ASYMMETRIC SYNTHESES MEDIATED BY CHIRAL ACETAL TEMPLATES

手性缩醛模板介导的不对称合成

• 批准号: 3283728
• 负责人: WILLIAM S JOHNSON
• 金额: $ 25.99万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3283728
• 关键词: adrenergic agents; aminoacid; analgesics; anticonvulsants; antiinflammatory agents; cholecalciferol; diol; drug design /synthesis /production; ephedrine; erythromycin; hypocholesterolemia; insecticides; ketal; nutrition related tag; penicillins

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).

PI实验室最近的研究发现了 由手性二醇衍生的缩醛的刘易斯酸催化偶联， 例如，在一个实施例中，S，S-或R，R-2，4-戊二醇与许多亲核试剂，例如， 三甲基氰硅烷 这些反应高度非对映选择性地进行 除去手性助剂后，得到手性仲OH 化合物，例如，氰醇、α-羟基酯等，预计在 R或S形式，并且具有高光学纯度。 提出要 通过研究各种各样的反应来检查这种反应的范围。 亲核试剂以及许多手性二醇变体的缩醛， 希望找到“理想的”二醇，即，一种高效的 并且以高光学纯度廉价地制造。 提案的其余部分是 主要涉及新方法论的综合开发 它显示出提供简便、新的和改进的生产方法的希望， 一些重要的手性结构如下：（a）难以 可获得的、生物学上重要的α-氨基酸（例如，的组件 半合成青霉素）;（B）（S）-α-氰基-3-苯氧基苄醇 （重要的拟除虫菊酯类杀虫剂的成分）;（c）GABOB类型 （抗惊厥药）;（d）（+）-阴霉素（抗生素vs.革兰氏阴性菌 细菌）;（e）手性邻苯二甲酰-1，3-二醇系统，如图所示 用于合成（i）离子载体的关键合成子， nonactin，（ii）compactin（hypotheremic物质）和（iii）两种 用于生产抗生素阿替霉素B的手性片段;（f）a 形成邻位手性中心的方法 OH和Me基团，如在丙酸盐衍生的天然产物中发现的，以及 通过合成（i）用于生产的中间体的计划来说明， （ii）利福霉素S和抗白血病剂美登素， 洋地黄毒糖（强心苷的组分），（iii）橄榄糖（强心苷的组分）， 氯丝菌素）和（iv）萘普生（抗炎镇痛药）;（g） 在抗生素中发现的邻位二级-三级羟基阵列， 红霉素;（h）麻黄碱和相关拟交感神经药;（i）皮质激素; (j)稠环α-亚甲基丁内酯（肿瘤抑制剂）;（k） 维生素D3代谢物，包括骨化三醇（对骨营养不良有活性）。