Synlett, Table of Contents LETTER © Georg Thieme Verlag Stuttgart · New York Asymmetric Synthesis of Conformationally Constrained trans-2,3-Piperidinedicarboxylic Acid Derivatives Jincong Zhuo*, David M. Burns, Colin Zhang, Meizhong Xu, Lingkai Weng, Ding-Quan Qian, Chunhong He, Qiyan Lin, Yun-Long Li, Eric Shi, Costas Agrios, Brian Metcalf, Wenqing Yao*Incyte Corporation, Medicinal Chemistry Division, Experimental Station, Wilmington, DE 19880, USAFax: +1(302)4252704; e-Mail: JZhuo@incyte.com; e-Mail: WYao@incyte.com; Recommend Article Abstract Buy Article All articles of this category Abstract An efficient asymmetric synthesis of conformationally constrained (2S,3S)-piperidinedicarboxylic acid derivatives starting from l-aspartic acid β-tert-butyl ester and 3-chloro-2-(chloromethyl)-1-propene is described. The key steps involve N-alkylation of the aspartic acid ester followed by a stereoselective enolate intramolecular cyclization (>95:5 dr). Various synthetic strategies were explored to achieve the cyclopropanation of the resulting olefin, including the Simmons-Smith reaction and palladium-catalyzed cyclopropanation. Key words cyclopropanation - allylic amine - Simmons-Smith reagent - asymmetric synthesis - spiro piperidine Full Text References References 1a Prentis RA. Lis Y. Walker SR. Br. J. Clin. Pharmacol. 1988, 25: 387 1b Kassel DB. Curr. Opin. Chem. Biol. 2004, 8: 339 2a Lipinski CA. J. Pharmacol. Toxicol. Methods 2000, 44: 235 2b Lipinski CA. Lombardo F. Dominy BW. Feeney PJ. Adv. Drug Deliv. Rev. 2001, 46: 3 3 Veber DF. Johnson SR. Cheng H.-Y. Smith BR. Ward KW. Kopple KD. J. Med. Chem. 2002, 45: 2615 4 Horton DA. Bourne GT. Smythe ML. Chem. Rev. 2003, 103: 893 5 Xue C.-B. Chen X.-T. He X. Roderick J. Corbett RL. Ghavimi B. Liu R.-Q. Covington MB. Qian M. Ribadeneira MD. Vaddi K. Trzaskos J. Newton RC. Duan J. Decicco CP. Bioorg. Med. Chem. Lett. 2004, 14: 4453 6 Meltzer PC. Wang B. Chen Z. Blundell P. Jayaraman M. Gonzalez MD. George C. Madras BK. J. Med. Chem. 2001, 44: 2619 7 Fiallo MML. Deydier E. Bracci M. Garnier-Suillerot A. Halvorsen K. J. Med. Chem. 2003, 46: 1683 8 Moss N. Beaulieu P. Duceppe J.-S. Ferland J.-M. Gauthier J. Ghiro E. Goule S. Guse I. Llinas-Brunet M. Plante R. Plamondon L. Wernic D. Deziel R. J. Med. Chem. 1996, 39: 2178 9a Swahn B.-M. Edvinsson KM. Kallin E. Larsson U. Berge O.-G. Molin H. Pelcman B. Claesson A. Bioorg. Med. Chem. 1997, 5: 1293 9b Frydenvang K. Ebert B. Johansen TN. Brehm L. Krogsgaard-Larsen P. J. Med. Chem. 1996, 39: 183 9c Madsen U. Brehm L. Schaumburg K. Joergensen FS. Krogsgaard-Larsen P. J. Med. Chem. 1990, 33: 374 10a Maison W. Grohs DC. Prenzel AHGP. Eur. J. Org. Chem. 2004, 7: 1527 10b Williams PD. Bock MG. Tung RD. Garsky VM. Perlow DS. Erb JM. Lundell GF. Gould NP. Whitter WL. Hoffman JB. Kaufman MJ. Bradley BV. Clineschmidt V. Pettibone DJ. Freidinger RM. Veber DF. J. Med. Chem. 1992, 35: 3905 11 Agami C. Hamon L. Kadouri-Puchot C. Guen VL. J. Org. Chem. 1996, 61: 5736 12 Gmeiner P. Feldman PL. Chu-Moyer MY. Rapoport H. J. Org. Chem. 1990, 55: 3068 13 Xue C.-B. He X. Roderick J. Corbet RL. Decicco CP. J. Org. Chem. 2002, 67: 865 14 Simmons HE. Cairns TL. Vladuchick SA. Hoiness CM. Org. React. 1973, 20: 1 15 Nakamura M. Hirai A. Nakamura E. J. Am. Chem. Soc. 2003, 125: 2341 16 Takakis IM. Rhodes YE. J. Org. Chem. 1978, 43: 3496 17a Lorenz JC. Long J. Yang Z. Xue S. Xie Y. Shi Y. J. Org. Chem. 2004, 69: 327 17b Long J. Yuan Y. Shi Y. J. Am. Chem. Soc. 2003, 125: 13632 18 Denmark SE. Edwards JP. J. Org. Chem. 1991, 56: 6974 19a Aggarwal VK. Fang GY. Charmant JPH. Meek G. Org. Lett. 2003, 5: 1757 19b Aggarwal VK. Fang GY. Meek G. Org. Lett. 2003, 5: 4417 20 Charette AB. Juteau H. Lebel H. Molinaro C. J. Am. Chem. Soc. 1998, 120: 11943 21 Wipf P. Stephenson CRJ. Org. Lett. 2005, 7: 1137 22 Russ P. Ezzitouni A. Marquez VE. Tetrahedron Lett. 1997, 38: 723 23 Suda M. Synthesis 1981, 714 24a Davis FA. Chao B. Fang T. Szewczyk JM. Org. Lett. 2000, 2: 1041 24b Davis FA. Fang T. Chao B. Burns DM. Synthesis 2000, 2106
