Syntheses of Medium-Sized Cyclic Ethers from Carbohydrates via an ­Intramolecular Nitrile Oxide-Alkene Cycloaddition Strategy

Abstract

The regioselectivity of intramolecu1ar 1,3-dipolar cyclo­additions of nitrile oxides prepared from 3-O-alkenyl-1,2-O-iso­propylidene-α-d-pentodialdofuranoses is dependent on the length of the alkenyl chain. 3-O-Homoallyl nitrile oxide afforded exo-cyclization oxepane exclusively. 3-O-Pentenyl nitrile oxide produced a mixture of exo- and endo-cyclization adducts (oxocane and oxonane) whereas 3-O-hexenyl, heptenyl, and octenyl oxides all gave endo-cyclization adducts (ten-, eleven-, and twelve-membered ­cyclic ethers, respectively) exclusively.

Key words

cycloadditions - ethers - stereoselective synthesis - ­carbohydrates - nitrile oxides

References and Notes

• For reviews, see:
• 2a Yasumoto T. Chem. Rec.  2001,  1:  228 
• 2b Yasumoto T. Chem. Rec.  2001,  1:  228 
• 2c Shimizu Y. Chem. Rev.  1993,  93:  1685 
• 2d Yasumoto T. Murata M. Chem. Rev.  1993,  93:  1897 
• 3 Guella G. Mancini I. Chasera G. Pietra F. Helv. Chim. Acta  1992,  75:  310 
• 4a Irie T. Suzuki M. Masamune T. Tetrahedron  1968,  24:  4193 
• 4b Cameron AF. Cheung KK. Ferguson G. Robertson JM. J. Chem. Soc. B  1969,  559 
• 5a King TJ. Imre S. Öztunç A. Thomson RH. Tetrahedron Lett.  1979,  1453 
• 5b Howard BM. Schulte GR. Fenical W. Solheim B. Clardy J. Tetrahedron  1980,  36:  1747 
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• 7a Inoue M. Hirama M. Synlett  2004,  577 
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• 8 Shing TKM. Fung W.-C. Wong C.-H. J. Chem. Soc., Chem. Commun.  1994,  449 
• 9 Torssell KBG. In Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis   Feuer H. VCH; New York: 1988. 
• For reviews on 1,3-dipolar cycloaddition of sugar derivatives, see:
• 10a Koumbis AE. Gallos JK. Curr. Org. Chem.  2003,  7:  397 
• 10b Osborn HMI. Gemmell N. Harwood LM. J. Chem. Soc., Perkin Trans. 1  2002,  2419 
• 11 Zhong YL. Shing TKM. J. Org. Chem.  1997,  62:  2622 

1

New address: Merck & Co., Inc., One Merck Drive, Whitehouse Station, New Jersey, 08889, USA.

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General INOAC Procedure.
To a solution of oxime (1.00 mmol) in CH₂Cl₂ (800 mL), 10% aq NaOCl (6.2 mL, 10.0 mmol) was added and left to stir at r.t. for 1 h. The mixture was then heated under reflux for 10-240 h. The product was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic extracts were dried over anhyd MgSO₄, and filtered. The solvent was removed from the filtrate under reduced pressure. The crude residue was purified by flash chromatography to afford the isoxazoline.

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Selected Data.
Compound 30: colorless prisms, mp 146-147 °C; R _f = 0.20 (hexane-Et₂O, 1:1); [α]_D ²⁰ +40.9 (c 0.4, CHCl₃). ¹H NMR (500 MHz): δ = 1.33 (3 H, s), 1.52 (3 H, s), 1.65-1.71 (1 H, m), 2.09-2.13 (1 H, m), 3.51-3.56 (1 H, m), 3.56-3.65 (1 H, m), 3.90 (1 H, dt, J = 6.7, 5.5 Hz), 4.04 (1 H, d, J = 2.5 Hz), 4.13 (1 H, dd, J = 8.3, 5.7 Hz), 4.46 (1 H, dd, J = 10.1, 8.3 Hz), 4.56 (1 H, d, J = 3.6 Hz), 5.17 (1 H, d, J = 2.5 Hz), 5.96 (1 H, d, J = 3.6 Hz).
Compound 33: colorless needles (recrystallization from hexane-acetone), mp 88-89 °C; R _f = 0.26 (hexane-Et₂O, 2:1); [α]_D ²⁰ -57.2 (c 0.5, CHCl₃). ¹H NMR (300 MHz):
δ = 1.33 (3 H, s), 1.37-1.48 (2 H, m), 1.50 (3 H, s), 1.53-1.68 (3 H, m), 1.75-1.90 (1 H, m), 3.04 (1 H, dd, J = 17.1, 11.4 Hz), 3.25 (1 H, dd, J = 17.1, 2.7 Hz), 3.35 (1 H, ddd, J = 11.4, 4.5, 2.7 Hz), 3.84 (1 H, dt, J = 11.4, 1.8 Hz), 3.95 (1 H, d, J = 3.3 Hz), 4.55 (1 H, d, J = 3.6 Hz), 4.93 (1 H, m), 5.21 (1 H, d, J = 3.3 Hz), 6.02 (1 H, d, J = 3.6 Hz).
Compound 34: colorless prisms, mp 185-186 °C; R _f = 0.45 (hexane-EtOAc, 1:1); [α]_D ²⁰ -86.6 (c 0.4, CHCl₃). ¹H NMR (300 MHz): δ = 1.15-1.30 (2 H, m), 1.34 (6 H, s), 1.36-1.47 (4 H, m), 1.50 (6 H, s), 1.53-1.68 (4 H, m), 1.70-1.88 (2 H, m), 2.79 (2 H, dd, J = 17.1, 6.6 Hz), 3.17 (2 H, dd, J = 17.1, 10.5 Hz), 3.39-3.49 (2 H, m), 3.58-3.65 (2 H, m), 3.97 (2 H, d, J = 3.9 Hz), 4.49-4.56 (2 H, m), 4.58 (2 H, d, J = 3.6 Hz), 5.13 (2 H, d, J = 3.9 Hz), 5.98 (2 H, d, J = 3.6 Hz).
Compound 35: colorless prisms (recrystallization from hexane-acetone), mp 141-142 °C; R _f = 0.66 (hexane-EtOAc, 1:1); [α]_D ²⁰ - 40.8 (c 0.5, CHCl₃). ¹H NMR (300 MHz: δ = 1.22-1.29 (1 H, m), 1.32 (3 H, s), 1.33-1.43 (2 H, m), 1.48 (3 H, s), 1.50-1.59 (2 H, m), 1.63-1.74 (2 H, m), 1.87-1.96 (1 H, m), 3.06-3.24 (2 H, m), 3.51 (1 H, ddd, J = 12.0, 8.7, 3.3 Hz), 3.75-3.81 (1 H, m), 3.99 (1 H, d, J = 3.6 Hz), 4.56 (1 H, d, J = 3.6 Hz), 4.83-4.90 (1 H, m), 5.17 (1 H, d, J = 3.6 Hz), 5.99 (1 H, d, J = 3.6 Hz).
Compound 36: colorless needles, mp 195-196 °C; R _f = 0.25 (hexane-EtOAc, 1:1); [α]_D ²⁰ - 30.8 (c 0.2, CHCl₃). ¹H NMR (300 MHz): δ = 1.12-1.25 (1 H, m), 1.34 (3 H, s), 1.36-1.49 (3 H, m), 1.51 (3 H, s), 1.55-1.66 (2 H, m), 1.82-2.02 (2 H, m), 2.80 (1 H, dd, J = 16.5, 3.6 Hz), 3.06 (1 H, dd, J = 16.5, 11.7 Hz), 3.28 (1 H, ddd, J = 10.5, 8.7, 3.0 Hz), 3.98 (1 H, d, J = 3.6 Hz), 4.03-4.08 (1 H, m), 4.64 (1 H, d, J = 3.6 Hz), 4.91-4.99 (1 H, m), 5.02 (1 H, d, J = 3.6 Hz), 6.11 (1 H, d, J = 3.6 Hz).
Compound 37: colorless plates (recrystallization from hexane-Et₂O), mp 156-157 °C; R _f = 0.35 (hexane-Et₂O, 2:1); [α]_D ²⁰ -83.7 (c 0.4, CHCl₃).¹H NMR (300 MHz): δ = 1.17-1.30 (1 H, m), 1.34 (3 H, s), 1.37-1.49 (4 H, m), 1.50 (3 H, s), 1.52-1.55 (1 H, m), 1.56-1.70 (3 H, m), 1.88-1.98 (1 H, m), 3.08 (2 H, d, J = 9.0 Hz), 3.26 (1 H, m), 3.87 (1 H, m), 3.99 (1 H, d, J = 3.9 Hz), 4.60 (1 H, d, J = 3.9 Hz), 4.88 (1 H, m), 5.20 (1 H, d, J = 3.9 Hz), 6.00 (1 H, d, J = 3.9 Hz).
Compound 38: R _f = 0.21 (hexane-EtOAc, 2:1); [α]_D ²⁰
-146.5 (c 0.2, CHCl₃).
Compound 39: R _f = 0.18 (hexane-EtOAc, 1:2); [α]_D ²⁰ -62.7 (c 0.5, CHCl₃).