Methods for enantioselective allylic alkylation of esters, lactones, and lactams with unactivated allylic alcohols

#Synthetic methods for the generation of enantioenriched quaternary stereocenters are highly desirable given their prevalence as motifs in a wide variety of biologically active molecules of both natural and unnatural origin, and the pharmaceutical industries increasing recognition for the motif's applicability in drug design. Despite their importance, the number of highly enantioselective transformations that construct quaternary stereocenters under mild reaction conditions is limited, with respect to both cyclic and acyclic systems.

#Since 1965, transition metal-catalyzed allylic alkylation has emerged as one of the most powerful methods for the construction of stereocenters. In particular, with the use of prochiral nucleophiles that proceed through tetrasubstituted enolates, the transition metal-catalyzed enantioselective allylic alkylation has proven to be a formidable strategy for accessing chiral quaternary stereocenters in catalytic enantioselective fashion. Although this transformation has been studied for more than 50 years, the use of α-substituted lactones or lactams as prochiral nucleophiles remains significantly under-developed.

#It is particularly difficult to construct quaternary stereocenters in scaffolds containing an additional funcitonal handle for further synthetic manipulation, such as α-acyl lactones and lactams. Lactone products could also provide access to acyclic quaternary stereocenters via ring-opening reactions and reduction of the lactam products would enable direct access to functionalized piperidine rings, the most prevalent nitrogenous heterocycle in drug molecules.

#Described herein are the enantioselective allylic alkylation of α-acyl lactones and lactams by using an inexpensive nickel catalyst and easily accessible prochiral nucleophiles. The use of an intermolecular allylic alkylation simplifies the substrate synthesis and provides a more convergent approach to these α-quaternary products. Utilizing a commercially available chiral bisphosphine ligand, α-quaternary lactones and lactams can be constructed in good yield (up to 91% yield) and with high enantiomeric excess (up to 90% ee). A broad range of functional groups are compatible with the reaction conditions. A number of product derivatizations showed the synthetic utility of this methodology for constructing small chiral building blocks with multiple functional handles.

#The definitions for the terms described below are applicable to the use of the term by itself or in combination with another term.

#The term “about,” as used herein, is defined as being close to as understood by one of ordinary skill in the art. In one non-limiting embodiment, the term “about” is defined to be within 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%.