Natural Product Synthesis and Synthetic Methodology

我的研究目的是开发有助于构建复杂分子的技术的合成方法和策略，我做到了这一点：(A)通过明确开发新的方法；(B)通过合成具有生物活性的天然产物，其结构足够复杂，对当代有机化学构成困难的挑战，从而暴露出以前从未面临过的新的构造问题。 该提案描述了合成MPC1001(和相关的MPC1001F)、考利酮B、山梨内酯A和CP 225,917的计划。这些天然产物中的每一种都代表具有重要生物学特性的结构类型(MPC1001在体外试验中对前列腺癌细胞株具有极强的抑制作用；考酚酮抑制治疗相关的酶；山梨内酯A具有神经保护作用；CP 225,917具有与抗癌和降胆固醇药物设计相关的生物活性)&这些化合物提出了合成挑战，其解决方案将提供适用于其他有机合成领域的方法。 山梨内酯A对烷基化及其立体控制提出了不同寻常的挑战，我的方法是基于一种新的方法，即使用硅与自由基化学相结合来生成山梨内酯A的1，3-二羰基单元。该路线还将引入非经典的烷基化策略。 Colephomone提出了形成11元环的问题，我的方法之一是通过大内酯作用组装14元环-这是一个更容易的过程-然后进行环收缩，这依赖于卤素/金属交换技术。这种方法应该被证明是制造中等环醚的通用方法。到目前为止，我对Colephomone的初步研究已经发现了一系列制备取代苯环的一般方法，这些方法是任何其他方法都很难获得的&我计划将这种方法扩展到一系列与药物相关的苯基芳香族化合物，这些芳香族化合物含有广泛的取代基。 MPC分子无疑需要发明新的化学来响应相关中间体结构的异常行为，我的初步工作已经导致了一个新的硫保护基团，以及1，3-二酮基哌嗪和二氢奥西平的新路线。 通向CP 225,917的路线是基于我的分子内共轭置换方法(一种制造环化合物的方法)&[2，3]-Wittig重排的新等价物。 我计划探索一种基于乙炔碳磁化的非常简洁的路线来合成具有生物活性的吡咯里西定和吲哚里西定生物碱的通用方法。我还将开发一条合成烷氧基炔的一般路线(ROC≡CR‘)&通过将酯基碳结合到苯环中的方式从酯中制备苯的方法-这一过程将在制备治疗糖尿病的药物时有用。

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.