Infoscience

Thesis

Synthèse totale asymétrique des L-allose, L-talose, D-allonojirimycine et désoxypolyoxine C

Derivatives of 7-oxabicyclo[2.2.l]hept-5-en-2-yl ("naked sugars") are readily available through Diels-Alder cycloaddition of furan to an appropriate dienophile. Several methods allow one to obtain these molecules in optically pure form. They have been used as starting material for the syntheses of numerous natural products. In order to fully exploit the synthetic potential of "naked sugars", one must be able to functionalize regio- and stereoselectively their C(5)=C(6) double bond, as well as their C(3) position. Although several means for functionalizing the double bond had already been developed, no method was available for the C(3) center manipulation. The first objective of this work was to develop two stereoselective pathways for the functionalization of the C(3) atom by oxygen-containing groups, illustrated by the total syntheses of L-allose and L-talose. In the case of L-talose, which formally corresponds to the introduction of an hydroxyl group on C(3) by the endo face of (+)-5,6-(isopropylidenedioxy)-7-oxanorboman-2-one (+)-29, the synthesis is based on the exo α-bromation of the ketone and is followed by an intramolecular substitution, with inversion of the configuration at C(3). L-talose ((-)-13) was obtained in five steps starting from ketone (+)-29 with a 42% overall yield. In the case of L-allose, the introduction of the oxygen-containing function came from the oxidation of the double bond of the (-)-5,6-(isopropy1idenedioxy)-7-oxanorboman-2-one silylenolether ((+)-30) with a peracid. The direct precursor of this rare sugar, (+)-methyl 2,3-O-isopropylidène-L-allofuranoside (+)-61, was obtained in six steps from (-)-29 with a 30% overall yield. In the second part of this work, the objective was to introduce a nitrogen-containing function on the C(3) center of the "naked sugars" stereoselectively. The total syntheses of 5-amino-5-deoxy-D-allopyranose (-)-107 (allonojirimycin) and of deoxypolyoxin C (+)-123 are applications of the method developed. Allonojirimycin was the last isomer of gluconojirimycin which had not yet been characterized; it belongs to a class of potential glycosidase inhibitors. The starting molecule was a brominated intermediate from the synthesis of L-talose, to which a nitrogen-containing function was introduced by substitution with retention of configuration at C(3). Allonojirimycin was obtained in seven steps from (+)-29, in a 9.7% overall yield. The same principle was used in the synthesis of deoxypolyoxin C, the core structure of polyoxin and nikkomycin antibiotics. Deoxypolyoxin C was synthesized in nine steps from (+)-29 with an overall yield of 5.8%.

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