Asymmetric Synthesis of Antitumor Agents

这项研究计划反映了我们在不对称催化和无环立体控制领域开发新的反应过程和试剂的兴趣。我们打算追求的目标将集中在手性硅烷试剂的开发和应用上，尽管方法开发方面的密集活动不在本计划的范围内。在本拟议预算期间，一个新的方向将侧重于改进关于催化不对称卡宾插入杂原子-氢键的现有反应方法。我们还将继续开发双立体分化反应，并将其应用于合成来自陆地来源和海洋来源的抗肿瘤抗生素。我们打算继续我们的努力，旨在完成除草霉素A，格莱霉素，reblastatin的不对称合成。本论文的目的是合成环三烯苷及其类似物。将使用酿酒酵母作为模型生物和全基因组转录轮询技术评价细胞三烯素A对有丝分裂基因活化蛋白激酶途径的影响。我们的目标是完成乌拉酞A的不对称合成，并确认其立体化学归属。我们的目标是鉴定和开发手性金属催化剂，用于催化不对称的分子间烯插入到杂原子-氢键（cf Si-H和Sn-H）中的反应。虽然深入的机制评估是本计划的范围之外，这是我们的短期目标，开发一些有用的合成转换使用这种方法，其中包括新的方法来合成新的手性烯丙基硅烷和锡烷。

This research proposal reflects our interest in the development of new reaction processes and reagents in the areas of asymmetric catalysis and acyclic stereocontrol. The objectives that we intend to pursue will focus on the development and application of chiral silane reagents, although intensive activity in methodology development is outside the scope of this program. A new direction to be pursued during the budget period of this proposal will focus on the improvement of a existing reaction methodology concerning catalytic asymmetric carbene insertions into heteroatom-hydrogen bonds. We will also continue the development of double stereodifferentiating reactions and applications to the synthesis of anti-tumor antibiotics derived from terrestrial sources as well as marine sources. We intend to continue our efforts aimed at the completion of the asymmetric synthesis of herbimycin A, gledanamycin, and reblastatin. It is our objective to synthesize cyclotrienin and analogs. Cytotrienin A will be evaluated for its effect on the mitogene- activated protein kinase pathway using Saccharomyces cerevisiae as a model organism and genome-wide transcription polling techniques. It is our continuing objective to complete the asymmetric synthesis of ulapualide A, and confirm its stereochemical assignment. It is our continuing aim to identify and develop chiral metal catalysts for the catalyzed asymmetric intermolecular carene insertion reactions into heteroatom-hydrogen (cf Si-H and Sn-H) bonds. Although an in-depth mechanistic evaluation is outside the scope of this program, it is our short term objective to develop a number of useful synthetic transforms using this methodology, which include new approach to the synthesis of new chiral allylic silanes and stannanes.