C–H Functionalization of Peptides via Cyclic Aminal Intermediates

Abstract

Protected dipeptides can be converted into cyclic ketoaminals, which can be subjected to palladium-catalyzed regioselective C−H functionalization. The best results are obtained using the 2-(methylthio)aniline (MTA) directing group, which is superior to the commonly used 8-aminoquinoline (AQ) group. No epimerization of stereogenic centers is observed. Subsequent cleavage of the directing and protecting groups allows the incorporation of a modified dipeptide into larger peptide chains.

Pd-catalyzed site-selective C(sp2)–H chalcogenation of amino acids and peptides using a picolinamide auxiliary

“…[12][13][14][15][16][17][18][19][20] Recently, metal-catalyzed C-H activation has emerged as a powerful synthetic methodology for various types of challenging chemical transformations including the structural modification of amino acids/peptides. [21][22][23][24][25][26][27][28][29][30][31][32][33][34] Directing group (DG)-assisted metal-catalyzed C(sp 3 )-H bond functionalizations of amino acids and peptides have been well investigated, [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] in contrast to the poorly investigated C(sp 2 )-H activation on aromatic rings of aromatic amino acids and their peptides. [54][55][56][57]…”

“…12–20 Recently, metal-catalyzed C–H activation has emerged as a powerful synthetic methodology for various types of challenging chemical transformations including the structural modification of amino acids/peptides. 21–34 Directing group (DG)-assisted metal-catalyzed C(sp 3 )–H bond functionalizations of amino acids and peptides have been well investigated, 35–53 in contrast to the poorly investigated C(sp 2 )–H activation on aromatic rings of aromatic amino acids and their peptides. 54–59 However, the C–H functionalizations of phenylalanine and phenylglycine have shown significant progress.…”

Total synthesis and biological evaluation of histone deacetylase inhibitor WF-3161

“…30 This protocol is also suitable for the modification of peptides, as long as no acidic N–H-bond is present in the reacting amino acid. 31 To date, the best results have been obtained with amides of 8-aminoquinoline (AQ) 32 or 2-(methylthio)aniline (MTA), 33 with both directing groups developed by Daugulis et al 34 In general, (het)aryliodides or -bromides are employed for the functionalisation of cyclic or N -methylated amino acids at the β-position, whereas the introduction of alkyl groups is relatively rare. We were therefore inspired to determine if we could introduce a protected, highly functionalised side chain in a single step into a suitably protected alanine derivative, e.g.…”

Synthesis of HC-Toxin via Matteson Homologation and C–H Functionalization

“…In recent years, our group has also investigated modifications of amino acids and peptides via C–H functionalizations, which allow for the introduction of a residue onto the β-position of a suitably modified amino acid . This protocol should make it possible to synthesize Aeo by modifying an alanine subunit already bearing the desired stereogenic α-center.…”