Design of protecting groups for the beta-carboxylic group of aspartic acid that minimize base-catalyzed aspartimide formation.
With the objectives of developing new protecting groups for the beta-carboxyl group of aspartic acid that are resistant to base-catalyzed aspartimide formation and of evaluating the importance of sterical factors in the design of such protecting groups, four new alkyl ester derivatives of aspartic acid were synthesized. The beta-3-pentyl, beta-4-heptyl, beta-2,6-dimethyl-4-heptyl and the recently described beta-2,4-dimethyl-3-pentyl esters of Boc-aspartic acid were incorporated into model peptides, and the resin-bound protected peptides were treated with 20% piperidine for 10 h. The levels of aspartimide-related side products were compared with the previously reported beta-cyclohexyl, beta-menthyl and beta-2-adamantyl esters of aspartic acid. The results show that bulky, acyclic, aliphatic protecting groups (in particular the 2,4-dimethyl-3-pentyl ester) are significantly more resistant to base-catalyzed aspartimide formation than comparably rigid cyclic alkyl esters that under the same reaction conditions form several-fold more aspartimide-related side products. Using elevated temperatures to overcome difficult couplings leads to the formation of significant amounts of aspartimide when aspartic acid is protected with the cyclohexyl group, but the 2,4-dimethyl-3-pentyl protecting group offers excellent protection under these conditions. The use of the 2,4-dimethyl-3-pentyl protecting group will allow the use of orthogonally removable base-labile protecting groups in Boc chemistry and suggests a design of protecting groups for other nucleophile-sensitive trifunctional amino acids in both Boc and Fmoc chemistry.
Karlström
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Department of Neurochemistry and Neurotoxicology, Stockholm University, Sweden.
Undén
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D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004952:Esters / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry; D013696:Temperature; D013997:Time Factors
D004952:Esters; D009842:Oligopeptides; D010880:Piperidines; D001224:Aspartic Acid; C075871:aspartimide; C032727:piperidine