Catalytic Enantioselective Three‐Component Hetero‐[4+2] Cycloaddition/Allylboration Approach to α‐Hydroxyalkyl Pyrans: Scope, Limitations, and Mechanistic Proposal

Abstract

This article describes the design and optimization of a catalytic enantioselective three-component hetero-[4+2] cycloaddition/allylboration reaction between 3-boronoacrolein, enol ethers, and aldehydes to afford α-hydroxyalkyl dihydropyrans. The key substrate, 3-boronoacrolein pinacolate (2) was found to be an exceptionally reactive heterodiene in the hetero-[4+2] cycloaddition catalyzed by Jacobsen's chiral Cr^III catalyst 1. The scope and limitations of this process were thoroughly examined. The adduct of 3-boronoacrolein pinacolate and ethyl vinyl ether was obtained in high yield and with over 95 % enantioselectivity. This cyclic α-chiral allylboronate adds to a very wide variety of aldehyde substrates, including unsaturated aldehydes and α-chiral aldehydes to give diastereomerically pure products. Acyclic 2-substituted enol ethers can be employed, in which case the catalyst promotes a kinetically selective reaction that favors Z enol ethers over the E isomers. Surprisingly, 3-boronoacrolein pinacolate was found to be a superior heterodiene than ethyl (E)-4-oxobutenoate, and a mechanistic interpretation based on a possible [5+2] transition state is proposed.