Catalytic Asymmetric Addition of Meldrum’s Acid, Malononitrile, and 1,3‐Dicarbonyls to ortho‐Quinone Methides Generated In Situ Under Basic Conditions

Abstract

A new approach to the utilization of highly reactive and unstable ortho-quinone methides (o-QMs) in catalytic asymmetric settings is presented. The enantioselective reactions are catalysed by bifunctional organocatalysts, and the o-QM intermediates are formed in situ from 2-sulfonylalkyl phenols through base-promoted elimination of sulfinic acid. The use of mild Brønsted basic conditions for transiently generating o-QMs in catalytic asymmetric processes is unprecedented, and allows engaging productively in the reactions nucleophiles such as Meldrum's acid, malononitrile and 1,3-dicarbonyls. The catalytic transformations give new and general entries to 3,4-dihydrocoumarins, 4H-chromenes and xanthenones. These frameworks are recurring structures in natural product and medicinal chemistry, as testified by the formal syntheses of (R)-tolterodine and (S)-4-methoxydalbergione from the catalytic adducts.

Organocatalytic Friedel–Crafts Alkylation/Lactonization Reaction of Naphthols with 3‐Trifluoroethylidene Oxindoles: The Asymmetric Synthesis of Dihydrocoumarins

“…Fuelled by the rising demand of the pharmaceutical industry and the fundamental interest in synthetic organic chemistry,t he synthesis of this core structure has attracted great attention of chemists from both academia and industry. [12] Cinchona-alkaloid-derived bifunctional catalysts promoted the cyclization reaction of 1,3-dicarbonyls to o-QMs [13] and nitroalkenes. Guided by the donor/acceptor concept, [4+ +2] cycloaddition reactions of phenol derivatives bearing electrophilic carbon atoms on the ortho-position are most commonly used strategies to generate the dihydrocoumarin core.T hese strategies include reactions such as the N-heterocyclic carbine catalyzed enantioselective cycloaddition of o-quinone methides (o-QMs), and its equivalents with silylketene acetals, [9] ketenes, [10] acyl imidazoles, [11] and the cascade reaction of enals with nitroalkenes (Scheme 1).…”

“…As ar esult, many methods for the synthesis of dihydrocoumarin derivatives,e specially in an asymmetric manner,h ave been developed, among which organocatalysis [8] has recently been used as an efficient and mild approach. [12] Cinchona-alkaloid-derived bifunctional catalysts promoted the cyclization reaction of 1,3-dicarbonyls to o-QMs [13] and nitroalkenes. [12] Cinchona-alkaloid-derived bifunctional catalysts promoted the cyclization reaction of 1,3-dicarbonyls to o-QMs [13] and nitroalkenes.…”

“…Guided by the donor/acceptor concept, [4+ +2] cycloaddition reactions of phenol derivatives bearing electrophilic carbon atoms on the ortho-position are most commonly used strategies to generate the dihydrocoumarin core.T hese strategies include reactions such as the N-heterocyclic carbine catalyzed enantioselective cycloaddition of o-quinone methides (o-QMs), and its equivalents with silylketene acetals, [9] ketenes, [10] acyl imidazoles, [11] and the cascade reaction of enals with nitroalkenes (Scheme 1). [12] Cinchona-alkaloid-derived bifunctional catalysts promoted the cyclization reaction of 1,3-dicarbonyls to o-QMs [13] and nitroalkenes. [14] Despite these advances,t he development of new strategies allowing the direct and efficient construction of optically pure dihydrocoumarins bearing versatile functionalities remains ac hallenging task.…”

N‐Heterocyclic Carbene/Potassium Ion Cooperatively Catalyzed Phenylation Reactions of α,β‐Unsaturated Acylazoliums

“…Preliminary enantioselective studies of the reaction. [a] The absolute configuration of the major enantiomer was assigned based on a comparison of optical rotation data with literature values …”

ChemInform Abstract: Meldrum′s Acid: A Useful Platform in Asymmetric Organocatalysis

“…In 2015, the group of Bernardis ucceeded in the enantioselective conjugated addition reactiono fM eldrum's acid 1a to ortho-quinone methides 37,p rovidinga ne fficient asymmetric synthesis of lactone 36.The rather unstable substrates 37 were generatedi ns itu from 34 upon Brønsted base catalyzed sulfinate elimination by means of squaramide catalyst 35 in liquidliquid bi-phasic conditions (Scheme 14). [19] Then, the ammonium salt of catalyst 35 was deprotonated (regenerationo f35) in the presence of an aqueous solution of sodiumh ydrogen carbonate to promote the subsequent enantioselective conjugated addition of Meldrum's acid anion 1a' to 37.T his step is followed by ac yclocondensationr eaction leadingt od ihydrocoumarins 36 with good yields and excellent enantiomeric excesses. As econd set of conditions, consisting of heating in the presence of ac atalytic amount of acid, was required to ensure complete lactonization/decarboxylation for the formation of dihydrocoumarins 36.T he orchestration of this elegant multistep synthetic approach to dihydrocoumarins 36 embraces the use of Meldrum's acid 1a as aC 2s ynthon.…”