Syntheses of new azepane derivatives from monosaccharides

Synthetic routes to polyhydroxy azepanes from monosaccharides are described. The stereoselective formation of trans epoxyamides and regioselective epoxyde opening led to azido derivatives that could be transformed in azepanic structures. An anomalous result was obtained in the hydrogenation in MeOH with Pd/C of the azido derivative obtained from D-mannose. INTRODUCTION.Iminosugars have received considerable attention in carbohydrates and non-carbohydrates research groups because of their remarkable biological activities. In recent years, new iminosugars with structures of polyhydroxyazepane have proved their utility as glycosidases inhibitors and as potential therapeutic agents. These compounds have been also named polyhydroxyperhydroazepines or seven-membered iminocyclitols. We are interested in obtaining those structures that contain an hydroxymethyl arm, (Fig. 1) because they mimic better the sugar structures. We have planned diverse syntheses starting from 2,3epoxyamides, which are readily obtained from monosaccharides. The methodology to be applied, assumes a completely regioselective epoxide opening with nitrogen nucleophiles. This methodology has been developed by our group in the last years, and leads to iminocompounds with different ring sizes. The deprotected derivatives will be tested in order to study their biological activities.

In recent years, new iminosugars with structures of polyhydroxyazepane have proved their utility as glycosidases inhibitors and as potential therapeutic agents. 1 These compounds have been also named polyhydroxyperhydroazepines or seven-membered iminocyclitols.
We are interested in obtaining those structures that contain an hydroxymethyl arm, (Fig. 1) because they mimic better the sugar structures.We have planned diverse syntheses starting from 2,3epoxyamides, which are readily obtained from monosaccharides.The methodology to be applied, assumes a completely regioselective epoxide opening with nitrogen nucleophiles.This methodology has been developed by our group in the last years, 2,3,4 and leads to iminocompounds with different ring sizes.
The deprotected derivatives will be tested in order to study their biological activities.

RESULTS AND DISCUSSION
One of the synthetic strategies begins with the known D-mannose derivative 1 5 (Scheme 1).
Anomeric O-alkylation with benzyl chloride afforded a mixture 6:1 of benzyl glycosides 6 2α and 2β that were separated by chromatography.The following steps of the synthetic route were accomplished with both isomers, separately.Regioselective deprotection of an isopropylidene group in the major compound 2α followed by glycol cleavage afforded aldehyde 4.This compound reacted with the amide-stabilized sulphur ylide, generated in situ (two phases media) 7 giving epoxyamide 5 as unique product.Absolute configuration was tentatively assigned by comparison with other epoxyamides previously studied. 8Epoxide ring opening with NaN 3 gave the azido derivative 6 which was reduced by several methods.
Catalytic hydrogenation of compound 6 in EtOH with Pd/C afforded aminoderivative 7, surprisingly, when the hydrogenation of 6 was carried out in MeOH with Pd/C, a new product 8, different from the normal reduction product of azido group 7 was obtained. 1H-NMR, 13 C-NMR (Fig. 2 and 3), and HRMS were concordant with the proposal structures.The insertion of methylene in a catalytic reduction is difficult to explain, and to our knowledge, there are not similar results in the literature.However, several examples of anomalous transformations of azides under hydrogenation conditions have been reported. 9Possibly, the high steric hindrance due to the isopropylidene group is responsible for that anormal behaviour.Catalytic hydrogenation of 6 in either EtOH or EtOAc under the same conditions, gave the amine 7.
The benzyl glycosides were resistant in the hydrogenation conditions.Further reaction time led to mixture of compounds.
When the reaction was carried out with HCO 2 NH 4 and Pd/C, the azepane derivative 9 was obtained in good yield.
Reduction of the amide moiety in 6 and 9 was accomplished with LiBH 4 .This reduction was faster for the tetrahydrofuran derivative 6 than for the azepane 9, giving the primary alcohols moieties in compounds 10 or 11, respectively.In order to obtain azepane rings with a different configuration 12, we chose aldehyde 13 10 that was obtained from D-glucose.In a similar way epoxyamide 14 was also obtained with complete stereoselectivity and the azido group was regioselectively introduced by reaction with NaN 3 in DMF.
Catalytic hydrogenation of this group in 15, using MeOH as solvent did not give the methylene insertion product.The normal reduction product, amine 16, was obtained.Functional group transformations in 16 will permit us to obtain the azepane 12. (Scheme 2) In conclusion, the stereoselective formation of epoxyamides from monosaccharide derivatives, permitted us the formation of azepane rings with different configurations.The formiate method, for azide and benzyl glycoside reductions, showed to be more efficient than the use of H 2 , giving properly the azepane ring.The anomalous result obtained in the catalytic hydrogenation of the compound 6 (from D-mannose), can be attributed to their steric hindrance, since the azido compound 15 from Dgluco gave the normal reduction product.