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.

Chiral Diene Ligands in Asymmetric Catalysis

“…The three-component reaction of electron-deficient 1,3dienes 136, organoboronic acids, and aldehydes to produce Zhomoallylic alcohols 137 using a chiral diene−rhodium complex [RhCl((R,R)-L15b)] 2 as the catalyst has been reported (Scheme 35c). 186 The reaction proceeds by way of the allylrhodium intermediate A, which is generated by the asymmetric δ-arylation of 136 with an arylrhodium intermediate and attacks the aldehyde through the six-membered ring transition state to give 137 with high enantio-, diastereo-, and (Z)-selectivity. Mechanistic studies suggest that the allylrhodation of the aldehyde is the rate-determining step.…”

Dearomative Synthesis of Chiral Dienes Enables Improved Late-Stage Ligand Diversification

“…Foundational reports by Hayashi and Carreira demonstrated efficient aryl transfer reactions of organoboron reagents to prototypical Michael acceptors, and subsequent work has expanded the diversity of effective electrophiles to yield synthetically useful 1,2- and 1,4-aryl transfer reactions. In addition, Rh­(I)–chiral diene complexes have been employed as catalysts for asymmetric [4 + 2]-cycloadditions, arylative carbocyclizations, intermolecular carbene insertions, and α,γ-difunctionalization of electron-poor dienes . Chiral dienes have also been integrated into heterogeneous catalysts, allowing for facile catalyst recovery and recycling .…”

One-Step Asymmetric Construction of 1,4-Stereocenters via Tandem Mannich-Isomerization Reactions Mediated by a Dual-Functional Betaine Catalyst

“…Very recently, Wang and co-workers disclosed a tandem hydroalkylation-reduction reaction enabled by the combination of a chiral copper catalyst and a chiral ruthenium catalyst fulfilling the generation of 1,4-stereocenters . Lundgren and co-workers developed a tandem arylation-allylation reaction catalyzed by a chiral ruthenium catalyst, yielding homoallylic alcohols bearing 1,4-stereocenters . We envisaged that the 1,4-stereocenters could be constructed via a tandem addition-isomerization reaction (Scheme B).…”

“… 23 Lundgren and co-workers developed a tandem arylation-allylation reaction catalyzed by a chiral ruthenium catalyst, yielding homoallylic alcohols bearing 1,4-stereocenters. 24 We envisaged that the 1,4-stereocenters could be constructed via a tandem addition-isomerization reaction ( Scheme 2 B). Specifically, the initial enantioselective addition reaction of allyl-type carbanion generates the C1 stereocenter followed by the stereoselective olefin isomerization reaction that generates the remote C4 stereocenter.…”