CHIRAL CATALYSTS FOR ENANTIOSELECTIVE SYNTHESES

描述：在本更新提案中，主要研究者声明 这个项目的长期目标是 构建对映体纯的生物医学重要化合物， 并且其焦点在于使用手性催化剂来实现这一目标。 他报告说，具有手性羧酰胺配体的二铑（II）化合物 (from吡咯烷酮、恶唑烷酮和咪唑烷酮羧酸盐） 已被证明是非常有效的催化剂， 选择的对映选择性（大于90%ee）反应 重氮乙酸酯，其导致分子内环丙烷化，或 碳氢插入以及分子间环丙烯化 设计和开发的进一步进步将改善 选择性与现有的转换，他们承诺， 在新的应用中取得重大突破。指出了 分子内碳氢插入反应将用于 手性前列腺素前体，（-）-肠内酯， 内源性哺乳动物木脂素内酯家族的亲本，以及 独特的脱氧糖衍生物，包括2-脱氧木糖内酯，2- 脱氧核糖内酯及其甲基和杂原子衍生物。的 脱氧糖将被转化为它们的腺嘌呤和/或胸苷5 '- 三磷酸衍生物，然后进行体外评价， HIV逆转录酶和人类DNA聚合酶活性。的 首席研究员报告说，分子内环丙烷化 反应得到高度结构化的环丙烷衍生物， 应用已经包括前角烯醇和肾素 抑制剂，其未来有望提供光学活性 γ-氨基丁酸（GABA）的环丙烷类似物等。 他指出，正在开发的催化方法提供了 控制非对映选择性、化学选择性和 区域选择性与对映选择性一起，从而实现 对映体纯的单一产物的合成。是 表明，重氮酯，重氮酰胺，重氮酮，和 重氮膦酸酯是合适反应物，叶立德 生成/重排，N-H和O-H插入，C-H插入，和 环丙烷化是靶向转化。的影响变 重氮丙酸酯中甲基相对于重氮丙酸酯中氢的选择性 重氮基乙酸酯是要检查的。值得注意的是， 绝对立体化学的预测是可能的， 由C-H插入、环丙烷化和 环丙烯化，和计算模型是一致的。的 首席研究员表示，虽然有一系列的例子， 存在其中实现了94%或更好的ee的对映体控制， 据报道，还有更多的对映体控制程度较低至中等 从第一代手性铑（II）催化剂的使用， 第二代催化剂将使 可能显著增强对映体控制。他指出 此外，潜在应用的广度， 在拟议的赠款期间进行评估的目的是建立 该催化方法的总体合成优点/可行性。

DESCRIPTION: In this renewal proposal, the principal investigator states that the long-term objective of this project is the efficient construction of enantiomerically pure biomedically important compounds, and its focus is on the use of chiral catalysts to achieve this goal. He reports that dirhodium(II)compounds with chiral carboxamide ligands (from pyrrolidone, oxazolidinone-, and imidazolidinone-carboxylates) have proven to be remarkably effective catalysts for highly enantioselective (greater than 90 percent ee) reactions of selected diazoacetate esters that result in intramolecular cyclopropanation or carbon-hydrogen insertion as well as in intermolecular cyclopropenation and that further advances in design and development will improve selectivities with existing transformations, and that they promise significant breakthroughs in new applications. It is indicated that intramolecular carbon-hydrogen insertion reactions will be employed for the syntheses of chiral prostaglandin precursors, of (-)-enterolactone, the parent of a family of endogenous mammalian lignan lactones, and of unique deoxysugar derivatives, including 2-deoxyxylolactone, 2- deoxyribonolactone, and their methyl and heteroatom derivatives. The deoxysugars are to be converted to their adenine and/or thymidine 5'- triphosphate derivatives and then subjected to in vitro evaluation of HIV reverse transcriptase and human DNA polymerase activity. The principal investigator reports that intramolecular cyclopropanation reactions afford highly structured cyclopropane derivatives whose applications have already included presqualene alcohol and renin inhibitors, and whose future promises to deliver optically active cyclopropane analogs of gamma-aminobutyric acid (GABA), among others. He notes that the catalytic methodology being developed provides the opportunity to control diastereoselectivity, chemoselectivity, and regioselectvity, together with enantioselectivity, and thereby achieve the synthesis of single products that are enantiomerically pure. It is indicated that diazoesters, diazoamides, diazoketones, and diazophosphonates are suitable reactants and that ylide generation/rearrangement, N-H and O-H insertion, C-H insertion, and cyclopropanation are targeted transformations. The influence on selectivity of methyl in diazopropanoate esters relative to hydrogen in diazoacetate esters is to be examined. It is noted that accurate predictions of absolute stereochemistry are made possible by evaluations made of the transition state for C-H insertion, cyclopropanation, and cyclopropenation, and computational modeling is in agreement. The principal investigator indicates that although an array of examples exist in which enantiocontrol 94 percent or better ee has been achieved, there are many more for which low to modest enantiocontrol was reported from uses of first generation chiral dirhodium(II) catalysts and that the second generation catalysts that are becoming available will make possible significant enhancement in enantiocontrol. He states that furthermore, the breadth of potential applications that will be evaluated during the proposed grant period is intended to establish the overall synthetic advantages/feasibility of this catalytic methodology.