Synthesis of highly substituted - Springer Link

6 downloads 0 Views 85KB Size Report
and three isomeric pyrrolidines are obtained in the cycloaddition. Consequently, the use of three ..... amino-4-pentene-2,3-diols to lyxo-configurated deoxyimino.
Molecular Diversity 7: 175–180. KLUWER/ESCOM © 2003 Kluwer Academic Publishers. Printed in the Netherlands.

175

Short communication

Enhancing stereochemical diversity by means of microwave irradiation in the absence of solvent: Synthesis of highly substituted nitroproline esters via 1,3-dipolar reactions Angel D´ıaz-Ortiz1∗ , Antonio de la Hoz1 , M. Antonia Herrero1 , Pilar Prieto1 , Ana S´anchezMigall´on1, Fernando P. Coss´ıo2∗ , Ana Arrieta2 , Silvia Vivanco2 & Concepci´on Foces-Foces3 ´ Area de Qu´ımica Org´anica, Facultad de Qu´ımica, Universidad de Castilla-La Mancha, E-13071 Ciudad Real, Spain; 2 Departamento de Qu´ımica Org´anica I, Facultad de Qu´ımica, Universidad del Pa´ıs Vasco, Apto. 1072, 20080 Donostia, San Sebastian, Spain; 3 Departamento de Cristalograf´ıa, Instituto de Qu´ımica-F´ısica ‘Rocasolano’, CSIC, Serrano 119, E-28006 Madrid, Spain (∗ Author for correspondence, E-mail: [email protected], Fax: +34 926295318) 1

Received 27 May 2003; Accepted 20 June 2003

Key words: azomethine ylide, 1,3-dipolar cycloaddition, microwaves, proline esters, solventless

Summary Microwave irradiation induces the 1,3-dipolar cycloaddition of imines derived from α-aminoesters with βnitrostyrenes in the absence of solvent within 10–15 min. The reaction proceeds to give yields in the range 81–86% and three isomeric pyrrolidines are obtained in the cycloaddition. Consequently, the use of three imines and two βnitrostyrenes gives rise to a library of 18 nitroproline esters. The use of classical heating with longer reaction times (24 h) gives lower yields of products (below 50%) and only two stereoisomers can be detected in each reaction.

Introduction Combinatorial chemistry allows the synthesis of a large number of molecules by varying combinations of modular components. The application of this technique in the preparation of new compounds for drug discovery is well documented [1–5]. Microwave-assisted organic synthesis is a highspeed methodology with clear benefits: significant rate-enhancements and higher products yields are usually observed [6–10]. In several cases, the stereoand/or regiochemical outcome of microwave-assisted reactions has been found to be different to that observed under classical heating [11, 12]. The combination of the microwave heating methodology and combinatorial chemistry provides an increase in speed and effectiveness in the synthesis of organic compounds – changes that cannot be achieved by conventional heating methods. In recent years, a considerable number of publications have described the preparation of di-

verse libraries using a combination of microwave and combinatorial chemistry methodologies [13–15]. Imines derived from α-aminoesters can be thermally isomerized to azomethine ylides [16, 17] that undergo 1,3-dipolar cycloadditions with dipolarophiles to afford pyrrolidine derivatives [18–20]. These nitrogen heterocycles are the basis of a large number of biologically active alkaloids [21] that are of great interest in medicinal chemistry, e.g. as glycosidase inhibitors [22–24]. This cycloaddition reaction, which allows the preparation of highly-substituted five-membered heterocycles, has been employed in the synthesis of several libraries of functionalized pyrrolidines [25–31]. As a continuation of our current research [32, 33], we report here the 1,3-dipolar cycloaddition between imines derived from α-aminoesters and nitroalkenes under focused microwaves in the absence of solvent.

176

Scheme 1.

Results and discussion

Microwave irradiation induces the thermal isomerization of imines 1–3 to the corresponding azomethine ylides, which then undergo 1,3-dipolar cycloaddition with substituted β-nitrostyrenes 4, 5 within 10– 15 min to afford the pyrrolidines 6–10 in 81–86% yield (Scheme 1). Reactions were performed in open vessels at atmospheric pressure in a modified Prolabo MX350 microwave reactor with total control of power and temperature by an infrared sensor. Reaction conditions, yields and stereoisomer ratios are summarized in Table 1 [34]. Three stereoisomers were obtained in each of the cycloadditions. Therefore, by using a combination of two imines and three β-nitrostyrenes, a library of 18 racemic highly-substituted nitroproline esters can be obtained.

On using classical heating with an oil bath (toluene reflux, 24 h), these cycloadditions afforded yields below 50% and only stereoisomers a and b were obtained [35] (c.a., 50:50). Consequently, only 12 racemic nitroproline esters can be obtained with a combination of two imines and three β-nitrostyrenes. On the basis of these results, microwave irradiation has numerous benefits in comparison with classical heating methods: reaction times are shortened, product yields increased and a new stereoisomer can be obtained. These advantages are ideal for applications in combinatorial chemistry. The stereochemistry of cycloadducts a and b was easily deduced by comparison with the products obtained by classical heating and corresponds to the expected endo and exo approach, respectively. The stereochemistry of adducts c was inferred by X-ray crystallography of the N-acetyl derivative 11 [36] (Scheme 2 and Figure 1).

177 Table 1. 1,3-Cycloaddition reactions between imines 1–3 and β-nitrostyrenes 4–5 under microwave irradiation in the absence of solvent Reagents

R1

Reaction conditions

R2

Yield

Stereoisomer ratiosb

(%)a

a

Power

Temperature

Time

1+4

210 W

120 ◦ C

10 min

Me

OMe

86

33

2+4

210 W

110 ◦ C

10 min

Cl

OMe

84

31

3+4 1+5 2+5

270 W 240 W 270 W

120 ◦ C 120 ◦ C 120 ◦ C

15 min 13 min 10 min

OH Me Cl

OMe Cl Cl

84 82 81

39 31 37

a Isolated product. b Ratios observed under classical heating in boiling toluene (Ref. 35) are given in parentheses.

Scheme 2.

Figure 1. Molecular structure of compound 11.

b 44 (50/50) 45 (44/56) 41 49 42

c 23 24 20 20 21

178

Scheme 3.

The new stereoisomers c, which was not obtained by classical heating, could be formed by: (i) epimerization of the endo or exo adducts during the course of the reaction or (ii) thermal isomerization of the imine (Scheme 3). The first process can be excluded on the basis that a mixture of adducts 6a and 6b (obtained by classical heating) was stable when exposed to microwave irradiation under the appropiate reaction conditions for 15 min. We therefore propose a thermal isomerization of the imine by rotation in the carboxylic part of the ylide. In both conformers a hydrogen bond should stabilize the structure. The endo approach of the β-nitrostyrene to the second conformation of the ylide would explain the formation of stereoisomers c (Scheme 3). This process is observed exclusively under microwave irradiation – it may be that under these conditions it is possible to break the hydrogen bond in the first conformation (1 –3 ) and allow the subsequent rotation of this part of the ylide. Formation of the second dipole (1 –3 ) exclusively under microwave irradiation should be related to a higher polarity, hardness and a lower polarizability than the first dipole as we have previously showed in cycloaddition reactions to C70 [12]. Computational studies on model reactions are underway.

Table 2. Microwave irradiation (240 W/120 ◦ C/10 min) Reagents

Overall yield (%)

Products (ratio)

1 (0.5 equiv) + 2 (0.5 equiv) + 5 (1 equiv)

88

6a (12) + 6b (18) + 6c (13) + 9a (15) + 9b (32) + 9c (10)

1 (1 equiv) + 4 (0.5 equiv) + 5 (0.5 equiv)

90

9a (10) + 9b (19) + 9c (7) + 10a (16) + 10b (27) + 10c (21)

We also studied the cycloaddition of a mixture of imines 1 (0.5 equiv) and 2 (0.5 equiv) with the β-nitrostyrene 5 (1 equiv) as well as a mixture of β-nitrostyrenes 4 (0.5 equiv) and 5 (0.5 equiv) with the imine 1 (1 equiv). The results are summarized in Table 2. These results indicate that, in spite of the lower electrophilicity of β-nitrostyrene 4 with respect to 5, and the different nucleophilicity of azomethine ylides derived from imines 1 and 2, in both experiments the overall molecular diversities achieved are similar. This fact shows the potential and the wide scope of this methodology to generate large libraries of nitroproline esters using a very simple experimental device.

179 Conclusions In conclusion, imines derived from α-aminoesters can be thermally isomerized to azomethine ylides, which subsequently undergo 1,3-dipolar cycloadditions with β-nitrostyrenes. The use of microwave irradiation leads to dramatically reduced reaction times, improved product yields and a new stereoisomer that is not formed during classical heating. These important benefits can be advantageously applied in combinatorial chemistry to obtain large nitroproline ester libraries.

Acknowledgements Financial support from the Spanish DGESIC (Projects BQU2001-1095, BQU2001-0904 and BQU20000868), Gobierno Vasco/Eusko Jaurlaritza, Universidad del País Vasco/Euskal Herriko Unibertsitatea (Project 9/ UPV00170.215-13548/2001) and Junta de Comunidades de Castilla-La Mancha (Project PAI-02-019) is gratefully acknowledged.

References 1. Maclean, D., Baldwin, J. J., Ivanov, V. T., Kato, Y., Shaw, A., Schneider, P. and Gordon, A. E. M., Glossary of terms used in combinatorial chemistry, J. Comb. Chem., 2 (2000) 562–578. 2. Hermkens, P. H. H., Ottenheijm, H. C. J. and Rees, D. C., Solid phase organic reactions: A review of the recent literature, Tetrahedron, 52 (1996) 4527–4554. 3. Hermkens, P. H. H., Ottenheijm, H. C. J. and Rees, D. C., Solid phase organic reactions II: A review of the literature Nov 95–Nov 96, Tetrahedron, 53 (1997) 5643–5678. 4. Dolle, R. E. and Nelson, K. H., Comprehensive survey of combinatorial library synthesis: 1998, J. Comb. Chem., 1 (1998) 235–282. 5. Dolle, R. E., Comprehensive survey of combinatorial library synthesis: 1999, J. Comb. Chem., 2 (1999) 383–433. 6. Loupy, A., Petit, A., Hamelin, J., Texier-Boullet, F., Jacquault, P. and Mathé, D., New solvent-free organic synthesis using focused microwaves, Synthesis, (1998) 1213–1234. 7. Lidström, P., Tierney, J., Wathey, B. and Westman, J., Microwave assisted organic synthesis - A review, Tetrahedron, 57 (2001) 9225–9283. 8. Varma, R. S., Solvent-free organic syntheses using supported reagents and microwave irradiation, Green Chem., 1 (1999) 43–55. 9. Strauss, C. R., A combinatorial approach to the development of enviromentally benign organic chemical preparations, Aust. J. Chem., 52 (1999) 83–96. 10. Loupy, A. (ed.), Microwaves in Organic Synthesis, WileyVCH, Weinheim (FRG), 2002. 11. Bose, A. K., Banik, B. K. and Manhas, M. S., Stereocontrol of β-lactam formation using microwave irradiation, Tetrahedron Lett., 36 (1995) 213–216.

12. Langa, F., De la Cruz, P., De la Hoz, A., Espíldora, E., Cossío, F. P. and Lecea, B., Modification of regioselectivity in cycloadditions to C70 under microwave irradiation, J. Org. Chem., 65 (2000) 2499–2507. 13. Kappe, C. O., High-speed combinatorial synthesis utilizing microwave irradiation, Curr. Opin. Chem. Biol., 6 (2002) 314–320. 14. Larhed, M. and Hallberg, A., Microwave-assisted high-speed chemistry: A new technique in drug discovery, Drug Disc. Today, 6 (2001) 406–416. 15. Lew, A., Krutzik, P. O., Hart, M. E. and Chamberlin, A. R., Increasing rates of reactions: Microwave-assisted organic synthesis for combinatorial chemistry, J. Comb. Chem., 4 (2002) 95–105. 16. Grigg, R. and Kemp, J., 1,3-Dipolar cycloaddition reactions of imines of α-amino acid esters: X-ray crystal and molecular structure of methyl 4-(2-furyl)-2,7-diphenyl-6,8-dioxo3,7-diazabicyclo[3.3.0]octane-2-carboxylate, J. Chem. Soc., Chem. Commun., (1978) 109–111. 17. Grigg, R. and Kemp, J., X = Y – ZH systems as potential 1,3dipoles. The stereochemistry and regiochemistry of cycloaddition reactions of imines of α-amino-acid esters, Tetrahedron Lett., 21 (1980) 2461–2464. 18. Tsuge, O. and Kanemasa, S., ‘Recent Advances in Azomethine Ylide Chemistry’, in A. R. Katritzky (ed.), Advances in Heterocyclic Chemistry, Vol. 45, Academic Press, San Diego, 1989, pp. 231–349. 19. Lown, J. W., in A. Padwa (ed.), 1,3-Dipolar Cycloaddition Chemistry, Vol. 1, Wiley, New York, 1984, pp. 653–732. 20. Grigg, R., Prototopic routes to 1,3- and 1,5-dipoles, and 1,2-ylides: Applications to the synthesis of heterocyclic compounds, Chem. Soc. Rev., 16 (1987) 89–121. 21. Padwa, A., Chen, Y. Y., Chiacchio, U. and Dent, W., Diastereofacial selectivity in azomethine ylide cycloaddition reactions derived from chiral α-cyanoaminosilanes, Tetrahedron, 41 (1985) 3529–3535, and references therein. 22. Schwarz, R. T. and Datema, R., Inhibitors of trimming: New tools in glycoprotein research, Trends Biochem. Sci., 9 (1984) 32–34. 23. Fleet, G. W., Amino-sugar derivatives and related compounds as glycosidase inhibitors, Top. Med. Chem., 65 (1988) 149– 162. 24. Jäger, V. and Hümmer W., Cyclization of N-protected 1amino-4-pentene-2,3-diols to lyxo-configurated deoxyimino sugars (cis-dihydroxypyrrolidines): Synthesis of potential glycosidase inhibitors, Angew. Chem., Int. Ed. Engl., 29 (1990) 1171–1173. 25. Marx, M. A., Grillot, A. L., Louer, C. T., Beaver, K. A. and Barlett, P. A., Synthetic design for combinatorial chemistry. Solution and polymer-supported synthesis of polycyclic lactams by intramolecular cyclization of azomethine ylides, J. Am. Chem. Soc., 119 (1997) 6153–6167. 26. Fokas, D., Ryan, W. J., Casebier, D. S. and Coffen, D. L., Solution phase synthesis of a spiro[pyrrolidine-2,3’-oxindole] library via a three component 1,3-dipolar cycloaddition reaction, Tetrahedron Lett., 39 (1998) 2235–2238. 27. Murphy, M. M., Schullek, J. R., Gordon, E. M. and Gallop, M. A., Combinatorial organic synthesis of highly functionalizated pyrrolidines: Identification of a potent angiotensin converting enzyme inhibitor from a mercaptoacyl proline library, J. Am. Chem. Soc., 117 (1995) 7029–7030. 28. Hollinshead, S. P., Stereoselective synthesis of highly functionalized pyrrolidines via 1,3-dipolar cycloaddition reaction on a solid support, Tetrahedron Lett., 37 (1996) 9157–9160.

180 29.

30.

31.

32.

33.

Bicknell, A. J. and Hird, N. W., Synthesis of a highly functionalized rigid template by solid phase azomethine ylide cycloaddition, Bioorg. Med. Chem. Lett., 6 (1996) 2441– 2444. Hamper, B. C., Dukesherer, D. R. and South, M. S., Solidphase synthesis of proline analogs via a three component 1,3-dipolar cycloaddition, Tetrahedron Lett., 37 (1996) 3671– 3674. Gong, Y. D., Nadji, S., Olmstead, M. and Kurth, M. J., Solidphase synthesis: Intramolecular azomethine ylide cycloaddition (→ proline) and carbanilide cyclization (→ hydantoin) reactions, J. Org. Chem., 63 (1998) 3081–3086. De la Hoz, A., Díaz-Ortiz, A., Moreno, A. and Langa, F., Cycloadditions under microwave irradiation conditions: Methods and applications, Eur. J. Org. Chem., (2000) 3659–3673. Ayerbe, M., Arrieta, A., Cossío, F. P. and Linden, A., Stereocontrolled synthesis of highly substituted proline esters vis [3+2] cycloadditions between N-metalated azomethine ylides and nitroalkenes. Origins of the metal effect on the stereochemical outcome, J. Org. Chem., 63 (1998) 1795–1805.

34. General procedure: A mixture of the imine (1 equiv) and the β-nitrostyrene (1 equiv) was irradiated in a modified Prolabo MX350 microwave reactor at the power and for the time indicated in Table 1. The crude product was purified by silicagel flash column chromatography using hexane/ethyl acetate as the eluent. 35. Vivanco, S., Lecea, B., Arrieta, A., Prieto, P., Morao, I., Linden, A. and Cossío, F. P., Origins of the loss of concertedness in pericyclic reactions: Theoretical prediction and direct observation of stepwise mechanisms in [3+2] thermal cycloadditions, J. Am. Chem. Soc., 122 (2000) 6078–6092. 36. Beauseleil, E. and Lubell, W. D., Steric effects on the amide isomer equilibrium of prolyl peptides. Synthesis and conformational analysis of N-acetyl-5-terct-butylproline N methylamides, J. Am. Chem. Soc., 118 (1996) 12902–12908.