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: 7765576
• 负责人: BABAK BORHAN
• 金额: $ 23.44万
• 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/7765576
• 关键词: Acetylene; Alcohols; Alkenes; Area; Aziridines; Biological Assay; Biological Factors; Cancer cell line; Cells; Chemistry; Complex; Cyclization; Epoxy Compounds; Exhibits; Family; Glycols; Inorganic Sulfates; Investigation; Lead; Left; Libraries; Metals; Methodology; Methods; Molecular; Names; One-Step dentin bonding system; Pharmacologic Substance; Principal Investigator; Proteasome Inhibitor; Pyrrolidines; Reaction; Research; Secure; Structure; System; Unspecified or Sulfate Ion Sulfates; Work; acetogenin; analog; base; beta-Lactams; cancer therapy; cellular targeting; chiral molecule; crosslink; design; diene; functional group; inhibitor/antagonist; interest; lactacystin; multicatalytic endopeptidase complex; neoplastic cell; novel; potassium peroxymonosulfuric acid; programs; pyrrolidine; salinosporamide A; scaffold; stereochemistry; 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）：我们最近的努力集中在开发新的方法，这些方法能够从简单且易于获得的起始材料中有效合成杂环。我们在这一领域的研究在氧化化学领域取得了新的发现，包括二烯氧化环化以获得 THF 核和烯烃的氧化裂解。我们现在拥有一系列反应，可以在立体化学转移中完全保真地提供产物。我们开发了环氧化物区域控制开放的方法，以保护各种 THF 和 THP 环。官能团定向环氧化物打开方法已用于合成所提出的粘蛋白结构。计划努力阐明粘蛋白的真实结构。 mucoxin 的合成工作将被用于针对一组肿瘤细胞的各种结构和立体化学类似物的 SAR 研究。我们还建议设计一个乙酰丙酮类似物库，以便对基于细胞的测定以及微粒体筛选进行彻底研究。我们的研究还将集中于通过光亲和交联努力发现 acetogenins 的细胞靶点。粘蛋白的合成还导致了一种新的三醇环化方法的发现，以确保 THF 和 THP 环的安全。这一领域的研究将带来新的化学方法，用于通过区域和立体化学控制一步合成氧杂环和碳环形成1,2-二醇。我们假设的烯烃氧化裂解机制涉及 Oxone（过硫酸盐）的亲核攻击，随后 C-C 键裂解并排出硫酸盐。这种机制启发我们开发新的化学物质，即：使用其中含有良好离去基团的良好亲核试剂。我们已经证明，使用亚砜叶立德与 2,3-环氧醇一起可以形成具有区域和立体化学控制的 THF 环。建议将此方法扩展到可产生更复杂环系统的交替叶立德。此外，使用羟基氮丙啶导致吡咯烷的立体化学控制形成，对于开发杂环骨架策略具有巨大潜力。初步结果表明，这是合成各种取代吡咯烷的稳健且有效的方法。我们还发现了一种简单的、无金属的乙炔氢胺化（串联氮杂佩恩/氢胺化），可产生高度通用的合成子。这种化学反应将得到充分发展，其用途将通过盐孢菌酰胺 A、乳胞素及其类似物（这些类似物可能是有效的 20S 蛋白酶体抑制剂）的有效合成而得到强调。该提案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性的方式扩展通过所提出的转化可实现的分子库。该提案涉及开发新的反应方法，旨在合成生物医学和制药领域感兴趣的分子支架。我们还建议研究两个生物活性天然产物家族的功能，即乙酰丙酮和含有 20S 蛋白酶体抑制剂的 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，它们也正在成为令人兴奋的癌症治疗候选者。