Hydroxy[4-(propan-2-yl)phenyl]acetic acid rac-2d. 1. H NMR Spectrum of rac-2d (400 MHz, CDCl3). 13. C NMR Spectrum of rac-2d (100 MHz, CDCl3) ...
Eur. J. Org. Chem. 2017 · ISSN 1099–0690 https://doi.org/10.1002/ejoc.201700161 SUPPORTING INFORMATION Title: Chemoenzymatic Preparation of Enantiomerically Enriched (R)-(–)-Mandelic Acid Derivatives: Application in the Synthesis of the Active Agent Pemoline Author(s): Marcin Poterała,* Maciej Dranka, Paweł Borowiecki*
Table of contents X-ray diffraction data (Table S1)…………………………………............………………… S2 Table S2. Analytical separation conditions of different compounds by Chiralcel OD-H (Diacel) chiral column …………………………………………...………....................… S3-S4 Copies
of
NMR,
HRMS,
IR,
UV/VIS
spectra
and
HPLC
chromatograms
……….……………………………………..……………………………………....….. S5-S37
S1
X-ray crystallography
Table S1. Crystal data and structure refinement parameters for (R)-(–)-11. Compound Chemical formula M /g·mol−1 Crystal size /mm3 T /K Crystal system
(R)-(–)-11 C20H26F6NO3P 473.39 0.32 × 0.15 × 0.1 100.0(1) orthorhombic
Space group P212121 a /Å 6.11283(16) b /Å 10.7206(3) c /Å 32.3877(5) α,β,γ /° 90 3 V /Å 2122.47(8) Z 4 −3 Dcalc /g·cm 1.481 Radiation, λ/ Å CuKα (λ = 1.5418) −1 μ /mm 1.841 F(000) 984.0 2Θ Range /° 8.68–133.22° Reflections collected 17547 Independent refln. 3752 Rint 0.0352 Parameters/restraints 284/0 S (F2)[a] 1.053 [b] R1, wR2 (I>2σ(I)) 0.0270, 0.0661 R1, wR2 (all data) 0.0290, 0.0673 −3 Δρmin/max/eÅ +0.15/−0.28 Flack parameter −0.004(18) [a] Goodness-of-fit S={[w(Fo2−Fc2)2]/(n−p)}1/2 where n is the reflections number and p is the parameters number; [b] R1=||Fo|−|Fc||/|Fo|, wR2={[w(Fo2−Fc2)2]/[w(Fo2)2]}1/2.
S2
Table S2. Analytical separation conditions of different compounds by Chiralcel OD-H (Diacel) chiral column. Compound
Ratio of n-hexane to 2-propanol
Elution velocity [mL/min]
Retention time [min]
0.8
8.939 (S) and 14.612 (R)
0.4
22.997 (S) and 24.383 (R)
0.8
9.185 (S) and 12.946 (R)
0.25
34.677 (S) and 36.610 (R)
90:10a
0.8
8.939 (S) and 14.612 (R)
99:1a
0.25
21.782 (S) and 23.480 (R)
95:5a
0.8
11.062 (S) and 13.837 (R)
99:1a
0.4
18.176 (S) and 19.740 (R)
95:5a
0.8
10.437 (S) and 12.668 (R)
90:10
99:1
a
90:10
99:1
a
a
a
S3
99:1a
0.4
17.587 (S) and 19.371 (R)
90:10a
0.7
14.707 (S) and 24.420 (R)
0.4
22.440 (S) and 27.504 (R)
90:10a
0.8
14.588 (S) and 17.379 (R)
98:2a
0.2
55.647 (S) and 61.512 (R)
N.R.b
N.R.b
N.R.b
N.R.b
N.R.b
N.R.b
0.8
32.816 (R) and 40.669 (S)
96:4
a
90:10
c
a
The samples were carried out at 254 nm and at 30 °C. Not resolvable. c The samples were carried out at 215 nm and at 30 °C. b
S4
Hydroxy(4-methylphenyl)acetic acid rac-2b
1
H NMR Spectrum of rac-2b (400 MHz, CDCl3)
13
C NMR Spectrum of rac-2b (100 MHz, CDCl3)
S5
Hydroxy(3-methylphenyl)acetic acid rac-2c
1
H NMR Spectrum of rac-2c [500 MHz, (CD3)2SO]
13
C NMR Spectrum of rac-2c [126 MHz, (CD3)2SO]
S6
Hydroxy[4-(propan-2-yl)phenyl]acetic acid rac-2d
1
H NMR Spectrum of rac-2d (400 MHz, CDCl3)
13
C NMR Spectrum of rac-2d (100 MHz, CDCl3)
S7
(4-Tert-butylphenyl)(hydroxy)acetic acid rac-2e
1
H NMR Spectrum of rac-2e (400 MHz, CDCl3)
13
C NMR Spectrum of rac-2e (100 MHz, CDCl3)
S8
Hydroxy(4-methoxyphenyl)acetic acid rac-2f 1
H NMR Spectrum of rac-2f [500 MHz, (CD3)2SO]
13
C NMR Spectrum of rac-2f [126 MHz, (CD3)2SO]
S9
Hydroxy(naphthalen-2-yl)acetic acid rac-2g 1
H NMR Spectrum of rac-2g (400 MHz, CD3COCD3)
13
C NMR Spectrum of rac-2g (100 MHz, CD3COCD3)
S10
Hydroxy(naphthalen-1-yl)acetic acid rac-2h 1
H NMR Spectrum of rac-2h [500 MHz, (CD3)2SO]
13
C NMR Spectrum of rac-2h [126 MHz, (CD3)2SO]
S11
Methyl hydroxy(phenyl)acetate rac-3a 1
H NMR Spectrum of rac-3a (400 MHz, CDCl3)
13
C NMR Spectrum of rac-3a (100 MHz, CDCl3)
S12
Methyl hydroxy(4-methylphenyl)acetate rac-3b 1
H NMR Spectrum of rac-3b (400 MHz, CDCl3)
13
C NMR Spectrum of rac-3b (100 MHz, CDCl3)
S13
Methyl hydroxy(3-methylphenyl)acetate rac-3c 1
H NMR Spectrum of rac-3c (400 MHz, CDCl3)
13
C NMR Spectrum of rac-3c (100 MHz, CDCl3)
S14
Methyl hydroxy[4-(propan-2-yl)phenyl]acetate rac-3d 1
H NMR Spectrum of rac-3d (400 MHz, CDCl3)
13
C NMR Spectrum of rac-3d (100 MHz, CDCl3)
S15
Methyl (4-tert-butylphenyl)(hydroxy)acetate rac-3e 1
H NMR Spectrum of rac-3e (400 MHz, CDCl3)
13
C NMR Spectrum of rac-3e (100 MHz, CDCl3)
S16
Methyl hydroxy(4-methoxyphenyl)acetate rac-3f 1
H NMR Spectrum of rac-3f (500 MHz, CDCl3)
13
C NMR Spectrum of rac-3f (100 MHz, CDCl3)
S17
Methyl hydroxy(naphthalen-2-yl)acetate rac-3g 1
H NMR Spectrum of rac-3g (500 MHz, CDCl3)
13
C NMR Spectrum of rac-3g (126 MHz, CDCl3)
S18
Methyl hydroxy(naphthalen-1-yl)acetate rac-3h 1
H NMR Spectrum of rac-3h (400 MHz, CDCl3)
13
C NMR Spectrum of rac-3h (100 MHz, CDCl3)
S19
Methyl (acetyloxy)(phenyl)acetate rac-4a 1
H NMR Spectrum of rac-4a (500 MHz, CDCl3)
13
C NMR Spectrum of rac-4a (126 MHz, CDCl3)
S20
Methyl (acetyloxy)(4-methylphenyl)acetate rac-4b 1
H NMR Spectrum of rac-4b (400 MHz, CDCl3)
13
C NMR Spectrum of rac-4b (100 MHz, CDCl3)
S21
Methyl (acetyloxy)(3-methylphenyl)acetate rac-4c 1
H NMR Spectrum of rac-4c (400 MHz, CDCl3)
13
C NMR Spectrum of rac-4c (100 MHz, CDCl3)
S22
Methyl (acetyloxy)[4-(propan-2-yl)phenyl]acetate rac-4d 1
H NMR Spectrum of rac-4d (400 MHz, CDCl3)
13
C NMR Spectrum of rac-4d (100 MHz, CDCl3)
S23
Methyl (acetyloxy)(4-tert-butylphenyl)acetate rac-4e 1
H NMR Spectrum of rac-4e (500 MHz, CDCl3)
13
C NMR Spectrum of rac-4e (126 MHz, CDCl3)
S24
Methyl (acetyloxy)(4-methoxyphenyl)acetate rac-4f 1
H NMR Spectrum of rac-4f (400 MHz, CDCl3)
13
C NMR Spectrum of rac-4f (100 MHz, CDCl3)
S25
Methyl (acetyloxy)(naphthalen-2-yl)acetate rac-4g 1
H NMR Spectrum of rac-4g (500 MHz, CDCl3)
13
C NMR Spectrum of rac-4g (126 MHz, CDCl3)
S26
Methyl (acetyloxy)(naphthalen-1-yl)acetate rac-4h: 1
H NMR Spectrum of rac-4h (500 MHz, CDCl3)
13
C NMR Spectrum of rac-4h (126 MHz, CDCl3)
S27
2-Imino-5-phenyl-1,3-oxazolidin-4-one (Pemoline) rac-5b: 1
H NMR Spectrum of rac-5b [500 MHz, (CD3)2SO)]
13
C NMR Spectrum of rac-5b [126 MHz, (CD3)2SO)]
S28
HRMS spectrum of (R)-(+)-5 (ESI-TOF)
IR spectrum of rac-5 (Mineral oil, Nujol)
130
100
%T 50
0 4000
3000
2000
Wavenumber [cm-1] S29
1000
596
UV spectra of rac-5
Wavelength (nm) Abs ________________________________ 223.00 4.172 221.00 4.365 217.00 4.389 215.00 4.549 211.00 4.405 209.00 4.256
S30
HPLC analytical separation for both enantiomers of rac-5
HPLC chromatogram of optically active pemoline (R)-(+)-5 (98% ee)
S31
HPLC chromatogram of enantiomerically pure pemoline (R)-(+)-5 (>99% ee) obtained after two recrystallizations from EtOH
HPLC chromatograms of the optimization of the synthesis of pemoline (R)-(+)-5
S32
S33
S34
HPLC chromatograms of (R)-(+)-5 methanolic solution stored for 1, 4, and 8 days
S35
S36
1‐(2‐{[(2R)‐2‐(4‐Tert‐butylphenyl)‐2‐methoxyacetyl]oxy}ethyl)pyridin‐1‐ium hexafluoro-phosphate (R)-(-)-11: 1
H NMR Spectrum of (R)-(-)-11 (400 MHz, CD3COCD3)
13
C NMR Spectrum of (R)-(-)-11 (100 MHz, CD3COCD3)
S37
