Marine furanocembranoids-inspired macrocycles enabled by Pd-catalyzed unactivated C(sp3)-H olefination mediated by 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 synthesize 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 demonstrate that a formal 1,4-Pd shift could be involved in the mechanism. Moreover, the collected furanocembranoids-like macrolactams show significant anti-inflammatory activities against TNF-α, IL-6, and IL-1β and the cytotoxicity is comparable to Dexamethasone.

Fig. 1. A modular strategy for the synthesis of natural furanocembranoids-like compounds via intermolecular Pd-catalyzed unactivated Csp³–H olefination mediated by donor/donor carbenes.

a Marine cembranoids or furanobutenolide-based cembranoids which bear the alkene-substituted furan scaffold. b Modular strategy for the synthesis of polysubstituted alkene furan-embedded macrolactams. c The design of Pd-catalyzed unactivated Csp³‒H olefination mediated by donor/donor carbenes.

Fig. 2. Substrate scopes of aryl bromides and ene-yne-ketones.

[a] Reaction conditions: 1 (0.1 mmol, 1.0 equiv), 2 (0.2 mmol, 2.0 equiv), [Pd(Cl(allyl)]₂ (5 mol%), ^tBuXphos (30 mol%), NaOAc (3.0 equiv), DMF (1 mL), under N₂, 100 °C, 4 h. Yields of isolated products. [b] The reaction was run in 2.0 mmol scale.

Fig. 3. Substrate scopes of aryl bromides and allenes.

[a] Reaction conditions: 1 (0.1 mmol, 1.0 equiv), 4 (0.2 mmol, 2.0 equiv), [Pd(Cl(allyl)]₂ (5 mol%), ^tBuXphos (30 mol%), NaOAc (3.0 equiv), DMF (1 mL), under N₂, 100 °C, 4 h. Yields of isolated products.

Fig. 4. Substrate scopes of complex aryl bromides from modified drug molecules.

[a] Reaction conditions: 1k–1p (0.1 mmol, 1.0 equiv), 2a or 4c (0.2 mmol, 2.0 equiv), [Pd(Cl(allyl)]₂ (5 mol%), ^tBuXphos (30 mol%), NaOAc (3.0 equiv), DMF (1 mL), under N₂, 100 °C, 4 h. Yields of isolated products.

Fig. 5. Construction of macrolactams using polysubstituted alkenes and natural or unnatural amino acids as building blocks.

Reaction conditions: please see page 7–14 of Supplementary Information.

Fig. 6. Compound 6g suppressed the LPS-induced inflammatory responses in RAW264.7 macrophages.

IC₅₀: the concentration of the compound needed to inhibit inflammatory mediators by 50% relative to the control value. a Effect of 6g on LPS-induced TNF-α, IL-6, and IL-1β. Cells were treated with LPS alone (5 μg/mL) or with indicated concentrations of 6g for 24 h. b Effect of 6g on LPS-induced NF-κB activation. Dexamethasone was used as a positive control. IC₅₀ values were calculated by nonlinear regression (curve fit) applied log (inhibitor) vs. normalized response. Data are shown as the mean ± SEM, n = biologically independent three wells for cytokine assays and two wells for Western blotting examined over two independent experiments.

Fig. 7. Two possible catalytic cycles for the reaction.

This proposed mechanism contains two possible paths, and path B is more favorable according to DFT calculation results.

Fig. 8. Energy profiles calculated on the basis of the mechanistic cycles shown in Fig. 7.

a Oxidative addition followed by CMD leading to the key palladacycle intermediate IM4, b two different paths starting from IM4, and c catalyst regeneration for the favorable path (Cycle B). The solvation-corrected relative free energies and electronic energies (in parentheses) are given in kcal/mol.