Novel synthesis of the glycosidase inhibitor deoxymannojirimycin and of a synthetic precursor D-lyxo-hexos-5-ulose

[reaction: see text]. The synthesis of D-lyxo-hexos-5-ulose (5-ketomannose, 1,5-dicarbonyl sugar), a synthetic precursor to the glycoprocessing inhibitor deoxymannojirimycin, was carried out by an in situ epoxidation and hydrolysis of a trimethylsilyl-protected 6-deoxyhex-5-enopyranoside followed by facile removal of the protecting groups. A novel nine-step synthesis of deoxymannojirimycin has also been achieved from methyl alpha-D-mannopyranoside; this involved methanolysis of epoxides derived from an acetylated 1-azido-6-deoxyhex-5-enopyranoside followed by deprotection and catalytic hydrogenation.     

Asymmetric synthesis of hydroxy-skipped bishomo-inositols as potential glycosidase inhibitors

Four isomeric hydroxy-skipped bishomo-inositol analogs have been synthesized from both enantiomers of 5-hydroxymethyl-2-cyclohexenone. Sharpless asymmetric dihydroxylation and substrate-directed anionic hydroxymethylation are the key reactions which have been employed successfully for the synthesis of new cyclitols. The synthesized cyclitols have been screened for their inhibitory effect on α- and β-glycosidases.     

Synthesis of a sulfonium ion analogue of the glycosidase inhibitor swainsonine

The synthesis of a bicyclic sulfonium ion analogue of a naturally occurring indolizidine alkaloid, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, has been achieved by a multistep synthesis starting from (2S,3S,4R)-2,3-dibenzyloxy-4-formaldehyde-thiolane. The synthetic strategy relies on the intramolecular displacement of a leaving group on a pendant acyclic chain by a cyclic thioether. This bicyclic sulfonium salt provides a candidate with which to further probe the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective glycosidase inhibitor.     

Enantioselective approach to indolizidine and quinolizidine scaffolds. Application to the synthesis of peptide mimics

An enantioselective approach to substituted indolizidine and quinolizidine frameworks has been developed. Key steps of the synthesis are the enantioselective, palladium-catalyzed N-allylation of an imide, the nucleophilic allylation of an acyliminium ion and a ring closing metathesis. This general strategy has been applied to the synthesis of indolizidine peptide mimics, starting from a chiral imide derived from l-aspartic acid. It was observed that the preexisting stereogenic center of this substrate has a moderate influence on the stereoselectivity of the electrophilic allylation, which is mainly determined by the sense of chirality of the catalyst.     

Short synthesis of new salacinol analogues and their evaluation as glycosidase inhibitors

Versatile synthesis of some analogues of the naturally-occurring α-glucosidase inhibitor salacinol (1), involving thioanhydro alditol moieties with erythro, d,l-threo, xylo, ribo, d-arabino and d-manno configurations is described. Nucleophilic attack at the least-hindered carbon atom of an l- or d-protected erythritol cyclic sulfate by the thioanhydro alditol sulfur atom yielded the desired zwitterionic compounds. In addition, the preparation of the cyclic sulfates of 2,4-O-benzylidene-d-erythritol and 2,4-O-isopropylidene-l-erythritol was improved. Enzyme inhibition tests showed that most of the new compounds were weak but specific inhibitors, while good inhibitory activity was found for a six-membered ring analogue (β-glucosidase: K_i=16 μM).     

Enantioselective synthesis of new oxazolidinylthiazolidines as enzyme inhibitors

The synthesis of new oxazolidinylthiazolidines bicycles, oxygen analogues of bisthiazolidines, also known as metallo-β-lactamase inhibitors is described. The reaction of β-aminoalcohols and 2,5-dihydroxy-1,4-dithiane led to oxazolidinylthiazolidines and/or dithioazabicycles as the main products. The distribution pattern depends mainly on the aminoalcohol substituents. In a one-pot reaction, four new bonds are formed in good yields and with high atom efficiency. When the oxazolidinylthiazolidines are formed, two stereogenic centres are generated with high enantiospecificity. The reaction mechanism is discussed based on crystallographic data and interconversion studies. Two oxazolidinylthiazolidines were evaluated as inhibitors of the potent lactamase NDM-1 and compound 4f displayed competitive inhibition with K_i = 1.6 ± 0.6 μM.     

Combinatorial approaches to iminosugars as glycosidase and glycosyltransferase inhibitors

Oligosaccharide processing enzymes such as glycosidases and glycosyltransferases are important classes of biocatalysts involved in synthesising specific oligosaccharide structures on proteins and lipids. These enzymes are known to be involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins, lysosomal catabolism of glycoconjugates and inter-cellular recognition events. Inhibition of these enzymes can disrupt biosynthesis of oligosaccharides, thus interfering in all of these processes. Hence, "glyco-enzyme" inhibitors might have enormous therapeutic potential in many diseases such as viral infection, cancer and diabetes. This very important prospect has led to increasing interest and demand for these compounds. Interference in oligosaccharide processing is the basis for the anti-influenza neuraminidase inhibitors that have recently been marketed and also for the potential use of glycosidase inhibitors against HIV, Gaucher's disease, hepatitis, and cancer. Since a rational design and synthesis of inhibitors are often extremely difficult due to the limited information regarding the structure of the active site, combinatorial approaches are particularly promising. This review will focus on synthetic efforts for the preparation of combinatorial libraries of glyco-enzyme inhibitors.     

General approach to the synthesis of persubstituted hydrophilic and amphiphilic beta-cyclodextrin derivatives.

Heptakis(2,3,6-tri-O-allyl)-beta-cyclodextrin 2 was converted to heptakis[2,3,6-tri-O-(2,3-dihydroxypropyl)]-beta-cyclodextrin 3 by osmium tetroxide-catalyzed dihydroxylation. A diastereomeric mixture of 3 was treated with sodium periodate followed by sodium borohydride to give heptakis[2,3,6-tri-O-(2-hydroxyethyl)]-beta-cyclodextrin 5 in 86% yield. Compound 5 could be quantitatively transformed into heptakis(2,3,6-tri-O-carboxymethyl)-beta-cyclodextrin 6 by TEMPO-mediated oxidation. The same reaction sequence was also applied to heptakis(2,6-di-O-allyl-3-O-methyl)-beta-cyclodextrin 8, heptakis(2,3-di-O-allyl-6-O-methyl)-beta-cyclodextrin 12, and heptakis(2,3-di-O-allyl-6-O-butyl)-beta-cyclodextrin 16; the analogous corresponding hydroxyethyl and carboxymethyl derivatives were isolated in high yields. All products were proved to be chemically uniform.     

Novel approach to the zaragozic acids. Enantioselective total synthesis of 6,7-dideoxysqualestatin H5

The total synthesis of 6,7-dideoxysqualestatin H5 (3) has been completed by a concise approach that features the stereoselective intramolecular vinylogous aldol reaction of the furoic ester 25a to give 30 or its trimethylsilyl ether derivative 34, which possess the requisite absolute stereochemistry at C(3)-C(5) of 3. Compound 34 was reduced to the saturated bislactone 39, and the C(1) side chain subunit 47 was introduced leading to a mixture of the hemiacetals 48 and the corresponding ketone 49. When this mixture was stirred with methanolic acid, transketalization occurred to give a mixture of 50 and the spirocyclic methyl acetals 51a,b. Oxidation of the primary alcohol group in 50 followed by saponification of the two remaining ester groups gave 3. The longest linear sequence in the synthesis commences with commercially available erythronolactone (26) and requires 17 chemical steps with only 10 isolated intermediates.     

Enantioselective approach to functionalized quinolizidines: synthesis of (+)-julandine and (+)-cryptopleurine

An efficient synthesis of functionalized quinolizidines was developed from an enantiomerically enriched γ-nitroketone, which is easily prepared by an organocatalytic ketone-nitroalkene Michael addition. Oxidative ring expansion of the nitroketone followed by reductive ring-opening leads to a suitably functionalized nitrodiol which is an intermediate to the title compounds.     

Synthesis and evaluation of calystegine B2 analogues as glycosidase inhibitors.

A practical synthesis of polyhydroxylated 6-oxa-nor-tropanes incorporating the essential structural features of calystegine B(2) from 5-deoxy-5-thioureido and 5-ureido-L-idofuranose precursors is presented. The methodology relies on the ability of pseudoamide-type nitrogen atoms (thiourea, urea, and carbamate) to undergo nucleophilic addition to the masked aldehyde group of the monosaccharide. The generated hemiaminal functionality may further undergo in situ intramolecular glycosidation to give the bicyclic aminoacetal compounds, the whole process being favored by the anomeric effect. A series of derivatives bearing different substituents at nitrogen has been prepared and screened against several glycosidases in comparison with xylonojirimycin-type piperidine analogues. Interestingly, strong and highly specific inhibition of bovine liver beta-glucosidase was observed for 6-oxacalystegine B(2) analogues incorporating aromatic pseudoaglyconic groups. On the basis of these data, a 1-azasugar inhibition mode is proposed for this family of glycomimetics.     

Straightforward chemo-enzymatic synthesis of new aminocyclitols,analogues of valiolamine and their evaluation as glycosidase inhibitors

An efficient fructose-1,6-bisphosphate aldolase mediated synthesis of new aminocyclitol analogues of valiolamine is described. The one-pot process where four stereocentres are created involves the formation of two carbon–carbon bonds. One is catalysed by the aldolase, coupling dihydroxyacetone phosphate to nitrobutyraldehydes. The other is the result of a highly stereoselective intramolecular Henry reaction occurring on the intermediate nitroketones. Depending on the configuration of the hydroxyl which is α to the nitro group, two series of configuration are accessible. The lipase resolution of the nitroalcohol ketal, precursor of the nitroaldehyde, is presented. The inhibition properties of the aminocyclitols obtained after the reduction of the nitro group are evaluated towards five commercial glycosidases.     

Cycloaddition reactions of carbohydrate derivatives. Part V. A hetero Diels-Alder approach to swainsonine analogs

Diastereoselective hetero Diels-Alder reactions of sugar derived azomethines 4a–4g have been used for the construction of chiral piperidones 6 and 7. Configuration of the major products was 6,1′-threo in every case. The enone system of 6 and 7 was reduced diastereoselectively and subsequently swainsonine-analog hydroxyindolizidines 28–32 were prepared by an intramolecular reductive amination.     

All eight stereoisomeric D-glyconic-delta-lactams: synthesis, conformational analysis, and evaluation as glycosidase inhibitors

An efficient and general synthetic route to all eight stereoisomeric D-glycono-delta-lactams has been developed. The strategy involves, as a key step, a stereodivergent delta-lactam formation with configurational retention or inversion at C-4 of a starting gamma-lactone to lead to two epimers of delta-lactam from one parent gamma-lactone. Conformations of eight glycono-delta-lactams were examined by X-ray crystallographic analysis and molecular modeling. Analyses of conformation and glycosidase-inhibition provide useful information for the design of new glycosidase inhibitors.     

Convergent approach toward the synthesis of the stereoisomers of C-6 homologues of 1-deoxynojirimycin and their analogues: evaluation as specific glycosidase inhibitors

A new and stereoselective strategy is developed to synthesize an appropriate template 9 to obtain C-6 homologues of 1-deoxyazasugars such as 1-deoxy-D-galactohomonojirimycin (5), 1-deoxy-4-hydroxymethyl-D-glucohomonojirimycin (6), and their enantiomers. The template 9 is also used to obtain neutral nonbasic pseudo-glyconolactam (8), C-4 amino, and methyl analogues of 1-deoxy-homonojirimycin as new analogues of 1-deoxyhomoazasugars. Compound 5 is found to be a potent and specific inhibitor to alpha-galactosidase (Ki = 1.7 microM). Similarly compounds 6 (Ki= 28 microM), ent-5 (Ki= 129 microM), and ent-6 (Ki= 12 microM) exhibited specific inhibition of beta-glucosidase.     

Azidation of anomeric nitro sugars: application in the synthesis of spiroaminals as glycosidase inhibitors

6,5-Fused sugar-derived spiroaminals have been synthesized from the azido esters obtained via the nucleophilic substitution reactions of unstable Michael adducts derived from 1-nitro sugars. Most of the spiroaminals synthesized showed moderate but selective inhibitory activities toward some glycosidases.     

Synthesis of nitrogen analogues of salacinol and their evaluation as glycosidase inhibitors.

The syntheses of two nitrogen analogues (11 and 12) of the naturally occurring sulfonium ion, salacinol (7) are described. The latter compound is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of a 1,4-dideoxy-1,4-imino-D- or L-arabinitol at the least hindered carbon of 2,4-O-benzylidene D- or L-erythritol-1,3-cyclic sulfate. The nitrogen analogues bear a permanent positive charge and serve as mimics of the sulfonium ion. We reasoned that these ammonium derivatives should function in a manner similar to that of known glycosidase inhibitors of the alkaloid class such as castanospermine (4) and deoxynojirimycin (5). Enzyme inhibition assays indicate that salacinol (7) is a weak (K(i) = 1.7 mM) inhibitor of glucoamylase, whereas compounds 11 and 12 inhibit glucoamylase with K(i) values in the range approximately 10-fold higher. The nitrogen analogues 11 and 12 showed no significant inhibitory effect of either barley alpha-amylase (AMY1) or porcine pancreatic alpha-amylase (PPA) at concentrations of 5 mM. In contrast, salacinol (7) inhibited AMY1 and PPA in the micromolar range, with K(i) values of 15 +/- 1 and 10 +/- 2 microM, respectively.