Transition metal catalysis of acetals and pivalates: enantioselective and enantiospecific methods for C-C & C-B bond formation

Harathi Dwarakanath, Srinivas
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University of Delaware
This dissertation focuses on the development of transition metal-catalyzed reactions of acetal and pivalate substrates. These new methods enable efficient synthesis of highly enantioenriched organic molecules. The first chapter discusses an enantioselective alkynylation of chromene acetals using copper (I) catalysts. In this method, we have observed wide substrate scope, and high enantioselectivities were observed especially with 4-aryl chromene acetals. Use of dilute conditions, BF 3 OEt2 as Lewis acid and Cy2 NMe as base are critical for achieving high enantioselectivities. In this chapter, a mechanism and stereochemical model are proposed that rationalize the observed substituent effects and enantioselectivities. This method demonstrates the advantage of using transition metal catalysis to facilitate reactions involving oxocarbenium ion intermediates. Chapter 2 discusses enantiospecific, nickel-catalyzed cross-couplings of benzylic pivalates with mild and functional group tolerant arylboroxines as cross-coupling partners. The diarylalkane and triarylmethane products formed were obtained in high yields and levels of stereochemical fidelity. The success of this method depends on the use of Ni(cod) 2 as catalyst and NaOMe as base. In this method, we have shown broad substrate scope and wide functional group tolerance. Chapter 3 discusses an enantiospecific, nickel-catalyzed cross-coupling of 1,3-disubstituted secondary allylic pivalates with mild and functional group tolerant arylboroxines. The 1,3-diaryl allyl products are obtained with high levels of stereochemical fidelity and yields. Excellent regioselectivity and E/Z selectivity are also observed in this method. A wide variety of functional groups are tolerated, and the utility of this method is demonstrated in the synthesis of the anti-inflammatory drug (S )-ketoprofen. Chapter 4 discusses an enantiospecific, nickel-catalyzed cross-coupling of 1,3-disubstituted secondary allylic pivalates and bis(pinacolato)diboron (B2 Pin2 ) to form γ-aryl allyl boronates in high yields and ee's. In this method, the absolute configuration of the allylboronate product depends on the ligand and the solvent used. Thus, either enantiomer of allyl boronate is available from the same enantiomer of pivalate starting material. The optimized conditions for obtaining both retention and inversion products are discussed.