Development of an Asymmetric Aza-Nazarov Reaction and Synthesis of Nakadomarin A

Notte, Gregory

Abstract

We have identified the Nazarov cyclization as possessing a wealth of untapped potential for the stereospecific formation of carbon-carbon bonds. The corresponding aza-Nazarov reaction presents an even more challenging, and as yet, relatively unexplored avenue of research which would offer numerous advantages for the synthesis of historically challenging ring systems. We have recently discovered that we can accomplish an asymmetric aza-Nazarov reaction in good yield and with a significant degree of enantioselectivity. The key to harnessing this reaction's enormous potential is to recognize that from a single reaction intermediate, diverse chemical pathways can be accessed. The goals of this proposal are to employ strained silacycle Lewis acids to promote the asymmetric aza-Nazarov cyclization, explore the divergent chemical pathways and tandem reaction possibilities accessible from a single enamine intermediate, and to utilize the reactions proposed herein to accomplish the total synthesis of (-)- nakadomarin A with an unprecedented level of expediency and efficiency. This proposal contends that the asymmetric aza-Nazarov cyclization described herein represents an unparalleled means of access to a host of medicinally important structural motifs and greatly simplifies the construction of complex ring systems which appear in many biologically active natural products. We believe that the development of an this reaction would not only serve to fill a significant methodological gap in the literature, but we would also argue that were such a reaction in the chemist's arsenal it would find immediate application in the synthesis of biologically relevant targets. The research described in this proposal will benefit the realm of public health by making available to the synthetic community a powerful new reaction which will have immediate impact upon synthetic endeavors aimed at both biologically relevant natural products and therapeutic agents. In addition, we will use this reaction as a key step in the synthesis of a molecule which demonstrates an impressing array of biological activity including anticancer, antifungal, and antibacterial properties. ? ? ?