Imino sugar

Jager and coworkers have used the TBAF catalyzed-stereoselective niho-aldol reaction for the synthesis of cyclic amino alcohols such as iminopolyols, imino sugars, and cyclic amino acids. They are important classes of compounds and have the potential utility as anh-diabetic. 

Triazoline imino sugar derivatives 297 that are prospective glycosidase inhibitors have been prepared as single diastereomers in high yield via an lAOC reaction of in situ generated azido alkene 296 (Eq. 32) [78]. m-CPBA oxidation of the dithioacetal groups in the 0-acetylated 5-azido-5-deoxydibenzyl dithio-acetal of o-xylose or D-ribose 294 to the bis-sulfone 295, followed by loss of HOAc between C-1 and C-2 provided the lAOC precursor 296. 

There is considerable interest in imino-sugars and analogues as glycosidase enzyme inhibitors. The synthesis of a "homonojiritriazole" derivative 35 has now been reported... 

One last approach to thionocarbamates on carbohydrate scaffolds was developed in D-Fru series the intermediate imino sugar (2R,3R,4R,5R)-2,5-bis(hydroxymethyl)-3,4-dihydroxypyrrolidine (DMDP) obtained in... 

Henry reaction of nitro sugar 11 with formaldehyde allowed the introduction of two hydroxymethyl groups at the carbon bearing the nitro group, and hence opened a specific route for the preparation of branched-chain imino sugar 57 and analogues (Scheme 20).44... 

Thus, treatment of 11 with paraformaldehyde and TBAF in THF provided the novel branched-chain nitro sugar 54. Reduction of its nitro group to the amino group of 55 followed by deprotection of its anomeric position, resulted in the amine 56, that finally led to compound 57, the first reported branched-chain seven-membered imino sugar, after a synthetic sequence consisting of a reductive amination. 

Several, optically pure imino sugars have been synthesised by Fleet25 from simple mono-saccharides in a short, high yield synthetic sequences. The novelty of the presented approach involved an application of benzhydryl protecting group which allowed to avoid epimerisation at C-2 (Fig. 14). 

Fig. 14 Application of benzhydryl protecting group for the efficient synthesis of imino sugars.

The same group proposed also a general route to carbocycles of type 49.31 Starting from D-glucose, the precursor 46 was prepared in a few standard steps it could be used either for the synthesis of imino sugars or carbocycles... 

Replacement of the endocyclic oxygen with a nitrogen imino sugars... 

The replacement of the endocyclic oxygen of the sugar with a nitrogen atom generates a class of compounds defined imino sugars. 

Fig. 31 Examples of imino sugars nojirimicin, an antibiotic produces by several Streptomyces, Zavesca and Glyset, drug on the market.

The bioactivity of imino sugars is due to the fact that they inhibit glycosidases. Once protonated, the imino sugar mime the oxonium ion intermediate of the reaction catalysed by those enzymes (Fig. 32), and therefore binds the active site. 

Recently, imino sugars have found application as active site specific chaperones (ASSC) for the treatment of lysosomial storage disorders.65 An ASSC is a small molecule that bind the catalytic domain of an enzyme inducing the regeneration of the active conformation of misfolded proteins. 

In other words, beside the possibility to inhibit an active enzyme there is the possibility to use very low concentrations of an imino sugars to activate an inactive (misfolded) enzyme. 

The synthesis of an imino sugars can start from the parent sugar, in order to take advantage of the chirality and functionalisation of the part of the molecule not involved in the transformation. In this case the conversion requires (a) introduction of nitrogen, (b) cyclization. A feature of imino sugars must be taken into consideration in order to be stable they must lack of the anomeric oxygen. 

Fig. 33 General retrosynthetic scheme for imino sugars synthesis.

Fig. 34 Example of synthesis of an imino sugars by contemporaneous insertion of the nitrogen on the two carbons involved in the piperidine cycle.

The synthesis of imino sugars has been performed from non-carbohydrate starting materials. For example, a substituted pyridine has been used for an asymmetric synthesis of deoxynojirimicin (Fig. 37).68... 

Another example, in which the piperidine cycle is generated de novo, exploits a hetero Diels-Alder cycloaddition of 1 -/r-tolylsulfinyl-1,3-penta-diene 91 with benzylnitrosoformate, that generates an oxazine 92 with complete regioselectivity and 7i-facial diastereoselectivity.69 Osmilation of the double bond inserts stereoselectively two hydroxyl groups on the oxazine skeleton, protection and catalytic hydrogenation finally afforded the enantiomerically pure imino sugars 94 (Fig. 38). 

Fig. 37 Example of synthesis of an imino sugars starting from an achiral non-carbohydrate precursor. Reagents and conditions (a) BnOCH2(2-thienyl)CuCnLi2, THF, —78 °C 10% HC1 (b) NaOMe, MeOH, reflux HC1, i-PrOH (c) n-BuLi, PhOCOCl, THF, -78 °C (d) Pb(OAc)4, toluene, reflux (e) HC1, EtOH (f) Me4NBH(OAc)3, acetone, AcOH (g) 0s04, NMO (h) Pd(OH)2, H2.

Fig. 38 Synthesis of imino sugars via Diels-Alder cycloaddition on sulfinyl pentadiene. Reagents and conditions (a) CH2Cl2, -78 °C to 0 °C (b) 0s04, NMO (c) DMP, PTSA (d) Pd/C, H2 (e) ClC02Bn.

Fig. 39 Chemoenzymatic synthesis of imino sugars exploiting fructose 1,6-diphosppate (FDP) aldolase.

The anomeric appendage of imino sugars has been exploited to generate mimics of glycoconjugates. An example is reported in Fig. 42 for the synthesis of nojirimycinyl C-(L)-serine 109,73 in which the ozonolysis of the allylic appendage generates the aldehydes 106, on which the aminoacidic moiety was inserted by Wittig-Horner reaction. 

Fig. 44 Examples of naturally occurring bicyclic imino sugars.

A variety of naturally occurring imino sugars presenting interesting biological activity, such as castanospermine, swainsonine or australine are bicyclic compounds (Fig. 44). 

In order to modify the anomeric reactivity, also the anomeric carbon as been replaced with a different atom. The most studied case is that of the so defined 1-azasugars, in which a nitrogen is located at the anomeric position.81 Such compounds, like imino sugars to which are strictly related, are able to inhibit glycosidases. Interestingly, the presence of the trivalent... 

---