3,5-Dimethoxybenzyloxycarbonyl group

The 3,5-dimethoxybenzyloxycarbonyl group, introduced in 1966 by Chamberlin, undergoes solvolysis upon irradiation under conditions (254 nm) harmful to some amino acid residues, but quite harmless to many carbohydrate derivatives (see Scheme 16). 

Dimethoxy-aa-dimethyl-benzyloxycarbonyl constitutes an improvement over the 3,5-dimethoxybenzyloxycarbonyl group (see Scheme 16). The photochemical removal is easier (faster by a factor of 6), proceeding in high yield and, in numerous experiments, in quantitative yields. The group is, however, sensitive to mild acid, a disadvantage on many occasions. On the other hand, it can be photolyzed under conditions that do not affect a benzyloxycarbonyl group. 

Chamberlin, J.W. (1966) Use of the 3,5-dimethoxybenzyloxycarbonyl group as a photosensitive N-protecting group. Journal of Organic Chemistry, 31, 1658-1660. 

Scheme 16.—Photochemical Removal of 3,5-Dimethoxybenzyloxycarbonyl and 3,5-Di-methoxy-a,a-dimethylbenzyloxycarbonyl Groups.

Birr, C., Lochinger, W., Stahnke, G. and Lang, P. (1972) The a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl (Ddz) residue, an N-protecting group labile toward weak acids and irradiation. Justus Liebigs Annalen tier Chemie, 763,162-172. 

Ultraviolet spectrophotometric analysis of the incorporation or deblocking of the a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl (Ddz) group in solid phase synthesis has been used by Birr for the analysis of the coupling and deprotection reactions respectively 18 20). Similar spectroscopic properties of the N-protecting groups have been used for the analysis in the solid phase synthesis involving Nps-amino acids 21,22) and Bpoe-amino acids 23). In all these methods the uptake or release of a soluble reagent or byproduct is analyzed. 

Amino protecting groups fall into four broad categories nitrobenzyl (e.g., nitrobenzyloxy-carbonyl and 4,5-dimethoxy-2-nitrobenzyloxycarbonyl), phenacyl (e.g., 4-methoxyphen-acyloxycarbonyl), benzyloxycarbonyl (e.g., a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl), and arylsulfonamides (e.g., tosyl). All but the sulfonamides mask the amino group as a carbamate. Removal of the blocking moiety releases an unstable carbamic acid, which spontaneously decarboxylates to give the unprotected amine. 

There have been several reports of using the a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl [2-(3,5-dimethoxyphenyl)prop-2-yloxycarbonyl, Ddz] group 1 for N-protection of peptides (Scheme l).ti i7] group was evolved from the parent 3,5-dimethoxybenzyl group... 

Peptide synthesis, N-protection. Amino acids react with the reagent in aqueous THF in the presence of sodium hydroxide to give 3,5-dimethoxybenzyloxycarbonyl derivatives in yields of 55-75%, as illustrated for a sample of L-serine, ao+ 13.5°. The protective group can be cleaved in 42-85% yield without use of acid or base or... 

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