The primary objective of this proposal is to develop new methods that will allow synthetic chemists access to classes of compounds more quickly and stereoselectively than existing methods. A second objective is to demonstrate the applicability of these new methods by applying them to the synthesis of medicinally important compounds. The Pauson-Khand reaction is a multi-component reaction that has been used extensively and successfully in the synthesis of natural products. We have successfully demonstrated that allenes can be used in place of olefins in the P-K cycloaddition to generate cyclopentenones. Since the initial study to show the feasibility of this allenic P-K cycloaddition where only monosubstituted allenes were used, we have extended the scope of this allenic cycloaddition to 3,3- and 1,3-disubstituted allenes. Interestingly, the results from these new allenic cycloaddition substrates demonstrate a dependence of the substrate structure upon the course of the allenic-P-K reaction. Thus a more complete extension of the scope of this allenic-P-K reaction is very enticing and a number of ring systems possessing interesting functionality and substitution patterns are proposed. The allenic P-K reaction will also be used to prepare enantiopure cyclopentenones by using a chiral allene in the cycloaddition process. In addition, these exciting results offer routes into skeletons of two groups of natural products that have resurfaced as medicinally viable compounds, the illudins and the J-series of prostaglandins. The application of the allenic-P-K reaction to the synthesis of hydroxymethylacylfulvene, an illudin analog that is currently entering phase two clinical trials as an anticancer agent, is proposed within. We are proposing to use our methodology to rapidly assemble hydroxymethylacylfulvene structure. We are also applying this method to the synthesis of 15-deoxy-delta 12,14-prostaglandin J2 which has recently been identified as the first natural ligand for the peroxisome proliferator activated receptor. The key steps of both of these synthesis involve an allenic-P-K reaction during the end-game of the synthesis, minimizing the exposure of the methylene cyclopentenones to other chemical manipulations. A new method to prepare allenes has been discovered and developed in our group which involves the kinetic deprotonation of an allylic proton of an enol phosphate. We plan to extend this methodology to the one-pot preparation of allenynes from simple alkenones, which will then be used to access novel allenic P-K cycloaddition precursors. In addition, the attainment of chiral allenes by using chiral bases or bases in the presence of chiral ligands to effect the enantioselective deprotonation is proposed.
