1-Ethoxyethylidene, a New Group for the Stepwise SPPS of Aminooxyacetic Acid Containing Peptides

Abstract

For more than a decade, the oxime ether ligation has proven to be one of the most efficient technique for the preparation of various peptide conjugates. However, despite numerous reports, the preparation of aminooxy-containing peptides is still hampered by N-overacylation of the NH-O function either during its incorporation or through the peptide-chain elongation. This restricts the introduction of protected-NH-O function at the last acylation step and prevents the use of standard solid-phase peptide synthesis (SPPS) procedures for the preparation of more complex aminooxy-peptides. We have studied the coupling of modified Fmoc-lysine containing either N-Boc- or N,N'-bis-Boc-protected aminooxyacetic acids (Aoa) during the elongation of the peptide chain and found that none of them is adequate. To circumvent this limitation, we propose to protect the Aoa moiety with a 1-ethoxyethylidene group (Eei) to provide 2-(1-ethoxyethylideneaminooxy)acetic acid building block. We showed that the Eei group is fully compatible with standard SPPS conditions and safely allows the multiple incorporation of the aminooxy functionality into the growing peptide. Since Eei-protected Aoa remains as flexible as normal amino acids in peptide synthesis, it may become the rule for the straightforward preparation of aminooxy peptides.

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

“…This protective group was shown to be fully compatible with standard SPPS conditions. 47 The Alloc protective group at a lysine side chain was necessary to append a cysteine encompassing the activating nitro-pyridine sulfenyl residue. To append the targeting elements to the cyclodecapeptidic scaffold, we performed an aminooxy deprotection and an oxime ligation of the appropriate cyclopentapeptidic cyclo[-RGDfK (-COCHO)-] in one-pot reactions.…”

A Novel Conformationally Constrained Parallel G Quadruplex

“…[13] After deprotection of the side-chains of the lysine residues under acidic conditions, the oxyamino groups were introduced by using 2-(1-ethoxyethylideneaminooxy)acetic acid. [14] Final acidic deprotection provided the key intermediate 2. The oligonucleotide d ( 5' TTAGGGTX 3' ) 3, in which X represents the 3'-aldehyde linker, was synthesized as previously reported.…”

A Synthetic “Tour de Force”: Well‐Defined Multivalent and Multimodal Dendritic Structures for Biomedical Applications

“…[29] The 1-ethoxyethylidene (Eei, blue) protecting group was developed earlier by the same research group to prevent overacylation of the NHÀO functionality. [31] Scheme 8. Final desymmetrization using cyclic carbonates.…”