Dual Catalyst Control in the Chiral Diamine-Dipeptide-Catalyzed Asymmetric Michael Addition

Abstract

By example of conjugate addition of 2-nitropropane to 2-cyclohexen-1-one, it is shown that the combination of H-Leu-His-OH and (1R,2R)-(+)-1,2-diphenylethylenediamine as co-catalysts in a suitable ratio can lead to a new catalytic system for the C-C bond formation reactions. Although neither co-catalyst is sufficiently effective independently in terms of yield or enantioselectivity, their combination results in a drastic increase in yields (up to 86%) and absolute selectivities (up to 91% ee).

Key words

asymmetric organocatalysis - peptides - Michael additions - amines

References

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7

General Procedure for the Michael Reaction: 2-Nitro-propane (0.63 mmol) was added to a stirred solution of
2-cyclohexen-1-one (0.50 mmol), additive (0.50 mmol) and peptide catalyst (15 mol%) in pre-dried solvent (DMF or DMSO, 4 mL), and the reaction mixture was stirred at r.t. for 5 d. The solvent was evaporated and the residue was dissolved in CHCl₃ and washed with diluted aq HCl (3%). The organic layer was dried with Na₂SO₄ and filtered, and the solvents were evaporated. The residues were purified by column chromatography on SiO₂ (hexane-EtOAc) to afford the desired product. The ee of the product was determined by chiral HPLC analysis (Daicel Chiralpak AS) in comparison with authentic racemic material: n-hexan-2-propanol = 80:20, flow rate 1 mL/min, λ = 210 nm: t _R1 = 28.44 min, t _R2 = 30.31 min. ¹H NMR (300 MHz, CDCl₃): δ = 2.48-2.34 (m, 3 H), 2.31-2.21 (m, 1 H), 2.19-2.08 (m, 2 H), 1.85-1.76 (m, 1 H), 1.71-1.53 (m, 1 H), 1.58 (s, 3 H), 1.57 (s, 3 H), 1.48-1.34 (m, 1 H) ppm. ¹³C NMR (150.8 MHz, CDCl₃): δ = 208.9 (C=O), 90.6 (C_quat.), 46.5 (CH), 42.6 (CH₂), 40.7 (CH₂), 25.9 (CH₂), 24.3 (CH₂), 23.3 (CH₃), 22.5 (CH₃) ppm. ESI-MS (positive ion): m/z = 208.1 [M + Na]⁺.