UC Berkeley

Abstract

New Methods for the Synthesis of alpha-Amino Acid Derivatives From N-tert-Butanesulfinyl Imines

AND

The Synthesis and Application of Novel Amino Acid Based N-tert-Butanesulfinyl Amide Organocatalysts

by

Melissa Ann Herbage

Doctor of Philosophy in Chemistry

University of California, Berkeley

Professor Jonathan A. Ellman, Chair

Chapter 1. Methods for the synthesis of alpha-amino acid derivatives prepared from N-tert-butanesulfinyl imines are reviewed.

Chapter 2. The rhodium-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl imino esters is described. This chemistry is compatible with a variety of electronically and sterically diverse arylboronic acids providing the N-tert-butanesulfinyl protected alpha-arylglycine products in good yields and high diastereoselectivities. In addition, the utility of this method is demonstrated by subjecting the enantiomerically enriched N-tert-butanesulfinyl protected products to selective synthetic manipulations with little to no racemization. The synthesis of an N-tert-butanesulfinyl isatin imine and its use in the rhodium-catalyzed addition of arylboronic acids reaction is also described.

Chapter 3. The copper-catalyzed addition of bis(pinacolato)diboron to N-tert-butanesulfinyl imines is described. This chemistry is amenable to a variety of alkyl and aryl N-tert-butanesulfinyl imines and provides rapid access to use of a number of chiral alpha-amino boronate esters, a biologically relevant scaffold that is difficult to access by other means. The utility of this methodology was demonstrated by the efficient synthesis of bortezomib (Velcade®), the first FDA approved proteasome inhibitor drug. The further functionalization of the alpha-amino boronate products is also described. This includes the homologation of the alpha-amino boronate ester products as well as the conversion of the boronate ester to the potassium trifluoroborate salt. The application of this methodology for the enantioselective synthesis of alpha-amino boronate esters is also addressed.

Chapter 4. The synthesis of new N-tert-butanesulfinyl amide organocatalysts and their application to the intermolecular aldol reaction is described. A number of catalysts were prepared in one step from commercially available amino acid precursors and were tested for their activity in the intermolecular aldol reaction. However, preliminary results indicate that the primary amine catalysts are not competitive with other amino acid derived catalysts reported in the literature. Further optimization is necessary to fully evaluate the potential for this new class of catalysts.