Process Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Org Lett. 2013 Mar 15;15(6):1342-5. doi: 10.1021/ol400252p. Epub 2013 Mar 1.
A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of β3-AR agonists is synthesized in 38% overall yield.
描述了一种实用的、对映选择性合成顺式-2,5-二取代吡咯烷的方法。通过一种新颖的分子内 N→C 苯甲酰基迁移，容易得到酮酯，通过酶促 DKR 还原可以得到 >99%ee 和 >99:1dr 的 syn-1,2-氨基醇。随后，环状亚胺的氢化以高非对映选择性得到顺式吡咯烷。通过将生物技术整合到有机合成中，并在 11 步中仅分离出三个中间体，β3-AR 激动剂的核心支架以 38%的总收率合成。
