Organo-catalytic asymmetric synthesis of cannabinoids

大麻素类化合物是一类重要的生物活性分子，调节多种受体。其中，CB1和CB2受体均为膜结合的G蛋白偶联受体(G蛋白偶联受体)。因此，大麻素受体是重要的新药靶点。除了用作减肥药物外，CBI拮抗剂还有可能用于治疗包括帕金森氏症和亨廷顿病在内的神经退行性疾病，以及治疗药物依赖。在这项提案中，我们将重点介绍有机催化制备CB1和CB2调节分子的两种策略。第二种策略使用我们以目标为导向的天然大麻类化合物及其同系物的合成。在第一步中，利用有机催化的氧迈克尔反应形成色烯。随后的官能化，包括有机催化的Diels-Alder反应，将导致大麻类化合物的从头合成。一项应用将集中在两种迄今尚未合成的具有苯并吡喃骨架的天然产物上。第二种方法基于最近发现的卡宾介导的香豆素合成。后者在体内和体外都被证明是活性大麻素。我们将继续沿着这些路线进行，并将其扩展到非对称版本。

Cannabinoids belong to an important class of biologically active molecules modulating various receptors. Among them, the CB1 and the CB2 receptor which are both membrane bound GPCR (G-protein coupled receptors). Therefore, cannabinoid receptors are important new drug targets. Besides their use as anti-obesity drugs, CBi antagonists have potential for the treatment of neurodegenerative diseases including Parkinson's and Huntington's disease, and for the therapy of drug dependence. in this proposal we will focus on two strategies for the generation of CB1 and CB2 modulating molecules prepared by organo-catalysis. The second strategy uses our target-oriented synthesis of natural occurring cannabinoids and their congeners. In the first step, chromenes are formed using an organo-catalytic oxa-Michael reaction. Subsequent functionalization including the organo-catalyzed Diels-Alder reaction will lead to a de-novo synthesis of cannabinoids. An application will focus on two so-far no synthesized natural products having the Benzopyran skeleton. The second approach based on the recently discovered carbene-mediated synthesis of coumarins. The latter proofed to be active cannabinoids in vivo and in vitro. We will continue along these lines and expand this to an asymmetric version.