Direct Catalytic Asymmetric Synthesis of N‐Heterocycles from Commodity Acid Chlorides by Employing α,β‐Unsaturated Acylammonium Salts

Abstract

Taming the beast, asymmetrically: Modulation of the reactivity of acid chlorides, using cinchona alkaloid catalysts, results in chiral α,β-unsaturated acylammoniums, which react with nucleophiles enantioselectively to give pyrrolidinones, piperid-2-ones, and dihydropyridinones. This nucleophile-catalyzed Michael/proton transfer/lactamization or lactonization organocascade leads to chiral intermediates previously employed for the synthesis of bioactive pharmaceuticals.

Utility and NMR studies of α,β-unsaturated acylammonium salts: synthesis of polycyclic dihydropyranones and a dihydropyridone

“…7 These N-heterocyclic carbene (NHC) catalyzed reactions require either a stoichiometric amount of oxidant or functionalized aldehydes or esters as starting materials and have focused primarily on acyclic 1,3-dicarbonyl compounds. 8 These limitations, coupled to our recent studies of chiral α ,β -unsaturated acylammonium salts enabling Michael-aldol-β -lactonization, 9 Michael-proton transfer-lactamization, 10 and Diels-Alder-lactonization 11 organocascades, prompted us to reinvestigate the original idea of making cyclic enol lactones from unsaturated acid derivatives through organocatalysis with achiral and chiral Lewis bases under mild conditions. 12 In particular, the use of mono-and bicyclic 1,3-dicarbonyls in these reactions have not been described and thus we focused on these substrates.…”

“…Very recently, the Smith group 15 and our group 10 have independently disclosed the use of these intermediates in Michael-lactonization and Michael-lactamization organocascades (Scheme 1) in combination with simple, acyclic 1,3-dicarbonyl compounds. Furthermore, we also demonstrated the full potential of α,β-unsaturated acylammonium salts in enabling formation of three new bonds through Michael-aldol-lactonization 9 and Diels-Alder-lactonization organocascades.…”

“…During our previous studies of the asymmetric Michael enol-lactonization, 10 we briefly explored the cyclic 1,3-dicarbonyl, 1,3-cyclohexanedione (2a), as Michael donor with Otrimethylsilylquinine (TMSQN) as catalyst. However, one of the reaction conditions that worked well for acyclic 1,3-dicarbonyl compounds, gave a mixture of the desired enol lactone 3a (33%, 96% ee) and the enol ester 4 (29%) (Scheme 2).…”

The ever-expanding role of asymmetric covalent organocatalysis in scalable, natural product synthesis

“…Building on early work by Fu, who demonstrated the potential of acid fluorides and unsaturated aclylammonium catalysis for a tandem allylsilane/ene reaction, 20a Smith recently demonstrated the utility of mixed anhydrides and unsaturated acylammoniums for the enantioselective synthesis of enol lactones 87 (Scheme 11b). 20b In our own studies in this area, the full potential of the latent, triply reactive, α,β-unsaturated acylammonium catalysis was realized employing acid chlorides ( e.g. , 88 , 92 ) and carboxylic acids in a rapid assembly of complex cyclopentanes 20d 95 (Scheme 11d) and in a further extension, N-heterocycles 20c 91 (Scheme 11c).…”

“…Furthermore, this activation concept has recently been extended to unsaturated carbonyl systems prompting a diverse array of previously undisclosed complexity-generating organocascades. 20 …”