Natural product synthesis and synthetic methodology

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The proposal deals with the total synthesis of several natural products and with the development of new synthetic methodology. The natural products are (a) MPC1001, which exhibits potent activity against a prostate cancer cell line, (b) coleophomone B, an inhibitor of an enzyme involved in bacterial cell wall synthesis and (c) sorbicillactone A, which shows anti-leukemic, antiviral and neuroprotective properties. My route to MPC1001 is based on (i) a new method for making cyclic seven-membered ethers (dihydrooxepines), a conspicuous feature of the compound and many of its naturally occurring relatives, and (ii) on the use of a new sulfur protecting group. The approach to coleophomone B involves an unusual sequence of macrolactonization and ring contraction to construct the strained 11-membered cyclic ketone from a less strained 14-membered lactone. The sorbicillactone route is based on the stereocontrolled formation of a quaternary center carrying nitrogen, and on a new way of converting an amine into a nitro group. A metal-free method will be developed for converting phenols into diaryl ethers in which the ether oxygen (from the original phenol) is meta to a phenolic hydroxyl in the second benzene ring. The new process is an iterative one because the phenolic hydroxyl can then become an ether oxygen in the next iteration which adds a third benzene ring. The generality of a new method for converting an amino group into a nitro group will be examined. This is a very useful transformation for making carbon-carbon bonds. A new general method will be developed for making the core structures of indolizine and pyrrolizine alkaloids. In the former case, the amino acid derivative N-Boc prolinol will be converted to the corresponding boronic ester (OH replaced by Bpin) and Suzuki coupling with readily available (Z)-2,3-dialkyl-3-iodoprop-2-en-1-ols then sets the stage for cyclization to generate a hexahydroindolizine unit. A similar process starting from optically pure pipecolic acid will afford the hexahydroquinolizine framework. In the area of radical chemistry the possibility will be examined of radical cyclization onto a-substituted hydrazones derived from the known hydrazine 2,3-diphenylaziridine-1-amine. The a-substituent will be an arylthio group so that the radical cyclization generates a cyclic alkene directly. In the area of photo-induced radical chemistry the possibility will be examined of deprotecting MOM ethers and THP ethers by visible light mediated by tetrabutylammonium decatungstate.