Synthesis of Enantiopure Amino Polyols and Pyrrolidine Derivatives from 5-Bromo-1,2-oxazin-4-ones

Abstract

Diastereoselective electrophilic bromination of 3,6-dihydro-2H-1,2-oxazines syn-1 and anti-1 led to 5-bromo-1,2-oxazin-4-ones 2a and 3a, respectively. Reduction furnished 1,2-oxazin-4-ones 4 and 6 which could be transformed into enantiopure amino and imino sugar derivatives. Nucleophilic substitution of the bromo functionality gave amino substituted 1,2-oxazines 10. They were converted into diamino substituted sugar derivatives.

Key words

1,2-oxazine - bromination - amino alcohols - stereoselective synthesis - pyrrolidines

References

• 1 Schade W. Reissig H.-U. Synlett  1999,  632 
• 2 Synthesis: Dondoni A. Franco S. Junquera F. Merchan FL. Merino P. Tejero T. Synth. Commun.  1994,  24:  2537 
• 3 Pulz R. Watanabe T. Schade W. Reissig H.-U. Synlett  2000,  983 ; and references cited herein
• 4 Pulz R. Al-Harrasi A. Reissig H.-U. Synlett  2002,  817 
• 5 Pulz R. Al-Harrasi A. Reissig H.-U. Org. Lett.  2002,  4:  2353 
• 6a Wong C.-H. Halcomb RL. Ichikawa Y. Kajimoto T. Angew. Chem., Int. Ed. Engl.  1995,  34:  412 ; Angew. Chem. 1995, 107, 453
• 6b Wong C.-H. Halcomb RL. Ichikawa Y. Kajimoto T. Angew. Chem., Int. Ed. Engl.  1995,  34:  521 ; Angew. Chem. 1995, 107, 569
• 6c Iminosugars as Glycosidase Inhibitors   Stütz AE. Wiley-VCH; Weinheim: 1999. 
• 6d Heightman TD. Vasella AT. Angew. Chem. Int. Ed.  1999,  38:  750 ; Angew. Chem. 1999, 111, 794
• 6e Asano N. Nash RJ. Molyneux RJ. Fleet GWJ. Tetrahedron: Asymmetry  2000,  11:  1645 
• 6f Lillelund VH. Jensen HH. Liang X. Bols M. Chem. Rev.  2002,  102:  515 
• 6g Gerber-Lemaire S. Popowycz F. Rodríguez-García E. Asenjo ATC. Robina I. Vogel P. ChemBioChem  2002,  3:  466 
• 7 Pulz R. Schade W. Reissig H.-U. Rademacher O. Z. Kristallogr. NCS  2000,  215:  73 
• 8 Ballestri M. Chatgilialoglu C. Clark KB. Griller D. Giese B. Kopping B. J. Org. Chem.  1991,  56:  678 
• 9 Dehalogenation of α-halo ketones with Raney nickel: Barrero AF. Alvarez-Manzaneda EJ. Chahboun R. Meneses R. Romera JL. Synlett  2001,  485 
• 10 Keck GE. McHardy SF. Wager TT. Tetrahedron Lett.  1995,  36:  7419 
• 14 Ariza X. Urpi F. Viladomat C. Vilarrasa J. Tetrahedron Lett.  1998,  39:  9101 

11

13% of starting material 5 have been isolated.

12

With 2a this procedure led to the formation of a 1:1 mixture of diastereomeric azido oxazinones. Apparently, epimerization either of 2a or the resulting azido oxazinone is considerably faster here.

13

As a side product 8% of the N,O-diprotected 1,2-oxazine were obtained.

15

Correct spectroscopical data were obtained for all new compounds. Correct elemental analysis was achieved for all stable compounds.

16

Typical Procedure, anti -1 to 3a: To a solution of NBS (0.222 g, 1.25 mmol) in CH₃CN (13 mL) and H₂O (0.8 mL) a solution of anti-1 (0.382 g, 1.25 mmol) in CH₃CN (3 mL) was added at -40 °C. The mixture was stirred for 1 h at this temperature and then warmed up to r.t. After quenching with H₂O the solution was extracted with Et₂O and the combined extracts were dried with MgSO₄. After removal of the solvent the crude mixture was dissolved in n-hexane and the insoluble N-succinimide was separated by filtration. After evaporating the solvent 3a (dr 93:7, 0.450 g, 97%) was obtained. Recrystalization with n-hexane led to diastereo-merically pure 3a as colorless crystals (mp 53-60 °C).
Analytical data of (3R,5R,4′S)-2-Benzyl-5-bromo-3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-tetrahydro-1,2-oxazin-4-one (3a): [α]_D ²⁰ +46.0 (c 2.3, CHCl₃). ¹H NMR (CDCl₃, 500 MHz): δ = 7.36-7.26 (m, 5 H, Ph), 4.95 (dt, J = 2.9, 7.5 Hz, 1 H, 4′-H), 4.52, 3.76 (2 d, J = 14.6 Hz, 1 H each, CH₂Ph), 4.50 (t_brd_br, J ≈ 0.7 Hz, 8.0 Hz, 1 H, 5-H), 4.41 (d_brd, J ≈ 7.5, 11.2 Hz, 1 H, 6-H_A), 4.19 (dd, J = 8.8. 11.2 Hz, 1 H, 6-H_B), 4.13 (m_c, 2 H, 5′-H), 4.03 (dd, J = 0.6, 2.9 Hz, 1 H, 3-H), 1.42, 1.34 (2 s, 3 H each, Me). ¹³C NMR (CDCl₃, 75.5 MHz): δ = 196.2 (s, C-4), 136.9, 128.6, 128.5, 127.3 (s, 3 d, Ph), 108.9 (s, C-2′), 74.8 (d, C-3), 74.1 (d, C-4′), 73.8 (t, C-6), 64.7 (t, C-5′), 60.7 (t, CH₂Ph), 46.6 (d, C-5), 26.0, 24.0 (2 q, Me). IR (gas phase): ν = 2990-2890 (C-H), 1750 (C=O)
cm^-1. MS (EI, 70 eV): m/z (%) = 356 (1) [M⁺ - 14], 290 (1) [M⁺ - Br], 271, 269 (5 each), 190 (62), 101 (24), 91 (100) [CH₂Ph], 43(45) [C₃H₇]. C₁₆H₂₀BrNO₄ (370.2): Calcd C, 51.90; H, 5.44; N, 3.78. Found: C, 51.88; H, 5.46; N 3.84.
Typical Procedure, 3a to 10: To a solution of 3a (0.555 g, 1.50 mmol) in CH₂Cl₂ (4 mL) and H₂O (2 mL) NaN₃ (0.487 g, 7.50 mmol) and Me(Oct)₃NCl (15 mg) were added. The mixture was stirred for 3 d at r.t., the layers were separated and the organic layer was washed with H₂O. After drying with MgSO₄ the solvent was evaporated yielding spectroscopically pure 10 (dr = 92:8, 0.500 g, quant.) as viscose brown oil.
Analytical data of (3R,5S,4′S)-5-Azido-2-benzyl-3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-3,4,5,6-tetrahydro-2H-1,2-oxazin-4-one (10): ¹H NMR (CDCl₃, 500 MHz): δ = 7.38-7.27 (m, 5 H, Ph), 4.59-4.56 (m, 1 H, 4′-H), 4.55 (t, J = 8.7 Hz, 1 H, 5-H), 4.43 (dd, J = 8.7, 10.6 Hz, 1 H, 6-H_A), 4.13 (dd, J = 6.2, 8.4 Hz, 1-H, 5′-H_A), 4.12, 3.80 (2 d, J = 13.9 Hz, 1 H each, CH₂Ph), 3.92 (dd, J = 7.1, 8.4 Hz, 1 H, 5′-H_B), 3.74 (dd, J = 8.7, 10.6 Hz, 1 H, 6-H_B), 3.53 (d, J = 3.9 Hz, 1 H, 3-H), 1.35, 1.33 (2 s, 3 H each, Me). ¹³C NMR (CDCl₃, 125 MHz): δ = 200.3 (s, C-4), 135.4, 128.7, 128.4, 127.8 (s, 3 d, Ph), 110.4 (s, C-2′), 75.1 (d, C-3), 72.2 (d, C-4′), 70.8 (t, C-6), 67.4 (t, C-5′), 62.6 (d, C-5), 58.9 (t, CH₂Ph), 25.9, 25.6 (2 q, Me). IR (CCl₄): ν = 2990-2890 (C-H), 2120 (N₃), 1740 (C=O) cm^-1. According to ¹H NMR and ^¹³ C NMR purity >95%.