Grant: Discovery Grants Program - Individual

This research aims to develop innovative, efficient, and environmentally responsible methods for the preparation of nitrogenous substances of current biomedical interest, and apply such techniques to the synthesis of structurally complex natural products. The underlying theme of this research is that certain transformations that had been regarded as unlikely - or even impossible - are quite feasible. Not only they may be incorporated in the total synthesis of complex natural products at an early stage, but they also permit quantum improvements in the overall route. This constitutes the chemical significance of the work. In terms of practical significance, our targets are of interest in oncology, neurology, microbiology, immunology, and genetics. The PI's track record has shown these fundamental chemical studies, initially motivated only by scientific curiosity, to inevitably produce new leads of considerable pharmaceutical potential. Research in the next cycle of funding will focus on: (a) thiopeptide antibiotics (genetic modulators and inhibitors of protein synthesis), especially nosiheptide. This effort relies on methodology devised in this lab for the expeditious assembly of the pyridine-thiazole cluster found at the core of the target molecules, and on other techniques developed specifically in response to chemical problems associated with a synthesis of this class of molecules. (b) Methodology for the stereocontrolled creation of 1,2-diamines and its use in an approach to thiostrepton and saframycinoids. The synthesis of these challenging molecules should thus be greatly simplified. (c) Techniques for the stereocontrolled formation of azaspiro centers and application to tetrodotoxin (structurally complex neurotoxic agent that acts as a Na channel blocker), himandrine, and Amaryllidaceae alkaloids. (d) Routes to quinocarcin and cyanocyclin (antitumor agents) via Ugi reactions of aminoacids with aromatic aldehydes. (e) Avenues to mitomycinoids via silylaziridine fragmentation and aza-Payne rearrangement.