Synthesis of Enantiopure Functionalized β-Alkoxy γ-Amino Aldehydes by a New Internal Redox Ring Cleavage of Carbohydrate-Derived 1,2-Oxazines

Abstract

N-Methylation of 3,6-dihydro-2H-1,2-oxazines such as syn-1 or anti-1 followed by treatment with triethylamine smoothly furnished enantiopure β-alkoxy γ-amino aldehydes syn-2 and anti-2 in excellent yields. This mild N-O bond cleavage may be classified as internal redox process. Similar transformations of related 1,2-oxazines led to the expected compound anti-6 or to protected 4-amino hexose derivative 10. Starting from syn-2 or anti-2 condensation with hydrazine afforded new pyrazole derivatives syn-11 and anti-11 with stereodefined and protected amino diol side chain. ­Heterocycles syn- 12 and syn-13 were prepared from syn-2 by condensation with 2-aminoimidazole or 2-aminobenzimidazole, respectively.

alkylation - elimination - aldehydes - 1,2-oxazines - carbohydrates - pyrazoles - imidazoles

References

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1b Helms M. Schade W. Pulz R. Watanabe T. Al-Harrasi A. Fisera L. Hlobilová I. Zahn G. Reissig H.-U. Eur. J. Org. Chem.  2005,  1003 

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3

Schade, W.; Watanabe, T.; Bressel, B.; Reissig, H.-U. unpublished results.

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4b For fragmentations of 4H-5,6-dihydro-1,2-oxazines by N-alkylation followed by base treatment see: Lidor R. Shatzmiller S. J. Am. Chem. Soc.  1981,  103:  5916 

5 For a recent application of the Murahashi protocol see: Dugovic B. Wiesenganger T. Fisera L. Hametner C. Prónayová N. Heterocycles  2005,  65:  591 

6

Conversion of syn -1 into syn -2.
1,2-Oxazine syn-1 (350 mg, 1.15 mmol) was dissolved in MeCN (7 mL). The solution was treated with methyl triflate (1.26 mL, 1.26 mmol) at 0 °C. The reaction mixture was stirred at r.t. for 6 h until the starting material disappeared. The reaction mixture was then cooled to 0 °C and treated with Et₃N (0.47 mL, 3.95 mmol) and stirred for 1 h. Then, H₂O (5 mL) was added to the mixture and extracted three times with CH₂Cl₂, dried (Na₂SO₄) and concentrated to yield 283 mg. The crude product was purified by column chromatography (silica gel, hexane-EtOAc, 2:1) to yield 323 mg (87%) of syn-2 as colourless crystals. Analytical data for (4S,4′S)-4-(benzylmethylamino)-4-(2′,2′-dimethyl-[1′,3′]dioxolan-4′-yl)-3-methoxybut-2-enal: mp 42-44 °C. [α]_D ²² +118.2 (c 0.77, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.38, 1.41 (2 s, 3 H each, Me), 2.39 (s, 3 H, Me), 3.51 (m_c, 1 H, 5′-H_B), 3.52 (d, J = 13.5 Hz, 1 H, NCH ₂ Ph), 3.66 (s, 3 H, OMe), 3.90 (d, J = 13.5 Hz, 1 H, NCH ₂ Ph), 3.97 (dd, J = 6.5, 8.6 Hz, 1 H, 5′-H_A), 4.06 (d, J = 8.6 Hz, 1 H, 4-H), 4.65 (dt, J = 6.5, 8.6 Hz, 1 H, 4′-H), 5.50 (d, J = 7.5 Hz, 1 H, 2-H), 7.20-7.34 (m, 5 H, Ph), 9.47 (d, J = 7.5 Hz, 1 H, CHO) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 25.3, 26.6 (2 q, Me), 38.9 (q, NMe), 55.4 (q, OMe), 58.9 (t, NCH₂Ph), 63.8 (d, C-4), 66.9 (t, C-5′), 73.6 (d, C-4′), 107.4 (d, C-2), 109.7 (s, C-2′), 127.0, 128.2, 128.6, 138.5 (3 d, s, Ph), 174.4 (s, C-3), 189.6 (s, CHO) ppm. IR (KBr): ν = 3085-3030 (=C-H), 2985-2795 (C-H), 1660 (C=O), 1605 (C=C) cm^-1. MS (EI, 80 eV, 100 °C): m/z (%) = 319 (4) [M]⁺, 218 (14) [M - C₅H₉O₂]⁺, 91 (100) [CH₂Ph]⁺. Anal. Calcd for C₁₈H₂₅NO₄ (319.4): C, 67.69; H, 7.89; N, 4.39. Found: C, 67.38; H, 7.65; N, 4.36. HRMS (EI, 80 eV, 100 °C): m/z calcd for C₁₈H₂₅NO₄: 319.17834; found: 319.17744.

7 For related reaction conditions see: Sosnicki JG. Monatsh. Chem.  2000,  131:  475 

8

Conversion of syn-2 into syn-11: Aldehyde syn-2 (250 mg, 0.78 mmol) and hydrazine hydrate (0.40 mL, 9.50 mmol) were dissolved in dry EtOH (6 mL). TFA (58 µL, 0.78 mmol) was added and the mixture was stirred under reflux for 2 h. EtOH was removed in vacuo and H₂O (5 mL) was added to the residue which was extracted three times with CH₂Cl₂, dried (Na₂SO₄) and concentrated to yield 243 mg (quant.) of syn-11 as colourless crystals. Analytical data for (1S,4′S)-benzyl-[(2′,2′-dimethyl-[1′,3′]dioxolan-4′-yl)-(2H-pyrazol-3-yl)methyl]methylamine: mp 68-70 °C. [α]_D ²² -30.7 (c 1.72, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.40, 1.42 (2 s, 3 H each, Me), 2.23 (s, 3 H, NMe), 3.47 (d, J = 13.3 Hz, 1 H, NCH ₂ Ph), 3.58 (t, J = 7.7 Hz, 1 H, 5′-H_B), 3.83 (d, J = 13.3 Hz, 1 H, NCH ₂ Ph), 3.97 (m_c, 1 H, 5′-H_A), 3.90 (d, J = 6.5 Hz, 1 H, 1-H), 4.69 (td, J = 6.5, 7.7 Hz, 1 H, 4′-H), 6.17 (d, J = 2.2 Hz, 1 H, 4′′-H), 7.21-7.38 (m, 5 H, Ph), 7.50 (d, J = 2.2 Hz, 1 H, 5′′-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 25.4, 26.6 (2 q, Me), 38.5 (q, NMe), 59.2 (t, NCH₂Ph), 61.9 (d, C-1), 67.6 (t, C-5′), 75.5 (d, C-4′), 105.1 (d, C-4′′), 109.7 (s, C-2′), 127.0, 128.2, 129.2, 138.9 (3 d, s, Ph), 174.4 (s, C-3′′), 135.6 (d, C-6′′) ppm. IR (KBr): ν = 3260 (NH), 3085-3030 (=C-H), 2985-2800 (C-H), 1675 (C=C). cm^-1. MS (EI, 80 eV, 110 °C): m/z (%) = 301 (0.4) [M]⁺, 286 (1) [M - CH₃]⁺, 234 (0.3) [M - C₃H₃N₃]⁺, 210 (0.3) [M - C₇H₇]⁺, 200 (91) [M - C₅H₉O₂]⁺, 91 (100) [CH₂Ph]⁺. HRMS (EI, 80 eV, 110 °C): m/z calcd for C₁₇H₂₃N₃O₂: 301.17902; found: 301.17854.

9 Similar reactions of 2-aminobenzimidazole with carbohydrate derivatives: Bari A. Feist H. Michalik D. Michalik M. Peseke K. Synthesis  2004,  2863 

10 For synthesis of amino acids with pyrazolyl substituents see: De Luca L. Giacomelli G. Porcheddu A. Spanedda AM. Falorni M. Synthesis  2000,  1295