Deprotection of di-O -isopropylidene isocarbonucleosides

Deprotection of 5-glycosyl heterocyclic derivatives of 1,2:3:4-di-O -isopropylidene- α - D -galacto- 1,6-hexadialdo-1,5-pyranose allowed isocarbonucleoside analogues to be obtained with enhaced solubility in the aqueous medium used for antiviral assays. Looking for a deprotection method of isopropylidene groups which would not affect the heterocycle, we performed and compared different deprotection techniques using microwave radiation or thermal heating and found that, in most cases, this goal could be achieved, in short times and good yields, when the reactions were microwave-assisted.

Söderberg et al. 9 reported the microwave-assisted deprotection of 1,2:5:6-di-Oisopropylidene-α-D-glucofuranose in good yield.Due to the short times involved in the microwave-assisted reactions, the yields of sugars linked to an acid-labile heterocycle could be improved compared to those obtained using traditional thermal conditions.This paper reports the results obtained by comparing thermal and microwave-assisted deprotection of 5-[5′-(1′,2′:3′,4′-di-O-isopropylidene-β-L-arabinopyranosyl)]-tetrazole (1), 2- Thermal and microwave-assisted deprotection Performing deprotection reactions either with thermal or microwave heating, the results were closely related to the nature of the heterocyclic ring.Indeed, when thermal treatment was applied, the tetrazole derivative 1 could be deprotected using aqueous acetic acid (10%) in good yield.However, in the case of the oxadiazoles 3 and 4, best results were obtained using sulfuric acid (8 %).On the other hand, the thiadiazole derivative 2 did not resist treatment with hot acidic medium, decomposing.
Applying microwave radiation, as expected, deprotection times were shorter and the product yields were similar or higher.The greatest decrease in reaction time was observed for the deprotection of compound 1, in this case the reaction time decreased from 18 h to 5'30".It is important to point out that deprotection of compound 2 was only achieved when the reaction was microwave-assisted.
In the case of compound 4, full deprotection of the sugar moiety was achieved in a short time but studying the products obtained by 1 H and 13 C NMR, opening of the heterocycle occurred.The instability of the oxadiazoles under hydrolytic (acidic 10 or basic 11 ) thermal conditions was already known and, unfortunately, cleavage of the heterocycle could not be avoided using microwave radiation.As a matter of fact, when compound 4 was irradiated for only 40 seconds, partial sugar deprotection as well as partial heterocycle hydrolysis was also observed.
On the other hand, since aryl substituted oxadiazoles are less sensitive to hydrolysis than their alkyl analogues, 10 deprotection of compound 3 could be achieved in a short time and in high yield under microwave radiation.
The results are summarized in Table 1.According to the literature, 12,13 since deprotection of galactose residues releases the carbonyl groups, both pyranose and furanose (α and β) forms were present in most of the deprotected products.From compounds 1 and 4, although the pyranose forms predominated, smaller proportions of furanose forms (7 and 10 %, respectively) were also detected.Deprotection of compound 3 gave rise to a complex mixture of four structures with pyranose and furanose (α and β) forms, whereas the galactose residues arising from compound 2 were only found in the

NMR spectroscopy of deprotected compounds
In spite of the complexity of the 1 H NMR spectra of compounds 6, 7 and 9, almost all the signals could be assigned using first order analysis.To assign the signal corresponding to H-3 of the α and β structures of compound 6, a COSY spectrum was recorded.Results of these assignments are summarized in Table 2.
The 13 C NMR spectrum of compound 6 was assigned by HETCOR, and the chemical shifts of compound 6 were used as a model to assign the 13 C NMR resonances of 7a-9a and 7b-9b (Table 3).Galactofuranose 14 was the model compound used to assign the signals of 8c and 8d (Table 4).
In summary, carrying out the deprotection reactions under microwave radiation, rates were enhanced while the yields were similar or higher with respect to those obtained under thermal heating.Particulary relevant was the result obtained after the deprotection of 2-amino-5-[5′-(1′,2′:3′,4′-di-O-isopropylidene-β-L-arabinopyranosyl)]-1,3,4-thiadiazole since, in this case, the deprotected product could not be obtained without microwave assistance.This methodology offers a rapid and effective deprotective synthetic step when carbohydrates and an acid-labile heterocycle are involved.3. 13 C NMR data of 6a-9a and 6b-9b

Experimental Section
General Procedures.Compounds 1 and 4 were synthesized as described in the literature. 7icrowave irradiations were performed in a domestic oven at full power (1500 W) using an air condenser.Melting points were measured in a Thomas Hoover melting point apparatus and are uncorrected.The 1 H NMR spectra were recorded with a Bruker AC200 instrument at 200 MHz and the 13 C NMR spectra were recorded at 50 MHz with the same apparatus, using CDCl 3 or D 2 O, as reported in each case.Chemical shifts are given in δ (ppm) and coupling constants (J) are in Hz.The 2D-homo and heteronuclear experiments (COSY and HETCOR) were performed with a Bruker AC500 instrument.Acid concentrations are given in % v/v.Thin layer chromatography (TLC) was performed aluminium sheets coated with silica gel G 60 F254 (Merck, Darmstadt) and UV light and 1:10 v/v H 2 SO 4 /ethanol/heat were used for detection.
Microwave procedure: Compound 1 (113.1 mg, 0.38 mmol) was dissolved in aqueous acetic acid (10%, 10 mL) and the mixture was irradiated (3 x 40 sec).After that, AcOH solution was added (10 mL) and the solution was irradiated (2 x 40 sec, 1 x 20 sec).TLC showed the presence of starting material.Consequently, the mixture was concentrated to dryness and further extracted with CHCl 3 .The remaining insoluble material was compound 6 (68.6 mg, 75% yield), while the soluble product was identified as compound 1.To the remaining compound 1, aqueous AcOH (10%, 10 mL) was added and the mixture was irradiated (2 x 40 sec, 1 x 30 sec) and, after that, compound 1 was no longer detected.Compound 6 was obtained as a syrup by evaporation of the reaction medium (11.5
Microwave procedure: A mixture of compound 3 (110.2mg, 0.30 mmol) and aqueous AcOH (10%, 20 mL) was irradiated (7 x 20 sec) and no changes were observed.After that, compound 3 (5.5 mg, 0,015 mmol) was treated with aqueous H 2 SO 4 (1%, 1.3 mL), and irradiated (6 x 10 sec).No reaction was observed.Therefore, MeCN was added dropwise until complete dissolution of 3, and this solution was irradiated for 80 sec.The mixture was neutralized with BaCO 3 and filtered.The filtrate was concentrated to dryness and compound 8 was obtained (