. Title compound SI-28 (544 mg, not entirely pure) was isolated as a colorless oil and used without further purification. 1
H NMR (400 MHz, DMSO-d6, 27 °C) δ = 7.86 (br s, 3H; H-9), ~ 3.4 (H-1, coincides with water signal), 3.33 (t, J = 6.8, 2H; H-5), 2.59 (dd, J = 17.2, 5.8, 1H; H-6a), 2.55-2.49 (m, 1H; H-6b), 1.63-1.47 (m, 4H; H-2 and H-4), 1.43-1.31 (m, 2H; H-3); 171.8 (C-7), 50.4 (CH2), 47.4 (C-1), 36.6, 31.7, 27.9, 21.8 (each CH2); HRMS (ESI+) m/z = 187.1206 [M+H]+ found, C7H15N4O2+ required 187.1190.
Figure S7: Preparation of olefinic amine SI-31
Hex-5-en-1-yl 4-methylbenzenesulfonate SI-29
5-hexen-1-ol (1.00 g, 10.0 mmol, 1.00 eq) and pyridine (0.89 mL, 11.0 mmol, 1.1 eq) were dissolved in anhydrous CH2Cl2 (25 ml) and tosyl chloride (2.09 g, 11.0 mmol, 1.10 equiv.) was added in portions over 5 min at 0 °C. After stirring at ambient temperature for 18 h, additional pyridine (0.16 mL, 2 mmol, 0.2 equiv.) and tosyl chloride (0.38 g, 2 mmol, 0.2 equiv.) were added. After 42 h of stirring in total, CH2Cl2 (20 mL) was added and the organic phase was washed with 0.1 M aqueous HCl (2 × 25 mL), saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound SI-29 as a slightly yellow crude oil (2.8 g) which was used without further purification.
6-Azidohex-1-ene SI-30
The crude tosylate SI-29 was dissolved in DMF (20 ml). Sodium azide (0.846 g, 13.0 mmol, 1.3 eq) was added and the mixture was stirred at ambient temperature overnight. Et2O (40 mL) and 28 28
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water (15 mL) were added and the mixture was stirred for 5 min. The phases were separated and the organic phase was washed with water (30 mL), saturated aqueous NaHCO3 (30 mL) and water (30 mL), dried over Na2SO4 and filtered. The solution was concentrated under reduced pressure to leave 10-15 mL of solvent. The yellow solution of SI-30 was used in the next step without further purification.
HCl x Hex-5-en-1-amine SI-31
THF (25 ml) and PPh3 (2.89 g, 11.0 mmol, 1.10 equiv.) were added to the ethereal solution of crude azide SI-30 and the mixture was stirred for 1.5 h. Water (0.5 mL, 28 mmol, 2.8 equiv.) was added and the solution was stirred at ambient temperature for 4 days. The mixture was concentrated under reduced pressure to reduce the solvent volume by half, and the solution was diluted with water (40 mL). 10% aqueous HCl was added to adjust pH to 2 and the aqueous mixture was washed with CH2Cl2 (3 × 30 mL). Na2CO3 (s) was added to the aqueous phase until pH ≥ 12, and the aqueous phase was extracted with CH2Cl2 (17 × 15 mL). The organic phase was dried over MgSO4, filtered, and 4 M HCl in dioxane (3.5 mL, 14 mmol, 1.4 equiv.) was added. The cloudy solution was concentrated under reduced pressure to afford a slightly yellow, viscous oil. Et2O (20 mL) was added to afford a white precipitate. The solvent was decanted, and additional Et2O (20 mL) was added. The solvent was decanted again and the residue was dried under reduced pressure to give title compound SI-31 (0.83 g, 6.1 mmol, 61% over 3 steps) as a white solid. TLC Rf = 0.14 (MeOH/CH2Cl2 1:9); IR (neat) νmax = 2929 (br, NH3+); 1H NMR (400 MHz, DMSOd6, 27 °C) δ = 8.13 (br s, 3H; H-7), 5.78 (ddt, J = 17.2, 10.4, 6.8, 1H; H-5), 5.02 (ddt, J = 17.2, 2.0, 1.6, 1H; H-6a), 4.96 (ddt, J = 10.4, 2.0, 1.2, 1H; H-6b), 2.75-2.72 (br m, 2H; H-1), 2.02 (dt, J = 7.2, 6.8, 2H; H-4), 1.60-1.53 (m, 2H; H-2), 1.43-1.35 (m, 2H; H-3); 13C NMR (100 MHz, DMSOd6, 27 °C) δ = 138.2 (C-5), 115.1 (C-6), 38.5 (C-1), 32.6 (C-4), 26.4 (C-2), 25.1 (C-3); HRMS (ESI+) m/z = 100.1121 [M+H]+ found, C6H14N+ required 100.1121.
Preparation of Linear Ureas Linear urea SI-32
Azide building block 17 (180 mg, 0.629 mmol, 1.0 eq) was reacted with amine HCl-salt SI-24 (192 mg, 0.817 mmol, 1.30 eq) according to GP2 using P(n-Bu)3 (1.10 eq in total) and DIPEA 29 29
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(1.30 eq). After purification by flash column chromatography (EtOAc), title compound SI-32 (160 mg, 0.330 mmol, 52%) was isolated as a colorless foam. TLC Rf = 0.21 (EtOAc); HPLC tr = 9.36 min (20-70% B), peak area 98%; IR (neat) νmax = 2915 (w), 2094 (m, N3), 1747 (m, C=O), 1623 (s, C=O), 1537 (m), 1451 (m), 1209 (s); HRMS (ESI+) m/z = 486.2458 [M+H] + found, C23H32N7O5+ required 486.2459.
Linear urea SI-33
Azide building block 17 (50 mg, 0.18 mmol, 1.0 eq) was reacted with amine HCl-salt SI-25 (48 mg, 0.23 mmol, 1.3 eq) according to GP2 using PPh3 (1.00 eq) and DIPEA (4.00 eq). Instead of stirring at room temperature overnight, the reaction was stirred at 50 °C for two days. After purification solely by flash column chromatography (CH2Cl2/MeOH/HCOOH 100:5:0.1), title compound SI-33 (60 mg, mixed with Ph3P=O) was isolated as a colorless oil and used in the next step without further purification. TLC Rf = 0.16 (CH2Cl2/MeOH/HCOOH 100:5:0.1); HPLC tr = 9.45 min (20-70% B), peak area 83%; HRMS (ESI+) m/z = 459.1995 [M+H] + found, C23H32N7O5+ required 459.1987.
Linear urea SI-34
Azide building block 17 (0.18 g, 0.63 mmol, 1.00 eq) was reacted with amine HCl-salt SI-31 (98 mg, 0.72 mmol, 1.15 eq) according to GP2 using P(n-Bu)3 (1.1 eq) and DIPEA (2.0 eq). After purification solely by flash column chromatography (petroleum ether/EtOAc 1:2), title compound SI-34 (0.17 g, 0.43 mmol, 69 %) was isolated as a colorless film. TLC Rf = 0.25 (petroleum ether/EtOAc 2:3); HPLC tr = 10.52 min (5-100% B), peak area 100%; IR (neat) νmax = 3369 (NH), 1748 ((C=O)O), 1694 (NH(C=O)NH), 1638 ((C=O)N); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.58 (d, J = 8.0, 1H; H-12), 7.52 (br s, 1H; H-14), 7.18-7.15 (m, 2H; H-9 and H-11), 6.99 (t, J = 7.5, 1H; H-10), 6.04 (br s, 1H; H-16), 5.84 (ddt, J = 17.5, 10.5, 6.5, 1H; H-21), 5.03 (d, J = 17.0, 1H; H-22a), 4.96 (d, J = 10.0, 1H; H-22b), 4.28 (s, 2H; H-3), 4.25 (s, 2H; H-2), 3.72 (s, 2H; H-7), 3.69 (s, 3H; H-23), 3.12 (dt, J = 6.5, 2H; H-17), 3.01 (br s, 1H; H-5), 2.08 (dt, J = 7.0, 2H; H-20), 1.54-1.42 (m, 4H; H-18 and H-19); 13C NMR (125 MHz, DMSO-d6, 30 30
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120 °C) δ = 170.3 (C-6), 168.6 (C-1), 155.2 (C-15), 138.0 (C-21), 137.9 (C-13), 128.9 (C-9), 126.9 (C-8), 126.4 (C-11), 123.2 (C-12), 122.5 (C-10), 113.7 (C-22), 78.1 (C-5), 74.2 (C-4), 51.0 (C-23), 47.3 (C-2), 38.8 (C-17), 35.1 (C-7), 32.0 (C-20), 28.6 (C-18), 25.1 (C-19); HRMS (ESI+) m/z = 408.1904 [M+Na]+ found, C21H27N3O4Na+ required 408.1894.
Linear urea 21
Azide building block 3 (816 mg, 1.16 mmol, 1.00 eq) was reacted with amine HCl-salt SI-24 (300 mg, 1.28 mmol, 1.10 eq) according to GP2 using PPh3 (1.00 eq) and DIPEA (1.20 eq). Title compound 21 (1.03 g, 1.13 mmol, 97 %) was isolated as a white foam. HPLC tr = 8.28 min (60-100% B), peak area 95%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.69 (s, 1H; H-13), 7.54 (t, J = 1.9, 1H; H-12), 7.39 (br d, J = 8.3, 1H; H-8 or H-10), 7.29 (d, J = 7.8, 1H; H-9), 6.94 (d, J = 7.7, 1H; H-8 or H-10), 6.35 (d, J = 8.4, 1H; H-15), 4.72 (dt, J = 8.0, 5.3, 1H; H-16), 4.43 (t, J = 6.2, 2H; H-25), 4.24-4.19 (m, 4H; H-2 and H-3), 3.31 (t, J = 6.8, 2H; H-20), 3.11 (t, J = 2.5, 1H; H-5), 3.09-2.82 (m; H-23 and H-24, coincides with water signal), 2.67 (tt, J = 19.2, 6.2, H2; H-26), 1.74-1.66 (m, 1H; H-17a), 1.65-1.49 (m, 3H; H-17b and H-19), 1.46-1.36 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.5, 170.1, 167.9, 154.2 (each C=O), 140.2, 134.9 (both quat. C), 128.3 (C-9), 118.8 (C-8 or C-10), 118.7 (C-8 or C-10), 115.5 (C-12), 78.1 (C-4), 74.7 (C-5), 56.3 (C-25), 50.3 (C-20), 48.2 (C-16), 31.6 (C-17), 29.6 (C-26), 27.6 (C-19), 21.7 (C-18); HRMS (ESI+) m/z = 904.2104 [M+H]+ found, C31H31F17N7O5+ required 904.2110.
Linear urea SI-35
Azide building block 3 (70.4 mg, 0.100 mmol, 1.00 eq) was reacted with amine SI-22 (20.4 mg, 0.110 mmol, 1.10 eq) according to GP2 using PPh3 (1.00 eq) but without additional base. Title compound SI-35 (86 mg, 0.097 mmol, 97 %) was isolated as a white foam. HPLC tr = 7.34 min (60-100% B); NMR Appropriate NMR data could not be obtained for this compound due to the presence of rotamers at room temperature and triazole formation at elevated temperature; HRMS (ESI+) m/z = 890.1954 [M+H]+ found, C30H29F17N7O5+ required 890.1953. 31 31
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Linear urea 22
Azide building block 3 (169 mg, 0.240 mmol, 1.00 eq) was reacted with amine HCl-salt SI-25 (65 mg, 0.31 mmol, 1.3 eq) according to GP2 using PPh3 (1.05 eq) and DIPEA (4.0 eq). After purification solely by flash column chromatography (CH2Cl2/MeOH/HCOOH 100:1:0.1 to 100:4:0.2), title compound 22 (133 mg, 0.152 mmol, 63%) was isolated as a white foam. TLC Rf = 0.32 (CH2Cl2/MeOH/HCOOH 10:0.5:0.05); HPLC tr = 10.11 min (50-100% B), peak area 89%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.64 (s, 1H; H-13), 7.54 (t, J = 1.5, 1H; H12), 7.40 (d, J = 7.9, 1H; H-8 or H-10), 7.29 (t, J = 7.8, 1H; H-9), 6.94 (d, J = 7.3, 1H; H-8 or H10), 6.35 (d, J = 7.8, 1H; H-15), 4.43 (t, J = 6.1, 2H; H-23), 4.26-4.18 (m, 5H; H-16, H-2, H-3), 3.33 (t, J = 6.8, 2H; H-20), 3.11 (s; H-5, coincides with water signal), 2.67 (tt, J = 19.4, 6.1, 2H; H-24), 1.84-1.75 (m, 1H; H-17a), 1.71-1.65 (m, 1H; H-17b), 1.63-1.55 (m, 2H; H-19), 1.46-1.38 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 173.2 (C-21), 170.1 (C-6), 167.9 (C-1), 154.3 (C-14), 140.1 (C-7 or C-11), 134.9 (C-7 or C-11), 128.3 (C-9), 118.8 (C-8 or C-10), 118.8 (C-8 or C-10), 115.6 (C-12), 78.1 (C-4), 74.7 (C-5), 56.4 (C-23), 51.9 (C-16), 50.3 (C-20), 31.2 (C-17), 29.6 (t, J = 21.8; C-24), 27.5 (C-19), 21.9 (C-18); HRMS (ESI+) m/z = 877.1599 [M+H]+ found, C29H26F17N6O6+ required 877.1637.
Linear urea 23
Azide building block 3 (399 mg, 0.566 mmol, 1.00 eq) was reacted with amine TFA-salt SI-28 (187 mg, 0.623 mmol, 1.10 eq) according to GP2 using PPh3 (1.00 eq) and DIPEA (2.40 eq). Title compound 23 (190 mg, 0.214 mmol, 38%) was isolated as a white foam. HPLC tr = 7.66 min (60-100% B), peak area 96%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.52 (s, 1H; H-13), 7.55 (t, J = 1.9, 1H; H-12), 7.41 (d, J = 8.3, 1H; H-8 or H-10), 7,27 (t, J = 7.9, 1H; H-9), 6.92 (d, J = 7.6 1H; H-8 or H-10), 6.10 (br s, 1H; H-15), 4.43 (t, J = 6.1, 2H; H-24), 4.254.19 (m, 4H; H-2 and H-3), 3.97 (m, 1H; H-16), 3.31 (t, J = 6.8, 2H; H-20), 3.11 (t, J = 2.5, 1H; H5), 2.68 (tt, J = 19.3, 6.2, 2H; H-25), 2.44 (dd, J = 15.4, 6.1, 1H; H-21a), 2.41 (dd, J = 15.4, 6.3, 1H; H-21b), 1.65-1.49 (m, 4H; H-17 and H-19), 1.48-1.33 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 172.0, 170.2, 167.9, 154.2 (each C=O), 140.5, 134.9 (both quat. C), 128.2 (C-9), 118.8 (C-8 or C-10), 118.5 (C-8 or C-10), 115.6 (C-12), 78.1 (C-4), 74.7 (C-5), 56.4 (C32 32
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DOI: 10.1038/NCHEM.1729
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24), 50.3 (C-20), 45.9 (C-16), 39.3 (C-21), 33.4 (C-17), 29.6 (C-25), 27.6 (C-19), 22.3 (C-18); HRMS (ESI+) m/z = 891.1808 [M+H]+ found, C30H28F17N6O6+ required 891.1793.
Linear urea 20
Azide building block 3 (300 mg, 0.426 mmol, 1.00 eq) was reacted with amine HCl-salt SI-31 (63 mg, 0.469 mmol, 1.1 eq) according to GP2 using PPh3 (1.00 eq) and DIPEA (1.2 eq). After additional purification by flash column chromatography (CH2Cl2/MeOH 50:1), title compound 20 (302 mg, 0.376 mmol, 88%) was isolated as a colorless wax. HPLC tr = 9.83 min (60-100% B), peak area 95%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.32 (s, 1H; H-13), 7.55 (t, J = 1.9, 1H; H-12), 7.40 (d, J = 8.3, 1H; H-8 or H-10), 7.28 (t, J = 7.8, 1H; H-9), 6,92 (d, J = 7.7, 1H; H-8 or H-10), 6.00 (t, J = 5.7, 1H; H-15), 5.83 (ddt, J = 16.9, 10.2, 6.6, 1H; H-20), 5.02 (m, 1H; H-21a), 4.95 (m, 1H; H-21b), 4.43 (t, J = 6.1, 2H; H-22), 4.25 (s, 4H; H-2 and H-3), 3.15-3.09 (m, 3H; H-5 and H-16), 2.68 (tt, J = 19.2 and 6.3, 2H; H-23), 2.07 (q, J = 6.9, 2H; H-19), 1.52-1.38 (m, 4H; H-17 and H-18); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 170.1, 167.9, 154.7 (each C=O), 140.5 (quat. C), 138.1 (C-20), 134.8 (quat. C), 128.2 (C-9), 118.8 (C-8 or C-10), 118.5 (C-8 or C-10), 115.6 (C-12), 114.0 (C-21), 78.1 (C-4), 74.7 (C-5), 56.3 (C-22), 38.6 (C-16), 32.2 (C-19), 29.6 (C-23), 28.7 (C-17), 25.2 (C-18); HRMS (ESI+) m/z = 804.1761 [M+H]+ found, C29H27F17N3O4+ required 804.1725, 826.1565 [M+Na]+ found, C29H26F17N3O4Na+ required 826.1544.
Linear urea SI-36
Azido building block 16 (113 mg, 0.159 mmol, 1.00 eq) was reacted with amine HCl-salt SI-24 (42 mg, 0.18 mmol, 1.1 eq) according to GP2 using PPh3 (1.00 eq) and DIPEA (1.20 eq). Title compound SI-36 (132 mg, 0.146 mmol, 91%) was isolated as a white foam. TLC Rf = 0.23 (petroleum ether/EtOAc 1:3); HPLC tr = 10.27 min (50-100% B), peak area 96%; mp 72-80 °C (CH2Cl2); [α]D28.7 = +0.9 (c = 0.763 in MeOH); IR (neat) νmax = 2096 (m, N3), 1752 (m, C=O), 1700 (w, C=O), 1623 (m, C=O), 1597 (m), 1536 (m), 1403 (m), 1199 (s, C-F), 1177 (s, C-F), 1145 (s, C-F), 1134 (s, C-F); 1H NMR (500 MHz, DMSO-d6, 70 °C) δ = 8.83 (s, 1H; H-11), 33 33
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DOI: 10.1038/NCHEM.1729
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7.46-7.44 (m, 2H; H-9), 7.34 (d, J = 8.4, 2H; H-8), 6.45 (d, J = 8.4, 1H; H-13), 4.71 (dt, J = 8.1, 5.1, 1H; H-14), 4.41 (t, J = 6.0, 2H; H-22), 4.21-4.20 (m, 4H; H-2, H-3), 3.32 (t, J = 6.8, 2H; H18), 3.20 (t, J = 2.4, 1H; H-5), 3.07 (s; H-20, coincides with water signal), 2.87 (s, 3H; H-21), 2.67 (tt, J = 19.4, 6.2, 2H; H-23), 1.72-1.65 (m, 1H; H-15a), 1.63-1.49 (m, 3H; H-15b, H-17), 1.42-1.37 (m, 2H; H-16); 13C NMR (125 MHz, DMSO-d6, 70 °C) δ = 171.5 (C-19), 170.1 (C-6), 168.2 (C-1), 154.1 (C-12), 142.0 (C-10), 127.5 (C-8), 126.7 (C-7), 116.7 (C-9), 78.5 (C-4), 74.9 (C-5), 56.4 (C-22), 50.4 (C-18), 48.2 (C-14), 36.2 (C-20), 34.8 (C-21), 31.7 (C-15), 29.5 (t, J = 21.0; C-23), 27.8 (C-17), 21.8 (C-16); HRMS (ESI+) m/z = 904.2115 [M+H]+ found, C31H31F17N7O5+ required 904.2110, 926.1972 [M+Na]+ found, C31H30F17N7O5Na+ required 926.1929.
Linear urea SI-37
Azido building block 14 (100 mg, 0.139 mmol, 1.00 eq) was reacted with amine HCl-salt SI-24 (36 mg, 0.15 mmol, 1.1 eq) according to GP2 using P(n-Bu)3 (1.10 eq in total) and DIPEA (1.20 eq). Title compound SI-37 (89 mg, 0.097 mmol, 69%) was isolated as a colorless oil. TLC Rf = 0.37 (CH2Cl2/MeOH 20:1); HPLC tr = 9.85 min (50-100% B), peak area 97%; IR (neat)
νmax = 2925 (w, C-H), 2095 (m, N3), 1754 (s, C(=O)OR), 1622 (s, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.40 – 7.35 (m, 2H; H-8 and H-10), 7.34 (s, 1H; H-12), 7.28 (t, J = 4.3,
1H; H-9), 6.42 (t, J = 5.8, 1H; H-14), 5.95 (d, J = 8.7, 1H; H-16), 4.67 (td, J = 8.0, 5.4, 1H; H-17), 4.44 (t, J = 6.1, 2H; H-25), 4.26 (d, J = 5.9, 2H; H-13), 4.23 (s, 2H; H-2), 4.21 (d, J = 2.6, 2H; H3), 3.29 (t, J = 6.8, 2H; H-21), 3.04 (t, J = 2.5, 1H; H-5), 2.95 (s, 6H; H-23 and H-24), 2.67 (tt, J = 18.8, 5.9, 2H; H-26), 1.71 – 1.45 (m, 4H; H-18 and H-20), 1.43 – 1.33 (m, 2H; H-19); 13C NMR (125 MHz, DMSO-d6, 90°C) δ = 171.9 (C=O), 170.2 (C=O), 167.9 (C=O), 157.1 (C-15), 141.0 (quat. C), 134.4 (quat. C), 128.3 (C-8 or C-10), 127.8 (C-8 or C-10), 124.9 (C-12), 124.3 (C-9), 56.36 (C-25), 50.4 (C-21), 48.4 (C-17), 42.4 (C-13), 31.8 (C-20), 29.6 (C-26), 28.3 (C-18), 21.8 (C-19); HRMS (ESI+) m/z = 918.2275 [M+H]+ found, C32H33F17N7O5+ required 918.2266.
Linear urea SI-38
Azido building block 14 (847 mg, 1.18 mmol, 1.00 eq) was reacted with amine HCl-salt SI-25 (495 mg, 2.37 mmol, 2.00 eq) according to GP2 using P(n-Bu)3 (1.10 eq in total) and DIPEA 34 34
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DOI: 10.1038/NCHEM.1729
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(4.00 eq). After purification solely by extraction (i.e. the crude product was dissolved in a mixture of H2O and EtOAc, the mixture was acidified with 5% HCl to pH 3 and extracted 3x with EtOAc. The combined organic layers were dried over MgSO4, filtrated and the solvent was removed under reduced pressure.), title compound SI-38 (837 mg, not pure) was isolated as a colorless oil and used in the next step without further purification. HRMS (ESI+) m/z = 913.1594 [M+H]+ found, C30H27F17N6O6Na+ required 913.1613.
Linear urea SI-39
Azido building block 14 (300 mg, 0.418 mmol, 1.00 eq) was reacted with amine HCl-salt SI-31 (69 mg, 0.51 mmol, 1.2 eq) according to GP2 using P(n-Bu)3 (1.2 eq in total) and DIPEA (2.0 eq). Title compound SI-39 (305 mg, 0.373 mmol, 89%) was isolated as a colorless gum. TLC Rf = 0.18 (petroleum ether/EtOAc 2:3); HPLC tr = 8.91 min (60-100 % B), peak area 94%; IR (neat) νmax = 3345 (NH), 1742 ((C=O)O), 1626 ((C=O)N); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.40-7.38 (m, 2H, H-9; H-10), 7.33 (br s, 1H; H-12), 7.27 (br s, 1H; H-8), 6.15 (t, J = 6.5, 1H; H-14), 5.81 (ddt, J = 17.0, 10.0, 7.0, 1H; H-21), 5.72 (t, J = 6.0, 1H; H-16), 5.00 (dd, J = 17.0, 1.5, 1H; H-22a), 4.94 (d, J = 10.0, 1H; H-22b), 4.43 (t, J = 6.0, 2H; H-23), 4.25 (d, J = 6.5, 2H; H-13), 4.22 (s, 2H; H-2), 4.20 (s, 2H; H-3), 3.13 (s, 1H; H-5), 3.04 (dt, J = 6.5, 6.0, 2H; H17), 2.67 (m, 2H; H-24), 2.04 (dt, J = 7.0, 2H; H-20), 1.46-1.27 (m, 4H, H-18; H-19); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 170.2 (C-6), 167.8 (C-1), 157.6 (C-15), 141.3 (C-11), 138.2 (C21), 134.4 (C-7), 128.3 (C-10), 127.8 (C-9), 124.9 (C-12), 124.2 (C-8), 113.9 (C-22), 78.1 (C-4), 74.7 (C-5), 56.3 (C-23), 47.5 (C-2), 42.4 (C-13), 38.9 (C-17), 32.2 (C-20), 29.6 (C-24), 29.0 (C18), 25.2 (C-19); HRMS (ESI+) m/z = 818.1886 [M+H]+ found, C30H29F17N3O4+ required 818.1881.
Linear urea SI-40
Azido building block 15 (300 mg, 0.410 mmol, 1.00 eq) was reacted with amine HCl-salt SI-24 (106 mg, 0.450 mmol, 1.10 eq) according to GP2 using P(n-Bu)3 (1.10 eq in total) and DIPEA (1.20 eq). Title compound SI-40 (272 mg, 0.292 mmol, 71%) was isolated as a pale yellow oil.
35 35
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DOI: 10.1038/NCHEM.1729
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TLC Rf = 0.50 (CH2Cl2/MeOH 20:1); HPLC tr = 10.07 min (50-100% B), peak area 90%; IR (neat) νmax = 2934 (m, C-H), 2097 (s, N3), 1753 (s, C(=O)OR), 1645 (br & s, C(=O)NR2); HRMS (ESI+) m/z = 932.2425 [M+H]+ found, C33H35F17N7O5+ required 932.2423.
Linear urea SI-41
Azido building block 15 (125 mg, 0.171 mmol, 1.00 eq, dissolved in dry THF (6 mL)) was reacted with amine HCl-salt SI-25 (46 mg, 0.22 mmol, 1.3 eq, dissolved in dry DMF (12 mL)) according to GP2 using P(n-Bu)3 (1.15 eq in total) and DIPEA (4.00 eq). During the second step the reaction was stirred at 35 °C. After filtration through a pad of silica (CH2Cl2/MeOH/HCOOH 100:5:0.5), title compound SI-41 (180 mg, not pure) was isolated as a white foam and used in the next step without further purification. TLC Rf = 0.48 (CH2Cl2/MeOH/HCOOH 10:0.5:0.05); HPLC tr = 9.91 min (50-100% B), peak area 65%; HRMS (ESI+) m/z = 905.1995 [M+H]+ found, C31H30F17N6O6+ required 905.1950.
Linear urea 34
Azido building block 15 (353 mg, 0.482 mmol, 1.00 eq) was reacted with amine HCl-salt SI-31 (73 mg, 0.54 mmol, 1.1 eq) according to GP2 using P(n-Bu)3 (1.1 eq in total) and DIPEA (2 eq). Title compound 34 (365 mg, 0.439 mmol, 91%) was isolated as a colorless gum. TLC Rf = 0.23 (petroleum ether/EtOAc 2:3); HPLC tr = 9.10 min (60-100% B), peak area 100%; IR (neat) νmax = 1745 ((C=O)O), 1656 (HN(C=O)NH), 1626 ((C=O)N), 1195 (CF); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.38-7.32 (m, 2H; H-9 and H-10), 7.27-7.24 (m, 2H; H-8 and H-12), 5.85-5.77 (m, 1H; H-22), 5.60 (br s, 2H; H-15 and H-17), 5.00 (d, J = 17.0, 1H; H-23a), 4.94 (d, J = 10.5, 1H; H-23b), 4.43 (t, J = 6.0, 2H; H-24), 4.22 (s, 2H; H-2), 4.20 (s, 2H; H-3), 3.28 (dt, J = 7.0, 6.5, 2H; H-14), 3.13 (s, 1H; H-5), 3.04-2.96 (m; H-18 coincides with water signal), 2.75 (t, J = 7.0, 2H; H-13), 2.67 (m, 2H; H-25), 2.03 (dt, J = 7.0, 6.5, 2H; H-21), 1.41-1.35 (m, 4H; H-19 and H-20); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 170.2 (C-6), 167.9 (C-1), 157.6 (C-16), 139.9 (C-11), 138.2 (C-22), 134.5 (C-7), 129.9 (C-10), 127.9 (C-9), 126.3 (C-12), 123.7 (C-8), 113.9 (C-23), 78.2 (C-4), 74.7 (C-5), 56.3 (C-24), 47.4 (C-2), 40.2 (C-14), 38.8 (C-18), 35.3 (C13), 32.6 (C-21), 29.6 (C-25), 29.0 (C-19), 25.3 (C-20); HRMS (ESI+) m/z = 832.2044 [M+H]+ found, C31H31F17N3O4+ required 832.2038. 36
36
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DOI: 10.1038/NCHEM.1729
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Linear urea 4
Azido building block 2 (138 mg, 0.194 mmol, 1.00 eq) was reacted with amine HCl-salt SI-24 (51 mg, 0.22 mmol, 1.1 eq) according to GP2 using P(n-Bu)3 (1.10 eq in total) and DIPEA (1.30 eq). After additional purification by flash column chromatography (EtOAc), title compound 4 (132 mg, 0.145 mmol, 75%) was isolated as a white foam. TLC Rf = 0.17 (neat EtOAc); HPLC tr = 9.42 min (50-100% B), peak area 100%; IR (neat) νmax = 2943 (w), 2095 (m, N3), 1754 (m, C=O), 1621 (m, C=O), 1556 (m), 1528 (m), 1236 (m), 1199 (s, C-F), 1146 (s, C-F), 1115 (m); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.00 (d, J = 3.4, 1H; H8), 6.44 (t, J = 5.8, 1H; H-12), 6.32 (d, J = 3.4, 1H; H-9), 6.08 (d, J = 8.6, 1H; H-14), 4.63 (dt, J = 8.1, 5.4, 1H; H-15), 4.43-4.40 (m, 4H; H-3, H-23), 4.37 (s, 2H; H-2), 4.23 (d, J = 5.8, 2H; H-11), 3.28 (t, J = 6.8, 2H; H-19), 3.09 (t, J = 2.4, 1H; H-5), 3.06-2.79 (br s; H-21 and H-22, coincides with water signal), 2.66 (t, J = 19.1, 6.0, 2H; H-24), 1.66-1.60 (m, 1H; H-16a), 1.59-1.51 (m, 2H; H-18), 1.50-1.43 (m, 1H; H-16b), 1.38-1.31 (m, 2H; H-17); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.8 (C-20), 168.0 (C-1), 158.6 (C-6), 156.8 (C-13), 156.3 (C-10), 144.8 (C-7), 117.1 (C-8), 107.3 (C-9), 78.4 (C-4), 74.5 (C-5), 56.3 (C-23), 50.4 (C-19), 48.4 (C-15), 48.0 (C-2), 36.2 (C-11), 31.7 (C-16), 29.6 (t, J = 21.5; C-24), 27.6 (C-18), 21.8 (C-17); HRMS (ESI+) m/z = 908.2068 [M+H]+ found, C30H31F17N7O6+ required 908.2059, 930.1882 [M+Na]+ found, C30H30F17N7O6Na+ required 930.1878.
Linear urea SI-42
Azido building block 2 (326 mg, 0.460 mmol, 1.00 eq) was reacted with amine HCl-salt SI-25 (125 mg, 0.598 mmol, 1.30 eq) according to GP2 using P(n-Bu)3 (1.05 eq in total) and DIPEA (4.00 eq). After purification solely by flash column chromatography (CH2Cl2/MeOH/HOAc 100:5:0.1), title compound SI-42 (275 mg, 0.312 mmol, 68%) was isolated as a white foam. TLC Rf = 0.57 (CH2Cl2/MeOH/HOAc 10:1:0.1); HPLC tr = 9.26 min (50-100% B), peak area 90%; mp 180 °C decomposition (CH2Cl2); [α]D28.4 = +3.9 (c = 0.387 in MeOH/CHCl3 2:1); IR (neat) νmax = 2098 (m, N3), 1753 (m, C=O), 1625 (m, C=O), 1428 (w), 1198 (s, C-F), 1145 (s, C-F), 968 (w), 704 (m); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.01 (d, J = 3.4, 1H; H-8), 6.45 (br s, 1H; H12), 6.34 (d, J = 3.5, 1H; H-9), 6.11 (br s, 1H; H-14), 4.43 (m, 4H; H-22, H-3), 4.39 (s, 2H; H-2), 37 37
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DOI: 10.1038/NCHEM.1729
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4.25 (d, J = 4.1, 2H; H-11), 4.14 (t, J = 6.5, 1H; H-15), 3.30 (t, J = 6.8, 2H; H-19), 3.08 (t, J = 2.5, 1H; H-5), 2.67 (tt, J = 19.2, 6.2, 2H; H-23), 1.79-1.68 (m, 1H; H-16a), 1.64-1.53 (m, 3H; H-16b, H-18), 1.43-1.35 (m, 2H; H-17); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 173.8 (C-20), 168.0 (C-1), 158.6 (C-6), 157.0 (C-13), 156.3 (C-10), 144.8 (C-7), 117.1 (C-8), 107.3 (C-9), 78.4 (C-4), 74.4 (C-5), 56.3 (C-22), 52.3 (C-15), 50.3 (C-19), 48.0 (C-2), 37.4 (C-3), 36.2 (C-11), 31.4 (C16), 29.6 (t, J = 21.3; C-23), 27.5 (C-18), 22.0 (C-17); HRMS (ESI+) m/z = 881.1578 [M+H]+ found, C28H26F17N6O7+ required 881.1586.
Linear urea SI-43
Azido building block 2 (0.30 g, 0.42 mmol, 1.0 eq) was reacted with amine HCl-salt SI-31 (70 mg, 0.52 mmol, 1.2 eq) according to GP2 using P(n-Bu)3 (1.1 eq in total) and DIPEA (2 eq). Title compound SI-43 (0.30 g, 0.37 mmol, 86%) was isolated as a white solid. TLC Rf = 0.35 (petroleum ether/EtOAc 3:7); HPLC tr = 14.94 min (5-100 % B) peak area 98%; IR (neat) νmax = 3285 (NH), 1751 ((C=O)O), 1621 ((C=O)N), 1194 (CF); 1H NMR (500 MHz, DMSOd6, 90 °C) δ = 7.01 (d, J = 3.5, 1H; H-8), 6.33 (d, J = 3.5, 1H; H-9), 6.09 (t, J = 5.5, 1H; H-12), 5.81 (ddt, J = 17.0, 10.0, 7.0, 1H; H-19), 5.77 (t, J = 4.5, 1H; H-14), 5.02 (ddt, J = 17.0, 2.0, 2.0, 1H; H-20a), 4.94 (ddt, J = 10.5, 2.0, 1.0, 1H; H-20b), 4.44-4.41 (m, 4H, H-21; H-3), 4.39 (s, 2H; H-2), 4.24 (d, J = 6.0, 2H; H-11), 3.10 (t, J = 3.0, 1H; H-5), 3.04 (dt, J = 6.5, 6.0, 2H; H-15), 2.67 (m, 2H; H-22), 2.04 (dt, J = 7.0, 2H; H-18), 1.45-1.34 (m, 4H; H-16 and H-17); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 168.0 (C-1), 158.6 (C-6), 157.3 (C-13), 156.5 (C-10), 144.7 (C-7), 138.1 (C-19), 117.1 (C-8), 113.9 (C-20), 107.2 (C-9), 78.4 (C-4), 74.4 (C-5), 56.3 (C-21), 48.0 (C-2), 38.9 (C-15), 37.3 (C-3), 36.2 (C-11), 32.2 (C-18), 29.6 (C-22), 28.9 (C-16), 25.2 (C-17); HRMS (ESI+) m/z = 808.1678 [M+H]+ found, C28H27F17N3O5+ required 808.1674.
Linear urea SI-44
Azide building block 13 (118 mg, 0.140 mmol, 1.00 eq) was reacted with amine HCl-salt SI-24 (36 mg, 0.15 mmol, 1.1 eq) according to GP2 using PPh3 (1.05 eq) and DIPEA (1.20 eq). Title compound SI-44 (111 mg, 0.106 mmol, 76%) was isolated as a pale yellow oil. 38 38
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TLC Rf = 0.63 (CH2Cl2/MeOH 9:1); NMR Appropriate NMR data could not be obtained for this compound due to the existence of rotamers at a temperature range of 25-90 °C and partial NBoc-deprotection at higher temperatures; HRMS (ESI+) m/z = 1043.2706 [M+H]+ found, C38H40F17N8O7+ required 1043.2743.
Preparation of Linear Oxalyl Ureas Linear oxalyl urea SI-45
Linear urea SI-32 (92 mg, 0.19 mmol, 1.0 eq) was reacted with oxalyl chloride (2.1 eq) according to GP3. Title compound SI-45 (103 mg, 0.185 mmol, 97%) was isolated as an off-white foam. TLC Rf = 0.65 (neat EtOAc); HPLC tr = 11.65 min (20-70% B), peak area 97%; [α]D28.7 = -9 (c = 0.142 in MeOH); IR (neat) νmax = 2940 (w), 2097 (m, N3), 1733 (s, C=O), 1648 (s, C=O), 1396 (s), 1211 (m), 1179 (m), 755 (m); HRMS (ESI+) m/z = 540.2204 [M+H]+ found, C25H30N7O7+ required 540.2201, 562.2022 [M+Na]+ found, C25H29N7O7Na+ required 562.2021.
Linear oxalyl urea 24
Linear urea 21 (500 mg, 0.553 mmol, 1.00 eq) was reacted with oxalyl chloride (1.30 eq) according to GP3. Title compound 24 (509 mg, 0.531 mmol, 96%) was isolated as a white foam. HPLC tr = 8.99 min (60-100% B), peak area 95%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.66-7.58 (m, 2H; H-9 and H-8 or H-10), 7.56 (br s, 1H; H-12), 7.52 (br d, J = 7.1, 1H; H-8 or H10), 5.01 (dd, J = 9.3, 5.6, 1H; H-16), 4.43 (t, J = 6.1, 2H; H-24), 4.30-4.19 (m, 4H; H-2 and H-2), 3.33 (t, J = 6.8, 2H; H-20), 3.13 (t, J = 2.4, 1H; H-5), 3.07-2.88 (m; H-22 and H-23, coincides with water signal), 2.67 (tt, J = 19.2, 6.2, 2H; H-25), 2.25 (m, 1H; H-17a), 2.06 (m, 1H; H-17b), 1.681.55 (m, 2H; H-19), 1.55-1.42 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 169.0, 167.8, 166.5, 155.9, 154.8, 152.1 (each C=O), 135.2, 130.4 (both quat. C), 129.0 (C-9), 127.5 (C-8 or C-10), 126.3 (C-8 or C-10), 124.3 (C-12), 77.9 (C-4), 74.9 (C-5), 56.5 (C-24), 52.5 (C39
39
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16), 50.3 (C-20), 35.7 (br; C-22 and C-23), 29.6 (t, J = 21.5; C-25), 27.4 (C-19), 27.1 (C-17), 22.6 (C-18); HRMS (ESI+) m/z = 958.1817 [M+H]+ found, C33H29F17N7O7+ required 958.1852.
Linear oxalyl urea SI-46
Linear urea 4 (197 mg, 0.217 mmol, 1.00 eq) was reacted with oxalyl chloride (1.50 eq) according to GP3. After additional purification by flash column chromatography (petroleum ether/EtOAc 1:2), title compound SI-46 (164 mg, 0.171 mmol, 79%) was isolated as a white foam. TLC Rf = 0.30 (petroleum ether/EtOAc 1:2); HPLC tr = 10.84 min (50-100% B), peak area 98%; [α]D28.7 = -2.8 (c = 0.836 in MeOH); IR (neat) νmax = 2103 (m, N3), 1737 (s, C=O), 1651 (m, C=O), 1428 (m), 1405 (m), 1120 (s, C-F), 1145 (s, C-F); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.05 (d, J = 3.5, 1H; H-8), 6.58 (d, J = 3.5, 1H; H-9), 4.95 (dd, J = 9.7, 5.3, 1H; H-15), 4.79 (s, 2H; H11), 4.44-4.39 (m, J = 11.2, 5.5, 6H; H-2, H-3, H-23), 3.31 (t, J = 6.8, 2H; H-19), 3.06 (t, J = 2.4, 1H; H-5), 2.92 (s, 6H; H-21, H-22), 2.67 (tt, J = 19.2, 6.1, 2H; H-24), 2.27-2.19 (m, 1H; H-16a), 2.04-1.97 (m, 1H; H-16b), 1.63-1.54 (m, 2H; H-18), 1.47-1.40 (m, 2H; H-17); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 167.9 (C-1), 166.5 (C-20), 158.3 (C-6), 156.2 (C-13), 155.4 (C-14), 152.6 (C-12), 150.0 (C-10), 146.0 (C-7), 117.2 (C-8), 110.0 (C-9), 78.2 (C-4), 74.4 (C-5), 56.3 (C-23), 52.6 (C-15), 50.2 (C-19), 48.0 (C-2), 37.4 (C-3), 35.6 (br, C-21, C-22), 34.9 (C-11), 29.6 (t, J = 21.3; C-24), 27.3 (C-18), 26.9 (C-16), 22.6 (C-17); HRMS (ESI+) m/z = 962.1779 [M+H]+ found, C32H28F17N7O8+ required 962.1801, 984.1648 [M+Na]+ found, C32H28F17N7O8Na+ required 984.1620.
Preparation of Linear Hydantoins Linear hydantoin SI-47 O O
N
O
N3
O N O
NH
SI-47
Linear urea SI-33 (60 mg, not pure, max. 0.13 mmol, 1.0 eq) was reacted according to GP4. After purification by flash column chromatography (petroleum ether/EtOAc 1:2), title compound 40 40
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SI-47 (30 mg, mixed with PPh3=O) was isolated as a colorless oil and used in the next step without further purification. TLC Rf = 0.30 (petroleum ether/EtOAc 1:2); HPLC tr = 9.37 min (20-70% B), peak area 80%; HRMS (ESI+) m/z = 441.1882 [M+H]+ found, C21H25N6O5+ required 441.1881, 463.1697 [M+Na]+ found, C21H24N6O5Na+ required 463.1700.
Linear hydantoin 25
Linear urea 22 (109 mg, 0.124 mmol, 1.00 eq) was reacted according to GP4. After purification by F-SPE and flash column chromatography (petroleum ether/EtOAc 1:1), title compound 25 (42 mg, 0.049 mmol, 39%) was isolated as a white foam. TLC Rf = 0.35 (petroleum ether/EtOAc 1:1); HPLC tr = 8.31 min (60-100% B), peak area 97%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.31 (s, 1H; H-14), 7.58-7.51 (m, 2H; H-9 and H-8 or H10), 7.48 (br s, 1H; H-12), 7.42 (br d, J = 7.1, 1H; H-8 or H-10), 4.43 (t, J = 6.2, 1H; H-21), 4.25 (s, 4H; H-2 and H-3), 4.21 (ddd, J = 6.7, 5.1, 1.5, 1H; H-15), 3.35 (t, J = 6.8, 2H; H-20), 3.14 (t, J = 2.5, 1H; H-5), 2.67 (tt, J = 19.2, 6.1, 2H; H-22), 1.91-1.81 (m, 1H; H-17a), 1.79-1.69 (m, 1H; H17b), 1.66-1.58 (m, 2H; H-19), 1.57-1.45 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 172.5, 169.2, 167.7, 154.8 (each C=O), 134.8, 132.2 (both quat. C-Ar), 128.5, 127.3 (both CAr), 125.2 (C-8 or C-10), 123.9 (C-12), 77.9 (C-4), 74.9 (C-5), 56.4 (C-21), 55.8 (C-15), 50.2 (C20), 30.4 (C-17), 29.6 (C-22), 27.5 (C-19), 21.0 (C-18); HRMS (ESI+) m/z = 859.1553 [M+H]+ found, C29H24F17N6O5+ required 859.1531.
Linear hydantoin SI-48
Linear urea SI-38 (700 mg, not pure, max. 0.79 mmol, 1.0 eq) was reacted according to GP4. After purification by flash column chromatography (petroleum ether/EtOAc 1:1), title compound SI-48 (289 mg, not pure) was isolated as white crystals and used in the next step without further purification. TLC Rf = 0.36 (petroleum ether/EtOAc 1:2); HRMS (ESI+) m/z = 873.1653 [M+H]+ found, C30H26F17N6O5+ required 873.1688. 41 41
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Linear hydantoin SI-49
Linear urea SI-41 (180 mg, not pure, max. 0.171 mmol, 1.00 eq) was reacted according to GP4. After purification by F-SPE, title compound SI-49 (96 mg, not pure) was isolated as a white foam and used in the next step without further purification. TLC Rf = 0.17 (petroleum ether/EtOAc = 1:1); HPLC tr = 10.80 min (50-100% B), peak area 74%; HRMS (ESI+) m/z = 887.1863 [M+H]+ found, C31H28F17N6O5+ required 887.1844, 909.1682 [M+Na]+ found, C31H29F17N6O5Na+ required 909.1664.
Linear hydantoin SI-50
Linear urea SI-42 (275 mg, 0.312 mmol, 1.00 eq) was reacted according to GP4. After purification by flash column chromatography (petroleum ether/EtOAc 2:3), title compound SI-50 (204 mg, 0.236 mmol, 76%) was isolated as a white foam. TLC Rf = 0.23 (petroleum ether/EtOAc 2:3); HPLC tr = 10.28 min (50-100% B), peak area 95%; [α]D28.7 = -12.6 (c = 0.941 in MeOH); IR (neat) νmax = 3274 (w), 2934 (w), 2099 (m, N3), 1755 (w, C=O), 1713 (s, C=O), 1631 (m, C=O), 1529 (w), 1440 (m), 1348 (w), 1236 (m), 1198 (s, C-F), 1146 (s, C-F), 1116 (m); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.08 (s, 1H; H-13), 7.02 (d, J = 3.5, 1H; H-8), 6.43 (d, J = 3.5, 1H; H-9), 4.59 (s, 2H; H-11), 4.43 (t, J = 6.2, 2H; H-20), 4.40 (d, J = 2.5, 2H; H-3), 4.39 (s, 2H; H-2), 4.09 (ddd, J = 6.6, 5.0, 1.4, 1H; H-14), 3.30 (t, J = 6.8, 2H; H-19), 3.07 (t, J = 2.5, 1H; H-5), 2.67 (tt, J = 19.1, 6.2, 2H; H-21), 1.80-1.73 (m, 1H; H-16a), 1.68-1.52 (m, 3H; H-16b, H-18), 1.50-1.33 (m, 2H; H-17); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 173.1 (C-15), 167.9 (C-1), 158.3 (C-6), 155.4 (C-12), 151.7 (C-10), 145.4 (C-7), 117.2 (C-8), 108.9 (C-9), 78.2 (C-4), 74.4 (C-5), 56.3 (C-20), 55.9 (C-14), 50.2 (C-19), 48.0 (C-2), 37.3 (C-3), 34.0 (C-11), 30.3 (C-16), 29.6 (t, J = 21.3; C-21), 27.4 (C-18), 21.0 (C-17); HRMS (ESI+) m/z = 863.1439 [M+H]+ found, C28H24F17N6O6+ required 863.1480, 885.1281 [M+Na]+ found, C28H23F17N6O6Na+ required 885.1300.
42 42
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Preparation of Linear Dihydrouracils Linear dihydrouracil 26
Linear urea 23 (173 mg, 0.195 mmol, 1.00 eq) was reacted according to GP5 using N-hydroxysuccinimide (37 mg, 0.32 mmol, 1.60 eq), N,N'-diisopropylcarbodiimide (49 µL, 0.32 mmol, 1.60 eq) and DMAP (39 mg, 0.32 mmol, 1.6 eq). After purification by F-SPE and subsequent flash column chromatography (CH2Cl2/EtOAc 1:1), title compound 26 (95 mg, 0.11 mmol, 56%) was isolated as a white foam. HPLC tr = 7.81 min (60-100% B), peak area 94%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.76 (d, J = 2.3, 1H; H-14), 7.49 (t, J = 7.8, 1H; H-9), 7.40 (d, J = 7.7, 1H; H-8 or H-10), 7.29 (ddd, J = 7.9, 2.0, 1.2, 1H; H-8 or H-10), 7.23 (t, J = 1.9, 1H; H-12), 4.41 (t, J = 6.2, 2H; H-22), 4.25-4.20 (m, 4H; H-2 and H-3), 3.65-3.58 (m, 1H; H-15), 3.35 (t, J = 6.9, 2H; H-21), 3.14 (t, J = 2.5, 1H; H5), 2.86 (dd, J = 16.2, 5.1, 1H; H-16a), 2.67 (tt, J = 19.2, 6.2, 2H; H-23), 2.59 (dd, J = 16.2, 8.0, 1H; H-16b), 1.71-1.40 (m, 6H; H-18, H-19 and H-20); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 169.4, 168.8, 167.8, 152.5 (each C=O), 135.8, 134.4 (both quat. C), 130.6 (C-8 or C-10), 128.2 (C-9), 127.2 (C-12), 125.3 (C-8 or C-10), 78.0 (C-4), 74.8 (C-5), 56.4 (C-22), 50.3 (C-21), 47.3 (br C-2 and/or C-3), 45.2 (C-15), 36.4 (C-16), 33.3 (C-18), 29.6 (t, J = 20.3; C-23), 27.6 (C-20), 21.4 (C-19); HRMS (ESI+) m/z = 873.1719 [M+H]+ found, C30H26F17N6O5+ required 873.1688.
Preparation of Linear Guanidines Linear guanidine 5
Azide building block 3 (200 mg, 0.284 mmol, 1.00 eq) was reacted with phenyl isocyanate (30 µL, 0.28 mmol, 1.0 eq) and amine HCl-salt SI-31 (42 mg, 0.31 mmol, 1.1 eq) according to GP6 using P(n-Bu)3 (1.15 eq). After purification by flash column chromatography (CH2Cl2/MeOH 92:8), title compound 5 (161 mg, 0.183 mmol, 65%) was isolated as a slightly yellow gum. 43 43
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TLC Rf = 0.28 (CH2Cl2/MeOH, 9:1); HPLC tr = 7.40 min (60-100% B), peak area 98%; IR (neat) νmax = 1752 ((C=O)O), 1638 ((C=O)N), 1198 (CF); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.23 (t, J = 8.0, 1H; Ar-H), 7.19-7.16 (m, 2H; Ar-H), 7.09 (d, J = 8.0, 1H; Ar-H), 7.04-7.03 (m, 3H; Ar-H), 6.91-6.88 (m, 2H; Ar-H), 5.81 (ddt, J = 17.0, 10.5, 6.5, 1H; H-20), 5.00 (ddt, J = 17.0, 2.0, 1.5, 1H; H-21a), 4.94 (d, J = 10.5, 1H; H-21b), 4.41 (t, J = 6.5, 2H; H-26), 4.19 (s, 2H; H-2), 4.15 (s, 2H; H-3), 3.22 (t, J = 7.0, 2H; H-16), 3.11 (t, J = 2.0, 1H; H-5), 2.66 (tt, J = 19.0, 6.5, 2H; H27), 2.05 (dt, J = 7.5, 7.0, 2H; H-19), 1.56 (quint, J = 7.5, 2H; H-17), 1.42 (quint, J = 7.5, 2H; H18); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 170.0 (C-6), 167.8 (C-1), 149.4 (C-14), 144.1 (CAr), 141.8 (C-Ar), 138.0 (C-20), 134.9, 128.3, 128.1, 122.7, 121.6, 120.8, 119.2, 119.0 (each CAr), 114.0 (C-21), 78.1 (C-4), 74.7 (C-5), 56.3 (C-26), 47.1 (C-2), 41.5 (C-16), 32.1 (C-19), 29.6 (C-27), 28.1 (C-17), 25.1 (C-18); HRMS (ESI+) m/z = 879.2204 [M+H]+ found, C35H32F17N4O3+ required 879.2197.
Linear guanidine SI-51
Azide building block 15 (412 mg, 0.563 mmol, 1.00 eq) was reacted with phenyl isocyanate (62 µL, 0.59 mmol, 1.05 eq) and amine HCl-salt SI-31 (84 mg, 0.62 mmol, 1.1 eq) according to GP6 using P(n-Bu)3 (1.15 eq). After purification by flash column chromatography (CH2Cl2/MeOH 9:1) and preparative HPLC (60-85% B), title compound SI-51 (218 mg, 0.21 mmol, 40%) was isolated as a white solid. TLC Rf = 0.31 (CH2Cl2/MeOH, 9:1); HPLC tr = 7.98 min (60-100% B), peak area 96%; IR (neat) νmax = 1754 ((C=O)O), 1680 (NH(C=N-)NH), 1638 ((C=O)N), 1196 (CF); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 9.24 (br s, 1H; H-24 (NH+)), 7.58 (m, 2H; H-15 and H-17), 7.43-7.26 (m, 7H; Ar-H), 7.12-7.10 (m, 2H; Ar-H), 5.81 (ddt, J = 17.0, 10.0, 7.0, 1H; H-22), 5.02 (ddt, J = 17.0, 2.0, 1H; H-23a), 4.96 (ddt, J = 10.0, 2.0, 1.0, 1H; H-23b), 4.24 (t, J = 7.5, 2H; H-29), 4.23 (s, 2H; H-2), 4.19 (s, 2H; H-3), 3.56 (dt, J = 7.0, 6.5, 2H; H-14), 3.21 (dt, J = 7.0, 6.0, 2H; H-18), 3.15 (s, 1H; H-5, coincides with water signal), 2.93 (t, J = 7.0, 2H; H-13), 2.67 (tt, J = 19.0, 6.0, 2H; H30), 2.04 (dt, J = 7.5, 7.0, 2H; H-21), 1.54 (m, 2H; H-19), 1.39 (m, 2H; H-20); 13C NMR (125 MHz, DMSO-d6, 90 °C): δ = 170.0 (C-6), 167.9 (C-1), 153.7 (C-16), 138.4 (C-Ar), 137.8 (C-22), 135.6, 134.7, 130.0, 129.1, 128.0, 126.7, 125.8, 124.2, 123.9 (each C-Ar), 114.2 (C-23), 78.1 (C4), 74.8 (C-5), 56.4 (C-31), 47.2 (C-2), 42.2 (C-14), 41.4 (C-18), 33.8 (C-13), 32.0 (C-21), 29.6 (C-32), 27.4 (C-19), 24.9 (C-20). TFA-signals do not appear clearly; HRMS (ESI+) m/z = 907.2504 [M+H]+ found, C37H36F17N4O3+ required 907.2510.
44 44
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Preparation of Linear Amides Linear amide SI-52
According to GP7, azide building block 17 (133 mg, 0.465 mmol, 1.00 eq) was reacted with P(nBu)3 (1.10 eq) and subsequently with the corresponding acyl chloride prepared from 6azidohexanoic acid[12] (116 mg, 0.736 mmol, 1.60 eq). After flash column chromatography (petroleum ether/EtOAc 1:1), title compound SI-52 (70 mg, 0.18 mmol, 38%) was isolated as a yellow oil. TLC Rf = 0.36 (petroleum ether/EtOAc 1:1); HPLC tr = 10.95 min (20-70% B), peak area 92%; IR (neat) νmax = 3265 (w), 2938 (w), 2094 (s, N3), 1747 (s, C=O), 1647 (s, C=O), 1605 (m), 1589 (m), 1516 (m), 1451 (s), 1208 (s), 1179 (s), 757 (s); HRMS (ESI+) m/z = 400.1998 [M+H]+ found, C20H26N5O4+ required 400.1979.
Linear amide 27
According to GP7, azide building block 3 (317 mg, 0.449 mmol, 1.00 eq) was reacted with P(nBu)3 (1.05 eq) and subsequently with the corresponding acyl chloride prepared from 7azidoheptanoic acid[12] (100 mg, 0.584 mmol, 1.30 eq). After flash column chromatography (petroleum ether/EtOAc 2:1), title compound 27 (299 mg, 0.359 mmol, 80%) was isolated as a colorless wax. TLC Rf = 0.18 (petroleum ether/ethyl acetate 2:1); HPLC tr = 10.22 min (60-100% B), peak area 96%; 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 9.57 (s, 1H; H-13), 7.72 (t, J = 1.7, 1H; H-12), 7.61 (m, 1H; H-10), 7.35 (t, J = 7.8, 1H; H-9), 7.08 (dt, J = 7.6, 1.3, 1H; H-8), 4.44 (t, J = 6.5, 2H; H-21), 4.24-4.23 (m, 4H; H-2 and H-3), 3.02 (t, J = 2.4, 2H; H-20), 3.02 (t, J = 2.4, 1H; H-5), 2.67 (tt, J = 19.1, 6.1, 2H; H-22), 2.33 (t, J = 7.4, 2H; H-15), 1.68-1.63 (m, 2H; H-16), 1.62-1.56 (m, 2H; H-19), 1.43-1.37 (m, 4H; H-17 and H-18); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 171.0 (C-14), 170.0 (C-6), 167.9 (C-1), 139.2 (C-7 or C-11), 134.9 (C-7 or C-11), 128.3 (C-9), 120.5 (C-8), 120.3 (C-10), 117.2 (C-12), 78.1 (C-4), 74.7 (C-5), 56.4 (C-21), 50.4 (C-20), 35.9 (C-15), 45 45
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29.6 (t, J = 20.9; C-22), 27.67 (C-17 or 18 or 19), 27.63 (C-17 or 18 or 19), 25.43 (C-17 or 18), 24.32 (C-16); HRMS (ESI+) m/z = 832.1796 [M+H]+ found, C29H27F17N5O4+ required 832.1786.
Linear amide SI-53
According to GP7, azide building block 14 (250 mg, 0.348 mmol, 1.00 eq) was reacted with P(nBu)3 (1.10 eq) and subsequently with the corresponding acyl chloride prepared from 6azidohexanoic acid[12] (71 mg, 0.45 mmol, 1.3 eq). After flash column chromatography (petroleum ether/EtOAc 1:1), title compound SI-53 (140 mg, 0.169 mmol, 48%) was isolated as a colorless oil. TLC Rf = 0.17 (petroleum ether/EtOAc 1:1); HPLC tr = 10.89 min (50-100% B), peak area 96%; IR (neat) νmax = 2940 (br, C-H), 2098 (s, N3), 1753 (w, C(=O)OR), 1691 (br, C(=O)NR2 and C(=O)NRH); 1H NMR (500 MHz, DMSO-d6, 90°C) δ = 8.03 (t, J = 5.0, 1H; H-14), 7.41 – 7.37 (m, 2H; H-8 and H-10), 7.35 (s, 1H; H-12), 7.30 (t, J = 4.2, 1H; H-9), 4.44 (t, J = 6.2, 2H; H-21), 4.33 (d, J = 6.0, 2H; H-13), 4.24 (s, 2H; H-2), 4.22 (s, 2H; H-3), 3.30 (t, J = 6.9, 2H; H-16), 3.10 (t, J = 2.0, 1H; H-5), 2.67 (tt, J = 19.1, 6.2, 2H; H-22), 2.19 (t, J = 7.4, 2H; H-20), 1.65 – 1.53 (m, 4H; H17 and H-19), 1.44 – 1.33 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 90°C) δ = 171.6 (C=O), 170.1 (C=O), 167.9 (C=O), 140.0 (quat. C), 134.5 (quat. C), 128.5 (C-8 or C-10), 127.8 (C-9), 125.2 (C-12), 124.4 (C-8 or C-10), 78.0 (C-4), 74.6 (C-5), 56.4 (C-21), 50.4 (C-16), 41.6 (C-13), 34.8 (C-20), 29.6 (t, J = 21.2; C-22), 27.5 (C-17), 25.4 (C-18), 24.3 (C-19); HRMS (ESI+) m/z = 854.1566 [M+Na]+ found, C29H26F17N5O4Na+ required 854.1606.
Linear amide SI-54
According to GP7, azide building block 14 (300 mg, 0.418 mmol, 1.00 eq) was reacted with P(nBu)3 (1.10 eq) and subsequently with the corresponding acyl chloride prepared from 8azidooctanoic acid[12] (102 mg, 0.551 mmol, 1.3 eq). After flash column chromatography (petroleum ether/EtOAc 1:1), title compound SI-54 (310 mg, 0.360 mmol, 86%) was isolated as a pale yellow oil. TLC Rf = 0.49 (petroleum ether/EtOAc 1:1); HPLC tr = 12.01 min (50-100% B), peak area 96%; IR (neat) νmax = 2934 (m, C-H), 2096 (s, N3), 1753 (m, C(=O)OR), 1646 (m, C(=O)OR); 1H NMR 46 46
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(500 MHz, DMSO-d6, 90°C) δ = 7.99 (s, 1H; H-14), 7.40 – 7.37 (m, 2H; H-8 and H-9), 7.33 (s, 1H; H-12), 7.29 (d, J = 6.5, 1H; H-10), 4.43 (t, J = 6.1, 2H; H-23), 4.31 (d, J = 5.9, 2H; H-13), 4.23 (s, 2H; H-2), 4.21 (s, 2H; H-3), 3.30 (t, J = 6.7, 2H; H-16), 3.13 (t, J = 2.5, 1H; H-5), 2.68 (tt, J = 19.2, 6.2, 2H; H-24), 2.16 (t, J = 7.4, 2H; H-22), 1.61 – 1.50 (m, 4H; H-17 and H-21), 1.38 – 1.26 (m, 6H; H-18, 19, and 20); 13C NMR (125 MHz, DMSO-d6, 90°C) δ = 171.7 (C=O), 170.1 (C=O), 167.8 (C=O), 140.0 (quat. C), 134.4 (quat. C ), 128.5 (C-8 or C-10), 127.8 (C-9), 125.1 (C-12), 124.4 (C-8 or C-10), 78.1 (C-4), 74.7 (C-5), 56.4 (C-23), 50.4 (C-16), 48.1 (C-2), 41.5 (C13), 35.0 (C-22), 29.6 (t, J = 21.0; C-24), 28.0 (C-18, 19, or 20), 27.7 (C-17 or C-21), 27.4 (C-18, 19, or 20), 25.5 (C-18, 19 or 20), 24.6 (C-17 or C-21); HRMS (ESI+) m/z = 860.2076 [M+H]+ found, C31H31F17N5O4+ required 860.2099.
Linear amide SI-55
According to GP7, azide building block 15 (250 mg, 0.341 mmol, 1.00 eq) was reacted with P(nBu)3 (1.10 eq) and subsequently with the corresponding acyl chloride prepared from 6azidohexanoic acid[12] (70 mg, 0.44 mmol, 1.3 eq). After flash column chromatography (petroleum ether/EtOAc 1:1), title compound SI-55 (55 mg, 0.065 mmol, 19%) was isolated as a colorless oil. TLC Rf = 0.71 (neat EtOAc); HPLC tr = 11.05 min (50-100% B), peak area 94%; IR (neat) νmax = 2962 (br, alkyl C-H), 2096 (s, N3), 1753 (w, C(=O)OR), 1647 (m, C(=O)NR2), HRMS (ESI+) m/z = 846.1953 [M+H]+ found, C30H29F17N5O4+ required 846.1948.
Linear amide SI-56
According to GP7, azide building block 15 (350 mg, 0.478 mmol, 1.00 eq) was reacted with P(nBu)3 (1.1 eq) and subsequently with the corresponding acyl chloride prepared from 8azidooctanoic acid[12] (115 mg, 0.621 mmol, 1.30 eq). After flash column chromatography (petroleum ether/EtOAc 1:1), title compound SI-56 (177 mg, 0.202 mmol, 42%) was isolated as a pale yellow oil. TLC Rf = 0.81 (neat EtOAc); HPLC tr = 11.91 min (50-100% B), peak area 97%; IR (neat) νmax = 2091 (m, N3), 1742 (m, C(=O)OR), 1628 (m, C(=O)NR2); HRMS (ESI+) m/z = 874.2230 [M+H]+ found, C32H33F17N5O4+ required 874.2261. 47 47
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Linear amide SI-57
According to GP7, azide building block 2 (473 mg, 0.668 mmol, 1.00 eq) was reacted with P(nBu)3 (1.10 eq) and subsequently with the corresponding acyl chloride prepared from 6azidohexanoic acid[12] (168 mg, 1.07 mmol, 1.60 eq). After flash column chromatography (petroleum ether/EtOAc 1:2), title compound SI-57 (404 mg, 0.492 mmol, 74%) was isolated as a white foam. TLC Rf = 0.35 (petroleum ether/EtOAc 1:2); HPLC tr = 10.63 min (50-100% B), peak area 100%; IR (neat) νmax = 3295 (w), 2933 (w), 2097 (m, N3), 1753 (s, C=O), 1636 (m, C=O), 1526 (m), 1455 (w), 1426 (w), 1236 (m), 1199 (s, C-F), 1146 (s, C-F), 703 (m); 1H NMR (500 MHz, DMSOd6, 90 °C) δ = 8.00 (s, 1H; H-12), 7.02 (d, J = 3.5, 1H; H-8), 6.36 (d, J = 3.5, 1H; H-9), 4.44-4.39 (m, 6H; H-2, H-3, H-19), 4.30 (d, J = 5.7, 2H; H-11), 3.30 (t, J = 6.9, 2H; H-18), 3.10 (t, J = 2.5, 1H; H-5), 2.67 (tt, J = 19.2, 6.2, 2H; H-20), 2.15 (t, J = 7.4, 2H; H-14), 1.60-1.53 (m, 4H; H-15, H17), 1.39-1.32 (m, 2H; H-16); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.6 (C-13), 168.0 (C1), 158.5 (C-6), 155.1 (C-10), 144.9 (C-7), 117.1 (C-8), 107.7 (C-9), 78.3 (C-4), 74.4 (C-5), 56.3 (C-19), 50.3 (C-18), 48.0 (C-2), 37.3 (C-3), 35.2 (C-11), 34.6 (C-14), 29.6 (t, J = 21.0; C-20), 27.5 (C-17), 25.4 (C-16), 24.1 (C-15); HRMS (ESI+) m/z = 822.1562 [M+H]+ found, C27H25F17N5O5+ required 822.1579, 844.1402 [M+Na]+ found, C27H24F17N5O5Na+ required 844.1398.
Figure S8: Preparation of azido aldehyde SI-64
48 48
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3-Bromobenzyl acetate SI-58
Title compound SI-58 was prepared according to a published procedure.[13]
3-(4-Hydroxybut-1-yn-1-yl)benzyl acetate SI-59
3-Bromobenzyl acetate SI-58 (5.00 g, 21.8 mmol, 1.00 eq) was dissolved in dry DMF (60 mL) and 3-butyn-1-ol (2.0 mL, 26 mmol, 1.2 eq) and triethylamine (15 mL, 109 mmol, 5.0 eq) were added. Argon was bubbled through the solution for 20 min. CuI (208 mg, 1.09 mmol, 0.05 eq) and PdCl2(PPh3)2 (766 mg, 1.09 mmol, 0.05 eq) were added and the mixture was stirred at 50 °C overnight. The reaction mixture was diluted with Et2O and washed with 10% aqueous HCl (3 x), saturated NaHCO3 and brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure. After flash column chromatography (petroleum ether/EtOAc 2:1), title compound SI-59 (3.27 g, 15.0 mmol, 68%) was isolated as a yellow oil. TLC Rf = 0.23 (petroleum ether/EtOAc 3:1); HPLC tr = 9.33 min (5-100% B); IR (neat) νmax = 3420 (br w, OH), 2943 (w), 2887 (w), 1737 (s, C=O), 1605 (w), 1583 (w), 1484 (w), 1431 (w), 1378 (m), 1362 (m), 1223 (s), 1040 (s), 790 (m), 692 (m); 1H NMR (400 MHz, CDCl3, 27 °C) δ = 7.41 (s, 1H; H-7), 7.39-7.34 (m, 1H; H-3), 7.31-7.27 (m, 2H; H-4 and H-5), 5.06 (s, 2H; H-1), 3.82 (t, J = 6.3, 2H; H-11), 2.69 (t, J = 6.3, 2H; H-10), 2.11 (s, 3H; H-14); 13C NMR (100 MHz, CDCl3, 27 °C) δ = 171.0 (C-13), 136.3 (C-2), 131.6 (C-5 or C-7), 131.5 (C-7 or C-5), 128.7 (C-4), 127.8 (C-3), 123.8 (C-6), 87.0 (C-9), 82.2 (C-8), 65.9 (C-1), 61.3 (C-11), 24.0 (C-10), 21.1 (C14); HRMS (ESI+) m/z = 219.1009 [M+H]+ found, C13H15O3+ required 219.1016.
3-(4-Hydroxybutyl)benzyl acetate SI-60
3-(4-hydroxybut-1-yn-1-yl)benzyl acetate SI-59 (3.28 g, 15.0 mmol) was dissolved in dry methanol (85 mL). Pd/C (10%; 145 mg) was added and the reaction atmosphere was exchanged to H2. The mixture was stirred at room temperature for 2 h (reaction control by NMR!). The Pd-C was filtered off through a pad of Celite and the filtrate was concentrated under reduced pressure to give title compound SI-60 (2.82 g) mixed with some 4-(m-tolyl)butan-1-ol as a yellow oil that was used in the next step without further purification. TLC Rf = 0.23 (petroleum ether/EtOAc 3:1); HPLC tr = 9.52 min (5-100% B); IR (neat) νmax = 3351 (br w, OH), 2936 (w), 2861 (w), 1737 (s, C=O), 1610 (w), 1591 (w), 1489 (w), 1447 (w), 49
49
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1380 (w), 1361 (w), 1224 (s), 1027 (s), 701 (m); 1H NMR (400 MHz, CDCl3, 27 °C) δ = 7.30-7.26 (m; H-4, coincides with solvent signal), 7.22-7.12 (m, 3H; H-3 and H-7 and H-5), 5.08 (s, 2H; H1), 3.66 (t, J = 6.4, 2H; H-11), 2.66 (t, J = 7.6, 2H; H-8), 2.10 (s, 3H; H-14), 1.77-1.66 (m, 2H; H9), 1.66-1.57 (m; H-10, coincides with water signal); 13C NMR (100 MHz, CDCl3, 27 °C) δ = 171.1 (C-13), 142.9 (C-6), 136.0 (C-2), 128.7 (C-4), 128.5 (C-7 and C-5), 125.9 (C-3), 66.5 (C-1), 62.9 (C-11), 35.7 (C-8), 32.5 (C-10), 27.6 (C-9), 21.2 (C-14); HRMS (ESI+) m/z = 223.1323 [M+H]+ found, C13H19O3+ require 223.1329.
3-(4-(Tosyloxy)butyl)benzyl acetate SI-61
3-(4-hydroxybutyl)benzyl acetate SI-60 (2.64 g, not pure, max 11.9 mmol) was dissolved in dry CH2Cl2 (50 mL) and triethylamine (2.0 mL, 14 mmol, 1.2 eq) and DMAP (73 mg, 0.60 mmol, 0.05 eq) were added. 4-Toluenesulfonyl chloride (2.72 g, 14.3 mmol, 1.20 eq) were added at 0 °C. After stirring at room temperature overnight, the mixture was washed with 5% aqueous HCl, saturated NaHCO3 and brine, dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Crude title compound SI-61 (4.68 g) was isolated as yellow oil that was used in the next step without further purification. TLC Rf = 0.33 (petroleum ether/EtOAc 3:1); IR (neat) νmax = 2939 (w), 1736 (m, C=O), 1598 (w), 1449 (w), 1357 (m), 1224 (s), 1138 (s), 933 (m), 663 (m); 1H NMR (400 MHz, CDCl3, 27 °C) δ = 7.78 (d, J = 8.4, 2H; H-13), 7.33 (d, J = 8.0, 2H; H-14), 7.29-7.23 (m; H-4, coincides with solvent signal), 7.17 (d, J = 7.5, 1H; H-3), 7.11 (t, J = 2.0, 1H; H-7), 7.07 (d, J = 7.7, 1H; H-5), 5.07 (s, 2H; H-1), 4.04 (t, J = 6.0, 2H; H-11), 2.56 (t, J = 7.4, 2H; H-8), 2.44 (s, 3H; H-16), 2.10 (s, 3H; H18), 1.74-1.62 (m, 4H; H-9 and H-10); 13C NMR (100 MHz, CDCl3, 27 °C) δ = 171.0 (C-17), 144.8 (C-15), 142.1 (C-6), 136.1 (C-2), 133.3 (C-12), 130.0 (C-14), 128.8 (C-4), 128.4 (C-7 and C-5), 128.0 (C-13), 126.0 (C-3), 70.4 (C-11), 66.4 (C-1), 35.1 (C-8), 28.5 (C-9 or C-10), 27.2 (C-10 or C-9), 21.8 (C-16), 21.2 (C-18); HRMS (ESI+) m/z = 399.1232 [M+Na]+ found, C20H24O5NaS+ require 399.1237.
3-(4-Azidobutyl)benzyl acetate SI-62
3-(4-(tosyloxy)butyl)benzyl acetate SI-61 (4.68 g, not pure, max. 11.7 mmol, 1.00 eq) was dissolved in dry DMF (30 mL) and sodium azide (0.91 g, 14 mmol, 1.2 eq) was added. After stirring at room temperature overnight, the mixture was diluted with Et2O and washed with water, saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. After purifiavtion by flash column chromatography (petroleum ether/EtOAc 15:1), title 50 50
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compound SI-62 (1.97 g, 7.97 mmol, 57% over three steps from SI-59) was isolated as a colorless oil. TLC Rf = 0.83 (petroleum ether/EtOAc 3:1); HPLC tr = 12.64 min (5-100% B), peak area 90%; IR νmax (neat) = 2942 (w), 2862 (w), 2092 (m, N3), 1737 (s, C=O), 1610 (w), 1592 (w), 1489 (w), 1450 (w), 1379 (w), 1361 (w), 1222 (s), 1026 (m), 701 (m); 1H NMR (400 MHz, CDCl3, 27 °C) δ = 7.29 (t, J = 7.5, 1H; H-4), 7.20-7.14 (m, 3H; H-3 and H-7 and H-5), 5.09 (s, 2H; H-1), 3.29 (t, J = 6.7, 2H; H-11), 2.66 (t, J = 7.4, 2H; H-8), 2.11 (s, 3H; H-13), 1.74-1.68 (m, 2H; H-9), 1.68-1.62 (m, 2H; H-10); 13C NMR (100 MHz, CDCl3, 27 °C) δ = 171.0 (C-12), 142.4 (C-6), 136.2 (C-2), 128.8 (C-4), 128.5 (C-7 and C-5), 126.1 (C-3), 66.5 (C-1), 51.5 (C-11), 35.4 (C-8), 28.6 (C-9 or C-10), 28.5 (C-9 or C-10), 21.2 (C-13); HRMS (ESI+) m/z = 270.1211 [M+Na]+ found, C13H17O2N3Na+ require 270.1213.
[3-(4-Azidobutyl)phenyl]methanol SI-63
3-(4-azidobutyl)benzyl acetate SI-62 (1.97 g, 7.97 mmol) was dissolved in dry methanol (20 mL) and 0.05 M NaOMe/MeOH (16 mL, 0.80 mmol, 0.1 eq) was added. After stirring at room temperature for 3 h, the solvent was removed under reduced pressure. The residue was dissolved in Et2O and was washed with 5% aqueous HCl, saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduce pressure. After purification by flash column chromatography (petroleum ether/EtOAc 3:1), title compound SI-63 (1.42 g, 6.92 mmol, 87%) was isolated as an opaque oil. TLC Rf = 0.35 (petroleum ether/EtOAc 3:1); HPLC tr = 11.05 min (5-100% B), peak area 90%; IR (neat) νmax = 3324 (br w, OH), 2930 (m), 2861 (m), 2091 (s, N3), 1609 (w), 1488 (w), 1447 (m), 1352 (w), 1245 (m), 1014 (m), 701 (m); 1H NMR (400 MHz, CDCl3, 27 °C) δ = 7.31-7.27 (m, 1H; H-4), 7.21-7.17 (m, 2H; H-7 and H-3), 7.11 (d, J = 7.5, 1H; H-5), 4.67 (s, 2H; H-1), 3.28 (t, J = 6.7, 2H; H-11), 2.66 (t, J = 7.4, 2H; H-8), 1.7-1.54 (m, 5H; H-9 and H-10 and H-12); 13C NMR (100 MHz, CDCl3, 27 °C) δ = 142.4 (C-6), 141.1 (C-2), 128.8 (C-4), 127.9 (C-5), 127.1 (C-7), 124.7 (C-3), 65.5 (C-1), 51.5 (C-11), 35.4 (C-8), 28.6 (C-9 or C-10), 28.5 (C-9 or C-10). HRMS The desired mass could not be obtained for this compound.
3-(4-Azidobutyl)benzaldehyde SI-64
Dimethyl sulfoxide (209 µL, 2.94 mmol, 4.0 eq) in dry CH2Cl2 (4 mL) was added dropwise to a solution of oxalyl chloride (124 µL, 1.47 mmol, 2.0 eq) in dry CH2Cl2 (3 mL) at -78 °C under argon. After stirring the mixture for 10 min at -78 °C, (3-(4-azidobutyl)phenyl)methanol SI-63 (151 mg, 0.736 mmol, 1.00 eq) in dry CH2Cl2 (5 mL) was added. After stirring the mixture for 10 min at -78 °C, DIPEA (641 µL, 3.68 mmol, 5.0 eq) was added and the mixture was allowed to 51 51
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warm to room temperature. The reaction mixture was washed with water, 10% aqueous HCl, saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduce pressure. Title compound SI-64 (157 mg, quantitative) was obtained as yellow oil and used in the aza-Wittig reactions without further purification. TLC Rf = 0.78 (petroleum ether/EtOAc 3:1); IR νmax (neat) = 2939 (w), 2862 (w), 2091 (s, N3), 1695 (s, C=O), 1604 (m), 1586 (m), 1450 (w), 1386 (w), 1352 (w), 1291 (m), 1241 (m), 1142 (m), 692 (m); 1H NMR (400 MHz, CDCl3, 27 °C) δ = 10.01 (s, 1H; H-1), 7.78-7.67 (m, 2H; H-4 and H3), 7.51-7.40 (m, 2H; H-5 and H-7), 3.31 (t, J = 6.7, 2H; H-11), 2.74 (t, J = 7.5, 2H; H-8), 1.801.70 (m, 2H; H-9), 1.70-1.60 (m; H-10, coincides with water signal); 13C NMR (100 MHz, CDCl3, 27 °C) δ = 192.6 (C-1), 143.1 (C-6), 136.8 (C-2), 134.8 (C-7 or C-5), 129.3*2 (C-7 or C-5 and C4), 128.1 (C-3), 51.4 (C-11), 35.2 (C-8), 28.6 (C-9 or C-10), 28.4 (C-9 or C-10); HRMS (ESI+) m/z = 226.0946 [M+Na]+ found, C13H17O2N3Na+ required 226.0951.
Preparation of Linear Amines Linear amine 30
According to GP8, azide building block 3 (244 mg, 0.347 mmol, 1.00 eq) was reacted with P(nBu)3 (1.10 eq in total) and subsequently with aldehyde SI-64 (78 mg, 0.38 mmol, 1.1 eq). After flash column chromatography (petroleum ether/EtOAc 3:1 to 2:1), title compound 30 (81 mg, 0.18 mmol, 53%) was isolated as a colorless oil. TLC Rf = 0.28 (petroleum ether/EtOAc 2:1); HPLC tr = 12.59 min (5-100% B), peak area 98%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.25-7.17 (m, 3H; H-17, H-20 and H-16), 7.12 (t, J = 7.8, 1H; H-9), 7.06 (d, J = 7.5, 1H; H-18), 6.72 (dd, J = 8.1, 2.5, 1H; H-10), 6.63 (s, 1H; H-12), 6.56 (d, J = 7.6, 1H; H-8), 4.27 (s, 2H; H-14), 4.16 (s, 4H; H-2 and H-3), 3.67 (s, 3H; H-25), 3.32 (t, J = 6.7, 2H; H-24), 3.10 (t, J = 2.5, 1H; H-5), 2.61 (t, J = 7.5, 2H; H-21), 1.69-1.62 (m, 2H; H-22), 1.61-1.54 (m, 2H; H-23); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 170.7 (C-6), 168.7 (C-1), 148.4 (C-11), 141.4 (C-19), 139.3 (C-15), 135.2 (C-7), 128.5 (C-9), 127.7 (C-17), 126.7 (C-20), 126.2 (C-18), 124.2 (C-16), 113.6 (C-10), 113.4 (C-8), 109.9 (C-12), 78.3 (C-4), 74.6 (C-5), 51.3 (C-25), 50.3 (C-24), 46.3 (C-14), 34.1 (C-21), 27.4 (C-23 or C-22), 27.3 (C-22 or C-23); HRMS (ESI+) m/z = 434.2202 [M+H]+ found, C24H28N5O3+ required 434.2187, 456.2025 [M+Na]+ found, C24H27N5O3Na+ required 456.2006.
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DOI: 10.1038/NCHEM.1729
Linear amine SI-65
According to GP8, azide building block 2 (434 mg, 0.613 mmol, 1.00 eq) was reacted with P(nBu)3 (1.15 eq in total) and subsequently with aldehyde SI-64 (157 mg, crude product, ~1.2 eq). After flash column chromatography (EtOAc), title compound SI-65 (110 mg, 0.260 mmol, 42%) was isolated as a yellow oil. TLC Rf = 0.52 (neat EtOAc); HPLC tr = 9.68 min (5-100% B), peak area 93%; IR (neat) νmax = 3295 (w), 2935 (w), 2859 (w), 2094 (s, N3), 1748 (s, C=O), 1631 (s, C=O), 1527 (m), 1435 (s), 1264 (s), 1180 (s), 1205 (s), 1159 (s), 1015 (m), 966 (m); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.22 (t, J = 7.5, 1H; H-16), 7.17 (s, 1H; H-19), 7.14 (d, J = 7.6, 1H; H-15), 7.06 (d, J = 7.5, 1H; H-17), 7.03 (d, J = 3.4, 1H; H-8), 6.41 (d, J = 3.4, 1H; H-9), 4.42 (d, J = 2.2, 2H; H-3), 4.38 (s, 2H; H-2), 3.75 (s, 2H; H-11), 3.73 (s, 2H; H-13), 3.67 (s, 3H; H-24), 3.34 (t, J = 6.7, 2H; H23), 3.08 (t, J = 2.4, 1H; H-5), 2.62 (t, J = 7.5, 2H; H-20), 1.72-1.64 (m, 2H; H-21), 1.64-1.56 (m, 2H; H-21); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 168.8 (C-1), 158.6 (C-6), 157.2 (C-10), 145.0 (C-7), 141.2 (C-18), 140.0 (C-14), 127.5 (C-19 or C-16), 127.3 (C-16 or C-19), 126.0 (C17), 124.9 (C-15), 117.1 (C-8), 107.9 (C-9), 78.5 (C-4), 74.3 (C-5), 51.8 (C-13), 51.2 (C-24), 50.3 (C-23), 48.0 (C-2), 44.6 (C-11), 37.3 (C-3), 34.1 (C-20), 27.4 (C-21 or C-22), 27.3 (C-21 or C22); HRMS (ESI+) m/z = 438.2148 [M+H]+ found, C23H28N5O4+ required 438.2136.
Preparation of Linear Dihydropyridinones Linear dihydropyridinone 31
Azido building block 3 (232 mg, 0.330 mmol, 1.00 eq) was dissolved in dry THF (12 mL) under argon with 4 Å molecular sieves. P(n-Bu)3 (95 µL, 0.38 mmol, 1.15 eq) was added. The reaction mixture was stirred at room temperature for 3 h. Aldehyde SI-64 (81 mg, 0.4 mmol, 1.2 eq) dissolved in dry THF (6 mL) was added. The reaction mixture was stirred at room temperature overnight and at 40 oC for 5 h. Subsequently, AgOTf (20 mg, 0.078 mmol, 0.24 eq) and Danishefsky’s diene (128 µl, 0.66 mmol, 2.0 eq) were added and the mixture was stirred at room temperature overnight. Additional portions of Danishefsky’s diene (in total 89 µl, 0.46 mmol, 1.4 53 53
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eq) and AgOTf (in total 60 mg, 0.23 mmol, 0.70 eq) were added and the reaction was stirred for additional 6 h until TLC indicated complete turnover. The solvent was removed by nitrogen gas flow and the residue was dissolved in EtOAc. The organic phase was washed with 10% aqueous HCl, saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. After flash column chromatography (petroleum ether/EtOAc 1:1), title compound 31 (123 mg, 0.132 mmol, 40%) was isolated as a yellow foam. TLC Rf = 0.16 (petroleum ether/EtOAc 1:1); HPLC tr = 12.24 min (50-100% B), peak area 99%; IR (neat) νmax = 2931 (w), 2096 (m, N3), 1752 (m, C=O), 1646 (m, C=O), 1573 (s), 1199 (s, C-F), 1146 (s, C-F); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.87 (d, J = 8.0, 1H; H-13), 7.39 (t, J = 7.9, 1H; H-9), 7.27 (dd, J = 8.3, 2.4, 1H; H-8 or H-10), 7.24-7.20 (m, 2H; H-20 and H-12), 7.157.10 (m, 3H; H-23, H-19 and either H-8 or H-10), 7.09 (d, J = 7.3, 1H; H-21), 5.49 (dd, J = 6.9, 4.0, 1H; H-17), 5.12 (d, J = 7.9, 1H; H-14), 4.41 (t, J = 6.1, 2H; H-28), 4.18 (s, 2H; H-2), 4.14 (s, 2H; H-3), 3.29 (t, J = 6.7, 2H; H-27), 3.19 (dd, J = 16.4, 7.1, 1H; H-16a), 3.06 (t, J = 2.4, 1H; H5), 2.72-2.56 (m, 5H; H-29, H-16b and H-24), 1.67-1.58 (m, 2H; H-25), 1.56-1.51 (m, 2H; H-26); 13 C NMR (125 MHz, DMSO-d6, 120 °C) δ = 188.4 (C-15), 169.3 (C-6), 167.5 (C-1), 147.4 (C-13), 144.0 (C-11), 141.8 (C-22), 138.2 (C-18), 135.5 (C-7), 128.9 (C-9), 127.9 (C-20), 126.8 (C-21), 125.6 (C-23), 123.1 (C-19), 121.3 (C-8 or C-10), 120.1 (C-8 or C-10), 116.8 (C-12), 101.9 (C14), 77.8 (C-4), 74.5 (C-5), 60.1 (C-17), 56.2 (C-28), 50.2 (C-27), 42.8 (C-16), 33.8 (C-24), 29.7 (C-29), 27.1 (C-25 or C-26), 26.9 (C-25 or C-26); HRMS (ESI+) m/z = 932.2092 [M+H]+ found, C37H31N5O4F17+ required 932.2099.
CuAAC and RuAAC Macrocyclizations Macrocyclic urea SI-66
Linear urea SI-32 (29 mg, 0.060 mmol, 1.0 eq) was reacted according to GP9 for 24 h. After purification by preparative HPLC (10-80% B), title compound SI-66 (24 mg, 0.049 mmol, 83%) was isolated as a white powder. TLC Rf = 0.45 (CH2Cl2/MeOH 10:1); HPLC tr = 6.73 min (10-60% B), peak area 100%; mp 117120 °C (H2O); [α]D28.7 = -75 (c = 0.220 in MeOH); IR (neat) νmax = 3385 (w), 2951 (w), 1743 (w, C=O), 1643 (s, C=O), 1541 (s), 1455 (m), 1405 (m), 1203 (s), 1176 (s), 755 (m); 1H NMR (500 MHz, DMSO-d6, 120 °C) due to interconversion, H-14 and H-3b are missing, δ = 7.90 (br.s, 1H; H-5), 7.41-6.91 (m, 4H; H-9, H-10, H-11 and H-12), 6.26 (br.s, 1H; H-16), 4.86 (br.d, J = 20.7 Hz, 1H; H-3a), 4.65 (br.d, J = 6.0 Hz, 1H; H-17), 4.50 (d, J = 17.4 Hz, 1H; H-2a), 4.46-4.30 (m, 2H; H-21), 4.23 (br.s, 1H; H-2b), 3.84 (d, J = 16.8 Hz, 1H; H-7a), 3.72 (s, 3H; H-25), 3.51 (br.s; 54 54
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H-23, H-24 and H-7b), 1.97-1.87 (m, 1H; H-20a), 1.84-1.75 (m, 1H; H-20b), 1.67-1.59 (m, 1H; H18a), 1.49-1.40 (m, 1H; H-18b), 1.25-1.08 (m, 2H; H-19). HRMS (ESI+) m/z = 508.2259 [M+Na]+ found, C23H31N7O5Na+ required 508.2279.
Macrocyclic urea SI-67
Linear urea SI-32 (32 mg, 0.066 mmol, 1.0 eq) was reacted according to GP10 for 24 h. After purification by preparative HPLC (10-60% B), title compound SI-67 (14 mg, 0.029 mmol, 44%) was isolated as an off-white powder. TLC Rf = 0.34 (CH2Cl2/MeOH 10:1); HPLC tr = 6.94 min (10-60% B), peak area 99%; mp 103107 °C (H2O); [α]D28.7 = -15 (c = 0.238 in MeOH); IR (neat) νmax = 3346 (w), 2951 (w), 1745 (m, C=O), 1630 (s, C=O), 1540 (m), 1403 (m), 1176 (s); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.85 (br s, 1H; H-14), 7.56 (s, 1H; H-5), 7.33 (br s, 1H; either H-9 or H-12), 7.30-7.17 (m, 2H; either H-9 or H-12, and either H-10 or H-11), 7.12 (t, J = 7.1 Hz, 1H; either H-10 or H-11), 6.17 (br.s, 1H; H-16), 4.86 (d, J = 16.6 Hz, 1H; H-3a), 4.82-4.68 (dt, J = 9.6, 3.8 Hz, 1H; H-17), 4.54 (d, J = 16.6 Hz, 1H; H-3b), 4.37-4.25 (m, 1H; H-21a), 4.25-4.10 (m, 2H; H-21b and H-2a), 4.053.86 (m, 2H; H-2b and H-7a), 3.69-3.56 (m, 4H; H-25 and H-7b), 2.95 (s; H-23 and H-24, coincides with water signal), 2.03-1.82 (m, 2H; H-20), 1.82-1.66 (m, 1H; H-18a), 1.55-1.46 (m, 1H; H-18b), 1.44-1.22 (m, 2H; H-19); HRMS (ESI+) m/z = 508.2264 [M+Na]+ found, C23H31N7O5Na+ required 508.2279.
Fluorous-tagged macrocyclic urea SI-68
Linear urea SI-35 (50 mg, 0.056 mmol, 1.0 eq) was reacted according to GP9 for 19 h. After purification by flash column chromatography (CH2Cl2/MeOH 33:1 to 15:1), title compound SI-68 (37 mg, 0.041 mmol, 73%) was isolated as a white solid. HPLC tr = 5.17 min (60-100% B), peak area 94%; 1H NMR (400 MHz, DMSO-d6, 27 °C) δ = 8.70 (s, 1H; H-13), 8.12-8.05 (m, 2H; H-5 and H-22), 7.89 (br s, 1H; H-12), 7.31 (t, J = 7.8, 1H; H-9), 6.98 (d, J = 7.7, 1H; H-8 or H-10), 6.81 (m, 1H; H-8 or H-10), 6.33 (d, J = 8.9, 1H; H-15), 4.504.31 (m, 7H; 3 x CH2 and CHaHb), 4.27 (m, 1H; H-16), 4.01 (d, J = 17.1, 1H; CHaHb), 2.78-2.62 55 55
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(m, 2H; H-25), 2.60 (d, J = 4.7, 3H; H-23), 2.40-2.24 (m, 1H; H-19a), 1.72-1.59 (m, 2H; H-17a and H-19b), 1.43 (m, 1H; H-17b), 1.30-1.02 (m, 2H; H-18); 13C NMR (100 MHz, DMSO-d6, 27 °C) δ = 172.3 (C-21), 171.8 (C-6), 168.7 (C-1), 154.5 (C-14), 143.7, 139.5, 135.0 (each quat. C), 129.3 (C-9), 122.3 (C-5), 56.6 (C-24), 50.5 (C-16), 50.2, 47.6, 46.7 (each C-2, C-3 or C-20), 34.8 (C-17), 29.5 (C-25), 28.4 (C-19), 25.5 (C-23), 22.5 (C-18); HRMS (ESI+) m/z = 890.1976 [M+H]+ found, C30H29F17N7O5+ required 890.1953.
Fluorous-tagged macrocyclic urea SI-69
Linear urea SI-35 (50 mg, 0.056 mmol, 1.0 eq) was reacted according to GP10 for 15 h. After purification by preparative HPLC (55-65% B), title compound SI-69 (21 mg, 0.024 mmol, 42%) was isolated as a white solid. HPLC tr = 4.15 min (60-100% B), peak area 97%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.24 (s, 1H; H-13), 7.69 (s, 1H; H-5), 7.58 (m, 1H; H-22), 7.42-7.36 (m, 2H; H-9 and H-12), 7.18 (m, 1H; H-8 or H-10), 7.12 (d, J = 8.1, 1H; H-8 or H-10), 6.11 (br s, 1H; H-15); 4.81 (br s, 2H; H-3); 4.42 (t, J = 6.1, 2H; H-24), 4.18-4.06 (m, 5H; H-2, H-16 and H-20), 2.72-2.58 (m, 5H; H-23 and H-25), 1.96-1.86 (m, 1H; H-19a), 1.80-1.70 (m, 2H; H-17a and H-19b), 1.56-1.46 (m, 1H; H-17b), 1.26-1.16 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.9, 170.0, 168.0, 155.5 (each C=O), 139.3 (C-Ar), 132.7 (br, C-5), 129.1 (C-9), 119.2 (C-12), 56.3 (C-24), 53.1 (C-16), 48.0 (C-2 or C-20), 47.3 (C-2 or C-20), 31.5 (C-17), 29.6 (t, J = 22.3; C-25), 28.5 (C-19), 24.9 (C-23), 22.0 (C-18); HRMS (ESI+) m/z = 890.1923 [M+H]+ found, C30H29F17N7O5+ required 890.1953.
Fluorous-tagged macrocyclic urea SI-70
Linear urea SI-36 (147 mg, 0.163 mmol, 1.00 eq) was dissolved in dry dioxane (0.65 mM) and DIPEA (0.17 ml, 0.98 mmol, 6.0 eq) was added. After bubbling argon through the solution for 20 min, CuI (124 mg, 0.652 mmol, 4.00 eq) was added and the mixture was heated to reflux for 6 days. Subsequently, the solvent was removed and the residue dissolved in CH2Cl2/MeOH 10:1 was filtered through a pad of SiO2. After purification by preparative HPLC (50-70% B), title compound SI-70 (59 mg, 0.065 mmol, 40%) was isolated as a white powder.
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TLC Rf = 0.52 (CH2Cl2/MeOH 10:1); HPLC tr = 6.65 min (50-100% B), peak area 100%; mp 172 °C decomposition (H2O); [α]D28.7 = +4.2 (c = 0.590 in MeOH); IR (neat) νmax = 1753 (w, C=O), 1640 (m, C=O), 1516 (w), 1469 (w), 1421 (w), 1202 (s, C-F), 1147 (s, C-F), 704 (w); 1H NMR (500 MHz, DMSO-d6, 27 °C) δ = 8.43 (s, 1H; H-11), 7.65 (s, 1H; H-5), 7.06 (d, J = 8.5, 2H; H-9), 6.92 (d, J = 8.2, 2H; H-8), 6.28 (d, J = 7.5, 1H; H-13), 4.52-4.41 (m, 2H; H-2), 4.48-4.46 (m, 1H; H-14), 4.44-4.42 (m, 2H; H-22), 4.42-4.35 (m, 2H; H-3), 4.31 (ddd, J = 13.8, 6.5, 4.1, 1H; H-18a), 4.21 (ddd, J = 13.5, 9.2, 3.7, 1H; H-18b), 3.06 (s, 3H; H-20), 2.83 (s, 3H; H-21), 2.72 (tt, J = 19.5, 5.7, 2H; H-23), 1.86-1.79 (m, 1H; H-17a), 1.74-1.67 (m, 1H; H-17b), 1.66-1.59 (m, 1H; H15a), 1.58-1.51 (m, 1H; H-15b), 1.19-1.11 (m, 2H; H-16); 13C NMR (125 MHz, DMSO-d6, 27 °C) δ = 172.2 (C-6), 171.9 (C-19), 169.0 (C-1), 155.8 (C-12), 143.7 (C-4), 141.7 (C-10), 130.3 (C-7), 127.0 (C-8), 122.1 (C-5), 121.7 (C-9), 56.7 (C-22), 50.0 (C-14), 49.6 (C-2), 48.5 (C-18), 45.5 (C3), 36.5 (C-20), 35.3 (C-21), 29.5 (C-15), 29.5 (t, J = 20.4; C-23), 28.0 (C-17), 21.5 (C-16); HRMS (ESI+) m/z = 904.2103 [M+H]+ found, C31H31F17N7O5+ required 904.2110, 926.1926 [M+Na]+ found, C31H30F17N7O5Na+ required 926.1929.
Fluorous-tagged macrocyclic urea SI-71
Linear urea SI-36 (149 mg, 0.165 mmol, 1.00 eq) was dissolved in dry dioxane (0.65 mM) and argon was bubbled through the solution for 20 min. [Cp*RuCl]4 (27 mg, 0.025 mmol, 0.15 eq) was added and the mixture was heated to reflux for 24 h. Subsequently, the solvent was removed. After purification by flash column chromatography (CH2Cl2/MeOH 15:1), title compound SI-71 (64 mg, 0.071 mmol, 43%) was isolated as a yellow foam. TLC Rf = 0.53 (CH2Cl2/MeOH 10:1); HPLC tr = 6.68 min (50-100% B), peak area 100%; mp 118 °C decomposition (H2O); [α]D28.4 = +38 (c = 0.242 in MeOH); IR (neat) νmax = 2930 (w), 1644 (m, C=O), 1510 (w), 1402 (w), 1202 (s, C-F), 1146 (s, C-F); 1H NMR (500 MHz, DMSO-d6, 27 °C) δ = 8.42 (s, 1H; H-11), 7.86 (s, 1H; H-5), 7.29-7.12 (m, 4H; H-8, H-9), 5.43 (d, J = 8.4, 1H; H-13), 4.58 (d, J = 18.1, 1H; H-3a), 4.49-4.39 (m, 5H; H-14, H-2a, H-22, H-3b), 4.16 (d, J = 17.2, 1H; H2b), 3.94 (m, 2H; H-18), 3.00 (s, 3H; H-20), 2.80 (s, 3H; H-21), 2.70 (tt, J = 19.7, 5.9, 2H; H-23), 1.76-1.70 (m, 1H; H-17a), 1.64-1.56 (m, 2H; H-17b, H-15a), 1.50-1.43 (m, 1H; H-15b), 0.98-0.89 (m, 2H; H-16); 13C NMR (125 MHz, DMSO-d6, 27 °C) δ = 171.7 (C-19), 171.3 (C-6), 168.7 (C-1), 156.6 (C-12), 141.3 (C-10 or C-7), 135.7 (C-4), 131.5 (C-5), 131.1 (C-10 or C-7), 127.0 (br, C-8 or C-9), 125.8 (C-9 or C-8), 56.7 (C-22), 49.3 (C-14), 48.0 (C-2), 47.4 (C-18), 45.5 (C-3), 36.4 (C-20), 35.2 (C-21), 29.8 (C-15), 29.5 (t, J = 20.7; C-23), 29.2 (C-17), 20.8 (C-16); HRMS (ESI+) m/z = 904.2128 [M+H]+ found, C31H31F17N7O5+ required 904.2110.
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Fluorous-tagged macrocyclic urea SI-72
Linear urea SI-37 (20 mg, 0.022 mmol, 1.0 eq) was reacted according to GP9 for 15 h. After purification by preparative HPLC (50-80% B), title compound SI-72 (12 mg, 0.013 mmol, 59%) was isolated as a pale yellow oil. TLC Rf = 0.52 (CH2Cl2/MeOH 10:1); HPLC tr = 7.29 min (50-100% B), peak area 98%; IR (neat) νmax =2928 (br, C-H), 1752 (m, C(=O)OR), 1641 (s, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.78 (s, 1H; H-5), 7.38 (t, J = 7.6, 1H; H-9), 7.30 (d, J = 7.4, 1H; H-8 or H-10), 7.26 (d, J = 7.5, 1H; H-8 or H-10), 7.21 (s, 1H; H-12), 6.39 (dd, J = 8.7, 3.5, 1H; H-14), 5.89 (d, J = 8.7, 1H; H-16), 4.74-4.51 (m, 4H; H-13a, H-3, and H-17), 4.43 (t, J = 6.1, 2H; H-25), 4.41-4.36 (m, 2H; H-21), 4.21 (d, J = 12.1, 2H; H-2), 3.87 (d, J = 15.8, 1H; H-13b), 2.98- 2.92 (m, 6H; H-23 and H-24), 2.66 (tt, J = 19.0, 6.2, 2H; H-26), 2.01-1.78 (m, 2H; H-20), 1.70-1.38 (m, 2H; H-18), 1.38-1.21 (m, 2H; H-19); HRMS (ESI+) m/z = 918.2250 [M+H]+ found, C32H33F17N7O5+ required 918.2266.
Fluorous-tagged macrocyclic urea SI-73
Linear urea SI-37 (20 mg, 0.022 mmol, 1.0 eq) was reacted according to GP10 for 15 h. After purification by preparative HPLC (50-70% B), title compound SI-73 (12 mg, 0.013 mmol, 59%) was isolated as a pale yellow oil. TLC Rf = 0.49 (CH2Cl2/MeOH 10:1); HPLC tr = 7.18 min (50-100% B), peak area 100%; IR (neat) νmax = 2971 (w, C-H), 1638 (m, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.65 (s, 1H; H-5), 7.41 – 7.35 (m, 2H; H-12 and H-9), 7.33 (d, J = 7.3, 1H; H-8 or H-10), 7.27 (d, J = 7.3, 1H; H-8 or H-10), 6.55 (s, 1H; H-14), 5.99 (d, J = 8.9, 1H; H-16), 4.94 (d, J = 16.0, 1H; H-3a), 4.74 (d, J = 15.8, 1H; H-3b), 4.68 (t, J = 8.3, 2H; H-17), 4.55 (d, J = 15.4, 1H; H-13a), 4.38 (t, J = 6.1, 2H; H-25), 4.12 (br s, 2H; H-2), 4.03 (s, 2H; H-21), 3.91 (d, J = 15.8, 1H; H-13b), 2.61 (tt, J = 19.0, 6.3; 2H), 2.54 (s, 3H; H-23 or H-24), 2.50 (s, 3H; H-23 or H-24), 2.01 – 1.88 (m, 1H; H-20a), 1.88 – 1.79 (m, 1H; H-20b), 1.71 – 1.56 (m, 1H; H-18a), 1.53 – 1.39 (m, 1H; H18b), 1.31 – 1.19 (m, 2H; H-19); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 172.5 (C=O), 171.8 (C=O), 168.7 (C=O), 158.1 (C-15), 142.5 (C-11 or C-7), 135.4 (C-7 or C-11), 134.9 (C-4), 134.6 58 58
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DOI: 10.1038/NCHEM.1729
(C-5), 132.5 (C-10 or C-8), 129.4 (C-9), 128.7 (C-12), 125.4 (C-8 or C-10), 57.4 (C-25), 49.0 (C17), 48.6 (C-21), 48.3 (C-2), 43.3 (C-13), 41.5 (C-3), 40.98 (C-23 and C-24), 32.6 (C-20), 30.7 (t, J = 22.1; C-26), 29.2 (C-18), 22.6 (C-19); HRMS (ESI+) m/z = 918.2236 [M+H]+ found, C32H33F17N7O5+ required 918.2266.
Fluorous-tagged macrocyclic urea SI-74
Linear urea SI-40 (150 mg, 0.161 mmol, 1.0 eq) was reacted according to GP9 for 15 h. After purification by preparative HPLC (50-70% B), title compound SI-74 (87 mg, 0.094 mmol, 58%) was isolated as a yellow oil. TLC Rf = 0.59 (CH2Cl2/MeOH 10:1); HPLC tr = 7.47 min (50-100% B), 95%; IR (neat) νmax = 2969 (br, C-H), 1752 (m, C(=O)OR), 1630 (m, C(=O)NR2); HRMS (ESI+) m/z = 954.2202 [M+Na]+ found, C33H34F17N7O5Na+ required 954.2242.
Fluorous-tagged macrocyclic urea SI-75
Linear urea SI-40 (150 mg, 0.161 mmol, 1.00 eq) was reacted according to GP10 for 15 h. After purification by preparative HPLC (50-70% B), title compound SI-75 (39 mg, 0.042 mmol, 26%) was isolated as a yellow oil. TLC Rf = 0.64 (CH2Cl2/MeOH 10:1); HPLC tr = 7.40 min (50-100% B), peak area 99%; IR (neat) νmax = 2935 (br, C-H), 1730 (w, C(=O)OR), 1646 (br, m, C(=O)NR2); HRMS (ESI+) m/z = 954.2199 [M+Na]+ found, C33H34F17N7O5Na+ required 954.2242.
Fluorous-tagged macrocyclic urea 6 21
N N N 5 C8F17
O
23 24
O
1
19 18
O
15 16
3
N 6
7 8
O
N
20
17
4
2
O
NH14
13
HN12 10
22
O
11
9
6
59 59
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DOI: 10.1038/NCHEM.1729
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Linear urea 4 (113 mg, 0.125 mmol, 1.00 eq) was reacted according to GP9 for 24 h. After purification by flash column chromatography (CH2Cl2/MeOH 25:1), title compound 6 (100 mg, 0.110 mmol, 88%) was isolated as a colorless foam. TLC Rf = 0.45 (CH2Cl2/MeOH 10:1); HPLC tr = 7.04 min (50-100% B), peak area 99%; mp 119 °C decomposition (CH2Cl2); [α]D28.4 = -12.7 (c = 0.572 in MeOH/CHCl3 2:1); IR (neat) νmax = 3356 (w), 2941 (w), 1751 (m, C=O), 1622 (m, C=O), 1544 (m), 1432 (w), 1403 (w), 1199 (s, C-F), 1145 (s, C-F); 1H NMR (500 MHz, DMSO-d6, 70 °C) δ = 7.74 (s, 1H; H-5), 7.02 (d, J = 3.4, 1H; H-8), 6.50 (dd, J = 8.0, 2.9, 1H; H-12), 6.44 (d, J = 3.3, 1H; H-9), 6.03 (d, J = 8.7, 1H; H-14), 4.92 (s, 2H; H-3), 4.73-4.58 (m, 2H; H-11a, H-15), 4.44-4.32 (m, 4H; H-19, H-23), 4.27 (d, J = 17.1, 1H; H-2a), 4.20 (d, J = 17.1, 1H; H-2b), 3.96 (dd, J = 15.5, 3.0, 1H; H-11b), 3.01 (s, 3H; H21), 2.83 (s, 3H; H-22), 2.62 (tt, J = 19.1, 6.0, 2H; H-24), 2.01-1.92 (m, 1H; H-18a), 1.81-1.73 (m, 1H; H-18b), 1.64-1.59 (m, 1H; H-16a), 1.42-1.35 (m, 1H; H-16b), 1.22-1.13 (m, 2H; H-17); 13 C NMR (125 MHz, DMSO-d6, 70 °C) δ = 171.7 (C-20), 168.1 (C-1), 158.7 (C-6), 156.7 (C-13), 155.1 (C-10), 146.5 (C-7), 142.9 (C-4), 122.3 (C-5), 117.9 (C-8), 108.8 (C-9), 56.2 (C-23), 48.7 (C-2), 47.9 (C-19), 47.9 (C-15), 43.7 (C-3), 36.1 (C-11 and C-21), 34.8 (C-22), 30.8 (C-16), 29.6 (t, J = 21.2; C-24), 27.5 (C-18), 20.6 (C-17); HRMS (ESI+) m/z = 908.2064 [M+H]+ found, C30H31F17N7O6+ required 908.2059, 930.1900 [M+Na]+ found, C30H30F17N7O6Na+ required 930.1878.
Fluorous-tagged macrocyclic urea SI-76
Linear urea 4 (82 mg, 0.090 mmol, 1.0 eq) was reacted according to GP10 for 3 h. After purification by preparative HPLC (50-70% B), title compound SI-76 (48 mg, 0.053 mmol, 59%) was isolated as a white powder. TLC Rf = 0.55 (CH2Cl2/MeOH 10:1); HPLC tr = 6.68 min (50-100% B), peak area 100%; mp 9293 °C (H2O), [α]D28.7 = -17.2 (c = 0.599 in MeOH); IR (neat) νmax = 3372 (w), 2949 (w), 1752 (w, C=O), 1624 (m, C=O), 1534 (w), 1402 (w), 1201 (s, C-F), 1146 (s, C-F), 1115 (m); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.53 (s, 1H; H-5), 7.06 (d, J = 3.4, 1H; H-8), 6.39 (d, J = 3.4, 1H; H9), 6.34 (br s, 1H; H-12), 5.88 (br s, 1H; H-14), 5.19 (d, J = 14.0, 1H; H-3a), 5.02 (d, J = 16.4, 1H; H-3b), 4.65 (dd, J = 10.0, 3.5, 1H; H-15), 4.55 (d, J = 15.8, 1H; H-11a), 4.35 (t, J = 6.2, 2H; H-23), 4.27-4.22 (m, 1H; H-19a), 4.18-4.11 (m, 2H; H-19b, H-2a), 4.08 (d, J = 17.3, 1H; H-2b), 3.94 (d, J = 15.8, 1H; H-11b), 2.92 (s, 6H; H-21, H-22), 2.59 (tt, J = 19.1, 6.2, 2H; H-24), 1.961.87 (m, 1H; H-18a), 1.85-1.74 (m, 1H; H-18b), 1.63-1.56 (m, 1H; H-16a), 1.45-1.37 (m, 1H; H16b), 1.27-1.13 (m, 2H; H-17); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 171.4 (C-20), 167.5 (C-1), 158.9 (C-6), 156.7 (C-13), 156.0 (C-10), 145.5 (C-7), 132.8 (C-5), 132.1 (C-4), 117.7 (C8), 107.6 (C-9), 56.0 (C-23), 47.8 (C-15), 47.3 (C-19 or C-2), 47.2 (C-19 or C-2), 35.8 (C-11), 60 60
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DOI: 10.1038/NCHEM.1729
35.1 and 34.8 (C-21 and C-22), 31.4 (C-16), 29.6 (t, J = 21.3; C-24), 28.3 (C-18), 21.5 (C-17); HRMS (ESI+) m/z = 908.2070 [M+H]+ found, C30H31F17N7O6+ required 908.2059.
Fluorous-tagged macrocyclic urea SI-77
Linear urea SI-44 (69 mg, 0.066 mmol, 1.0 eq) was reacted according to GP9 for 16 h. After purification by preparative HPLC (60-80% B), title compound SI-77 (20 mg, 0.019 mmol, 29%) was isolated as a colorless lyophilisate. TLC Rf = 0.52 (CH2Cl2/MeOH 9:1); mp 125 °C decomposition; HPLC tr = 10.77 min (50-100% B); NMR Appropriate NMR data could not be obtained for this compound due to the existence of rotamers at a temperature range of 25-90 °C and partial N-Boc-deprotection at higher temperatures; HRMS (ESI+) m/z = 1043.2709 [M+H]+ found, C38H40F17N8O7+ required 1043.2743.
Fluorous-tagged macrocyclic urea SI-78
Linear urea SI-44 (94 mg, 90 µmol, 1.0 eq) was reacted according to GP10 for 4 h. The crude product SI-78 was directly used without further purification to obtain SI-125.
Macrocyclic oxalylurea SI-79
Linear oxalylurea SI-45 (33 mg, 0.061 mmol, 1.0 eq) was reacted according to GP9 for 24 h. After purification by preparative HPLC (20-70% B), title compound SI-79 (30 mg, 0.056 mmol, 92%) was isolated as a white powder. 61 61
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DOI: 10.1038/NCHEM.1729
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TLC Rf = 0.39 (CH2Cl2/MeOH 10:1); HPLC tr = 8.67 min (10-60% B), peak area 100%; mp 144148 °C (H2O); [α]D28.7 = +3 (c = 0.136 in MeOH); IR (neat) νmax = 2951 (w), 1733 (s, C=O), 1651 (m, C=O), 1499 (w), 1454 (w), 1438 (w), 1396 (m), 1216 (m), 1180 (m), 759 (m); HRMS (ESI+) m/z = 562.2004 [M+Na]+ found, C25H29N7O7Na+ required 562.2021.
Macrocyclic oxalylurea 39
Linear oxalylurea SI-45 (39 mg, 0.072 mmol, 1.0 eq) was reacted according to GP10 for 7 h. After purification by preparative HPLC (20-70% B), title compound 39 (17 mg, 0.032 mmol, 44%) was isolated as a white powder. TLC Rf = 0.43 (CH2Cl2/MeOH 10:1); HPLC tr = 9.38 min (10-60% B), peak area 100%; mp 145150 °C (H2O); [α]D28.7 = -17 (c = 0.132 in MeOH); IR (neat) νmax = 1737 (s, C=O), 1650 (m, C=O), 1499 (w), 1460 (w), 1399 (m), 1179 (m), 1139 (m), 753 (m); HRMS (ESI+) m/z = 540.2182 [M+H]+ found, C25H30N7O7+ required 540.2201.
Fluorous-tagged macrocyclic oxalylurea SI-80
Linear oxalylurea 24 (225 mg, 0.234 mmol, 1.00 eq) was reacted according to GP9 for 27 h. Without the need for any further purification, title compound SI-80 (207 mg, 0.217 mmol, 93%) was isolated as a yellow foam. HPLC tr = 6.22 min (60-100% B), peak area 95%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.94 (s, 1H; H-5), 7.70-7.64 (m, 2H; H-9 and H-8 or H-10), 7.64-7.60 (m, 1H; H-8 or H-10), 7.35-7.33 (m, 1H; H-12), 5.00 (dd, J = 11.8, 3.6, 1H; H-16), 4.61 (s, 2H; H-3), 4.48-4.34 (m, 6H; H-2, H-20 and H-24), 3.01-2.88 (m, H-22 and H-23, coincides with water signal), 2.69 (tt, J = 19.3, 6.1, 2H; H-25), 2.30 (m, 1H; H-17a), 2.08 (m, 1H; H-18a), 1.89-1.73 (m, 2H; H-17b and H-19b), 1.49-1.17 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 169.2, 168.0, 166.4, 155.8, 154.5, 152.1 (each C=O), 142.6, 134.8 (each quat. C), 129.5 (C-9), 129.3 (quat. C), 128.2 (C-8 or C10), 128.2 (C-8 or C-10), 124.1 (C-12), 121.8 (C-5), 56.1 (C-24), 51.8 (C-16), 48.8 (C-20), 48.0 (C-2), 45.8 (C-3), 35.7 (br; C-22 and C-23), 29.6 (t, J = 22.1; C-25), 28.0 (C-19), 27.0 (C-17), 21.7 (C-18); HRMS (ESI+) m/z = 958.1831 [M+H]+ found, C33H29F17N7O7+ required 958.1852. 62 62
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DOI: 10.1038/NCHEM.1729
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Fluorous-tagged macrocyclic oxalylurea SI-81
Linear oxalylurea 24 (231 mg, 0.241 mmol, 1.00 eq) was reacted according to GP10 overnight. After purification by preparative HPLC (58-68% B) and freeze-drying of the pooled fractions, title compound SI-81 (44 mg, 0.046 mmol, 19%) was isolated as a white solid. HPLC tr = 6.45 min (60-100% B), peak area 96%; 1H NMR (500 MHz, DMSO-d6, 60 °C) δ = 7.88 (dt, J = 7.9, 1.5, 1H; H-8 or H-10), 7.76 (s, 1H; H-5), 7.70 (t, J = 7.9, 1H; H-9), 7.64 (dt, J =8.0, 1.6, 1H; H-8 or H-10), 7.27 (t, J = 1.9, 1H; H-12), 5.04 (d, J = 17.8, 1H; H-2a or H-3a), 4.96 (dd, J = 12.3, 3.6, 1H; H-16), 4.77 (d, J = 17.8, 1H; H-2b or H-3b), 4.45 (d, J = 16.9, 1H; H-2a or H3a), 4.41 (t, J = 6.0, 2H; H-24), 4.16 (t, J = 6.1, 2H; H-20), 4.02 (d, J = 17.0, 1H; H-2b or H-3b), 3.06 (br s, 3H; H-22), 2.85 (br s, 3H; H-23), 2.66 (tt, J = 19.4, 6.1, 2H; H-25), 2.46-2.36 (m, 2H; H-17a and H-19a), 1.88 (m, 1H; H-17b), 1.76 (m, 1H; H-19b), 1.52 (m, 1H; H-18a), 1.21-2.11 (m, 1H; H-18b); 13C NMR (125 MHz, DMSO-d6, 60 °C) δ = 168.1, 167.2, 167.1, 157.0, 154.1, 153.4 (each C=O), 134.2 (quat. C), 132.7 (C-5), 132.4 (quat. C), 130.5, 129.8, 129.7 (each C-Ar), 129.5 (quat. C), 126.4 (C-12), 56.3 (C-24), 53.2 (C-16), 49.2 (C-2 or C-3), 47.0 (C-20), 45.4 (C-2 or C-3), 36.2 (br; C-22), 35.3 (br; C-23), 29.6 (t, J = 20.5; C-25), 26.9 (C-17), 25.8 (C-19), 21.0 (C-18); HRMS (ESI+) m/z = 958.1813 [M+H]+ found, C33H29F17N7O7+ required 958.1852.
Fluorous-tagged macrocyclic oxalylurea SI-82
Linear oxalylurea SI-46 (85 mg, 0.088 mmol, 1.0 eq) was reacted according to GP9 for 24 h. After purification by preparative HPLC (60-80% B), title compound SI-82 (57 mg, 0.059 mmol, 67%) was isolated as a white powder. TLC Rf = 0.52 (CH2Cl2/MeOH 10:1); HPLC tr = 8.43 min (50-100% B), peak area 100%; mp 104 °C decomposition (H2O); [α]D28.3 = -6 (c = 0.533 in MeOH); IR (neat) νmax = 1739 (s, C=O), 1628 (m, C=O), 1534 (w), 1431 (w), 1405 (w), 1201 (s, C-F), 1146 (s, C-F); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.73 (s, 1H; H-5), 7.07 (d, J = 3.4, 1H; H-8), 6.64 (d, J = 3.5, 1H; H-9), 4.99 (d, J = 16.4, 1H; H-3a), 4.93-4.84 (m, 3H; H-3b, H-15, H-11a), 4.80 (d, J = 15.9, 1H; H11b), 4.39 (t, J = 6.2, 2H; H-23), 4.36-4.33 (m, J = 7.1, 4.6, 1.7, 2H; H-19), 4.20 (d, J = 17.0, 1H; H-2a), 4.19 (d, J = 17.0, 1H; H-2b), 2.92 (s; H-21 and H-22, coincides with water signal), 2.63 (tt, J = 19.3, 6.1, 2H; H-24), 2.36-2.28 (m, 1H; H-16a), 1.97-1.89 (m, 1H; H-18a), 1.87-1.70 (m, 2H; 63 63
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DOI: 10.1038/NCHEM.1729
H-16b, H-18b), 1.27-1.19 (m, 1H; H-17a), 1.18-1.10 (m, 1H; H-17b); 13C NMR (125 MHz, DMSOd6, 120 °C) δ = 167.6 (C-1), 166.4 (C-20), 158.3 (C-6), 155.8 (C-13), 154.9 (C-14 or C-12), 152.2 (C-14 or C-12), 148.8 (C-10), 147.2 (C-7), 142.7 (C-4), 121.9 (C-5), 117.2 (C-8), 110.9 (C9), 55.9 (C-23), 52.4 (C-15), 48.3 (C-2 or C-19), 48.2 (C-2 or C-19), 43.6 (C-3), 35.5 (br, C-21 and C-22), 34.7 (C-11), 29.7 (t, J = 21.3; C-24), 27.5 (C-18), 26.0 (C-16), 21.6 (C-17); HRMS (ESI+) m/z = 962.1766 [M+H]+ found, C32H29F17N7O8+ required 962.1801.
Fluorous-tagged macrocyclic oxalylurea SI-83
Linear oxalylurea SI-46 (112 mg, 0.116 mmol, 1.00 eq) was reacted according to GP10 overnight. After purification by preparative HPLC (60-80% B), title compound SI-83 (80 mg, 0.083 mmol, 72%) was isolated as a white powder. TLC Rf = 0.55 (CH2Cl2/MeOH 10:1); HPLC tr = 8.01 min (50-100% B), peak area 99%; mp 111 °C decomposition (H2O); [α]D28.3 = -11 (c = 0.513 in MeOH); IR (neat) νmax = 1739 (s, C=O), 1655 (m, C=O), 1540 (w), 1404 (m), 1202 (s, C-F), 1146 (s, C-F), 704 (m); 1H NMR (500 MHz, DMSOd6, 120 °C) δ = 7.52 (s, 1H; H-5), 7.07 (d, J = 3.5, 1H; H-8), 6.64 (d, J = 3.5, 1H; H-9), 4.99 (d, J = 16.3, 1H; H-3a), 4.93 (br s, 1H; H-3b), 4.90 (dd, J = 11.5, 3.7, 1H; H-15), 4.83 (s, 2H; H-11), 4.35 (t, J = 6.2, 2H; H-23), 4.31-4.24 (m, 1H; H-19a), 4.20-4.13 (m, 1H; H-19b), 4.11 (d, J = 17.6, 1H; H-2a), 4.04 (d, J = 17.5, 1H; H-2b), 2.89 (s; H-21 and H-22, coincides with water signal), 2.60 (tt, J = 19.1, 6.3, 2H; H-24), 2.26-2.18 (m, 1H; H-16a), 2.01-1.87 (m, 1H; H-18a), 1.84-1.74 (m, 2H; H-16b, H-18b), 1.22-1.14 (m, 2H; H-17); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 167.4 (C-1), 166.1 (C-20), 159.1 (C-6), 155.5 (C-13), 154.8 (C-14), 152.3 (C-12), 149.1 (C-10), 146.5 (C-7), 132.8 (C-5), 132.1 (C-4), 117.4 (C-8), 110.4 (C-9), 56.1 (C-23), 51.7 (C-15), 47.3 (C-2), 46.9 (C-19), 35.5 (C-21 and C-22), 34.6 (C-11), 29.6 (t, J = 21.6; C-24), 27.9 (C-18), 26.7 (C-16), 21.9 (C-17); HRMS (ESI+) m/z = 962.1776 [M+H]+ found, C32H29F17N7O8+ required 962.1801.
Macrocyclic hydantoin SI-84
64 64
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SUPPLEMENTARY INFORMATION
DOI: 10.1038/NCHEM.1729
Linear hydantoin SI-47 (15 mg, not pure, max. 0.034 mmol, 1.0 eq) was reacted according to GP9 overnight. After purification by preparative HPLC (15-35% B), title compound SI-84 (8.3 mg, 0.019 mmol, 21% over three steps) was isolated as a white powder. TLC Rf = 0.45 (CH2Cl2/MeOH 10:1); HPLC tr = 5.91 min (10-60% B), peak area 100%; [α]D25.1 = +5 (c = 0.038 in MeOH); IR (neat) νmax = 1712 (s, C=O), 1652 (m, C=O) , 1499 (w), 1410 (m), 1176 (m), 765 (m); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.84 (m, 2H; H-5 and H-15), 7.397.31 (m, 3H; H-10, H-11, and either H-9 or H-12), 7.15 (dd, J = 8.0, 1.3 Hz, 1H; H-9 or H-12), 4.69 (d, J = 16.9 Hz, 1H; H-3a), 4.56 (s, 1H; H-3b), 4.44 (t, J = 5.9 Hz, 2H; H-21), 4.39 (d, J = 17.2 Hz, 1H; H-2a), 4.29 (d, J = 17.4 Hz, 1H; H-2b), 4.13 (br s, 1H; H-16), 3.72 (s, 3H; H-22), 3.50 (br d, J = 16.1 Hz, 1H; H-7a), 3.36 (d, J = 16.9 Hz, 1H; H-7b), 1.96-1.83 (m, 2H; H-20), 1.46 (br s, 2H; H-18), 1.36 (br s, 2H; H-19); HRMS (ESI+) m/z = 441.1894 [M+H]+ found, C21H25N6O5+ required 441.1881, 463.1722 [M+Na]+ found, C21H24N6O5Na+ required 463.1700.
Macrocyclic hydantoin SI-85
Linear hydantoin SI-47 (16 mg, not pure, max. 0.036 mmol, 1.0 eq) was reacted according to GP10 overnight. After purification by preparative HPLC (15-35% B), title compound SI-85 (9.3 mg, 0.021 mmol, 23% over three steps) was isolated as a white powder. TLC Rf = 0.45 (CH2Cl2/MeOH 10:1); HPLC tr = 6.19 min (10-60% B), peak area 99%; [α]D25.0 = 57 (c = 0.052 in MeOH); IR (neat) νmax = 3293 (br w), 1713 (s, C=O), 1660 (m, C=O), 1498 (w), 1410 (m), 1354 (w), 1181 (m), 1132 (w), 765 (m); 1H NMR (500 MHz, DMSO-d6, 120 °C) due to interconversion, one aromatic proton is missing, δ = 7.84 (s, 1H; H-15), 7.60 (s, 1H; H-5), 7.427.32 (m, 2H; ArH), 7.26-7.19 (m, 1H; H-9 or H-12), 4.87 (br.d, J = 14.2 Hz, 1H; H-3a), 4.46 (br.s, 1H; H-3b), 4.32-4.16 (m, 5H; H-2, H-21 and H-16), 3.79-3.64 (m, 4H; H-7a and H-22), 3.58 (d, J = 17.2 Hz, 1H; H-7b), 2.00-1.90 (m, 1H; H-20a), 1.90-1.80 (m, 2H; H-20b and H-18a), 1.80-1.66 (m, 1H; H-18b), 1.35-1.19 (m, 1H; H-19a), 1.19-1.05 (m, 1H; H-19b); HRMS (ESI+) m/z = 441.1894 [M+H]+ found, C21H25N6O5+ required 441.1881, 463.1699 [M+Na]+ found, C21H24N6O5Na+ required 463.1700.
Fluorous-tagged macrocyclic hydantoin SI-86
65 65
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SUPPLEMENTARY INFORMATION
DOI: 10.1038/NCHEM.1729
Linear hydantoin 25 (48 mg, 0.056 mmol, 1.0 eq) was reacted according to GP9 for 17 h. After purification by preparative HPLC (55-60% B), title compound SI-86 (34 mg, 0.040 mmol, 71%) was isolated as a yellowish solid. HPLC tr = 5.37 min (60-100% B), peak area 97%; 1H NMR (500 MHz, DMSO-d6, 60 °C) δ = 8.26 (s, 1H; H-14), 7.88 (s, 1H; H-5), 7.61 (t, J = 7.8, 1H; H-9), 7.51 (dt, J = 7.8, 1.4, 1H; H-8 or H-10), 7.94 (ddd, J = 7.9, 2.0, 1.2, 1H; H-8 or H-10), 6.81 (t, J = 1.8, 1H; H-12), 4.52-4.31 (m, 8H; H-2, H-3, H-20 and H-21), 4.30 (m, 1H; H-15), 2.70 (dt, J = 19.4, 6.1, 2H; H-23), 1.92-1.81 (m, 2H; H17 or H-19), 1.80-1.69 (m, 2H; H-17 or H-19), 1.32-1.19 (m, 1H; H-18a), 0.47-0.34 (m, 1H; H18b); 13C NMR (125 MHz, DMSO-d6, 60 °C) δ = 173.9, 170.8, 169.0, 155.7 (each C=O), 144.0, 136.3, 131.9 (each quat. C), 130.3 (C-9), 129.4 (C-8 or C-10), 127.4 (C-8 or C-10), 124.2 (C-12), 123.4 (C-5), 57.1 (CH2), 56.6 (C-15), 49.6, 49.3, 46.3 (each CH2), 30.3 (t, J = 21.2; C-22), 29.8 (C-17 or C-19), 29.6 (C-17 or C-19), 19.2 (C-18); HRMS (ESI+) m/z = 858.1534 [M+H]+ found, C29H24F17N6O5+ required 858.1531.
Fluorous-tagged macrocyclic hydantoin SI-87
Linear urea 25 (47 mg, 0.055 mmol, 1.0 eq) was reacted according to GP10 for 5 h. In this case, a mixture of the title compound SI-87 and the corresponding 1,4-substituted triazole SI-86 was obtained that could not be separated by preparative HPLC. Thus the crude product was directly used in the transesterification to obtain SI-128.
Fluorous-tagged macrocyclic hydantoin SI-88 4
O
22
F17C8 23
O
1
3
N 2
N N N 5
6
O 7
8
12
10
SI-88
19 18
O
17
N
11
9
20 21
13
16 14
NH 15
O
Crude product of linear hydantoin SI-48 (120 mg, not pure, max. 0.137 mmol, 1.00 eq) was reacted according to GP9 for 15 h. After purification by preparative HPLC (50-80% B), title compound SI-88 (75 mg, 0.085 mmol, 21% over 3 steps) was isolated as a yellow oil. TLC Rf = 0.59 (CH2Cl2/MeOH 10:1); HPLC tr = 7.83 min (50-100% B), peak area 98%; IR (neat) νmax = 2988 (br, C-H), 1708 (s, C=O), 1646 (s, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.69 (s, 1H; H-15), 7.65 (s, 1H; H-5), 7.43 (d, J = 7.7, 1H; H-8 or H-10), 7.40 (t, J = 7.3, 1H; H-9), 7.34 (d, J = 7.2, 1H; H-8 or H-10), 6.94 (s, 1H; H-12), 4.70 (d, J = 16.3, 1H; H-3a), 4.59 (m, 2H; H-3b and H-13a), 4.48 (d, J = 15.5, 1H; H-13b), 4.44 (t, J = 6.2, 2H; H-22), 4.40 – 66 66
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DOI: 10.1038/NCHEM.1729
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4.36 (m, 1H; H-21a), 4.34 – 4.25 (m, 2H; H-21b and H-2a), 4.19 (d, J = 17.4, 1H; H-2b), 4.10 (t, J = 4.2, 1H; H-16), 2.67 (tt, J = 19.1, 6.3, 2H; H-23), 1.89 – 1.74 (m, 2H; H-20), 1.67 – 1.57 (m, 2H; H-18), 1.35 – 1.21 (m, 1H; H-19a), 0.93 – 0.81 (m, 1H; H-19b); 13C NMR (125 MHz, DMSOd6, 120°C) δ = 174.2 (C=O), 171.3 (C=O), 168.9 (C=O), 157.0 (C=O), 143.8 (quat. C), 137.9 (quat. C), 136.7 (quat. C), 129.8 (C-9), 128.7 (C-10 or C-8), 125.5 (C-8 or C-10), 124.6 (C-12), 123.1 (C-5), 57.2 (C-22), 56.9 (C-16), 49.9 (C-21), 49.5 (C-2), 44.9 (C-3), 42.6 (C-13), 30.8 (t, J = 21.5; C-23), 30.1 (C-18), 29.4 (C-20), 20.2 (C-19); HRMS (ESI+) m/z = 873.1703 [M+H]+ found, C30H25F17N6O5+ required 873.1688.
Fluorous-tagged macrocyclic hydantoin SI-89
Crude product of linear hydantoin SI-48 (120 mg, not pure, max. 0.137 mmol, 1.00 eq) was reacted according to GP10 for 15 h. After purification by preparative HPLC (50-80% B), title compound SI-89 (66 mg, 0.076 mmol, 18% over 3 steps) was isolated as a pale yellow oil. TLC Rf = 0.61 (CH2Cl2/MeOH 10:1); HPLC tr = 7.86 min (50-100% B), peak area 99%; IR (neat) νmax = 2934 (br, C-H), 1753 (w, C(=O)OR), 1708 (s, hydantoin C=O), 1648 (m, C=O 6); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.75 (s, 1H; H-15), 7.63 (s, 1H; H-5), 7.49 (d, J = 7.8, 1H; H-8 or H-10), 7.42 (t, J = 7.9, 1H; H-9), 7.33 (d, J = 7.5, 1H; H-8 or H-10), 7.07 (s, 1H; H-12), 4.87 (d, J = 16.6, 1H; H-3a), 4.65 – 4.56 (m, 3H; H-3b and H-13), 4.38 (t, J = 6.2, 2H; H-22), 4.17 (t, J = 3.0, 1H; H-16), 4.15 – 3.97 (m, 4H; H-2 and H-21), 2.62 (tt, J = 19.1, 6.2, 2H; H-23), 1.94 – 1.74 (m, 3H; H-20 and H-18a), 1.74 – 1.63 (m, 1H; H-18b), 1.21 – 1.07 (m, 1H; H-19a), 0.90 – 0.80 (m, 1H; H-19b); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 174.1 (C=O), 171.5 (C=O), 168.6 (C=O), 156.7 (C=O), 137.2 (quat. C), 135.7 (quat. C), 133.9 (C-5), 133.3 (quat. C), 130.5 (C-8 or C-10), 129.4 (C-9), 126.7 (C-8 or C-10), 124.2 (C-12), 57.4 (C-22), 56.5 (C-16), 49.0 (C-2 or C21), 48.0 (C-2 or C-21), 41.4 (C-13), 30.7 (t, J = 21.7; C-23), 29.7 (C-18), 29.5 (C-20), 20.1 (C19); HRMS (ESI+) m/z = 873.1677 [M+H]+ found, C30H25F17N6O5+ required 873.1688.
Fluorous-tagged macrocyclic hydantoin SI-90
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
Crude product of linear hydantoin SI-49 (44 mg, not pure, max. 0.050 mmol, 1.0 eq) was reacted according to GP9 overnight. After purification by preparative HPLC (60-80% B), title compound SI-90 (22 mg, 0.025 mmol, 32% over 3 steps) was isolated as white powder. TLC Rf = 0.40 (CH2Cl2/MeOH 20:1); HPLC tr = 8.23 min (50-100% B), peak area 96%; [α]D25.0 = +46 (c = 0.043 in MeOH); IR (neat) νmax = 2921 (w, C-H), 1708 (br, m, C(=O)OR and C(=O)NR2); 1 H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.80 (s, 1H; H-5), 7.51 (s, 1H; H-16), 7.37-7.29 (m, 2H; H-9, H-8 or H-10), 7.22-7.14 (m, 1H; H-8 or H-10), 6.96 (s, 1H; H-12), 4.72 (d, J = 15.9 Hz, 1H; H-3a), 4.51 (d, J = 15.9 Hz, 1H; H-3b), 4.46 (t, J = 6.2 Hz, 2H; H-23), 4.42-4.37 (dt, J = 5.4, 1.7 Hz, 2H; H-22), 4.17 (d, J = 17.6 Hz, 1H; H-2a), 4.13 (d, J = 17.6 Hz, 1H; H-2b), 3.86 (t, J = 5.6 Hz, 1H; H-17), 3.70-3.62 (m, 1H; H-14a), 3.58-3.50 (m, 1H; H-14b), 2.89 (ddd, J = 13.1, 8.9, 4.1 Hz, 1H; H-13a), 2.81 (ddd, J = 14.6, 6.2, 3.9 Hz, 1H; H-13b), 2.68 (tt, J = 19.0, 6.0 Hz, 2H; H-24), 1.96-1.85 (m, 2H; H-21), 1.55-1.41 (m, 2H; H-19), 1.34-1.23 (m, 1H; H-20a), 1.15-1.06 (m, 1H; H-20b); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 173.3 (C-18), 170.3 (C-6), 168.1 (C1), 155.9 (C-15), 142.7 (C-4), 139.2 (C-7 or C-11), 134.9 (C-7 or C-11), 129.4 and 127.7 (C-9 and either C-8 or C-10), 125.8 (C-12), 123.6 (C-8 or C-10), 122.4 (C-5), 56.1 (C-23), 55.7 (C17), 48.4 and 48.3 (C-22 and C-2), 38.3 (C-14), 33.3 (C-13), 29.7 (t, J = 21.7 Hz; C-24), 29.3 (C19), 27.8 (C-21); HRMS (ESI+) m/z = 887.1870 [M+H]+ found, C31H28F17N6O5+ required 887.1844, 909.1705 [M+Na]+ found, C31H29F17N6O5Na+ required 909.1664.
Fluorous-tagged macrocyclic hydantoin SI-91
Crude product of linear hydantoin SI-49 (52 mg, not pure, max. 0.059 mmol, 1.0 eq) was reacted according to GP10 overnight. After purification by preparative HPLC (50-70% B), title compound SI-91 (23 mg, 0.026 mmol, 28% over 3 steps) was isolated as white powder. TLC Rf = 0.38 (CH2Cl2/MeOH 20:1); HPLC tr = 7.93 min (50-100% B), peak area 98%; [α]D25.0 = 3 (c = 0.046 in MeOH); IR (neat) νmax = 2928 (w, C-H), 1751 (w, C(=O)OR), 1704 (s, hydantoin C=O), 1635 (C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ =7.70 (s, 1H; H-5), 7.49 (s, 1H; H-16), 7.42 (d, J = 7.8 Hz, 1H; H-10), 7.37 (t, J = 7.6 Hz, 1H; H-9), 7.26 (d, J = 7.5 Hz, 1H; H-8), 7.14 (s, 1H; H-12), 4.86 (d, J = 16.2 Hz, 1H; H-3a), 4.69 (d, J = 16.1 Hz, 1H; H-3b), 4.38 (t, J = 6.1 Hz, 2H; H-23), 4.16-3.99 (m, 4H; H-22 and H-2), 3.95-3.83 (m, 2H; H-17 and H-14a), 3.64 (dt, J = 13.9, 5.3 Hz, 1H; H-14b), 3.01 (t, J = 5.9 Hz, 2H; H-13), 2.62 (tt, J = 19.1, 6.1 Hz, 2H; H-24), 1.82-1.70 (m, 2H; H-21), 1.50-1.42 (m, 1H; H-18a), 1.42-1.33 (m, 1H; H-18b), 1.080.98 (m, 1H; H-19a), 0.79-0.67 (m, 1H; H-19b); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 173.3 (C-15 or C-18), 170.0 (C-6), 167.6 (C-1), 156.0 (C-15 or C-18), 138.1 (C-11), 134.0 (C-7), 133.3 (C-5), 131.7 (C-4), 130.1 (C-10), 127.9 (C-9), 126.7 (C-12), 124.4 (C-8), 56.1 (C-23), 55.3 (C-17), 46.7 (C-2), 46.2 (C-22), 37.2 (C-14), 31.9 (C-13), 29.6 (t, J = 21.5 Hz; C-24), 29.2 (C-18 68 68
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DOI: 10.1038/NCHEM.1729
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or C-21), 28.2 (C-18 or C-21), 19.1 (C-19); HRMS (ESI+) m/z = 887.1858 [M+H]+ found, C31H28F17N6O5+ required 887.1844.
Fluorous-tagged macrocyclic hydantoin SI-92
Linear hydantoin SI-50 (119 mg, 0.138 mmol, 1.00 eq) was reacted according to GP9 overnight. After purification by preparative HPLC (50-80% B), title compound SI-92 (77 mg, 0.089 mmol, 64%) was isolated as a white powder. TLC Rf = 0.57 (CH2Cl2/MeOH 10:1); HPLC tr = 7.43 min (50-100% B), peak area 98%; mp 146150 °C (H2O); [α]D28.3 = +26 (c = 0.158 in MeOH); IR (neat) νmax = 1770 (w), 1711 (s, C=O), 1635 (m, C=O), 1538 (w), 1436 (m), 1200 (s, C-F), 1147 (s, C-F); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.82 (s, 1H; H-13), 7.58 (s, 1H; H-5), 7.05 (d, J = 3.4, 1H; H-8), 6.51 (d, J = 3.4, 1H; H-9), 5.09 (d, J = 16.9, 1H; H-3a), 4.88 (d, J = 16.8, 1H; H-3b), 4.61 (d, J = 15.4, 1H; H-11a), 4.47 (d, J = 15.4, 1H; H-11b), 4.41 (t, J = 6.1, 2H; H-20), 4.37-4.28 (m, 3H; H-19, H-2a), 4.25 (d, J = 17.1, 1H; H-2b), 4.06 (dt, J = 1.2, 5.2, 1H; H-14), 2.65 (tt, J = 19.1, 6.2, 2H; H-21), 1.79-1.73 (m, 2H; H-18), 1.63-1.56 (m, 2H; H-16), 1.16-1.08 (m, 1H; H-17a), 0.69-0.60 (m, 1H; H-17b); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 172.8 (C-15), 168.0 (C-1), 158.8 (C-6), 155.4 (C-12), 150.9 (C-10), 146.4 (C-7), 143.2 (C-4), 122.6 (C-5), 117.1 (C-8), 110.6 (C-9), 56.1 (C-20), 55.8 (C-14), 49.2 (C-2), 48.2 (C-19), 44.3 (C-3), 33.8 (C-11), 29.6 (t, J = 20.8; C-12), 28.4 (C-16), 28.1 (C-18), 18.3 (C-17); HRMS (ESI+) m/z = 863.1472 [M+H]+ found, C28H24F17N6O6+ required 863.1480, 885.1287 [M+Na]+ found, C28H23F17N6O6Na+ required 885.1300.
Fluorous-tagged macrocyclic hydantoin SI-93
Linear hydantoin SI-50 (140 mg, 0.162 mmol, 1.00 eq) was reacted according to GP10 overnight. After purification by preparative HPLC (50-80% B), title compound SI-93 (53 mg, 0.061 mmol, 38%) was isolated as a white powder. TLC Rf = 0.58 (CH2Cl2/MeOH 10:1); HPLC tr = 7.44 min (50-100% B), peak area 100%; mp 128129 °C (H2O); [α]D28.4 = +16.5 (c = 0.818 in MeOH); IR (neat) νmax = 1713 (m, C=O), 1635 (w, C=O), 1536 (w), 1441 (w), 1353 (w), 1198 (s, C-F), 1144 (s, C-F), 703 (m); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.74 (s, 1H; H-13), 7.58 (s, 1H; H-5), 7.08 (d, J = 3.4, 1H; H-8), 6.56 (d, J 69 69
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
= 3.5, 1H; H-9), 5.00 (s, 2H; H-3), 4.66 (d, J = 15.9, 1H; H-11a), 4.58 (d, J = 15.9, 1H; H-11b), 4.35 (t, J = 6.2, 2H; H-20), 4.27-4.21 (m, 1H; H-19a), 4.16-4.13 (m, 2H; H-2a, H-14), 4.07-4.00 (m, 2H; H-2b, H-19b), 2.60 (tt, J = 19.0, 6.3, 2H; H-21), 1.82-1.75 (m, 3H; H-18, H-16a), 1.691.62 (m, 1H; H-16b), 1.12-1.03 (m, 1H; H-17a), 0.88-0.79 (m, 1H; H-17b); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 172.7 (C-15), 167.3 (C-1), 158.9 (C-6), 155.3 (C-12), 150.6 (C-10), 146.1 (C-7), 132.9 (C-5), 131.9 (C-4), 118.0 (C-8), 109.8 (C-9), 56.1 (C-20), 55.4 (C-14), 47.1 (C-2 or C-19), 47.1 (C-2 or C-19), 33.9 (C-11), 29.6 (t, J = 22.0; C-21), 28.8 (C-18 or C-16), 28.7 (C-18 or C-16), 19.0 (C-17); HRMS (ESI+) m/z = 863.1467 [M+H]+ found, C28H24F17N6O6+ required 863.1480.
Fluorous-tagged macrocyclic dihydrouracil 32
Linear dihydrouracil 26 (47 mg, 0.054 mmol, 1.0 eq) was reacted according to GP9 for 42 h. After purification by preparative HPLC (55-65% B), title compound 32 (38 mg, 0.044 mmol, 81%) was isolated as a white solid. HPLC tr = 4.93 min (60-100% B), peak area 99%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.03 (s, 1H: H-5), 7.72 (d, J = 4.7, 1H; H-14), 7.54-7.48 (m, 2H; H-9 and H-8 or H-10), 7.29 (d, J = 7.2, 1H; H-8 or H-10), 6.89 (s, 1H; H-12), 4.54 (s, 1H; H-3), 4.49-4.37 (m, 4H; H-21 and H-22), 4.36-4.26 (m, 2H, H-2), 3.57 (m, 1H; H-15), 3.09 (dd, J = 16.7, 7.8, 1H; H-16a), 2.69 (tt, J = 19.2, 6.2; H-23), 2.45 (d, J = 16.6, 1H; H-16b), 2.03-1.84 (m, 2H; H-20), 1.55-1.40 (m, 2H, H-18), 1.19-1.02 (m, 2H; H-19); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 170.8, 169.6, 169.0, 153.0 (each C=O), 144.2, 135.6, 135.5 (each quat. C), 132.0 (C-8 or C-10), 129.6 (C-9), 127.5 (C-8 or C-10), 126.2 (C-12), 123.6 (C-5), 57.1 (C-22), 49.9 (C-21), 49.0 (C-2), 47.0 (C-3), 45.1 (C-15), 36.2 (C-18), 36.0 (C-16), 30.6 (t, J = 21.2; C-23), 29.4 (C-20), 20.6 (C-19); HRMS (ESI+) m/z = 873.1715 [M+H]+ found, C30H26F17N6O5+ required 873.1688.
Fluorous-tagged macrocyclic dihydrouracil 33
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
Linear dihydrouracil 26 (48 mg, 0.055 mmol, 1.0 eq) was reacted according to GP10 for 3.5 h. After purification by preparative HPLC (55-65% B), title compound 33 (15 mg, 0.017 mmol, 31%) was isolated as a white solid. HPLC tr = 5.16 min (60-100% B), peak area 99%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.79 (br d, J = 5.0, 1H; H-14), 7.76 (ddd, J = 7.9, 1.7, 1.3, 1H; H-8 or H-10), 7.71 (br s, 1H; H-5), 7.54 (t, J = 7.9, 1H; H-9), 7.44 (ddd, J = 7.9, 2.0, 1.2, 1H; H-8 or H-10), 6.89 (t, J = 1.9, 1H; H-12), 5.00 (d, J = 18.2, 1H; H-2a or H-3a), 4.86 (d, J = 18.2, 1H; H-2b or H-3b), 4.43 (t, J = 6.2, 1H; H22), 4.38 (d, J = 16.9, 1H; H-2a or H-3a), 4.27 (dt, J = 14.1, 5.1, 1H; H-21a), 4.20-4.12 (m, 2H; H-21b and H-2b or H-3b), 3.66-3.60 (m, 1H; H-15), 3.11 (dd, J = 16.6, 7.7, 1H; H-16a), 2.67 (tt, J = 19.3, 6.1, 2H; H-23), 2.45 (dt, J = 16.7, 1.5, 1H; H-16b), 2.02 (m, 2H; H-20), 1.61-1.46 (m, 2H; H-18), 1.13-0.95 (m, 2H; H-19); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 168.7, 167.9, 167.2, 152.3 (each C=O), 135.0, 134.1 (quat. C), 131.9 (C-8 or C-10), 131.8 (quat C), 131.3 (C-5), 128.9 (C-8 or C-10), 128.2 (C-9), 125.2 (C-12), 56.1 (C-22), 49.3 (C-2 and C-3), 46.9 (C-21), 45.7 (C-2 and C-3), 43.9 (C-15), 35.5 (C-18), 35.4 (C-16), 29.7 (t, J = 21.4; C-23), 29.1 (C-20), 19.0 (C-19); HRMS (ESI+) m/z = 873.1696 [M+H]+ found, C30H26F17N6O5+ required 873.1688.
Macrocyclic amide SI-94
Linear amide SI-52 (31 mg, 0.078 mmol, 1.0 eq) was reacted according to GP9 overnight. After purification by preparative HPLC (10-40% B), title compound SI-94 (27 mg, 0.068 mmol, 87%) was isolated as a white powder. TLC Rf = 0.48 (CH2Cl2/MeOH 10:1); HPLC tr = 6.67 min (10-60% B), peak area 98%; mp 164166 °C (H2O); [α]D28.7 = +0.7 (c = 0.417 in MeOH); IR (neat) νmax = 3345 (w), 2931 (w), 1729 (s, C=O), 1635 (s, C=O), 1589 (m), 1525 (m), 1438 (m), 1211 (s), 1131 (s), 761 (s); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 8.44 (s, 1H; H-14), 7.95 (s, 1H; H-5), 7.53-6.99 (m, 4H; H-9, H-10, H-11 and H-12), 4.64 (br s, 2H; H-3), 4.45-4.40 (t, 2H, J = 6.1 Hz; H-20), 4.38 (s, 2H; H-2), 3.72 (s, 3H; H-21), 3.59 (s, 2H; H-7), 2.18 (t, J = 6.6 Hz, 2H; H-16), 1.92-1.83 (m, 2H; H-19), 1.431.36 (br s, 2H; H-17), 1.16-1.06 (m, 2H; H-18); HRMS (ESI+) m/z = 422.1820 [M+Na]+ found, C20H25N5O4Na+ required 422.1799.
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
Macrocyclic amide SI-95
Linear amide SI-52 (33 mg, 0.083 mmol, 1.00 eq) was reacted according to GP10 overnight. After purification by preparative HPLC (10-40% B), title compound SI-95 (23 mg, 0.058 mmol, 69%) was isolated as a white powder. TLC Rf = 0.46 (CH2Cl2/MeOH 10:1); HPLC tr = 7.67 min (10-60% B), peak area 99%; mp 257260 °C (H2O); IR (neat) νmax = 3378 (w), 2928 (w), 1727 (s, C=O), 1676 (s, C=O), 1634 (s, C=O), 1591 (m), 1525 (s), 1433 (s), 1188 (s), 1137 (s), 981 (m), 767 (s); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 8.60 (br s, 1H; H-14), 7.71-7.58 (m, 2H; H-5 and ArH), 7.34-7.16 (m, 2H; ArH), 7.137.08 (m, 1H; ArH), 4.72 (s, 2H; H-3), 4.28 (t, J = 7.2 Hz, 3H; H-20), 4.24 (s, 2H; H-2), 3.77 (s, 2H; H-7), 3.69 (s, 3H; H-21), 2.39-2.27 (m, 2H; H-16), 1.83 (quint, J = 7.8 Hz, 2H; H-19), 1.68 (quint, J = 6.7 Hz, 2H; H-17), 1.34-1.26 (m, 2H; H-18); HRMS (ESI+) m/z = 400.1973 [M+H]+ found, C20H26N5O4+ required 400.1979.
Fluorous-tagged macrocyclic amide SI-96
Linear amide 27 (123 mg, 0.148 mmol, 1.00 eq) was reacted according to GP9. After refluxing for 48 h, additional CuI (56 mg, 0.30 mmol, 2.0 eq) was added and the mixture was refluxed for another 48 h. After filtration, the crude product SI-96 was directly used in the transesterification to form SI-137. TLC Rf = 0.61 (CH2Cl2/MeOH 10:1); HPLC tr = 6.63 min (60-100% B); HRMS (ESI+) m/z = 832.1774 [M+H]+ found, C29H27F17N5O4+ required 832.1786.
Fluorous-tagged macrocyclic amide SI-97
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
Linear amide 27 (133 mg, 0.160 mmol, 1.00 eq) was reacted according to GP10 for 3.5 h. After purification by preparative HPLC (55-85% B), title compound SI-97 (81 mg, 0.098 mmol, 61%) was isolated as an off-white solid. TLC Rf = 0.56 (CH2Cl2/MeOH 10:1); HPLC tr = 6.41 min (60-100% B), peak area 98%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 9.60 (s, 1H; H-13), 7.73 (s, 1H; H-5), 7.52 (d, J = 8.2, 1H; H10), 7.47 (s, 1H; H-12), 7.42 (t, J = 7.8, 1H; H-9), 7.20 (d, J = 7.6, 1H; H-8), 4.65 (s, 2H; H-3), 4.41 (t, J = 6.1, 2H; H-21), 4.25 (s, 2H; H-2), 4.03 (t, J = 6.6, 2H; H-20), 2.66 (tt, J = 19.2, 6.0, 2H; H-22), 2.22 (t, J = 6.5, 2H; H-15), 1.76 (dt, J = 15.1, 7.6, 2H; H-19), 1.67 (dt, J = 12.7, 6.3, 2H; H-16), 1.31-1.25 (m, 2H; H-17), 1.14 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.9 (C-14), 169.9 (C-6), 167.9 (C-1), 138.2 (C-7 or C-11), 134.0 (C-11 or C-7), 133.3 (C-4), 132.1 (C-5), 129.0 (C-9), 122.7 (C-8), 56.2 (C-21), 47.7 (C-2), 47.1 (C-20), 44.1 (C-3), 35.5 (C15), 29.7 (t, J = 22.7; C-22), 28.4 (C-19), 27.0 (C-17), 24.3 (C-16 or C-18), 24.2 (C-18 or C-16); HRMS (ESI+) m/z = 832.1782 [M+H]+ found, C29H27F17N5O4+ required 832.1786, 854.1597 [M+Na]+ found, C29H26F17N5O4Na+ required 854.1606.
Fluorous-tagged macrocyclic amide SI-98
Linear amide SI-53 (65 mg, 0.078 mmol, 1.00 eq) was reacted according to GP9 for 15 h. After purification by preparative HPLC (50-80% B), title compound SI-98 (29 mg, 0.035 mmol, 45%) was isolated as clear oil. TLC Rf = 0.68 (CH2Cl2/MeOH 10:1); HPLC tr = 8.21 min (50-100% B), peak area 99%; IR (neat) νmax = 2945 (br, C-H), 1759 (s, C(=O)OR), 1631 (s, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.79 (s, 1H; H-14), 7.76 (s, 1H; H-5), 7.38 (t, J = 7.6, 1H; H-9), 7.32 (d, J = 7.8, 1H; H-8 or H-10), 7.28 (d, J = 7.7, 1H; H-8 or H-10), 7.09 (s, 1H; H-12), 4.60 (s, 2H; H-2), 4.44 (t, J = 6.2, 2H; H-21), 4.41 – 4.36 (m, 2H; H-20), 4.30 (d, J = 5.4, 2H; H-13), 4.25 (s, 2H; H-3), 2.67 (tt, J = 19.0, 6.2, 2H; H-22), 2.18 – 2.12 (m, 2H; H-16), 1.87 – 1.77 (m, 2H; H-19), 1.56 – 1.49 (m, 1H; H-17), 1.18 – 1.11 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 172.5 (C=O), 171.6 (C=O), 168.9 (C=O), 143.8 (C-4), 140.7 (C-11 or C-7), 136.5 (C-7 or C-11), 129.1 (C-8 or C-10), 128.6 (C-9), 125.1 (C-8 or C-10), 124.3 (C-12), 122.3 (C-5), 57.2 (C-21), 50.0 (C-20), 48.9 (C-3), 42.6 (C-13),35.4 (C-16), 30.8 (t, J = 21.3, C-22), 29.4 (C-19), 25.7 (C-18), 24.4 (C17); HRMS (ESI+) m/z = 854.1580 [M+Na]+ found, C29H26F17N5O4Na+ required 854.1606.
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
Fluorous-tagged macrocyclic amide SI-99
Linear amide SI-53 (65 mg, 0.078 mmol, 1.0 eq) was reacted according to GP10 for 15 h. After purification by preparative HPLC (50-80% B), title compound SI-99 (20 mg, 0.024 mmol, 31%) was isolated as a white solid. TLC Rf = 0.62 (CH2Cl2/MeOH 10:1); HPLC tr = 7.94 min (50-100% B), peak area 99%; mp 147°C (MeCN/H2O); IR (neat) νmax = 2926 (br, C-H), 1745 (m, C(=O)OR), 1637 (s, C(=O)NR2); 1 H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.98 (s, 1H; H-14), 7.64 (s, 1H; H-5), 7.40 – 7.33 (m, 2H; H-8 and H-10), 7.31 – 7.23 (m, 2H; H-9 and H-12), 4.80 (s, 2H; H-2), 4.40 (t, J = 6.2, 2H; H21), 4.29 (d, J = 6.0, 2H; H-13), 4.11 (t, J = 7.1, 2H; H-20), 4.04 (s, 2H; H-3), 2.63 (tt, J = 19.1, 6.2, 2H; H-22), 2.20 – 2.12 (m, 2H; H-16), 1.87 – 1.75 (m, 2H; H-19), 1.65 – 1.55 (m, 2H; H-17), 1.21 – 1.11 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 172.5 (C=O), 171.9 (C=O), 168.7 (C=O), 140.8 (C-11 or C-7), 135.4 (C-11 or C-7), 134.4 (C-4), 132.7 (C-5), 129.8 (C-12), 128.9 (C-8 or C-10), 125.8 (C-9), 125.1 (C-10 or C-8) , 57.4 (C-21), 48.7 (C-3), 48.3 (C20), 42.5 (C-13), 35.2 (C-16), 30.9 (t, J = 21.3; C-22), 29.4 (C-19), 25.5 (C-18), 25.0 (C-17); HRMS (ESI+) m/z = 854.1600 [M+Na]+ found, C29H26F17N5O4Na+ required 854.1606.
Fluorous-tagged macrocyclic amide SI-100
Linear amide SI-54 (120 mg, 0.140 mmol, 1.00 eq) was reacted according to GP9 for 15 h. After purification by preparative HPLC (50-80% B), title compound SI-100 (11 mg, 0.012 mmol, 9%) was isolated as a yellow oil. TLC Rf = 0.58 (CH2Cl2/MeOH 10:1); HPLC tr = 9.24 min (50-100% B), peak area 97%; IR (neat) νmax = 2934 (br, C-H), 1756 (m, C(=O)OR), 1628 (s, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.86 (s, 1H; H-14), 7.79 (s, 1H; H-5), 7.38 – 7.27 (m, 2H; H-8/H-10 and H-9), 7.24 – 7.15 (m, 2H; H-12 and H-8/H-10), 4.65 (s, 2H; H-2), 4.42 – 4.34 (m, 4H; H-23 and H-22), 4.32 (d, J = 5.9, 2H; H-13), 4.13 (s, 2H; H-3), 2.63 (tt, J = 19.2, 6.3, 2H; H-24), 2.12 (t, J = 7.2, 2H; H-16), 1.88 – 1.79 (m, 2H; H-21), 1.53 – 1.44 (m, 2H; H-17), 1.33 – 1.21 (m, 4H; H-18 and H-19), 1.16 – 1.08 (m, 2H; H-20); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 171.7 (C=O), 170.3 (C=O), 167.9 (C=O), 142.1 (C-7 or C-11), 139.7 (C-7 or C-11), 135.3 (C-4), 127.8 (C-8/C-10 or C-9), 74 74
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SUPPLEMENTARY INFORMATION
DOI: 10.1038/NCHEM.1729
127.4 (C-8/C-10 or C-9), 123.8 (C-12 or C-10/C-8), 123.4 (C-12 or C-10/C-8), 122.7 (C-5), 56.2 (C-23), 48.6 (C-22 and C-3), 41.2 (C-2), 40.7 (C-13), 35.0 (C-16), 29.6 (t, J = 21.8; C-24), 28.2 (C-21), 27.4 (C-17), 26.7 (C-19, C-20, or C-18), 24.1 (two of C-19, C-20, or C-18); HRMS (ESI+) m/z = 860.2104 [M+H]+ found, C31H31F17N5O4+ required 860.2099.
Fluorous-tagged macrocyclic amide SI-101 5
3
23 24
O
1
2
O
18
20 21
4
O C8F17
19
N N N
17
22
N 6
7
16 15
12
HN 14 11
O
13
10
8 9
SI-101
Linear amide SI-54 (150 mg, 0.177 mmol, 1.00 eq) was reacted according to GP10 for 15 h. After purification by preparative HPLC (50-80% B), title compound SI-101 (3.6 mg, 0.024 mmol, 2%) was isolated as a yellow oil. TLC Rf = 0.54 (CH2Cl2/MeOH 10:1); HPLC tr = 8.77 min (50-100% B), peak area 92%; IR (neat) νmax = 2988 (s, C-H), 1741 (w, C(=O)OR), 1643 (s, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.91 (s, 1H; H-14), 7.91 (s, 1H; H-5), 7.38 (d, J = 7.8, 1H; H-8 or H-10), 7.34 (t, J = 7.5, 1H; H-9), 7.27 (s, 1H; H-12), 7.21 (d, J = 7.2, 1H; H-8 or H-10); 4.83 (s, 2H; H-2), 4.38 (t, J = 6.2, 2H; H-23), 4.31 (d, J = 6.0, 2H; H-13), 4.27 (br t, J = 5.8, 2H, H-22), 4.06 (s, 2H; H-3); 2.60 (tt, J = 25.7, 6.1, 2H; H-24), 2.17 – 2.12 (m, 2H; H-16), 1.68 (br s, 1H; H-21a), 1.59 – 1.51 (m, 3H; H-17 and H-21b), 1.36 – 1.14 (m, 6H; H-20, H-19, and H-18); HRMS (ESI+) m/z = 860.2088 [M+H]+ found, C31H31F17N5O4+ required 860.2099.
Fluorous-tagged macrocyclic amide SI-102
Linear amide SI-55 (30 mg, 0.035 mmol, 1.0 eq) was reacted according to GP9 for 15 h. After purification by preparative HPLC (50-80% B), title compound SI-102 (14 mg, 0.017 mmol, 47%) was isolated as a colorless oil. TLC Rf = 0.45 (CH2Cl2/MeOH 10:1); HPLC tr = 8.39 min (50-100% B), peak area 100%; IR (neat) νmax = 3361 (br, m, N-H), 2977 (w, C-H), 1643 (m, C(=O)NR2); HRMS (ESI+) m/z = 846.1943 [M+H]+ found, C30H29F17N5O4+ required 846.1948.
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
Fluorous-tagged macrocyclic amide SI-103
Linear amide SI-55 (30 mg, 0.035 mmol, 1.0 eq) was reacted according to GP10 for 15 h. After purification by preparative HPLC (50-80% B), title compound SI-103 (20 mg, 0.024 mmol, 68%) was isolated as a colorless oil. TLC Rf = 0.48 (CH2Cl2/MeOH 10:1); HPLC tr = 7.95 min (50-100% B), peak area 100%; IR (neat) νmax = 2938 (w, C-H), 1751 (m, C(=O)OR), 1641 (m, C(=O)NR2); HRMS (ESI+) m/z = 846.1934 [M+H]+ found, C30H29F17N5O4+ required 846.1948.
Fluorous-tagged macrocyclic amide SI-104
Linear amide SI-56 (80 mg, 0.092 mmol, 1.0 eq) was reacted according to GP9 for 15 h. After purification by preparative HPLC (50-80% B), title compound SI-104 (60 mg, 0.069 mmol, 75%) was isolated as a colorless oil. TLC Rf = 0.55 (CH2Cl2/MeOH 10:1); HPLC tr = 9.33 min (50-100% B), peak area 100%; IR (neat) νmax = 2938 (w, C-H), 1747 (w, C(=O)OR), 1640 (m, C(=O)NR2); HRMS (ESI+) m/z = 874.2241 [M+H]+ found, C32H33F17N5O4+ required 874.2261.
Fluorous-tagged macrocyclic amide SI-105
Linear amide SI-56 (80 mg, 0.092 mmol, 1.0 eq) was reacted according to GP10 for 15 h. After purification by preparative HPLC (50-80% B), title compound SI-105 (52 mg, 0.059 mmol, 64%) was isolated as a pale yellow oil.
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
TLC Rf = 0.46 (CH2Cl2/MeOH 10:1); HPLC tr = 8.87 min (50-100% B), peak area 98%; IR (neat) νmax = 2938 (w, C-H), 1749 (m, C(=O)OR), 1642 (m, C(=O)NR2); HRMS (ESI+) m/z = 874.2255 [M+H]+ found, C32H33F17N5O4+ required 874.2261.
Fluorous-tagged macrocyclic amide SI-106
Linear amide SI-57 (142 mg, 0.173 mmol, 1.00 eq) was reacted according to GP9 for 24 h. After purification by preparative HPLC (50-90% B), title compound SI-106 (63 mg, 0.077 mmol, 44%) was isolated as a white powder. TLC Rf = 0.56 (CH2Cl2/MeOH 10:1); HPLC tr = 7.76 min (50-100% B), peak area 100%; mp 176178 °C (H2O); IR (neat) νmax = 1746 (m, C=O), 1634 (m, C=O), 1529 (m), 1436 (m), 1196 (s, CF), 1145 (s, C-F), 1019 (w), 704 (m); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.88 (t, J = 5.1, 1H; H-12), 7.85 (s, 1H; H-5), 7.06 (d, J = 3.4, 1H; H-8), 6.48 (d, J = 3.4, 1H; H-9), 4.93 (s, 2H; H3), 4.40 (t, J = 6.1, 2H; H-19), 4.38-4.36 (m, 2H; H-18), 4.30 (d, J = 5.1, 2H; H-11), 4.25 (s, 2H; H-2), 2.65 (tt, J = 19.1, 6.2, 2H; H-20), 2.11-2.09 (m, 2H; H-14), 1.82-1.77 (m, 2H; H-17), 1.571.51 (m, 2H; H-15), 1.05 (quint, J = 7.5, 2H; H-16); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.3 (C-13), 168.0 (C-1), 158.7 (C-6), 153.7 (C-10), 146.6 (C-7), 143.5 (C-4), 122.3 (C-5), 117.6 (C-8), 109.8 (C-9), 56.1 (C-19), 48.5 (C-18 and C-2), 44.5 (C-3), 35.4 (C-11), 34.0 (C-14), 29.6 (t, J = 21.6; C-20), 27.8 (C-17), 23.7 (C-16), 23.1 (C-15); HRMS (ESI+) m/z = 822.1553 [M+H]+ found, C27H25F17N5O5+ required 822.1579, 844.1396 [M+Na]+ found, C27H24F17N5O5Na+ required 844.1398.
Fluorous-tagged macrocyclic amide SI-107
Linear amide SI-57 (161 mg, 0.196 mmol, 1.00 eq) was reacted according to GP10 for 6 h. After purification by preparative HPLC (50-80% B), title compound SI-107 (84 mg, 0.102 mmol, 52%) was isolated as a white powder. TLC Rf = 0.54 (CH2Cl2/MeOH 10:1); HPLC tr = 7.54 min (50-100% B), peak area 100%; mp 9396 °C (H2O); IR (neat) νmax = 1751 (w, C=O), 1636 (m, C=O), 1536 (w), 1430 (w), 1200 (s, C-F), 1147 (s, C-F), 1019 (w), 704 (m); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.06 (t, J = 5.3, 1H; H-12), 7.57 (s, 1H; H-5), 7.11 (d, J = 3.4, 1H; H-8), 6.47 (d, J = 3.4, 1H; H-9), 5.17 (s, 2H; H-3), 77 77
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
4.35 (t, J = 6.1, 2H; H-19), 4.24 (d, J = 5.3, 2H; H-11), 4.19 (t, J = 6.6, 2H; H-18), 4.11 (s, 2H; H2), 2.60 (tt, J = 19.2, 6.2, 2H; H-20), 2.10-2.07 (m, 2H; H-14), 1.78-1.72 (m, 2H; H-17), 1.57-1.52 (m, 2H; H-15), 1.07-1.01 (m, 2H; H-16); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.3 (C-13), 167.8 (C-1), 154.1 (C-10), 146.1 (C-7), 132.7 (C-4), 132.5 (C-5), 118.6 (C-8), 109.2 (C-9), 56.1 (C-19), 47.7 (C-2), 47.5 (C-18), 35.2 (C-11), 33.9 (C-14), 29.6 (t, J = 21.3; C-20), 28.4 (C-17), 24.2 (C-16), 24.0 (C-15); HRMS (ESI+) m/z = 822.1572 [M+H]+ found, C27H25F17N5O5+ required 822.1579, 844.1406 [M+Na]+ found, C27H24F17N5O5Na+ required 844.1398.
Macrocyclic amine SI-108
Linear amide 30 (22 mg, 0.051 mmol, 1.0 eq) was reacted according to GP9 for 20 h. After purification by flash column chromatography (EtOAc) and preparative HPLC (5-100% B, without addition of TFA), title compound SI-108 (9.1 mg, 0.021 mmol, 41%) was isolated as white powder. TLC Rf = 0.38 (CH2Cl2/MeOH 40:1); HPLC tr = 10.28 min (5-100% B, without addition of TFA), peak area 96%; 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.57 (s, 1H; H-5), 7.19-7.12 (m, 2H; H-16, H-17), 7.12-7.07 (m, 2H; H-9, H-20), 6.98 (d, J = 6.9, 1H; H-18), 6.74 (dd, J = 8.2, 1.6, 1H; H-10), 6.52 (d, J = 7.3, 1H; H-8), 6.33 (s, 1H; H-12), 6.18 (t, J = 5.6, 1H; H-13), 4.59 (s, 2H; H-3), 4.38 (t, J = 6.3, 2H; H-24), 4.23 (d, J = 6.2, 2H; H-14), 4.01 (s, 2H; H-2), 3.63 (s, 3H; H-25), 2.55 (t, J = 7.4, 2H; H-21), 1.88-1.77 (dt, J = 14.6, 6.7, 2H; H-23), 1.41 (dt, J = 15.0, 7.5, 2H; H-22); 13 C NMR (125 MHz, DMSO-d6, 120 °C) δ = 170.8 (C-6), 168.6 (C-1), 148.2 (C-11), 142.6 (C-4), 141.2 (C-19), 139.9 (C-15), 135.8 (C-7), 128.0 (C-9), 127.5 (C-17), 126.3 (C-20), 126.1 (C-18), 123.7 (C-16), 122.2 (C-5), 114.7 (C-10), 113.1 (C-18), 108.1 (C-12), 50.9 (C-25), 48.6 (C-2), 48.4 (C-24), 46.3 (C-14), 33.5 (C-21), 28.1 (C-23), 26.8 (C-22); HRMS (ESI+) m/z = 456.2015 [M+Na]+ found, C24H27N5O3Na+ required 456.2006.
Macrocyclic amine 45
Linear amide 30 (38 mg, 0.088 mmol, 1.0 eq) was reacted according to GP10 for 48 h. After purification by preparative HPLC (30-40% B, without addition of TFA), title compound 45 (2.0 mg, 0.0046 mmol, 5%) was isolated as an off-white powder. 78 78
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DOI: 10.1038/NCHEM.1729
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HPLC tr = 10.74 min (20-70% B, without addition of TFA), peak area 97%; 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.58 (s, 1H; H-5), 7.21-7.13 (m, 3H; H-17 and H-18 or H-16), 7.10 (s, 1H; H-20), 7.04 (t, J = 7.6, 1H; H-9), 6.96 (d, J = 7.0, 1H; H-18 or H-16), 6.71 (dd, J = 8.2, 1.5, 1H; H-8 or H-10), 6.42 (d, J = 7.4, 1H; H-8 or H-10), 6.34 (br s, 1H; H-12), 6.28 (t, J = 6.7, 1H; H-13), 4.53 (s, 2H; H-2 or H-3), 4.31 (d, J = 5.9, 2H; H-14), 4.11 (br s, 2H; H-24), 3.91 (br s, 2H; H-2 or H-3), 3.60 (s, 3H; H-25), 2.61 (t, J = 5.2, 2H; H-21), 1.56 (br s, 4H; H-22 and H-23); HRMS (ESI+) m/z = 456.2000 [M+Na]+ found, C24H27N5O3Na+ required 456.2006.
Macrocyclic amine 40
Linear amine SI-65 (39 mg, 0.089 mmol, 1.0 eq) was reacted according to GP9 for 24 h. After purification by flash column chromatography (CH2Cl2/MeOH 35:1), title compound 40 (22 mg, 0.050 mmol, 56%) was isolated as an off-white gum. TLC Rf = 0.41 (CH2Cl2/MeOH 20:1); HPLC tr = 7.23 min (5-100% B), peak area 95%; IR (neat) νmax = 2922 (m, NH), 2851 (w), 1745 (s, C=O), 1621 (s, C=O), 1534 (m), 1432 (s), 1206 (s), 1175 (s), 1155 (s), 745 (m); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.92 (s, 1H; H-5), 7.20 (d, J = 7.5, 1H; H-16), 7.11 (d, J = 7.7, 1H; H-15), 7.08 (s, 1H; H-19), 7.05-7.03 (m, 2H; H-8 and H-17), 6.44 (d, J = 3.4, 1H; H-9), 4.88 (s, 2H; H-3), 4.32 (t, J = 6.9, 2H; H-23), 4.22 (s, 2H; H-2), 3.74 (br s, 4H; H-11 and H-13), 3.65 (s, 3H; H-24), 2.60 (t, J = 7.1, 2H; H-20), 1.80 (quint, J = 7.1, 2H; H-22), 1.55 (quint, J = 7.1, 2H; H-21); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 168.7 (C-1), 158.7 (C-6), 156.4 (C-10), 146.0 (C-7), 143.1 (C-4), 140.8 (C-18), 139.3 (C-14), 127.7 (C16), 127.6 (C-19), 126.5 (C-17), 125.4 (C-15), 122.7 (C-5), 117.6 (C-8), 108.2 (C-9), 51.9 (C-11 or C-13), 51.1 (C-24), 48.6 (C-23), 48.0 (C-2), 44.5 (C-11 or C-13), 43.7 (C-3), 33.3 (C-20), 28.0 (C-22), 26.4 (C-21); HRMS (ESI+) m/z = 460.1966 [M+Na]+ found, C23H27N5O4Na+ required 460.1955.
Fluorous-tagged macrocyclic dihydropyridinone SI-109
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
Linear 31 (55 mg, 0.059 mmol, 1.0 eq) was reacted according to GP9 for 20 h. After purification by preparative HPLC (70-90% B), title compound SI-109 (18 mg, 0.019 mmol, 33%) was isolated as a yellow powder. TLC Rf = 0.34 (CH2Cl2/MeOH 20:1); HPLC tr = 9.59 min (50-100% B), peak area 97%; IR (neat) νmax = 1752 (w, C=O), 1645 (m, C=O), 1576 (m), 1200 (s, C-F), 1145 (s, C-F); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.89 (d, J = 7.9, 1H; H-13), 7.58 (s, 1H; H-5), 7.46-7.39 (m, 2H; H-9 and either H-8 or H-10), 7.16 (t, J = 7.5, 1H; H-20), 7.12-7.07 (m, 3H; H-23, H-19 and either H10 or H-8), 7.04 (d, J = 7.4, 1H; H-21), 6.82 (s, 1H; H-12), 5.36 (d, J = 5.8, 1H; H-17), 5.13 (d, J = 7.9, 1H; H-14), 4.70 (d, J = 15.6, 1H; H-3a), 4.54 (d, J = 15.6, 1H; H-3b), 4.43-4.31 (m, 4H; H28 and H-27), 4.05 (d, J = 18.0, 1H; H-2a), 4.00 (d, J = 17.4, 1H; H-2b), 3.23 (dd, J = 16.4, 7.4, 1H; H-16a), 2.63 (tt, J = 19.2, 5.7, 2H; H-29), 2.56 (t, J = 7.4, 2H; H-24), 2.52-5.49 (m; H-16a, coincides with solvent signal), 1.88-1.73 (m, 2H; H-26), 1.44-1.30 (m, 2H; H-25); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 188.2 (C-15), 169.4 (C-6), 167.8 (C-1), 147.1 (C-13), 144.0 (C-11), 142.4 (C-4), 142.2 (C-22), 138.6 (br, C-18), 136.2 (C-7), 128.9 (C-9), 127.8 (C-20), 127.1 (C-21), 125.5 (C-23), 122.6 (C-19), 122.2 (C-5), 120.8 (C-8 or C-10), 119.5 (C-10 or C-8), 115.3 (C-12), 102.0 (C-14), 60.1 (C-17), 56.2 (C-28), 48.9 (C-2), 48.4 (C-27), 33.6 (C-24), 29.6 (t, J = 21.2; C29), 28.2 (C-26 or C-25), 27.1 (C-25 or C-26); HRMS (ESI+) m/z = 932.2104 [M+H]+ found, C37H31N5O4F17+ required 932.2099, 954.1906 [M+Na]+ found, C37H30N5O4F17Na+ required 954.1917.
Fluorous-tagged macrocyclic dihydropyridinone SI-110
Linear 31 (67 mg, 0.072 mmol, 1.0 eq) was reacted according to GP10 for 2 days. After purification by preparative HPLC (70-100% B), title compound SI-110 (13 mg, 0.014 mmol, 19%) was isolated as a yellow powder. TLC Rf = 0.34 (CH2Cl2/MeOH 20:1); HPLC tr = 9.32 min (50-100% B), peak area 94%; IR (neat) νmax = 1752 (w, C=O), 1647 (m, C=O), 1574 (s), 1462 (w), 1200 (s, C-F), 1145 (s, C-F); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.77 (d, J = 8.0, 1H; H-13), 7.64 (s, 1H; H-5), 7.40-7.32 (m, 2H; H-9 and either H-8 or H-10), 7.20-6.92 (m, 6H; H-20, H-23, H-19, H-21, H-12 and either H-8 or H-10), 5.42 (br s, 1H; H-17), 5.13 (d, J = 8.0, 1H; H-14), 4.54 (s, 2H; H-3), 4.35 (t, J = 6.0, 2H; H-28), 4.15 (s, 2H; H-27), 3.89 (s, 2H; H-2), 3.04-3.02 (m; H-16a, coincides with water signal), 2.69-2.59 (m, 5H; H-16b, H-29 and H-24), 1.50 (br s, 4H; H-25 and H-26); HRMS (ESI+) m/z = 932.2072 [M+H]+ found, C37H31N5O4F17+ required 932.2099.
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DOI: 10.1038/NCHEM.1729
Metathesis Macrocyclizations Macrocyclic diene SI-111
Linear urea SI-34 (80 mg, 0.21 mmol, 1.0 eq) was reacted according to GP11 for 50 h in total, using only 0.1 eq of the Grubbs 2nd generation catalyst at the beginning but making further catalyst additions (0.1 eq each) after 20 h and 28 h. After pre-purification by short flash column chromatography (petroleum ether/EtOAc 1:19, then EtOAc/MeOH 19:1) and purification by preparative HPLC (30-60% B), title compound SI-111 (54 mg, 0.14 mmol, 68%) was isolated as white solid. TLC Rf = 0.25 (petroleum ether/EtOAc 1:19); HPLC tr = 9.62 min (5-100% B), peak area 100%; IR (neat) νmax = 3344 (m, NH), 1734 (s, (C=O)O), 1648 (s, (C=O)N); 1H NMR (500 MHz, DMSOd6, 120 °C) δ = 7.38-7.28 (m, 2H, H-9; H-12), 7.18 (dt, J = 8.0, 1.0; Ar-H), 7.06 (t, J = 8.0, 1H; Ar-H), 6.04-6.00 (m, 1H; H-22), 5.90 (m, 1H; H-21), 5.15 (s, 1H; H-5a), 4.98 (s, 1H; H-5b), 4.15 (s, 2H; H-3), 4.08 (br s, 2H; H-2), 3.69 (br s, 5H; H-23 and H-7), 3.10 (m, 2H; H-17), 2.11 (m, 2H; H-20), 1.50 (br s, 4H; H-18 and H-19); 13C NMR (125 MHz, DMSO-d6, 27 °C) major rotamer signals only, δ = 171.4 (C-6), 169.5 (C-1), 156.1 (C-15), 141.0 (C-4), 137.4 (C-13), 131.8 (C-21), 131.5 (C-9), 129.7 (C-8), 129.2 (C-22), 126.9 (C-11), 125.9 (C-12), 124.3 (C-10), 119.0 (C-5), 51.7 (C-23), 47.4 (C-3), 47.0 (C-2), 39.5 (C-17, coincides with solvent signal), 35.2 (C-7), 31.4 (C-20), 27.6 (C-18), 25.9 (C-19); HRMS (ESI+) m/z = 386.2092 [M+H]+ found, C21H28N3O4+ required 386.2074.
Fluorous-tagged macrocyclic diene SI-112
Linear urea 20 (30 mg, 0.037 mmol, 1.0 eq) was reacted according to GP11 for 42 h in total, using only 0.1 eq of the Grubbs 2nd generation catalyst at the beginning but making a further catalyst addition (0.1 eq) after 24 h. After purification by flash column chromatography (petroleum ether/EtOAc 1:2 to 1:3), title compound SI-112 (10 mg, 0.012 mmol, 34%) was isolated as beige solid. HPLC tr = 9.14 min (60-100% B), peak area 96%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.06 (s, 1H; H-13), 7.42 (br s, 1H; H-12), 7.28 (t, J = 7.8, 1H; H-9), 7.00 (d, J = 8.3, 1H; H-8 or H-10), 81 81
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
6.91 (d, J = 7.9, 1H; H-8 or H-10), 6.16 (br s, 1H; H-15), 6.02 (d, J = 16.0, 1H; H-21), 5.74 (dt, J = 15.8, 7.2, 1H; H-20), 5.19 (s, 1H; H-5a), 5.01 (s, 1H; H-5b), 4.41 (t, J = 6.1, 2H; H-22), 4.02 (br s, 4H; H-2 and H-3), 3.19 (s, 2H; H-16), 2.65 (m, 2H; H-23), 2.11 (br s, 2H; H-19), 1.45 (br s, 4H; H-17 and H-18); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 170.7, 168.2, 155.4 (each C=O), 140.8, 140.4, 136.0, 131.9 (C-20), 128.9 (C-21), 128.8 (C-9), 120.6 (C-8 or C-10), 119.2 (C-8 or C-10), 117.2, 56.2 (C-22), 46.8, 38.0 (C-16), 30.9 (C-19), 29.6 (C-23), 27.9 (C-17 or C-18), 25.1 (C-17 or C-18); HRMS (ESI+) m/z = 804.1707 [M+H]+ found, C29H27F17N3O4+ required 804.1725.
Fluorous-tagged macrocyclic diene SI-113
Linear urea SI-39 (123 mg, 0.150 mmol, 1.00 eq) was reacted according to GP11 for 25 h in total, making a further catalyst addition (0.1 eq) after 22 h. After pre-purification by short flash column chromatography (EtOAc/MeOH 39:1) and purification by preparative HPLC (60-100%), title compound SI-113 (74 mg, 0.091 mmol, 62 %) was isolated as white solid. TLC Rf = 0.39 (EtOAc/MeOH 19:1); HPLC tr = 9.41 min (60-100% B), peak area 100%; IR (neat) νmax = 1751 ((C=O)O), 1639 ((C=O)N), 1146 (CF); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.33-7.22 (m, 3H; Ar-H), 7.15 (d, J = 7.5, 1H; H-8), 6.20 (br s, 1H; H-14), 5.97 (d, J = 16.0, 1H; H-22), 5.78 (br s, 1H; H-21), 5.16 (s, 1H; H-5a), 5.02 (s, 1H; H-5b), 4.40 (t, J = 6.0, 2H; H-23), 4.32-4.23 (m, 4H; H-13 and H-3), 3.92 (s, 2H; H-2), 3.14 (br s, 2H; H-17), 2.68-2.58 (m, 2H; H24), 2.10-2.08 (m, 2H; H-20), 1.41 (br s, 4H; H-18 and H-19); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 170.6 (C-6), 167.8 (C-1), 157.8 (C-15), 141.7 (C-11), 140.4 (C-4), 135.5 (C-7), 132.3 (C-21), 127.9 (C-22), 127.2 (C-Ar), 127.1 (C-Ar), 123.4 (C-Ar), 122.9 (C-Ar), 117.1 (C-5), 56.2 (C-23), 41.9 (C-13), 38.0 (C-17), 31.2 (C-20), 29.6 (C-24), 29.3 (C-18), 25.4 (C-19); HRMS (ESI+) m/z = 818.1910 [M+H]+ found, C30H29F17N3O4+ required 818.1881.
Fluorous-tagged macrocyclic diene 35
Linear urea 34 (153 mg, 0.183 mmol, 1.00 eq) was reacted according to GP11 for 25 h in total. After purification by short flash column chromatography (EtOAc), title compound 35 (120 mg, 0.144 mmol, 79%) was isolated as beige solid.
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
TLC Rf = 0.16 (neat EtOAc); HPLC tr = 9.54 min (60-100% B), peak area 96%; IR (neat) νmax = 3353 (NH), 1745 ((C=O)O), 1634 ((C=O)N), 1198 (CF); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.34-7.28 (m, 2H; H-8, H-9), 7.17 (d, J = 7.0, 1H; H-10), 7.12 (s, 1H; H-12), 6.00 (d, J = 16.0, 1H; H-23), 5.80 (m, 1H; H-22), 5.42-5.39 (m, 2H; H-15 and H-17), 5.16 (s, 1H; H-5a), 5.03 (s, 1H; H-5b), 4.41 (t, J = 6.0, 2H; H-23), 4.25 (s, 2H; H-3), 4.01 (s, 2H; H-2), 3.32 (m, 2H; H-14), 3.01 (m, 2H; H-18), 2.79-2.76 (m, 2H; H-13), 2.64 (tt, J = 19.0, 6.0, 2H; H-24), 2.09-2.05 (m, 2H; H-21), 1.40-1.32 (m, 4H; H-19 and H-20); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 170.7 (C6), 167.9 (C-1), 157.5 (C-16), 140.7 (C-11), 140.0 (C-4), 135.1 (C-7), 131.8 (C-22), 129.3 (C-10), 128.4 (C-23), 127.5 (C-9), 126.3 (C-12), 123.5 (C-8), 56.1 (C-23), 47.0 (C-2), 40.1 (C-14), 38.0 (C-18), 34.9 (C-13), 30.9 (C-21), 29.7 (C-24), 28.6 (C-19), 25.1 (C-20); HRMS (ESI+) m/z = 832.2009 [M+H]+ found, C31H31F17N3O4+ required 832.2038.
Fluorous-tagged macrocyclic diene SI-114
Linear urea SI-43 (0.120 g, 0.149 mmol, 1.00 eq) was reacted according to GP11 for 20 h in total. After pre-purification by short flash column chromatography (EtOAc) and purification by preparative HPLC (60-90% B), title compound SI-114 (56 mg, 0.069 mmol, 46%) was isolated as white solid. TLC Rf = 0.26 (neat EtOAc); HPLC tr = 8.31 min (60-100% B), peak area 100%; IR (neat) νmax = 3340 (NH), 1751 ((C=O)O), 1632 ((C=O)N), 1146 (CF); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 6.88 (d, J = 2.6, 1H; H-8), 6.31 (d, J = 2.8, 1H; H-9), 6.02 (d, J = 16.0, 1H; H-20), 5.93 (br s, 1H; H-12), 5.68 (dt, J = 15.8, 7.1, 1H; H-19), 5.57 (br s, 1H; H-14), 5.12 (s, 1H; H-5a), 4.95 (s, 1H; H-5b), 4.43 (s, 2H; H-3), 4.39 (t, J = 5.8, 2H; H-21), 4.25 (s, 2H; H-11), 4.19 (s, 2H, H-2), 3.04 (br s, 2H; H-15), 2.63 (tt, J = 19.2, 5.6, 2H; H-22), 2.06 (dt, J = 6.1, 5.4, 2H; H-18), 1.39 (br s, 4H; H-16 and H-17); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 167.9 (C-1), 159.8 (C-6), 157.4 (C-13), 155.2 (C-10), 145.9 (C-7), 141.5 (C=C), 140.5 (C=C), 131.5 (C=C), 128.8 (C-20), 116.0 (C-8), 107.1 (C-9), 56.0 (C-21), 49.5 (C-3), 46.8 (C-2), 38.6 (C-15), 35.8 (C-11), 31.1 (C18), 29.7 (C-22), 28.3 (C-16), 24.9 (C-17); HRMS (ESI+) m/z = 808.1684 [M+H]+ found, C28H27F17N3O5+ required 808.1674.
Fluorous-tagged macrocyclic diene 7
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
Linear guanidine 5 (115 mg, 0.131 mmol, 1.00 eq) was reacted according to GP11 for 45 h in total, making further catalyst additions after 8 h (0.1 eq), 22 h (0.05 eq) and 31 h (0.1 eq). After pre-purification by short flash column chromatography (CH2Cl2/MeOH/NEt3, 90:10:0.1) and purification by preparative HPLC (60-85% B), title compound 7 (9.4 mg, 0.0095 mmol, 7%) was isolated as a white solid. TLC Rf = 0.46 (CH2Cl2/MeOH, 85:15); HPLC tr = 8.01 min (60-100% B), peak area 97%; IR (neat) νmax = 2944 (CH2), 1751 ((C=O)O), 1678 (C=N), 1640 ((C=O)N), 1199 (CF); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 9.63 (br s, 2H; H-13 and H-22 (NH+)), 8.18 (br s, 1H; H-15), 7.477.42 (m, 3H, 3 x Ar-H), 7.30-7.21 (m, 5H; Ar-H), 7.16 (d, J = 8.0, 1H; H-8), 6.03 (d, J = 16.0, 1H; H-21), 5.73 (dt, J = 16.0, 7.5, 1H; H-20), 5.22 (s, 1H; H-5a), 5.09 (s, 1H; H-5b), 4.45 (t, J = 6.0, 2H; H-27), 4.20 (br s, 2H; H-2 or H-3), 4.05 (br s, 2H; H-2 or H-3), 3.34-3.32 (m, 2H; H-16), 2.67 (tt, J = 19.0, 6.0, 2H; H-28), 2.16 (m, 2H; H-19), 1.57-1.50 (m, 4H; H-17 and H-18); 13C NMR (125 MHz, DMSO-d6, 27 °C) major rotamer signals only δ = 170.3 (C-6), 168.9 (C-1), 157.7 (q, J = 31; TFA C=O), 152.7 (C-16), 140.4 (C-4), 137.7 (C-Ar), 137.4 (C-23), 136.8 (C-Ar), 131.9 (C20), 130.2 (C-21), 130.1 (C-Ar), 129.6 (C-24), 125.8 (C-Ar), 123.0 (C-Ar), 122.9 (C-Ar), 121.6 (C8), 119.9 (C-5), 118.7 (C-12), 117.8 (q, J = 31; TFA CF3), 57.1 (C-27), 47.5 (C-2), 46.4 (C-3), 42.8 (C-16), 32.4 (C-19), 29.4 (C-28), 27.8 (C-17 or C-18), 25.9 (C-17 or C-18); HRMS (ESI+) m/z = 879.2162 [M+H]+ found, C35H32F17N4O3+ required 879.2197.
Fluorous-tagged macrocyclic diene SI-115
Linear guanidine SI-51 (110 mg, 0.108 mmol, 1.00 eq) was reacted according to GP11 for 16 h in total, making a further catalyst addition (0.1 eq) after 8 h. After pre-purification by short flash column chromatography (CH2Cl2/MeOH/NEt3, 90:10:0.1) and purification by preparative HPLC (60-85% B), title compound SI-115 (7.5 mg, 0.0073 mmol, 7%) was isolated as a white solid. TLC Rf = 0.17 (CH2Cl2/MeOH/NEt3, 90:10:0.1); HPLC tr = 8.02 min (60-100% B), peak area 99%; IR (neat) νmax = 1752 ((C=O)O), 1680 (C=N), 1634 ((C=O)N), 1198 (CF); 1H NMR (500 MHz, DMSO-d6, 100 °C) δ = 9.14 (br s, 1H; H-24 (NH+)), 7.56 (t, J = 5.5, 1H; H-17), 7.52 (t, J = 6.0, 1H; H-15), 7.40-7.42 (m, 4H; Ar-H), 7.27-7.21 (m, 3H; Ar-H), 6.90 (d, J = 7.0, 2H; Ar-H), 6.06 (d, J = 16.0, 1H; H-23), 5.81 (br m, 1H; H-22), 5.20 (s, 1H; H-5a), 5.09 (s, 1H; H-5b), 4.41 (t, J = 6.0, 2H; H-29), 4.28 (br s, 2H; H-2), 4.02 (br s, 2H; H-3), 3.62 (dt, J = 6.5, 6.0, 2H; H-14), 3.25 (dt, J = 6.5, 6.0, 2H; H-18), 2.99-2.94 (m, 2H; H-13, coincides with water signal), 2.66 (tt, J = 19.5, 6.0, 2H; H-30), 2.13 (dd, J = 6.5, 2H; H-21), 1.54-1.40 (m, 4H; H-19 and H-20); 13C NMR (125 MHz, DMSO-d6, 27 °C) major rotamer signals only δ = 170.7 (C-6), 168.5 (C-1), 157.7 (q, J = 31.0; TFA C=O), 153.3 (C-16), 140.9 (C-4), 140.2 (C-Ar), 139.1 (C-11), 136.1 (C-Ar), 132.0 (C-22), 130.8 (C-Ar), 129.5 (C-23), 129.4, 129.0, 128.4, 126.9, 125.5, 125.1, 124.5 (each C-Ar), 119.6 (C-5), 117.9 (TFA CF3), 57.0 (C-29), 48.2 (C-3), 46.4 (C-2), 42.0 (C-14), 41.2 (C-18), 33.1 84 84
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DOI: 10.1038/NCHEM.1729
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(C-13), 32.2 (C-21), 29.3 (C-30), 26.7 (C-19 or C-20), 25.6 (C-19 or C-20); HRMS (ESI+) m/z = 907.2516 [M+H]+ found, C37H36F17N4O3+ required 907.2510
Diels-Alder Reaction Fluorous-tagged macrocyclic Diels-Alder product 36
A microwave vial was charged with diene 35 (100 mg, 0.120 mmol, 1.00 eq), dry dioxane (7 mL) and N-Methyl maleimide (53 mg, 0.48 mmol, 4.0 eq) was added. The vial was flushed with argon and the mixture was stirred in the microwave at 45 °C for 36 h. The solvent was removed under reduced pressure to give a beige crude solid. After purification by flash column chromatography (CH2Cl2/MeOH, 95:5) the title compound 36 (47 mg, 0.050 mmol, 41%) was isolated as an offwhite solid. TLC Rf = 0.25 (CH2Cl2/MeOH 19:1); HPLC tr = 6.66 min (60-100% B), peak area 95%; [α]D27.7 +4.0° (c = 0.117, CHCl3); IR (neat) νmax = 2931 (CH3), 1757 ((C=O)O), 1700 (N(C=O)2), 1623 ((C=O)N), 1198 (CF); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.35-7.28 (m, 2H; H-9 and H10), 7.18 (d, J = 7.5, 1H; H-8), 7.15 (s, 1H; H-12), 5.58 (br s, 1H; H-15 or H-17), 5.54 (m, 1H; H5), 5.44 (br s, 1H; H-15 or H-17), 4.41 (t, J = 6.0, 2H; H-29), 4.14 (d, J = 17.5, 2H: H-2a and H3a), 3.72 (d, J = 17.5, 1H; H-2b or H-3b), 3.70 (d, J = 17.5, 1H; H-2b or H-3b), 3.33 (m, 1H; H14a), 3.24-3.18 (m, 2H; H-14b and H-27), 3.12-3.08 (m, 2H; H-23 and H-18a), 3.02 (m, 1H; H18b), 2.78 (s, 3H; H-25), 2.77-2.68 (m, 2H; H-13), 2.65 (tt, J = 19.5, 6.0, 2H; H-30), 2.33-2.29 (m, 2H; H-22 and H-28a), 2.18 (dd, J = 15.0, 7.0, 1H; H-28b), 1.71-1.66 (m, 2H; H-21), 1.60-1.45 (m, 2H; H-19a and H-20a), 1.42-1.29 (m, 2H; H-19b and H-20b); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 178.6 (C-24 or C-26), 176.8 (C-24 or C-26), 170.4 (C-6), 167.8 (C-1), 157.5 (C-16), 140.1 (C-11), 134.6 (C-7), 133.8 (C-4), 129.6 (C-10), 127.8 (C-9), 126.0 (C-12), 123.9 (C-5 or C8), 123.8 (C-5 or C-8), 56.1 (C-29), 43.5 (C-23), 40.5 (C-14), 40.2 (C-27), 38.0 (C-18), 35.6 (C13 or C-22), 35.2 (C-13 or C-22), 29.9 (C-21), 29.6 (C-30), 28.9 (C-20), 25.5 (C-28), 24.2 (C-25), 23.2 (C-19); HRMS (ESI+) m/z = 943.2332 [M+H]+ found, C36H36F17N4O6+ required 943.2358.
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Transesterifications Macrocyclic urea SI-116
EtOH (43 µL, 0.74 mmol, 16 eq) was added to dry THF (2 mL) and n-BuLi (1.45M in hexanes; 250 µL, 0.360 mmol, 8.0 eq) was added at 0 °C. After stirring for 10 min, the fluorous-tagged macrocycle SI-68 (40 mg, 0.045 mmol, 1.0 eq) was added in dry THF (1 mL). After stirring for 45 min, the reaction mixture was neutralized by the stepwise addition of acidic ion exchange resin (DOWEX 50WX8), filtered and the solvent was removed under reduced pressure. After purification preparative HPLC (10-40% B), title compound SI-116 (8 mg, 0.017 mmol, 38%) was isolated as a white solid. HPLC tr = 8.30 min (5-30% B), peak area 100%; 1H NMR (400 MHz, DMSO-d6, 27 °C) δ = 8.71 (s, 1H; H-13), 8.12-8.06 (m, 2H; H-22 and H-5), 7.91 (br s, 1H; H-12), 7.32 (t, J = 7.8, 1H; H-9), 7.00 (d, J = 7.8, 1H; H-8 or H-10), 6.81 (m, 1H, H-8 or H-10), 6.34 (d, 1H; H-15), 4.51-4.23 (m, 6H; H-16, H-20, CH2 and CHaHb), 4.19-4.10 (m, 2H; H-24), 4.00 (d, J = 17.1, 1H; CHaHb), 2.60 (d, 3H, J = 4.6; H-23); 2.41-2.25 (m, 1H; H-19a); 1.73-1.59 (m, 2H; H-17a and H-19b), 1.50-1.36 (m, 1H; H-17b), 1.32-1.04 (m, 5H; H-16 and H-25); 13C NMR (100 MHz, DMSO-d6, 27 °C) δ = 172.3, 171.8, 168.9, 154.5 (each C=O), 143.7, 139.6, 135.2 (each quat. C), 129.4 (C-9), 122.3 (C-5), 119.9 (C-8 or C-10), 119.4 (C-8 or C-10), 116.0 (C-12), 60.6 (C-24), 50.5 (C-16), 50.2, 47.6, 46.9 (each C-2, C-3 or C-20), 34.9 (C-17), 28.3 (C-19), 25.5 (C-23), 22.5 (C-18), 14.1 (C25); HRMS (ESI+) m/z = 472.2313 [M+H]+ found, C22H30N7O5+ required 472.2303.
Macrocyclic urea SI-117
Fluorous-tagged macrocycle SI-69 (19 mg, 0.021 mmol, 1.0 eq) was suspended in dry EtOAc (2 mL) and EtONa in EtOH (2.68M; 8 µL, 0.021 mmol, 1.0 eq) was added. After stirring for 30 min, the reaction mixture was neutralized by the addition of AcOH and subsequently the solvent was removed in a stream of nitrogen. After purification by preparative HPLC (5-30% B), title compound SI-117 (6 mg, 0.013 mmol, 61%) was isolated as a white solid.
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DOI: 10.1038/NCHEM.1729
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HPLC tr = 7.46 min (5-60% B), peak area 98%; 1H NMR (500 MHz, DMSO-d6, 100 °C) δ = 8.19 (br s, 1H; H-13), 7.68 (s, 1H; H-5), 7.52 (br s, 1H; H-22), 7.42-7.38 (m, 2H; H-9 and H-12), 7.17 (d, J = 7.6, 1H; H-8 or H-10), 7.12 (d, J = 7.9, 1H; H-8 or H-10), 6.09 (br s, 1H; H-15), 4.80 (s, 2H, H-2 or H-3), 4.19-4.01 (m, 7H; H-16, H-20, H-24 and H-2 or H-3), 2.61 (d, J = 4.5, 3H; H-23), 1.92 (m, 1H; H-19a), 1.81-1.71 (m, 2H; H-17a and H-19b), 1.54 (m, 1H; H-17b), 1.29-1.18 (m, 5H; H-18 and H-25); HRMS (ESI+) m/z = 472.2318 [M+H]+ found, C22H30N7O5+ required 472.2303.
Macrocyclic urea SI-118
Title compound SI-118 (2 mg, 0.0045 mmol, 21%) was isolated as a side product of the transesterification of SI-69 described above. HPLC tr = 5.23 min (5-60% B), peak area 99%; 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 8.09 (s, 1H; H-13), 7.65 (s, 1H; H-5), 7.46-7.36 (m, 3H; H-9, H-12 and H-22), 7.18 (d, J = 7.7, 1H; H-8 or H-10), 7.11 (d, J = 7.9, 1H; H-8 or H-10), 6.02 (d, J = 8.6, 1H; H-15), 4.84 (d, J = 16.3, 1H; CHaHb), 4.77 (d, J = 16.3, 1H; CHaHb), 4.17 (t, J = 6.9, 2H; H-20), 4.11 (m, 1H; H-16), 4.03-3.90 (m, 2H; CH2), 2.62 (d, J = 4.6, 3H; H-23), 1.92 (m, 1H; H-19a), 1.83-1.73 (m, 2H; H-17a, H-19b), 1.56 (m, 1H; H-17b), 1.32-1.21 (m, 2H; H-18); HRMS (ESI+) m/z = 444.2003 [M+H]+ found, C20H26N7O5+ required 444.1990.
Macrocyclic urea SI-119
Fluorous-tagged macrocycle SI-70 (23 mg, 0.025 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 15:1), title compound SI-119 (5.3 mg, 0.011 mmol, 44%) was isolated as a white foam. TLC Rf = 0.47 (CH2Cl2/MeOH 10:1); HPLC tr = 6.27 min (10-40% B), peak area 100%; [α]D27.3 = +7.9 (c = 0.457 in MeOH/CHCl3 2:1); IR (neat) νmax = 2933 (w), 1743 (m, C=O), 1631 (s, C=O), 1610 (s, C=O), 1512 (m), 1132 (s); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.14 (s, 1H; H-11), 7.34 (s, 1H; H-5), 7.15-7.13 (m, 2H; H-9), 7.10-7.07 (m, 2H; H-8), 5.87 (d, J = 7.9, 1H; H-13), 4.59 (dt, J = 7.4, 4.2, 1H; H-14), 4.50 (s, 2H; H-3), 4.49 (d, J = 17.0, 1H; H-2a), 4.43 (d, J = 17.0, 1H; H-2b), 4.26 (ddd, J = 13.9, 6.4, 5.2, 1H; H-18a), 4.18 (ddd, J = 13.8, 8.6, 4.9, 1H; H-18b), 3.74 (s, 3H; H-22), 3.00 (s; H-20 and H-21, coincides with water signal), 1.79-1.69 (m, 2H; H87 87
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DOI: 10.1038/NCHEM.1729
17), 1.68-1,59 (m, 2H; H-15), 1.20-1.14 (m, 1H; H-16a), 1.14-1.05 (m, 1H; H-16b); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.2 (C-6 or C-19), 171.2 (C-19 or C-6), 169.2 (C-1), 155.2 (C-12), 142.9 (C-4), 140.8 (C-7), 130.8 (C-10), 126.7 (C-8), 121.4 (C-9), 121.2 (C-5), 51.2 (C-22), 49.4 (C-2), 49.2 (C-14), 48.4 (C-18), 45.4 (C-3), 35.5 (br, C-20 and C-21), 29.5 (C-15), 27.9 (C-17), 20.8 (C-16); HRMS (ESI+) m/z = 472.2299 [M+H]+ found, C22H30N7O5+ required 472.2303, 494.2119 [M+Na]+ found, C22H29N7O5Na+ required 494.2122.
Macrocyclic urea 46
Fluorous-tagged macrocycle SI-71 (33 mg, 0.037 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 15:1), title compound 46 (11 mg, 0.023 mmol, 62%) was isolated as a white foam. TLC Rf = 0.49 (CH2Cl2/MeOH 10:1); HPLC tr = 6.38 min (10-40% B), peak area 100%; [α]D27.3 = +41.5 (c = 0.651 in MeOH/CHCl3 2:1); IR (neat) νmax = 2936 (w), 1744 (m, C=O), 1638 (s, C=O), 1609 (s, C=O), 1132 (s), 877 (s); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.09 (s, 1H; H-11), 7.75 (s, 1H; H-5), 7.29-7.27 (m, 2H; H-8), 7.23-7.21 (m, 2H; H-9), 5.19 (d, J = 8.6, 1H; H-13), 4.57 (dt, J = 8.5, 5.1, 1H; H-14), 4.50 (d, J = 18.1, 1H; H-3a), 4.45 (d, J = 18.0, 1H; H-3b), 4.43 (d, J = 17.1, 1H; H-2a), 4.22 (d, J = 17.1, 1H; H-2b), 3.96 (dt, J = 13.4, 6.5, 1H; H-18a), 3.87 (dt, J = 14.1, 7.0, 1H; H-18b), 3.73 (s, 3H; H-22), 2.93 (s; H-20 and H-21, coincides with water signal), 1.64-1.48 (m, 4H; H-17, H-15), 1.06-0.97 (m, 1H; H-16a), 0.94-0.85 (m, 1H; H-16b); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.1 (C-19), 170.7 (C-6), 168.7 (C-1), 155.9 (C-12), 140.6 (C-10), 134.4 (C-4), 131.6 (C-7), 131.1 (C-5), 126.6 (C-8), 125.5 (C-9), 51.3 (C-22), 48.7 (C-14), 47.6 (C-2), 47.1 (C-18), 44.8 (C-3), 35.6 (br, C-20 and C-21), 29.7 (C-15 or C-17), 29.0 (C-15 or C-17), 20.5 (C-16); HRMS (ESI+) m/z = 472.2316 [M+H]+ found, C22H30N7O5+ required 472.2303.
Macrocyclic urea SI-120 N 4
O
25
O
1
3 2
O
N 6 7
N
19
20
18
16
O
12
8
HN 15 14
11 9
21
N 5
17
NH O
23 22
N 24
13
10
SI-120
Fluorous-tagged macrocycle SI-72 (32 mg, 0.035 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-120 (9.6 mg, 0.020 mmol, 57%) was isolated as a yellow oil. 88 88
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DOI: 10.1038/NCHEM.1729
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TLC Rf = 0.45 (CH2Cl2/MeOH 10:1); HPLC tr = 7.38 min (10-40% B), peak area 96%; [α]D20 = 15.1 (c = 0.41 in MeOH); IR (neat) νmax = 2947 (w, C-H), 1747 (m, C(=O)OR), 1619 (s, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.78 (s, 1H; H-5), 7.40 (t, J = 7.6, 1H; H9), 7.30 (d, J = 7.7, 1H; H-8 or H-10), 7.27 (d, J = 7.6, 1H; H-8 or H-10), 7.20 (s, 1H; H-12), 6.40 (d, J = 7.6, 1H; H-14), 5.90 (d, J = 8.7, 1H; H-16), 4.75 – 4.31 (m, 4H; H-13a, H-3a, and H-17), 4.54 (d, J = 15.8, 1H; H-3b), 4.49 – 4.32 (m, 2H; H-21), 4.29 – 4.08 (m, 2H; H-2), 3.87 (dd, J = 15.9, 3.1, 1H; H-13b), 3.68 (s, 3H; H-25), 2.96 (s, 6H; H-23, H-24), 2.04 – 1.77 (m, 2H; H-20), 1.70 – 1.60 (m, 1H; H-18a), 1.50 – 1.40 (m, 1H; H-18b), 1.37 – 1.21 (m, 2H; H-19); 13C NMR (125 MHz, DMSO-d6, 90°C) δ = 172.0 (C=O), 170.6 (C=O), 168.7 (C=O), 157.1 (C-15), 142.5 (C-4), 141.7 (C-5), 141.0 (C-11 or C-7), 135.4 (C-7 or C-11), 128.0 (C-8 or C-10), 123.3 (C-12), 123.0 (C-9), 51.3 (C-25), 49.0 (C-17), 48.2 (C-21), 31.6 (C-20), 28.4 (C-18), 21.3 (C-19); HRMS (ESI+) m/z = 486.2471 [M+H]+ found, C23H32N7O5+ required 486.2465.
Macrocyclic urea SI-121
Fluorous-tagged macrocycle SI-73 (32 mg, 0.035 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-121 (11 mg, 0.022 mmol, 64%) was isolated as a pale yellow oil. TLC Rf = 0.45 (CH2Cl2/MeOH 10:1); HPLC tr = 7.58 min (10-40% B), peak area 100%; [α]D20 = 11.5 (c = 1 in MeOH); IR (neat) νmax = 3399 (br m, N-H), 1747 (w, C(=O)OR), 1634 (s, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.66 (s, 1H; H-5), 7.40 – 7.29 (m, 2H; H12 and H-9), 7.33 (d, J = 7.5, 1H; H-8), 7.26 (d, J = 7.4, 1H; H-10), 6.53 (t, J = 6.1, 1H; H-14), 5.98 (d, J = 8.7, 1H; H-16), 4.92 (d, J = 165.9, 1H; H-3a), 4.73 (d, J = 15.7, 1H; H-3b), 4.68 (td, J = 9.2, 3.6, 2H; H-17), 4.56 (dd, J = 15.7, 8.2, 2H; H-13a), 4.13 (t, J = 4.5, 2H; H-2), 4.00 (s, 2H; H-21), 3.91 (dd, J = 15.8, 4.5, 1H; H-13b), 3.63 (s, 3H; H-25), 2.94 (s, 6H; H-23 and H-24), 2.01 – 1.87 (m, 1H; H-20a), 1.88 – 1.78 (m, 1H; H-20b), 1.71 – 1.57 (m, 1H; H-18a), 1.53 – 1.40 (m, 1H; H-18b), 1.34 – 1.17 (m, 2H; H-19); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 172.5 (C=O), 171.8 (C=O), 169.3 (C=O), 158.1 (C-15), 142.5 (C-11 or C-7), 135.5 (C-7 or C-11), 134.7 (C-4 and C-5), 132.6 (C-8 or C-10), 129.2 (C-9), 128.8 (C-12), 125.4 (C-8 or C-10), 52.3 (C-25), 49.0 (C-17), 48.3 (C-21), 43.3 (C-13), 32.7 (C-20), 29.2 (C-18), 22.6 (C-19); HRMS (ESI+) m/z = 486.2458 [M+H]+ found, C23H32N7O5+ required 486.2465.
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DOI: 10.1038/NCHEM.1729
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Macrocyclic urea SI-122
Fluorous-tagged macrocycle SI-74 (60 mg, 0.065 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-122 (15 mg, 0.030 mmol, 47%) was isolated as a yellow oil. TLC Rf = 0.56 (CH2Cl2/MeOH 10:1); HPLC tr = 8.40 min (10-40% B), peak area 100%; [α]D20 = 18.3 (c = 0.54 in MeOH); IR (neat) νmax = 3389 (br, m, N-H), 1743 (w, C(=O)OR), 1635 (m, C(=O)NR2); HRMS (ESI+) m/z = 500.2612 [M+H]+ found, C24H34N7O5+ required 500.2616.
Macrocyclic urea SI-123
Fluorous-tagged macrocycle SI-75 (33 mg, 0.035 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-123 (8.2 mg, 0.016 mmol, 47%) was isolated as a yellow oil. TLC Rf = 0.60 (CH2Cl2/MeOH 10:1); HPLC tr = 8.47 min (10-40% B), peak area 97%; [α]D20 = 28.7 (c = 0.81 in MeOH); IR (neat) νmax = 3363 (br, w, N-H), 2927 (w, C-H), 1744 (m, C(=O)OR), 1627 (s, C(=O)NR2); HRMS (ESI+) m/z = 500.2606 [M+H]+ found, C24H34N7O5+ required 500.2616.
Macrocyclic urea 8
Fluorous-tagged macrocycle 6 (40 mg, 0.044 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 15:1), title compound 8 (21 mg, 0.044 mmol, quant.) was isolated as a white foam. 90 90
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DOI: 10.1038/NCHEM.1729
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TLC Rf = 0.37 (CH2Cl2/MeOH 10:1); HPLC tr = 6.49 min (10-40% B), peak area 100%; [α]D27.2 = 15.5 (c = 0.652 in MeOH/CHCl3 2:1); IR (neat) νmax = 1745 (w, C=O), 1619 (s, C=O), 1541 (m), 1433 (m), 1403 (m), 1210 (m), 750 (m); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.74 (s, 1H; H5), 7.03 (d, J = 3.3, 1H; H-8), 6.47 (dd, J = 8.1, 3.2, 1H; H-12), 6.44 (d, J = 3.4, 1H; H-9), 5.99 (d, J = 8.6, 1H; H-14), 4.92 (d, J = 16.0, 1H; H-3a), 4.91 (d, J = 16.0, 1H; H-3b) 4.76-4.60 (m, 2H; H15, H-11a), 4.44-4.31 (m, 2H; H-19), 4.27 (d, J = 17.0, 1H; H-2a), 4.20 (d, J = 17.1, 1H; H-2b), 3.98 (dd, J = 15.6, 3.2, 1H; H-11b), 3.66 (s, 3H; H-23), 2.94 (br s; H-21 and H-22, coincides with water signal), 2.04-1.92 (m, 1H; H-18a), 1.86-1.72 (m, 1H; H-18b), 1.67-1.61 (m, 1H; H-16a), 1.44-1.37 (m, 1H; H-16b), 1.33-1.10 (m, 2H; H-17); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.6 (C-20), 168.6 (C-1), 158.7 (C-6), 156.6 (C-13), 154.9 (C-10), 146.5 (C-7), 142.8 (C-4), 122.1 (C-5), 117.6 (C-8), 108.5 (C-9), 51.1 (C-23), 48.6 (C-19), 47.9 (C-15), 47.7 (C-2), 43.6 (C3), 36.0 (C-11), 30.7 (C-16), 27.5 (C-18), 20.6 (C-17); HRMS (ESI+) m/z = 476.2240 [M+H]+ found, C21H30N7O6+ required 476.2252, 498.2062 [M+Na]+ found, C21H29N7O6Na+ required 498.2072.
Macrocyclic urea SI-124
Fluorous-tagged macrocycle SI-76 (20 mg, 0.022 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 15:1), title compound SI-124 (8.7 mg, 0.018 mmol, 82%) was isolated as a white foam. TLC Rf = 0.54 (CH2Cl2/MeOH 10:1); HPLC tr = 6.13 min (10-40% B), peak area 99%; [α]D27.2 = 35 (c = 0.128 in MeOH/CHCl3 2:1); IR (neat) νmax = 3345 (w), 2925 (w), 2160 (w), 1759 (m, C=O), 1744 (m, C=O), 1628 (s, C=O), 1604 (s, C=O), 1539 (s), 1407 (m), 1211 (m), 1016 (m), 823 (m); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.53 (s, 1H; H-5), 7.08 (s, 1H; H-8), 6.41 (d, J = 3.4, 1H; H-9), 6.39 (br s, 1H; H-12), 5.95 (d, J = 9.0, 1H; H-14), 5.21 (br s, 1H; H-3a), 5.01 (d, J = 16.0, 1H; H-3b), 4.63 (dt, J = 9.6, 3.4, 1H; H-15), 4.54 (dd, J = 15.7, 8.1, 1H; H-11a), 4.294.23 (m, 1H; H-19a), 4.18-4.12 (m, 2H; H-19b, H-2a), 4.06 (d, J = 16.3, 1H; H-2b), 3.94 (dd, J = 15.8, 4.0, 1H; H-11b), 3.61 (d, J = 0.9, 3H; H-23), 2.91 (s; H-21 and H-22, coincides with water signal), 1.92-1.85 (m, 1H; H-18a), 1.83-1.71 (m, 1H; H-18b), 1.61-1.55 (m, 1H; H-16a), 1.44-1.33 (m, 1H; H-16b), 1.24-1.06 (m, 2H; H-17); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.5 (C20), 168.5 (C-1), 156.9 (C-13), 156.1 (C-10), 145.6 (C-7), 133.0 (C-5), 132.4 (C-4), 118.1 (C-8), 107.9 (C-9), 51.2 (C-23), 47.8 (C-15), 47.5 (C-2), 47.4 (C-19), 36.0 (C-11), 31.6 (C-16), 28.5 (C18), 21.6 (C-17); HRMS (ESI+) m/z = 476.2253 [M+H]+ found, C21H30N7O6+ required 476.2252, 498.2073 [M+Na]+ found, C21H29N7O6Na+ required 498.2072.
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DOI: 10.1038/NCHEM.1729
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Macrocyclic urea 42
Fluorous-tagged macrocyclic urea SI-77 (19 mg, 0.018 mmol, 1.0 eq) was dissolved in DMSO (6 mL) and the solution was stirred at 120 °C for 4 h.[14] The solvent was removed under reduced pressure and the residue was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 19:1-9:1), title compound 42 (9 mg, 0.018 mmol, 97% over 2 steps) was isolated as a colorless solid. TLC Rf = 0.29 (CH2Cl2/MeOH 9:1); mp 190 °C decomposition; HPLC tr = 6.73 min (10-60% B), peak area 98%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 11.29 (br s, 1H; NHInd), 8.31 (s, 1H; H15), 8.09 (s, 1H; H-5), 7.79 (br s, 1H; H-13), 7.62 (d, J = 2.8, 1H; H-8), 7.33 (d, J = 8.6, 1H; H10), 6.69 (dd, J = 8.6, 2.0, 1H; H-11), 6.13 (d, J = 8.5, 1H; H-17), 4.96 (d, J = 15.8, 1H; H-3a), 4.79-4.75 (m, 1H; H-18), 4.54 (d, J = 15.8, 1H; H-3b), 4.47-4.37 (m, 2H; H-22), 4.26 (d, J = 17.1, 1H; H-2a), 3.98 (d, J = 17.1, 1H; H-2b), 3.66 (s, 3H; H-26), 2.96 (br s, 6H; H-24 and H-25), 2.382.30 (m, 1H; H-21a), 1.85-1.77 (m, 1H; H-21b), 1.72-1.66 (m, 1H; H-19a), 1.55-1.48 (m, 1H; H19b), 1.43-1.37 (m, 2H; H-20); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.4 (C-23), 169.1 (C-1), 167.4 (C-6), 154.7 (C-16), 142.7 (C-4), 132.6 (C-12), 131.2 (C-9), 128.8 (C-8), 124.0 (C14), 122.2 (C-5), 115.4 (C-11), 111.6 (C-10), 110.0 (C-7), 109.6 (C-13), 50.9 (C-26), 49.6 (C-22), 47.0 (2C; C-18, C-2), 43.4 (C-3), 33.1 (C-19), 27.6 (C-21), 21.9 (C-20); HRMS (ESI+) m/z = 511.2438 [M+H]+ found, C24H31N8O5+ required 511.2417.
Macrocyclic urea SI-125
The crude SI-78 was taken up in DMSO (10 mL) and the resulting solution was stirred at 120 °C overnight.[14] The solvent was removed in vacuo and the residue was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 19:1-4:1), title compound SI-125 (13 mg, 0.026 mmol, 28% over 3 steps) was isolated as a yellow gum. TLC Rf = 0.27 (CH2Cl2/MeOH 9:1); HPLC tr = 6.39 min (5-50% B), peak area 94%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 11.37 (br s, 1H; NHInd), 7.96 (s, 1H; H-15), 7.70 (2 × s, 2 × 1H; H-13 and H-5), 7.57 (d, J = 2.8, 1H; H-8), 7.41 (d, J = 8.5, 1H; H-10), 6.89 (dd, J = 8.5, 2.1, 1H; H-11), 5.56 (d, J = 8.6, 1H; H-17), 5.23 (d, J = 15.5, 1H; H-3a), 4.70-4.66 (m, 1H; H-18), 4.63 (d, J = 15.5, 1H; H-3b), 4.52-4.47 (m, 1H; H-22a), 4.26-4.22 (m, 2H; H-22b and H-2a), 4.10 (d, J = 18.1, 92 92
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DOI: 10.1038/NCHEM.1729
1H; H-2b), 3.64 (s, 3H; H-26), 2.92 (br s, 6H; H-24 and H-25), 2.08-2.01 (m, 1H; H-21a), 1.941.88 (m, 1H; H-21b), 1.74-1.69 (m, 1H; H-19a), 1.53-1.43 (m, 3H; H-19b and H20); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.3 (C-23), 169.1 (C-1), 166.6 (C-6), 155.4 (C-16), 134.2 (C5), 132.4 (C-9), 132.1 (C-12), 131.7 (C-4), 127.4 (C-8), 126.0 (C-14), 118.6 (C-11), 114.2 (C-13), 111.9 (C-10), 108.6 (C-7), 51.3 (C-26), 48.5 (C-18), 48.2 (C-2), 47.2 (C-22), 37.3 (C-3), 30.8 (C19), 28.2 (C-21), 22.1 (C-20); HRMS (ESI+) m/z = 511.2424 [M+H]+ found, C24H31N8O5+ required 511.2417.
Macrocyclic hydantoin SI-126
Fluorous-tagged macrocycle SI-86 (41 mg, 0.048 mmol, 1.0 eq) was suspended in dry THF (4 mL) and EtONa in EtOH (2.68M; 18 µL, 0.048 mmol, 1.0 eq) was added. After stirring for 30 min, the reaction mixture was neutralized by the addition of AcOH and subsequently the solvent was removed in a stream of nitrogen. After purification by preparative HPLC (5-30% B), title compound SI-126 (7 mg, 0.016 mmol, 33%) was isolated as a white solid. HPLC tr = 8.34 min (5-60% B), peak area 99%; 1H NMR (500 MHz, DMSO-d6, 27 °C) δ = 8.44 (s, 1H; H-15), 7.94 (s, 1H; H-5), 7.63 (t, J = 7.8, 1H; H-9), 7.52 (dt, J = 7.8, 1.4, 1H; H-8 or H-10), 7.44 (m, 1H; H-8 or H-10), 6.78 (s, 1H; H-12), 4.52-4.28 (m, 6H; H-2, H-3, H-15 and H-20), 4.16 (q, J = 7.1, 2H; H-21), 1.88-1.64 (m, 4H; H-17 and H-19), 1.31-1.19 (m, 4H; H-18a and H-22), 0.38-0.22 (m, 1H; H-18b); 13C NMR (125 MHz, DMSO-d6, 27 °C) δ = 173.6, 170.3, 168.9, 155.3 (each C=O), 143.6, 135.9, 131.3 (quat. C), 130.1 (C-9), 129.0 (C-8 or C-10), 127.2 (C-8 or C10), 123.6 (C-12), 123.2 (C-5), 60.6 (C-21), 56.0 (C-15), 49.2, 48.8, 46.0 (each CH2), 29.4 (C-17 or C-19), 29.2 (C-17 or C-19), 18.7 (C-18), 14.1 (C-22); HRMS (ESI+) m/z = 441.1882 [M+H]+ found, C21H25N6O5+ required 441.1881.
Macrocyclic hydantoin SI-127
Title compound SI-127 (9 mg, 0.022 mmol, 45%) was isolated as a side product of the transesterification of SI-86 described above.
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DOI: 10.1038/NCHEM.1729
HPLC tr = 5.87 min (5-60% B), peak area 100%; 1H NMR (500 MHz, DMSO-d6, 27 °C) δ = 12.77 (br s, 1H; H-21), 8.44 (s, 1H; H-14), 7.95 (s, 1H; H-5), 7.62 (t, J = 7.8, 1H; H-9), 7.52 (dt, J = 7.8, 1.4, 1H; H-8 or H-10), 7.42 (m, 1H; H-8 or H-10), 6.77 (s, 1H; H-12), 4.53-4.26 (m, 7H; H-2, H-3, H-15 and H-20), 1.88-1.64 (m, 4H; H-17 and H-19), 1.30-1.17 (m, 1H; H-18a), 0.36-0.21 (m, 1H; H-18b); 13C NMR (125 MHz, DMSO-d6, 27 °C) δ = 173.6, 170.3 (2x), 155.3 (each C=O), 143.7, 136.0, 131.2 (quat C.), 130.0 (C-9), 129.0 (C-8 or C-10), 127.2 (C-8 or C-10), 123.6 (H-12), 123.2 (C-5), 56.1 (C-15), 49.2, 48.7, 45.9 (each CH2), 29.4 (C-17 or C-19), 29.2 (C-17 or C-19), 18.7 (C-18); HRMS (ESI+) m/z = 413.1562 [M+H]+ found, C19H21N6O5+ required 413.1568.
Macrocyclic hydantoin SI-128
The crude product of fluorous-tagged macrocycle SI-87 mixed with SI-86 (~ 0.055 mmol, 1.0 eq) was suspended in dry EtOAc (2 mL) and EtONa in EtOH (2.68M; 20 µL, 0.055 mmol, 1.0 eq) was added. After stirring for 1 h, the reaction mixture was neutralized by the addition of AcOH and subsequently the solvent was removed in a stream of nitrogen. After purification by preparative HPLC (15-22% B), title compound SI-128 (6 mg, 0.014 mmol, 25% over two steps) was isolated as a white solid. HPLC tr = 8.72 min (5-60% B), peak area 99%; 1H NMR (500 MHz, DMSO-d6, 27 °C) δ = 8.42 (s, 1H; H-14), 7.88 (s, 1H; H-5), 7.69-7.64 (m, 2H; H-9 and H-8 or H-10), 7.54-7.49 (m, 1H; H-8 or H-10), 6.81-6.79 (m, 1H; H-12), 4.81 (d, J = 18.3, 1H; H-3a), 4.57 (d, J = 18.3, 1H; H-3b), 4.56 (d, J = 16.9, 1H; H-2a), 4.33 (t, J = 3.8, 1H; H-15), 4.26-4.09 (m, 4H; H-20 and H-21), 3.95 (d, J = 17.0, 1H; H-2b), 1.86-1.75 (m, 2H; H-17), 1.66-1.55 (m, 1H; H-19a), 1.29-1.17 (m, 4H; H-19b and H-22), 1.14-1.05 (m, 1H; H-18a), 1.04-0.94 (m, 1H; H-18b); 13C NMR (125 MHz, DMSO-d6, 27 °C) δ = 173.9, 168.7 (2x), 155.3 (each C=O), 135.3 (quat. C), 133.3 (quat. C), 131.9 (C-5), 131.1 (quat. C), 130.2 (C-Ar), 129.8 (C-8 or C-10), 128.8 (C-Ar), 123.6 (C-12), 60.6 (C-21), 55.5 (C-15), 49.3 (C-2), 47.6 (C-20), 46.6 (C-3), 30.3 (C-17), 29.4 (C-19), 19.3 (C-18), 14.1 (C-22); HRMS (ESI+) m/z = 441.1877[M+H]+ found, C21H25N6O5+ required 441.1881.
Macrocyclic hydantoin SI-129
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DOI: 10.1038/NCHEM.1729
Fluorous-tagged macrocycle SI-88 (70 mg, 0.080 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-129 (18 mg, 0.040 mmol, 50%) was isolated as a yellow oil. TLC Rf = 0.59 (CH2Cl2/MeOH 10:1); HPLC tr = 7.65 min (10-40% B), peak area 99%; [α]D20 = +32.1 (c = 1 in MeOH); IR (neat) νmax = 3431 (br, m, N-H), 2920 (w, C-H), 1708 (s, C(=O)OR), 1638 (m, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.74 (s, 1H; H-15), 7.67 (s, 1H; H-5), 7.45-7.39 (m, 2H; H-10/H-8 and H-9), 7.37-7.32 (m, 1H; H-8/H-10), 6.91 (s, 1H; H-12), 4.70 (d, J = 17.4, 1H; H-3a), 4.64-4.55 (m, 2H; H-3b and H-13a), 4.47 (d, J = 15.6, 1H; H-13b), 4.44-4.35 (m, 1H; H-21a), 4.35-4.27 (m, 1H; H-21b), 4.25 (d, J = 17.2, 1H; H-2a), 4.15 (d, J = 17.2, 1H; H-2b), 4.11 (t, J = 4.8, 1H; H-16), 3.69 (s, 3H; H-22), 1.88-1.76 (m, 2H; H-20), 1.671.58 (m, 2H; H-18), 1.33-1.21 (m, 1H; H-19a), 0.92-0.80 (m, 1H; H-19b); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 174.2 (C=O), 171.3 (C=O), 169.6 (C=O), 157.0 (C=O), 143.8 (quat. C), 137.9 (quat. C), 136.7 (quat. C), 129.7 (C-9), 128.8 (C-8 or C-10), 125.6 (C-8 or C-10), 124.5 (C12), 123.2 (C-5), 56.9 (C-16), 52.1 (C-22), 49.9 (C-21), 49.5 (C-2), 44.9 (C-3), 41.6 (C-13), 30.1 (C-18), 29.4 (C-20), 20.2 (C-19); HRMS (ESI+) m/z = 441.1908 [M+H]+ found, C21H25N6O5+ required 441.1881.
Macrocyclic hydantoin SI-130
Fluorous-tagged macrocycle SI-89 (60 mg, 0.069 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-130 (18 mg, 0.040 mmol, 50%) was isolated as a yellow oil. TLC Rf = 0.55 (CH2Cl2/MeOH 10:1); HPLC tr = 8.10 min (10-40% B), peak area 100%; [α]D20 = +7.5 (c = 0.83 in MeOH); IR (neat) νmax = 3422 (br, w, N-H), 2928 (w, C-H), 1753 (w, C(=O)OR), 1707 (s, hydantoin C=O), 1646 (m, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.76 (s, 1H; H-15), 7.64 (s, 1H; H-5), 7.49 (d, J = 7.8, 1H; H-8 or H-10), 7.44 (t, J = 7.5, 1H; H-9), 7.33 (d, J = 7.6, 1H; H-8 or H-10), 7.04 (s, 1H; H-12), 4.88 (d, J = 16.4, 1H; H-3a), 4.63-4.54 (m, 3H; H-3b and H-13), 4.18 (t, J = 4.0, 1H; H-16), 4.16-3.95 (m, 4H; H-2 and H-21), 3.63 (s, 3H; H-22), 1.97-1.74 (m, 3H; H-20 and H-18a), 1.74-1.64 (m, 1H; H-18b), 1.23-1.10 (m, 1H; H-19a), 0.920.80 (m, 1H; H-19b); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 174.1 (C=O), 171.6 (C=O), 169.2 (C=O), 156.8 (C=O), 137.1 (quat. C), 135.8 (quat. C), 134.0 (C-5), 133.4 (quat. C), 130.3 (C-8 or C-10), 129.5 (C-9), 126.6 (C-8 or C-10), 124.0 (C-12), 56.5 (C-16), 52.3 (C-22), 49.0 (C2 or C-21), 48.0 (C-2 or C-21), 41.4 (C-13), 29.8 (C-18), 29.5 (C-20), 20.2 (C-19); HRMS (ESI+) m/z = 441.1900 [M+H]+ found, C21H25N6O5+ required 441.1881.
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DOI: 10.1038/NCHEM.1729
Macrocyclic hydantoin SI-131
Fluorous-tagged macrocycle SI-90 (6.0 mg, 0.0068 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-131 (1.5 mg, 0.0033 mmol, 49%) was isolated as a colorless oil. TLC Rf = 0.52 (CH2Cl2/MeOH 10:1); HPLC tr = 8.85 min (10-40% B), peak area 98%; [α]D20 = +15 (c = 0.14 in MeOH); IR (neat) νmax = 3223 (w, br, N-H), 2923 (w, C-H), 1714 (m, C(=O)OR), 1631 (s, C(=O)NR2); HRMS (ESI+) m/z = 455.2054 [M+H]+ found, C22H27N6O5+ required 455.2037.
Macrocyclic hydantoin SI-132
Fluorous-tagged macrocycle SI-91 (3.0 mg, 0.0034 mmol, 1.0 eq) was reacted according to GP12. After purification by preparative HPLC (10-40% B), title compound SI-132 (1.1 mg, 0.0025 mmol, 73%) was isolated as a colorless oil. TLC Rf = 0.70 (CH2Cl2/MeOH 10:1); HPLC tr = 8.55 min (10-40% B), peak area 97%; [α]D20 = +23 (c = 0.08 in MeOH); IR (neat) νmax = 3399 (w, br, N-H), 2924 (w, C-H), 1698 (s, C(=O)NR2), 1637 (m, C=O); HRMS (ESI+) m/z = 455.2047 [M+H]+ found, C22H27N6O5+ required 455.2037.
Macrocyclic hydantoin 43
Fluorous-tagged macrocycle SI-92 (35 mg, 0.040 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 15:1) and preparative HPLC (10-40% B), title compound 43 (18 mg, 0.042 mmol, quant.) was isolated as a white powder. 96 96
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DOI: 10.1038/NCHEM.1729
TLC Rf = 0.45 (CH2Cl2/MeOH 10:1); HPLC tr = 6.21 min (10-40% B), peak area 100%; [α]D28.4 = +47 (c = 0.158 in MeOH); IR (neat) νmax = 3298 (w), 1768 (m, C=O), 1708 (s, C=O), 1621 (m, C=O), 1526 (w), 1466 (w), 1435 (m); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.67 (s, 1H; H13), 7.53 (s, 1H; H-5), 7.03 (d, J = 3.5, 1H; H-8), 6.50 (d, J = 3.6, 1H; H-9), 5.05 (d, J = 16.9, 1H; H-3a), 4.89 (d, J = 16.8, 1H; H-3b), 4.62 (d, J = 15.6, 1H; H-11a), 4.48 (d, J = 15.6, 1H; H-11b), 4.37-4.30 (m, 2H; H-19), 4.27-4.23 (m, 2H; H-2), 4.05 (t, J = 4.9, 1H; H-14), 3.68 (s, 3H; H-20), 1.79-1.75 (m, 2H; H-18), 1.63-1.55 (m, 2H; H-16), 1.17-1.09 (m, 1H; H-17a), 0.75-0.69 (m, 1H; H-17b); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 172.6 (C-15), 168.5 (C-1), 158.7 (C-6), 155.3 (C-12), 150.7 (C-10), 146.5 (C-7), 143.1 (C-4), 122.3 (C-5), 116.7 (C-8), 110.3 (C-9), 55.7 (C-14), 50.9 (C-20), 48.93(C-2), 48.2 (C-19), 44.1 (C-3), 33.8 (C-11), 28.4 (C-16), 27.9 (C-18), 18.3 (C-17); HRMS (ESI+) m/z = 431.1676 [M+H]+ found, C19H23N6O6+ required 431.1674, 453.1497 [M+Na]+ found, C19H22N6O6Na+ required 453.1493.
Macrocyclic hydantoin SI-133
Fluorous-tagged macrocycle SI-93 (24 mg, 0.028 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 15:1) and preparative HPLC (10-40% B), title compound SI-133 (11 mg, 0.026 mmol, 93%) was isolated as a white powder. TLC Rf = 0.48 (CH2Cl2/MeOH 10:1); HPLC tr = 6.47 min (10-40% B), peak area 100%; [α]D28.4 = +33 (c = 0.092 in MeOH); IR (neat) νmax = 1710 (s, C=O), 1627 (m, C=O), 1532 (w), 1439 (m), 1352 (w), 1203 (m); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.75 (s, 1H; H-13), 7.59 (s, 1H; H-5), 7.09 (d, J = 3.5, 1H; H-8), 6.57 (d, J = 3.5, 1H; H-9), 5.00 (br s, 2H, H-3), 4.67 (d, J = 15.9, 1H; H-11a), 4.59 (d, J = 15.8, 1H; H-11b), 4.24 (ddd, J = 14.1, 6.6, 5.1, 1H; H-19a), 4.15-4.12 (m, 2H; H-15, H-2a), 4.07-4.01 (m, 1H; H-19b), 3.99 (d, J = 17.5, 1H; H-2b), 3.61 (s, 3H; H-20), 1.82-1.74 (m, 3H; H-18, H-16a), 1.69-1.62 (m, 1H; H-16b), 1.12-1.03 (m, 1H; H-17a), 0.87-0.78 (m, 1H; H-17b); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 172.7 (C-15), 168.0 (C-1), 155.3 (C-12), 150.5 (C-10), 146.1 (C-7), 132.9 (C-5), 132.0 (C-4), 125.2 (C-8), 117.9 (C-9), 55.4 (C14), 51.0 (C-20), 47.1 (C-19 and C-2), 34.0 (C-11), 28.9 (C-18 or C-16), 28.7 (C-18 or C-16), 19.0 (C-17); HRMS (ESI+) m/z = 431.1685 [M+H]+ found, C19H23N6O6+ required 431.1674, found 453.1495 [M+Na]+, C19H22N6O6Na+ required 453.1493.
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DOI: 10.1038/NCHEM.1729
Macrocyclic dihydrouracil SI-134
Fluorous-tagged macrocycle 32 (37 mg, 0.042 mmol, 1.0 eq) was suspended in dry EtOAc (1.5 mL) and EtONa in EtOH (2.68M; 32 µL, 0.085 mmol, 2.0 eq) was added. After stirring for 2 h, the reaction mixture was neutralized by the addition of AcOH and subsequently the solvent was removed in a stream of nitrogen. After purification by preparative HPLC (5-30% B), title compound SI-134 (12 mg, 0.026 mmol, 63%) was isolated as a white solid. HPLC tr = 7.80 min (5-60% B), peak area 100%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 8.02 (br s, 1H; H-5), 7.72 (br d, J = 4.8, 1H; H-14), 7.54 (t, J = 7.6, 1H; H-9), 7.51 (br d, J = 7.6, 1h; H8 or H-10), 7.28 (dt, J = 7.4, 1.9, 1H; H-8 or H-10), 6.89 (br s, 1H; H-12), 4.53 (s, 2H; H-3), 4.504.37 (m, 2H; H-21), 4.28 (br s, 2H; H-2), 4.19 (q, J = 7.1, 2H; H-22), 3.57 (m, 1H; H-15), 3.09 (dd, J = 16.6, 7.8, 1H; H-16a), 2.46 (d, J = 16.6, 1H; H-16b), 2.02-1.84 (m, 2H; H-20), 1.54-1.41 (m, 2H; H-18), 1.25 (t, 3H; H-23), 1.18-1.02 (m, 2H; H-19); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 169.8, 168.6, 168.2, 152.1 (each C=O), 143.3, 134.7 (quat. C), 131.0 (C-8 or C-10), 128.7 (C-9), 126.6 (C-8 or C-10), 125.2 (C-12), 122.7 (C-5), 60.0 (C-22), 49.0 (C-21), 48.1 (C-2), 46.1 (C-3), 44.2 (C-15), 35.2 (C-18), 35.0 (C-16), 28.4 (C-20), 19.6 (C-19), 13.5 (C-23); HRMS (ESI+) m/z = 455.2047 [M+H]+ found, C22H27N6O5+ required 455.2037.
Macrocyclic dihydrouracil 38
Title compound 38 (5 mg, 0.012 mmol, 30%) was isolated as a side product of the transesterification of 32 described above. HPLC tr = 5.38 min (5-60% B), peak area 100%; HRMS (ESI+) m/z = 427.1751 [M+H]+ found, C20H23N6O5+ required 427.1724.
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Macrocyclic dihydrouracil SI-135
Fluorous-tagged macrocycle 33 (15 mg, 0.017 mmol, 1.0 eq) was suspended in dry EtOAc (1.5 mL) and EtONa in EtOH (2.68M; 28 µL, 0.069 mmol, 4.0 eq) was added. After stirring for 2 h, the reaction mixture was neutralized by the addition of AcOH and subsequently the solvent was removed in a stream of nitrogen. After purification by preparative HPLC (5-30% B), title compound SI-135 (5 mg, 0.011 mmol, 64%) was isolated as a white solid. HPLC tr = 8.29 min (5-60% B), peak area 100%; 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.817.75 (m, 2H; H-13 and H-8 or H-10), 7.70 (s, 1H; H-5), 7.55 (t, J = 7.9, 1H; H-9), 7.44 (m, 1H; H8 or H-10), 6.89 (t, J = 1.9, 1H; H-12), 4.99 (d, J = 18.4, 1H; H-2a or H-3a), 4.86 (d, J = 18.4, 1H; H-2b or H-3b), 4.34 (d, J = 16.9, 1H; H-2a or H-3a), 4.27 (dt, J = 14.1, 5.1, 1H; H-21a), 4.20-4.11 (m, 4H; H-2b or H-3b, H-21b and H-22), 3.65-3.60 (m, 1H; H-15), 3.11 (dd, J = 16.7, 7.8, 1H; H16a), 2.45 (m, 1H; H-16b), 2.05-1.98 (m, 2H; H-20), 1.69-1.46 (m, 2H; H-18), 1.24 (t, J = 7.1, 3H; H-23), 1.14-0.95 (m, 2H; H-19); 13C NMR (125 MHz, DMSO-d6, 27 °C) δ =169.4, 168.8, 167.3, 152.8 (each C=O), 136.1, 134.3 (both quat. C), 132.6 (C-8 or C-10), 132.1 (quat. C), 131.6, 129.6 (both C-Ar), 128.8 (C-9), 125.7 (C-12), 60.5 (C-22), 49.9 (C-2 or C-3), 47.0 (C-21), 46.5 (C-2 or C-3), 44.1 (C-15), 36.2 (C-18), 35.4 (C-16), 29.8 (C-20), 19.0 (C-19), 14.1 (C-23); HRMS (ESI+) m/z = 455.2061 [M+H]+ found, C22H27N6O5+ required 455.2037.
Macrocyclic dihydrouracil SI-136
Title compound SI-136 (2.7 mg, 0.063 mmol, 36%) was isolated as a side product of the transesterification of 33 described above. HPLC tr = 5.60 min (5-60% B), peak area 100%; HRMS (ESI+) m/z = 427.1736 [M+H]+ found, C20H23N6O5+ required 427.1724.
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Macrocyclic amide SI-137
The crude product of fluorous-tagged macrocycle SI-96 (~ 0.148 mmol) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 20:1) and preparative HPLC (15-60% B), title compound SI-137 (48 mg, 0.12 mmol, 81% over two steps) was isolated as a white solid. TLC Rf = 0.58 (CH2Cl2/MeOH 10:1); HPLC tr = 6.83 min (5-100% B), peak area 96%; 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 9.43 (s, 1H; H-13), 7.67 (s, 1H; H-5), 7.51 (s, 1H; H-12), 7.39 (t, J = 7.8, 1H; H-9), 7.25 (d, J = 8.0, 1H; H-8), 7.14 (d, J = 7.5, 1H; H-10), 4.44 (s, 2H; H-3), 4.36 (s, 2H; H-2), 4.33 (t, J = 5.9, 2H; H-20), 3.73 (s; H-21, coincides with water signal), 2.27-2.24 (m, 2H; H-15), 1.87 (dt, J = 12.0, 7.1, 2H; H-19), 1.71-1.66 (m, 2H; H-16), 1.37 (dt, J = 14.4, 7.2, 2H; H-17), 1.23 (dt, J = 15.0, 8.2, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 171.1 (C14), 170.8 (C-6), 168.7 (C-1), 142.9 (C-4), 137.9 (C-11 or C-7), 135.5 (C-7 or C-11), 128.4 (C-9), 121.5 (C-5), 121.0 (C-8), 120.8 (C-10), 118.4 (C-12), 51.0 (C-21), 49.3 (C-20), 47.7 (C-2), 45.6 (C-3), 35.6 (C-15), 28.5 (C-19), 27.9 (C-17), 25.0 (C-18), 23.0 (C-16); HRMS (ESI+) m/z = 400.1996 [M+H]+ found, C20H26N5O4+ required 400.1979.
Macrocyclic amide SI-138
Fluorous-tagged macrocycle SI-97 (57 mg, 0.069 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 20:1) and preparative HPLC (15-60% B), title compound SI-138 (23 mg, 0.058 mmol, 83%) was isolated as a white solid. TLC Rf = 0.53 (CH2Cl2/MeOH 10:1); HPLC tr = 7.02 min (5-100% B), peak area 98%; 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 9.47 (s, 1H; H-13), 7.70 (s, 1H; H-5), 7.52-7.49 (m, 2H; H-10 and H-12), 7.43 (t, J = 7.8, 1H; H-9), 7.21 (d, J = 7.6, 1H; H-8), 4.66 (s, 2H; H-3), 4.23 (s, 2H; H2), 4.03 (t, J = 6.8, 2H; H-20), 3.69 (s, 3H; H-21), 2.25 (t, J = 6.5, 2H; H-15), 1.78 (dt, J = 15.0, 7.4, 2H; H-19), 1.68 (dt, J = 12.8, 6.3, 2H; H-16), 1.31 (dt, J = 13.8, 7.0, 2H; H-17), 1.23-1.11 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 171.7 (C-14), 169.7 (C-6), 168.3 (C-1), 138.1 (C-11 or C-7), 134.2 (C-11 or C-7), 132.9 (C-4), 132.1 (C-5), 128.8 (C-9), 122.4 (C-8), 121.9 (C-10), 117.0 (C-12), 50.9 (C-21), 47.4 (C-2), 46.9 (C-20), 43.6 (C-3), 35.2 (C-15), 28.1 100 100
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(C-19), 26.7 (C-17), 24.2 (C-18), 24.0 (C-16); HRMS (ESI+) m/z = 400.1998 [M+H]+ found, C20H26N5O4+ required 400.1979.
Macrocyclic amide SI-139
Fluorous-tagged macrocycle SI-98 (25 mg, 0.030 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-139 (7.8 mg, 0.020 mmol, 65%) was isolated as a yellow oil. TLC Rf = 0.63 (CH2Cl2/MeOH 10:1); HPLC tr = 7.27 min (10-40% B), peak area 99%; IR (neat) νmax = 2927 (w, C-H), 1744 (m, C(=O)OR), 1639 (s, C(=O)OR); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.80 (s, 1H; H-14), 7.76 (s, 1H; H-5), 7.40 (t, J = 7.6, 1H; H-9), 7.32 (d, J = 7.9, 1H; H-8 or H-10), 7.29 (d, J = 7.4, 1H; H-8 or H-10), 7.08 (s, 1H; H-12), 4.60 (s, 2H; H-2), 4.43 – 4.35 (m, 2H; H-20), 4.31 (d, J = 5.9, 2H; H-13), 4.22 (s, 2H; H-3), 3.69 (s, 3H; H-21), 2.21 – 2.06 (m, 2H; H-16), 1.86 – 1.79 (m, 2H; H-19), 1.59 – 1.48 (m, 2H; H-17), 1.22 – 1.10 (m, 2H; H-18); 13 C NMR (125 MHz, DMSO-d6, 120°C) δ = 172.5 (C=O), 171.6 (C=O), 169.6 (C=O), 143.9 (quat. C), 140.7 (quat. C), 136.6 (quat. C), 129.0 (C-8 or C-10), 128.7 (C-9), 125.1 (C-8 or C-10), 124.3 (C-12), 122.9 (C-5), 52.1 (C-21), 50.0 (C-20), 42.6 (C-13), 35.4 (C-16), 29.4 (C-19), 25.8 (C-18), 24.4 (C-17); HRMS (ESI+) m/z = 400.1992 [M+H]+ found, C20H26N5O4+ required 400.1979.
Macrocyclic amide SI-140
Fluorous-tagged macrocycle SI-99 (15 mg, 0.018 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-140 (5.5 mg, 0.014 mmol, 76%) was isolated as white crystals. TLC Rf = 0.57 (CH2Cl2/MeOH 10:1); HPLC tr = 7.28 min (10-40% B), peak area 100% pure; mp 197°C (DMSO); IR (neat) νmax = 2956 (w, C-H), 1743 (m, C(=O)OR), 1662 (m, C(=O)NRH), 1627 (s, C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.99 (s, 1H; H-14), 7.65 (s, 1H; H-5), 7.41 – 7.35 (m, 2H; H-8 and H-10), 7.29 – 7.25 (m, 2H; H-9 and H-12); 4.79 (s, 2H; H-2), 4.29 (d, J = 6.1, 2H; H-13), 4.12 (t, J = 7.1, 2H; H-20), 4.01 (s, 2H; H-3), 3.65 (s, 3H; H-21), 2.19 – 2.14 (m, 2H; H-16), 1.86 – 1.76 (m, 2H; H-19), 1.64 – 1.56 (m, 2H; H-17), 1.20 – 1.13 (m, 1H; H101 101
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18); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 173.0 (C=O), 168.2 (C=O), 166.4 (C=O), 139.7 (C-7 or C-11), 139.5 (C-7 or C-11), 134.4 (C-4), 133.3 (C-5), 131.7 (C-12), 127.9 (C-8 or C-10), 124.6 (C-9), 123.9 (C-8 or C-10), 51.1 (C-21), 47.1 (C-3 and C-20), 40.4 (C-13), 34.1 (C-16), 28.2 (C-19), 24.4 (C-18), 24.0 (C-17); HRMS (ESI+) m/z = 400.2003 [M+H]+ found, C20H26N5O4+ required 400.1979.
Macrocyclic amide SI-141
Fluorous-tagged macrocycle SI-100 (11 mg, 0.012 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-141 (2.3 mg, 0.054 mmol, 44%) was isolated as colorless oil. TLC Rf = 0.52 (CH2Cl2/MeOH 10:1); HPLC tr = 10.75 min (10-40% B), peak area 98%; IR (neat) νmax = 2922 (w, C-H), 1748 (w, C(=O)OR), 1636 (m, C(=O)NR2); HRMS (ESI+) m/z = 428.2287 [M+H]+ found, C22H30N5O4+ required 428.2292.
Macrocyclic amide SI-142
Fluorous-tagged macrocycle SI-101 (3.6 mg, 0.0042 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-142 (1.7 mg, 0.0040 mmol, 94%) was isolated as colorless oil. TLC Rf = 0.50 (CH2Cl2/MeOH 10:1); HPLC tr = 10.51 min (10-40% B), peak area 100%; IR (neat) νmax = 3295 (w, N-H), 2926 (w, C-H), 1678 (br, s, C(=O)OR and C(=O)NR2); 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.92 (s, 1H; H-14), 7.69 (s, 1H; H-5), 7.40 – 7.32 (m, 2H; H-8/H-10 and H-9), 7.25 (s, 1H; H-12), 7.21 (d, J = 6.5, 1H; H-8 or H-10); 4.82 (s, 2H; H-2), 4.31 (d, J = 6.1, 2H, H-13), 4.28 (br s, 2H; H-22), 4.03 (s, 2H; H-3), 3.62 (s, 3H; H-23), 2.18 – 2.12 (m, 2H; H-16), 1.69 (br s, 2H; H-21), 1.59 – 1.50 (m, 2H; H-17), 1.36 – 1.10 (m, 6H, H-18, H-19, and H20); HRMS (ESI+) m/z = 428.2311 [M+H]+ found, C22H30N5O4+ required 428.2292.
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Macrocyclic amide SI-143
Fluorous-tagged macrocycle SI-102 (10 mg, 0.012 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-143 (3.9 mg, 0.0094 mmol, 80%) was isolated as colorless oil. TLC Rf = 0.42 (CH2Cl2/MeOH 10:1); HPLC tr = 8.45 min (10-40% B), peak area 98%; IR (neat)
νmax = 2936 (w, C-H), 1745 (w, C(=O)OR), 1634 (s, C(=O)NR2); HRMS (ESI+) m/z = 414.2149 [M+H]+ found, C21H28N5O4+ required 414.2136.
Macrocyclic amide SI-144
Fluorous-tagged macrocycle SI-103 (18 mg, 0.021 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-144 (7.6 mg, 0.018 mmol, 86%) was isolated as colorless oil. TLC Rf = 0.44 (CH2Cl2/MeOH 10:1); HPLC tr = 7.75 min (10-40% B), peak area 99%; IR (neat) νmax = 2942 (w, C-H), 1747 (m, C(=O)OR), 1636 (m, C(=O)NR2); HRMS (ESI+) m/z = 414.2133 [M+H]+ found, C21H28N5O4+ required 414.2136.
Macrocyclic amide SI-145
Fluorous-tagged macrocycle SI-104 (58 mg, 0.066 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-145 (22 mg, 0.050 mmol, 75%) was isolated as white needle-like crystals.
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TLC Rf = 0.52 (CH2Cl2/MeOH 10:1); HPLC tr = 11.74 min (10-40% B), peak area 100%; mp 136138°C (MeCN/H2O); IR (neat) νmax = 1728 (m, C(=O)OR), 1637 (C(=O)NR2); HRMS (ESI+) m/z = 442.2471 [M+H]+ found, C23H32N5O4+ required 442.2449.
Macrocyclic amide SI-146
Fluorous-tagged macrocycle SI-105 (50 mg, 0.057 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 30:1), title compound SI-146 (17 mg, 0.039 mmol, 69%) was isolated as colorless oil. TLC Rf = 0.42 (CH2Cl2/MeOH 10:1); HPLC tr = 11.34 min (10-40% B), peak area 99%; IR (neat) νmax = 2936 (w, C-H), 1747 (m, C(=O)OR), 1637 (m, C(=O)NR2); HRMS (ESI+) m/z = 442.2446 [M+H]+ found, C23H32N5O4+ required 442.2449.
Macrocyclic amide SI-147
Fluorous-tagged macrocycle SI-106 (35 mg, 0.043 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 15:1) and preparative HPLC (10-40% B), title compound SI-147 (16 mg, 0.041 mmol, 95%) was isolated as white powder. TLC Rf = 0.47 (CH2Cl2/MeOH 10:1); HPLC tr = 6.16 min (10-40% B), peak area 100%; IR (neat) νmax = 3320 (w), 1751 (s, C=O), 1664 (m, C=O), 1611 (s), 1523 (s), 1437 (s), 1366 (w), 1198 (m), 1159 (m), 1010 (m), 753 (m); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.87 (s, 1H; H-12), 7.85 (s, 1H; H-5), 7.07 (d, J = 3.4, 1H; H-8), 6.48 (d, J = 3.4, 1H; H-9), 4.92 (s, 2H; H-3), 4.394.36 (m, 2H; H-18), 4.30 (d, J = 5.1, 2H; H-11), 4.23 (s, 2H; H-2), 3.67 (s, 3H; H-19), 2.11-2.09 (m, 2H; H-14), 1.83-1.77 (m, 2H; H-17), 1.57-1.51 (m, 2H; H-15), 1.05 (quint, J = 7.5, 2H; H-16); 13 C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.3 (C-13), 168.7 (C-1), 158.7 (C-6), 153.7 (C-10), 146.6 (C-7), 143.5 (C-4), 122.3 (C-5), 117.6 (C-8), 109.8 (C-9), 51.1 (C-19), 48.5 (C-18 or C-2), 48.4 (c-18 or C-2), 44.5 (C-3), 35.4 (C-11), 34.0 (C-14), 27.8 (C-17), 23.6 (C-16), 23.1 (C-15); HRMS (ESI+) m/z = 390.1777 [M+H]+ found, C18H24N5O5+ required 390.1772, 412.1610 [M+Na]+ found, C18H23N5O5Na+ required 412.1591. 104 104
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DOI: 10.1038/NCHEM.1729
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Macrocyclic amide SI-148
Fluorous-tagged macrocycle SI-107 (37 mg, 0.045 mmol, 1.0 eq) was reacted according to GP12. After purification by flash column chromatography (CH2Cl2/MeOH 15:1) and preparative HPLC (10-40% B), title compound SI-148 (14 mg, 0.036 mmol, 80%) was isolated as white powder. TLC Rf = 0.42 (CH2Cl2/MeOH 10:1); HPLC tr = 5.86 min (10-40% B), peak area 100%; IR (neat) νmax = 3286 (w), 2941 (w), 1742 (m, C=O), 1624 (s, C=O), 1530 (s), 1431 (s), 1202 (s), 1021 (m), 749 (s); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.93 (s, 1H; H-12), 7.55 (s, 1H; H-5), 7.10 (d, J = 3.4, 1H; H-8), 6.45 (d, J = 3.5, 1H; H-9), 5.16 (s, 2H; H-3), 4.27 (d, J = 5.4, 2H; H11), 4.20 (t, J = 6.6, 2H; H-18), 4.10 (s, 2H; H-2), 3.63 (s, 3H; H-19), 2.16-2.09 (m, 2H; H-14), 1.80-1.74 (m, 2H; H-17), 1.59-1.53 (m, 2H; H-15), 1.12-1.06 (m, 2H; H-16); 13C NMR (125 MHz, DMSO-d6, 120 °C) δ = 171.2 (C-13), 168.2 (C-1), 154.0 (C-10), 146.0 (C-7), 132.5 (C-4 or C-5), 132.4 (C-4 or C-5), 118.2 (C-8), 108.7 (C-9), 50.9 (C-19), 47.5 (C-2), 47.3 (C-18), 35.1 (C-11), 33.8 (C-14), 28.3 (C-17), 24.1 (C-16), 23.8 (C-15); HRMS (ESI+) m/z = 390.1787 [M+H]+ found, C18H24N5O5+ required 390.1772, 412.1581 [M+Na]+ found, C18H23N5O5Na+ required 412.1591.
Macrocyclic dihydropyridinone SI-149
Fluorous-tagged macrocycle SI-109 (17 mg, 0.019 mmol, 1.0 eq) was reacted according to GP12. After purification by preparative HPLC (20-70% B), title compound SI-149 (6.0 mg, 0.012 mmol, 65%) was isolated as an off-white powder. TLC Rf = 0.33 (CH2Cl2/MeOH 20:1); HPLC tr = 10.88 min (10-60% B), peak area 100%; IR (neat) νmax = 1747 (m, C=O), 1640 (m, C=O), 1575 (s), 1215 (s), 1175 (s), 1145 (s); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.89 (d, J = 7.9, 1H; H-13), 7.57 (s, 1H; H-5), 7.47-7.41 (m, 2H; H-9 and either H-8 or H-10), 7.17 (t, J = 7.7, 1H; H-20), 7.12-7.09 (m, 3H; H-19, H-23 and either H-8 or H-10), 7.05 (d, J = 7.4, 1H; H-21), 6.81 (s, 1H; H-12), 5.36 (d, J = 4.9, 1H; H-17), 5.13 (d, J = 7.9, 1H; H-14), 4.69 (d, J = 15.6, 1H; H-3a), 4.53 (d, J = 15.6, 1H; H-3b), 4.44-4.32 (m, 2H; H27), 4.03 (d, J = 17.7, 1H; H-2a), 3.98 (d, J = 17.6, 1H; H-2b), 3.62 (s, 3H; H-28), 3.22-3.20 (m; H-16a, coincides with water signal), 2.57 (t, J = 7.3, 2H; H-24), 2.55-2.51 (m, 1H; H-16b), 1.881.74 (m, 2H; H-26), 1.45-1.32 (m, 2H; H-25); HRMS (ESI+) m/z = 500.2316 [M+H]+ found, C28H30N5O4+ required 500.2292, 522.2134 [M+Na]+ found, C28H29N5O4Na+ required 522.2112. 105
105
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DOI: 10.1038/NCHEM.1729
Macrocyclic dihydropyridinone 44
Fluorous-tagged macrocycle SI-110 (4.5 mg, 0.0048 mmol, 1.0 eq) was reacted according to GP12. After purification by preparative HPLC (20-70% B), title compound 44 (2.3 mg, 0.0046 mmol, 95%) was isolated as a white powder. TLC Rf = 0.29 (CH2Cl2/MeOH 20:1); HPLC tr = 10.94 min (10-60% B), peak area 100%; IR (neat) νmax = 1743 (w, C=O), 1642 (m, C=O), 1574 (s), 1461 (w), 1305 (w), 1184 (s); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.78 (d, J = 8.0, 1H; H-13), 7.63 (s, 1H; H-5), 7.38-7.36 (m, 2H; H-9 and either H-8 or H-10), 7.18 (d, J = 4.5, 2H; H-20 and H-19), 7.06-6.95 (m, 4H; H-12, H-21, H23 and either H-8 or H-10), 5.41 (t, J = 6.2, 1H; H-17), 5.14 (d, J = 7.9, 1H; H-14), 4.53 (s, 2H; H3), 4.15 (br s, 2H; H-27), 3.88 (br s, 2H; H-2), 3.60 (s, 3H; H-28), 3.03 (dd, J = 16.4, 7.0; H-16a, coincides with water signal), 2.67 (dd, J = 16.2, 6.8, 1H; H-16b), 2.59 (d, J = 6.3, 2H; H-24), 1.51 (br s, 4H; H-25 and H-26); HRMS (ESI+) m/z = 500.2317 [M+H]+ found, C28H30N5O4+ required 500.2292.
Macrocyclic diene SI-150
Fluorous-tagged macrocycle SI-112 (30 mg, 0.037 mmol, 1.0 eq) was suspended in dry EtOAc (2 mL) and EtONa in EtOH (2.68M; 14 µL, 0.037 mmol, 1.0 eq) was added. After stirring for 2 h, the reaction mixture was neutralized by the addition of AcOH and subsequently the solvent was removed in a stream of nitrogen. After purification by preparative HPLC (15-60% B), title compound SI-150 (12 mg, 0.031 mmol, 84%) was isolated as a white solid. HPLC tr = 9.74 min (5-100% B), peak area 90%; HRMS (ESI+) m/z = 386.2085 [M+H]+ found, C21H28N3O4+ required 386.2074.
Macrocyclic diene SI-151
106 106
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Title compound SI-151 (2 mg, 0.0056 mmol, 15%) was isolated as a side product of the transesterification of SI-112 described above. HPLC tr = 8.08 min (5-100% B), peak area 90%; HRMS (ESI+) m/z = 358.1770 [M+H]+ found, C19H24N3O4+ required 358.1761.
Macrocyclic diene SI-152
Fluorous-tagged macrocycle SI-113 (66 mg, 0.081 mmol, 1.0 eq) was reacted according to GP12. After purification by preparative HPLC (30-55% B), title compound SI-152 (17 mg, 0.044 mmol, 55%) was isolated as white solid. TLC Rf = 0.38 (CH2Cl2/MeOH, 19:1); HPLC tr = 9.12 min (5-100% B), peak area 98%; IR (neat)
νmax = 3379 (NH), 2917 (CH), 1720 ((C=O)O), 1631 ((C=O)N); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.35-7.22 (m, 3H; Ar-H), 7.14 (d, J = 7.0, 1H; H-8), 6.20 (br s, 1H; H-14), 5.98 (d, J = 16.5, 1H; H-22), 5.78 (br m, 1H; H-21), 5.63 (br s, 1H; H-16), 5.17 (s, 1H; H-5a), 5.03 (s, 1H, H5b), 4.28-4.23 (m, 4H; H-13 and H-3), 3.89 (s, 2H; H-2), 3.66 (s, 3H; H-23), 3.14 (br s, 2H; H17), 2.11-2.05 (m, 2H; H-20), 1.44-1.38 (m, 4H; H-18 and H-19); 13C NMR (125 MHz, DMSO-d6, 27 °C) major rotamer signals only, δ = 171.2 (C-6), 169.4 (C-1), 158.6 (C-15), 142.4 (C-11), 140.7 (C-4), 136.2 (C-7), 132.8 (C-21), 128.9 (C-22), 128.8 (C-9), 127.5 (C-10), 123.5 (C-8), 122.5 (C-12), 120.3 (C-5), 52.3 (C-23), 47.6 (C-2), 46.3 (C-3), 42.0 (C-13), 37.3 (C-17), 32.9 (C20), 30.6 (C-18), 26.9 (C-19); HRMS (ESI+) m/z = 386.2085 [M+H]+ found, C21H28N3O4+ required 386.2074.
Macrocyclic diene SI-153
Fluorous-tagged macrocycle 35 (120 mg, 0.144 mmol, 1.00 eq) was reacted according to GP12 with neutralization performed at 0°C. After purification by preparative HPLC (30-60% B), title compound SI-153 (52 mg, 0.13 mmol, 90%) was isolated as white solid. TLC Rf = 0.46 (EtOAc/MeOH 19:1); HPLC tr = 9.47 min (5-100% B), peak area 99%; IR (neat)
νmax = 2928 (CH3), 1745 ((C=O)O), 1624 ((C=O)N); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ =
7.34 (dd, J = 7.6, 7.5, 1H; H-9), 7.29 (d, J = 7.6, 1H; H-10), 7.16 (d, J = 7.5, 1H; H-8), 7.10 (s, 1H; H-12), 6.00 (d, J = 16.0, 1H; H-23), 5.84-5.75 (m, 1H; H-22), 5.16 (s, 1H; H-5a), 5.03 (s, 1H; 107 107
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DOI: 10.1038/NCHEM.1729
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H-5b), 4.25 (s, 2H; H-3), 3.98 (s, 2H; H-2), 3.66 (s, 3H; H-24), 3.32 (t, J = 5.5, 2H; H-14), 3.01 (t, J = 6.0, 2H; H-18), 2.79-2.77 (m, 2H; H-13), 2.07 (dt, J = 6.5, 6.0, 2H; H-21), 1.39-1.34 (m, 4H; H-19 and H-20); 13C NMR (125 MHz, DMSO-d6, 120 °C): δ = 170.7 (C-6), 168.6 (C-1), 157.5 (C16), 140.7 (C-11), 140.0 (C-4), 135.2 (C-7), 131.7 (C-22), 129.3 (C-10), 128.5 (C-23), 127.6 (C9), 126.3 (C-12), 123.5 (C-8), 115.6 (C-5), 51.0 (C-24), 47.1 (C-2), 39.8 (C-14, coincides with solvent signal), 38.1 (C-18), 34.9 (C-13), 31.0 (C-21), 28.7 (C-19), 25.2 (C-20); HRMS (ESI+) m/z = 400.2230 [M+H]+ found, C22H30N3O4+ required 400.2231.
Macrocyclic diene SI-154
Fluorous-tagged macrocycle SI-114 (47 mg, 0.058 mmol, 1.0 eq) was reacted according to GP12 at 0°C. After purification by preparative HPLC (30-70% B), title compound SI-154 (19 mg, 0.051 mmol, 88%) was isolated as white solid. TLC Rf = 0.27 (EtOAc/MeOH 19:1); HPLC tr = 8.54 min (5-100% B), peak area 98%; IR (neat) νmax = 3374 (NH), 2972 (CH), 1745 ((C=O)O), 1616 ((C=O)N); 1H NMR (500 MHz, DMSO-d6, 100 °C) δ = 6.89 (d, J = 3.0, 1H; H-8), 6.32 (d, J = 3.0, 1H; H-9), 6.02 (d, J = 16.0, 1H; H-20), 5.66 (dt, J = 16.0, 7.0, 1H; H-19), 5.11 (s, 1H; H-5a), 4.95 (s, 1H; H-5b), 4.42 (s, 2H; H-3), 4.25 (s, 2H; H-11), 4.17 (s, 2H; H-2), 3.65 (s, 3H; H-21), 3.04-3.02 (m, 2H; H-15), 2.06 (dt, J = 6.5, 6.0, 2H; H-18), 1.40-1.36 (m, 4H; H-16 and H-17); 13C NMR (125 MHz, DMSO-d6, 100 °C) δ = 168.7 (C-1), 159.8 (C-6), 157.5 (C-13), 155.2 (C-10), 146.0 (C-7), 140.4 (C-4), 131.5 (C-19), 128.9 (C-20), 116.2 (C-8), 107.3 (C-9), 51.0 (C-21), 49.5 (C-3), 46.8 (C-2), 38.6 (C-15), 35.9 (C11), 31.2 (C-18), 28.4 (C-16), 25.0 (C-17). HRMS (ESI+) m/z = 376.1868 [M+H]+ found, C19H26N3O5+ required 376.1867.
Macrocyclic diene 12
The macrocycle 7 (11 mg, 0.011 mmol, 1.0 eq) was reacted according to GP12. After purification by preparative HPLC (15-65% B), title compound 12 (2.6 mg, 0.046 mmol, 42%) was isolated as a white powder. HPLC tr = 13.19 min (10-60% B), peak area 87%; HRMS (ESI+) m/z = 447.2408 [M+H]+ found, C26H31N4O3+ required 447.2391. 108 108
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DOI: 10.1038/NCHEM.1729
Macrocyclic diene SI-155
The macrocycle SI-115 (7.0 mg, 0.0069 mmol, 1.0 eq) was reacted according to GP12. After purification by preparative HPLC (15-65% B), title compound SI-155 (1.2 mg, 0.0020 mmol, 30%) was isolated as a white powder. HPLC tr = 13.55 min (10-60% B), peak area 91%; HRMS (ESI+) m/z = 475.2716 [M+H]+ found, C28H35N4O3+ required 475.2704.
Macrocyclic Diels-Alder product 37
Fluorous-tagged macrocycle 36 (41 mg, 0.044 mmol, 1.0 eq) was reacted according to GP12 at 0 °C. After purification by preparative HPLC (25-75% B), title compound 37 (14 mg, 0.027 mmol, 63%) was isolated as a white solid. TLC Rf = 0.59 (CH2Cl2/MeOH 9:1); HPLC tr = 7.83 min (5-100% B), peak area 96%; [α]D27.7 +4.0° (c = 0.125, CHCl3); IR (neat) νmax = 3388 (NH), 2927 (CH2), 1748 ((C=O)O), 1694 (N(C=O)2), 1641 ((C=O)N); 1H NMR (500 MHz, DMSO-d6, 120 °C) δ = 7.36 (dd, J = 7.5, 1H; H9), 7.30 (d, J = 8.0, 1H; H-10), 7.18 (d, J = 7.5, 1H; H-8), 7.14 (s, 1H; H-12), 5.67-5.33 (br m, 2H; H-15 and H-17), 5.55 (m, 1H; H-5), 4.14 (d, J = 17.5, 1H; H-2a or H-3a), 4.09 (d, J = 17.5, 1H; H2a or H-3a), 3.75 (d, J = 17.5, 1H; H-2b or H-3b), 3.72-3.68 (m, 1H; H-2b or H-3b), 3.68 (s, 3H, H-29), 3.32 (m, 1H; H-14a), 3.24-3.20 (m, 2H; H-14b and H-27), 3.11-3.05 (m, 3H; H-23 and H18), 2.79 (s, 3H; H-25), 2.77-2.65 (m, 2H; H-13), 2.34-2.30 (m, 2H; H-22 and H-28a), 2.19 (dd, J = 15.0, 6.5, 1H; H-28b), 1.73-1.64 (m, 2H; H-21), 1.60-1.46 (m, 2H; H-20a and H-19a), 1.43-1.36 (m, 1H; H-19b), 1.32-1.26 (m, 1H; H-20b); 13C NMR (125 MHz, DMSO-d6, 27 °C) major rotamer signals only δ = 179.6 (C-24 or C-26), 177.8 (C-24 or C-26), 171.1 (C-6), 169.0 (C-1), 158.1 (C16), 140.5 (C-11), 135.4 (C-4), 134.4 (C-7), 131.1 (C-10), 129.0 (C-9), 126.8 (C-5), 126.0 (C-8), 125.7 (C-12), 54.9 (C-3), 51.9 (C-29), 47.6 (C-2), 43.9 (C-23), 41.3 (C-14), 40.6 (C-27), 38.6 (C18), 37.0 (C-13), 35.7 (C-22), 30.8 (C-21), 30.1 (C-20), 26.1 (C-28), 25.2 (C-19), 24.2 (C-25); HRMS (ESI+) m/z = [M+H]+ found, 511.2560, C27H35N4O6+ required 511.2551.
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DOI: 10.1038/NCHEM.1729
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Transamidation Macrocyclic urea SI-156
Cyclohexylamine (14 µL, 0.12 mmol, 5.0 eq) was dissolved in dry THF (1.5 mL) and Me2AlCl as a solution in hexane (1 M, 125 µL, 0.125 mmol, 5.00 eq) was added. After stirring for 10 min, fluorous-tagged macrocycle SI-68 (22 mg, 0.025 mmol, 1.0 eq) in THF (1.5 mL) was added. The reaction was heated to reflux for 90 h with further additions of cyclohexylamine and Me2AlCl after 18 h (5.0 eq) and 66 h (10 eq). The solvent was removed under a steam of nitrogen and the residue was dissolved in water. The aqueous layer was extracted with CH2Cl2 (10 x) and the combined organic layers were dried over MgSO4, filtrated, and the solvent was removed under reduced pressure. After purification by preparative HPLC (20-27% B), title compound SI-156 (3.0 mg, 0.0057 mmol, 23%) was isolated as white solid. HPLC tr = 9.71 min (5-60% B), peak area 88%; 1H NMR (500 MHz, DMSO-d6, 27 °C) δ = 8.69 (s, 1H; H-13), 8.14-8.07 (m, 2H; H-5 and H-22), 7.95-7.84 (m, 2H; H-12 and H-24), 7.31 (t, J = 7.8, 1H; H-9), 6.99 (d, J = 7.7, 1H; H-8 or H-10); 6.79 (d, J = 7.9; H-8 or H-10), 6.33 (d, J = 8.8, 1H; H-15); 4.51-4.16 (m, 6 H; H-16, H-20, CH2 and CHaHb); 3.76 (m, 1H; CHaHb), 3.54 (m, 1H; H-25), 2.60 (d, J = 4.6, 3H; H-23), 2.38-2.24 (m, 1H; H-19a), 1.77-1.59 (m, 6H; H-17a, H-19b, H27a and H-26a), 1.59-1.50 (m, 1H; H-28a), 1.48-1.35 (m, 1H; H-17b), 1.32-1.03 (m, 7H; H-18, H26b, H-27b and H-28b); 13C NMR (125 MHz, DMSO-d6, 27 °C) δ = 172.4, 171.5, 166.7, 154.5 (each C=O), 143.8, 139.5, 135.7 (each quat. C), 129.3 (C-9), 122.4 (C-5), 120.1 (C-8 or C-10), 119.2 (C-8 or C-10), 115.9 (C-12), 50.5 (C-16), 50.2 (C-20), 48.1 (C-2 or C-3), 47.6 (C-25), 47.0 (C-2or C-3), 34.9 (C-17), 32.5 (C-26), 28.4 (C-19), 25.5 (C-23), 25.2 (C-28), 24.5 (C-27), 22.5 (C-18); HRMS (ESI+) m/z = 525.2919 [M+H]+ found, C26H37N8O4+ required 525,2932.
Macrocyclic urea SI-157
Fluorous-tagged macrocycle SI-98 (40 mg, 0.048 mmol, 1.0 eq) was dissolved in 2 mL CH2Cl2, then Me2AlCl as a 1 M solution in hexane (0.24 mL, 0.24 mmol, 5.0 eq), HNMe2 (20 mg, 0.24 mmol, 5.0 eq), and DIPEA (63 uL, 0.36 mmol, 7.5 eq) were added. The reaction was stirred for 18 h and since the reaction was progressing slowly additional equivalents of Me2AlCl solution 110 110
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DOI: 10.1038/NCHEM.1729
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(0.48 mL, 0.48 mmol, 10 eq) and HNMe2 (40 mg, 0.48 mmol, 10 eq) were added. The reaction was refluxed for additional 70 h until no starting material remained. The solvent was removed under reduced pressure and the crude mixture was filtered through a pad of silica (CH2Cl2/MeOH 10:1) and purified by preparative HPLC (10-25% B) to afford title compound SI-157 (13 mg, 0.032 mmol, 67%) as a colorless oil. TLC Rf = 0.09 (CH2Cl2/MeOH, 10:1); HPLC tr = 5.56 min (10-40% B), peak area 89%; 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.81 (br s, 1H; H-14), 7.78 (s, 1H; H-5), 7.37 (t, J = 7.3, 1H; H9), 7.32-7.25 (m, 2H; H-8 and H-10), 7.08 (s, 1H; H-12), 4.56 (s, 2H; H-3), 4.39 (dd, J = 6.3, 6.3, 2H; H-20), 4.35-4.20 (m, 8H; H-21 and H-13), 2.16 (t, J = 6.3, 2H; H-16), 1.86-1.80 (m, 2H; H19), 1.55-1.48 (m, 2H; H-17), 1.18-1.11 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 172.5 (C=O), 171.4 (C=O), 167.9 (C=O), 144.3 (C-7 or C-11), 140.5 (C-7 or C-11), 137.2 (C4), 128.7 (C-8 or C-10), 128.6 (C-9), 125.2 (C-8 or C-10), 124.3 (C-12), 123.0 (C-5), 50.0 (C-20), 42.6 (C-13), 36.0 (C-21), 35.4 (C-16), 29.5 (C-19), 25.9 (C-18), 24.5 (C-17); HRMS (ESI+) m/z = 435.2140 [M+Na]+ found, C21H28N6O3Na+ required 435.2115.
Macrocyclic urea 9
Fluorous-tagged macrocycle 6 (43 mg, 0.047 mmol, 1.0 eq) was reacted according to GP13 for 100 min at 80 °C in the microwave. After pre-purification by short flash column chromatography (CH2Cl2/MeOH, 9:1) and purification by preparative HPLC (5-65% B), title compound 9 (18 mg, 0.33 mmol, 72%) was isolated as an off-white powder. TLC Rf = 0.27 (CH2Cl2/MeOH, 9:1); HPLC tr = 7.25 min (5-100% B), peak area 99%; [α]D27.7 = 29.0° (c = 0.117 in MeOH); IR (neat) νmax = 3300 (NH), 2933 (CH2), 1621 ((C=O)N); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.72 (s, 1H; H-5), 7.49 (d, J = 6.5, 1H; H-23), 6.98 (d, J = 3.5, 1H; H-8), 6.45 (dd, J = 8.0, 2.5, 1H; H-12), 6.40 (d, J = 3.0, 1H; H-9), 5.99 (d, J = 8.5, 1H; H-14), 4.93 (d, J = 16.0, 1H; H-3a), 4.86 (d, J = 16.0, 1H; H-3b), 4.67-4.62 (m, 2H; H-11a and H-15), 4.40-4.32 (m, 2H; H-19), 4.11 (d, J = 16.0, 1H; H-2a), 3.99 (d, J = 16.5, 1H; H-2b), 3.96 (dd, J = 15.5, 2.5, 1H; H-11b), 3.60-3.55 (m, 1H; H-24), 2.95 (br s, 6H; H-21 and H-22), 1.97-1.90 (m, 1H; H-18a), 1.80-1.54 (m, 7H; H-18b, H-16a, 2 x CH2 and CHaHb), 1.43-1.36 (m, 1H; H-16b), 1.32-1.13 (m, 7H; H-17, 2 x CH2 and CHaHb); 13C NMR (125 MHz, DMSO-d6, 90 °C): δ = 171.6 (C-20), 166.3 (C-1), 158.7 (C-6), 156.6 (C-13), 154.5 (C-10), 147.0 (C-7), 143.1 (C-4), 122.2 (C5), 117.1 (C-8), 108.3 (C-9), 48.9 (C-2), 48.6 (C-19), 48.0 (C-15), 47.3 (C-24), 43.5 (C-3), 36.0 (C-11), 31.8 (CH2), 30.8 (C-16), 27.6 (C-18), 24.8 (C-27), 23.9 (CH2), 20.7 (C-17); HRMS (ESI+) m/z = 543.3052 [M+H]+ found, C26H39N8O5+ required 543.3038.
111 111
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DOI: 10.1038/NCHEM.1729
SUPPLEMENTARY INFORMATION
Hydrolysis Macrocyclic urea SI-158
Fluorous-tagged macrocycle SI-68 (40 mg, 0.045 mmol, 1.0 eq) was dissolved in dry THF (2.5 mL) and LiOH (9.4 mg, 0.23 mmol, 5.00 eq) in water (0.6 mL) was added. After 30 min the mixture was neutralized by the addition of 2 M HCl and the solvent was removed under a stream of N2. After purification by preparative HPLC (5-22% B), title compound SI-158 (13 mg, 0.029 mmol, 65%) was isolated as a white solid. HPLC tr = 8.00 min (5-30% B), peak area 95%; 1H NMR (500 MHz, DMSO-d6, 27 °C) δ = 8.77 (s, 1H; H-13), 8.12-8.07 (m, 2H; H-5 and H-22), 7.90 (br s, 1H; H-12), 7.32 (t, J = 7.8, 1H; H-9), 6.99 (d, J = 7.7, 1H; H-8 or H-10), 6.81 (d, J = 8.0, 1H; H-8 or H-10), 6.39 (d, J = 8.9, 1H; H-15), 4.50-4.22 (m, 6H; H-16, H-20, CH2 and CHaHb), 3.89 (d, 1H; CHaHb), 2.59 (d, J = 4.5, 3H; H-23), 2.40-2.26 (m, 1H; H-19a), 1.72-1.59 (m, 2H; H-19b and H-17a), 1.43 (m, 1H; H-17b), 1.28-1.16 (m, 1H; H-18a), 1.16-1.03 (m, 1H; H-18b); 13C NMR (125 MHz, DMSO-d6, 27 °C) δ = 172.4, 171.7, 170.3, 154.6 (each C=O), 143.8, 139.6, 135.4 (each quat. C), 129.4 (C-9), 122.3 (C-5), 120.0 (C-8 or C-10), 119.4 (C-8 or C-10), 116.1 (C-12), 50.5 (C-16), 50.2, 47.5, 46.8 (each C-2, C3 or C-20), 34.8 (C-17), 28.4 (C-19), 25.5 (C-23), 22.5 (C-18); HRMS (ESI+) m/z = 444.2015 [M+H]+ found, C20H26N7O5+ required 444.1990.
Macrocyclic urea SI-159
Fluorous-tagged macrocycle SI-98 (35 mg, 0.042 mmol, 1.0 eq) was reacted according to GP14. After purification by preparative HPLC (10-25% B), title compound SI-159 (17 mg, 0.044 mmol, quant.) was isolated as clear oil. HPLC tr = 5.37 min (10-40% B), peak area 98%; 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.78 (br s, 1H; H-14), 7.76 (s, 1H; H-5), 7.39 (t, J = 7.6, 1H; H-9), 7.31 (d, J = 7.6, 1H; H-8 or H-10), 7.29 (d, J = 7.2, 1H; H-8 or H-10), 7.07 (s, 1H; H-12), 5.0-3.9 (br s, 1H; H-21), 4.60 (s, 2H; H-3), 4.39 (dd, J = 5.7, 6.0, 2H; H-20), 4.30 (d, J = 5.7, 2H; H-13), 4.12 (s, 2H, H-2), 2.16 (t, J = 6.0, 2H; H-16), 1.86-1.80 (m, 2H; H-19), 1.56-1.48 (m, 2H; H-17), 1.17- 1.11 (m, 2H; H-18); 13C NMR 112 112
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(125 MHz, DMSO-d6, 120°C) δ = 172.5 (C=O), 171.5 (C=O), 170.2 (C=O), 144.0 (C-11 or C-7), 140.7 (C-7 or C-11), 136.8 (C-4), 128.9 (C-8 or C-10), 128.7 (C-9), 125.1 (C-8 or C-10), 124.3 (C-12), 122.9 (C-5), 50.0 (C-20), 42.6 (C-13), 35.4 (C-16), 29.5 (C-19), 25.8 (C-18), 24.5 (C-17); HRMS (ESI+) m/z = 386.1839 [M+H]+ found, C19H24N5O4+ required 386.1828.
Macrocyclic urea 10
Fluorous-tagged macrocycle 6 (75 mg, 0.083 mmol, 1.0 eq) was dissolved in dry THF (4 mL) and 1 M aqueous LiOH (165 µL, 0.165 mmol, 2.00 eq) was added at 0°C. After 30 min H2O (0.2 mL) was added and the solution was stirred at ambient temperature for 2 h. 4 M HCl in dioxane (0.05 mL, 2 mmol, 2.4 eq) was added and the solvent was removed under a stream of N2. After purification by prep-HPLC (5-30% B), title compound 10 (25 mg, 0.054 mmol, 65%) was isolated as a white solid. TLC Rf = 0.10 (EtOAc/AcOH 3:2); HPLC tr = 5.09 min (5-100% B), peak area 96%; [α]D28.7 = 26.3° (c = 0.417 in MeOH); IR (neat) νmax = 2988 (CH), 1733 ((C=O)OH), 1610 ((C=O)N); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.74 (s, 1H; H-5), 7.01 (d, J = 3.3, 1H; H-8), 6.46 (m, 1H; H-12), 6.43 (d, J = 3.3, 1H; H-9), 5.98 (d, J = 8.7, 1H; H-14), 4.93 (d, J = 16.2, 1H; H-3a), 4.88 (d, J = 16.2, 1H; H-3b), 4.70-4.64 (m, 2H; H-11a and H-15), 4.41-4.33 (m, 2H; H-19), 4.19 (d, J = 17.2, 1H; H-2a), 4.10 (d, J = 17.2, 1H; H-2b), 3.97 (dd, J = 15.8, 2.3, 1H; H-11b), 3.02 (br s; H21 and 22, signal coincides with water signal), 1.97 (m, 1H; H-18a), 1.79 (m, 1H; H-18b), 1.671.61 (m, 1H; H-16a), 1.44-1.37 (m, 1H; H-16b), 1.27-1.13 (m, 2H; H-17); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.6 (C-20), 169.3 (C-1), 158.6 (C-6), 156.6 (C-13), 154.7 (C-10), 146.7 (C-7), 142.9 (C-4), 122.1 (C-5), 117.3 (C-8), 108.5 (C-9), 48.6 (C-19), 47.9 (C-15), 47.6 (C-2), 43.4 (C-3), 36.0 (C-11), 30.7 (C-16), 27.5 (C-18), 20.6 (C-17); HRMS (ESI+) m/z = 462.2109 [M+H]+ found, C20H28N7O6+ required 462.2096.
Reduction Macrocyclic urea SI-160
113 113
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DOI: 10.1038/NCHEM.1729
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Fluorous-tagged macrocycle SI-68 (35 mg, 0.039 mmol, 1.0 eq) was reacted according to GP15. After purification by preparative HPLC (5-22% B), title compound SI-160 (10 mg, 0.023 mmol, 59%) was isolated as white solid. HPLC tr = 7.01 min (5-30% B), peak area 96%; 1H NMR (500 MHz, DMSO-d6, 27 °C) δ = 8.65 (s, 1H; H-13), 8.10 (q, J = 4.5 1H; H-22), 8.06 (s, 1H; H-5), 7.80 (br s, 1H; H-12), 7.29 (t, J = 7.7, 1H; H-9), 6.97 (d, J = 7.7, 1H; H-8 or H-10), 6.77 (d, J = 7.8, 1H; H-8 or H-10), 6.32 (d, J = 8.8, 1H; H-15), 4.58-4.22 (m, 5H; H-3, H-16 and H-20), 3.79-3.58 (m, 3H; H-1 and H-2a), 3.30-3.16 (m, 1H; H-2b), 2.59 (d, J = 4.5, 3H; H-23), 2.38-2.22 (m, 1H; H-19a), 1.73-1.57 (m, 2H; H-17a and H-19b), 1.47-1.34 (m, 1H; H-17b), 1.26-0.99 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 27 °C) δ = 172.4, 171.4, 154.6 (each C=O), 144.3, 139.5, 136.5 (each quat. C), 129.3 (C-9), 122.3 (C-5), 119.7 (C-8 or C-10), 118.8 (C-8 or C-10), 115.6 (C-12), 58.6 (C-1), 50.6 (C-16), 50.2 (C-20), 48.1 (C-2), 46.9 (C-3), 34.8 (C-17), 28.5 (C-19), 25.5 (C-23), 22.5 (C-18); HRMS (ESI+) m/z = 452.2039 [M+Na]+ found, C20H27N7O4Na+ required 452.2017.
Macrocyclic urea 41
Fluorous-tagged macrocycle SI-98 (35 mg, 0.042 mmol, 1.0 eq) was reacted according to GP15. After purification by preparative HPLC (10-25% B), title compound 41 (13 mg, 0.36 mmol, 85%) was isolated as a colorless oil. TLC Rf = 0.23 (CH2Cl2/MeOH 10:1); HPLC tr = 4.78 min (10-40% B), peak area 97%; 1H NMR (500 MHz, DMSO-d6, 120°C) δ = 7.81 (br s, 1H; H-14), 7.70 (s, 1H; H-5), 7.35 (t, J = 7.3, 1H; H9), 7.29 (d, J = 7.3, 1H; H-8 or H-10), 7.26 (d, J = 7.3, 1H; H-8 or H-10), 6.99 (s, 1H; H-12), 4.64 (s, 2H; H-3), 4.39 (t, J = 5.7, 2H; H-20), 4.29 (d, J = 6.0, 2H; H-13), 3.62 (t, J = 6.9, 2H; H-1), 3.44 (m, 2H; H-2), 2.16 (t, J = 6.3, 2H; H-16), 1.86-1.80 (m, 2H; H-19), 1.56-1.48 (m, 2H; H-17), 1.17-1.09 (m, 2H; H-18); 13C NMR (125 MHz, DMSO-d6, 120°C) δ = 172.4 (C=O), 171.6 (C=O), 144.7 (C-7 or C-11), 140.6 (C-7 or C-11), 137.8 (C-4), 128.5 (C-8 or C-10), 128.3 (C-9), 125.0 (C-8 or C-10), 124.4 (C-12), 122.9 (C-5), 59.6 (C-1), 50.1 (C-20), 50.0 (C-2), 42.5 (C-13), 36.0 (C-21), 35.5 (C-16), 29.7 (C-19), 26.0 (C-18), 24.7 (C-17); HRMS (ESI+) m/z = 372.2015 [M+H]+ found, C19H26N5O3+ required 372.2030.
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Macrocyclic urea 11
Fluorous-tagged macrocycle 6 (75 mg, 0.083 mmol, 1.0 eq) was reacted according to GP15. After purification by preparative HPLC (5-25% B), title compound 11 (28 mg, 0.063 mmol, 76%) was isolated as white solid. TLC Rf = 0.25 (MeOH/CH2Cl2 1:10); HPLC tr = 4.89 min (5-100% B), peak area 99%; [α]D28.7 = 38.0° (c = 0.417 in MeOH); IR (neat) νmax = 3348 (OH), 2938 (CH), 1611 ((C=O)N); 1H NMR (500 MHz, DMSO-d6, 90 °C) δ = 7.60 (s, 1H; H-5), 6.94 (d, J = 3.5, 1H; H-8), 6.43 (br s, 1H; H-12), 6.38 (d, J = 3.5, 1H; H-9), 5.96 (br s, 1H; H-14), 4.95 (d, J = 16.0, 1H: H-3a), 4.89 (d, J = 16.0, 1H; H-3b), 4.64-4.59 (m, 2H; H-11a and H-15), 4.39-4.30 (m, 2H; H-19), 3.93 (d, J = 15.5, 1H; H-11b), 3.62-3.50 (m, 4H; H-1 and H-2), 2.93 (br s, 6H; H-21 and H-22), 1.93-1.87 (m, 1H; H18a), 1.82-1.75 (m, 1H; H-18b), 1.65-1.58 (m, 1H; 16a), 1.42-1.35 (m, 1H; H-16b), 1.22-1.12 (m, 2H; H-17); 13C NMR (125 MHz, DMSO-d6, 90 °C) δ = 171.7 (C-20), 158.9 (C-6), 156.6 (C-13), 154.4 (C-10), 147.2 (C-7), 143.6 (C-4), 121.9 (C-5), 116.4 (C-8), 108.1 (C-9), 58.4 (C-1), 49.0 (C-2), 48.7 (C-19), 48.0 (C-15), 43.3 (C-3), 36.0 (C-11), 30.8 (C-16), 27.8 (C-18), 20.8 (C-17); HRMS (ESI+) m/z = 448.2319 [M+H]+ found, C20H30N7O5+ required 448.2302.
Principal Moment of Inertia Calculations We compared the molecular shape diversity of our macrocycle library with established reference sets of 40 top-selling brand-name drugs, 60 diverse natural products and 24 macrocyclic natural products.[15] The stochastic conformational search algorithm in the Molecular Operating Environment (MOE) software package[16] was used to generate 3D conformers for each compound. The MMFF94x force field was used with the generalized Born solvation model for the minimizations. Sampling and minimization parameters were implemented as follows: Stochastic Search Limit: 7 Refinement Conformation Limit: 300 Stochastic Search Failure Limit: 100 Stochastic Search Iteration Limit: 1000 Energy Minimization Iteration Limit: 200 Energy Minimization Gradient Test: 0.01 115 115
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Only the conformer with the lowest energy was retained for principal moment of inertia (PMI) calculations in each conformational sampling run. Normalized PMI ratios (I1/I3 and I2/I3) of these conformers were obtained from MOE and then plotted on a triangular graph, with the coordinates (0,1), (0.5,0.5) and (1,1) representing a perfect rod, disc and sphere respectively.
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Drugs[15]
Natural Products[15]
Compound
npr1
npr2
Abilify Aciphex Aciphex Actos Adderall Ambien Avandia Benazepril Celebrex Concerta Coreg Crestor Cymbalta Diovan Effexor Flonase Fosamax Imitrex Lamictal Levaquin Lexapro Lipitor Nexium Norvasc Plavix Prevacid Prevacid Protonix Protonix Risperdal Serevent Seroquel Singulair Topamax Toprol Tricor Valtrex Wellbutrin Zetia Zocor Zoloft Zyprexa Zyrtec
0,295654 0,075929 0,082531 0,463255 0,187001 0,377477 0,375426 0,445433 0,363167 0,429713 0,656530 0,270494 0,396282 0,275662 0,353232 0,253542 0,677628 0,247709 0,229390 0,190810 0,455280 0,529854 0,275484 0,427443 0,296689 0,099878 0,303180 0,089751 0,094608 0,090427 0,509771 0,165779 0,272087 0,351737 0,136820 0,207635 0,287954 0,195106 0,246216 0,403071 0,299490 0,348574 0,199646
0,778329 0,980037 0,982998 0,696069 0,927327 0,680460 0,822949 0,816395 0,687574 0,689608 0,721788 0,811394 0,751873 0,849159 0,802320 0,963402 0,780477 0,819678 0,911644 0,844335 0,723125 0,809632 0,797230 0,811931 0,880172 0,966122 0,886000 0,955345 0,959908 0,936130 0,760083 0,929957 0,916115 0,800199 0,913152 0,830835 0,751349 0,948008 0,805541 0,711209 0,953590 0,692557 0,836693
Compound Actinonin Adriamycin AmphotericinB Apoptolidin Bleomycin BrefeldinA BrevetoxinB CalyculinA Colchicine Colchicine Colchicine Colchicine CytochalasinB Discodermolide DuocarmycinA EpothiloneA ErythromycinA Fumagillin Geldanamycin Geldanamycin GinkgolideB Lactacystin Monensin MycobactinS PenicillinG PhorbolMA PhorbolMA Radicicol RifamycinB RifamycinB RifamycinB RifamycinB RifamycinB RifamycinB RifamycinB RifamycinB SalicylihalamideA Staurosporine Streptomycin TalaromycinB Telomestatin TrapoxinB Trichostatin Vancomycin Vincristine Quinine
npr1
npr2
0,314978 0,283220 0,215551 0,301694 0,404781 0,255142 0,149647 0,442236 0,395296 0,258193 0,458247 0,513293 0,431674 0,182128 0,104513 0,447710 0,485996 0,066479 0,369201 0,392818 0,363537 0,478299 0,221267 0,567410 0,227679 0,403734 0,512005 0,490589 0,534830 0,544966 0,618686 0,524795 0,648821 0,678080 0,627544 0,601820 0,191225 0,464212 0,335744 0,186426 0,496427 0,460215 0,288807 0,516891 0,482176 0,303785
0,841802 0,800172 0,847453 0,830875 0,826205 0,817388 0,899486 0,896401 0,837965 0,846521 0,773003 0,755147 0,740608 0,981632 0,945885 0,804309 0,813810 0,974218 0,725345 0,769442 0,879045 0,938709 0,914230 0,787169 0,840740 0,770927 0,787906 0,823386 0,679088 0,674059 0,762072 0,868426 0,813721 0,844921 0,817624 0,886052 0,848920 0,664055 0,786998 0,935125 0,509642 0,680871 0,802339 0,626096 0,946784 0,834042
117 117
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Spongistatin1 ZaragozicAcidA Arglabin Artemisinin Bestatin CephamycinC Coformycin Compactin Forskolin Mizoribine Plaunotol Spergualin SQ26180 Thienamycin AvermectinB1a Calicheamicin CyclosporinA Daptomycin EchinocandinB FK506 Lipstatin MidecamycinA1 PseudomonicAcidA Rapamycin Taxol Validamycin
Macrocyclic Natural Products[15] Compound DecarestrictineA1 DecarestrictineB DecarestrictineC1 DecarestrictineD DiplodialideA Jasmineketolactone PhoracantholideI PhoracantholideJ Pinolidoxin PyrenolideA Ferrulactone1 '2,4,6,8-Tetramethyl3,4-dihydroxydec-8(9)enolide' ApicularenA CladospolideA CladospolideB CladospolideD
npr1
npr2
0,469217 0,610153 0,523140 0,460594 0,395167 0,361150 0,533624 0,463326 0,297314 0,343546 0,560992
0,640137 0,676987 0,616675 0,707181 0,735937 0,799690 0,723704 0,712112 0,861372 0,781822 0,709680
0,577023 0,354153 0,320632 0,438580 0,377547
0,641499 0,885766 0,796694 0,721334 0,753806
0,428667 0,287707 0,402854 0,541282 0,297570 0,488698 0,298204 0,430983 0,520873 0,239424 0,460051 0,541169 0,435835 0,476680 0,278083 0,227585 0,418415 0,762741 0,317238 0,377179 0,462998 0,325184 0,380836 0,445581 0,437027 0,451444
0,817984 0,920770 0,721308 0,644874 0,838998 0,856650 0,821609 0,716564 0,688349 0,857007 0,900390 0,946050 0,794101 0,854387 0,812448 0,920330 0,935663 0,908347 0,945521 0,761235 0,738670 0,904263 0,748719 0,764618 0,832107 0,807012
This Library Compound
npr1
npr2
SI-120 SI-121 SI-122 SI-123 SI-139 SI-140 SI-129 SI-130 SI-131 SI-132 SI-124
0,426860 0,409236 0,378584 0,393541 0,458708 0,458689 0,337414 0,603342 0,603108 0,488014 0,419200
0,751808 0,984741 0,758819 0,827466 0,872686 0,898897 0,809335 0,893682 0,685070 0,837488 0,963682
SI-119 46 8 SI-66 SI-67
0,233825 0,216745 0,449897 0,381807 0,332882
0,869291 0,979512 0,792556 0,742562 0,822105
118 118
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Curvularin Lyngbouilloside Methymycin Neomethymycin PladienolideB FluvirucinA1 Hypothemycin Iriomoteolide3a
0,303779 0,249436 0,436257 0,496348 0,134666 0,243234 0,329504 0,277092
SI-79 39 SI-158 SI-116 SI-160 SI-156 SI-127 SI-126 SI-118 SI-117 SI-128 SI-151 SI-150 38 SI-134 SI-136 SI-135 SI-137 SI-138 SI-108 45 SI-111 SI-152 SI-153 10 11 SI-154 9 37 SI-155 12 SI-141 SI-142 SI-145 SI-143 SI-146 SI-159 SI-157 41 SI-147 SI-148 43 SI-133 SI-94 SI-95 SI-84 SI-85 40
0,797272 0,959705 0,864653 0,948657 0,972028 0,862219 0,776135 0,789016
0,511040 0,580409 0,260338 0,236901 0,287835 0,159901 0,359031 0,325257 0,264612 0,243017 0,368419 0,476803 0,274156 0,352325 0,315575 0,399747 0,393015 0,321154 0,346864 0,248383 0,790730 0,514504 0,504029 0,533017 0,415811 0,405758 0,349819 0,442345 0,427863 0,269188 0,293144 0,542832 0,438663 0,597207 0,585405 0,501556 0,538097 0,532269 0,532621 0,331164 0,434056 0,362235 0,392063 0,533816 0,459547 0,541387 0,567129 0,654203
0,819269 0,721200 0,855390 0,847831 0,808598 0,931005 0,782802 0,814490 0,823323 0,851862 0,855286 0,768890 0,856165 0,822556 0,851494 0,767379 0,804794 0,813190 0,810429 0,816229 0,908096 0,770504 0,902865 0,722536 0,772367 0,741674 0,774643 0,764378 0,814506 0,861131 0,839624 0,647469 0,728947 0,652775 0,648634 0,797826 0,650234 0,723660 0,625576 0,765974 0,795417 0,761515 0,824085 0,626828 0,626798 0,845483 0,673253 0,675161
119 119
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Crystal Structure of Compound SI-106
F F F
F F F F F F
N
F F F F F F F F
N
N
O O
N O
O
HN
O
Identification code
ds1211
Empirical formula
C27 H24 F17 N5 O5
Formula weight
821.51
Temperature
220(2) K
Wavelength
0.71073 Å
Crystal system
Monoclinic
Space group
P2(1)/c
Unit cell dimensions
a = 19.1193(8) Å
= 90°.
b = 10.0007(4) Å
= 90.680(2)°.
c = 17.1728(7) Å
= 90°.
Å3
Volume
3283.3(2)
Z
4
Density (calculated)
1.662 Mg/m3
Absorption coefficient
0.178 mm-1
F(000)
1656
Crystal size
0.42 x 0.07 x 0.02 mm3
Theta range for data collection
3.77 to 25.04°.
Index ranges
-22