· (MW 204.27)
(reagent used for the protection of vicinal diols)
Physical Data: bp 54 °C (0.4 Torr); nD20 1.4540-1.4600.
Solubility: soluble in most organic solvents.
Form Supplied in: colorless liquid; available from Avocado, Alfa Aesar, Acros Organics.
Purification: fractionally distilled at 0.4 Torr.
Handling, Storage, and Precautions: store below 4 °C, Toxicity: cancer suspect agent.
Use as a Protecting Group
1,1,2,2-Tetramethoxycyclohexane (TMC) was developed for selective protection of 1,2-diequatorial diols in sugars, in the presence of other hydroxyl group combinations.1 Similar to 3,3´4,4´-tetrahydro-6,6´-bis(2H-pyran), TMC preferentially reacts under acidic catalysis [camphorsulfonic acid, (CSA)] with trans-diequatorial vicinal hydroxyls of a variety of hexopyranosides in the D-gluco,2 L-rhamno,1-3 D-manno,1,2,4 D-galacto,1,2 L-lyxo,1 L-arabino,1 and D-glucosamine5 series to form the corresponding (1´,2´-dimethoxycyclohexane-1´,2´-diyl)-hexopyranosides (1). The major product is the often highly crystalline cyclohexane-1,2-diacetals, with the spiroketal as the minor product.
Usually, the regioselectivity is high for 1,2-trans diequatorial hydroxyls when only 1,2-cis diols are present, as in L-rhamnosides (1).6 However, problems may arise when several 1,2-trans diequatorial hydroxyls are accessible in a glycoside. This is the case in which D-glucopyranosides provide unseparable mixtures of the 2,3- and 3,4-protected counterparts.2,6,7 Yields of blocked glycosides may also be medium in the galacto, arabino, and fuco series where the protection with 3,3´,4,4´-tetrahydro-6,6´-bis(2H-pyran) is recommended, but are high in the manno series.3,4 Removal of the dimethoxycyclohexane protecting group is conveniently performed by hydrolysis in aqueous acetic acid2b or aqueous trifluoroacetic acid.5 Beside glycopyranosides, TMC has also been used for the selective protection of the trans-diol in quinic acid (2).8
The reaction of benzyl a-L-rhamnopyranoside with TMC was carried out without adding trimethyl orthoformate to prevent transglycosylation (3).3 The thermodynamically controlled 3,4-diprotected product in 61% yield was separated from the 1,2-diprotected product (17%) by flash chromatography. In contrast, use of 3,3´,4,4´-tetrahydro-6,6´-bis(2H-pyran) gave a 3:2 mixture of 3,4- and 2,3-diprotected product in 79% yield and could not be used for further study. The restricted conformational mobility of the 3,4-protected product facilitated the subsequent transformations for the synthesis of the required 2,-difluorooleandrose.3
Use for Oligosaccharide Synthesis
An especially useful feature of dimethoxycyclohexane-protected glycosides is their reduced reactivity in glycosylation reactions. For example, ethyl 2,3,4-tri-O-benzyl-1-thio-a-L-rhamnopyranoside can be selectively activated in the presence of a dimethoxycyclohexane protected ethyl 1-thio-a-L-rhamnopyranoside, resulting in a disaccharide which in turn can be used as a glycosyl donor for further glycosylations (4).2b Thus, simple one-pot syntheses of complex oligosaccharides can be established using this protecting group in combination with the selective activation of 1-thioglycosides or 1-selenoglycosides.2b,9
The torsional deactivation resulting from the rigid structural features of the 1,2-diacetals based on TMC protection has been effectively exploited in mediating glycosidic couplings for the construction of high-density oligosaccharides and complex carbohydrates.10
Benzaldehyde dimethyl acetal [1125-88-8];
butane-2,3-dione; cyclohexane-1,2-dione [765-87-7];
- 1. Grice, P.; Ley, S. V.; Pietruszka, J.; Priepke, H. W. M.; Warriner, S. L., J. Chem. Soc., Perkin Trans. 1 1997, 351.
- 2. (a) Ley, S. V.; Priepke, H. W. M.; Warriner, S. L., Angew. Chem. Intl. Ed. Engl. 1994, 33, 2290. (b) Ley, S. V.; Priepke, H. W. M.; Warriner, S. L., Angew. Chem. Intl. Ed. Engl. 1994, 33, 2292.
- 3. Barrena, M. I.; Matheu, M. I.; Castillión, S., J. Org. Chem. 1998, 63, 2184.
- 4. (a) Ley, S. V.; Osborn, H. M. I.; Priepke, H. W. M.; Warriner, S. L., Org. Synth. 1998, 75, 170. (b) Hassan, H. H. A. M., Heterocycles 2000, 53, 397.
- 5. Saotome, C.; Kanie, Y.; Kanie, O.; Wong, C.-H., Bioorg. Med. Chem. 2000, 8, 2249.
- 6. Ley, S. V.; Boons, G.-J.; Leslie, R.; Woods, M.; Hollinshead, D. M., Synthesis 1993, 689.
- 7. Hughes, A. B.; Ley, S. V.; Priepke, H. W. M.; Woods, M., Tetrahedron Lett. 1994, 35, 773.
- 8. Gebauer, O.; Brueckner, R., Liebigs Ann. 1996, 1559.
- 9. Grice, P.; Ley, S. V.; Pietruszka, J.; Priepke, H. W. M.; Walther, E. P. E., Synlett 1995, 781.
- 10. Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.; Priepke, H. W. M.; Reynolds, D. J., Chem. Rev. 2001, 101, 53.
Thomas Ziegler, Lakshminarayanapuram R. Subramanian & Gregor Lemanski
University of Tübingen, Tübingen, Germany
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