ASYMMETRIC SYNTHESIS OF IONOPHORE/MACROLIDE ANTIBIOTICS

这项研究的目的是为具有临床意义的生物活性的天然物质的全合成做出创造性贡献。这笔赠款将继续致力于开发新的立体选择性反应，并将这种方法应用于聚酮衍生抗生素和抗肿瘤药物的不对称合成。合成目标将包括黄曲霉素A、amphidinol 3、pectenotoxin、callipeltoside A、耳蜗霉素和六环酸。本研究计划中开发的对映体选择性方法已被整合到指定目标结构的拟议合成计划中。与反应发现有关的方法学研究将强调控制和最终预测复杂羟醛缩合过程的立体化学过程的反应的发展。这些研究正在进行的目标是揭示一些预测复杂的羟醛片段偶联反应的立体化学结果的一般规则。与多核苷酸、肽和多糖一起，聚酮化合物沿着代表由共同亚基组装的天然存在的材料的第四大家族。在扩展通过复杂的羟醛加成反应组装的天然存在的材料的家族中，比酰胺结构类比具有更大的挑战。我们的长期目标是开发所有必要的工具，用于有效组装复杂的聚丙酸酯和聚乙酸酯目标。不对称催化已经被用于手性结构单元的构建。手性烯醇化物方法学已经发展用于立体调控的Aldol过程，并且对双立体分化Aldol反应的研究已经揭示了如何提高这些片段偶联反应的设计可预测性。我们的目标一直是设置在所有的反应所需的任何聚酮化合物的目标结构的快速组装。

The objectives of this proposed research are to make creative contributions to the total synthesis of naturally occurring substances possessing clinically significant biological activity. This grant will continue to address the development of new stereoselective reactions and the application of this methodology to the asymmetric synthesis of polyketide-derived antibiotics and anti-neoplastic agents. The synthesis targets will include aflastatin A, amphidinol 3, pectenotoxin, callipeltoside A, cochleamycin, and hexacyclinic acid. Enantioselective processes developed within this research program have been integrated into the proposed synthesis plans for the indicated target structures. The methodological studies dealing with reaction discovery will emphasize the development of reactions for controlling and ultimately predicting the stereochemical course of complex aldol processes. The ongoing goal of these studies has been to reveal some of the general rules for predicting the stereochemical outcome of complex aldol fragment coupling reactions. 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 family of naturally occurring materials that are assembled through complex aldol addition reactions is a far greater challenge than the amide construction analogy. Our long-term objective has been the development all of the necessary tools for the efficient assemblage of complex polypropionate and polyacetate targets. Asymmetric catalysis has been directed to the construction of chiral building blocks. Chiral enolate methodology has been developed for stereoregulated aldol processes, and studies on double stereodifferentiating aldol reactions have revealed how to improve the design predictability of these fragment coupling reactions. Our goal has been to set in place all of the reactions necessary for the rapid assemblage of any polyketide target structure.