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43948-B1
Stereospecific Intramolecular Carbenoid Insertions on Furanose Platforms as a Route to Branched-Chain Sugars, C-Glycosides and Fused Heterocycles

Peter Norris, Youngstown State University

   The use of enantiomerically pure carbohydrates for the synthesis of other complex molecules relies on the availability of methodologies that are compatible with the associated functionality present in the saccharide substrate.  To expand the available methods we are investigating the application of carbenoid insertion chemistry for the formation of carbon-carbon bonds on conformationally restricted furanose platforms.  The method holds great promise for the stereospecific formation of chiral heterocycles, including those related to C-glycosides, and the frameworks of several classes on natural products. 

   Recently we have constructed diazoesters attached through O-3 of several D-xylofuranose platforms and studied their Rh(II)-catalyzed decomposition chemistry, which results in remarkably different outcomes in each case.  For an O-3 linked compound in which O-5 is blocked by a trityl protecting group, the major process involves regioeselective intramolecular C-H insertion into the C-2 – H-2 bond of the xylofuranose ring to generate fused bisfuran products.  The reaction is stereospecific with respect to the xylose ring, however there is little selectivity seen in the formation of the new chiral center alpha to the ester carbonyl.  The structures of both diastereomers have been solved by X-ray diffraction which proves the stereochemical relationships between the two fused furan rings.  Decomposition of an O-3 linked diazoester featuring an azide group in place of O-5 results in quite different products in which the azido group becomes involved in the chemistry.  The major isolated products are an oxazepine, the product of an intramolecular cyclization process, and a 14-membered macrocyle which is the outcome of the intermolecular cyclization variant.  The structures of both of these compounds have been solved by X-ray diffraction (Figures 1 and 2).  The mechanism for this remarkable, and seemingly unprecedented, transformation is currently under investigation.     

   Our preliminary work on sugar-derived diazoesters led to the discovery of a new one-pot synthesis of glycosyl azides from the corresponding lactol precursors and we have expanded the scope of this reaction to non-carbohydrate alcohols and subsequently to sequential one-pot processes such as 1,2,3-triazole synthesis.  Displacement of azide from p-acetamidobenzenesulfonyl azide by the alkoxide gives an intermediate sulfonate ester, and subsequent displacement on an alkyl or acyl halide with azide anion affords the alkyl or acyl azide.  Reaction progress is monitored conveniently using IR spectroscopy since each of the azide species involved has a distinct absorbance frequency.  Isolation of the potentially dangerous azide product is unnecessary and subsequent reaction, for example with terminal alkynes in the presence of a Cu(I) catalyst, is proving to be a promising route to 1,2,3-triazoles in one flask from the precursor alkyl or acyl halide.  These reactions are also amenable to the application of microwave heating.      

Figure 1.

Figure 2.

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