Albert Defoin

Chiral 5-Methyl-trihydroxypyrrolidines—Preparation from 1,2-Oxazines and Glycosidase Inhibitory Properties

Abstract Chemical transformations of chiral 1,2-oxazines 4, 5 gave the 2,5,6-trideoxy-2,5-imino d -alditols 12b, 13b in the d -altritol and d -talitol series, respectively. Basic aldehyde epimerisation led to the d -allitol isomer 15b. Compound 12b is a potent α- l -fucosidase and α- d -galactosidase inhibitor.

Asymmetric synthesis of potent glycosidase and very potent α-mannosidase inhibitors: 4-amino-4-deoxy-l-erythrose and 4-amino-4,5-dideoxy-l-ribose

Abstract Pyrrolidine amino-sugars, cyclic iminoalditols as well as linear aminoalditols in 4-amino- l -erythrose and 4-amino-5-deoxy- l -ribose series were synthesised by asymmetric hetero-Diels–Alder reaction followed by chemical transformations. 4-Amino-4-deoxy- l -erythrose and 4-amino-4,5-dideoxy- l -ribose were potent β- d -glucosidase, α- d -mannosidase, α- and β- d -galactosidase inhibitors. We have shown that the ribose derivative was a very potent inhibitor of α- d -mannosidase.

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.

Asymmetric Diels-Alder cycloadditions with acylnitroso dienophiles obtained from L-proline

Abstract N-acylnitroso derivatives of L-proline were formed in situ from the corresponding hydroxamic acids. They reacted easily with 1,3-cyclohexadiene to give the corresponding diastereoisomeric pairs of Diels-Alder cycloadducts with d.e. values ranging from 52 to 68 %.

Two-photon absorption and polymerization ability of intramolecular energy transfer based photoinitiating systems.

We design a new photoinitiating system where the two-photon absorption of a 2,7 bisaminofluorene moiety leads to the photoactivation of a camphorquinone subunit through a Förster-type intramolecular energy transfer: the application to a two-photon polymerization reaction is demonstrated.

6-Deoxy-allo-nojirimycin in the racemic and d-series, 6-deoxy-d,l-talo-nojirimycin, their 1-deoxyderivatives and 6-deoxy-2-d,l-allosamine via hetero-Diels-Alder cycloadditions

Abstract Diels-Alder cycloaddition of hexadienal dimethylacetal 3 to achiral acylnitroso-dienophile 5a gave the racemic cycloadducts 7a-c and, to chiral chloronitroso-dienophile 6, enantiomerically pure D-10a as sole adduct. Simple chemical transformations led to 6-deoxy-2- d,l -allosamine 15b, to 6-deoxy- d,l and d -allo-nojirimycin 15a, D-15a, to 6-deoxy- d,l -talo-nojirimycin 15c as well as to their 1-deoxy-derivatives 16a, D-16a, 16c via their crystalline 1-deoxy-1-sulfonic acid derivatives (sulfite adducts). Amino-sugars 16a,c are mixtures of α- and β-anomers and of the corresponding imines.

Amino-benzosuberone: A novel warhead for selective inhibition of human aminopeptidase-N/CD13

This paper describes the design and synthesis of compounds belonging to a novel class of highly selective mammalian CD13 inhibitors. Racemic homologues of 3-amino-2-tetralone 1 were synthesised and evaluated for their ability to selectively inhibit the membrane-bound, zinc-dependent aminopeptidase-N/CD13 (EC 3.4.11.2). Some of these novel non-peptidic compounds are potent, competitive inhibitors of the mammalian enzyme, with K(i) values in the low micromolar range in spite of their minimal size (MW <200 Da). Moreover, they show an interesting selectivity profile against representative members of the aminopeptidase family, that is leucine aminopeptidase (EC 3.4.11.1), Aeromonas proteolytica aminopeptidase (EC 3.4.11.10) and the aminopeptidase activity of leukotriene A4 hydrolase (EC 3.3.2.6). The amino-benzosuberone derivative 4 is the most promising compound in terms of potency, stability and selectivity. A hypothetical binding mode of 4 to the catalytic zinc and several conserved active site residues is proposed, based on the observed structure-activity relationships, structural insights from aminopeptidase-N homologues of known three-dimensional structure.

CHIRAL N-DIENYL-L-PYROGLUTAMIC ESTERS IN ASYMMETRIC HETERO-DIELS-ALDER REACTIONS WITH ACYLNITROSO DIENOPHILES

Abstract Asymmetric Diels-Alder reaction of the N-dienyl-L-pyroglutamic esters 1a-h with acyl nitroso dienophiles 4a-h gave diastereoisomeric adducts 6a-n, 7a-n with 12–90 % de, depending on solvents and temperature. An interpretation was gived. The “allylic effect” ( π C=C − σ ∗ N-C MO interactions) was found to be effective to account for the conformations of the adducts.

One-pot structural conversion of magadiite into MFI zeolite nanosheets using mononitrogen surfactants as structure and shape-directing agents

MFI-type materials with a lamellar morphology were successfully synthesized by using mononitrogen surfactants specifically designed by molecular modelling. The mononitrogen surfactants directed the recrystallization of a crystalline layered polysilicate formed in situ, the magadiite, into a zeolite ZSM-5. Moreover, the surfactants allow the preservation of the lamellar shape of the magadiite and inhibit a further growth into one dimension, leading to the formation of zeolite ZSM-5 nanosheets with a thickness comprised between 2 and 3 nm and a Si/Al ratio of 24. This simple approach paves a new way for obtaining zeolite materials of controlled size and shape for specific catalytic applications.

Synthesis of 4-amino-4,5-dideoxy-l-lyxofuranose derivatives and their evaluation as fucosidase inhibitors

The nitrone 4 (4,5-dideoxy-4-hydroxylamino-3,4-O-isopropylidene-L-lyxofuranose) was synthesised from D-ribose and used as key intermediate for the preparation of fucosidase inhibitors. We describe two transformations of 4. Hydrolysis with aqueous sulfur dioxide gave the known potent nanomolar inhibitor 4-amino-4,5-dideoxy-L-lyxofuranose (3). 1,3-Dipolar cycloaddition with enol ethers led to the related 1,2,5,6-tetradeoxy-2,5-imino-L-altroheptonic ester 2a, acid 2b and the corresponding heptitol 2c. The new iminosugars have been evaluated for their inhibitory activity against α-L-fucosidase from bovine kidney. The alcohol 2c turned out to be a potent inhibitor in the same range as the amino-sugar 3 (K(i)=8 vs 10nM).