C5‐Disubstituted Meldrum's Acid Derivatives as Platform for the Organocatalytic Synthesis of C3‐Alkylated Dihydrocoumarins

Abstract

C5-disubstituted Meldrum's acid precursors were shown to be a useful platform for the synthesis of an array of 3-alkylated dihydrocoumarins with up to 93:7 er, thanks to an enantioselective domino cyclization-decarboxylative-protonation reaction triggered by an unprecedented benzhydrylderived cupreine organocatalyst. This cyclization sequence was extended to an emerging organocatalytic decarboxylative-chlorination reaction in the presence of trichloroquinolinone and by means of a bifunctional cinchona derived Brønsted base which gave rise to the formation of dihydrocoumarins (up to 79:21 er) with a tertiary chlorinated stereocenter.Amongst the privileged coumarin scaffolds in medicinal chemistry, the dihydrocoumarin derivatives are widely distributed within naturally occurring molecules and bioactive compounds. [1] Consequently, several groups have developed catalytic enantioselective syntheses of 3,4-disubstituted chroman-2-ones [2] and, to a much lesser extent, 3,3-disubstituted homologues (Scheme 1). [3] Nevertheless, the construction of enantioenriched 3-substituted derivatives turned out to be more challenging. To the best of our knowledge, the group of Scheidt has reported the single one-step asymmetric construction of 3-substituted dihydrocoumarins upon NHC organocatalysis eliciting a (4 + 2) cycloaddition reaction with er ranging from 75:25 to 93:7. [4] Beside the elegant but two steps enamine-based approaches developed by Xie and Liu, [5a-e] requiring the final oxidation of a lactol intermediate, List and co-workers have pioneered the challenging enantiose-lective delivery of a small proton atom to ketene dithioacetals. [5f] One of the obtained product was hydrolyzed into an a-phenyl dihydrocoumarin with high enantiomeric excess. In view of this background, an expedious synthetic sequence furnishing C3-substituted dihydrocoumarin remains desirable.Very recently, the group of Guiry achieved the synthesis of a series of 3-aryl dihydrocoumarins with er ranging from 65:35 to 94:6 (Scheme 1b). [6] This functionalization strategy takes advantage of the palladium-catalyzed decarboxylative protonation reaction [7] in the presence of ephedrine as a chiral stoichiometric source of proton. Although several teams ventured into this convenient enantioselective protonation (EP) strategy, mostly from hemimalonic esters in organocatalysis, only the groups of Brunner, Rouden, Zhang and Song succeeded in getting good er (rarely > 95:5) albeit at the expense of the use of high catalyst loading (up to 1 equiv.). [8,9] Scheme 1.

Palladium-catalyzed ring-opening [5+2] annulation of vinylethylene carbonates (VECs) and C5-substituted Meldrum's acids: rapid synthesis of 7-membered lactones

“…On the basis of these results and previous reports, 4 f ,14,15 the possible mechanism of this reaction primarily involves two pathways (Scheme 5): (a) the reaction starts with nucleophilic attack by the C-5 of Meldrum's acid on the π-allyl palladium intermediate. Then, the intramolecular attack of the oxygen anion to the carbonyl occurs to deliver CO 2 , acetone and the final product 3 .…”

Recent Advances on Catalytic Enantioselective Protonation for Construction of α-Tertiary Carbonyl Compounds

“…2019 年, Brière 与 Oudeyer 等 [19] 利用金鸡纳碱衍生 物催化剂, 实现了 C5-烷基取代米氏酸 13 向 3-烷基二氢 香豆素 14 的不对称转化. 与他们 [20] 之前报道的米氏酸 类底物与苯酚的分子间脱羰/不对称质子化反应机理类 似, 底物 [24] 方法, 同时保证 了高活性和高立体选择性.…”

Catalytic Strategies for the Asymmetric Construction of Cyclic Frameworks with a Halogenated Tetrasubstituted Stereocenter

“…Brière, Oudeyer and co‐workers reported the asymmetric construction of C−Cl bonds by using 9‐ epi ‐aminoquinine derivative C9 as a bifunctional organocatalyst through an interesting domino cyclization‐decarboxylative chlorination reaction. The use of trichloroquinolinone 5 as the chlorinating reagent allowed the preparation of enantioenriched coumarin derivatives 40 , albeit with moderate enantioselectivities (Scheme ) …”