Natural Product Synthesis and Synthetic Methodology

天然产物合成及合成方法

• 批准号: RGPIN-2016-04503
• 负责人: Clive, Derrick
• 金额: $ 3.35万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=615107
• 关键词: Natural; Product; Synthesis; Synthetic; Methodology

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.

我研究的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，我这样做（a）通过明确开发新方法学&（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，从而暴露出以前没有遇到过的新的结构问题。 该提案描述了合成MPC 1001（及相关的MPC 1001 F）、鞘氨醇B、山梨酸内酯A和CP 225，917的计划。这些天然产物中的每一种都代表了具有重要生物学特性的结构类型（MPC 1001在体外试验中对前列腺癌细胞系极其有效;鞘氨醇抑制治疗相关酶;山梨酸内酯A具有神经保护作用; CP 225，917具有与抗癌和降胆固醇药物的设计相关的生物活性）和这些化合物提出了合成挑战，其解决方案将提供可应用于有机合成的其它领域的方法。 山梨酸内酯A，对烷基化及其立体控制提出了不寻常的挑战，我的方法是基于一种新的方法，使用硅与自由基化学相结合来产生山梨酸内酯A的1，3-二羰基单元。该路线还将引入烷基化的非经典策略。 Coleophomone提出了形成一个十一元环的问题，我的方法之一是通过大环内酯化组装一个十四元环-这是一个更容易的过程-然后进行环收缩，这取决于卤素/金属交换技术。这种方法应证明是制备中环醚的通用方法。到目前为止，我的初步coleophomone研究已经发现了一系列制造取代苯环的方法，这些方法很难通过任何其他方法获得，我计划将这种方法扩展到一系列具有广泛取代基的药学相关的苯型芳族化合物。 MPC分子无疑需要发明新的化学来应对相关中间体结构的不寻常行为，我的初步工作已经导致了硫的新保护基，以及1，3-二酮哌嗪和二氢氧杂卓的新路线。 CP 225，917的路线是基于我的分子内共轭置换方法（一种制备环状化合物的方法）&[2，3]-维蒂希重排的新等价物。 我计划探索一种基于乙炔碳镁化的合成吡咯里西啶和吲哚里西啶生物碱的简便方法。我也将开发一个一般路线烷氧基炔（ROC炔）&方法从酯的苯的方式，将酯羰基碳纳入苯环-一个过程，将是有用的，在制备药物治疗糖尿病。