Thio-sugars. Part 5: From d-glucal to 3-deoxy-(1→2)-2-S-thiodisaccharides through isolevoglucosenone—a simple approach

doi:10.1016/S0957-4166(99)00567-4

Tetrahedron: Asymmetry

Volume 11, Issue 2, 11 February 2000, Pages 519-532

https://doi.org/10.1016/S0957-4166(99)00567-4 Get rights and content

Abstract

A new synthesis of isolevoglucosenone and its stereoselective functionalization into 3-deoxy-(1-2)-2-S-thiodisaccharides is described. The base-catalyzed conjugate addition of 1-thiosugars to isolevoglucosenone followed by the reduction of the C-4 keto function constitute a new two-step general approach to these classes of biologically important thio-sugars.

Introduction

In our efforts towards preparing thiodisaccharides,1., 2. we employed enones 1 and 2. Both enones, levoglucosenone1., 2., 3., 4. (1,6-anhydro-3,4-dideoxy-β-d-glycero-hex-3-enopyranos-2-ulose, 1) and isomeric isolevoglucosenone5., 6., 7., 8., 9., 10., 11., 12., 13. (1,6-anhydro-2,3-dideoxy-β-d-glycero-hex-2-enopyranos-4-ulose, 2), are, synthetically, extremely attractive versatile chiral building blocks because of their high functionality and conformational bicyclic rigidity, as depicted in Fig. 1.

The 1,6-anhydro bridge in both enones 1 and 2 eliminates the need for protecting groups at the anomeric carbon and the C-6-OH. Moreover, the bridge fixes the conformation of the system and sterically hinders the β-d-face of both molecules. Therefore, both enones have already been used in the synthesis of various natural products and their intermediates.10., 11. However, isolevoglucosenone 2 is considerably less accessible than levoglucosenone 1 and relatively unstable,¹³ decomposing over several months while in storage at −25°C. Levoglucosenone 1 was also used for the synthesis of isolevoglucosenone 2 in ca. ∼25% overall yield.¹³

As our need for larger quantities of enones 1 and 2 increased, we have been constantly exploring methods that would make them more readily available for exploratory studies and multistep syntheses. Thus, a convenient and efficient synthetic approach to isolevoglucosenone 2 is extremely important and in demand.

The pioneering work of Achmatowicz et al.⁵ on the versatility of furfuryl alcohol and its conversion to various enones, including a racemic mixture of isolevoglucosenone 2, was the first report of the preparation of isolevoglucosenone and other racemic 2,3-dideoxy-dl-hex-2-enopyranos-4-uloses.6., 7., 8., 9.

Recently, Ogasawara et al.10., 11. developed a new approach to both enones 1 and 2 and their enantiomers, exploring the utility of the non-carbohydrate precursor 2-vinylfuran. Köll and co-workers¹² synthesized isolevoglucosenone from levoglucosenone and from 1,6-anhydro-2,3-isopropylidene-β-d-mannopyranose. Furneaux and co-workers¹³ reported the synthesis of isolevoglucosenone 2 directly from levoglucosenone 1 in a five-step sequence. Through the rearrangement of 3-deoxy-1,2:5,6-di-O-isopropylidene-α-d-erythro-hex-3-enofuranose, Horton and co-workers14., 15. reported a completely different and good yielding approach to isolevoglucosenone. Although overall yields in all of these methods were acceptable, synthesis usually required a large number of steps and the use of air-sensitive reagents such as sodium hydride and aluminum chloride (AlCl₃) on a rather large scale.

Section snippets

Results and discussion

Studying the formation of the 1,6-anhydro ring, Oberdorfer and co-workers16., 17. recently reported a novel rearrangement of unprotected d-glucal 3 to allyl alcohol 4 under anhydrous conditions and in the presence of anhydrous copper sulfate and molecular sieves. The fact that allyl alcohol 4 could be produced in good yield directly from d-glucal, and could serve as an excellent precursor to target isolevoglucosenone through simple oxidation of the -OH function at C-4, prompted us to explore

Conclusion

The conjugate addition of protected 1-thiosugars to isolevoglucosenone, followed by the tandem reaction of C-4 keto group reduction and deprotection, is a new short stereoselective approach to (1→2)-2-S-thiodisaccharides. All functionalized new thiodisaccharides are stable glycomimetic compounds of potential biological interest.

General methods

Unless otherwise noted, starting materials were obtained from commercial suppliers and used without purification. All melting points were uncorrected and were measured in open capillary tubes. Optical rotations were determined on a Jasco Model DIP-370 polarimeter in CHCl₃ solutions. Thin-layer chromatography (TLC) was performed on precoated silica gel 60F₂₅₄ plates from E. Merck and visualized by spraying with 10% ethanolic sulfuric acid and subsequent heating. Column chromatography was

Acknowledgements

Financial support from the American Cancer Society Institutional Grant to University of Connecticut Health Center, ACSIN 152L-132 grant program, is gratefully acknowledged.

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