A Practical Diastereoselective Synthesis of syn-α-Hydroxyaminonitriles

Abstract

An efficient and practical one pot two-step synthesis of syn-α-hydroxyaminonitriles through an acylation-diastereoselective reduction sequence from lithiated α-aminonitrile is achieved.

Key words

amino alcohols - reduction - diastereoselectivity - acyl cyanide - dynamic kinetic resolution

References

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7

Typical Procedure: To a cooled (-78 °C) solution of LDA (2 mmol) in anhyd THF(10 mL), under an argon atmosphere, was added dropwise a THF (3 mL) solution of N-dibenzyl-aminoacetonitrile 1 (236 mg, 1 mmol). The reaction mixture was warmed to -60 °C over 30 min, cooled to -78 °C and ester (R)-5 was added dropwise over 5 min. The reaction mixture was warmed to room temperature over 1 h, quenched with MeOH (2 mL), and the solvents were removed in vacuo. The resulting solid was dissolved in MeOH (25 mL), MgBr₂·Et₂O (0.5 g, 2 mmol) was added and the solution was cooled to -20 °C. NaBH₄ (350 mg, 4 mmol) was slowly added and the resulting suspension was allowed to reach room temperature and stirred for 20 h. The solvents were removed in vacuo, the resulting solid was dissolved in CH₂Cl₂ (50 mL) and saturated NH₄Cl (50 mL) were added. After standard work-up, the crude product was purified by column chromatography over silica gel (pentane-Et₂O, 90:10) to yield pure 6a (216 mg, 59% yield) as colourless crystals (mp 95 °C). [α]_D ²⁰ = +73 (c 0.81, CH₂Cl₂). ¹H NMR (200 MHz): δ = 7.40-7.30 (m, 10 H), 4.31-4.23 (m, 1 H), 4.04 (d, J = 13.4 Hz, 2 H), 4.02-3.97 (m, 1 H), 3.92-3.85 (m, 2 H), 3.80-3.72 (m, 1 H), 3052 (2, J = 13.4 Hz, 2 H), 3.21 (br s, 1 H), 1.31 (s, 3 H), 1.21 (s, 3 H). ¹³C (100 MHz): δ = 136.8, 129.3, 128.9, 127.7, 115.2, 110.0, 74.8, 77.3, 68.9, 65.3, 57.3, 54.4, 26.6, 25.2. Anal. Calcd for C₂₂H₂₆N₂O₃: C, 72.11; H, 7.15; N, 7.14. Found: C, 72.19; H, 7.23; N, 7.35.

13

Crystallographic data for the structural analysis have been deposited at the Cambridge Crystallographic Data Center, CCDC no. 261989.