SYNTHESIS OF MANZAMINE A VIA NOVEL DIELS-ALDER REACTION

通过新型狄尔斯-阿尔德反应合成曼扎胺

• 批准号: 2172971
• 负责人: CHARLES E CHASE
• 金额: $ 2.26万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-14 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2172971
• 关键词: SYNTHESIS; MANZAMINE; VIA; NOVEL; DIELS

The proposed research concerns the development of a convergent asymmetric total synthesis of manzamine A. The range of cytotoxic and antibacterial activity, as well as the formidable structural challenges of the various manzamines, warrant the development of a convergent asymmetric synthesis amenable to analogue studies. The key feature of the proposed synthesis is a novel intramolecular macrocyclic Diels-Alder reaction of an alpha,beta-unsaturated amidine and an electron rich diene. Asymmetry is induced by the use of an enantiomerically pure bicyclic amidine obtained in 4 steps from a readily available L-serine derivative. The initial grant period (3-4 months) will be spent on an intermolecular variation of this key reaction. The diene and dienophile used will closely resemble those proposed in the total synthesis. Optimized conditions in the intermolecular case should be easily modified for the intramolecular reaction. The remainder of the grant period will be devoted towards the synthesis of manzamine A. Convergence is maintained by independent synthesis of the diene and dienophile. Coupling and subsequent cyclization result in the isoquinoline core of manzamine A with the intact 13-membered azacine. The functionality necessary for introduction of the C and E rings also serve as the stereocontrol element in the Diels-Alder cycloaddition, thereby eliminating the removal of chiral auxiliary. The introduction of the beta-carboline moiety and can be achieved by known chemistry. The synthesis should allow easy access into the manzamine skeleton and be amenable to systematic variations; an attribute particularly attractive for analogue studies.

所提出的研究涉及收敛的不对称的发展 甘露糖胺A的全合成及其细胞毒性和抗菌作用的范围 活动，以及各种不同国家面临的巨大结构性挑战 曼扎明，保证了收敛不对称合成的发展 易于进行类比研究。提议的合成的主要特点是 是一种新的分子内大环Diels-Alder反应 α，β-不饱和胺和富含电子的二烯。不对称是 通过使用得到的具有对映体纯度的双环酰胺来诱导 用4个步骤从现成的L-丝氨酸衍生物中分离得到。首字母 授权期(3-4个月)将用于分子间变异 这一关键反应。使用的二烯烃和亲二烯分子将密切相关 与总合成中提出的相似。中的优化条件 对于分子内的，分子间的情况应该很容易修改 反应。授权期的剩余时间将专门用于 甘露糖胺A的合成由独立维持收敛 双烯和亲双烯化合物的合成。耦合和后续 环合反应得到甘露糖胺A的异喹啉核 完整的13元氮杂环己烷。介绍所需的功能 环的C和E环也作为立体控制元素 Diels-Alder环加成反应，从而消除了手性的去除 辅助性。引入了β-咔啉部分，并可以 通过已知的化学作用实现的。合成应该允许容易地访问 甘露糖胺的骨架，并能适应系统的变化； 属性对于类比研究特别有吸引力。