Development of Nickel-Catalyzed Asymmetric Reductive Cross-Coupling of Benzylic Electrophiles

Citation

Cherney, Alan Hayden (2015) Development of Nickel-Catalyzed Asymmetric Reductive Cross-Coupling of Benzylic Electrophiles. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z99W0CDW. https://resolver.caltech.edu/CaltechTHESIS:06012015-102412340

Abstract

Over the last forty years, the advent of transition metal-catalyzed cross-coupling has revolutionized the synthetic chemist’s ability to generate C–C bonds. Since the 1970s, a parallel effort to control the stereochemical outcome of such transformations has yielded a variety of chiral catalyst complexes that deliver enantioenriched cross-coupled products. Nonetheless, challenges in the use of C(sp³)-hybridized coupling partners have limited asymmetric variants to a narrow fraction of the total number of cross-coupling methodologies published each year.

Herein, we report studies on the asymmetric cross-coupling of benzylic groups under either Pd or Ni catalysis. We have developed a Pd-catalyzed Fukuyama cross-coupling of thioesters and secondary benzylzinc halides to deliver racemic ketones under mild conditions. Investigations with chiral catalysts revealed that a promising asymmetric transformation could be achieved to give modestly enantioenriched ketones.

Reductive cross-coupling, involving the union of two different electrophiles, has the added advantage of avoiding harsh or expensive organometallic reagents. We have discovered the first highly enantioselective Ni-catalyzed reductive cross-couplings of two organohalide electrophiles. Treatment of an acid chloride and a secondary benzyl chloride with a chiral nickel/bis(oxazoline) complex and Mn(0) as the stoichiometric reductant furnishes ketone products in good yield and high enantioselectivity. Expanding on this result, we have demonstrated that vinyl bromides and secondary benzyl chlorides can be cross-coupled using a different chiral nickel/bis(oxazoline) complex, illustrating the generality of an asymmetric reductive coupling platform. Preliminary studies directed toward other coupling partners are also disclosed.

Thesis Files