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Synlett 2006(16): 2673-2675  
DOI: 10.1055/s-2006-950434
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Stereoselective Oxy-Michael Route to Protected β-Aryl-β-Hydroxy-α-Amino Acids

Felix A. Hernandez-Juana, Robert D. Richardsona, Darren J. Dixon*b
a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
b School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
Fax: +44(161)2754939; e-Mail: Darren.Dixon@manchester.ac.uk;
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Publication History

Received 1 May 2006
Publication Date:
22 September 2006 (online)

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Abstract

The stereoselective oxy-Michael addition of the ‘naked’ anion of (S)-6-methyl tetrahydropyran-2-ol to α-nitro-α,β-unsaturated esters followed by reduction and in situ protection of the corresponding amine provides a new and efficient route to protected β-aryl-β-hydroxy-α-amino acids.

Key words

oxy-Michael addition - (S)-6-methyl tetrahydropyran-2-ol - β-hydroxy-α-amino acids - stereoselectivity

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In this and in all other oxy-Michael addition reactions using 6-methyl tetrahydropyran-2-ol (1) reported by us, only the cis-THP* ether products are observed in the reaction mixtures.

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General Experimental Procedure.To a stirred solution of (S)-6-methyl tetrahydropyran-2-ol (1, 116mg, 1 mmol) in THF (15 mL) at -78 °C was added KHMDS (2 mL, 1 mmol, 0.5 M solution in toluene) dropwise. The reaction mixture was then stirred for 10 min at -78 °C before a toluene solution of 18-crown-6 (1 mmol) was added via syringe. The reaction mixture was then stirred for 15 min at -78 °C before a solution of the Michael acceptor (0.67 mmol) in THF (5 mL) was added dropwise. Stirring was maintained for 30 min at -78 °C. The reaction was then quenched with glacial AcOH (0.12 mL, 3 mmol) via syringe and the resulting mixture was allowed to warm to r.t. Then, Et2O (15 mL) and H2O (15 mL) were added and the aqueous layer separated and extracted with Et2O (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo. The reaction diastereoselectivity was determined by inspection of the crude 500 MHz NMR. A solution of the crude oxy-Michael product in EtOH was then added to a suspension of Raney nickel in EtOH and stirred for 20 h at r.t. The reaction mixture was filtered through Celite®, partially concentrated in vacuo, and Boc2O (3 equiv) was added. The reaction mixture was stirred for a further 20 h before the solvent was removed in vacuo and the crude product purified by column chromatography.tert -Butyl (1 S ,2 R )-2-[(2 R ,6 S )-Tetrahydro-6-methyl-2 H -pyran-2-yloxy]-1-(ethoxycarbonyl)-2-phenylethyl-carbamate [ syn -4 (major)].[α]D 20 -10.0 (c 0.3, CHCl3). IR (film): νmax = 1719, 1498, 1366, 1160, 1069, 1031 cm-1. 1H NMR (500 MHz, CDCl3): δ = 7.42 (d, J = 7.7 Hz, 2 H), 7.32 (t, J = 7.2 Hz, 2 H), 7.26 (t, J = 7.2 Hz, 1 H), 5.44 (d, J = 9.1 Hz, 1 H), 5.24 (d, J = 3.0 Hz, 1 H), 4.54 (dd, J = 9.1, 3.0 Hz, 1 H), 4.47 (dd, J = 9.5, 2.1 Hz, 1 H), 4.21 (m, 2 H), 3.43 (ddd, J = 12.3, 6.1, 2.0 Hz, 1 H), 1.84-1.68 (m, 2 H), 1.47-1.10 (m, 4 H), 1.34 (s, 9 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.12 (d, J = 6.1 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 170.7, 155.5, 138.8, 128.0, 127.6, 126.8, 102.0, 79.5, 78.7, 72.8, 61.4, 59.1, 32.1, 30.5, 28.2, 22.1, 21.5, 14.2. HRMS (EI): m/z calcd for [M + Na]+: 430.2206; found: 430.2205.tert -Butyl (1 R ,2 R )-2-[(2 R ,6 S )-Tetrahydro-6-methyl-2 H -pyran-2-yloxy]-1-(ethoxycarbonyl)-2-phenylethyl-carbamate [ anti -4 (minor)].[α]D 20 -25.0 (c 1.0, CHCl3). IR (film): νmax = 1717, 1503, 1367, 1163, 1071, 1028 cm-1. 1H NMR (500 MHz, CDCl3): δ = 7.35-7.25 (m, 5 H), 5.26 (d, J = 4.0 Hz, 1 H), 5.23 (d, J = 9.1 Hz, 1 H), 4.78 (dd, J = 9.1, 4.0 Hz, 1 H), 4.73 (d, J = 8.4 Hz, 1 H), 4.10 (m, 2 H), 3.56 (m, 1 H), 1.85-1.74 (m, 2 H), 1.59-1.10 (m, 4 H), 1.45 (s, 9 H), 1.17 (t, J = 7.1 Hz, 3 H), 1.16 (d, J = 7.2 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 170.1, 155.4, 138.2, 128.0, 127.7, 126.7, 100.5, 79.7, 72.6, 61.2, 57.3, 32.2, 30.3, 29.7, 28.3, 22.2, 21.5, 14.0. HRMS (EI): m/z calcd for [M + Na]+: 430.2206; found: 430.2221.