Asymmetric Total Syntheses of Euphol and Tirucallol

• Published in: Organic letters Vol. 25; no. 30; pp. 5687 - 5691
• Main Authors: Nicholson, Joshua M., Micalizio, Glenn C.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 04-08-2023
• ISSN: 1523-7060; 1523-7052; 1523-7052
• DOI: 10.1021/acs.orglett.3c02187

Asymmetric de novo syntheses of euphol and tirucallol have been accomplished by way of a concise sequence of chemical steps featuring several modern stereoselective transformations. The preparative solution described for these complex problems in natural product synthesis departs significantly from biomimetic polyene cyclization chemistry, which has been leveraged to address related tetracyclic triterpenoid targets. In particular, a diastereoselective Friedel–Crafts-type cyclization was employed to establish a tetracycle bearing a stereodefined quaternary center at C9 (steroid numbering) that provided access to intermediates of relevance for introducing the C10 and C14 quaternary centers by sequential stereospecific 1,2-alkyl shifts (C9 → C10 and C15 → C14). Finally, the stereodefined C17 side chain was introduced in a single step by late-stage stereoselective conjugate addition to an intermediate possessing a D-ring enone. Notably, these de novo asymmetric syntheses are the first of their kind, providing completely synthetic access to enantiodefined euphane and tirucallane systems. Overall, each synthesis has been accomplished in fewer than 20 linear chemical steps from a simple Hajos–Parrish-derived ketone through a sequence that features just 15 chromatographic operations.