Part I: Development of novel methods for the synthesis of homoallylic alcohols Part II: Multigrams synthesis of (-)-epibatidine

Abstract

Two conceptual strategies to access to cis- and trans-linear homoallylic alcohols have been developed. These methodologies feature the following highlights: (1) first efficient method that controls, in situ, both the enantioselectivity and the olefinic geometry; (2) the transfer is highly feasible for aliphatic substrates; (3) excess starting materials generated from the reaction can be recovered and reused; (4) the whole rearrangement is thermodynamically favorable and a steric effect is the driving force of this reaction. Subsequently, a large scale process has been developed for the synthesis of (a??)-epibatidine. The significant features include: (1) the synthesis requires only a total of 12 steps with a 12% yield over the longest linear sequence; (2) both enantiomers of epibatidine can be obtained by simply switching the chiral auxiliary; (3) the first ring closing metathesis of alkylated amines have been achieved; (4) the bottleneck of the synthesis was overcame by a recycling procedure; (5) the entire synthetic route is straightforward and convenient for grams scale synthesis.