Diastereo-, Enantio-, and Z-Selective α,δ-Difunctionalization of Electron-Deficient Dienes Initiated by Rh-Catalyzed Conjugate Addition.

Abstract

Metal-catalyzed enantioselective conjugate additions are highly reliable methods for stereoselective synthesis; however, multicomponent reactions that are initiated by conjugate arylation of acyclic π-systems are rare. These reactions generally proceed with poor diastereoselectivity while requiring basic, moisture sensitive organometallic nucleophiles. Here, we show that Rh-catalysts supported by a tetrafluorobenzobarrelene ligand (Ph-tfb) enable the enantio-, diastereo-, and Z-selective α,δ-difunctionalization of electron-deficient 1,3-dienes with organoboronic acid nucleophiles and aldehyde electrophiles to generate Z-homoallylic alcohols with three stereocenters. The reaction accommodates diene substrates activated by ester, amide, ketone, or aromatic groups and can be used to couple aryl, alkenyl, or alkyl aldehydes. Diastereoselective functionalization of the Z-olefin unit in the addition products allows for the generation of compounds with five stereocenters in high dr and ee. Mechanistic studies suggest aldehyde allylrhodation is the rate-determining step, and unlike reactions of analogous Rh-enolates, the Rh-allyl species generated by δ-arylation undergoes aldehyde trapping rather than protonolysis, even when water is present as a cosolvent. These findings should have broader implications in the use of privileged metal-catalyzed conjugate addition reactions as entry points toward the preparation of acyclic molecules containing nonadjacent stereocenters.