Asymmetric Alkyne Addition to Aldehydes Catalyzed by BINOL and Its Derivatives

Abstract

This Account describes our research over the past decade in the asymmetric alkyne addition to aldehydes to generate optically active propargylic alcohols. Our methods employ a dialkylzinc reagent to react with a terminal alkyne to form an alkynylzinc nucleophile, and can be grouped into the BINOL-catalyzed reactions and the functionalized BINOL catalyzed reactions. We first describe the development of the BINOL-ZnEt₂-Ti(Oi-Pr)₄ catalyst system, and its modification through the use of Lewis base additives to form the alkynylzinc at room temperature. The substrate scope compatible with these methods and the enantioselectivities achieved are discussed. We then describe the functionalized BINOL and H₈BINOL catalyst systems, which can be further divided into classes based on the manner in which the BINOL framework has been modified. Generally, these functionalized BINOL and H₈BINOL derivatives contain internal Lewis basic sites which can both promote the formation of the nucleophilic alkynylzinc reagents at reduced temperature and modify the catalytic properties of the chiral biaryl unit. In a few cases, these catalysts also show good efficiency even without the use of the Ti(IV) reagent. The catalytic methods in this Account have demonstrated that a wide range of alkyne and aldehyde substrates can be subjected to the asymmetric addition reactions to generate structurally diverse chiral propargylic alcohols with high enantioselectivity. Some of these methods have exhibited high practicality in synthesis.

1 Introduction

2 BINOL-Based Catalytic Systems

2.1 Catalysis by BINOL-ZnEt₂-Ti(Oi-Pr)₄

2.2 Catalysis by BINOL-ZnEt₂-Ti(Oi-Pr)₄-HMPA

2.3 Catalysis by BINOL-ZnEt₂-Ti(Oi-Pr)₄-NMI

2.4 Catalysis by BINOL-ZnEt₂-Ti(Oi-Pr)₄-Cy₂NH

3 Functionalized BINOL-Based Catalytic Systems

3.1 Catalysis by 3,3′-Dianisyl-BINOLs and -H₈BINOLs

3.2 Catalysis by 3,3′-Bis(diphenylmethoxy)methyl Substituted BINOLs

3.3 Catalysis by Acyclic and Macrocyclic Binaphthyl Salens

3.4 Catalysis by 3,3′-Bismorpholinomethyl H₈BINOL

3.5 Catalysis by C ₁-Symmetric BINOL-Terpyridine

4 Summary

Key words

alkyne addition to aldehydes - BINOL-based catalytic systems -

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15

When the first step was allowed to proceed for 2 h for the reaction shown in Scheme  [9] b, the propargylic alcohol was formed in only 25% yield and 84% ee.