Highly Stereoselective Reduction of β-Keto Amides: The First General and Efficient Approach to N-mono- and non-Substituted anti-α-Alkyl β-Hydroxy Amides

Abstract

The first general protocol for the anti-selective reduction of α-alkyl-β-keto amides is described. This simple and efficient methodology based on an open-chain Felkin-Anh model pathway, allows the isolation of N-mono- and non-substituted anti-α-substituted β-hydroxy amides in good yields and with high diastereo­selectivity.

Key words

stereoselectivity - β-keto amides - reduction - anti-β-hydroxy amides - Felkin-Anh model

References

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18

Compound 4a was isolated by chromatography (pentane/Et₂O) in 87% yield, anti/syn>99/1. ¹H NMR (300 MHz, CDCl₃): δ = 0.86 (d, 3 H, J _HH = 7.2 Hz), 0.90-1.00 (m, 21 H), 2.45-2.50 (m, 1 H), 2.79 (d, 3 H, J _HH = 4.8 Hz), 4.91 (d, 1 H, J _HH = 7.8 Hz), 5.80 (br s, 1 H, NH), 7.20-7.35 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 12.3 (CH), 14.1 (CH₃), 17.7 (CH₃), 17.8 (CH₃), 26.0 (CH₃), 50.5 (CH), 77.4 (CH), 126.9 (CH), 127.5 (CH), 127.8 (CH), 142.7 (C), 175.1 (C).

19

A typical case is reported: ( R *, S *)-2-ethyl-3-hydroxy- N -methylhexanamide ( 2h). [20] The title compound was isolated by column chromatography (CH₂Cl₂/EtOAc) as a white solid (mp = 135-137 °C); yield 77%; anti/syn = 99/1. ¹H NMR (300 MHz, CDCl₃): δ = 0.85-0.95 (m, 6 H, 2 × CH₃), 1.30-1.55 (m, 4 H), 1.55-1.70 (m, 1 H, CH₂), 1.70-1.85 (m, 1 H, CH₂), 1.95-2.05 (m, 1 H, CH), 2.80 (d, 3 H, CH₃, J _HH = 4.8 Hz), 3.00 (bs, 1 H, OH), 3.60-3.70 (m, 1 H, CH), 6.00 (br s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 12.0 (CH₃), 14.0 (CH₃), 19.2 (CH₂), 23.6 (CH₂), 25.9 (CH₃), 38.2 (CH₂), 53.5 (CH), 71.9 (CH), 176.2 (C). Anal. Calcd for C₉H₁₉NO₂: H, 11.05; C, 62.39; N, 8.08. Found: H, 11.36; C, 62.18; H, 7.90.

20

Descriptors R*, S* indicate that diastereomeric compounds are obtained as racemates. We prefer this terminology to avoid the ambiguities that could arise from syn-anti descriptors.