Synlett 2013; 24(17): 2271-2273
DOI: 10.1055/s-0033-1339843
letter
© Georg Thieme Verlag Stuttgart · New York

Improved Synthesis of 6-Azido-6-deoxy- and 6,6′-Diazido-dideoxy-α,α-trehaloses

Mina R. Narouz
a   Department of Chemistry, Faculty of Science, Damanhour University, Damanhour, Beheira, Egypt
,
Sameh E. Soliman
b   Department of Chemistry, Faculty of Science, Alexandria University, Ibrahimia, PO Box 426, Alexandria 21321, Egypt   Fax: +203(487)0564   Email: mina4na@yahoo.com
c   NIDDK, LBC, National Institutes of Health, Bethesda, MD 20892-0815, USA
,
Rafik W. Bassily
b   Department of Chemistry, Faculty of Science, Alexandria University, Ibrahimia, PO Box 426, Alexandria 21321, Egypt   Fax: +203(487)0564   Email: mina4na@yahoo.com
,
Ramadan I. El-Sokkary
b   Department of Chemistry, Faculty of Science, Alexandria University, Ibrahimia, PO Box 426, Alexandria 21321, Egypt   Fax: +203(487)0564   Email: mina4na@yahoo.com
,
Adel Z. Nasr
a   Department of Chemistry, Faculty of Science, Damanhour University, Damanhour, Beheira, Egypt
,
Mina A. Nashed*
b   Department of Chemistry, Faculty of Science, Alexandria University, Ibrahimia, PO Box 426, Alexandria 21321, Egypt   Fax: +203(487)0564   Email: mina4na@yahoo.com
› Author Affiliations
Further Information

Publication History

Received: 14 July 2013

Accepted after revision: 22 August 2013

Publication Date:
23 September 2013 (online)

 


Abstract

An efficient synthesis of 6-azido-6-deoxy and 6,6′-diazido-dideoxy-α,α-trehalose derivatives was achieved by reaction of trifluoromethanesulfonic anhydride with partially trimethylsilylated heptakis- and hexakis-O-(trimethylsilyl)-α,α-trehalose in the presence of pyridine and 4-(N,N-dimethylamino)pyridine. Displacement with azide and desilylation afforded the title compounds, which represent potential precursors for the corresponding 6-amino- and 6,6′-diamino-trehaloses.


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In a previous communication, we reported the synthesis of trehalose esters of corynomycolic acid, the simplest of the mycolic acids, for studies of trehalose-mycoloyl transferase.[1] [2] We also reported the synthesis of a gluco-galacto analogue of trehalose for the same purpose.[3,4] Trehalosamines have been isolated from microorganisms and been synthesized and found to have antimicrobial activity,[5,6] and several groups of investigators have recently reported the syntheses of 6-amino- and 6,6′-diamino-α,α-trehalose.[7] [8] [9] In the present study, we describe a convenient synthesis of 6-azido- and 6,6′-diazido-α,α-trehalose compounds in which we have used the triflate derivatives of the partially trimethylsilylated-α,α-trehaloses, displacing the trifluoromethanesulfonate group by azide in the presence of a crown ether in N,N-dimethylformamide at room temperature.

As shown in Scheme [1], partially protected trehalose derivatives 2 and 3 were obtained from the known 2,3,4,6,2′,3′,4′,6′-octakis-O-(trimethylsilyl)-α,α-trehalose (1) by controlled alkaline hydrolysis.[1] [10] The 2,3,4,2′,3′,4′-hexakis-O-(trimethylsilyl)-α,α-trehalose 2 was obtained from 1 as described by Toubiana et al. [methanolic K2CO3 solution for 2 h at 0 °C].[10] This hexakis ester 2 was isolated by direct crystallization in excellent yield (90%).[11] On the other hand, 2,3,4,2′,3′,4′,6′-heptakis-O-(trimethylsilyl)-α,α-trehalose 3 was prepared from 1 following the method developed by Anderson et al. [methanolic K2CO3 solution for ca. 20 min at 0–4 °C].[1] The yield of 3 was limited by the symmetry of its precursor, but a better than expected value of 65% was achieved. Isolation of 3 required chromatography; however, the unchanged starting material 1, and any over-hydrolyzed product could be recovered for recycling.

Zoom Image
Scheme 1 Synthesis of 6-azido-6-deoxy- and 6,6′-diazido-dideoxy derivatives of α,α-trehalose, and related compounds

The hexakis-O-(trimethylsilyl)-α,α-trehalose 2, thus obtained, permitted the synthesis of symmetrically substituted trehaloses. Hence, acylation of the 6,6′-OH groups of 2 with trifluoromethanesulfonic anhydride (triflic anhydride) gave 6,6′-ditriflate derivative 4 in almost quantitative yield.[12] Reaction of the latter compound with sodium azide in N,N-dimethylformamide in the presence of dicyclopentano-15-crown-5 at ambient temperature gave 6-azido-6-deoxy-2,3,4-tri-O-(trimethylsilyl)-α-d-glucopyranosyl-(1→1)-6-azido-6-deoxy-2,3,4-tri-O-(trimethylsilyl)-α-d-glucopyranoside (5).[13] The combination of triflate as the leaving group and azide as the nucleophile, in the presence of crown ether, provided an excellent yield of the displacement product 5.

Desilylation of 5 afforded crystalline 6,6′-diazido-dideoxy-α,α-trehalose 6 in 65% overall yield from 2.[14] The characterization of 6 was based on 1H NMR spectroscopic analysis; irradiation of the 5,5′-H resonance at δ = 3.94–3.90 ppm simplified the triplet at δ = 3.40 ppm to a doublet (J = 9.5 Hz, H-4,4′) and simplified the double double doublet at δ = 3.56 ppm into a double doublet (H-6a,b,6′a,b), indicating a symmetrical structure for which the 1,1-H signal was observed as a doublet with a small coupling constant (J = 4.0 Hz).

Acetylation of 6 afforded hexa-acetyl derivative 7 in almost quantitative yield. The structure of 7 was again confirmed by 1H NMR spectroscopy, indicating a symmetrical structure for which the signal of the 1,1′-H appeared as a doublet with a small coupling constant (J = 4.0 Hz) at δ = 5.34 ppm and the ring protons, except for (6a,b,6′a,b-H) were shifted downfield. Irradiation of the H-2,2′ resonance at δ = 5.09 ppm simplified the triplet at δ = 5.48 ppm to a doublet with a large coupling (H-3,3′), and collapsed the doublet at δ = 5.34 ppm to a singlet (H-1,1′). Irradiation of the H-4,4′ resonance at δ = 5.00 ppm collapsed the triplet at δ = 5.48 ppm to a doublet (H-3,3′) and simplified the multiplet at δ = 4.12–3.99 ppm (H-5,5′).

In an analogous manner, heptakis-O-(trimethylsilyl)-α,α-trehalose 3 was also converted into 6′-triflate 8, which, on treatment with sodium azide, afforded 6′-azido-6′-deoxy-α,α-trehalose derivative 9.[12] [13] Desilylation of 9 afforded crystalline 6′-azido-6′-deoxy-α,α-trehalose (10; 56% overall yield from 3).[14] The characterization of 10 was based on 1H NMR spectroscopy, indicating an unsymmetrical structure for which the signals for H-1 and H-1′ appeared as two doublets at δ = 5.15 ppm (J = 4.5 Hz) and δ = 5.14 ppm (J = 4.0 Hz), respectively. In the 1H NMR spectrum of hepta-acetyl derivative 11, all the ring proton signals were shifted downfield except the signal of H-6′a,b carrying the azido group.

The 1H NMR spectrum of unsymmetrical trehalose disaccharide 10 possesses a combination of the features of both the 6,6′-diazido derivative 6 and the unsubstituted α,α-trehalose. A noteworthy feature of the 1H NMR spectrum of 11 is that it is similar to that of 7, with additional signals at δ = 5.51 (t, 3′-H), 5.32 (d, 1′-H), 5.07 (t, 4′-H-), 5.05 (dd, 2′-H), 4.27 (dd, 6′a-H), 4.11–4.07 (m, 5′-H), 4.01 (dd, 6′b-H), and an additional methyl signal at δ = 2.04 ppm (s, 3H, COCH3).

In summary, we have investigated the azido-triflate displacement of readily prepared heptakis- and hexakis-O-(trimethylsilyl) derivatives of α,α-trehalose as a practical route to obtain the corresponding mono- or diazido analogues.


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Supporting Information

  • References and Notes

  • 1 Datta AK, Takayama K, Nashed MA, Anderson L. Carbohydr. Res. 1991; 218: 95
  • 2 Sathyamoorthy N, Takayama K. J. Biol. Chem. 1987; 262: 13417
  • 3 Bassily RW, El-Sokkary RI, Silwanis BA, Nematalla AS, Nashed MA. Carbohydr. Res. 1993; 239: 197
  • 4 Bassily RW, El-Sokkary RI, Youssef RH, Assad AN, Nashed MA. Spectrosc. Lett. 1997; 30: 849
  • 5 Youssef RH, Bassily RW, Assad AN, El-Sokkary RI, Nashed MA. Carbohydr. Res. 1995; 277: 347
  • 6 Naganawa H, Usui N, Takita T, Hamada M, Maeda K, Umezawa H. J. Antibiot. 1974; 27: 145
  • 7 De Bona P, Giuffrida ML, Caraci F, Copani A, Pignataro B, Attanasio F, Cataldo S, Pappalardo G, Rizzarelli E. J. Pept. Sci. 2009; 15: 220
  • 8 Cucinotta V, Gluffrida A, Maccarrone G, Messina M, Pulisi A, Vecchio G. Electrophoresis 2007; 28: 2580
  • 9 Wang M, Tu PF, Xu ZD, Yu XL, Yang M. Helv. Chim. Acta 2003; 86: 2637
  • 10 Toubiana R, Das BC, Defaye J, Mompon B, Toubiana MJ. Carbohydr. Res. 1975; 44: 308
  • 11 Liav A, Goren MB. Carbohydr. Res. 1986; 155: 229
  • 12 General procedure for sulfonylation: To a dry round-bottom flask, equipped with a magnetic stirring bar, was added trimethylsilylated trehalose 2 or 3 (1 equiv), and a catalytic amount of 4-dimethylaminopyridine (DMAP) and the vessel was sealed with a rubber septum and subjected to high vacuum for 2–3 h to ensure anhydrous conditions. Anhydrous CH2Cl2 (10 mL/g) and pyridine (5 equiv for each OH) were added and the reaction mixture was stirred for 15 min at room temperature, and then cooled to –5 °C. Triflic anhydride (2.5 equiv for each OH) was injected dropwise with stirring while the reaction mixture was continually maintained at –5 °C. The reaction mixture was then allowed to warm gradually to room temperature and stirred for a further 30 min, when TLC (toluene–EtOAc, 19:1) showed the absence of starting material. The mixture was diluted with CH2Cl2, filtered, washed successively with cold aq HCl (1%), aq NaHCO3 (5%), and water, dried (Na2SO4), filtered and evaporated to give an amorphous solid that was used for the next step without further purification.
  • 13 General procedure for displacement reaction: To a solution of trehalose derivative 4 or 8 (1 equiv) in anhydrous N,N-dimethylformamide (3 mL/g) were added dicyclopentano-15-crown-5 (0.15 equiv for each OH) and anhydrous sodium azide (3 equiv for each OH). The suspension was stirred at room temperature, and reaction was shown to be complete after 2 h by TLC (toluene–EtOAc, 19:1). The mixture was then diluted with CH2Cl2 and then processed by conventional work-up.
  • 14 General procedure for deprotection: Compound 5 or 9 was dissolved in a mixture of trifluoroacetic acid–tetrahydrofuran–water (8:17:33) and kept at room temperature until TLC analysis showed the hydrolysis to be complete (ca. 1 h). The product was purified by chromatography on silica, eluting successively with hexane–diethyl ether (19:1) and EtOAc–1-propanol (9:3).

  • References and Notes

  • 1 Datta AK, Takayama K, Nashed MA, Anderson L. Carbohydr. Res. 1991; 218: 95
  • 2 Sathyamoorthy N, Takayama K. J. Biol. Chem. 1987; 262: 13417
  • 3 Bassily RW, El-Sokkary RI, Silwanis BA, Nematalla AS, Nashed MA. Carbohydr. Res. 1993; 239: 197
  • 4 Bassily RW, El-Sokkary RI, Youssef RH, Assad AN, Nashed MA. Spectrosc. Lett. 1997; 30: 849
  • 5 Youssef RH, Bassily RW, Assad AN, El-Sokkary RI, Nashed MA. Carbohydr. Res. 1995; 277: 347
  • 6 Naganawa H, Usui N, Takita T, Hamada M, Maeda K, Umezawa H. J. Antibiot. 1974; 27: 145
  • 7 De Bona P, Giuffrida ML, Caraci F, Copani A, Pignataro B, Attanasio F, Cataldo S, Pappalardo G, Rizzarelli E. J. Pept. Sci. 2009; 15: 220
  • 8 Cucinotta V, Gluffrida A, Maccarrone G, Messina M, Pulisi A, Vecchio G. Electrophoresis 2007; 28: 2580
  • 9 Wang M, Tu PF, Xu ZD, Yu XL, Yang M. Helv. Chim. Acta 2003; 86: 2637
  • 10 Toubiana R, Das BC, Defaye J, Mompon B, Toubiana MJ. Carbohydr. Res. 1975; 44: 308
  • 11 Liav A, Goren MB. Carbohydr. Res. 1986; 155: 229
  • 12 General procedure for sulfonylation: To a dry round-bottom flask, equipped with a magnetic stirring bar, was added trimethylsilylated trehalose 2 or 3 (1 equiv), and a catalytic amount of 4-dimethylaminopyridine (DMAP) and the vessel was sealed with a rubber septum and subjected to high vacuum for 2–3 h to ensure anhydrous conditions. Anhydrous CH2Cl2 (10 mL/g) and pyridine (5 equiv for each OH) were added and the reaction mixture was stirred for 15 min at room temperature, and then cooled to –5 °C. Triflic anhydride (2.5 equiv for each OH) was injected dropwise with stirring while the reaction mixture was continually maintained at –5 °C. The reaction mixture was then allowed to warm gradually to room temperature and stirred for a further 30 min, when TLC (toluene–EtOAc, 19:1) showed the absence of starting material. The mixture was diluted with CH2Cl2, filtered, washed successively with cold aq HCl (1%), aq NaHCO3 (5%), and water, dried (Na2SO4), filtered and evaporated to give an amorphous solid that was used for the next step without further purification.
  • 13 General procedure for displacement reaction: To a solution of trehalose derivative 4 or 8 (1 equiv) in anhydrous N,N-dimethylformamide (3 mL/g) were added dicyclopentano-15-crown-5 (0.15 equiv for each OH) and anhydrous sodium azide (3 equiv for each OH). The suspension was stirred at room temperature, and reaction was shown to be complete after 2 h by TLC (toluene–EtOAc, 19:1). The mixture was then diluted with CH2Cl2 and then processed by conventional work-up.
  • 14 General procedure for deprotection: Compound 5 or 9 was dissolved in a mixture of trifluoroacetic acid–tetrahydrofuran–water (8:17:33) and kept at room temperature until TLC analysis showed the hydrolysis to be complete (ca. 1 h). The product was purified by chromatography on silica, eluting successively with hexane–diethyl ether (19:1) and EtOAc–1-propanol (9:3).

Zoom Image
Scheme 1 Synthesis of 6-azido-6-deoxy- and 6,6′-diazido-dideoxy derivatives of α,α-trehalose, and related compounds