We report herein a total synthesis of conidiogenone B, a complex cyclopiane diterpene exhibiting potent antibacterial activity against multidrug-resistant pathogens. Conidiogenone B and its natural congeners feature a congested 6/5/5/5 (A/B/C/D) tetracyclic carbon framework and multiple stereocenters, including four all-carbon quaternary centers. The challenge of conidiogenone total synthesis lies in how to efficiently construct the tetracyclic carbon framework, especially the A/B hydrindane moiety with two vicinal all-carbon quaternary centers at the ring junction. We developed an efficient strategy with a metal-hydride hydrogen atom transfer (MHAT)-initiated reductive olefin-nitrile radical cyclization to close the six-membered A ring and construct the angular methyl containing all-carbon quaternary center adjacent to an existing one, which was formed via a stereoselective Johnson-Claisen rearrangement. Two approaches were investigated to form the B ring. The first one involves a four-step sequence featuring an intramolecular aldol condensation to close the B ring. The second one-step approach utilizes a doubly activated cyclopropane derivative (1-(ethoxycarbonyl)cyclopropyl)triphenylphosphonium tetrafluoroborate as a formal 1,3-dipole in a one-pot stepwise (3 + 2) annulation, namely, α-alkylation followed by Wittig olefination, to construct the B ring. In addition, a MHAT-initiated Baran reductive olefin-enone cyclization (BROC) was employed to form the D ring, and a Stork-Danheiser alkylation transposition protocol was used to produce the BROC precursor. Overall, these enabling transformations delivered conidiogenone B in only 7 steps without using any protecting groups by maximizing C-C bond-forming events and minimizing individual functional group manipulation steps to achieve high efficiency and 100% ideality in terms of strategic step count.
Bernard et al. (Tue,) studied this question.