American Chemical Society
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Asymmetric Synthesis of cis-2,5-Disubstituted Pyrrolidine, the Core Scaffold of β3‑AR Agonists

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journal contribution
posted on 2013-03-15, 00:00 authored by Feng Xu, John Y. L. Chung, Jeffery C. Moore, Zhuqing Liu, Naoki Yoshikawa, R. Scott Hoerrner, Jaemoon Lee, Maksim Royzen, Ed Cleator, Andrew G. Gibson, Robert Dunn, Kevin M. Maloney, Mahbub Alam, Adrian Goodyear, Joseph Lynch, Nobuyashi Yasuda, Paul N. Devine
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.