Decarboxylative Peptide Macrocyclization through Photoredox Catalysis

Abstract

A method for the decarboxylative macrocyclization of peptides bearing N-terminal Michael acceptors has been developed. This synthetic protocol enables the efficient synthesis of γ-amino acid-containing cyclic peptides and is tolerant of functionality present in both natural and non-proteinogenic amino acids. Linear precursors ranging from 3 to 15 amino acids cyclize effectively under this photoredox protocol. To demonstrate the preparative utility of this method in the context of bioactive molecules, we have generated COR-005, a somatostatin analog currently in clinical trials.

Photochemical Dual‐Catalytic Synthesis of Alkynyl Sulfides

“…[18] Thes ulfur atom of the alkynyl sulfide can also undergo oxidation to the corresponding sulfoxide (6)a nd sulfone (7), and such activated alkynes have already been demonstrated as valuable building blocks able to undergo conjugate additions. [24] Macrocyclizations in batch normally require highly dilute reaction mixtures which make efficient light penetration asignificant challenge.Assuch, it was hoped that the continuous flow protocol developed herein, would aid in the development of anovel macrocyclization protocol. [20] AR u-catalyzed azide-alkyne cycloaddition afforded the corresponding triazole 9 in 77 % yield; [21] alkynyl sulfides are representative of asmall class of internal alkynes known to undergo selective azide-alkyne cycloaddition.…”

Catalyst‐Free Decarboxylation of Carboxylic Acids and Deoxygenation of Alcohols by Electro‐Induced Radical Formation

“…Natural product derivatives ( 21 and 22 ) from steroid oleanolic acid were easily generated in excellent yields and high stereoselectivity. Furthermore, we extended this method to peptide macrocyclization . Unprotected peptide 23 was readily accessed via an intramolecular Giese Addition reaction in 39 % yield.…”

Decarboxylative couplings as versatile tools for late‐stage peptide modifications

“…The methodology employed iridium photocatalyst 54 (see Scheme ) and visible‐light irradiation to forge a new CC bond at the peptide C‐terminus ( 82 ‐ 84 ). The extension of this methodology to an intramolecular variant for peptide macrocyclization was accomplished shortly thereafter and concurrently with the nickel‐catalyzed Giese macrocyclization approach discussed in section 2.3.1 . Subjecting peptide substrates bearing an N‐terminal acrylamide unit and a free carboxylic acid at the C‐terminus (e.g., 85 , Scheme B) to Ir‐catalyzed PET conditions, MacMillan and coworkers were able to successfully access a range of intriguing macrocyclic peptide variants ( 86 ‐ 89 ).…”

“…Reactions were selective for C‐terminal acids in the presence of unprotected side‐chain acids ( 87 ) owing to the enhanced stability of the α‐amino radical intermediate. Several other protected amino acid side‐chains were tolerated in the transformation, as were varying ring‐sizes in the products, which ranged from 11‐member ring 89 to a 47‐membered (15‐amino acid) macrocyclic product …”

“…Such methods facilitate the formation of diverse CC bonds, including C‐terminal decarboxylative alkylation and arylation, as well as strategies for Cheteroatom bond formation. Application of these methodologies to the versatile synthesis of unnatural amino acids, peptide macrocycles, peptide functionalized polymers, and even proteins is a powerful testament to the robust nature of the coupling strategies. The majority of available methods utilize photocatalytic and, in some cases, electrochemical approaches to convert carboxylic acids under mild conditions into the corresponding peptide alkyl radicals following the extrusion of CO 2 .…”