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Intramolecular carbenoid insertions on furanose platforms

Many furanose derivatives of sugars are easy to produce and serve as useful platforms upon which to attach carbenoid precursors such as diazo groups. Controlled decomposition, for example with a metal catalyst, then leads to products of intra- or inter-molecular insertion depending upon the particular stereochemical structure of the furanose.

Several examples of intermolecular insertion into water have been observed by us in the cases of manno-, gluco, and allo-furanoses with these reactions occurring with surprisingly high stereoselectivity (Carbohydr. Res., 2008, 343, 1819-1823).

When rigorously anhydrous conditions are employed, intramolecular C-H insertion on the furanose back-bone is possible. Examples at C-2 of mannofuranose, xylofuranose, and glucofuranose have been observed with the carbenoid insertion resulting in the formation of a new 5-membered ring annealed onto the furanose (Sacui, Patton, Berndt MS theses, YSU). These model studies suggest that this chemistry may provide a convenient route to the synthesis of natural products such as canadensolide and the secosyrins. Stereoselective C-H insertion to form a lactone ring on a furanose platform could result in truncated syntheses of a variety of metabolites.

As this project has developed we have discovered several new modes of reactivity, for example between alcohols and sulfonyl azides (Tetrahedron. Lett., 2011, 52, 2670-2672) and an intramolecular cyclization between a carbenoid attached to an azidodeoxysugar. We are now investigating these interesting pathways as potentially useful routes to heterocyclic systems.


Intra- and intermolecular N-cyclization reactions for the synthesis of diverse heterocycles

We have a general interest in the use of functional groups such as diazos and azides in the synthesis of heterocyclic systems. During our work on furanose-based diazo decomposition, we found that generating a metal-stabilized carbenoid in a suitable azidodeoxysugar framework resulted in a novel cyclization event to produce a cyclic imine (Malich MS thesis, YSU).

The generality of this process is currently being studied with a view to producing different sized nitrogen heterocycles with a variety of different substitution patterns. This chemistry should also prove to be useful in the synthesis of novel amino acids.

The Cu(I)-catalyzed variant of the Huisgen 1,3-dipolar cycloaddition is now widely accepted as a reliable and robust method for conjugation within bioorganic chemistry. We have used this reaction for some time now to produce a wide variety of sugar-derived molecules that are linked through 1,2,3-triazole groups in a linear or globular fashion. In experiments aimed at developing novel carbohydrate-based materials, we have built model compounds in which three sugars are linked through two amides or two triazoles (Carbohydr. Res., 2006, 341, 1081-1090 and 1645-1656). Studies towards oligomers and polymers are now in progress.

Using monosaccharides as stereochemically well-defined starting materials is a useful way to learn many of the fundamental topics of synthetic organic chemistry. Many of these compounds are easy to produce in large scales, have interesting NMR spectroscopic properties, and are usually well-behaved during chromatographic purification. Novel results using sugars are then applied to non-carbohydrate systems in order to study their general usefulness.


Synthetic methods; one-pot formation of alkyl and acyl azides

An unexpected result from our furanose-diazo chemistry has opened up some novel and useful applications of arylsulfonyl azides, particularly in the direct azidation of alcohols and alkyl/acyl halides. Treatment of representative sugar-derived alcohols with DBU/ArSO2N3 provides the corresponding azidodeoxy sugar or intermediate sulfonate ester (Tetrahedron. Lett., 2011, 52, 2670-2672).

Exploring different bases and ArSO2N3 reagents has provided conditions for the generation of organic-soluble azide sources which allow for the one-pot conversion of alkyl and acyl halides to the corresponding azide derivative. Subsequent reaction, for example thermolysis of the acyl azide in alcohol solvent to promote the Curtius rearrangement, constitutes a one-pot synthesis of useful derivatives without having to use metallic azides or handling organic azide intermediates.

We continue to use the Cu(I)-catalyzed variant of the Huisgen 1,3-dipolar cycloaddition to generate novel structures and have employed parallel synthesis methods for the synthesis of sugar-derived 1,2,3-triazoles (Carbohydr. Res., 2006, 341, 1081-1090). Using polymer-supported reagents, we have also produced collections of glycosyl amides (Carbohydr. Res., 2006, 341, 1645-1656) as potential glycosidase inhibitors (Curr. Top. Med. Chem., 2008, 8, 101-113).

While much of our work centres upon the use of sustainable precursors such as carbohydrates, as well as the application of many of the tenets of green chemistry (microwave heating, water as solvent, etc.), we are now moving towards applying our chemistry in the sythesis of several interesting natural products as well as novel materials.



Department of Chemistry, Youngstown State University, 1 University Plaza Youngstown, Ohio 44555; Contact: 330-941-1553; pnorris@ysu.edu