Natural Product Synthesis and Synthetic Methodology

点击翻译按钮获取中文摘要

The aim of my research is to develop synthetic methods & strategies that contribute to the techniques for constructing complex molecules, & I do this (a) by explicit development of new methodology & (b) by synthesizing biologically active natural products whose structures are sufficiently complex to pose difficult challenges to contemporary organic chemistry so that new constructional problems are exposed that have not been faced before. The proposal describes plans to synthesize MPC1001 (& related MPC1001F), coleophomone B, sorbicillactone A, & CP 225,917. Each of these natural products represents structural types with important biological properties (MPC1001 is extremely potent in in vitro tests against a prostate cancer cell line; coleophomone inhibits therapeutically relevant enzymes; sorbicillactone A is neuroprotective; CP 225,917 has biological activities relevant to the design of anticancer & cholesterol-lowering drugs) & the compounds present synthetic challenges whose solution would provide methods applicable in other areas of organic synthesis. Sorbicillactone A, poses unusual challenges of alkylation & its stereocontrol, & my approach is based on a new way of using silicon in combination with radical chemistry to generate the 1,3-dicarbonyl unit of sorbicillactone A. The route will also introduce non-classical strategies for alkylation. Coleophomone presents the problem of forming an eleven-membered ring, & one of my approaches is to assemble a fourteen-membered ring by macrolactonization — which is an easier process — & then to carry out a ring contraction that depends on the technique of halogen/metal exchange. This approach should prove general for making medium ring ethers. My preliminary coleophomone studies have so far led to the discovery of a general family of methods for making substituted benzene rings that would be extremely difficult to access by any other method & I plan to expand this methodology to a range of pharmaceutically relevant benzenoid aromatics bearing a wide range of substituents. The MPC molecules will undoubtedly require the invention of new chemistry in response to the unusual behavior of the relevant intermediate structures, & my preliminary work has already led to a new protecting group for sulfur, & new routes to 1,3-diketopiperazines & to dihydrooxepins. The route to CP 225,917 is based in my method of intramolecular conjugate displacement (a way of making ring compounds) & new equivalents for the [2,3]-Wittig rearrangement. I plan to explore a general synthetic method for making bioactive pyrrolizidine & indolizidine alkaloids by a very concise route based on carbomagnesiation of acetylenes. I will also develop a general route to alkoxyalkynes (ROC≡CR') & methods for making benzenes from esters in a way that incorporates the ester carbonyl carbon into the benzene ring—a process that will be useful in preparing drugs for treating diabetes.