Natural product synthesis and synthetic methodology

该提案涉及几种天然产物的全合成和新合成方法的开发。天然产物是（a）MPC 1001，其对前列腺癌细胞系表现出有效的活性，（B）鞘氨醇（coleophomone）B，一种参与细菌细胞壁合成的酶的抑制剂，和（c）山梨酸内酯A，其表现出抗白血病、抗病毒和神经保护特性。我的路线MPC 1001是基于（i）一种新的方法，用于制造环状七元醚（二氢氧杂环庚烯），一个显着的特点，化合物和许多天然存在的亲属，和（ii）在使用一个新的硫保护基。合成鞘氨醇B的方法涉及一系列不寻常的大环内酯化和环收缩，以从张力较小的14元内酯构建张力较大的11元环酮。山梨酸内酯路线是基于带氮的季中心的立体控制形成，以及将胺转化为硝基的新方法。 将开发一种无金属的方法，用于将酚转化为二芳基醚，其中醚氧（来自原始酚）位于第二苯环中的酚羟基的间位。新的过程是一个迭代过程，因为酚羟基可以在下一次迭代中变成醚氧，从而增加第三个苯环。 将检查用于将氨基转化成硝基的新方法的一般性。这是一个非常有用的碳-碳键转化。 这将为中氮茚和吡咯嗪类生物碱的核心结构的合成提供一种新的通用方法。在前一种情况下，氨基酸衍生物N-Boc脯氨醇将转化为相应的硼酸酯（OH被Bpin替代），然后与容易获得的（Z）-2，3-二烷基-3-碘代丙-2-烯-1-醇的Suzuki偶联为环化设置阶段以产生六氢吲嗪单元。从光学纯的哌啶甲酸开始的类似方法将提供六氢喹嗪骨架。 在自由基化学领域中，将研究由已知的肼2，3-二苯基氮丙啶-1-胺衍生的α-取代的腙的自由基环化的可能性。α-取代基将是芳硫基，使得自由基环化直接产生环烯烃。在光诱导自由基化学领域，将研究由十聚钨酸四丁基铵介导的可见光使三氟醚和THP醚脱保护的可能性。

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.