Enantioselective Synthesis of Aliphatic Cyanohydrin Acetates

Abstract

When the standard conditions for the enantioselective synthesis of cyanohydrin acetates via dynamic kinetic resolution are applied to aliphatic substrates, only a kinetic resolution is observed. However, by exchanging the base (Amberlite) against NaCN, quantitative conversions and good enantioselectivities are obtained.

cyanohydrins - asymmetric synthesis - Candida antarctica lipase B - enzyme catalysis - dynamic kinetic resolution

References

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For the procedure see the analytical scale experiment in ref. 6b.

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All conversion and enantiomeric purity was determined by chiral GC using a β-cyclodextrin column (CP-Chirasil-Dex CB 25m × 0.25 mm) using He with a linear gas velocity of 75 cm/s.

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Racemic 3c: ¹H NMR (300 MHz, CDCl₃): δ = 0.89 (t, J = 7.0 Hz, 3 H, CH ₃-CH₂), 1.25-1.40 (m, 8 H, CH₃-CH ₂-CH ₂-CH ₂-CH ₂), 1.50 (m, 2 H, CH ₂-CH₂-CH), 1.90 (m, 2 H, CH ₂-CH), 2.13 (s, 3 H, CH ₃-C=O), 5.31 (t, J = 6.8 Hz, 1 H, CH-CN). ¹³C NMR (75 MHz, CDCl₃): δ = 14.0 (C8), 20.4 (CH₃-C=O), 22.6 (C7), 24.6 (C6), 28.8 (C5), 29.0 (C4), 31.6 (C3), 32.3 (C2), 61.2 (C-O), 117.0 (CN), 169.2 (C=O).
Racemic 3d: ¹H NMR (300 MHz, CDCl₃): δ = 0.88 (t, J = 6.8 Hz, 3 H, CH ₃-CH₂), 1.20-1.40 (m, 10 H, CH₃-CH ₂-CH ₂-CH ₂-CH ₂-CH ₂), 1.50 (m, 2 H, CH ₂-CH₂-CH), 1.90 (m, 2 H, CH ₂-CH), 2.12 (s, 3 H, CH ₃-CO), 5.30 (t, J = 6.8 Hz, 1 H, CH-CN). ¹³C NMR (75 MHz, CDCl₃): δ = 14.1 (C10), 20.4 (CH₃-C=O), 22.7 (C9), 24.6 (C8), 28.9 (C7), 29.3 (C6), 29.3 (C5), 29.4 (C4), 31.9 (C3), 32.3 (C2), 61.2 (C-O), 117.0 (CN), 169.2 (C=O).

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For the procedure, see the preparative scale experiment in ref. 6b.

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Compound (S)-3a: [α]_D ²⁵ -47,7 (c 1, MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 1.10-1.40 (m, 5 H, ring CH and CH₂), 1.70-1.90 (m, 6 H, ring CH₂), 2.14 (s, 3 H, CH ₃), 5.17 (d, J = 6.0 Hz, 1 H, CH-CN). ¹³C NMR (75 MHz, CDCl₃): δ = 20.3 (CH₃), 25.3, 25.4, 25.8, 28.0, 28.1 and 40.5 (ring C), 65.6 (CH-O), 116.2 (CN), 169.3 (C=O).

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Compound (S)-3b: [α]_D ²⁵ -36.9 (c 1, MeOH). ¹H NMR (400 MHz, CDCl₃): δ = 0.90 (m, 3 H, CH ₃-CH₂), 1.33 (m, 4 H, CH₃-CH ₂-CH ₂), 1.50 (m, 2 H, CH ₂-CH₂-CH), 1.90 (m, 2 H, CH ₂-CH), 2.14 (s, 3 H, CH ₃-CO), 5.31 (t, J = 6.8 Hz, 1 H, CH-CN). ¹³C NMR (100 MHz, CDCl₃): δ = 13.9 (C6), 20.4 (CH₃-C=O), 22.3 (C5), 24.2 (C4), 30.9 (C3), 32.3 (C2), 61.2 (CH), 117.0 (CN), 169.2 (C=O).