Facile Preparation of Spirolactones by an Alkoxycarbonyl Radical Cyclization–Cross‐Coupling Cascade

Abstract

An alkoxycarbonyl radical cyclization–cross‐coupling cascade has been developed that allows functionalized γ‐butyrolactones to be prepared in one step from simple tertiary alcohol‐derived homoallylic oxalate precursors. The reaction succeeds with aryl and vinyl electrophiles and is compatible with heterocyclic fragments in both coupling partners. This chemistry allows for the rapid construction of spirolactones, which are of interest in drug discovery endeavors.

Visible-light-driven spirocyclization of epoxides via dual titanocene and photoredox catalysis

“…paid to their synthesis. 37,38 Against this backdrop, here we describe our efforts on the synthesis of various heterospirocycles with the aid of photoredox catalysis.…”

Economical, Green, and Safe Route Towards Substituted Lactones by Anodic Generation of Oxycarbonyl Radicals

“…[20] Generally, these procedures rely on the use of expensive and toxic metal catalysts at high loadings (ca. 5mol %t omultiple equivalents) based on copper, [22,23] ruthenium, [15,24] palladium, [25] or iridium [26,27] in order to increase yields,and with the exception of halolactonisation, [28] examples of metal-free reactions remain rare. [29,30] Unfortunately,t hese approaches are not ideal due to their reliance on expensive and potentially toxic metal catalysts and undesirable solvents,e specially within apharmaceutical environment.…”

“…Theu se of photochemical methods to generate acyl radicals is well established, with aw ide variety of photocatalysts and substrates utilised. [27,[31][32][33] In contrast, the generation of acyl radicals using electrochemical methods remains scarcely explored. [34,35] This is perhaps surprising considering that the latter is significantly cheaper (1 mol of electrons costs % £0.83/E0.93 vs £60-140/E67-156 per 100 mg of commercially available iridium-based photocatalysts), [36,37] less toxic, greener, and easier to scale-up to industrial scale.…”

“…Moreover,itiscurrently limited to sp 2 -sp 3 coupling cascades and requires the use of ac aesium salt. [27] Through an adaptation of our previously reported electrochemical methodology,weseek to complement this study and hereby report the synthesis of various substituted g-butyrolactones from alcohol-derived hemioxalates using an unusual free radical sp 3 -sp 3 cross-coupling.…”

“…Initial studies utilised the hemioxalate ammonium salt 1. While attempts to electrolyse the precursors,u nder their acidic hemioxalate form, afforded the desired outcome,their inherent instability precluded reproducibility.W hile other reports propose the use of caesium salts, [27] the synthetic routes can be long and non-trivial, whereas the corresponding ammonium salts are significantly cheaper,faster and easier to prepare,and lead to CO 2 and NH 3 as the volatile by-products of the reaction. Furthermore,cyclic voltammetry studies have shown the expected chemically and electrochemically irreversible oxidation and suggested that these salts can be oxidised at reasonably low potentials compared to usual aliphatic acids ( % 0.9 VvsFc).…”