Stereoselective Cycloaddition on Carbohydrates for the Synthesis of New Bicyclic Oxazolidines Bearing a Quaternary Bridgehead

George Bashiardes; Céline Cano; Bernard Mauzé

doi:10.1055/s-2005-869836

LETTER

Stereoselective Cycloaddition on Carbohydrates for the Synthesis of New Bicyclic Oxazolidines Bearing a Quaternary Bridgehead

George Bashiardes*, Céline Cano, Bernard Mauzé
Département de Chimie, Equipe Methodologie et Synthèse de Biomolécules, SFA - CNRS UMR 6514, Université de Poitiers, 40 Avenue du Recteur Pineau, 86022 Poitiers, France
Fax: +33(5)49454588; e-Mail: george.bashiardes@univ-poitiers.fr;

Abstract

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Abstract

A new carbohydrate nitrone intramolecular cycloaddition reaction is described for the enantioselective synthesis of bicyclic oxazolidines. By choice of the precursor, the products possess a chiral quaternary bridgehead aryl substitution. Also described is the diverse synthesis of 6-keto and 6-alkenyl carbohydrates by a general approach. The overall protocol provides versatility through the possibility of introducing diverse reagents at several entry points.

Key words

carbohydrates - cycloaddition - nitrone - oxazolidine - quaternary

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References

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It should be noted that this is a suitable entry point for introducing diversity, since hydroxylamines of multiple variation are very readily accessible.

Typical Procedure for the Synthesis of (3a S ,4 R ,5 S ,6 R ,7 S ,7a S )-1-methyl-3a-phenyloctahydrobenzo[ c ]isoxazole-4,5,6,7-tetraol Tetraacetate 12c.
Thermal conditions: in a two-necked, round-bottomed flask equipped with a magnetic stirring bar, a reflux condenser and a thermometer, NaHCO₃ (218 mg, 2.6·10^-3 mol, 2.6 equiv) was added to a solution of carbohydrate 10 (252 mg, 1.0·10^-3 mol) and N-isopropylhydroxylamine hydrochloride (290 mg, 2.6·10^-3 mol, 2.6 equiv) in 80% aq EtOH (15 mL). The mixture was stirred under reflux during 48 h. After cooling and removal of the solvent under reduced pressure, Ac₂O (0.6 mL), pyridine (1 mL), DMAP (cat.), and CH₂Cl₂ were added. The mixture was stirred at r.t. during 6 h. The mixture was then washed with 3 × 6 mL of H₂O. The solvent was removed under reduced pressure and the resulting oil was purified by flash chromatography on silica gel (EtOAc-CH₂Cl₂, 20:80, R _f = 0.36) to provide 12c in 61% yield as a yellowish oil.
¹H NMR (CDCl₃): δ = 2.16 (s, 12 H, CH ₃-CO-), 2.54 (s, 3 H, H-8), 2.74 (dd, J _7,7 _′ = 13.9 Hz, J_7-1 = 7.1 Hz, 1 H, H-7), 3.10 (d, J ₇ _′ _,7 = 13.9 Hz, 1 H, H-7′), 3.58-3.60 (m, 1 H, H-1), 5.00-5.60 (m, 4 H, H-2, H-3, H-4, H-5), 7.23-7.39 (m, 5 H, H-10, H-11, H-12, H-13, H-14) ppm.
¹³C NMR (CDCl₃): δ = 20.3, 20.8, 21.0, 21.1 (CH₃-CO-), 33.8 (C-7), 47.0 (C-8), 63.1 (C-1), 71.3 (C-2), 71.4, 71.5, 71.6 (C-3, C-4 et C-5), 86.5 (C-6), 126.5 (C-12), 127.6, 127.7 (C-11, C-13, C-10, C-14), 143.4 (C-9), 168.4, 169.2, 170.1, 170.5 (C=O) ppm.
IR: 3023 s (arom. =CH), 2966 m, 2930 w (CH_n), 1742 s (C=O), 1538 w, 1493 w, 1448 s (arom. C=C), 1372 s (C-N), 1217 s (C-O), 754 s, 703 s (arom. C-H) cm^-1.
Compound 12a Major Conformer:
¹H NMR (CDCl₃): δ = 1.99, 2.02, 2.04, 2.13 (4 s, 12 H, CH ₃), 2.27 (dd, J _8,8bis = 13.0 Hz, J _8,7a = 10.0 Hz, 1 H, H-8), 3.01 (d, J _8bis,8 = 13.0 Hz, 1 H, H-8bis), 3.60 (dd, J _7a,8 = 10.0 Hz, J _7a,7 = 2.0 Hz, 1 H, H-7a), 4.18 (d, J _3,3bis = 13.4 Hz, 1 H, H-3), 4.21 (d, J _3bis,3 = 13.4 Hz, 1 H, H-3bis), 5.11 (dd, J _7,6 = 8.8 Hz, J _7,7a = 2.0 Hz, 1 H, H-7), 5.31 (d, J _4,5 = 8.6 Hz, 1 H, H-4), 5.40 (dd, J _5,4 = 8.6 Hz, J _5,6 = 1.4 Hz, 1 H, H-5), 5.43 (dd, J _6,7 = 8.8 Hz, J _6,5 = 1.4 Hz, 1 H, H-6), 7.13-7.31 (m, 10 H, H-arom.) ppm.
¹³C NMR (CDCl₃): δ = 20.1, 20.5, 20.9, 21.0 (CH₃), 34.6 (C-3), 62.9 (C-8), 63.9 (C-7a), 70.2 (C-7), 73.5, 73.6 (C-5, C-6), 74.1 (C-4), 87.0 (C-3a), 126.1, 128.0, 128.2, 128.6, 129.8 (C-10, C-11, C-12, C-13, C-14, C-16, C-17, C-18, C-19, C-20), 134.3 (C-9), 140.0 (C-15), 168.4, 169.3, 169.7, 170.5 (C=O) ppm.
IR: 3020 m (arom. =CH), 2989 s, 2934 m (CH_n), 1741 s (C=O), 1497 m, 1450 m (arom. C=C), 1370 s (C-N), 1218 s (C-O), 755 s, 701 s (arom. C-H) cm^-1.
Compound 12a Minor Conformer:
¹H NMR (CDCl₃): δ = 1.99, 2.02, 2.04, 2.13 (4 s, 12 H, CH ₃), 2.81 (dd, J _8,8bis = 13.8 Hz, J _8,7a = 6.7 Hz, 1 H, H-8), 3.19 (d, J _8bis,8 = 13.8 Hz, 1 H, H-8bis), 3.57 (d, J _3,3bis = 12.9 Hz, 1 H, H-3), 3.86 (dd, J _7a,8 = 6.7 Hz, J _7a,7 = 3.9 Hz, 1 H, H-7a), 3.86-3.96 (m, 2 H, H-6, H-4), 3.91 (d, J _3bis,3 = 12.9 Hz, 1 H, H-3bis), 5.04 (dd, J _5,4 = 4.1 Hz, J _5,6 = 1.3 Hz, 1 H, H-5), 5.17 (dd, J _7,7a = 3.9 Hz, J _7,6 = 3.8 Hz, 1 H, H-7), 7.13-7.31 (m, 10 H, H-arom.) ppm.
¹³C NMR (CDCl₃): δ = 20.1, 20.5, 20.9, 21.0 (CH₃), 34.3 (C-3), 62.1 (C-8), 66.2 (C-7a), 71.9 (C-7), 72.4, 72.6 (C-4, C-6), 75.5 (C-5), 88.2 (C-3a), 126.7, 127.7, 127.8, 128.4, 128.9 (C-10, C-11, C-12, C-13, C-14, C-16, C-17, C-18, C-19, C-20), 135.8 (C-9), 142.1 (C-15), 168.4, 169.3, 169.7, 170.5 (C=O) ppm.
IR: 3020 m (arom. =CH), 2989 s, 2934 m (CH_n), 1741 s (C=O), 1497 m, 1450 m (arom. C=C), 1370 s (C-N), 1218 s (C-O), 755 s, 701 s (arom. C-H) cm^-1.
Compound 12b:
¹H NMR (CDCl₃): δ = 2.16 (s, 12 H, CH ₃-CO-), 2.54 (s, 3 H, H-8), 2.74 (dd, J _3,3bis = 13.9 Hz, J _3-7a = 7.1 Hz, 1 H, H-3), 3.10 (d, J _3bis,3 = 13.9 Hz, 1 H, H-3bis), 3.58-3.60 (m, 1 H, H-7a), 5.00-5.60 (m, 4 H, H-4, H-5, H-6, H-7), 7.23-7.39 (m, 5 H, H-10, H-11, H-12, H-13, H-14) ppm.
¹³C NMR (CDCl₃): δ = 20.3, 20.8, 21.0, 21.1 (CH₃-CO-), 33.8 (C-3), 47.0 (C-8), 63.1 (C-7a), 71.3 (C-7), 71.4, 71.5, 71.6 (C-4, C-5, C-6), 86.5 (C-3a), 126.5 (C-12), 127.6, 127.7 (C-11, C-13, C-10, C-14), 143.4 (C-9), 168.4, 169.2, 170.1, 170.5 (C=O) ppm.
IR: 3023 s (arom. =CH), 2966 m, 2930 w (CH_n), 1742 F (C=O), 1538 w, 1493 w, 1448 s (arom. C=C), 1372 s (C-N), 1217 s (C-O), 754 s, 703 s (arom. C-H) cm^-1.

<A NAME="RD39204ST-16A">16a</A> Perreux L. Loupy A. Tetrahedron 2001, 57: 9199 ; and references therein

<A NAME="RD39204ST-16B">16b</A> Bashiardes G. Safir I. Said Mohamed A. Barbot F. Laduranty J. Org. Lett. 2003, 5: 4915

<A NAME="RD39204ST-16C">16c</A> De La Hoz A. Diaz-Ortiz A. Langa F. In Microwaves in Organic Synthesis Loupy A. Wiley-VCH; Germany: 2003.

Typical procedure for the synthesis of (3a S ,4 R ,5 S ,6 R ,7 S ,7a S )-1-methyl-3a-phenyloctahydrobenzo[c]isoxazole-4,5,6,7-tetraol tetraacetate 12c.
Microwave conditions: in a pyrex test tube (2 × 15), NaHCO₃ (218 mg, 2.6·10^-3 mol, 2.6 equiv), N-isopropyl-
hydroxylamine hydrochloride (290 mg, 2.6·10^-3 mol, 2.6 equiv), carbohydrate 10 (252 mg, 1.0·10^-3 mol) and 80% aq EtOH (1 mL) were submitted to microwave irradiations (CEM Discover apparatus. Settings: 70 °C, 100 W) during 80 min. After cooling and the solvent evaporated under reduced pressure, the crude product was acetylated and purified as in Ref. 15.