ASYMMETRIC SYNTHESES MEDIATED BY CHIRAL ACETAL TEMPLATES

最近在PI的实验室中进行的研究导致了 由手性二醇衍生的缩醛的Lewis酸催化偶联， 例如S、S或R，R-2，4-戊二醇，与许多亲核试剂，例如， 三甲基硅基氰化物。这些反应以高度非对映选择性进行。 去掉手性助剂后，得到手性仲羟基 化合物，例如氰醇、α-羟基酯等，可预测在 无论是R形还是S形，都具有较高的光学纯度。现建议： 通过研究一大批不同的 一些手性二醇变体的亲核性和缩醛 希望找到“理想”的二元醇，即一种高效的二元醇 并以高光学纯度廉价制造。提案的其余部分是 主要关注新方法论的综合开发 它展示了提供方便、新的和改进的生产方式的希望 某些重要的手性结构如下：(A)难以 可获得的、具有生物重要性的α-氨基酸(例如， (B)(S)-α-氰基-3-苯氧基苯甲醇 (重要拟除虫菊酯类杀虫剂的成分)；(C)GABOB型 (抗惊厥药)；(D)()--负霉素(抗生素与革兰氏阴性 细菌)；(E)如计划所示的手性赤道红-1，3-二醇体系 用于合成(I)离子载体的关键合成子--非乳酸 非肌动蛋白，(Ii)致密蛋白(低胆固醇物质)和(Iii)两者 用于生产抗生素两性霉素B的手性片段；(F)a 形成交变邻域手性中心的广义方法 丙酸衍生天然产品中发现的羟基和Me基团，以及 由(I)生产中间体的合成计划说明 赤藓内酯A、利福霉素S和抗白血病药物美坦辛，(II) 洋地黄(强心苷的成分)，(Iii)橄榄糖( (四)萘普生(抗炎止痛剂)； 在抗生素中发现的邻位二-三羟基阵列 红霉素；(H)麻黄素和相关的交感神经； (J)稠环α-亚甲基丁内酯(肿瘤抑制剂)； 维生素D3代谢物，包括骨化三醇(有效抗骨营养不良)。

Recent studies in the PI's laboratories have led to the discovery of the Lewis acid-catalyzed coupling of an acetal derived from a chiral diol, e.g., S,S- or R,R-2,4-pentanediol, with a number of nucleophiles, e.g., trimethylsilylcyanide. These reactions proceed highly diastereoselectively to give, after removal of the chiral auxiliary, chiral secondary OH compounds, e.g., cyanohydrins, Alpha-hydroxy esters, etc., predictably in either the R or S form and in high optical purity. It is proposed to examine the scope of this reaction by studying a large variety of nucleophiles as well as acetals of a number of chiral diol variants with the hope of finding the "ideal" diol, i.e., one that is highly effective and inexpensively made in high optical purity. The rest of the proposal is mainly concerned with the synthetic exploitation of the new methodology which shows promise of providing facile, new and improved ways of producing certain important chiral structures as follows: (a) difficultly accessible, biologically important Alpha-amino acids (e.g., components of semisynthetic penicillins); (b) (S)-Alpha-cyano-3-phenoxybenzyl alcohol (component of important pyrethroid insecticides); (c) GABOB types (anticonvulsants); (d) (+)-negamycin (antibiotic vs. gram-negative bacteria); (e) the chiral erythro-1,3-diol system, as illustrated by plans for synthesizing (i) nonactic acid, the key synthon for the ionophore nonactin, (ii) compactin (hypocholesteremic substance) and (iii) the two chiral fragments for producing the antibiotic amphotericin B; (f) a generalized method or forming vicinal chiral centers carrying alternating OH and Me groups as found in propionate-derived natural products, and illustrated by plans for the synthesis of (i) intermediates for producing erythronolide A, rifamycin S, and the antileukemic agent maytansine, (ii) digitoxose (component of cardiac glycosides), (iii) olivose (component of chlorothricin) and (iv) naproxen (anti-inflammatory analgesic); (g) the vicinal secondary-tertiary hydroxy array found in antibiotics like erythromycin; (h) ephedrine and related sympathomimetics; (i) corticoids; (j) fused-ring Alpha-methylenebutyrolactones (tumor-inhibitors); (k) vitamin D3 metabolites including calcitriol (active against osteodystrophy).