Regio- and diastereoselective rhodium-catalyzed allylic substitution with acyclic alpha-alkoxy-substituted copper(I) enolates: stereodivergent approach to 2,3,6-trisubstituted dihydropyrans

Abstract

The regio- and diastereoselective transition metal-catalyzed allylic alkylation using alpha-heteroatom-substituted ketones and carboxylic acid derivatives represents a challenging and important synthetic transformation. We have developed a regio- and diastereoselective rhodium-catalyzed allylic alkylation reaction utilizing the copper(I) enolates derived from alkyl protected acyclic alpha-alkoxy aryl ketones. This study suggests that the ability to form a chelated enolate intermediate is crucial for obtaining high diastereoselectivity, whereas excellent regioselectivity is obtained regardless of the substituent. Hence, the excellent selectivity coupled with the synthetic utility of alpha-alkoxy aryl ketone enolates makes this an important new method for the construction of acyclic adjacent ternary stereogenic centers. Finally, the synthetic utility of this protocol was highlighted through the conversion of the aryl ketone to the ester and the development of a stereodivergent approach to 2,3,6-trisubstituted dihydropyrans relevant to target-directed synthesis.