Strategies for Efficient Routes to Bioactive Substances

生物活性物质的有效途径策略

• 批准号: 6679750
• 负责人: STEVEN D. BURKE
• 金额: $ 23.46万
• 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/6679750
• 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(由申请者提供)：我们将开发和展示一种强大的双环缩醛合成和精加工新策略。我们将把这种酮化/闭环复分解技术应用于四种不同结构的天然产物的合成，以说明它的多功能性。这一战略的主要特点是协同行动，提供到选定目标的极短合成路线： 。通过分子间缩酮作用实现亚基聚合(一种可靠、高产的净脱水方法)； 。分子内C-C键是通过闭环复分解作用形成的； 。由C2对称的二烯二醇合成不对称双环缩醛 。桥联双环缩醛中二氢吡喃的构象锁定，允许利用立体和立体电子偏置进行氢化吡喃官能化； 。聚合亚单位中二烯二醇和酮“R”基团的残留乙烯基团在两个方向上的链精化潜力； 。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解除保护步骤。 我们将在这些考虑因素的支持下，通过快速序列来合成以下目标： 。20-脱氧溴他汀类，代表临床上重要的抗肿瘤药物类； 。Didemniserinolipid B，含有生物活性物质中常见的6，8-二恶二环[3.2.1]辛烷骨架； 。血栓素B2(TXBz)是血小板聚集介质TXA2的天然降解产物，是临床开发血栓形成抑制剂治疗心血管疾病的模型； 。新近分离的一种ANSA大环喹酮甲酸酯，它显示出作为内皮素受体拮抗剂的生物活性，作为对MRSA菌株的抗菌剂，作为一种有效的抗癌药物，对几种细胞株的细胞毒活性与阿霉素和顺铂相似或更好。 建议的合成是这些目标的比较基准的三分之一到一半，说明了这一发展战略的有效性，显著影响了合成效率。