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Synlett 2004(1): 73-76  
DOI: 10.1055/s-2003-43354
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Giuseppe Bartoli*a, Marcella Boscoa, Enrico Marcantonib, Paolo Melchiorrea, Samuele Rinaldia, Letizia Sambria
a Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, v.le Risorgimento 4, 40136 Bologna, Italy
b Dipartimento Scienze Chimiche, Università di Camerino, via S.Agostino 1, 62032 Camerino, (MC), Italy
Fax: +39(51)2093654; e-Mail: giuseppe.bartoli@unibo.it;
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Received 26 September 2003
Publication Date:
26 November 2003 (online)

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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

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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.