Natural product synthesis and development of synthetic methodology

天然产物合成及合成方法学开发

• 批准号: 17-2011
• 负责人: Clive, Derrick
• 金额: $ 7.29万
• 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: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=568087
• 关键词: Natural; product; synthesis; development; synthetic

The research proposal deals with (1) plans for the total synthesis of several biologically important and complex natural products and with the development of new synthetic methodology to deal with the constructional problems posed by these compounds, and (2) the development of general synthetic methods that should have wide applicability to a range of target substances. The main natural products are (1) CP-225,917, an anticancer and cholesterol-lowering substance; (2) marinopyrrole B, an unprecedented class of antibiotic; (3) coleophomone B, an inhibitor of an enzyme involved in bacterial cell wall synthesis; (4) sorbicillactone A, which shows selective anti-leukemic activity, and also has antiviral (HIV) and neuroprotective properties; and (5) MPC1001, which exhibits very powerful activity against a prostate cancer cell line. These natural products, besides having biological properties that identify them as important synthetic targets, also pose constructional problems that are of general occurrence and the solution to these problems will fill gaps in current technology. In relation to these target molecules, new routes to pyrroles, macrolactams and tricarbonyl compounds will be studied. In the area of general methodology I plan to greatly expand the process of intramolecular conjugate displacement (ICD) so that it affords benzo-fused carbocycles and benzo-fused nitrogen heterocycles as single enantiomers; such substances are of considerable value as privileged structures in the pharmaceutical industry and as subunits for complex molecule synthesis. The ICD process will also be developed to fit into a tandem sequence that serves to assemble several rings in a single operation and a version of the ICD reaction will be examined that gives biologically important bicyclic amides. The possibility of effecting radical reactions without stannanes or silanes will be examined.

研究建议涉及(1)几种具有生物重要性和复杂性的天然产物的全合成计划，并开发新的合成方法来处理这些化合物带来的结构问题，以及(2)开发对一系列目标物质具有广泛适用性的一般合成方法。其主要天然产物为：(1)抗癌和降胆固醇物质CP-225,917；(2)前所未有的抗生素类化合物Marinopyrole B；(3)细菌细胞壁合成相关酶的抑制剂Colephomone B；(4)山梨内酯A，它具有选择性抗白血病活性，同时还具有抗病毒(HIV)和神经保护特性；以及(5)MPC1001，它具有非常强的抗前列腺癌细胞系活性。这些天然产物除了具有将其确定为重要合成目标的生物学特性外，还带来了普遍存在的结构问题，这些问题的解决将填补当前技术的空白。关于这些目标分子，将研究合成吡咯、大环内酰胺和三酮类化合物的新路线。 在一般方法学领域，我计划极大地扩展分子内共轭置换(ICD)的过程，以便提供苯并稠合碳环和苯并稠氮杂环作为单一对映体；这些物质在制药工业中作为特权结构和作为复杂分子合成的亚单位具有相当大的价值。还将开发ICD工艺，以适应在一次操作中组装几个环的串联序列，并将研究获得具有生物重要性的双环酰胺的ICD反应的一个版本。我们将研究在没有锡烷或硅烷的情况下发生自由基反应的可能性。