Acid-Mediated Transformations of Enantiopure 3,6-Dihydro-2H-1,2-oxazines into Functionalised Aminotetrahydrofuran Derivatives

Abstract

Two new routes to substituted aminotetrahydrofuran derivatives have been investigated. Treatment of 3,6-dihydro-2H-1,2-oxazines with hydrochloric acid in the presence of zinc provided 4-benzylamino-5-hydroxy furanose derivatives which contain a quaternary anomeric centre with a vinyl unit. Upon mesylation and subsequent heating in aqueous media 5-hydroxy-3,4,5,6-tetrahydro-1,2-oxazines were converted into novel bicyclic 1,2-oxazines with complete regio- and stereoselectivity. Cleavage of the N-O bond and subsequent debenzylation furnished enantiopure polyhydroxylated aminotetrahydrofuran derivatives which are promising ligands for selectin inhibition studies.

Key words

1,2-oxazine - furan - amine - reduction - zinc - amino sugar

References and Notes

• For reviews, see:
• 1a Zimmer R. Synthesis  1993,  165 
• 1b Zimmer R. Reissig H.-U. In Modern Allene Chemistry   Krause N. Hashmi ASK. Wiley-VCH; Weinheim: 2004.  p.425 
• For reviews, see:
• 2a Reissig H.-U. Hormuth S. Schade W. Okala Amombo M. Watanabe T. Pulz R. Hausherr A. Zimmer R. J. Heterocycl. Chem.  2000,  37:  597 
• 2b Reissig H.-U. Schade W. Okala Amombo MG. Pulz R. Hausherr A. Pure Appl. Chem.  2002,  74:  175 
• 2c Brasholz M. Reissig H.-U. Zimmer R. Acc. Chem. Res.  2009,  42:  45 
• 3a Flögel O. Reissig H.-U. Eur. J. Org. Chem.  2004,  2797 
• 3b Chowdhury MA. Reissig H.-U. Synlett  2006,  2383 
• 3c Brasholz M. Reissig H.-U. Synlett  2007,  1294 
• 3d Brasholz M. Reissig H.-U. Angew. Chem. Int. Ed.  2007,  46:  1634 ; Angew. Chem. 2007, 119, 1659
• 3e Brasholz M. Reissig H.-U. Eur. J. Org. Chem.  2009,  3595 
• 4a Pfrengle F. Al-Harrasi A. Reissig H.-U. Synlett  2006,  3498 
• 4b Bressel B. Egart B. Al-Harrasi A. Pulz R. Reissig H.-U. Brüdgam I. Eur. J. Org. Chem.  2008,  467 
• 4c Pfrengle F. Al-Harrasi A. Brüdgam I. Reissig H.-U. Eur. J. Org. Chem.  2009,  282 
• 5a Schade W. Reissig H.-U. Synlett  1999,  632 
• 5b Helms M. Schade W. Pulz R. Watanabe T. Al-Harrasi A. Fišera L. Hlobilová I. Zahn G. Reissig H.-U. Eur. J. Org. Chem.  2005,  1003 
• 6 Kumaran S. Shaw DM. Ley SV. Chem. Commun.  2006,  3211 
• 9a Pulz R. Al-Harrasi A. Reissig H.-U. Org. Lett.  2002,  4:  2353 
• 9b Dekaris V. Reissig H.-U. Synlett  2010,  42 
• 11 For the examination of another carbohydrate mimetic as component of gold-nanoparticle-based multivalent selectin inhibitors, see: Dernedde J. Enders S. Reissig H.-U. Roskamp M. Schlecht S. Yekta S. Chem. Commun.  2009,  932 

7

Typical Procedure for Furan Synthesis, Conversion of ent - syn -1 into ent -2
1,2-Oxazine ent-syn-1 (200 mg, 0.655 mmol) was dissolved in MeOH (13 mL). Then Zn dust (214 mg, 3.27 mmol) and 3 N HCl (4.36 mL, 13.1 mmol) were added. The mixture was stirred for 6 h at r.t. Upon completion of the reaction the mixture was neutralised with solid NaHCO₃, H₂O was added and extracted three times with EtOAc. The combined organic layers were dried with MgSO₄ and filtrated, and solvents were removed in vacuo. Purification via silica gel column chromatography (hexane-EtOAc) afforded ent-2 (70 mg, 43%) as a colourless oil.
Analytical Data of Methyl-4-benzylamino-1,2,4-trideoxy-α- l - threo -hex-1-en-3-ulofuranoside ( ent -2)
[α]_D ^²0 +64.3 (c 0.80, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 2.84 (s_br, 2 H, NH, OH), 2.93 (d, J = 6.7 Hz, 1 H, 4-H), 3.20 (s, 3 H, OMe), 3.68 (dd, J = 5.3, 9.3 Hz, 1 H, 6-H), 3.74, 3.97 (2 d, J = 12.9 Hz, 2 H, NCH₂), 4.01 (dd, J = 7.1, 9.3 Hz, 1 H, 6-H), 4.17 (ddd, J = 5.3, 6.7, 7.1 Hz, 1 H, 5-H), 5.32 (dd, J = 1.6, 10.8 Hz, 1 H, 1-H), 5.55 (dd, J = 1.6, 17.4 Hz, 1 H, 1-H), 5.87 (dd, J = 10.8, 17.4 Hz, 1 H, 2-H), 7.23-7.26, 7.30-7.34 (2 m, 5 H, Ph) ppm. ^¹³C NMR (126 MHz, CDCl₃): δ = 49.3 (q, OMe), 52.2 (t, NCH₂), 70.8 (t, C-6), 73.9 (d,
C-4), 76.5 (d, C-5), 105.0 (s, C-3), 118.2 (t, C-1), 127.1, 128.2, 128.4, 139.9 (3 d, s, Ph) 136.2 (d, C-2) ppm. IR (film): 3410, 3330 (OH, NH), 3090-3030 (=CH), 2990-2830 (CH), 1605, 1585, 1495 (C=C) cm^-¹. HRMS (ESI-TOF-MS): m/z calcd for C₁₄H₁₉NO₃ [M + H]⁺: 250.1438; found: 250.1443. Anal. Calcd for C₁₄H₁₉NO₃ (249.3): C, 67.45; H, 7.68; N, 5.62. Found: C, 67.01; H, 7.66; N, 5.53.

8

Product 4 contained small amounts (ca. 5%) of one byproduct, possibly the second epimer with respect to the newly formed stereogenic centre.

10

Typical Procedure for the Synthesis of Bicyclic 1,2-Oxazines, Conversion of 5a into 6a
To a solution of 5a (734 mg, 2.27 mmol) in pyridine (10 mL) under argon at r.t. MsCl (0.296 mL, 3.82 mmol) was added. The mixture was stirred 1 d at r.t., quenched with 5% CuSO₄ solution (4 mL), and extracted three times with Et₂O. The combined organic layers were washed twice with H₂O and dried with MgSO₄. After filtration and removal of the solvents the crude product was dissolved in MeCN (2.5 mL), H₂O (2.5 mL) was added, the mixture was placed in a sealed tube and heated 1 d at 100 ˚C. After completion of the reaction the mixture was extracted with Et₂O (3 × 5 mL), the combined organic layers were dried with MgSO₄, filtrated, and the solvents removed in vacuo. Purification via silica gel column chromatography (hexane-EtOAc) afforded bicyclic compound 6a (440 mg, 73% over both steps) as a colourless oil.
Analytical Data of (1 S ,5 S ,7 S ,8 R )-(2-Benzyl-8-methoxy-3,6-dioxa-2-azabicyclo[3.2.1]oct-7-yl)methanol (6a)
[α]_D ^²0 +23.4 (c 0.71, CHCl₃). ^¹H NMR (500 MHz, CD₃CN): δ = 2.84 (t, J = 5.8 Hz, 1 H, OH), 3.33 (s, 3 H, OMe), 3.51 (m_c, 1 H, 1-H), 3.55 (ddd, J = 0.8, 4.1, 11.4 Hz, 1 H, 4-H_A), 3.56 (d, J = 11.4 Hz, 1 H, 4-H_B), 3.98-4.02 (m, 3 H, 8-H,
1′-H), AB system (δ_A = 4.03, δ_B = 4.10, J = 13.9 Hz, 2 H, NCH₂), 4.10-4.14 (m, 1 H, 7-H), 4.26 (dd, J = 0.8, 4.1 Hz, 1 H, 5-H), 7.24-7.28, 7.31-7.36 (2 m, 5 H, Ph) ppm. ^¹³C NMR (126 MHz, CD₃CN): δ = 55.8 (q, OMe), 58.5 (t, NCH₂), 61.7 (t, C-1′), 65.6 (d, C-1), 69.6 (t, C-4), 76.3 (d, C-5), 81.0 (d, C-8), 81.6 (d, C-7), 128.1, 129.2, 129.6, 139.3 (3d, s, Ph) ppm. IR (film): 3420 (OH), 3085-3030 (=CH), 2930-2830 (CH) cm^-¹. MS (EI, 80 eV, 150 ˚C): m/z (%) = 265 (21) [M⁺], 91 (100) [C₇H₇]⁺, 71 (29), 43 (28). Anal. Calcd for C₁₄H₁₉NO₄ (265.3): C, 63.38; H, 7.22; N, 5.28. Found: C, 62.90; H, 7.51; N, 5.27.

12

Gold nanoparticles with sulfated aminotetrahydrofuran derivative 7a were tested in a similar way as described in
ref. 11. Excellent activity and selectivity were observed with IC₅₀ values of 390 pm for L-selectin and 50 pm for
P-selectin. Dekaris, V.; Dernedde, J.; Enders, S.; Reissig,
H.-U.; Roskamp, M.; Schlecht, unpublished results.