Syntesis of Polypropionate Antibiotics Via Epoxide Chemistry

描述（由申请人提供）：大环内酯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其广泛的生物和药物活性以及其复杂的大环结构和连续立体中心阵列有关。本提案的主要目标是发展一种对映体选择性方法，用于合成scytophycin C和lankanetrin的聚丙酸酯链。这些靶分子的选择是基于其有趣和相关的生物活性以及代表在其聚丙酸酯单元中发现的不同碳构型的阐述的挑战。近年来，在这一领域产生的越来越多的科学文献证明了对它们的研究的极大兴趣。与许多其他聚丙酸酯系统一样，这些目标的报道合成方法通常基于羟醛和相关化学。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并入到这些重要目标化合物的通用，灵活和立体选择性路线中。在我们成功地使用第一代基于环氧化物的方法合成生物学重要靶分子的更简单的聚丙酸酯片段之后，我们希望将我们在环氧化物的立体选择性制备和区域选择性裂解领域的知识、经验和进展应用于这些新的更高要求的靶的阐述。这将通过开发和采用更灵活和有效的第二代基于环氧化物的方法来实现。我们的新方法是一个简单的和重复的，是基于高烯丙基或烯丙基醇的立体选择性环氧化，然后用有机铝烷或alcohol，或烯基格氏化学裂解。这种方法的主要优点是切割反应的立体特异性（SN 2）性质，确保了新形成的碳-碳键的手性。通过这种组合方法，我们可以控制每个带有甲基和羟基的碳的构型，而不管表征每个不同聚丙酸酯单元的所需绝对构型如何。不仅在这项研究中提出的所需的化学转化将被完成。的范围，限制，立体选择性和关键反应的机械影响将被检查。虽然我们的方法将应用于这些特定的目标，但原则上，它应该适用于许多其他聚丙酸酯系统，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饰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.