SYNTHETIC APPLICATIONS OF CARBENE COMPLEXES

拟议工作的广泛范围涉及将费舍尔卡宾络合物的化学发展到有机合成领域和对人类健康具有重要意义的有机化合物的合成领域。将研究Fischer卡宾络合物与炔烃的反应，以合成血小板激活因子拮抗剂phomactin D，以及已被研究用于治疗痛风、家族性地中海热和肝硬变的秋水仙碱和异秋水仙碱的合成。该反应的不对称版本还将用于制备1，2-甲基秋水仙碱甲醚的AS，7S和Ar，7S异构体，以测试关于秋水仙碱和异秋水仙素与微管蛋白结合的立体化学要求的悬而未决的问题。将探索一种新的抗癌药物eluetherobin的合成新策略，其中一个关键步骤是分子内的外选择性Diels-Alder反应。Fischer卡宾络合物的Aldol反应将被用于抗癌药物Fostriecin及其类似物的首次合成，这些药物更稳定，因此更有临床应用价值。Fischer卡宾络合物与1，6-烯炔的反应将作为一种快速获得紫杉醇抗肿瘤药物家族的方法进行探索。手性卡宾络合物的环丙化反应将用于氨基环丙烷的合成和抗肿瘤药物Helenalin的合成，其中包括串联的环丙化/COPE重排序列。

The broad scope of the work proposed involves the development of the chemistry of Fischer carbene complexes to the field of organic synthesis and to the synthesis of organic compounds of importance in human health. The reactions of Fischer carbene complexes with alkynes will be examined for the synthesis of the platelet activating factor antagonist phomactin D and for the synthesis of colchicine and allocolchicinoids that have been investigated for the treatment of gout, familial Mediterranean fever and liver cirrhosis. Asymmetric versions of this reaction will also be used to prepare aS,7S and aR,7S isomers of 1 2 - methylcolchinyl methyl ether to test an unresolved issue regarding the stereochemical requirements for binding of colchicine and allocolchicinoids to tubulin. A new strategy for the synthesis of the new anticancer agent eluetherobin will be explored which involves an intramolecular exo-selective Diels-Alder reaction as a key step. The aldol reaction of Fischer carbene complexes will be utilized in the first synthesis of the anticancer agent fostriecin and analogs of fostriecin which are more stable and thus more useful in the clinic. The reaction of Fischer carbene complexes with 1,6-enynes will be explored as a method for rapid access to the taxol family of antitumor agents. The the cyclopropanation reactions of chiral carbene complexes will be examined for the synthesis of aminocyclopropanes and for a synthesis of the antitumor agent helenalin which involves a tandem cyclopropanation/Cope rearrangement sequence.