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Synlett 2005(7): 1090-1094  
DOI: 10.1055/s-2005-865212
LETTER
© Georg Thieme Verlag Stuttgart · New York

Stereoselective Rearrangement of β-Hydroxy-N-acyloxazolidin-2-ones to Afford N-2-Hydroxyethyl-1,3-oxazinane-2,4-diones

Fred J. P. Feuillet, D. Gangani Niyadurupola, Rachel Green, Matt Cheeseman, Steven D. Bull*
Department of Chemistry, University of Bath, BA2 7AY, UK
Fax: +44(1225)386231; e-Mail: s.d.bull@bath.ac.uk;
Further Information

Publication History

Received 8 February 2005
Publication Date:
14 April 2005 (online)

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Abstract

Zinc alkoxides of syn- or anti-β-hydroxy-N-acyloxazol­idin-2-ones undergo stereoselective rearrangement to afford their corresponding syn- or anti-N-2-hydroxyethyl-1,3-oxazinane-2,4-diones in good yield.

Key words

aldol reaction - diastereoselective - intramolecular rearrangement - 1,3-oxazinane-2,4-dione - zinc alkoxide

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Representative Synthetic Protocol for syn -Aldol Reactions.
A 0.5 M solution of 9-BBN·OTf in hexanes (1.2 equiv) was added to a stirred solution of N-acyloxazolidin-2-one (1 equiv) in CH2Cl2 at 0 °C and allowed to stir for 5 min. N,N-Diisopropylethylamine (1.4 equiv) was added, the reaction stirred for 25 min at 0 °C and cooled to -78 °C. An aldehyde (1.1 equiv) was then added, the reaction was stirred for 2 h and the reaction then allowed to warm to 0 °C for 30 min. Then, pH 7.0 phosphate buffer was added, followed by a 2:1 solution of MeOH-H2O2. The reaction was extracted with CH2Cl2 (3 ×) and the combined organic extracts washed with aq NaHCO3, brine, dried (MgSO4) and concentrated in vacuo to afford the appropriate syn-aldol which was then purified by chromatography.

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Representative Synthetic Protocol for Rearrangement Reaction.
A 1.0 M solution of Et2Zn in toluene (0.1 equiv) was added dropwise to a stirred solution of the syn-aldol (1 equiv) in CH2Cl2 at r.t. The reaction was stirred for 2 h. Then, sat. aq NH4Cl was added and the reaction extracted with CH2Cl2 (3 ×). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo to afford the desired syn-1,3-oxazinane-2,4-dione which was then purified by chromatography.

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All new compounds were fully characterised. Selected data for new compounds:
syn -6-Ethyl-3-(2-hydroxyethyl)-5-isopropyl-1,3-oxazinane-2,4-dione (10b): 1H NMR (300 MHz, CDCl3): δ = 0.97 [3 H, d, J = 7.0 Hz, CH(CH 3)2], 1.00 (3 H, t, J = 7.5 Hz, CH2CH 3), 1.02 [3 H, d, J = 7.0 Hz, CH(CH 3)2], 1.60 (1 H, dqd, J = 14.0, 7.5, 5.0 Hz, CH AHBCH3), 1.80 (1 H, ddq, J = 14.0, 9.0, 7.5 Hz, CHA H BCH3), 2.08-2.21 [1 H, m, J = 7.0, 5.0, CH(CH3)2], 2.25 (1 H, br s, OH), 2.52 (1 H, dd, J = 5.0, 4.0 Hz, CHi-Pr), 3.74 (2 H, app t, J = 5.5 Hz, CH 2OH), 3.89 (1 H, app dt, J = 14.0, 5.5 Hz, CH A HBN), 4.01 (1 H, app dt, J = 14.0, 5.5 Hz, CHA H B N), 4.39 (1 H, ddd, J = 9.0, 5.0, 4.0 Hz, CHO). 13C NMR (100 MHz, CDCl3): δ = 9.0, 18.8, 21.2, 22.3, 14.5, 43.1, 48.4, 59.8, 78.0, 151.6, 170.0. IR: 3436 (br, OH), 1749 (C=O), 1691 (C=O) cm-1.
syn -3-(2-Hydroxyethyl)-5-isopropyl-6-[( E )-1-propenyl]-1,3-oxazinane-2,4-dione (10d): 1H NMR (300 MHz, CDCl3): δ = 0.97 [3 H, d, J = 7.0, CH(CH 3)2], 1.03 [3 H, d, J = 7.0 Hz, CH(CH 3)2], 1.71 (3 H, d, J = 7.0 Hz, CH 3CH=CH), 1.97 (1 H, t, J = 5.5 Hz, OH), 2.10 [1 H, m, J = 7.0 Hz, CH(CH3)2], 2.55 (1 H, dd, J = 7.0, 4.5 Hz, CHi-Pr), 3.74 (2 H, app dt, J = 5.5, 5.5 Hz, CH 2OH), 3.94-3.98 (2 H, m, CH 2N), 4.92 (1 H, app t, J = 7.0 Hz, CHO), 5.47 (1 H, ddd, J = 15.0, 7.0, 1.5 Hz, CH3CH=CH), 5.91 (1 H, dq, J = 15.0, 7.0 Hz, CH3CH=CH). 13C NMR (75 MHz, CDCl3): δ = 17.0, 19.7, 20.3, 24.8, 43.2, 49.5, 60.1, 76.6, 122.1, 132.7, 151.3, 169.7. IR: 3430 (br, OH), 1755 (C=O), 1699 (C=O) cm-1. (5 S ,6 R )-3-[( S )-1-Benzyl-2-hydroxyethyl]-6-ethyl-5-methyl-1,3-oxazinane-2,4-dione (10e): [α]D 20 -6.4 (c 0.47, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.82 (3 H, t, J = 7.5 Hz, CH2CH 3), 0.99 (3 H, d, J = 7.5, CH 3CH), 1.33 (2 H, m, CH 2 CH3), 2.50 (1 H, qd, J = 7.5, 3.5 Hz, CHCH3), 2.99 (1 H, dd, J = 14.0, 7.0 Hz, PhCH ACHB), 3.16 (1 H dd, J = 14.0, 10.5 Hz, PhCHACH B), 3.68 (2 H, obscured m, CHO), 3.82 (1 H, dd, J = 12.0, 4.0 Hz, CH AHBOH), 4.01 (1 H, dd, J = 12.0, 7.0 Hz, CHA H BOH), 5.04 (1 H, app dtd, J = 10.5, 7.0, 4.0 Hz, CHN), 7.10-7.15 (5 H, m, Ph). 13C NMR (75 MHz, CDCl3): δ = 9.2, 9.5, 22.6, 33.7, 39.2, 56.5, 63.3, 78.4, 126.6, 128.5, 129.1, 137.4, 151.8, 173.1. IR: 3462 (br, OH), 1755 (C=O), 1700 (C=O) cm-1.
(5 S ,6 R )-3-[( S )-1-Benzyl-2-hydroxyethyl]-6-ethyl-5-isopropyl-1,3-oxazinane-2,4-dione (10h): [α]D 20 -6.8 (c 0.59, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.84 (3 H, t, J = 7.5 Hz, CH2CH 3), 0.85 [3 H, d, J = 7.0 Hz, CH(CH 3)2], 0.92 [3 H, d, J = 7.0 Hz, CH(CH 3)2], 1.31-1.46 (1 H, dqd, J = 14.0, 7.5, 5.0 Hz, CH AHBCH3), 1.45-1.61 (1 H, m, CHA H BCH3), 1.94-2.05 [1 H, m, CH(CH3)2], 2.18 (1 H, app t, J = 4.5 Hz, CHi-Pr), 2.53 (1 H, br s, OH), 2.99 (1 H, dd, J = 14.0, 7.0 Hz, CH AHBPh), 3.13 (1 H, dd, J = 14.0, 10.5 Hz, CHA H BPh), 3.64 (1 H, obscured m, CHO), 3.82 (1 H, dd, J = 12.0, 4.0 Hz, CH AHBOH), 4.02 (1 H, dd, J = 12.0, 7.0 Hz, CHA H BOH), 5.04-5.14 (1 H, app dtd, J = 10.5, 7.0, 4.0 Hz, CHN), 7.08-7.22 (5 H, m, Ph). 13C NMR (75 MHz, CDCl3): δ = 10.4, 20.2, 22.6, 23.4, 25.5, 34.3, 50.2, 56.5, 63.7, 79.4, 127.0, 128.9, 129.5, 135.0, 152.5, 171.4. IR: 3423 (br, OH), 1754 (C=O), 1691 (C=O) cm-1.
syn -3-(2-Hydroxyethyl)-5-methyl-6-phenyl-1,3-oxazinane-2,4-dione (10i): 1H NMR (300 MHz, CDCl3): δ = 1.01 (3 H, d, J = 7.5 Hz, CH 3), 2.17 (1 H, s, OH), 2.99 (1 H, qd, J = 7.5, 3.5 Hz, CHCH3), 3.75-3.82 (2 H, m, CH 2OH), 3.97 (1 H, app dt, J = 14.0, 5.5 Hz, CH A HBN), 4.05 (1 H, app dt, J = 14.0, 5.5 Hz, CHA H B N), 5.62 (1 H, d, J = 3.5 Hz, CHO), 7.24-7.38 (5 H, m, Ph-H). 13C NMR (75 MHz, CDCl3): δ = 10.4, 41.5, 44.6, 61.2, 78.1, 126.0, 129.2, 129.4, 134.4, 152.4, 173.2. IR: 3447 (br, OH), 1755 (C=O), 1703 (C=O) cm-1.
syn -3-(2-Hydroxyethyl)-5-isopropyl-6-(4-methoxy-phenyl)-1,3-oxazinane-2,4-dione (10k): mp 79-81 °C. 1H NMR (300 MHz, CDCl3): δ = 0.87 [3 H, d, J = 7.0 Hz, CH(CH 3)2], 0.98 (3 H, d, J = 7.0 Hz, CH(CH 3)2], 1.96 [1 H, m, J = 7.0, 4.0 Hz, CH(CH3)2], 2.26 (1 H, br s, OH), 2.79 (1 H, t, J = 4.0 Hz, CHi-Pr), 3.83 (3 H, s, ArOCH 3), 3.81-3.87 (2 H, m, CH 2OH), 4.02 (1 H, app dt, J = 14.0, 5.5 Hz, CH A HBN), 4.16 (1 H, app dt, J = 14.0, 5.5 Hz, CHA H B N), 5.71 (1 H, d, J = 4.0 Hz, CHO), 6.94 (2 H, d, J = 8.5 Hz, Ar-H), 7.29 (2 H, d, J = 8.5 Hz, Ar-H). 13C NMR (75 MHz, CDCl3): δ = 19.8, 23.1, 26.0, 44.7, 52.0, 55.7, 61.3, 78.4, 114.6, 126.7, 127.1, 152.9, 160.1, 171.4. IR: 3353 (br, OH), 1740 (C=O), 1691 (C=O) cm-1.

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syn-1,3-Oxazinane-2,4-diones exhibit J ( 5,6) coupling constants of <4.5 Hz, whilst anti-1,3-oxazinane-2,4-diones exhibit J ( 5,6) coupling constants of >10.0 Hz; see ref. 13c, 14, 16.

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An alternative mechanism involving zinc alkoxide-catalysed epimerisation of the α-stereocentres of syn-β-aryl-aldols 9i-l (or syn-β-aryl-1,3-oxazinane-2,4-diones 10i-l) was discounted because their acidities are similar to those of the α-stereocentres of syn-β-alkyl-aldols 9a-k that had been shown to rearrange with no loss of stereocontrol under these conditions.

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N-Acyl-oxazolidin-2-one-anti-aldol 15 was prepared using Evans’ magnesium halide-catalysed protocol, see ref. 12.

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anti -3-(2-Hydroxyethyl)-5-methyl-6-phenyl-1,3-oxazinane-2,4-dione (16). 1H NMR (300 MHz, CDCl3): δ = 1.02 (3 H, d, J = 7.0 Hz, CH 3), 2.21 (1 H, br s, OH), 2.89 (1 H, dq, J = 11.5, 7.0 Hz, CHCH3), 3.77-3.80 (2 H, app t, J = 5.5 Hz, CH 2OH), 3.94 (1 H, dt, J = 14.0, 5.5 Hz, CH A HBN), 4.06 (1 H, app dt, J = 14.0, 5.5 Hz, CHA H B N), 5.04 (1 H, d, J = 11.5 Hz, CHPh), 7.24-7.38 (5 H, m, Ph-H). 13C NMR (75 MHz, CDCl3): δ = 10.1, 40.4, 43.5, 59.6, 80.5, 126.1, 127.9, 128.7, 134.2, 151.1, 170.5. IR: 3435 (br, OH), 1755 (C=O), 1694 (C=O) cm-1.