Contributors: Dirk Trauner, Daniel W. Zuschlag
Significance
The veragranine alkaloids are a class of steroidal natural products isolated in 2022 from Veratrum grandiflorum, a flowering plant with a history of use in traditional medicine. Veragranine A has been shown to possess analgesic properties, likely due to its ability to block voltage-gated calcium channels (Cav2.2 IC50 = 45.76 ± 1.14). Khanna, Dai, and co-workers report the first laboratory preparation of veragranine A through a semisynthesis from commercially available dehydroepiandrosterone (DHEA). Additionally, the authors report the synthesis of a number of unnatural F-ring analogs, several of which possess similar analgesic activity to veragranine A.
Comment
Veragranine A was accessed in eleven steps from the commercially available steroid dehydroepiandrosterone (DHEA). Key steps include a Schönecker oxidation to functionalize the C12 position, a Suzuki–Miyaura cross-coupling reaction to install the pyridine F ring, and a Minisci-type radical cyclization to form the E ring. Use of different aryl boronates in the cross-coupling reaction allowed for the preparation of a small library of compounds. Two of these synthetic analogues, 27a and 27eb, demonstrated in vivo efficacy as calcium channel blockers.
Ma D, Duran P, Al-Ahmad R, Hestehave S, Joa M, Alsbiei O, Rodríguez-Palma EJ, Li Y, Wang S, Khanna R, Dai M. * University of Florida, Gainesville and Emory University, Atlanta, USA
C–H Functionalization-Enabled 11-Step Semisynthesis of (–)-Veragranine A and Characterization of Synthetic Analogs in Osteoarthritis-related Pain Treatment.
J. Am. Chem. Soc. 2024;
146: 16698-16705
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