Synthesis of esters derived from 2 , 3 , 4-triO-benzyl-alpha-D-methylglucoside

Carbohydrates and glycoconjugates are involved in many normal and pathologic biological processes including cellular recognition, tumour metastasis, bacterial and viral infections. The biological activity of carbohydrates depends generally on their ability to bind to specific receptors namely those containing O-sulfate esters. These carbohydrate derivatives occur widely in nature and play an essential role in many biological processes. The regiospecific synthesis of sugar esters is a difficult and challenging task. One approach described in the literature involves sugar derivatives soluble in organic media, namely the esterification of methyl glucosides. In this communication we discuss the synthesis of a set of esters obtained from the D-glucose derivative 1 (R=H) by reaction with several carboxylic acids: benzoic, phenylacetic, acetylsalicylic (commercially available), 2-(3-bromopropoxy)benzoic acid and 4-(toluene-4sulfonylamino)benzoic acid. Details on the synthesis and characterization of the final compounds will be presented.


Introduction
Salicylic acid derivatives are widely known either as natural products or as synthetic derivatives displaying different types of activity.Salicylate esters display immunity against other organisms 1,2 in plants, regeneration effects 3 and possibly a protective effect against UV radiation in plants. 4Synthetic salicylic acid derivatives are well known as biological active compounds such as analgesic and antifungal 5 and are also part of cosmetic formulations. 6ome recent works refer to application of salicylic esters and salicylic acid-based dendrimers as potential drug carriers. 7,8arbohydrates and glycoconjugates are involved in many normal and pathologic biological processes including cellular recognition, tumour metastasis, bacterial and viral infections. 9The biological activity of carbohydrates depends generally on their ability to bind to specific receptors namely those containing O-sulfate esters.These carbohydrate derivatives occur widely in nature and play an essential role in many biological processes. 10The sulfate groups have been demonstrated to be essential for binding. 11Due to their amphiphilic, emulsifying and bioactive properties carbohydrate fatty acid esters have become particularly important for pharmaceutical applications, 12 food and as biodegradable detergents. 13The regiospecific synthesis of sugar esters is a difficult and challenging task.One approach described in the literature involves sugar derivatives soluble in organic media, namely the esterification of methyl glucosides. 14t was decided to prepare a set of esters from the 6-hydroxyl group of the D-glucose which was obtained by published methods starting from methylglucoside.15a As the acid components, derivatives of benzoic acid were used, including analogues of salicylic acid containing bromine as a reactive site for further modifications.

Results and Discussion
Different methods of the preparation of the alcohol 4 starting from α-methylglucoside are reported. 15The availability of the reagents led us to use the route involving tetrabenzylation, selective deprotection and simultaneous acetylation in position 6 followed by removal of the acetyl group.15a α-D-Methylglucoside 1 was treated with sodium hydride and benzyl bromide in DMF and the tetrabenzylated product 2 was obtained in 81% yield. 16Selective debenzylation 17 using zinc chloride in Ac 2 O-AcOH gave the product 3, acetylated in position six, in 47% yield (Scheme 1).In the proton NMR it may be seen that one of the benzyl groups disappeared and had been replaced by a COCH 3 group at 2.04 ppm.
Selective de-O-acetylation was accomplished by a known method. 18The overall yield for the preparation of the alcohol 4 was 26%.In its proton NMR spectrum the loss of the singlet at 2.04 ppm and the change of the signals of protons in position 6 to higher field, confirmed the structure.
Acid component 5 19 was prepared in 14% yield by alkylation of salicylaldehyde and further oxidation of the product (Scheme 2).The sulphonamide 6 (Figure 1) was prepared according to a literature method. 20he reactions between each carboxylic acid and the alcohol 4 were performed using DCC and DMAP. 21The preparation of the esters 8 and 9 were achieved in high yields (75 and 77%), however compounds 7 and 10 were obtained in 27 and 9 % yields, respectively.The low yields for the latter esters were possibly due to difficulties in purification.For compound 10 selective precipitation of the urea by-product followed by preparative chromatography caused a greater loss of the target compound.

O
When the same preparative conditions were applied to acetylsalicylic acid with the alcohol 4, the only product isolated was the 2,3,4-tri-O-benzyl-6-O-acetyl-α-Dmethylglucoside 3, in 53% yield.Under these conditions, the acetyl group was transferred to the OH group of the glucose derivative and this transesterification was the only reaction observed.
From the NMR data it may be observed that position of protons 6 give information on the acylation since for the alcohol 4 the chemical shifts are lower, below 3.8 ppm, than for the ester derivatives.The highest values are observed for compound 7, 4.50 ppm for H-6' a (J=12 and 4.8 Hz) and 4.58 ppm for H-6' b (J=12 and 2.0 Hz).

Experimental Section
General.Melting points were determined on a Gallenkamp melting point apparatus and are uncorrected. 1H NMR (300 MHz) and 13 C NMR (75.4 MHz) spectra were recorded on a Varian Unity Plus Spectrometer at 298 K or on a Bruker Avance II 400 spectrometer (400 MHz for 1 H and 100.6 MHz for 13 C) or on a AC Bruker 250 MHz spectrometer.Chemical shifts are reported in ppm relative to solvent peak or TMS; coupling constants (J) are given in Hz; C-q stands for quaternary carbon.Double resonance, HMQC (heteronuclear multiple quantum coherence) and HMBC (heteronuclear multiple bond correlation) experiments were carried out for complete assignment of 1 H and 13 C signals in the NMR spectra.Highresolution mass spectra (ESI-TOF) were obtained on a Bruker FTMS APEXIII spectrometer.Elemental analyses were obtained on a Leco CHNS-932 instrument.TLC was carried out on plates coated with silica gel 60 F254.Column chromatography was performed on silica gel (70-230 or 230-400 mesh).Light petroleum refers to the fraction boiling in the range 40-60ºC.