Chiral Phosphinyl Enamines and Their Asymmetric Reduction through Group-Assisted Purification Chemistry Leading to Enantiopure β-Amino Esters/Amides

Abstract

A series of new chiral N-phosphinyl β-enamino esters and amides were successfully prepared with excellent Z-stereoselectivity (Z/E > 99:1 in nearly all cases). Group-assisted purification chemistry proved to be an efficient method for the asymmetric reduction of the resulting β-enamino esters/amides to give enantiopure β-amino esters/amides. The asymmetric reduction can be controlled efficiently by using a combination of sodium cyanoborohydride and acetic acid.

Key words

group-assisted purification - asymmetric reduction - amino esters - amino amides - phosphinyl enamines

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• 23 Phosphinyl Enamines 2; General Procedure A mixture of phosphinamide P3 (200 mg, 0.74 mmol) , β-keto ester 1 (2.21mmol), 4 Å MS (50 mg), and TsOH (5.0 mg) in toluene (3.0 ml) was heated in a sealed vial for 10 h at 100 °C until the limiting reactant was consumed (TLC). The mixture was then filtered, diluted with EtOAc (5 mL), washed with sat. aq NaHCO₃ and brine, and evaporated to dryness. The residue was purified by flash chromatography [silica gel, EtOAc–hexane (1:3)]. The eluting solvents were combined and evaporated under vacuum to afford the phosphinyl enamide as a yellow oil. All new compounds were characterized by spectroscopy (³¹P, ¹H, and ¹³C NMR). Ethyl (2Z)-3-{[(2S,5S)-1-Oxido-2,5-diphenylphospholan-1-yl]amino}but-2-enoate (2c) Yellow oil; yield: 277 mg (98%). ¹H NMR (400 MHz, CDCl₃): δ = 9.78 (d, J = 16.2 Hz, 1 H), 7.37–7.25 (m, 10 H), 4.59 (s, 1 H), 4.14 (q, J = 5.7 Hz, 2 H), 3.68–3.58 (m, 1 H), 3.18–3.12 (m, 1 H), 2.51–2.32 (m, 2 H), 2.16–2.08 (m, 2 H), 1.42–1.39 (m, 3 H), 1.27 (t, J = 5 Hz, 3 H). ³¹P NMR (162 MHz, CDCl₃): δ = 51.8. Ethyl (3S)-3-{[(2S,5S)-1-Oxido-2,5-diphenylphospholan-1-yl]amino}butanoate White solid; yield: 88 mg (76%); mp 186–198 °C , [α]₂₅ ^D –55.2 (c 0.36, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): δ = 7.44–7.08 (m, 10 H), 4.01–3.92 (m, 2 H), 3.52–3.50 (m, 1 H), 3.37–3.29 (m, 1 H), 3.06–2.95 (m, 1 H), 2.65 (t, J = 11 Hz, 1 H), 2.36–2.28 (m, 2 H), 2.55–2.42 (m, 2 H), 2.14–2.39 (m, 1 H), 2.08–2.02 (m, 1 H), 1.20 (t, J = 6.0 Hz, 3 H), 0.70 (t, J = 3.0 Hz, 3 H). ³¹P NMR (162 MHz, CDCl₃): δ = 53.4; HRMS (TOF-ES+): m/z [M + H]⁺ calcd for C₂₂H₂₉NO₃P: 386.1880; found: 386.1879.