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

被引：38

作者：

Xu, Feng ^{[1
]}

Chung, John Y. L. ^{[1
]}

Moore, Jeffery C. ^{[1
]}

Liu, Zhuqing ^{[1
]}

Yoshikawa, Naoki ^{[1
]}

Hoerrner, R. Scott ^{[1
]}

Lee, Jaemoon ^{[1
]}

Royzen, Maksim ^{[1
]}

Cleator, Ed ^{[2
]}

Gibson, Andrew G. ^{[2
]}

Dunn, Robert ^{[1
]}

Maloney, Kevin M. ^{[1
]}

Alam, Mahbub ^{[2
]}

Goodyear, Adrian ^{[2
]}

Lynch, Joseph ^{[1
]}

Yasuda, Nobuyashi ^{[1
]}

Devine, Paul N. ^{[1
]}

机构：

[1] Merck Res Labs, Rahway, NJ 07065 USA

[2] Merck Sharp & Dohme Res Labs, Hoddesdon EN11 9BU, Herts, England

来源：

ORGANIC LETTERS | 2013年 / 15卷 / 06期

关键词：

ENANTIOSELECTIVE SYNTHESIS; HYDROGENATION; LITHIUM; ESTERS; ROUTE;

D O I：

10.1021/ol400252p

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

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 beta(3)-AR agonists is synthesized In 38% overall yield.

引用

页码：1342 / 1345

页数：4

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