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.
The research program described in this proposal will enable the discovery of new small-molecule-based therapeutic agents. In addition, these efforts will advance the field of chemical synthesis and uncover catalysts that will be used in both industry and academia for the synthesis of biologically important compounds.
|Kaplan, Will; Khatri, Hem Raj; Nagorny, Pavel (2016) Concise Enantioselective Total Synthesis of Cardiotonic Steroids 19-Hydroxysarmentogenin and Trewianin Aglycone. J Am Chem Soc 138:7194-8|
|Cichowicz, Nathan R; Kaplan, Will; Khomutnyk, Yaroslav et al. (2015) Concise Enantioselective Synthesis of Oxygenated Steroids via Sequential Copper(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions. J Am Chem Soc 137:14341-8|