APPROACHES TO MACROLIDE & IONOPHORE ANTIBIOTIC SYNTHESIS

大环内酯的研究方法

• 批准号: 3280713
• 负责人: ANTHONY J PEARSON
• 金额: $ 14.45万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3280713
• 关键词: cardiac glycoside aglycone; chemical structure function; drug design /synthesis /production; ionophores; lactones; macrolide antibiotics; steroid glycoside aglycone

A new route for the asymmetric total synthesis of 16-membered ring macrolide antibiotic aglycones tylonolide and carbonolide B is being developed. Attachment of an iron carbonyl moiety to a cycloheptadienyl cation ligand allows stereocontrolled successive introduction of two substituents to give, ultimately, 5,7-disubstituted cycloheptadienes which can be further elaborated to C(1) - C(11) sections of the macrolides. Detailed study and development of the phenomenon of chiral recognition during reactions of cycloheptadienyliron complexes with optically pure sulfoximinyl ester enolate nucleophiles will allow access to these subunits as the natural antipodes. Completion of the synthesis of the macrolide aglycones by attachment of C(12) - C(16) units will be studied. The approach described has considerable potential fexibility and allows planned variations in substitution around the macrolide ring, thereby making available compounds which can be used to study structure/activity relationships in the macrolide series. The chemistry of 2-alkoxy-substituted cycloheptadienyliron complexes will be studied in detail, leading to a flexible preparation of subunits for synthesis of the ionophore antibiotic ionomycin, in optically active form. Detailed studies into cyclofunctionalization of dienes and their iron complexes will be undertaken, as will studies into the asymmetric functionalization of cycloheptadiene and 5,7-dimethyl cycloheptadiene. These studies will culminate in asymmetric syntheses of the alkaloid luciduline and the Prelog-Djerassi lactone. Detailed studies into the chemistry and potential synthetic utility of cyclooctadienyliron complexes will be undertaken.

不对称全合成16元环的新路线 大环内酯类抗生素苷元、泰诺内酯和内酯B 发展起来的。铁的羰基部分与环庚二烯基的结合 阳离子配体允许立体控制的两个连续引入 最终得到5，7-二取代环庚二烯，其 可进一步阐述到C(1)-C(11)大环内酯类化合物。 手性识别现象的深入研究与发展 环七碳二烯与光学纯化合物的反应 亚磺酰亚胺酯烯醇化亲核试剂将允许访问这些亚基。 作为天然的对极。完成大环内酯类化合物的合成 将研究C(12)-C(16)单元连接的苷元。这个 所描述的方法具有相当大的潜在灵活性，并允许计划 大环内酯环周围的取代变化，从而使 可用于研究结构/活性的可用化合物 大环内酯类系列中的关系。 2-烷氧基取代的环庚二烯基配合物的化学 要进行详细的研究，从而灵活地制备用于 光学活性形式的离子载体抗生素离子霉素的合成。 二烯及其铁的环官能化详细研究 将进行复杂的研究，以及对不对称的研究 环庚二烯和5，7-二甲基环庚二烯的官能化。 这些研究将最终导致生物碱的不对称合成。 Luciduline和Prelog-DJerassi内酯。 对化学和潜在的合成用途的详细研究 将进行环辛二烯亚甲基络合物。