Aqueous Enantioselective Aldol Reaction of Methyl- and Phenylglyoxal Organocatalyzed by N-Tosyl-(S _a)-binam-l-prolinamide

Abstract

The direct aldol reaction between methylglyoxal (40% aqueous solution) or phenylglyoxal monohydrate and ketones or aldehydes is catalyzed by N-tosyl-(S _a)-binam-l-prolinamide to afford the corresponding chiral γ-oxo-β-hydroxy carbonyl compounds, mainly as anti isomers with enantioselectivities up to 97%.

Key words

methylglyoxal - organocatalysis - aldol - prolinamide - aqueous conditions

• References and Notes

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• 16 Stereochemistry was assigned by comparison of the optical rotation values given in the literature, in reference 5a.
• 17 To a mixture of the methylglyoxal (40% aqueous solution, 0.25 mmol, 0.038 mL) and catalyst (10 mol%) at the indicated temperature was added the corresponding ketone (1.25 mmol). The reaction was stirred until the methylglyoxal was consumed (monitored by TLC). The resulting residue was purified by chromatography (hexanes–EtOAc) to yield the pure aldol product. During purification aldols 7d–f underwent a slight epimerization. Analytical data of compound 7b are given as a representative compound (see the Supporting Information for the rest of the compound data): (2S,1′R)-isomer; yellow oil (yield: 0.034 g, 80%); [α]²⁶ _D –29 (c = 0.5, CHCl₃); R_f 0.43 (hexane–EtOAc, 7:3; revealed with KMnO₄). IR: 3460.6 (OH), 1733.69 (C=O), 1703.8 (C=O), 1421.3 (MeC=O) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 3.87 (dd, J = 7.9, 3.0 Hz, 1 H, CHOH), 3.56 (d, J = 7.9 Hz, 1 H, OH), 3.03–3.15 (m, 1 H, H_cyclo), 2.32–2.51 (m, 2 H, H_cyclo), 2.30 (s, 3 H, Me), 2.06–2.20 (m, 2 H, H_cyclo), 1.65–2.06 (m, 4 H, H_cyclo). ¹³C NMR (75 MHz, CDCl₃): δ = 212.3 (C), 210.0 (C), 77.9 (CH), 53.7 (CH), 42.0 (CH₂), 30.3 (CH₂), 26.9 (CH₂), 25.7 (Me), 24.8 (CH₂). HRMS: m/z [M⁺ + H] calcd for C₉H₁₄O₃: 171.1021; found: 171.1020. To a mixture of methylglyoxal (40% aqueous solution, 0.25 mmol, 0.038 mL) and catalyst (10 mol%) at the indicated temperature was added the corresponding aldehyde (0.5 mmol). The reaction was stirred until the methylglyoxal was consumed (monitored by TLC). Ph₃PCHCO₂Et (0.178 g, 0.5 mmol) was added and the reaction mixture was stirred for 2 h. Upon completion, the reaction was quenched by passing the reaction mixture through a silica gel pad, and concentrated in vacuo. The resulting residue was purified by chromatography (hexanes–EtOAc) to yield the α,β-unsaturated ester. Analytical data of compound 10e are given as a representative compound (see the Supporting Information for the rest of the compound data): obtained as a diastereoisomer mixture (61:39, anti:syn); colorless oil (yield: 0.035 g, 53%); [α]²⁶ _D –12 (c = 1.2; CHCl₃); R_f 0.30 (hexane–EtOAc, 70:30; revealed with KMnO₄). IR: 3439.4 (OH), 1708.6 (C=O), 11692.2 (C=O), 1269.9 (MeC=O) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.88–7.98 (m, 2 H, ArH), 7.50–7.73 (m, 3 H, ArH), 7.15 (dd, J = 15.7, 7.4 Hz, 1 H, CH=CH), 5.94 (dd, J = 15.7, 1.4 Hz, 1 H, CH=CH), 5.20 (dd, J = 6.4, 2.4 Hz, 1 H, CHOH), 4.22 (q, J = 7.1 Hz, 2 H, OCH ₂CH₃), 3.78 (d, J = 6.4 Hz, 1 H, OH), 2.78–2.91 (m, 1 H), 1.32 (t, J = 7.1 Hz, 3 H, OCH₂CH ₃), 0.87 (d, J = 6.8 Hz, 3 H, CHMe).¹³C NMR (75 MHz, CDCl₃): δ = 200.6 (C), 166.3 (C), 149.8 (CH), 134.3 (CH), 133.5 (C), 129.1 (2 × CH), 128.5 (2 × CH), 121.7 (CH), 75.0 (CH), 60.4 (CH₂), 40.7 (CH), 14.3 (Me), 11.5 (Me). HRMS: m/z [M⁺ + Na] calcd for C₁₅H₁₈O₄: 285.1103; found: 285.1111.
• 18 Arylglyoxals are important reagents for the synthesis of heterocyclic compounds. See, for instance: Eftekhari-Sis B, Zirak M, Akbari A. Chem. Rev. 2013; 113: 2953
• 19 To a mixture of the phenylglyoxal monohydrate (0.25 mmol, 0.028 g) and catalyst (10 mol%) at the indicated temperature was added the corresponding aldehyde (0.5 mmol). The reaction was stirred until the phenylglyoxal was consumed (monitored by TLC). Ph₃PCHCO₂Et (0.178 g, 0.5 mmol) was added and the reaction mixture was stirred for 2 h. Upon completion, the reaction was quenched by passing the reaction mixture through a silica gel pad, and the filtrate concentrated in vacuo. The resulting residue was purified by chromatography (hexanes–EtOAc) to yield the α,β-unsaturated ester.