Asymmetric nitro-De-n-bearing quaternary stereocenters are ubiquitous structural motifs found in an enormous number of bioactive molecules. Consequently the development of synthetic methods is of fundamental importance. The long-term objectives of this project therefore are a) to investigate the pi-face selective Ar1-n spirocyclization of N-alkoxy-N-acylnitrenium ions as a novel approach to the preparation of such stereocenters and b) to utilize the azaspirodienone products of this dearomatization reaction as building blocks in the synthesis of a diverse range of important natural products and other pharmacologically active target molecules.
The specific aims of the research to be undertaken are: i) to expand our investigation of the diastereoselective Ar1-5 nitrenium ion cyclization in order to optimize n-facial selectivity and develop a more detailed understanding of the key stereochemical features of this versatile reaction; ii) to develop an ortho-aryl auxiliary-based strategy to control the absolute pi-facial selectivity of nitrenium ion cyclization and subsequently utilize this in a concise synthesis of (-)-perhydrohistrionicotoxin; iii) to investigate the stereocontrolled Ar1-6 nitrenium ion cyclization as a novel and efficient method for the asymmetric preparation of 1-azaspiro[5.5]undecanes including fasicularin, a novel cytotoxic marine alkaloid; iv) to evaluate the Ar1-7 nitrenium ion spirocyclization as a method for the synthesis of [5.6]azaspiranes. The dienone-phenol rearrangement of this ring system will be studied since it will provide rapid access to the benzazocine core of the potent anticancer agent FR900482; v) to utilize the azaspirodienone products of nitrenium ion-induced dearomatization as masked 2-amino-l,3- dicarbonyl and 2-amino-l,6-dicarbonyl synthons. Specifically, this novel synthetic strategy will be employed in the preparation of a range of bioactive alpha,alpha-disubstituted pyrrolidine natural products, including the neuroexcitotoxin (-)-dysibetaine, the neurotrophic agent (+)-Iactacystin, and (-)-kaitocephalin, the only naturally occurring AMPA receptor antagonist; and vi) to investigate the endo-trig Ar1-n nitrenium ion cyclization of arylalkylhydroxamates and then utilize this process in an expeditious asymmetric synthesis of the structural core of (-)-tetrodotoxin. Since the synthetic potential of N-alkoxy-N-acylnitrenium ions remains untapped and the issue of stereccontrol during Ar1-n oxidative dearomatizations has hitherto been largely unexplored, it is anticipated that this project will represent a significant contribution to the field of organic synthesis.
