Natural product synthesis and synthetic methodology

该提案涉及几种天然产物的全合成和新的合成方法的发展。天然产物是(a) MPC1001，它对前列腺癌细胞系表现出有效的活性，(b)色素酮b，一种参与细菌细胞壁合成的酶的抑制剂，(c)山梨酸内酯a，具有抗白血病、抗病毒和神经保护特性。我对MPC1001的研究是基于(i)一种制造环七元醚（二氢氧平）的新方法，这是该化合物及其许多自然存在的亲戚的显著特征，以及（ii）使用新的硫保护基团。合成色啡酮B的方法涉及一系列不寻常的大内酯化和环收缩，从张力较小的14元内酯构建张力的11元环酮。山梨酸内酯路线是基于立体控制形成的带氮的季中心，以及一种将胺转化为硝基的新方法。将开发一种无金属的方法，将苯酚转化为二芳醚，其中醚氧（来自原始苯酚）在第二苯环上被转化为酚羟基。这个新过程是一个迭代过程，因为在下一次迭代中，酚羟基可以变成醚氧，增加第三个苯环。将研究一种将氨基转化为硝基的新方法的通用性。这是一个非常有用的碳碳键转化。建立了一种新的合成吲哚嗪类和吡咯嗪类生物碱核心结构的通用方法。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酯（OH被Bpin取代），并与容易获得的(Z)-2,3-二烷基-3-碘丙-2-烯-1-ol Suzuki偶联，然后为环化生成六氢吲哚嗪单元奠定了基础。从光学纯的细果酸开始的类似过程可以得到六氢喹啉骨架。在自由基化学领域，将研究由已知的2,3-二苯基肼-1-胺衍生的a-取代腙上的自由基环化的可能性。取代基是芳基，所以自由基环化直接生成环烯烃。在光诱导自由基化学领域，探讨了十钨酸四丁基铵介导的可见光对MOM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.