title: Asymmetric synthesis of cis-2,5-disubstituted pyrrolidine, the core scaffold of β3-AR agonists.
abstract: 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.
authors: Process Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. feng_xu@merck.com
authors: Feng
authors: F
authors: Xu
authors: John Y L
authors: JY
authors: Chung
authors: Jeffery C
authors: JC
authors: Moore
authors: Zhuqing
authors: Z
authors: Liu
authors: Naoki
authors: N
authors: Yoshikawa
authors: R Scott
authors: RS
authors: Hoerrner
authors: Jaemoon
authors: J
authors: Lee
authors: Maksim
authors: M
authors: Royzen
authors: Ed
authors: E
authors: Cleator
authors: Andrew G
authors: AG
authors: Gibson
authors: Robert
authors: R
authors: Dunn
authors: Kevin M
authors: KM
authors: Maloney
authors: Mahbub
authors: M
authors: Alam
authors: Adrian
authors: A
authors: Goodyear
authors: Joseph
authors: J
authors: Lynch
authors: Nobuyashi
authors: N
authors: Yasuda
authors: Paul N
authors: PN
authors: Devine
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000605:Amino Alcohols / Q000737:chemistry; D002384:Catalysis; D006865:Hydrogenation; D007097:Imines / Q000737:chemistry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000605:Amino Alcohols; D007097:Imines; D011759:Pyrrolidines