Proline-Catalyzed α-Aminooxylation of β-Amino Aldehydes: Access to Enantiomerically Pure syn- and anti-3-Amino-3-aryl-1,2-alkanediols

Abstract

A new synthetic method for enantioselective synthesis of syn or anti-3-amino-3-aryl-1,2-alkanediols via proline catalyzed α-aminooxylation of β-amino aldehydes are described. This methodology is successfully applied to a concise and protecting group-free asymmetric synthesis of (–)-cytoxazone, (+)-epi-cytoxazone and formal synthesis of N-thiolated 2-oxazolidinone.

Key words

amino aldehydes - asymmetric synthesis - catalysis - diastereoselectivity - enantioselectivity - natural product

• References and Notes

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• 17 As we have obtained the major diastereomer of >99% with enantiopurity of 93%, we believe that the stereoinduction of newly generated chiral center (C–O bond) is fully controlled by the type of proline we used, irrespective of the stereocenter in the substrate (Figure 2).
• 18 General Experimental Procedure for the Preparation of 3-Amino-1,2-alkane Diols 1a–f To a stirred precooled (–10 °C) MeCN (25 mL) solution of β-amino aldehydes 6a–f (17 mmol) and nitrosobenzene (13.6 mmol) was added l-proline (0.039 g, 20 mol%). The reaction mixture was allowed to stir at the same temperature for 20 h followed by the addition of MeOH (10 mL) and NaBH₄ (25 mmol) to the reaction mixture, which was stirred for further 10 min. After addition of phosphate buffer, the resulting mixture was extracted with EtOAc (3 × 30 mL), the combined organic phases were dried over anhydrous Na₂SO₄ and concentrated to give the crude aminooxy alcohol, which was directly taken up for the next step without purification. To a MeOH (25 mL) solution of the above crude aminooxy alcohol was added Cu(OAc)₂·H₂O (2.6 mmol) at 25 °C, and the reaction mixture was allowed to stir for 10 h at that temperature. After addition of phosphate buffer, the resulting mixture was extracted with CHCl₃ (3 × 30 mL), and the combined organic phases were dried over anhydrous Na₂SO₄ and concentrated to give the crude product, which was then purified by column chromatography over silica gel using PE–EtOAc to give 3-amino-1,2-alkane diols 1a–f.
• 19 (2R,3R)-3-(tert-Butoxycarbonylamino)-3-(p-tolyl)-1,2-propanediol (1c) Yield 63%; colorless solid recrystallized from CHCl₃; mp 126–129 °C. [α]_D ²⁵ –57.87 (c 2.7, CHCl₃); 95% ee from chiral HPLC analysis [Chiracel AD-H, n-hexane–i-PrOH (90:10), 0.5 mL min^–1]: t _R = 21.6 min (97%) and 27.1 min (2%). IR (CHCl₃): ν_max = 727, 780, 815, 884, 1049, 1101, 1163, 1247, 1287, 1365, 1391, 1506, 1683, 2929, 2976, 3366 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 1.42 (s, 9 H), 2.34 (s, 3 H), 2.82 (br s, 1 H), 3.31 (br s, 1 H), 3.51–3.62 (m, 2 H), 3.78 (br s, 1 H), 4.59–4.66 (m, 1 H), 5.25 (d, J = 6.7 Hz, 1 H), 7.09–7.22 (m, 4 H). ¹³C NMR (50 MHz, CDCl₃ + DMSO-d ₆): δ = 20.5, 27.9, 56.4, 62.8, 73.2, 78.4, 127.0, 128.3, 135.9, 136.4, 155.0. ESI-HRMS: m/z calcd for C₁₅H₂₃NO₄ [M + Na]⁺: 304.1519, found: 304.1514. Anal. Calcd for C₁₅H₂₃NO₄: C, 64.04; H, 8.24; N, 4.98. Found: C, 63.91; H, 8.12; N, 4.93.
• 20 (2R,3R)-3-(tert-Butoxycarbonylamino)-3-(o-chlorophenyl)-1,2-propanediol (1d) Yield 55%; colorless gum; [α]_D ²⁵ –7.50 (c 0.32, CHCl₃); 99% ee from chiral HPLC analysis [Chiracel AS-H, n-hexane–i-PrOH (95:05), 0.5 mL min^–1]: t _R = 25.9 min (0.5%) and 28.8 min (99.5%). IR (CHCl₃): ν_max = 702, 704, 1036, 1164, 1264, 1367, 1393, 1498, 1694, 2928, 3420 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.43 (s, 9 H), 2.97 (br s, 1 H), 3.39 (br s, 1 H), 3.64–3.79 (m, 2 H), 3.98–3.99 (m, 1 H), 5.15–5.17 (m, 1 H), 5.55 (br s, 1 H), 7.19–7.25 (m, 2 H), 7.27–7.42 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 28.3, 54.1, 62.8, 72.2, 80.4, 127.1, 129.0, 130.1, 133.8, 136.6, 156.3. ESI-HRMS: m/z calcd for C₁₄H₂₀ClNO₄ [M + Na]⁺: 324.0973; found: 324.0970. Anal. Calcd for C₁₄H₂₀ClNO₄: C, 55.72; H, 6.68; N, 4.64. Found: C, 55.56; H, 6.48; N, 4.47.
• 21 (2R,3R)-3-(tert-Butoxycarbonylamino)-3-(1-naphthyl)-1,2-propanediol (1e) Yield 62%; colorless gum; [α]_D ²⁵ –13.00 (c 0.2, CHCl₃); 92% ee from chiral HPLC analysis [Chiracel AD-H, n-hexane–i-PrOH (90:10), 0.5 mL min^–1]: t _R = 12.55 min (3.92%) and 21.64 min (96.1%). IR (CHCl₃): ν_max = 774, 1019, 1038, 1121, 1159, 1351, 1408, 1499, 1687, 2921, 2991, 3382 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.44 (s, 9 H), 2.66 (br s, 1 H), 3.48 (br s, 1 H), 3.76–3.86 (dd, J = 12.0, 29.3 Hz, 2 H), 4.10–4.12 (m, 1 H), 5.14 (d, J = 8.1 Hz, 1 H), 5.53–5.57 (m, 1 H), 7.48–7.57 (m, 4 H), 7.81 (d, J = 8.1 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 1 H), 8.06 (d, J = 8.3 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 28.3, 51.7, 62.9, 72.9, 80.6, 122.9, 123.9, 125.3, 125.9, 126.8, 128.8, 129.1, 131.8, 134.2, 134.7, 156.8. ESI-HRMS: m/z calcd for C₁₈H₂₃NO₄ [M + Na]⁺: 340.1519; found: 340.1515. Anal. Calcd for C₁₈H₂₃NO₄: C, 68.12; H, 7.30; N, 4.41. Found: C, 67.93; H, 7.12; N, 4.31.
• 22 (2R,3S)-3-(tert-Butoxycarbonylamino)-3-(furfuryl)-1,2-propanediol (1f) Yield 58%; colorless gum; [α]_D ²⁵ –44.32 (c 0.46, CHCl₃); 90% ee. IR (CHCl₃): ν_max = 784, 1089, 1066, 1178, 1263, 1398, 1469, 1508, 1699, 2824, 2841, 3384, 3421 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.44 (s, 9 H), 2.95 (br s, 2 H), 3.67 (s, 2 H), 3.81 (br s, 1 H), 4.76–4.79 (m, 1 H), 5.29 (br s, 1 H), 6.32–6.34 (m, 2 H), 7.37 (br s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 28.3, 50.7, 62.8, 73.1, 80.6, 108.1, 110.5, 142.2, 151.7, 156.2. ESI-HRMS: m/z calcd for C₁₂H₁₉NO₅ [M + Na]⁺: 280.1169; found: 280.1177. Anal. Calcd for C₁₂H₁₉NO₅: C, 56.02; H, 7.44; N, 5.44. Found: C, 56.07; H, 7.36; N, 5.32.