Synthesis of 1- and 4-substituted piperazin-2-ones via Jocic-type reactions with N-substituted diamines

Abstract

Enantiomerically-enriched trichloromethyl-containing alcohols, obtained by asymmetric reduction, can be transformed regioselectively into 1-substituted piperazinones by modified Jocic reactions with little or no loss of stereochemical integrity. This methodology can be easily used to synthesise important pharmaceutical compounds such as the fluorobenzyl intermediate of a known PGGTase-I inhibitor.

Peptidomimetic small-molecule inhibitors of 3CLPro activity and Spike-ACE2 interaction: towards dual-action molecules against Coronavirus infections

“…19 These structures, firstly reported by Arora and coworkers, 19 possess a highly structured rod-like arrangement able to reproduce the spatial orientation of i, i+4, and i+7 key side chains on an α-helix. Several synthetic approaches for the achievement of piperazinone scaffolds have been reported in the literature (Figure 2a), such as those involving the 2-amino-N-(2,2-dimethoxyethyl)acetamides I through the use of cyclic iminium intermediates, followed by hydrogenation, 20 including in a solid-phase synthetic strategy, 21 the Mitsunobu alkylation between amide and alcohol functions of derivative II, 22,23 Jocictype reactions of enantiomerically enriched trichloromethylsubstituted alcohol III (95% ee) with unsymmetrical mixedprimary-secondary 1,2-diamine IV, 24 a reductive cyclization of cyanomethylamino pseudopeptide V 25 and reductive amination of allyl containing peptide VI with ozone. 19 Thus, starting from our expertise in the preparation of dipeptide isosteres, 26,27,28 we envisioned to develop a short and versatile synthetic strategy for the formation of differently substituted piperazinones and diazepanones VIII starting from N-(2,2-dimethoxyethyl)acetamides VII (Figure 2b).…”

A Jocic-type approach for a practical and scalable synthesis of pyrrolonaphthoxazepine (PNOX)-based potent proapoptotic agents

“…The epoxide readily undergoes a regioselective substitution reaction with the added nucleophile, to afford the corresponding a-substituted acyl halide intermediate (14), finally generating the carboxylic acid 15 upon nucleophilic acyl substitution. Variations of the original Jocic reaction, including the popular Corey-Link reaction [23,24], have been the basis for a variety of new synthetic methods and served as featured steps in target-directed synthesis [25][26][27][28] and in drug discovery and development [29][30][31][32][33][34][35].…”

Enantioselective Organocatalytic Synthesis of 2-Oxopiperazines from Aldehydes: Identification of the Elusive Epoxy Lactone Intermediate

“…Unfortunately, until very recently, only approaches based on chiral pool techniques were available in the arsenal of a synthetic chemist . This daunting challenge was recently addressed with complementary methods based on chiral-auxiliary-promoted dynamic resolutions and multistep metal-catalyzed processes . In 2015, Stoltz and co-workers reported an elegant palladium-catalyzed asymmetric allylic alkylation approach for the synthesis of chiral 2-oxopiperazines …”

“…5 This daunting challenge was recently addressed with complementary methods based on chiral-auxiliary-promoted dynamic resolutions 6 and multistep metal-catalyzed processes. 7 In 2015, Stoltz and coworkers reported an elegant palladium-catalyzed asymmetric allylic alkylation approach for the synthesis of chiral 2oxopiperazines. 8 Having been actively involved in the field of organocatalysis, 9 and in particular in the field of organocatalytic oxidation, 10 and being inspired by MacMillan's enantioselective linchpin SOMO catalysis, 11,12 we introduce herein the use of enamine-promoted linchpin catalysis for the enantioselective synthesis of 2oxopiperazines 13 along with mechanistic investigations regarding the reaction outcome.…”