Oridonin (1), a highly oxygenated 7,20-epoxy-ent-kaurane-type diterpenoid isolated from the traditional Chinese herb rabdosia rubescens, is primarily characterized by its densely functionalized and stereochemistry-rich frameworks. This natural product has been attracting considerable attention in recent years due to its remarkably unique and safe anticancer pharmacological profile. To date, little chemical effort has been directed toward modifications of the oridonin A-ring to generate diversity, likely owing to the synthetic challenges arising from its structural complexity with multiple reactive functionalities. Herein, we, for the first time, disclose our effort for the efficient synthesis of novel nitrogen-enriched oridonin derivatives with azide and 1,2,3-triazole functionalizations at the C-1, C-2 or C-3 position in a highly regio- and stereo-specific manner while keeping key reactive pharmacophores intact by utilizing preactivation strategies based on a common synthon. Further functionalizations of these azides through click chemistry yielding 1,2,3-triazole derivatives readily provided access to an expanded natural scaffold-based compound library. Our success in the efficient construction of oridonin-based azides or triazoles opens a fruitful synthetic avenue to the development of novel natural product-like anticancer agents. Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/239nm/uploads/3690_figure1.jpg' alt='' />

Overcoming synthetic challenges of oridonin A-ring structural diversification: Regio- and stereoselective installation of azides and 1,2,3-triazoles at the C-1, C-2, or C-3 position

246th National Meeting (2013)

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