Simple Modifications of Enantiopure 1,2-Oxazines Leading to Building Blocks for Carbohydrate and Peptide Mimetics

Abstract

Starting from easily available enantiopure pyran derivatives we prepared bicyclic γ-lactam 6, azide 10, and alkyne 18 using simple procedures. These compounds were crucial intermediates for the synthesis of γ-amino acid 8 and dipeptide 9 as well as ­triazoles 13, 14, and 19, all containing a carbohydrate-mimicking aminopyran moiety. The generation of triazoles was particularly ­efficient by use of a recently reported modification of the click ­reaction.

Key words

pyrans - carbohydrates - peptides - sugar amino acids - oxidations - 1,3-dipolar cycloadditions

References and Notes

• 1a Nicolaou KC. Mitchell HJ. Angew. Chem. Int. Ed.  2001,  40:  1576 ; Angew. Chem. 2001, 113, 1624
• 1b Gruner SAW. Locardi E. Lohof E. Kessler H. Chem. Rev.  2002,  102:  491 
• 1c Schweizer F. Angew. Chem. Int. Ed.  2002,  41:  230 ; Angew. Chem. 2002, 114, 240
• 2a Schade W. Reissig H.-U. Synlett  1999,  632 
• 2b 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 
• 3 Al-Harrasi A. Reissig H.-U. Angew. Chem. Int. Ed.  2005,  44:  6227 ; Angew. Chem. 2005, 117, 6383
• 4 Al-Harrasi A. Dissertation   Freie Universität; Berlin: 2005. 
• 7a Campagne J.-M. Coste J. Jouin P. J. Org. Chem.  1995,  60:  5214 
• 7b Castro B. Dormoy JR. Evin G. Selve C. Tetrahedron Lett.  1975,  1219 
• 8 Veljkovic I. Zimmer R. Reissig H.-U. Brüdgam I. Hartl H. Synthesis  2006,  2677 
• 9a Huisgen R. Angew. Chem., Int. Ed. Engl.  1963,  2:  565 ; Angew. Chem. 1963, 75, 604
• 9b Rostovtsev VV. Green LG. Fokin VV. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  2596 ; Angew. Chem. 2002, 114, 2708
• 9c Tornoe CW. Christensen C. Meldal M. J. Org. Chem.  2002,  67:  3057 
• 10a Zhu S.-Z. J. Chem. Soc., Perkin Trans. 1  1994,  2077 
• 10b

  Nonafluorobutanesulfonyl azide (Nf-N₃) is a substitute for the typically used trifluoromethanesulfonyl azide. Unlike the latter, Nf-N₃ is not explosive and is stable at r.t.

• 11 Alper PB. Hung S.-C. Wong C.-H. Tetrahedron Lett.  1996,  37:  6029 
• 13 Chan TR. Hilgraf R. Sharpless KB. Fokin VV. Org. Lett.  2004,  6:  2853 
• 14 Groothuys S. Kuijpers BHM. Quaedflieg PJLM. Roelen HCPF. Wiertz RW. Blaauw RH. van Delft FL. Rutjes FPJT. Synthesis  2006,  3146 
• 16 Peri F. Marinzi C. Barath M. Granucci F. Urbano M. Nicotra F. Bioorg. Med. Chem.  2006,  14:  190 
• 17 Basak P. Lowary TL. Can. J. Chem.  2002,  80:  943 
• For examples of triazole-linked pseudo-oligosaccharides, see:
• 18a Hotha S. Kashyap S. J. Org. Chem.  2006,  71:  364 
• 18b Beckmann HSG. Wittmann V. Org. Lett.  2007,  9:  1 

5

Compound 4b is obtained by the reduction of the corresponding TBS-protected ketone (see ref. 3) followed by protection of the secondary alcohol with BnBr.

6

Typical Procedure for the Conversion of 5 into 6
Alcohol 5 (0.320 g, 0.629 mmol) was dissolved in anhyd DMF (10 mL), then PDC (0.946 g, 2.52 mmol) and Ac₂O (0.24 mL, 2.5 mmol) were added. The mixture was stirred for 12 h at r.t. Then, Et₂O and H₂O were added and the layers were separated. The organic layer was successively washed with H₂O, dried (MgSO₄), and the solvent was removed under reduced pressure. Purification by column chromatography (silica gel, hexane-EtOAc, 4:1 to 1:1) yielded 0.250 g (79%) of 6 as a colorless solid.
Analytical Data for tert -Butyl (1 S ,4 S ,5 R ,8 S )-8-Benzyl-oxy-4-( tert -butyl-dimethylsiloxymethyl)-2,2-dimethyl-7-oxo-3-oxa-6-azabicyclo[3.2.1]octane-6-carboxylate ( 6)
[α]_D ²² +14.1 (c 1.43, CHCl₃); mp 64-65 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.05, 0.06 (2 s, 3 H each, SiMe), 0.88 (s, 9 H, t-Bu), 1.29, 1.47 (2 s, 3 H each, Me), 1.51 (s, 9 H, t-Bu), 2.43 (dd, J = 1.6, 4.9 Hz, 1 H, 5-H), AB part of ABX system (δ_A = 3.57, δ_B = 3.58, J _A-X = J _B-X = 6.5 Hz, J _A-B = 10.6 Hz, 2 H, 4-CH₂), 4.14 (t, J = 6.5 Hz, 1 H, 4-H), 4.15 (t, J = 4.9 Hz, 1 H, 8-H), 4.30 (dd, J = 1.6, 4.9 Hz, 1 H, 1-H), 4.60 (br s, 2 H, CH₂Ph) 7.25-7.38 (m, 5 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = -5.3, -5.1 (2 q, SiMe), 18.1 (s, t-Bu), 25.9 (q, t-Bu), 24.5, 29.0 (2 q, Me), 28.0 (q, t-Bu), 53.3 (d, C-5), 55.0 (d, C-1), 63.7 (t, 4-CH₂), 68.1 (d, C-4), 71.8 (t, CH₂Ph), 72.9 (s, C-2), 75.6 (d, C-8), 83.1 (s, t-Bu), 127.5, 128.1, 128.6, 136.8 (3 d, s, Ph), 149.4 (s, NCO₂), 170.9 (s, NCO) ppm. IR (KBr): ν = 3115-3030 (=C-H), 2955-2855 (C-H), 1790 (C=O), 1720 (NCO₂) cm^-1. Anal. Calcd for C₂₇H₄₃NO₆Si (505.3): C, 64.12; H, 8.57; N, 2.77. Found: C, 64.22; H, 8.75; N, 2.78.

12

Typical Procedure for the Conversion of 7 into 10 To a solution of amino alcohol 7 (150 mg, 0.73 mmol) in MeOH-H₂O (2:1, 3 mL) at r.t. were added CuSO₄·5H₂O (18 mg, 0.073 mmol, 1 M solution in H₂O) and K₂CO₃ (101 mg, 0.73 mmol), followed by slow addition of Nf-N₃ (475 mg, 1.46 mmol) via syringe. The mixture was stirred for 24 h, then glycine hydrochloride (554 mg, 5 mmol) was added in order to quench the reaction mixture and the suspension was stirred for another 24 h. The mixture was filtered and the solvents were removed. The crude solid was dissolved in pyridine (6 mL) and cooled to 0 °C. Then DMAP (3 mg, 0.02 mmol) and Ac₂O (0.69 mL, 7.3 mmol) were added and the mixture was stirred at r.t. for 12 h. The residue was taken up in Et₂O and washed with a 1 M solution of HCl and brine followed by a sat. solution of NaHCO₃. The organic layer was dried (MgSO₄) and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, hexane-EtOAc, 9:1 to 6:4) to give 10 (150 mg, 57% over two steps) as a colorless oil.

Analytical Data for (3 S ,4 S ,5 R ,6 S )-Acetic Acid 3,6-Bis-acetoxymethyl-5-azido-2,2-dimethyltetrahydropyran-4-yl ester ( 10) [α]_D ²² +28.0 (c 0.5, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.21, 1.37 (2 s, 3 H each, Me), 2.01 (m_c, 1 H, 3-H), 2.08 (s, 6 H, COMe), 2.10 (s, 3 H, COMe) 3.60 (dd, J = 2.5, 3.8 Hz, 1 H, 5-H), 4.09-4.19 (m, 4 H, 3-CH₂, 6-CH₂, 4-H), 4.40 (dd, J = 6.5, 11.4 Hz, 1 H, 3-CH₂), 5.35 (dd, J = 4.2, 5.2 Hz, 1 H, 4-H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 20.8, 20.9, 21.1 (3 q, COMe), 26.0, 26.3 (2 q, Me), 42.6 (d, C-3), 60.1 (d, C-5), 62.2 (t, 6-CH₂), 63.7 (t, 3-CH₂), 66.4 (d, C-4), 69.7 (d, C-6), 74.0 (s, C-2), 169.6, 170.6, 170.7 (3 s, CO) ppm. IR (film): ν = 2980-2715 (C-H), 2110 (N₃), 1745 (C=O) cm^-1. MS (pos. FAB): m/z = 380 [M + Na]⁺, 358 [M + H]⁺. HRMS (EI): m/z calcd for C₁₃H₂₀N₃O₆ [M - CH₃CO]⁺: 314.1349; found: 314.1352.

15

Typical Procedure for the Conversion of 10 into 14
To a solution of azide 10 (15 mg, 42 µmol) and phenyl acetylene 12 (5.0 µL, 42 µmol) in MeCN (0.78 mL) were added solutions of Et₃N (840 µL, 8.4 µmol, 10 mM solution in MeCN), TBTA (8.4 µmol, 840 µL of a 10 mM solution in MeCN), and CuI (8.4 µmol, 840 µL of a 10 mM solution in MeCN). Argon was bubbled through the mixture for 15 min and the reaction was stirred for 24 h at 40 °C. Then H₂O (5 mL) and EtOAc (5 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 3 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, hexane-EtOAc, 6:4 to pure EtOAc) to give 14 (18 mg, 90% yield) as a colorless solid.
Analytical Data for (3 S ,4 S ,5 R ,6 S )-Acetic Acid 4-Acetoxy-6-acetoxymethyl-2,2-dimethyl-5-{4-phenyl-[1,2,3]triazol-1-yl}tetrahydropyran-3-yl Methylester ( 14)
[α]_D ²² +75.2 (c 0.25, CHCl₃); mp 136-138 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.39, 1.42 (2 s, 3 H each, Me), 1.98, 2.00, 2.05 (3 s, 3 H each, COMe), 2.37 (m_c, 1 H, 3-H), 3.72 (dd, J = 7.3, 11.8 Hz, 1 H, 6-CH₂), 3.81 (dd, J = 5.2, 11.8 Hz, 1 H, 6-CH₂), 4.05 (dd, J = 5.2, 11.8 Hz, 1 H, 3-CH₂), 4.25 (dd, J = 5.8, 11.8 Hz, 1 H, 3-CH₂), 4.47 (m_c, 1 H, 6-H), 5.07 (dd, J = 5.0, 7.0 Hz, 1 H, 5-H), 5.53 (dd, J = 7.0, 12.3 Hz, 1 H, 4-H), 7.34 (m_c, 1 H, Ph), 7.43 (m_c, 2 H, Ph), 7.85 (m_c, 2 H, Ph), 7.97 (s, 1 H, triazole) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 20.6, 20.6, 20.9 (3 q, COMe), 23.5, 25.9 (2 q, Me), 44.3 (d, C-3), 61.2 (t, 3-CH₂), 62.0 (t, 6-CH₂), 65.2 (d, C-5), 67.9 (d, C-6), 71.8 (d, C-4), 118.3 (d, triazole), 125.9, 128.3, 128.8, 130.2 (3 d, s, Ph), 148.5 (s, triazole), 169.7, 170.2, 170.4 (3 s, CO) ppm. IR (KBr): ν = 3030-3135 (=C), 2850-2975 (C-H), 1745 (C=O) cm^-1. HRMS (ESI): m/z calcd for C₂₃H₃₀N₃O₆ [M + H]⁺: 460.2078; found: 460.2091.

19

These compounds are currently being tested as selectin binding substrates in collaboration with J. Dernedde, R. Tauber, Charité-Universitätsmedizin Berlin, CBF, Zentralinstitut für Laboratoriumsmedizin und Pathobiochemie.