Asymmetric Synthesis of Antitumor Agents

这一研究建议反映了我们在不对称催化和非环立体控制领域开发新的反应工艺和试剂的兴趣。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，尽管在方法开发方面的密集活动不在本计划的范围内。在本提案预算期内要追求的一个新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重立体区分反应，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。我们打算继续努力，以完成不对称合成除草霉素A、格列达那霉素和瑞布拉斯丁。我们的目标是合成环三烯及其类似物。将使用酿酒酵母作为模式生物和全基因组转录轮询技术来评估细胞三烯A对有丝分裂基因激活的蛋白激酶途径的影响。完成乌拉帕里内酯A的不对称合成，并确认其立体化学归属是我们一直以来的目标。我们一直致力于寻找和开发手性金属催化剂，用于催化不对称分子间卡宾插入杂原子-氢(参看Si-H和锡-H)键的反应。虽然深入的机理评估超出了这个计划的范围，但我们的短期目标是利用这一方法开发一些有用的合成转化，包括合成新的手性烯丙基硅烷和锡烷的新方法。

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.