Hans Peter Wessel

Reduction of arenediazonium salts by tetrakis(dimethylamino)ethylene (TDAE): Efficient formation of products derived from aryl radicals

Summary Tetrakis(dimethylamino)ethylene (TDAE 1), has been exploited for the first time as a mild reagent for the reduction of arenediazonium salts to aryl radical intermediates through a single electron transfer (SET) pathway. Cyclization of the aryl radicals produced in this way led, in appropriate substrates, to syntheses of indolines and indoles. Cascade radical cyclizations of aryl radicals derived from arenediazonium salts are also reported. The relative ease of removal of the oxidized by-products of TDAE from the reaction mixture makes the methodology synthetically attractive.

Inhibition of Selectin-mediated Cell Adhesion and Prevention of Acute Inflammation by Nonanticoagulant Sulfated Saccharides STUDIES WITH CARBOXYL-REDUCED AND SULFATED HEPARIN AND WITH TRESTATIN A SULFATE

Selectins play a major role in the inflammatory reaction by initiating neutrophil attachment to activated vascular endothelium. Some heparin preparations can interact with L- and P-selectin; however, the determinants required for inhibiting selectin-mediated cell adhesion have not yet been characterized. We now report that carboxyl-reduced and sulfated heparin (prepared by chemical modifications of porcine intestinal mucosal heparin leading to the replacement of carboxylates by O-sulfate groups) and trestatin A sulfate (obtained by sulfation of trestatin A, a non-uronic pseudo-nonasaccharide extracted from Streptomyces dimorphogenes) exhibit strong anti-P-selectin and anti-L-selectin activity while lacking antithrombin-mediated anticoagulant activity.In vitro experiments revealed that both compounds inhibited P-selectin- and L-selectin-mediated cell adhesion under laminar flow conditions. Moreover, carboxyl-reduced and sulfated heparin and trestatin A sulfate were also active in vivo, as assessed by experiments showing 1) that microinfusion of trestatin A sulfate reduced by 96% leukocyte rolling along rat mesenteric postcapillary venules and 2) that both compounds inhibited (by 58–81%) neutrophil migration into thioglycollate-inflamed peritoneum of BALB/c mice. These results indicate that nonanticoagulant sulfated saccharides targeted at P-selectin and L-selectin may have therapeutic potential in inflammatory disorders.

Comparison of catalysts in α-glucosylation reactions and identification of triflic anhydride as a new reactive promoter

Triflic anhydride is shown to be a highly reactive promoter in the cisglycosylation reaction of 2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl fluoride with an unreactive glycosyl acceptor.

Use of Trifluoromethanesulfonic Acid in Fischer Glycosylations

Abstract The Fischer glycosylation1 is one of the standard reactions in carbohydrate chemistry, in which a reducing sugar is reacted under acid catalysis with a simple alcohol to give a glycoside. Hydrochloric acid is the classical catalyst, but other proton, Lewis acid, or acid form ion echange resins have also been used. Now, the use of trifluoromethanesulfonic acid (triflic acid) as a catalyst is communicated.

Heparin, carboxyl-reduced sulfated heparin, and Trestatin A sulfate. Antiproliferative and anticoagulant activities

Human smooth muscle cells were used to investigate the antiproliferative activities of sulfated carbohydrates. The antiproliferative potencies of coarse heparin fractions prepared by ultrafiltration increased with the mean molecular-weight, whereas the anticoagulant activities of a high-molecular-weight fraction had submaximal values. Furthermore, the dependence of antiproliferative activity on sulfate content is discussed. Carboxyl-reduction of heparin abolished both antiproliferative and anticoagulant activities. Sulfation of this compound yielded CRS-heparin with restored antiproliferative potency but devoid of antithrombin III-mediated anticoagulant activity. Sulfation of the pseudo-nonasaccharide, Trestatin A, yielded a compound having the highest antiproliferative activity, so far observed for a low-molecular-weight compound, and having only weak anticoagulant properties.

Aryl- and heteroaryl-substituted aminobenzo[a]quinolizines as dipeptidyl peptidase IV inhibitors.

Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.

Novel oligosaccharide mimetics by solid-phase synthesis

The amide-linked tetrasaccharide mimetic 8 is synthesised on a solid phase support from a carbohydrate amino acid building block without hydroxy protection using activation with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU)

ISOLATION OF DI(HYDROXYMETHYL)DIHYDROXYPYRROLIDINE FROM THE CYANOBACTERIAL GENUS CYLINDROSPERMUM THAT EFFECTIVELY INHIBITS DIGESTIVE GLUCOSIDASES OF AQUATIC INSECTS AND CRUSTACEAN GRAZERS1

An effective glucosidase inhibitor was isolated from the cyanobacterial genus Cylindrospermum. Its chemical structure was determined by MS and NMR spectrometry to be di(hydroxymethyl)dihydroxypyrrolidine (DMDP; 2(R),5(R)‐bis‐(hydroxymethyl)‐3(R), 4(R)‐dihydroxypyrrolidine). Its identity was established by comparison with an authentic compound. All five species of Cylindrospermum investigated synthesized this compound but accumulated it to a different extent intracellularly. Particularly active producers were the axenic C. licheniforme (22 pmol·nmol chl a− 1 ) and a monoxenic unknown species of Cylindrospermum that contained the maximum amount (159 pmol·nmol chl a− 1 ). The major part of DMDP was found to be extracellular for all species investigated. The isolated compound inhibited digestive α‐ and β‐glucosidases isolated from crustacean zooplankton (IC50 19 and 49 nM, respectively). The bacterial 1‐deoxynojirimycin, which was used as a well‐studied reference glucosidase inhibitor, was less inhibitory (IC50 520 and 2190, respectively). Digestive enzymes of macrozoobenthos (chironomids, trichoptera, and ephemeroptera) were less sensitive to DMDP. The insect digestive β‐glucosidase was more effectively inhibited than the α‐glucosidase. Beside others, the ecological function of the glucosidase inhibitor may be the reduction of the digestibility of the cyanobacterium for grazers.

α-Glucosylation Reactions with 2,3,4,6-Tetra-O-Benzyl-β-D-Glucopyranosyl Fluoride and Triflic Anhydride as Promoter

ABSTRACT Triflic anhydride is a suitable promoter for the glucosylation of glycosyl aceptors of medium or low reactivity using 2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl fluoride as donor. In the glucosylation of reactive hydroxyl groups competing triflate formation was observed. The use of molecular sieves as acid scavenger allows the formation of triflates of reactive alcohols under non-basic conditions.

Conformational flexibility in highly sulfated β-d-glucopyranoside derivatives

Abstract Triggered by findings on heparin-like disaccharides, the conformation of sulfated glucopyranosides was investigated. Sodium (methyl 2,3,4-tri- O -sulfonato-β- d -glucopyranosid)uronate tetrasodium salt is in a conformational equilibrium, to which a non-chair conformation contributes. The same is true for methyl (methyl 2,3,4-tri- O -sulfonato-β- d -glucopyranosid)uronate trisodium salt, methyl 2,3,4,6-tetra- O -sulfonato-β- d -glucopyranoside tetrasodium salt, and octa- O -sulfonato-β,β-trehalose octasodium salt, with less obvious non-chair contributions. The effect is charge related. The conformational effect, which does not occur in analogous α- d -glucopyranoside derivatives, is discussed in terms of the anomeric effect.