Synthesis of Cyclophane-Braced Peptide Macrocycles via Palladium-Catalyzed Intramolecular C(sp³)–H Arylation of N-Methyl Alanine at C-Termini

Abstract

A method for the construction of cyclophanebraced peptide macrocycles via Pd-catalyzed aminoquinolinedirected intramolecular C(sp 3 )−H arylation with aryl iodides is developed. Unlike our previous AQ-directed exo-type intramolecular C−H arylation of long alkyl tails, this endo-type C−H cyclization reaction takes places on the β-methyl group of Nmethyl alanine at the C-termini of peptides. Unusual C−N cleavage side products of Ala were observed and attributed to intramolecular deprotonation-assisted α,β-elimination of the palladacycle intermediate.

Postassembly Modifications of Peptides via Metal-Catalyzed C–H Functionalization

“…Chen developed a Pd-catalyzed AQ-directed intramolecular C-H arylation of C-terminal N-methyl Ala with aryl iodides to construct peptide macrocycles (see 44 in Scheme 10e). 142 The N,N -bidentate AQ auxiliary for Pd-catalyzed C-H arylation of alkyl carboxylic acids was first introduced by Zaitsev et al 114 and Daugulis et al. 115 The N-methyl substitution of Ala weakens the coordinating ability of the N in tertiary amide, suppressing the interference of the AQ-directed C-H palladation.…”

Recent Advances in Late‐Stage Construction of Stapled Peptides via C−H Activation

“…recently established a robust process for the synthesis of cyclophane‐braced stapled peptide via palladium‐catalyzed Intramolecular β‐C(sp 3 )−H arylation (Scheme 15). [65] This method avoided the long alkyl tails, which were used in previous report, [64] and directly arylated the β‐methyl group of N ‐Methyl‐L‐alanine at the C‐terminal of the peptide sequences. Through this method, dipeptide, tripeptide, tetrapeptide, and pentapeptide substrates 29 afforded single diastereomeric stapled peptides 30 in moderate to good yields.…”

C–H Functionalization of Peptides via Cyclic Aminal Intermediates

“…Early examples have reported the stereoselective functionalization of N -protected proline and pipecolic acid derivatives (Scheme A) or phthaloyl-protected amino acids and peptides. , Interestingly, no examples are described for amino acids with an unsubstituted N–H bond, while N -alkylated amino acids undergo C–H activation without any difficulty (Scheme B) . Since it is known that late transition metals can form stable complexes with amino acids and peptides, complexation of the catalyst by the substrate may explain the failure of the C–H functionalization.…”