Direct Organocatalytic Reductive Alkylation of Syncarpic Acid: Scope and Applications

Abstract

Biologically important 4-alkylsyncarpic acids, which resemble the core structure of many natural products, were synthesized in one-pot through the organocatalytic three-component reductive alkylation with excellent yields and C-selectivity. Synthetic applications of 4-alkylsyncarpic acids were demonstrated by converting into the functionally rich molecules through different reactions like Michael, retro-Michael, reduction, and oxidation reactions. In a continuation, formal total synthesis of (±)-triumphalone, (±)-isotriumphalone, and monomeric phloroglucinol derivatives was reported in a few steps starting from 4-alkylsyncarpic acids in overall very good yields. Further showcasing the importance of C-alkylated products, 4-benzylsyncarpic acid and its Michael adduct with methyl vinyl ketone were synthesized in a gram scale without compromising rate/yields.

Direct Organocatalytic Chemoselective Reductive Alkylation of Chiral 2-Aroylcyclopropanecarbaldehydes: Scope and Applications

“…Lewis-acid-catalyzed annulative ring opening of (−)-5fa with BF 3 •OEt 2 (30 mol %) in DCM at 25 °C for 60 min furnished the dihydropyran product (−)-10fa in 70% yield with >50:1 dr. Chiral dihydropyrans are part of the many biological and medicinally important compounds (Scheme 4). 9 When we treated compound (−)-9ba with NaBH 4 in methanol at 25 °C for 3 h, the selective carbonyl reduction product (+)-11ba was Table 2. Reaction Scope with Various Chiral 2-Benzoyl-3-Aryl-cyclopropanecarbaldehydes (−)-2 a,b a Reactions were carried out in DCM (1.0 mL) with 1.1 equiv of (−)-2 (0.275 mmol) and 1.1 equiv of 3 (0.275 mmol) relative to 1a (0.25 mmol) in the presence of 10 mol % of (s)-4a, and yield refers to the column-purified product.…”

“…There is no report on 2-aroylcyclopropanecarbaldehyde activation through amine catalysis (iminium/ enamine formation). To accomplish this synthetic challenge, based on our previous discovery of the organocatalytic reductive coupling reaction, 9 herein we have designed a high-yielding chemoselective synthesis of functionally rich chiral 2-aroylcyclopropanes 5 without ring-opening/epimerization from the different CH-acids 1, optically active 2-aroylcyclopropanecarbaldehydes (−)-2, and Hantzsch ester 3 through mild amino acid (s)-proline 4a catalysis (Scheme 2). Reaction design suggests that commercially available simple amino acid 4a would catalyze the three-component reductive coupling between CH-acids 1, chiral 2-aroylcyclopropanecarbaldehydes (−)-2, and Hantzsch ester 3 in DCM at the ambient conditions.…”

Organocatalytic Reductive Amination of the Chiral Formylcyclopropanes: Scope and Applications

“…Interestingly, organocatalytic reductive amination of chiral formylcyclopro-panes with primary amines/Hantzsch ester is not reported till date and will be challenging to study in many aspects. Based on our previous practice on the development of organocatalytic reductive coupling reactions, 7 herein we envisioned to accomplish the synthetic challenge by designing a high-yielding conversion of the formyl group of chiral donor−acceptor cyclopropanes into the secondary amine compounds 5 without epimerization and ring-opening from the primary aromatic/ aliphatic amines 1, chiral donor−acceptor formylcyclopropanes (-)-2, and Hantzsch ester 3 through the organocatalytic reductive coupling reaction (Scheme 2). 8…”