Development of a concise and scalable synthesis of the C13-hydroxy-ent-kaurane diterpenoids via a Lewis acid-induced cascade cyclization approach

Project: Research project

Project Details


Natural product-based drug discovery has been a very promising strategy in drug development. In the past 30 years, about 34% of new medicines approved by US Food and Drug Administration (FDA) were based on natural products or their derivatives (Harvey AL, et al., Nature Rev., 2015, 14, 111). ent-Kaurane diterpenoids represent a large family of natural products (more than 1300 members have been isolated) bearing a tetracyclic core with highly varied oxygenation and bond-cleavage patterns with skeletal rearrangements. Many family members have exhibited a variety of important biological activities such as antibacterial, anticancer, anti-inflammatory, and immunosuppressive activities. Although ent-kaurane diterpenoids have been popular targets for synthetic and medicinal chemists, there are only three C13-hydroxy-ent-kaurane diterpenoids, including gibberellic acid, steviol and 13-methoxy-15- oxozopatlin have been synthesized, and the biological activities of the synthetic compounds have not been studied. Thus, developing a practical synthetic route to the 13-hydroxy-ent- kaurane diterpenoids and their structural analogues will enable systematic SAR and comparison studies that could provide valuable information for rational design of second generation ent- kaurane analogues with better safety profiles and efficacy.

One of the long-standing interests in our group is to develop efficient synthesis of bioactive natural products via cascade cyclization strategies for biological studies. In our previous study, we have developed a scalable and versatile synthesis to the 7,20-epoxy-ent-kaurane diterpenoids and successfully identified neolaxiflorin L as a potent lead compound for further development. In this proposal, we have decided to develop a synthetic route for the synthesis of the C13-hydroxy-ent-kaurane diterpenoids based on our recently developed Lewis acid- induced cascade cyclization, which could established the C,D ring systems with the C13- hydroxy in a single operation. The target natural products include enanderianin L and laxiflorin M were selected due to their same tetracyclic core structures with different position of the oxygen-bridge. After establishing an efficient and versatile synthetic route, we will prepare a focus library of C13-hydroxy-ent-kaurane derivatives based on the single-variable principle for studying the importance of a particular functional group. These studies could lead to a great extension of the scope of the structure-activity relationship study and the development of ent- kaurane-based molecular probes for studying the mode of actions that associate with their anti- cancer activities.
Effective start/end date1/01/2231/12/24


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