Théophile Tschamber

Single and double asymmetric induction in Diels-Alder cycloadditions with chiral acylnitroso dienophiles

Abstract Diels-Alder reaction of the achiral 1-silyloxybutadiene 1a with the chiral acyinitroso dienophile 2a gave cycloadduct 4 in high diastereomeric excess (d.e. > 98 %), a result which is undoubtedly due to the C-2 symmetrical chiral dimethylpyrrolidine inductor. Excellent d.e. was also observed when the (R)-prolinol dienophile 2d was reacted with the chiral diene 1b (d.e. = 96 %), whereas cycloaddition of the (S) enantiomer 2e with 1b gave only poor asymmetric induction (d.e. = 4 %). These two latter examples nicely illustrate the influence of “matched pair” (1b/2d) versus “mismatched pair” (1b/2e) upon double asymmetric induction. All herein reported Diels-Alder cycloadditions were regiospecific.

Stereospecific double glycolisation of 1,2-dihydropyridines with OsO4. Synthesis of (±) aminoarabinose- and of (±) aminoaltrose derivatives [1].

Abstract Double glycolisation of 1,2-dihydropyridines 1 led stereospecifically and in good yield to the corresponding (±) aminoarabinose- and (±) aminoaltrose derivatives 5 . Hydrogenolysis of the N-benzyloxy carbonyl piperidinose 5b gave directly the 1-desoxy derivative 7a .

Stereoselective catalytic double osmylation of 1,2-dihydropyridines leading to amino-arabinose and to amino-altrose derivatives and to potential glycosidase inhibitors.

Abstract Catalytic double osmylation of 1,2-dihydropyridines 1b and 1c proceeded stereospecifically and in good yields to the corresponding aminoarabinose 2b, and 2c derivatives. respectively. In basic medium these piperidinoses equilibrated with their furanose isomers 6b and 6c (both α- and β-anomers). Hydrogenolysis of their urethane moieties led to the corresponding piperidine triols 7a and 7b.

Stereoisomeric Imidazolo-Pentoses − Synthesis, Chiroptical Properties, and Evaluation as Glycosidase Inhibitors

The syntheses of all four imidazolo-piperidino-pentoses in the L-series ent-2 to ent-5, and of three out of the four possible stereomers in the D-series 3, 4, and 5, are reported. The linear imidazolo sugar precursors were prepared, either by double condensation of formamidine with protected aldohexoses, or by nucleophilic addition of a lithiated imidazole derivative to protected aldotetroses. Cyclisation of these linear imidazolo-carbohydrates was performed by intramolecular SN2 reactions. These were followed by deprotection to the target molecules. The four pairs of opposite enantiomers showed pronounced mirror-image-type Cotton effects in their CD spectra. All stereomers of the D-series show a negative rotatory power ([α]D), while the stereomers of the L-series show a positive one. None of the eight imidazolo sugars inhibited the replication of HIV-1. Some of them proved to be rather selective but only moderately potent inhibitors of α-glycosidases, as determined by Michaelis-Menten kinetics.

SYNTHESIS OF AN IMIDAZOLO-L-LYXO-PIPERIDINOSE DERIVATIVE

Abstract Imidazolo-L-lyxo-piperidinose 4 was synthesised from the D-galactose derivative 8 by two reaction sequences, via removal of a terminal carbon atom, stepwise incorporation of an imidazole moiety, and eventually intramolecular SN2 reaction to the corresponding piperidine ring. Piperidinose 4 proved to be a poor glycosidase inhibitor.

A simple asymmetric synthesis of 2-substituted 2,3-dihydro-4-pyridones

A pronounced asymmetric induction (d.e. = 95 %) was observed during methylation of pyridinium salt 7 with MeMgI which led ultimately to (2R) 2-methyl-2,3-dihydro-4-pyridone 9. This result is best explained by assuming chelate-control during the asymmetric alkylation step.

Increasing the inhibitory potency of L-arabino-imidazolo-[1,2]-piperidinose towards β-D-glucosidase and β-D-galactosidase

The synthesis of some potent inhibitors of two retaining β-glycosidases was achieved by introducing aglycon-mimics into the imidazole moiety of l-arabino azasugar 1. The strongest inhibition was observed with the phenyl-ethyl substituent at C(2) of 1 against β-d-galactosidase and β-d-glucosidase, whereas the hydroxymethyl group at C(2) increased only slightly the inhibitory properties.

Carbohydrate transition state mimics: synthesis of imidazolo-Pyrrolidinoses as potential nectrisine surrogates

The syntheses of four glyco-imidazoles, which are pentose-derivatives belonging to the D-series, as well as the syntheses of their L-enantiomers, are reported. Starting from the known linear xylo, lyxo, arabino, and ribo imidazolo-pentoses in both the L- and the D-series, intramolecular Walden inversion led to the corresponding arabino, ribo, xylo, and lyxo pyrrolidinopentoses in the D- and the L-series, respectively, protection and deprotection steps being unavoidable prerequisites. The structures and configurations of all eight pyrrolidinopentoses were determined unambiguously, by a combination of 1H/13C NMR spectroscopy, circular dichroism and [alpha](D) values, in conjunction with single-crystal X-ray diffraction analysis of the L-xylo stereoisomer. Examination of the inhibitory properties of these imidazolo-pyrrolidinoses against six commonly encountered glycosidases led to the conclusion that by and large the L-stereoisomers are inactive, whereas three out the four D-stereoisomers proved to be poor to moderate inhibitors. It appears therefore that the most basic N(1) atom is not located in an optimal topology to be protonated easily inside the enzymes active site.

Stereocontrolled synthesis of imidazolo[1,5]hexopiperidinoses and imidazol-4(5)-yl-C-glycosides

Abstract The syntheses of imidazolo[1,5]hexopiperidinoses 2–6 and imidazol-4(5)-yl C-glycosides 7–9 are reported. The crucial step of this approach relies upon the SN2-type cyclisation of selectively protected C(1), C(2), C(3) and C(5)-substituted 1-[imidazol-4(5)-yl]pentitols in which the imidazole nitrogen or the C(1)-connected oxygen are involved as the competitive nucleophilic centers, respectively. Six selected imidazolosugars were evaluated as potential inhibitors of glycosidases.

Stereomeric Pyrrolidinopentoses Bearing an Imidazole Ring − Synthesis, Chiroptical Properties, and Evaluation as Potential Sugar‐Mimic Glycosidase Inhibitors

The syntheses of the imidazolo-pyrrolidino-pentoses ent-2 (L-arabino), 3 (D-xylo), 4 (D-lyxo), ent-4 (L-lyxo), and 5 (D-ribo) are reported, completing the series of all eight possible stereomers. The corresponding five linear imidazolo sugar precursors were prepared by nucleophilic addition of C(4)-metallated imidazole derivatives to the appropriately configured and protected aldotetroses. Cyclisation of the resulting linear imidazolo-carbohydrates was performed by means of intramolecular Walden inversion processes, followed by deprotection to afford the five target imidazolo-sugars. Three of the four D-configured stereomers proved to be good to moderate glycosidase inhibitors, as determined by Michaelis−Menten kinetics.