Mono-selective β-C–H arylation of N-methylated amino acids and peptides promoted by the 2-(methylthio)aniline directing group

Abstract

2-(Methylthio)aniline (MTA) directed C(sp3)–H functionalisations are efficient and straightforward protocols for the selective β-modification of N-methylated amino acids.

Rationales Design von Phe‐BODIPY‐Aminosäuren als fluorogene Bausteine für den peptidbasierten Nachweis von Candida‐Infektionen im Harntrakt

“…First, we prepared the Phe-BODIPY amino acid 5 (Figure 1) resembling the structure of Trp-BODIPY (4). In this synthesis, we used Pd-catalysed C(sp 3 )-H arylation [22] to couple a TAMprotected alanine surrogate and a tetramethyl iodinated BODIPY scaffold. After isolation of the free amino acid 5, we examined its response in environments with markedly different viscosity (i.e., glycerol vs methanol, with 1200 and 0.5 cp, respectively) and compared it to the Trp-BODIPY counterpart 4, obtained using previously reported methods.…”

C–H Functionalization of Peptides via Cyclic Aminal Intermediates

“…The AQ is the more reactive directing group but sometimes causes double functionalization, 12 unlike the less reactive MTA group. 13 Nevertheless, both directing groups are in principle well suited for the functionalization of β-C−H bonds of protected amino acids. 2b,14 Early examples have reported the stereoselective functionalization of N-protected proline and pipecolic acid derivatives (Scheme 1A) 15 or phthaloyl-protected amino acids and peptides.…”

“…So far, the best results have been obtained in Pd-catalyzed reactions with amides of 8-aminoquinoline (AQ) or 2-(methylthio)­aniline (MTA), both pioneered by Daugulis et al These directing groups have a slightly different reactivity and selectivity. The AQ is the more reactive directing group but sometimes causes double functionalization, unlike the less reactive MTA group . Nevertheless, both directing groups are in principle well suited for the functionalization of β-C–H bonds of protected amino acids. , …”

Post-Assembly Modification of Peptides by Ligand-Enabled β-C(sp3)–H Arylation of Alanine at the C-Terminus: Overcoming the Inhibition Effect of Peptide Bonds

“…With 2-(methylthio)aniline as the auxiliary linked to the C-terminus, Kazmaier developed β-C(sp 3 )−H arylation of N-methyl alanine at the C-terminus of short peptides. 11 Meanwhile, Chen used C-linked 8-aminoquinoline as the auxiliary to facilitate an intramolecular β-C(sp 3 )−H arylation of N-methyl alanine at the C-terminus for the synthesis of macrocyclic peptides. 12 The methyl substitution on the nitrogen of C-terminal Ala was found to be crucial to the above two reactions due to the inhibition effect of the secondary amide in C−H activation.…”

“…The inhibition effect of peptide bonds (secondary amides) is a major obstacle for palladium-catalyzed C(sp 3 )−H functionalization of peptides. 4 In the catalytic cycle for C-terminal Ala functionalization (Scheme 1), 11,12 With this idea in mind, we chose tripeptide 1a as the test substrate for β-C(sp 3 )−H arylation of Ala at the C-terminus (Table 1). With 2-(methylthio)ethylamine (MTEA) as the auxiliary, 1a reacted with PhI in the presence of 20 mol % Pd(OAc) 2 and 1.5 equiv of AgOAc in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) at 100 °C for 18 h, yielding the Ala C−H arylation product 3a as the single product (12%).…”