Stereospecific synthesis of N-tosyl derivatives of dihydroconduramine E-2 and ent -F-2

Conduramines, dihydroconduramines and structurally related compounds belong to an important class of glycosidase inhibitors which are essential elements of many biologically active compounds. The synthesis and characterization of N-tosyl dihydroconduramine derivatives 9a and 10a starting from cyclohexadiene were carried out in the current study. The oxazolidinone 15 was prepared by the palladium-catalyzed reaction of bis-carbamate 14, synthesized from cyclohexenediol, derived in two steps from cyclohexadiene. Hydrolysis of 15 was achieved with methanolic potassium carbonate to afford 18 and the ketalization gave 21 in good yield. Osmylation of the double bond and acid-mediated acetonide removal of 21 gave 4-methyl-N -((1 S ,2 R ,3 S ,6 S )-2,3,6-trihydroxycyclohexyl)benzenesulfonamide 9a . The epoxidation of 21 followed by acid-mediated epoxide ring opening and subsequent acetonide removal produced 4-methyl-N -((1 S ,2R,3 R ,6 S )- 2,3,6-trihydroxycyclohexyl)benzenesulfonamide 10a . The molecules may be evaluated for biological activity.


Introduction
2][3][4] The possibility of modifying or blocking these processes using glycosidaseinhibiting sugar mimics for biological and therapeutic applications has attracted much attention, 5,6 especially in relation to cancer, 7,8 viral infection, 9,10 genetic disorders, [11][12][13] diabetes 14 and obesity. 15he biomedical and biotechnological applications of glycosidase-inhibiting sugar mimics have been reviewed. 16Inhibitors of glycoside-processing enzymes share structural homology with the natural enzymatic substrates that are often aminohydroxy-substituted five or six-membered heterocyclic rings. 17,18[30]  These features contribute to the importance of conduramines and have motivated the efforts made towards the development of new and efficient synthetic routes.Synthesis of conduramines 7 and 8, their dihydroconduramines analogues 9 and 10, and N-tosyl derivatives 9a and 10a have not yet been described (Figure 2). 31onsequently in the current study we report the synthesis and characterization of N-tosyl dihydroconduramine derivatives ()9a and ()10a starting from cyclohexadiene.The compounds 9a and 10a are likely to have similar biological activities with their analogues and may be used as intermediates for the synthesis of new biologically active substances.

Results and Discussion
The oxazolidinone 15 was first prepared by the palladium-catalyzed reaction of bis-carbamate 14, that was available from cyclohexadiene in three steps (Scheme 1).The starting material cyclohexene endoperoxide 12 was synthesized from the photooxygenation reaction of 1,3-cyclohexadiene 11 as reported by Balci. 32The endoperoxide 12 was performed with thiourea under mild conditions to give diol 13 in quantitative yield.In this reaction, since only the oxygen-oxygen bond in 12 was cleaved, the configurations of carbon atoms were preserved.The reaction of diol 13 with 2 equivalents of toluenesulfonyl isocyanate formed bis-carbamate 14. 33 The palladium-catalyzed desymmetrization of bis-carbamate 14 was confirmed to give the monosubstitution product oxazolidin-2-one 15.The mechanism of this desymmetrization reaction has been reported by Trost (Scheme 2). 34,35

Scheme 2
The bis-carbamate 14 was treated with 2.5 mol% of palladium catalyst solution that was prepared with tris (dibenzylideneacetone)-dipalladium chloroform complex and 7.5 mol % of the ligand triisopropylphosphine. 36The mixture was purified by chromatography on a silica gel column with CH2Cl2/hexane (30:70) as eluent to give oxazolidinone 15 in 40% yield.The structure of 15 was confirmed by 1 H and 13 C NMR spectroscopy.Initially, for the synthesis of N-tosyl derivatives of dihydroconduramine E-2 and ent-F-2, direct epoxidation and cis-dihydroxylation of the double bound in 15 was attempted with m-CPBA and catalytic osmium tetraoxide at various temperatures and durations, however both reactions were unsuccessful.
As a second strategy, cis-aminoalcohol 18 was prepared by the hydrolysis of 15 with methanolic potassium carbonate.The compound 18 was converted into acetate 19 by the treatment with AcCl in methylene chloride.The dihydroxylation of 19 was obtained as a mixture of 9a and 9b isomers, and the epoxidation of 19 also formed a mixture of 20a and 20b isomers.The results of 1  NMR showed that 9a was the main product of the first reaction and 20a was the main product of the second reaction (Scheme 3).Since the aim of this study was the stereospecific synthesis of N-tosylhydroconduramine derivatives 9a and 10a, we followed the third strategy for their synthesis (Scheme 4).In order to decrease the conformational flexibility of the cyclohexene skeleton and to influence the further stereoselective transformations, the ketalization of 18 was conducted.The bicyclic ring is cis-fused and the methyl groups of the oxazolidine 21 that point above the plane of the olefin may also force the electrophile to approach anti, thus reinforcing the anti directing effect of the allylic amino moiety. 37Such a directing effect may also rationalize the stereochemical outcome of both the osmylation of 21 followed by acid-mediated acetonide removal, which provides (±)9a as a single isomer and the epoxidation of 21, which provides 22 as a single isomer.In addition, the steric and conformational effects of the bicyclic ring system influenced stereoselectivity of the epoxide opening reaction.Thus, acid-mediated epoxide ring opening and subsequent acetonide removal of 22 obtained (±)10a as a single isomer.Compounds (±)9a and (±)10a were characterized by 2D spectroscopy, namely COSY, NOESY as well as by the 13 C NMR data.Careful examination of all these reaction mixtures did not reveal the formation of any other diastereoisomer.
In conclusion, we have described syntheses of N-tosyl derivatives of dihydroconduramine E-2 and ent-F-2 that can be used for various biological studies.

Experimental Section
General.Solvents were purified and dried by the standard procedures before use.Melting points were determined on Electrotermal BI-9100 capillary melting apparatus and uncorrected.The 1 H and 13 C NMR spectra were recorded on a 300 (75) MHz Varian spectrometer.Infrared spectra were obtained from Shimatzu Fourier Transform Infrared Spectrophotometer (IR Prestige-21, 200VCE).Column chromatography was performed on silica gel 60 (70-230 mesh).Thin layer chromatography was carried out on Merck 0.2 mm silica gel, 60 F254 analytical aluminum plates.