Regio and Stereoselective Reactions in Synthesis of Heterocycles

杂环合成中的区域和立体选择性反应

• 批准号: 7559726
• 负责人: BABAK BORHAN
• 金额: $ 23.77万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559726
• 关键词: Acetylene; Alcohols; Alkenes; Applications Grants; Area; Aziridines; Biological; Biological Assay; Biological Factors; Biology; Breathing; Cancer cell line; Categories; Cells; Chemicals; Chemistry; Complex; Cyclization; Epoxy Compounds; Evaluation; Exhibits; Family; Glycols; Inorganic Sulfates; Investigation; Lead; Left; Libraries; Metals; Methodology; Methods; Molecular; One-Step dentin bonding system; Organic Chemistry; Pathway interactions; Pharmacologic Substance; Process; Proteasome Inhibitor; Pyrrolidines; Reaction; Research; Secure; Source; Structure; System; Unspecified or Sulfate Ion Sulfates; Work; acetogenin; analog; base; beta-Lactams; cancer therapy; carbene; cellular targeting; chiral molecule; crosslink; design; diene; functional group; inhibitor/antagonist; interest; lactacystin; multicatalytic endopeptidase complex; neoplastic cell; novel; potassium peroxymonosulfuric acid; pyrrolidine; salinosporamide A; scaffold; stereochemistry; success; ylide

DESCRIPTION (provided by applicant): Our recent efforts have centered on developing new methodologies that enable the efficient synthesis of heterocycles from simple and easy to obtain starting materials. Our research in this area has led to novel discoveries in the area of oxidative chemistry, both in oxidative cyclizations of dienes to access THF cores and oxidative cleavage of olefins. We now possess a repertoire of reactions that deliver products with complete fidelity in transfer of stereochemistry. We have developed methodologies for the regiocontrolled opening of epoxides to secure a variety of THF and THP rings. The functional group directed epoxide-opening methodology has been utilized to synthesize the proposed structure of mucoxin. Efforts towards elucidation of the real structure of mucoxin are planned. The synthetic work on mucoxin will be parlayed into SAR studies with a variety of structural and stereochemical analogs against a panel of tumor cells. We also propose the design of a library of acetogenin analogs for a thorough investigation in cell-based assays, along with microsomal screens. Our studies will also focus on discovering the cellular target(s) of acetogenins through photoaffinity crosslinking efforts. Synthesis of mucoxin has also led to the discovery of a new triol cyclization methodology to secure THF and THP rings. Investigations in this area will lead to new chemistries for the one- step synthesis of oxarings and carbocycles form 1,2-diols with regio- and stereochemical control. Our postulated mechanism for the oxidative cleavage of olefins involves the nucleophilic attack of Oxone (peroxysulfate), with the subsequent cleavage of the C-C bond and expulsion of sulfate. This mechanism has inspired us to develop new chemistry, i.e.; the use of good nucleophiles that contain within them good leaving groups. We have demonstrated the use of sulfoxonium ylides in concert with 2,3-epoxy alcohols leads to the formation of THF rings with regio- and stereochemical control. Extension of this methodology for use with alternate ylides that would yield more complex ring systems is proposed. Furthermore, use of hydroxy- aziridines, leading to the stereochemically controlled formation of pyrrolidines has great potential for developing strategies for heterocyclic framework. Preliminary results indicate that this is a robust and efficient method for synthesizing a variety of substituted pyrrolidines. We have also discovered a simple, metal-free, hydroamination of acetylenes (tandem aza-Payne/hydroamination) that leads to a highly versatile synthon. This chemistry will be developed fully, and its use will be highlighted through an efficient synthesis of salinosporamide A, lactacystin, and their analogs (the analogs could be potent 20S proteasome inhibitors). This proposal concerns itself with developing new synthetic methodologies that utilize simple molecules from the chiral pool, and in a regio- and stereoselective manner expands upon the repertoire of molecules that are attainable through the proposed transformations. This proposal concerns itself with developing new reaction methodologies that are geared towards the synthesis of molecular scaffolds of interest for the biomedical and pharmaceutical fields. We also propose to study the function of two families of bioactive natural products, namely, the acetogenins and beta-lactam containing 20S proteasome inhibitors. Acetogenins exhibit very high activity against many cancer cell lines, and so do inhibitors of the 20S proteasome, which are also emerging as exciting candidates for cancer therapy.

描述（由申请人提供）：我们最近的工作集中在开发新的方法，使杂环化合物能够从简单和容易获得的起始材料中有效地合成。我们在这一领域的研究导致了氧化化学领域的新发现，包括二烯的氧化环化以获得四氢呋喃核和烯烃的氧化裂解。我们现在拥有的一系列反应，提供产品与完全保真的立体化学转移。我们已经开发了区域控制环氧化物开放的方法，以确保各种THF和THP环。利用官能团导向环氧化物打开方法合成了所提出的粘毒素结构。计划努力阐明粘毒素的真实结构。粘毒素的合成工作将被应用于各种结构和立体化学类似物对一组肿瘤细胞的SAR研究。我们还建议设计一个醋酸原类似物库，以便在基于细胞的分析中进行彻底的研究，以及微粒体筛选。我们的研究也将集中在通过光亲和交联的努力发现醋酸原的细胞靶点。粘毒素的合成也导致了一种新的三醇环化方法的发现，以确保THF和THP环。在这一领域的研究将导致新的化学一步合成的oxarings和碳环形式的1,2-二醇具有区域和立体化学控制。我们假设的烯烃氧化裂解机制包括氧酮（过氧硫酸盐）的亲核攻击，随后的C-C键裂解和硫酸盐的排出。这种机制激发了我们发展新的化学，即；好的亲核试剂含有好的离去基团。我们已经证明，使用亚砜鎓化物与2,3-环氧醇协同作用，可以形成具有区域和立体化学控制的THF环。提出了将这种方法扩展到可产生更复杂环系的替代环的方法。此外，利用羟基-叠氮吡啶，导致立体化学控制的形成吡咯烷具有很大的潜力，发展策略的杂环框架。初步结果表明，这是一种合成多种取代吡咯烷的稳定、高效的方法。我们还发现了一种简单的、无金属的乙炔氢胺化反应（串联aza-Payne/氢胺化反应），它可以产生一种高度通用的合成物。这种化学将得到充分的发展，其用途将通过有效合成盐孢酰胺A、乳酸菌素及其类似物（类似物可能是有效的20S蛋白酶体抑制剂）而得到强调。这一建议涉及开发新的合成方法，利用手性池中的简单分子，并以区域和立体选择的方式扩展通过提议的转化可以获得的分子库。本提案涉及发展新的反应方法，这些方法面向生物医学和制药领域感兴趣的分子支架的合成。我们还建议研究两个具有生物活性的天然产物家族的功能，即含有20S蛋白酶体抑制剂的乙酰素和β -内酰胺。Acetogenins对许多癌细胞系表现出非常高的活性，20S蛋白酶体抑制剂也是如此，它们也成为令人兴奋的癌症治疗候选者。