New methods and strategies for the synthesis of bioactive steroids and terpinoids

描述（由申请人提供）：本提案的重点是开发新的对映选择性手性催化剂控制的生物活性类固醇和二萜的方法。由于甾体激素对人体重要生物过程的调节的重要性，很大一部分天然产物为基础的药物来源于各种天然或非天然类固醇。类固醇类药物用于治疗炎症、过敏反应、心脏病、癌症、代谢疾病以及重要的健康相关领域，如避孕和健身。大多数类固醇类药物是用从植物或动物中分离出来的原料半合成的。虽然现在这些过程可以在工业规模上进行，但对半合成方法的依赖极大地限制了可用于生物评价的基于类固醇的小分子的结构多样性。相比之下，完全合成的方法可以显著提高难以制备的具有不寻常取代或氧化模式的立体异构体支架的可用性。本研究的目的是建立立体选择性迈克尔/双醛醇级联反应，并将其应用于心脏类固醇和异吡玛烷家族二萜的快速组装。为了实现这一目标，我们提出了以下具体目标：(1)开发新的立体选择性催化Michael/双醛醇级联反应，用于立体选择性合成香梨内酯和蟾二烯内酯；(2)开发手性磷酸（CPA）控制区域选择性和立体选择性糖基化cardenolides基多元醇；(3)建立生物活性异吡烷的不对称合成方法。

DESCRIPTION (provided by applicant): This proposal is focused on the development of new enantioselective chiral catalyst-controlled approaches to bioactive steroids and diterpenes. Due to the importance of steroidal hormones for the regulation of vital biological processes in the human body, a significant portion of natural product-based drugs are derived from various natural or unnatural steroids. Steroid-based drugs are utilized for the treatment of inflammation, allergic reactions, heart diseases, cancer, metabolic diseases, and in important health-related areas such as contraception and fitness. The majority of steroid-based drugs are obtained by semi-synthesis using feedstock isolated from plant or animal sources. While nowadays such processes could be conducted on an industrial scale, the reliance on semi-synthetic methods significantly limits the structural diversity of the steroid-based small molecules available for biological evaluation. In contrast, fully synthetic approaches could significantly improve the availability of otherwise difficult-to-prepare stereoisomeric steroidal scaffolds with unusual substitution or oxidation patterns. The objective of the proposed research is to develop stereoselective Michael/double aldol cascade reactions and apply them to the rapid assembly of cardiac steroids and diterpenes of the isopimarane family. To achieve this objective, we propose the following specific aims: (1) to develop new stereoselective catalytic Michael/double aldol cascade reactions for the stereoselective synthesis of cardenolides and bufadienolides; (2) to develop chiral phosphoric acid (CPA)-controlled regioselective and stereoselective glycosylation of cardenolide-based polyols; (3) To develop an asymmetric approach to bioactive isopimaranes.