Enantioselective Tertiary Electrophile (Hetero)Benzylation: Pd-Catalyzed Substitution of Isoprene Monoxide with Arylacetates

The enantioselective generation of quaternary carbon centers remains challenging but is of growing importance for the preparation of functional molecules. Transition metal catalyzed allylic alkylations of tertiary electrophiles have provided access to these substructures but remain generally incompatible with organometallic benzyl nucleophiles. In this study we demonstrate that electron-deficient arylacetates can serve as benzyl nucleophile surrogates to generate enantioenriched acyclic molecules containing a quaternary carbon center via a two-step substitution-decarboxylation process using isoprene monoxide. The reaction gives products typically in >90% ee using a commercially available catalyst system and tolerates an array of electron-withdrawing functional groups on the arylacetate moiety. The lactone intermediate generated by the initial substitution reaction can be used in further stereoselective transformations to prepare molecules with acyclic vicinal quaternary stereocenters

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

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

Site-Selective Hydrogenation of Electron-Poor Alkenes and Dienes Enabled by a Rh-Catalyzed Hydride Addition/Protonolysis Mechanism

The transition metal catalyzed hydrogenation of alkenes is a well-developed technology used on a lab scale as well as on large scales in the chemical industry. Site- and chemoselective mono-hydrogenations of polarized conjugated dienes remain challenging. Instead, stoichiometric main-group hydrides are used rather than H2. As part of an effort to develop a scalable route to prepare geranylacetone, we discovered that Rh(CO)2acac/xantphos based catalysts enable the selective monohydrogenation of electron-poor 1,3-dienes, enones, and other polyunsaturated substrates. D-labeling and DFT studies support a mechanism where a nucleophilic Rh(I)-hydride selectively adds to electron-poor alkenes and the resulting Rh-enolate undergoes subsequent inner-sphere protonation by alcohol solvent. The finding that (Ln)Rh(H)(CO) type catalysts can enable selective mono-hydrogenation of electron-poor (poly)enes provides a valuable tool in the design of related chemoselective reduction processes of unsaturated substrates