Enantioselective a,d-Difunctionalization of Dienes Initiated by Rh-Catalyzed Conjugate Addition

Abstract

Metal-catalyzed enantioselective conjugate additions are highly reliable methods for stereoselective synthesis, however multi-component reactions that are initiated by conjugate arylation of acyclic p-systems are rare. These processes 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 a,d-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 allow 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 d-arylation undergoes aldehyde trapping rather than protonolysis, even when water is present as a co-solvent. These findings should have broader implications in the use of privileged metal-catalyzed conjugate addition reactions as entry points towards the preparation of acyclic molecules containing non-adjacent stereocenters.

Efficient Enantio-, Diastereo, E/Z-, and Site-Selective Nickel-Catalyzed Fragment Couplings of Aldehydes, Dienes, and Organoborons

“…10 More recently, an elegant enantioselective Rh-catalyzed method for the α,δ-dicarbofunctionalization of electron-deficient dienes was reported by Lundgren (e.g., 1b). 11 Nickel-catalyzed coupling of dienes has emerged as an effective strategy for C−C bond formation with olefins and organoboron reagents. 12 We recently disclosed an enantioselective Ni-catalyzed hydroarylation of 1,3-dienes with C(sp 2 ) organoborons and an alcohol controlled by a sterically congested phosphoramidite ligand.…”