Enantioconvergent Synthesis by Sequential Asymmetric Horner−Wadsworth−Emmons and Palladium-Catalyzed Allylic Substitution Reactions

Abstract

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different alpha-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major alpha,beta-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single gamma-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.

Deconvoluting the Memory Effect in Pd‐Catalyzed Allylic Alkylation: Effect of Leaving Group and Added Chloride

“…For example, almost complete stereoretention can be achieved by increasing the reactivity of the nucleophile, [24] whereas complete isomerization within an isolated manifold coupled with substrate-directed regioselectivity forms the basis of a recent enantioconvergent procedure. [25] New leaving groups: Two alternative types of leaving groups were included in the current studies, isoureas and imidates. Dicyclohexylisoureas were employed previously, [26] however, in our hands, it was difficult to isolate these in pure form.…”

Asymmetric Wittig Type Reactions

“…The first example of use of asymmetric HWE reactions for enantioconvergent synthesis was reported very recently. 62 The overall stereoconvergence was accomplished by combining the asymmetric HWE reaction with a subsequent Pd-catalyzed allylic substitution (Scheme 38). In the illustrated example, reaction of racemic aldehyde 102 with chiral phosphonate 25d afforded a close to 1:1 mixture of alkenes (R,E)-103 42 and (S,Z)-103, 42 both with good to excellent diastereoselectivity.…”

Breaking conjugation: unusual regioselectivity with 2-substituted allylic substrates in the Tsuji–Trost reaction

“…Another complicating factor of η 3 -allyls bearing terminal substituents is the possibility of syn-anti isomerization, as shown in the center of Scheme 1. 8 This isomerization can be fast, with all of the isomeric substrates feeding into the (η 3 -allyl)Pd manifold and giving rise to the same product distribution (Scheme 1). 9 …”