Studies towards the total synthesis of Phormidolide A and the synthesis of C4'-modified nucleoside analogues

The research presented in this thesis details efforts towards the total synthesis of the natural product phormidolide A. The synthesis of various fragments and eventual completion of the macrocyclic fragment of phormidolide A is reported. As part of these efforts, a stereochemical reassignment of phormidolide A was undertaken. Finally, the discovery and use of a unique halide effect in Grignard reactions of β-hydroxyketones was identified and exploited for the synthesis of C4'-modified nucleoside analogues. Phormidolide A is a THF-containing marine macrolide natural product, isolated from a marine cyanobacterium Leptolyngbya sp. by the Gerwick group. Reported in 2002, its planar structure was determined primarily through 1D and 2D NMR spectral analysis while the relative stereochemistry of phormidolide A was assigned using nuclear Overhauser effect (NOE) information and Murata's J-based configurational analysis. In collaboration with the Paterson group at Cambridge University, we developed a synthesis of 5 key fragments of phormidolide A. Collaborative efforts, including the synthesis of C10-C23 fragments of the natural product and comparison of computational results to data reported for the natural product led to a stereochemical reassignment. Following this, the prepared fragments were used to construct the macrocycle of phormidolide A. These synthesis efforts included the examination of a wide range of macrocyclization strategies, ultimately using macrolactonization to form the macrocycle. Finally, efforts towards linking the side chain fragments to the macrocycle are described. During an investigation of the 1,2-addition of Grignard and other organometallic reagents to β-hydroxy ketones, we identified a unique effect of halide on diastereoselectivity, with alkylmagnesium iodide reagents demonstrating the highest levels of stereoselectivity. Detailed DFT calculations and mechanistic studies suggest that the Lewis acidity of a chelated magnesium alkoxide can be tuned by choice of halide. Exploiting this finding, we demonstrate that the diastereoselective addition of alkyl magnesium iodide reagents to ketofluorohydrins enables rapid access to naturally configured C4'-modified nucleosides. This work now provides a platform to support antiviral and anticancer drug discovery and development efforts.