Catalytic Cyclopropanol Ring Opening for Divergent Syntheses of γ-Butyrolactones and δ-Ketoesters Containing All-Carbon Quaternary Centers

Abstract

Catalytic ring opening cross coupling reactions of strained cyclopropanols have been useful for the syntheses of various β-substituted carbonyl products. Among these ring opening cross coupling reactions, the formation of α,βunsaturated enone byproducts often competes with the desired cross coupling processes and has been a challenging synthetic problem to be addressed. Herein, we describe our efforts in developing divergent syntheses of a wide range of γbutyrolactones and δ-ketoesters containing all-carbon quaternary centers via copper-catalyzed cyclopropanol ring opening cross couplings with 2-bromo-2,2-dialkyl esters. Our mechanistic studies reveal that unlike the previously reported cases, the formation of α,β-unsaturated enone intermediates is actually essential for the γ-butyrolactone synthesis and also contributes to the formation of the δ-ketoester product. The γ-butyrolactone synthesis is proposed to go through an intermolecular radical conjugate addition to the in situ generated α,β-unsaturated enone followed by an intramolecular radical cyclization to the ester carbonyl double bond. The reactions are effective to build all-carbon quaternary centers and have broad substrate scope.

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

“…Second, a metal oxidant-mediated transformation of glycals to γ-butyrolactones was reported [131]. Third, the copper-catalyzed-cyclopropanol ring-opening cross-coupling reaction was utilized to synthesize γ-butyrolactones containing quaternary carbon centers [132]. An epoxide is a useful three-atom building block in the [3 + 2] annulation strategy because of its susceptibility to the attack of suitable carbon nucleophiles such as ester enolates.…”

Metal-Catalyzed Transformations of Cyclopropanols via Homoenolates

“…In 2018, Dai and coworkers reported divergent synthesis of γ-butyrolactones and δ-ketoesters by Cu-catalyzed ring-opening cross-coupling of cyclopropanols and 2-bromo-2,2-dialkyl esters (Scheme 19). 30 Under the reaction system comprised of Cu(OTf)2, 1,10-phenanthroline (phen), K2CO3, and KI, γbutyrolactones were selectively obtained. On the other hand, the reaction system comprised of CuCl, phen or 4,7-diphenyl-1,10phenanthroline (4,7-diPh-phen), iPr2NH, with or without KI depending on the ligand used, selectively afforded δ-ketoesters.…”

Radical Strategy for the Transition-Metal-Catalyzed Synthesis of γ-Lactones: A Review

“…Changing the catalyst to CuCl resulted in the formation of -keto esters and the formation of lactones was detected. 33 The synthesis of -lactones was further developed in 2018 by Kokotos and co-workers, who employed Ru(bpy) 3 Cl 2 as the photocatalyst for the photocatalytic tandem annulations of alkenes with iodoacetic acids, irradiat-ing the reaction with two 80-W household bulbs, to give a series of -lactones in high to excellent yields (Scheme 19). They also successful monitored the photocatalytic reactions and radical intermediates via high-resolution mass spectrometry, which suggested the reaction takes place by a radical pathway.…”