Abstract
Although peptide chemistry has made great progress, the frequent occurrence of aspartimide formation during peptide synthesis remains a formidable challenge. Aspartimide formation leads to low yields in addition to costly purification or even inaccessible peptide sequences. Here, we report an alternative approach to address this longstanding challenge of peptide synthesis by utilizing cyanosulfurylides to mask carboxylic acids by a stable C–C bond. These functional groups—formally zwitterionic species—are exceptionally stable to all common manipulations and impart improved solubility during synthesis. Deprotection is readily and rapidly achieved under aqueous conditions with electrophilic halogenating agents via a highly selective C–C bond cleavage reaction. This protecting group is employed for the synthesis of a range of peptides and proteins including teduglutide, ubiquitin, and the low-density lipoprotein class A. This protecting group strategy has the potential to overcome one of the most difficult aspects of modern peptide chemistry.
Highlights
Peptide chemistry has made great progress, the frequent occurrence of aspartimide formation during peptide synthesis remains a formidable challenge
We have introduced an alternative approach for preventing aspartimide formation during peptide synthesis by employing stable CSYs as masked aspartic acids
Upon treatment with electrophilic halogen species under aqueous acidic conditions, the ylide is quantitatively converted to the free acid
Summary
Peptide chemistry has made great progress, the frequent occurrence of aspartimide formation during peptide synthesis remains a formidable challenge. We report an alternative approach to address this longstanding challenge of peptide synthesis by utilizing cyanosulfurylides to mask carboxylic acids by a stable C–C bond. Deprotection is readily and rapidly achieved under aqueous conditions with electrophilic halogenating agents via a highly selective C–C bond cleavage reaction This protecting group is employed for the synthesis of a range of peptides and proteins including teduglutide, ubiquitin, and the low-density lipoprotein class A. Advances in organic chemistry have enabled defined, scalable, and cost-efficient synthesis of peptides on solid support as a versatile platform for the reliable preparation of peptides, with particular successes in the discovery of bioactive molecules[1,2,3,4] Improvements such as new coupling agents, dipeptide building blocks, optimized resins, and suppression of racemization allow the production of peptides on a multi-gram scale[5,6,7]. In the late 1990s, it was reported that a decrease in aspartimide formation is observed by increasing the steric bulk of the aspartic acid ester moiety (e.g., Mbe ester)[19,20]
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