康 · 学术 | Reaction of the Day No. 1208_新浪财经

Copper-catalyzed Dehydrogenation orLactonization of C(sp3)−HBonds

Shupeng Zhou, Zi-Jun Zhang & Jin-Quan Yu

Department of Chemistry, The ScrippsResearch Institute, 10550 North Torrey Pines Road, La 4 Jolla, California92037, United States.

—Nature, 2024, doi:10.1038/s41586-024-07341-z.

Recommended by Depei Meng_MC4

ABSTRACT: Herewe report the development of Cu(I)-catalyzed bimodaldehydrogenation/lactonization reactions of synthetically common N-methoxyamides viaradical abstractions of the γ-aliphatic C−H bonds. The feasibility of switchingfrom dehydrogenation to lactonization hasalso been demonstrated by altering reaction conditions. The use of a readilyavailable amide as both radical precursor and internal oxidant allowed for thedevelopment of a redox-neutral C−H functionalization reactions with methanol asthe sole side product. These C−H functionalization reactions using Cu(I)catalyst of loading as low as 0.5 mol% have been applied to thediversification of a wide range of aliphatic acids including drug molecules andnatural products. The exceptional compatibility of this catalytic system with awide range of oxidatively sensitive functionality demonstrates the unique advantage of using simple amidesubstrate as the mild internal oxidant.

Bimodaloxidation via a common radical intermediate

(a) Nature’s approach: hepatic P450-mediated bimodal oxidation of valproic acid. (b) Our design of Cu-catalyzed bimodaloxidation of N-methoxyamides viaa common alkyl radical intermediate. (c) Synthetic approach: dual desaturation/lactonization reactivity enables rapid diversification of carboxylic acids.

Selectedsubstrates for dehydrogenation (left) or lactonization (right)

Plausible mechanism

SummaryandComments

Inconclusion,Prof. Jin-Quan Yu’s grouphave developed a bimodal Cu-catalyzeddehydrogenation/lactonizationofsynthetically common N-methoxyamides.This redox-neutral process led to two controllable reaction pathways forsynthesizingγ,δ-unsaturated primary amides andγ-lactones fromvarious carboxylicacids (asthe precursors of N-methoxyamides).Both thedehydrogenation and the lactonizationcould serve as strategies for the diversifications of a variety of drugmolecules and natural products. Further development of the current methodologyfor the synthesis of lactams is underway in their laboratory.

总的来说，余金权教授课题组报道了一种由常见的N-甲氧基酰胺出发，可控地被铜催化发生脱氢/内酯化反应的方法。这种氧化还原中性过程能够经由两种可控反应途径，使各种羧酸(作为N-甲氧基酰胺的前体) 转化为γ、δ-不饱和伯酰胺或γ-内酯。这两种反应途径，脱氢和内酯化，都可以作为多种药物分子和天然产物多样化的策略。此外，通过类似途径合成内酰胺的方法也正在开发当中。