Synthesis and Medicinal Chemistry of Veragranine Alkaloids

Key words

veragranine - voltage-gated calcium channel - Minisci cyclization

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 (Ca_v2.2 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.

Publication History

Article published online:
16 August 2024