Strategies for Efficient Routes to Bioactive Substances

生物活性物质的有效途径策略

• 批准号: 6765986
• 负责人: STEVEN D. BURKE
• 金额: $ 24.23万
• 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/6765986
• 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）：我们将开发并展示一种强大的双环缩醛合成和精制新策略。我们将应用这种缩酮化/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。该策略的关键属性共同作用，为所选目标提供极短的合成路线： 。通过分子间缩酮化实现亚基收敛（可靠、高产的净脱水）； 。通过闭环复分解形成分子内 C-C 键； 。由C2-对称二烯二醇生产不对称双环缩醛； 。将二氢吡喃构象锁定在桥联双环缩醛内，允许利用空间和立体电子偏向进行氢吡喃功能化； 。二烯二醇的残余乙烯基和会聚亚基中的酮“R”基团在两个方向上进行链加工的潜力； 。三个官能团（羟基、羟基和羰基）的内部掩蔽，从而避免了额外的保护和脱保护步骤。 我们将根据这些考虑因素通过快速序列合成以下目标： 。 20-脱氧苔藓抑素，具有临床意义的苔藓抑素类抗癌药物的代表； 。 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TXA2的天然降解产物以及用于心血管疾病治疗的血栓抑制剂的临床开发模型； 。 Kendomycin 是一种最近分离的安莎大环醌甲基化物，具有作为内皮素受体拮抗剂、针对 MRSA 菌株的抗菌剂以及作为有效抗癌剂的生物活性，其对多种细胞系的细胞毒性类似于或优于多柔比星和顺铂。 所提出的合成方法是这些目标的比较基准的三分之一到二分之一，说明了这种开发策略对显着影响合成效率的有效性。