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.

Remote C(sp3)–H activation: palladium-catalyzed intermolecular arylation and alkynylation with organolithiums and terminal alkynes

“…On the basis of both our aforementioned results and previous studies reported in the literature, [2][3][4][5][6][7][8][9][10][11] we proposed a mechanism for the palladium-catalyzed C(sp 3 )-H activation coupling reaction proceeding by a 1,4-Pd shift (Scheme 6). Initially, the Pd (0) catalyst coordinates to substrate 1a providing intermediate A, which undergoes oxidative addition to generate Pd(II) intermediate B.…”

“…In the past two decades, palladium-catalyzed activation of remote C(sp 3 )-H has emerged as a powerful method for the construction of a variety of C-C bonds, 1 most of which rely on the deployment of the 1,4-palladium shift strategy. 2,[5][6][7][8][9][10][11] As can be seen in Scheme 1, the in situ-generated diorganopalladacycle A via oxidative addition of Pd(0) to a C(sp 2 )-X bond and further cleavage of the proximate intramolecular C(sp 3 )-H bond leads to potential transformations. Alternatively, the ring-opening of palladacycle A through protonation or oxidative addition/reductive elimination provides an σ-alkylpalladium complex B, hence resulting in an overall 1,4-palladium shift as initially observed by Dyker.…”

“…6 b Soon after, Lin and co-workers reported a palladium-catalyzed alkyl C–H borylation with aryl bromides, furnishing alkyl boronates. 7 It must also be pointed out that Luan, 8 Zhang, 9 Martin 10 and Yang 11 have all contributed significantly to the palladium-catalyzed activation of inert C(sp 3 )–H bonds.…”

Synthesis of tetrasubstituted allenes via a 1,4-palladium migration/carbene insertion/β-H elimination sequence

“…10 In the meantime, palladium migration achieved site-specific C–H bond activation and has been utilized in synthetic transformations which are often inaccessible by conventional methods. 11 Palladium migrations have been well explored, including those from aryl to aryl, 12 aryl to alkyl, 13 aryl to benzyl, 14 and alkyl to aryl. 15 Our group introduced a controllable aryl to alkenyl 1,4-palladium migration process for the generation of alkenyl palladium species, which has been successfully applied to the highly regioselective and stereoselective functionalization of the corresponding vinylic C–H bonds, such as borylation, 16 alkenylation, 17 arylation, 18 annulation, 19 and alkylation 20 (Scheme 1b).…”

Phosphorylation of C(sp3)–H Bonds via 1,4-Palladium Migration

“…As a result, despite remarkable advancements in this area during the past two decades, the compatible transformations after palladium migration have focused on the application of carbon nucleophiles (Scheme a), and only very scarce examples with heteroatom nucleophiles have been reported to date (Scheme b). Buchwald and co-workers utilized aryl amines as coupling partners after the aryl to alkyl 1,4-palladium migration .…”