Selective removal of the (2-naphthyl)methyl protecting group in the presence of p -methoxybenzyl group by catalytic hydrogenation

Selective cleavage of the (2-naphthyl)methyl (NAP) group in the presence of p -methoxybenzyl (PMB), benzyl and benzylidene groups was achieved by catalytic hydrogenation with a series of monosaccharides. At a disaccharide level, the PMB group was stable upon hydrogenolysis of the NAP, however, partial cleavage of benzyl ether functions was observed


Introduction
In carbohydrate chemistry, the benzyl-type ethers are the most frequently used protecting groups, since they are removable upon mild catalytic hydrogenation, and, due to their different reactivities, adoptable in orthogonal protecting strategies. 1 The p-methoxybenzyl (PMB) ether can be cleaved selectively by DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) 2 or CAN (cerium(IV) ammonium nitrate) 3,4 leaving most of the protecting groups intact, therefore, it became one of the most popular tools for temporary hydroxyl protection.However, the PMB group has the disadvantage of extreme acid-sensitivity.The 2-(naphthyl)methyl (NAP) group, 5,6 being removable by either catalytic hydrogenation [6][7][8] or DDQ 9 in the presence of benzyl ether and, unlike its p-methoxybenzyl counterpart, being stable under acidic conditions, seems to be a remarkably useful protecting group for polyhydroxy systems.
Recently, Spencer et al. have demonstrated a sequential deprotection strategy for sugars based upon the PMB, NAP and benzyl groups, applying CAN as a selective reagent to cleave PMB in the presence of the NAP-ether. 4This set of benzyl-type protecting groups would be more useful, if orthogonal deprotection of NAP would be carried out in the presence of PMB.Investigating the relative stability of benzyl, p-methoxybenzyl, 2-(naphthyl)methyl, 1-(naphthyl)methyl, 10,11 diphenylmethyl, 9-fluorenyl and p-chlorobenzyl ethers to catalytic hydrogenation in competitive reactions, we have found that splitting of the substituted benzyl ethers such as PMB did not start until the removal of the extended aromatic system became complete. 12,13o explore the utility of this observation, a series of mono-and disaccharides carrying NAP and PMB groups were prepared and subjected to catalytic hydrogenation.

Results and Discussion
Fully protected glucoside derivatives 2 and 5 carrying benzyl, p-methoxybenzyl and 2-(naphthyl)methyl protecting groups were prepared by conventional alkylation, starting from 1 14 and 4, 14 respectively.Tlc monitoring of the Pd/C-catalyzed hydrogenolysis of 2 showed formation of a single product until the conversion reached at 80-90%; prolongation of the reaction time led to the formation of some polar side products.Therefore, the reaction mixture was worked up at 90% completion, and compound 3, selectively deprotected at position 4, could be isolated with 68% yield.Similarly, the NAP group could be removed from primary hydroxyl group of 5 in the presence of PMB and benzyl ethers, to yield 6 (Scheme 1).
Scheme 1. Removal of the (2-naphthyl)methyl group in the presence of the p-methoxybenzyl PMB and benzyl groups by catalytic hydrogenation.
Compound 7 was alkylated with (2-naphthyl)methyl bromide in the presence of phase transfer catalyst (Bu4NHSO4) affording a mixture of 8 15 and 9, respectively, whose separation has been accomplished by column chromatography.Subsequently, their p-methyoxybenzylation gave the acetal-containing substrates 10 and 12. Catalytic hydrogenolysis of 10 was let to go to completion, furnishing the mono-deprotected 11. 16 The NAP group of 12 could be selectively cleaved, as well, to give 13 16 in high yield (Scheme 2).Scheme 2. Removal of the (2-naphthyl)methyl group in the presence of the p-methoxybenzyl and benzylidene groups.
Starting from the galactopyranoside derivative 14, the synthesis of 17 and 18 was achieved by an analogous manner (14→15→17; 14→16→18), but the regioisomers formed in the phase transfer alkylation could only be separated after the introduction of the PMB group.The NAP group of 17 and 18 could be cleanly removed in the presence of the PMB and benzylidene functions to result in 19 and 20 in high yields, respectively.afforded 23 from which, after mild acidic hydrolysis of the mixed acetal group followed by p-methoxybenzylation compound 25 could be obtained.Upon catalytic hydrogenation, the NAP group could be cleaved selectively form the secondary hydroxyl group to give 26 in high yield (Scheme 4).Scheme 4. Removal of the (2-naphthyl)methyl group in the presence of isopropylidene groups by catalytic hydrogenation.
Treatment of the known lactoside 27 18 with p-methoxybenzyl chloride as a reagent furnished 28, as another disaccharide substrate, suitable for studying the selective removal of NAP in the presence of PMB and multiple benzyl ethers.Catalytic hydrogenolysis of 28 clearly demonstrated the limitation of the method, since the monodeproteced 29 could be isolated in rather low yield (Scheme 5).A side product formed in this transformation was also isolated in a similar amount; it could be identified, by NMR measurments and its single peak in the mass spectrum (m/z: 951.30), as a mixture of mono-debenzylated derivatives of 29 (m/z calcd for [M+Na] + : 951.40).
The higher hydrogenolytic stability of the p-methoxybenzyl ether in comparison to the benzyl can be explained by steric effect of the methoxy substituent which inhibits the effective binding of the aromatic ring to the catalyst surface. 6This phenomenon was utilized for selective hydrogenation of phenolic benzyl ether or ester in the presence of phenolic PMB ether using a Pd/C-pyridine combination as a catalyst. 19,20cheme 5. Removal of the (2-naphthyl)methyl group in the presence of benzyl groups by catalytic hydrogenation.

Conclusions
The (2-naphthyl)methyl (NAP) protecting group could be selectively removed by catalytic hydrogenation from primary and secondary hydroxyl groups in the presence of the pmethoxybenzyl (PMB), benzylidene and multiple benzyl functions in the case of monosaccharides.At a disaccharide level, the p-methoxybenzyl (PMB) group proved to be stable toward catalytic hydroganolysis, however, partial cleavage of benzyl ether functions was also observed.

Scheme 3 .
Scheme 3. Removal of the (2-naphthyl)methyl group in the presence of the p-methoxybenzyl and benzylidene groups.