Strategy Evolution in a Skeletal Remodeling and C-H Functionalization-Based Synthesis of the Longiborneol Sesquiterpenoids

Detailed herein are our synthesis studies of longiborneol and related natural products. Our overarching goals of utilizing a camphor first strategy enabled by skeletal remodeling of carvone, and late-stage diversification using C-H functionalizations, led to divergent syntheses of the target natural products. Our initial approach proposed a lithiate addition to unite two fragments followed by a Conia-ene or Pd-mediated cycloalkylation reaction sequence to install the seven-membered ring emblematic of the longibornane core. This approach was unsuccessful and evolved into a revised plan that employed a Wittig coupling and a radical cyclization to establish the core. A reductive radical cydization, which was explored first, led to a synthesis of copaborneol, a structural isomer of longiborneol. Alternatively, a metal-hydride hydrogen atom transfer-initiated cydization was effective for a synthesis of longiborneol. Late-stage C-H functionalization of the longibornane core led to a number of hydroxylated longiborneol congeners. The need for significant optimization of the strategies that were employed as well as the methods for C-H functionalization to implement these strategies highlights the ongoing challenges in applying these powerful reactions. Nevertheless, the reported approach enables functionalization of every natural product-relevant C-H bond in the longibornane skeleton.

Automated summary

This article describes the synthesis of longiborneol and related natural products. Through clever strategies and late-stage functionalizations, longiborneol and its derivatives were successfully synthesized. The methods employed in this study require extensive optimization but allow for functionalization of every C-H bond in the longiborneol skeleton.