Syntesis of Polypropionate Antibiotics Via Epoxide Chemistry

描述（由申请人提供）：大环内酯类和离子载体抗生素的合成被认为是合成有机研究的一个非常活跃和重要的领域。这些靶分子的吸引力与它们广泛的生物和药物活性以及它们复杂的大环结构和连续的立体中心阵列有关。发展一种对映选择性的方法来合成胞霉素C和lankanolide的聚丙酸链是本提案的主要目标。这些目标分子的选择是基于它们有趣的和相关的生物活性，以及在它们的聚丙酸单元中发现的不同碳构型所代表的挑战。近年来，越来越多的科学文献证明了人们对这一领域的研究产生了极大的兴趣。与许多其他聚丙酸体系一样，报道的这些靶标的合成方法通常基于醛醇和相关化学。我们希望证明环氧化物是一种可行的有利替代品，并且它们的使用可以纳入到这些重要目标化合物的一般，灵活和立体选择性的途径中。在我们使用第一代基于环氧化物的方法成功地合成了生物学上重要的目标分子的更简单的聚丙酸片段之后，我们希望将我们在立体选择性制备和环氧化物区域选择性切割领域的知识，经验和进展应用于这些新的更苛刻的目标的阐述。这将通过开发和采用更灵活和有效的第二代环氧化物方法来实现。我们的新方法是一种简单而重复的方法，它基于纯烯丙基或烯丙基醇的立体选择性环氧化反应，然后使用有机丙烷或丙酸酯或烯丙基格氏化学进行裂解。这种方法的主要优点是切割反应的立体特异性（SN2）性质确保了新形成的碳-碳键的手性。通过这种结合的方法，我们可以控制每个甲基和羟基碳的构型，而不需要绝对构型，这表征了每个不同的聚丙酸单元。不仅期望的化学转化提出了这项研究将完成。将审查关键反应的范围、局限性、立体选择性和机理意义。虽然我们的方法将应用于这些特定的靶点，但原则上，它应该适用于许多其他聚丙酸体系，并将为合成类似物打开大门，这些类似物可以提供增加或修改生物活性和治疗潜力的机会。

DESCRIPTION (provided by applicant): The synthesis of macrolide and ionophore antibiotics is regarded as a very active and important area of synthetic organic research. The attractiveness of these target molecules is related to their broad range of biological and medicinal activity together with their complex macrocyclic structure and array of contiguous stereogenic centers. The development of an enantioselective methodology for the synthesis of the polypropionate chains of scytophycin C and lankanolide is the main goal of this proposal. The selection of these target molecules is based on their interesting and relevant biological activity and the challenge that represents the elaboration of the different carbon configurations found in their polypropionate units. In recent years a great interest in their study has been evidenced by the increasing scientific literature being generated in this area. The reported synthetic approaches to these targets, as for many other polypropionate systems, have been usually based on aldol and related chemistry. We would like to demonstrate that epoxides are a viable advantageous alternative and that their use can be incorporated into a general, flexible and stereoselective route to these important target compounds. After our successful incursion into the synthesis of simpler polypropionate fragments of biologically important target molecules using a first-generation epoxide- based approach, we would like to apply our knowledge, experience and advances in the area of stereoselective preparation and regioselective cleavage of epoxides to the elaboration of these new more demanding targets. This will be achieved by developing and employing a more flexible and efficacious second- generation epoxide-based approach. Our newer approach is a simple and reiterative one, and is based on the stereoselective epoxidation of homoallylic or allylic alcohols followed by their cleavage using organoalane or alanate, or alkenyl Grignard chemistry. The major advantage of this approach is the stereospecific (SN2) nature of the cleavage reaction securing the chirality of the newly formed carbon-carbon bond. With this combined methodology, we can control the configuration of each methyl and hydroxy bearing carbon regardless of the required absolute configuration, which characterize each distinct polypropionate unit. Not only the desired chemical transformations proposed in this study will be accomplished. The scope, limitations, stereoselectivity and mechanistic implications of the key reactions will be examined. Although our methodology will be applied to these specific targets, in principle, it's should be applicable to many other polypropionate systems and will open the door for the synthesis of analogues which can presents opportunities for increased or modified biological activity and therapeutic potential.