C–H Functionalization of N-Methylated Amino Acids and Peptides as Tool in Natural Product Synthesis: Synthesis of Abyssenine A and Mucronine E

Abstract

N-Methylated amino acids and peptides with an 8-aminoquinoline (AQ) directing group can be subjected to stereoselective Pd-catalyzed β-functionalizations. The best results are obtained with aryl iodides, but alkyl and alkenyl side chains can also be introduced. The AQ protecting group can easily be removed, providing the free carboxylic acid, which can be used directly in peptide couplings. This protocol was used successfully as a key step in the synthesis of the cyclopeptide alkaloids abyssenine A and mucronine E.

A Guide to Directing Group Removal: 8‐Aminoquinoline

“…Not many examples exist of N ‐Boc activation and hydrolysis of simple aromatic AQ‐amides as acid/base hydrolysis or oxidative removal of the MQ directing group (Section 2.2) usually afford similar yields. The method's strength lies in its transformation of sterically hindered substrates such as ortho ‐substituted (hetero)aromatics ( 163 – 164 , Scheme 26) [52, 115] (though no examples have been found of ortho , ortho ‐substituted aromatic AQ‐amides) and alpha ‐substituted aliphatic AQ‐amides ( 167 – 174 ), [29, 116–124] though increased bulk around the amide bond decreases the efficiency of the N ‐Boc activation step which may require a large excess of Boc anhydride ( 165 – 167 ), high reaction temperatures ( 165 – 168 ) and long reaction times ( 169 – 171 , 174 ). Bulky alpha ‐phthaloyl groups are tolerated in some cases ( 169 – 171 ) but can require transformation to a smaller azide if a beta ‐substituent is also present ( 78 , 172 ).…”

Approaches to Cyclophane‐Types of Cyclopeptide Alkaloids

“…In 2018, Kazmaier and co‐workers completed the synthesis of abyssenine A and mucronine E again, based on the copper‐catalyzed macrocyclization strategy [56] . In this investigation, a novel C−H functionalization of N ‐methylated amino acids and peptides was developed, which provided a rapid, asymmetric synthesis of the acyclic skeleton prior to the key macrocyclization.…”

“…They were employed to investigate sedative and anxiolytic‐like effects [10] . Mucronines, the 15‐membered cyclopeptide alkaloids were found to have significant antifungal and antibacterial acitivities [11] . It should be noted that this macrocycle, in contrast with the 13‐ and 14‐membered rings lacks the oxygen in the ring.…”

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

“…In 2014, Yu and coworkers developed an efficient strategy to direct site‐selective arylation of inert C(sp 3 )−H bonds of N ‐phthaloyl peptides with the assistance of special peptide backbones, which were used as ligands [35] . In this study, phthaloyl is employed to avoiding the interference of secondary amide group to the β‐ C(sp 3 )−H activation [36] . The formation of N,N ‐bidentate or N,O ‐bidentate coordination with Pd(II) accelerated the C−H activation reaction.…”