Diastereoselective Aldol Reaction of Zincated 3-Chloro-3-methyl-1-azaallylic Anions as Key Step in the Synthesis of 1,2,3,4-Tetrasubstituted 3-Chloroazetidines

作者:Mangelinckx Sven; De Sterck Bart; Colpaert Filip; Catak Saron; Jacobs Jan; Rooryck Stijn; Waroquier Michel; Van Speybroeck Veronique; De Kimpe Norbert*
来源:Journal of Organic Chemistry, 2012, 77(7): 3415-3425.
DOI:10.1021/jo300203t

摘要

Zincated 3-chloro-3-methyl-1-azaallylic anions undergo a stereoselective aldol addition across aromatic aldehydes and subsequent mesylation to produce syn alpha-chloro-beta-mesyloxyketimines, which were isolated in 80-84% yield and high diastereomeric excess (dr %26gt; 97/3) after purification via flash chromatography. The syn alpha-chloro-beta-mesyloxyketimines were further stereoselectively reduced to give stereochemically defined 3-aminopropyl mesylates, which were cyclized to 1,2,3,4-tetrasubstituted 3-chloroazetidines containing three contiguous stereogenic centers. DFT calculations on the key aldol addition revealed the presence of a highly ordered bimetallic six-membered twist-boat-like transition state structure with a tetra-coordinated metal cyclic structure. DFT calculations revealed that chelation of both zinc and lithium cations in the transition state structure leads to the experimentally observed high syn diastereoselectivity of aldol reactions.

  • 出版日期2012-4-6