Stereoselective Synthesis of vic-Halohydrins via l-tert-Leucine-Catalyzed syn-Selective Aldol Reaction

Abstract

l-tert-Leucine was found to be an effective organocatalyst for the asymmetric aldol reaction of chloroacetone. The stereoselective synthesis of vic-halohydrins was accomplished with excellent regioselectivity (>99%) to generate α-chloro-β-hydroxy ketones with high syn selectivity (syn/anti = 16:1) and enantioselectivity (up to 95% ee).

aldol reaction - amino acids - asymmetric synthesis - chloroacetone - organocatalysis

References and Notes

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Optimized Procedure for the Synthesis of 3a To a mixture of chloroacetone (1a, 400 µL, 5 mmol) and l-tert-leucine (13 mg, 0.1 mmol), 4-nitrobenzaldehyde (2a, 76 mg, 0.5 mmol) was added, and the mixture was stirred at r.t. The reaction was monitored by TLC analysis. After 7 d, H₂O was added and extracted with CH₂Cl₂ (3×), dried over MgSO₄, and concentrated in vacuo. To determine the regioselectivity and the diastereomeric ratio, the remaining residue was analyzed by ^¹H NMR. Moreover, the ee value of the product 3a was determined by chiral-phase HPLC analysis of the residue. Then, the residue was purified by column chromatography on silica gel in gradient elution with hexane-EtOAc to give a 7:1 inseparable mixture of the desired products 3a and 4a (108 mg, 89%).
Analytical Data for Compound 3a
^¹H NMR (400 MHz, CDCl₃): δ = 8.24-8.20 (m, 2 H), 7.61-7.58 (m, 2 H), 5.47 (t, J = 3.6 Hz, 1 H), 4.46 (d, J = 3.2 Hz, 1 H), 3.43 (d, J = 4.0 Hz, 1 H), 2.40 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 203.4, 147.6, 146.2, 127.3, 123.5, 72.0, 67.3, 28.3. HPLC: 83% ee [Daicel CHRALCEL OJ-H, hexane-iPrOH (9:1), flow rate 1.0 mL/min, λ = 254 nm]: t _R(major) = 34.7 min; t _R(minor) = 39.1 min.

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<A NAME="RU64911ST-15B">15b</A>

In this paper (ref. 15a), Howard and co-workers claimed that chlorine in organic compound is able to work as an intramolecular hydrogen bond acceptor. Their results support the proposed mechanism of our reaction system.