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: 7351978
• 负责人: BABAK BORHAN
• 金额: $ 24.37万
• 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/7351978
• 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; Facility Construction Funding Category; Family; Glycol; Inorganic Sulfates; Investigation; Lead; Left; Libraries; Metals; Methodology; Methods; Molecular; Object Attachment; 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; aziridine; 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）：我们最近的努力集中在开发新的方法，使杂环化合物的有效合成从简单和容易获得的起始材料。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THF核和烯烃的氧化裂解。我们现在拥有的反应剧目，提供产品与完全保真度的立体化学转移。我们已经开发了用于环氧化物的区域控制的开放的方法，以确保各种THF和THP环。官能团导向的环氧化物开放方法已被用来合成粘毒素的拟议结构。计划努力阐明粘蛋白的真实的结构。粘毒素的合成工作将被用于SAR研究，其中包括针对一组肿瘤细胞的各种结构和立体化学类似物。我们还提出了一个图书馆的设计，在基于细胞的检测，沿着微粒体屏幕进行彻底调查的乙内酯类似物。我们的研究也将集中在发现细胞靶标的乙酸配基通过光亲和交联的努力。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方法，一步合成的恶环和碳环的形式与区域和立体化学控制的1，2-二醇。我们假设的烯烃氧化裂解机制涉及过硫酸氢钾（过硫酸盐）的亲核攻击，随后裂解的C-C键和驱逐硫酸盐。这一机制启发了我们发展新的化学，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-环氧醇导致形成的THF环的区域和立体化学控制。建议将这种方法扩展用于交替叶立德，从而产生更复杂的环系统。此外，使用羟基氮杂环丙烷，导致吡咯烷的立体化学控制的形成，对于开发杂环框架的策略具有巨大的潜力。初步结果表明，这是合成多种取代吡咯烷的一种稳健而有效的方法。我们还发现了一种简单的、不含金属的乙炔加氢胺化（串联的氮杂-Payne/加氢胺化），其导致高度通用的合成子。这种化学将得到充分发展，其用途将通过有效合成salinosporamide A，lactacystin及其类似物（类似物可能是有效的20 S蛋白酶体抑制剂）得到强调。该提案涉及开发新的合成方法，该方法利用来自手性池的简单分子，并以区域和立体选择性的方式扩展通过所提出的转化可获得的分子库。该提案涉及开发新的反应方法，其适合于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家族的生物活性天然产物，即，乙酸配基和β-内酰胺含20 S蛋白酶体抑制剂的功能。乙酸配基对许多癌细胞系表现出非常高的活性，20 S蛋白酶体的抑制剂也是如此，它们也正在成为令人兴奋的癌症治疗候选物。