CHIRAL CATALYSTS FOR ENANTIOSELECTIVE SYNTHESES

描述：在这份续签提案中，首席调查员表示 这个项目的长期目标是高效 构建对映体纯的生物医学重要化合物， 而它的重点是使用手性催化剂来实现这一目标。 他报道了含手性羧胺配体的镝(II)化合物 (来自吡咯烷酮、恶唑烷酮和咪唑烷酮羧酸盐) 已经被证明是非常有效的催化剂 所选的对映选择性(大于90%ee)反应 重氮乙酸酯，导致分子内环丙烷化或 碳氢插入反应和分子间环丙烯反应 在设计和开发方面的进一步进步将改善 现有转换的选择性，以及它们承诺的 新应用取得重大突破。有迹象表明， 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-脱氧基内酯、2-脱氧基内酯、 脱氧核糖内酯，以及它们的甲基和杂原子衍生物。这个 脱氧糖将被转化为腺嘌呤和/或胸腺嘧啶核苷5‘- 三磷酸盐衍生物，然后进行体外评价 HIV逆转录酶和人类DNA聚合酶活性。这个 首席研究员报告说，分子内环丙烷化 反应得到高结构的环丙烷衍生物，其 已有的应用包括预奎烯酒精和肾素 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 区域选择性和对映体选择性，从而实现 对映体纯的单一产物的合成。它是 表示重氮酯、重氮酰胺、重氮酮和 重氮膦酸盐是合适的反应物，叶立德 生成/重排、N-H和O-H插入、C-H插入和 环丙烷化是一种靶向转化反应。对……的影响 重氮丙酸甲酯对氢气的选择性 重氮乙酸酯要进行检验。值得注意的是，准确的 通过评估，绝对立体化学的预测成为可能 由用于C-H插入、环丙烷化和 环丙烯缩合反应，与计算模型一致。这个 首席调查员表示，尽管一系列的例子 存在其中已实现94%或更好的对映控制的情况， 据报道，还有更多的对映体控制程度较低或适度 从第一代手性镝(II)催化剂的使用和 即将面世的第二代催化剂将使 在对映体控制方面可能有显著的增强。他说 此外，潜在应用的广度将是 在拟议的授权期内进行评估的目的是确定 这一催化方法的总体综合优势/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.