Syntesis of Polypropionate Antibiotics Via Epoxide Chemistry

通过环氧化物化学合成聚丙酸酯抗生素

• 批准号: 8035373
• 负责人: JOSE Antonio PRIETO
• 金额: $ 33.19万
• 依托单位: UNIVERSITY OF PUERTO RICO RIO PIEDRAS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035373
• 关键词: 3-hydroxybutanal; Alcohols; Antibiotics; Area; Attention; Automation; Biological; Biological Factors; Carbon; Chemicals; Chemistry; Communities; Complex; Copper; Coupling; Development; Epoxy Compounds; Family; Funding; Generations; Goals; Health; Ionophores; Knowledge; Literature; Macrolides; Mainstreaming; Methodology; Methods; Molecular Models; Nature; Positioning Attribute; Preparation; Process; Productivity; Propionates; Publications; Reaction; Reagent; Reporting; Research; Route; Science; Secure; Structure; System; Therapeutic; Work; analog; base; combinatorial; design; experience; flexibility; improved; innovation; interest; microwave electromagnetic radiation; molecular modeling; novel strategies; programs; success; tool

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. PUBLIC HEALTH RELEVANCE: The development of new and efficient methods for the synthesis of compounds with important biological and medicinal activities continues is of paramount importance in the biomedical sciences. Among the many families of compounds that have attracted the attention of the scientific community, the so-called polypropionate natural products have gained wide recognition and interest. We are proposing a new methodology for polypropionate synthesis that will open the door for the preparation these compounds and other analogues, which can present opportunities for improved biological activity and therapeutic potential.

描述(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中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学和药用活性以及它们复杂的大环结构和一系列毗邻的立体生成中心有关。这项提议的主要目标是开发一种用于合成聚丙酸链的不对称方法学。这些目标分子的选择是基于它们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，在这一领域产生了越来越多的科学文献，证明了人们对它们的研究非常感兴趣。已报道的这些目标的合成方法，就像许多其他聚丙酸酯体系一样，通常是基于羟醛和相关的化学。我们想要证明，环氧化物是一种可行的、有利的替代品，它们的使用可以并入到这些重要目标化合物的一般、灵活和立体选择性的路线中。在我们成功地利用第一代基于环氧化物的方法合成了更简单的具有生物重要性的靶分子的聚丙酸酯片段之后，我们希望将我们在立体选择性制备和环氧化物的区域选择性切割领域的知识、经验和进展应用到这些新的更苛刻的目标的阐述中。这将通过开发和采用更灵活和更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和重复的方法，基于高烯丙醇或烯丙醇的立体选择性环氧化，然后用有机丙烷或丙氨酸或烯基格氏化学进行裂解。这种方法的主要优点是裂解反应的立体特异性(SN2)性质，确保了新形成的碳-碳键的手性。使用这种组合方法，我们可以控制每个甲基和羟基碳的构型，而不考虑所需的绝对构型，这是每个不同的聚丙酸酯单元的特征。不仅可以实现本研究中提出的所需的化学转化。将审查关键反应的范围、局限性、立体选择性和机制含义。尽管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酯体系，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。 与公共卫生有关：继续开发新的有效方法来合成具有重要生物和医药活性的化合物，这在生物医学科学中至关重要。在众多引起科学界关注的化合物家族中，所谓的聚丙酸酯类天然产物得到了广泛的认可和兴趣。我们正在提出一种合成聚丙酸酯的新方法，这将为制备这些化合物和其他类似物打开大门，这将为提高生物活性和治疗潜力提供机会。