Cyanoacetamide-based oxime carbonates: an efficient, simple alternative for the introduction of Fmoc with minimal dipeptide formation

• Published in: Tetrahedron 2012-04, Vol.68 (14), p.3056-3062
• Main Authors: Khattab, Sherine N., Subirós-Funosas, Ramon, El-Faham, Ayman, Albericio, Fernando
• Format: Article
• Language: English
• Subjects: 9-Fluorenylmethyloxycarbonyl; Amino acids; Carbonates; Chemistry; Cleavage; Exact sciences and technology; Formations; N-Protecting group; Organic chemistry; Oxime; Oximes; Peptide synthesis; Peptides; Polymers; Preparations and properties; Residues; Strategy
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2012.02.020

Nowadays, most peptides are chemically achieved by using the Fmoc/tBu protection strategy, due to its fully orthogonal character, mild temporary group removal and resin cleavage steps. However, its introduction into N-unprotected amino acids is not exempt of synthetic inconveniences, such as dipeptide formation. Lately, novel oxime carbonates were introduced in the arsenal of reagents for the introduction of Fmoc, presenting almost negligible percentage of side-products. Herein, an enforced version of this family of Fmoc-carbonates is presented, containing stable and highly acidic cyanoacetamide-based oximes as leaving group. Such reactive species, affordable in only two steps from simple, readily available starting materials, show unusual ability to obtain the corresponding Fmoc-protected residues in high yield and minimal impact of detrimental side-products, mainly Fmoc-dipeptides. [Display omitted]