?Carbohydrate-based drug discovery has been a growing area of research due to the biological processes in which carbohydrates are involved. However, multistep syntheses are often required using these multifunctional and stereochemically rich molecules as synthons. We have explored domino reactions involving furanulose scaffolds for the synthesis of bicyclic structures embodying a butenolide, which occurs in biologically active natural and synthetic products. An efficient and facile two-step stereoselective route was developed to access pyranose-fused butenolides, based on Wittig reaction followed by acid hydrolysis, which resulted in furanose ring opening, its closure to the pyranose form and intramolecular lactonization, in one single step. This reliable method has proven successful also for the synthesis of bicyclic thiosugar analogues. Interestingly, the D- or L-configuration of the target molecule can be controlled by the hexofuranulose C-5 configuration, opening the way to such complex systems in a facile and non-expensive two-step procedure. This route was applied to furanuloses bearing and amino group at C-5 but the required neutralization to release the amino group for cyclization resulted in transformation of the iminopentopyranose-fused butenolide intermediate into a butenolide with a C-C linked appendage. Exploitation of the 5-azido Wittig precursor gave an easy access to 1,2-dihydropyridin-3-ones in a two-step synthesis, based on hydrogenation, N-protection and acetic acid elimination after treatment with acetic anhydride in pyridine. Enones of this type have been key intermediates in the synthesis of nojirimycins and are usually obtained in low overall yield requiring multistep syntheses.Our exploratory work has been also devoted to a number of rearrangements to transform simple sugars into biologically active molecules. As example we present the conversion of aldonolactones into oxetane d-amino acids by a ring contraction rearrangement. Also transformation of penturono-5,1-lactone into glycomimetics embodying a difluoromethylene replacing the endocyclic oxygen, via Wittig-type difluoromethylenation and TIBAL promoted rearrangement, will be highlighted.

Domino reactions in glycochemistry: A strategy to build original frameworks with biological profile

248th National Meeting (2014)

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