UC Irvine

Transition metal catalyzed reactions are indispensable tools for the asymmetric construction of carbon–carbon bonds. Traditionally, cross-coupling reactions have relied on the use of aryl, vinyl or 1o alkyl electrophiles. Advances in asymmetric catalysis have permitted the use of 2o alkyl electrophiles in cross-coupling reactions allowing for the development of several stereoconvergent transformations. Herein, we report a complementary approach to asymmetric cross-coupling reactions by means of the development of stereospecific, nickel-catalyzed transformations of benzylic alcohol derivatives.

Our initial efforts were directed toward expanding upon a Kumada cross-coupling reaction of secondary benzylic ethers with methylmagnesium iodide previously reported by the Jarvo laboratory. We extended the scope of this reaction by developing conditions to enable the use of aryl Grignard reagents for the construction of enantioenriched triarylmethanes by stereospecific nickel-catalyzed cross-coupling of diaryl methanol derivatives. The reaction proceeds in high enantiospecificity and overall inversion. This methodology is used to prepare a single enantiomer of an anti-breast-cancer agent.

Further advances in our cross-coupling methodology are demonstrated in the development of a stereospecific Suzuki–Miyaura coupling of benzylic carbamates and pivolates with aryl- and heteroarylboronic esters. The reaction proceeds with selective inversion or retention at the electrophilic carbon depending on the nature of the ligand. Tricyclohexylphosphine ligand provides product with retention, while an NHC ligand provides product with inversion. The reaction proceeds in high enantiospecificity to afford either enantiomer of a variety of triarylmethanes.

Taking advantage of our growing expertise in nickel catalyzed reactions of secondary alkyl electrophiles, we designed the first alkyl Heck reaction with control of stereochemistry at the electrophilic carbon. Enantioenriched methylenecyclopentanes are synthesized by stereospecific, nickel-catalyzed Heck cyclizations of secondary benzylic ethers. The reaction proceeds in high yield and enantiospecificity for benzylic ethers of both π-extended and simple arenes. Ethers with pendant 1,2-disubstituted olefins form trisubstituted olefins with control of both absolute configuration and alkene geometry. The diastereoselective synthesis of a polycyclic furan is demonstrated.

In the final chapter of this work, we demonstrate a nickel-catalyzed generation of secondary benzylzinc reagents from 2-pyridyl carbinols that are phosphorylated in situ. A variety of benzylzinc reagents are formed in high yield, allowing for facile hydrogenolysis of 2-pyridyl carbinols. The utility of this transformation is highlighted in a high-yielding intramolecular addition of a secondary benzylzinc reagent to an α,β-unsaturated ester.