Seven-Step Total Synthesis of Conidiogenone B Enabled by Radical Cyclizations.

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Conidiogenone B is a complex cyclopiane diterpene with significant antibacterial activity against multidrug-resistant pathogens.
• Its structure is characterized by a congested 6/5/5/5 tetracyclic carbon framework with multiple stereocenters, including four all-carbon quaternary centers.

Purpose of the Study:

• To develop an efficient total synthesis strategy for conidiogenone B.
• To address the synthetic challenges posed by the congested tetracyclic framework, particularly the A/B hydrindane moiety with vicinal all-carbon quaternary centers.

Main Methods:

• Metal-hydride hydrogen atom transfer (MHAT)-initiated reductive olefin-nitrile radical cyclization for A ring formation.
• Johnson-Claisen rearrangement to construct an all-carbon quaternary center.
• Two distinct approaches for B ring construction: a four-step sequence with intramolecular aldol condensation, and a one-step (3 + 2) annulation using a cyclopropane derivative.
• MHAT-initiated Baran reductive olefin-enone cyclization (BROC) for D ring formation.
• Stork-Danheiser alkylation transposition protocol for BROC precursor synthesis.

Main Results:

• The total synthesis of conidiogenone B was achieved in an unprecedented 7 steps.
• The strategy efficiently constructed the complex tetracyclic framework, including the challenging vicinal all-carbon quaternary centers.
• The synthesis maximized C-C bond-forming events and minimized protecting group manipulations, demonstrating high efficiency and strategic ideality.

Conclusions:

• The developed synthetic strategy provides an efficient route to conidiogenone B.
• This synthesis highlights the utility of MHAT-initiated radical cyclizations and novel annulation strategies in complex molecule synthesis.
• The efficient synthesis of conidiogenone B facilitates further investigation into its potent antibacterial properties.