Iridium–SYNPHOS-Catalyzed Hydrogenation through Dynamic Kinetic Resolution of α-Amino β-Keto Ester Hydrochlorides

Abstract

The stereoselective synthesis of anti β-hydroxy α-amino esters by iridium–SYNPHOS-catalyzed asymmetric hydrogenation of α-amino β-keto ester hydrochlorides is reported. The reaction proceeded through dynamic kinetic resolution to afford a variety of β-hydroxy α-amino ester derivatives with good yields and high ­level of diastereo- and enantioselectivities (de up to 99%, ee up to 92%).

Key words

iridium - hydrogenation - asymmetric catalysis - enantio­selectivity - amino alcohols

• References and Notes


For selected reviews on dynamic kinetic resolution, see:
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Substrates 2a–k were prepared according to procedures reported in ref. 6b and in the references thereafter:
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• 14 Typical Procedure for the Ir-SYNPHOS-Catalyzed Asymmetric Hydrogenation of α-Amino-β-Ketoester Hydrochlorides: To a Teflon tube charged with α-sub-stituted β-keto ester 2 (0.44 mmol), NaOAc (36 mg, 0.44 mmol, 1 equiv) and AcOH (2 mL), was added solid catalyst [{Ir(H)[(S)-SYNPHOS]}₂(μ-I)₃]I (15 mg, 7 μmol, 1.5 mol%) in one portion and the reaction mixture was subjected to three vacuum/argon cycles. Under a flow of argon, the reaction vessel was placed in a stainless steel parallel hydrogenation system equipped with a central mechanical stirrer. The atmosphere of the autoclave was purged three times with argon and twice with H₂. The temperature was adjusted to 40 °C and the autoclave was filled with H₂ (100 bar). After 24 h of reaction, the autoclave was adjusted to r.t. and atmospheric pressure and finally purged three times with argon. The resulting mixture was concentrated under reduced pressure. The conversion was determined by ¹H NMR analysis of the crude product. To a solution of the previous β-hydroxyester hydrochloride (0.44 mmol, 1 equiv) in anhyd CH₂Cl₂ (2 mL) were added benzoyl chloride (67 mg, 55 μL, 1.1 equiv) and Et₃N (134 mg, 190 μL, 3 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 h and for 1 h at r.t., then diluted with CH₂Cl₂, quenched with sat. aq NH₄Cl, extracted with CH₂Cl₂ and dried over MgSO₄. The crude protected product was purified by flash chromatography to afford compound 3. The diastereomeric ratio was determined by ¹H NMR analysis of the crude product, and the enantiomeric ratio was determined by chiral SFC analysis of the purified product using a Chiralcel OD-H, Chiralpak IA, IC or AD-H column.