Regio and Stereoselective Reactions in Synthesis of Heterocycles

描述(申请人提供)：我们最近的努力集中在开发新的方法，使之能够从简单和容易获得的起始原料有效地合成杂环。我们在这一领域的研究在氧化化学领域取得了新的发现，包括二烯的氧化环化反应以访问四氢呋喃核心和烯烃的氧化裂解。我们现在拥有一系列反应，在立体化学的转移中提供完全保真的产品。我们已经开发了区域控制的环氧化物打开方法，以确保各种THF和THP环的安全。利用官能团导向的环氧化物开环方法合成了粘菌素的结构。为阐明粘菌素的真实结构所做的努力正在计划之中。粘毒素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合成孔径雷达研究。我们还建议设计一个乙酰生长素类似物的文库，用于在基于细胞的分析中进行彻底的研究，以及微体筛选。我们的研究还将集中于通过光亲和交联努力发现乙酰基元的细胞靶点(S)。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环的安全。在这一领域的研究将导致新的化学方法，在区域和立体化学控制下，从1，2-二醇一步合成草环和碳环。我们推测的烯烃氧化裂解机制包括氧酮(过氧硫酸酯)的亲核攻击，随后C-C键断裂和硫酸盐的排出。这一机制启发了我们发展新的化学，即使用良好的亲核剂，其中含有良好的离开基团。我们已经证明了亚砜叶立德与2，3-环氧醇的结合使用导致了区域和立体化学控制的四氢呋喃环的形成。建议将这一方法扩展到使用将产生更复杂环系的替代叶立德。此外，羟基氮杂环的使用，导致了立体化学控制的吡咯烷的形成，在开发杂环框架的策略方面具有很大的潜力。初步结果表明，该方法是一种合成多种取代吡咯烷的有效方法。我们还发现了一种简单的、不含金属的乙炔氢胺化反应(串联氮杂佩恩/氢胺化反应)，这导致了一种用途广泛的合成子。这一化学将得到充分发展，并将通过有效地合成盐孢子胺A、lactacystin及其类似物(类似物可能是有效的20S蛋白酶体抑制剂)来突出其用途。这项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性的方式扩展了可通过所提议的转化获得的分子的全套。这项建议涉及开发新的反应方法，以合成生物医学和制药领域感兴趣的分子支架。我们还建议研究两类具有生物活性的天然产物，即乙酸根素和含有20S蛋白酶体抑制剂的β-内酰胺。乙酸根素对许多癌症细胞株表现出非常高的活性，20s蛋白酶体的抑制剂也是如此，这也是癌症治疗的令人兴奋的候选药物。

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.