New asymmetric methods using tert-butanesulfinamide and the application of tert-butanesulfinamide methods to the total synthesis of the natural product tubulysin D

tert-Butanesulfinamide has been developed within the Ellman lab as a versatile reagent for the synthesis of chiral amine compounds. Upon condensation with aldehydes and ketones it forms imines that are both stable to hydrolysis and activated towards nucleophilic addition. The bulky tert-butyl group stereo selectively directs the addition of nucleophiles, and after addition, the sulfinyl group can easily be cleaved under mild acidic conditions to form chiral amines, which are very common in bioactive molecules. In this thesis, new tert-butanesulfinamide methods are described that provide access to classes of chiral amines that previously have been very difficult to synthesize. Moreover, the utility of these methods has been demonstrated through the first total synthesis of the anti-cancer natural product tubulysin D.; Chapter 1 describes a new method for the asymmetric synthesis of tertiary carbinamines starting from cyclic ketone structures. The alpha-substituted cyclohexylamine products are prevalent in drugs and drug candidates. These products are generated by addition of Grignard reagents to sulfinyl ketimines in a highly diastereoselective reaction. For these cyclic structures, the geometry of the ring is shown to be the basis of diastereofacial selectivity instead of the sulfinyl stereocenter.; Chapter 2 describes the conjugate addition of organocopper reagents to alpha,beta-unsaturated sulfinyl imines in a diastereoselective manner. This represents a general strategy for the synthesis of sulfinyl imines with a beta-stereocenter. Organocuprate additions were optimized for the addition to alpha,beta-unsaturated sulfinyl imines in both high yields and high diastereoselectivities. Careful manipulation of the reaction conditions enabled the selective organocuprate addition to either face of alpha,beta-unsaturated aldimines, which after addition of Grignard reagents to the resulting aldimine would allow for the preparation of any of the four possible diastereomers of alpha,gamma-chiral amines.; Chapter 3 describes the total synthesis of tubulysin D using sulfinamide-based methods. Tubulysin D is a natural product isolated from myxobacteria that has been shown to have very potent cytotoxic activity. This sequence provides the first reported total synthesis in a very efficient 16 steps for the longest linear sequence. This synthesis will be the basis for the synthesis of analogs of tubulysin D to probe for more viable therapeutic agents.