Synthesis of Polyketides and Terpenes

描述(由申请人提供)：这项正在进行的拟议研究的目标是为合成具有临床意义的生物活性的复杂自然发生物质做出创造性贡献。这笔赠款将继续开发新的立体选择性反应，并将这一方法应用于复杂聚酮类抗生素和抗肿瘤药物的不对称合成。合成目标将包括苯二醇3、黄曲霉素3、()鬼臼糖苷A、萨尔维甲素A、佛波醇和四环素类抗生素。以丹参素A、佛波醇和四环素为例，介绍了一种从无环前体合成多环结构的重要新方法。所有这些合成都是从键结构开始的，这些键结构受非环立体控制的立体化学调控。然后，碳骨架由一系列来自中环大环的分子内、跨环过程组装而成。与多核苷酸、多肽和多糖一样，聚酮类物质是由常见亚基组装而成的第四大类天然物质。在扩大与肽合成的比较中，通过复杂的Aldol键结构进行聚酮组装比类似的肽片段组装类似的挑战要大得多，因为在片段偶联事件中创建了多达两个新的立体中心。我们在这笔赠款中的长期目标是开发所有组装聚酮衍生天然产品的方法学。这一目标包括手性烯酸酯方法学的发展，对羰基和烯酸酯pi表面选择性的远程立体中心的研究，以及双立体区分Aldol加成反应的预测模型的发展。目标是提高反应设计的可预测性。聚酮类化合物的靶标是苯二醇A、黄曲霉素3、白藜芦苷和丹参素A。化学合成提供了产生化疗药物的能力，而化学反应是药物化学家从事药物发现过程中不可替代的工具。化学反应技术的进步缩短了将化学实体作为潜在候选药物的概念与其合成用于后续生物评价之间的间隔。因此，有机合成是一门关键学科，继续对医学和生物学领域产生重要影响。

DESCRIPTION (provided by applicant): The objectives of this ongoing proposed research are to make creative contributions to the synthesis of complex naturally occurring substances possessing clinically significant biological activity. This grant will continue to develop new stereoselective reactions and the application of this methodology to the asymmetric synthesis of complex polyketide antibiotics and antineoplastic agents. The synthesis targets will include amphinidinol 3, aflastatin 3, (+) peloruside A, salvinorin A, phorbol, and the tetracycline family of antibiotics. An important new approach in the synthesis of polycyclic structures from acyclic precursors has been illustrated in the design of salvinorin A, phorbol, and tetracycline. All of these syntheses begin with bond constructions that are stereochemically regulated by acyclic stereocontrol. The carbon framework is then assembled by a series of intramolecular, transannular processes from medium-ring macrocycles. Along with polynucleotides, peptides, and polysaccharides, polyketides represent the fourth broad family of naturally occurring materials that are assembled from common subunits. In extending the comparison with peptide synthesis, polyketide assembly through complex aldol bond constructions is a far greater challenge that the analogous peptide fragment assembly analogy since up to two new stereocenters are created during the fragment coupling event. Our long term objective in this grant has been the development of all of the methodology to assemble polyketide-derived natural products. This objective includes the development of chiral enolate methodology, the study of remote stereocenters on carbonyl and enolate pi-face selectivities, and the development of predictive models for double stereodifferentiating aldol addition reactions. The goal is to improve reaction design predictability. The polyketide targets are amphidinol A, aflastatin 3, peloruside, and salvinorin A. Chemical synthesis provides the capacity to produce chemotherapeutic agents, and chemical reactions are the irreplaceable tools of the medicinal chemist engaged in the drug discovery process. Advances in chemical reaction technology reduce the interval between the conception of the chemical entity as a potential drug candidate and its synthesis for subsequent biological evaluation. As a consequence, organic synthesis is a critical discipline that continues to have an important impact on the fields of both medicine and biology.