Construction of C−C & C−B bonds by enantiospecific nickel-catalyzed C−O bond activation

Watson, Mary P.Transition-metal catalyzed cross-coupling reactions have transformed organic synthesis to a new level. Traditionally, these reactions have focused on using halides and triflates as electrophiles. However, alcohol-based substrates show advantage of readily availability and environmental friendly. Chapter 1 is an introduction of applying nickel-based catalysts to the activation of strong carbon-oxygen bonds. In this case, aryl and vinyl pivalates have been successfully coupled with olefins in a Heck reaction to give the 1,2-disubstituted alkenes in good yield. 1,1'-Bis(diphenylphosphino)ferrocene (dppf) was identified as the most effective ligand. Various functional groups are tolerated in the optimized conditions, but high temperature was required to obtain synthetically useful yield. In Chapter 2, a stereospecific Suzuki cross-coupling of enantioenriched secondary benzylic pivalates with arylboroxines was achieved with a nickel-based catalyst to deliver diarylethanes and triarylmethanes. This reaction features high yields and high levels of stereochemical fidelity. Furthermore, benzylic alcohol precursors are readily available in high ee. The use of mild organoboron reagents enabled various base-sensitive functional groups to be tolerated and increased the convenience of this class of cross-coupling by avoid handling of air-sensitive Grignard reagents. Chapter 3 describe my development of stereospecific Suzuki cross-coupling of tertiary benzylic acetates to deliver di- and triarylalkanes with quaternary stereocenters. Exceptional high levels of stereochemical fidelities are observed, delivering these quaternary centers in remarkable enantiomeric enrichment. Both chapter 4 and 5 focus on the use of allylic pivalates as substrates in the nickel-catalyzed cross-coupling reactions. In chapter 4, a stereospecific Suzuki coupling of allylic pivalates with arylboroxines to deliver highly enantioenriched 1,3-diaryl alkenes. This method features in the use of mild reaction conditions, high regioselectivity, readily available and highly enantioenriched alcohol-based electrophile and excellent functional groups tolerance. Our study shows a π-allylnickel intermediate accounts for the regioselectivty. Chapter 5 describes a stereospecific Miyaura coupling of allylic pivalates with organodiboron reagents to afford highly enantioenriched α-chiral γ-alkyl/aryl allylic boronates. Notably, a significant solvent effect was observed. By the choice of solvent, either inversion or retention of stereochemistry can be selected. Under optimized conditions, either enantiomer was obtained from a single enantiomer of starting material. Overall, the main idea behind these methods was to develop non-precious metal-based catalysts, find mild conditions and use alcohol-based starting material. I hope the work discussed in this thesis will inspire future development in this field.University of Delaware, Department of Chemistry and BiochemistryPh.D