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; 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论上，这些方法可以从简单而易于获得的起始材料中有效合成异环的合成。我们在这一领域的研究导致了氧化化学领域的新发现，无论是在二烯的氧化环化中，都可以进入核心核心和氧化裂解。现在，我们拥有一系列反应的曲目，这些反应能够提供以完全忠诚的立体化学传递。我们已经开发了环氧化物开放的方法，以确保各种THF和THP环。官能团定向环氧开放方法已用于合成粘液毒素的拟议结构。计划阐明粘液毒素的真实结构。关于粘液毒素的合成工作将与SAR研究相结合，其对肿瘤细胞的各种结构和立体化学类似物。我们还提出了乙酰基蛋白类似物库的设计，以便在基于细胞的测定中进行彻底研究以及微粒体筛选。我们的研究还将集中于通过光附加性交联工作发现乙蛋白素的细胞靶标。粘液毒素的合成也导致发现了一种新的三醇环化方法来保护THF和THP环。在该领域进行的研究将导致新的化学成分，以使氧化剂和碳环弹性的一步合成具有1,2-二醇，并具有区域和立体化学对照。我们假定的烯烃氧化裂解机制涉及氧酮（过氧硫酸盐）的亲核攻击，随后C-C键的切割和硫酸盐的驱动。这种机制激发了我们开发新的化学反应，即；使用良好的亲核者的使用，其中包含在它们内部的良好离开组。我们已经证明了与2,3-环氧醇一起使用的磺氧酮Ylides会导致具有区域和立体化学控制的Thf环形成。提出了将此方法与替代YLIDE一起使用的扩展，该方法将提出更复杂的环系统。此外，使用羟基 - 齐里丁，导致吡咯烷立体控制的形成具有巨大的潜力，可以为杂环框架开发策略。初步结果表明，这是合成各种取代的吡咯烷的强大而有效的方法。我们还发现了一种简单的，无金属的乙酰乙烯（串联aza-payne/hydroamination）的盐水，可导致高度通用的合成。该化学将充分开发，并通过有效合成盐氧化盐A，乳酸化的和它们的类似物（类似物可能是20S的20S蛋白酶体抑制剂）来突出显示其使用。该提案涉及开发新的合成方法论，这些方法利用手性库中的简单分子，并以区域性和立体选择性的方式扩展了通过拟议的转换可实现的分子的曲目。该提案涉及开发新的反应方法，这些方法旨在构成生物医学和药物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，即含有20S蛋白酶体抑制剂的乙酸基因蛋白和β-内酰胺。乙蛋白素对许多癌细胞系表现出很高的活性，而20S蛋白酶体的抑制剂也是如此，这也是令人兴奋的癌症治疗候选者。