Strategies for Efficient Routes to Bioactive Substances

生物活性物质的有效途径策略

• 批准号: 6915571
• 负责人: STEVEN D. BURKE
• 金额: $ 24.21万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6915571
• 关键词: antibiotics; antineoplastics; bicyclic compound; biological products; bryostatin; chemical structure function; chemical substitution; conformation; cyclization; drug design /synthesis /production; endothelin; inhibitor /antagonist; ketal; method development; stereochemistry; thromboxanes

DESCRIPTION (provided by applicant): We will develop and demonstrate a powerful new strategy for bicyclic acetal synthesis and elaboration. We will apply this ketalization/ring-closing metathesis technique to the synthesis of four natural products of varying structure to illustrate its versatility. Key attributes of this strategy that act in concert to afford extremely short synthetic routes to the chosen targets are: . Subunit convergence by intermolecular ketalization (a reliable, high-yielding net dehydration); . Intramolecular C-C bond formation via ring-closing metathesis; . Production of a dissymmetric bicyclic acetal from a C2-symmetric diene-diol; . Conformational locking of a dihydropyran within the bridged bicyclic acetal, allowing exploitation of steric and stereoelectronic biases for hydropyran functionalization; . Potential for chain elaboration in two directions in the residual vinyl group of the diene-diol and the ketone "R" group in convergence subunits; . Internal masking of three functional groups (hydroxyl, hydroxyl, and carbonyl), thus avoiding extra steps for protection and deprotection. We will synthesize the targets below by expeditious sequences enabled by these considerations: . 20-Deoxybryostatins, representative of the clinically-significant bryostatin class of anticancer agents; . Didemniserinolipid B, containing the 6,8-dioxabicyclo[3.2.1]octane skeleton common in bioactive agents; . Thromboxane B2-(TXBz)., natural degradation product of platelet aggregation mediator TXA2and model for clinical development of thrombosis inhibitors for cardiovascular disease treatment; . Kendomycin, a recently isolated ansa macrocyclic quinone methide that has exhibited biological activity as an endothelin receptor antagonist, as an antibacterial against MRSA strains, and as a potent anticancer agent with cytotoxicities similar or superior to doxorubicin and cisplatin against several cell lines. The proposed syntheses are one-third to one-half as long as comparative benchmarks for these targets, illustrating the effectiveness of this developing strategy for dramatically affecting synthetic efficiency.

描述（由申请人提供）：我们将开发和展示一种强大的双环缩醛合成和精制新策略。我们将应用缩酮化/闭环复分解技术来合成四种不同结构的天然产物，以说明其多功能性。这一战略的关键属性是协同行动，为选定的目标提供极短的合成路线： .通过分子间缩酮化（一种可靠、高产的净脱水）实现亚基聚合; .通过闭环复分解形成分子内C-C键; .由C2-对称二烯-二醇制备不对称双环缩醛 .二氢吡喃在桥连双环缩醛内的构象锁定，允许利用空间和立体电子偏置进行二氢吡喃官能化; .在会聚亚基中二烯二醇的残余乙烯基和酮“R”基团中在两个方向上进行链加工的潜力; .内部掩蔽三个官能团（羟基、羟基和羰基），从而避免额外的保护和脱保护步骤。 我们将根据这些考虑因素，按快速顺序综合下列目标： . 20-脱氧苔藓抑素，代表具有临床意义的苔藓抑素类抗癌剂; . Didemniserinolipid B，含有生物活性剂中常见的6，8-二氧杂双环[3.2.1]辛烷骨架; .血栓素B2-（TXBz），血小板聚集介质TXA 2的天然降解产物和用于心血管疾病治疗的血栓形成抑制剂的临床开发的模型; . Kendomycin是一种最近分离的柄型大环醌甲基化物，作为内皮素受体拮抗剂、抗MRSA菌株的抗菌剂和对几种细胞系的细胞毒性类似于或上级于阿霉素和顺铂的强效抗癌剂，显示出生物活性。 建议的合成是三分之一至一半的比较基准，这些目标，说明了这种发展战略的有效性，大大影响合成效率。