Synthesis of (-)-Terpestacin Via Cyclopentannelation

通过环戊烷化合成 (-)-Terpestacin

• 批准号: 7049099
• 负责人: GIDEON O BERGER
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-11-16 至 2006-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049099
• 关键词: AIDS therapy; alkylation; antiAIDS agent; antiviral agents; biological products; biotherapeutic agent; chemical synthesis; cyclization; cycloalkene; cyclopentane; drug design /synthesis /production; method development; organic chemicals; stereoisomer

DESCRIPTION (provided by applicant): The proposed research involves the total synthesis of (-)-Terpestacin, a cellular inhibitor of the HIV virus. The primary goal is a brief, convergent synthesis anchored upon two powerful methodologies, asymmetric cyclopentannelation and ring closing metathesis. Asymmetric cyclopentannelation, developed by the Tius group, delivers complex chiral cyclopentanones, the core of Terpestacin. The target will be assembled in two pieces to be connected late in the synthesis and then cyclized using olefin metathesis. Asymmetric cyclopentannelation has demonstrated remarkable potential at delivering complex chiral cyclopentanones rapidly and in high stereopurity. The methodology is under continuing refinement including the development of new more powerful chiral auxiliaries for which this project serves as an excellent application. Ring closing metathesis has quickly become a mainstay method of macrocyclization. Some of the major challenges that still exist are the directing the regiospecificity of the olefination in the presence of competing reacting alkenes as well as the manipulation of the stereoselectivity of the final alkene formation. This proposed synthetic route would culminate with the olefination of two resident olefins in the presence of others. The selectivity for the desired olefination is based upon steric manipulations introduced by the Nicolaou group. This project represents an extended proving ground for this strategy of regiocontrol. Finally, the project represents a nice dichotomy of methodology development and total synthesis culminating in a rapid means of producing this possible anti-HIV drug.

描述（由申请人提供）：拟定研究涉及HIV病毒细胞抑制剂（-）-Terpestacin的全合成。主要目标是基于两种强大的方法（不对称环戊烷化和闭环复分解）进行简短、收敛的合成。Tius集团开发的不对称环戊烷酮，提供复杂的手性环戊酮，Terpestacin的核心。目标将被组装成两部分，在合成后期连接，然后使用烯烃复分解环化。不对称环戊烷酮在快速和高立体纯度地递送复杂手性环戊烷酮方面表现出显著的潜力。该方法正在不断完善，包括开发新的更强大的手性助剂，该项目作为一个很好的应用。关环复分解反应已迅速成为大环化的主要方法。仍然存在的一些主要挑战是在竞争反应烯烃的存在下指导烯烃化的区域特异性以及操纵最终烯烃形成的立体选择性。这一合成路线的最终结果是两种驻留烯烃在其他烯烃存在下发生烯化反应。所需烯化反应的选择性基于Nicolaou基团引入的空间操作。该项目是这一区域控制战略的一个扩大的试验场。最后，该项目代表了一个很好的二分法的方法开发和全合成最终在一个快速的手段，生产这种可能的抗艾滋病毒药物。