Marine Furanocembranoids-Inspired Macrocycles Enabled by Pd-catalyzed Unactivated C(sp3)-H Insertion Reaction of Donor/Donor Carbenes

Abstract

Biomimetic modularization and function-oriented synthesis of structurally diversified natural product-like macrocycles in a step-economical fashion is highly desirable. Inspired by marine furanocembranoids, herein, we unprecedentedly synthesized diverse alkenes substituted furan-embedded macrolactams via a modular biomimetic assembly strategy. The success of this assembly is the development of crucial Pd-catalyzed carbene coupling between ene-yne-ketones as donor/donor carbene precursors and unactivated Csp3‒H bonds which represents a great challenge in organic synthesis. Notably, this method not only obviates the use of unstable, explosive, and toxic diazo compounds, but also can be amenable to allenyl ketones carbene precursors. DFT calculations demonstrated that a 1,4-Pd shift could be involved in the mechanism. Moreover, the collected furanocembranoids-like macrolactams showed significant anti-inflammatory activities against TNF-α, IL-6, and IL-1β and the low cytotoxicity is comparable to Dexamethasone.