Photochemical Methods for Peptide Macrocyclisation

Abstract

Photochemical reactions have been the subject of renewed interest over the last two decades, leading to the development of many new, diverse and powerful chemical transformations. More recently, these developments have been expanded to enable the photochemical macrocyclisation of peptides and small proteins. These constructs benefit from increased stability, structural rigidity and biological potency over their linear counterparts, providing opportunities for improved therapeutic agents. In this review, an overview of both the established and emerging methods for photochemical peptide macrocyclisation is presented, highlighting both the limitations and opportunities for further innovation in the field.

Keywords: macrocyclisation; peptides; photochemistry.

Figure 1

Peptide macrocyclisation modes and generalised layout of figures in this review.

Figure 2

Mechanism of the photoactivated thiol‐“ene” reaction. A photoinitiator can be used to accelerate the formation of a thiyl radical via S−H abstraction.

Figure 3

First example of peptide macrocyclisation by a photoactivated thiol‐“ene” reaction. On‐resin cyclisation onto both alloc and norbornene alkene partners was achieved in the presence of a DMPA photoinitiator. ^[67]

Figure 4

On‐resin macrocyclisation of unactivated alkenes by a photoactivated thiol‐“ene” reaction. ^[69]

Figure 5

Aqueous photoactivated thiol‐“ene” reaction, enabled by the use of the water‐soluble initiator VA‐044 10. ^[74]

Figure 6

Aqueous di‐cyclisation of a tetra‐cysteine protein mutant by photoinitiated thiol‐“ene” chemistry. ^[74]

Figure 7

Mechanism of the photoactivated thiol‐“yne” reaction. A photoinitiator can be used to accelerate the formation of a thiyl radical by S−H abstraction.

Figure 8

Photoactivated thiol‐“yne” macrocyclisation to generate a vinyl sulfide‐linked cyclic peptide. ^[71]

Figure 9

Mechanism of the intermolecular reaction between a photoexcited benzophenone and an accessible C−H bond.

Figure 10

Macrocyclisation through the conjugation of benzophenone to methionine under UV irradiation. By placing the unnatural amino acid Aib at all other positions, potential side reactions with α‐hydrogens are prevented. ^[80]

Figure 11

Structures of the unnatural benzophenone‐containing amino acids Bpa 28 and BpAib 31.

Figure 12

Mechanism of 5‐bromo‐7‐nitroindoline (Bni)‐amide photoactivation and nucleophilic cleavage. In water, intermediate 34 generates nitroso‐indole 35. In contrast, in the presence of a nucleophile or nucleophilic solvent nitro‐indoline 36 is generated.[ ⁸³ , ⁸⁴ ]

Figure 13

Solution‐phase head‐to‐tail macrocyclisation of a peptide containing a C‐terminal Bni‐amide under UV irradiation. ^[86]

Figure 14

Mechanism of 2,5‐diaryl tetrazole photoactivation to form a nitrile imine, and subsequent 1,3‐dipolar cycloaddition with a suitable dipolarophile.

Figure 15

Macrocyclisation of tetrazole‐ and alkene‐containing peptides under UV irradiation, by the formation of an intermediate reactive nitrile imine and subsequent 1,3‐dipolar cycloaddition. ^[97]

Figure 16

Thiomaleimide [2+2] cycloaddition under UV irradiation to generate a macrocyclic peptide. ^[101]

Figure 17

First example of a PET‐initiated macrocyclisation by Griesbeck and co‐workers. a) Mechanism of cyclisation. b) Cyclisation of an amide‐containing substrate. ^[106]

Figure 18

PET‐initiated macrocyclisation of phthalimide‐containing peptide substrates under UV irradiation.[ ¹⁰⁷ , ¹⁰⁸ ]

Figure 19

PET‐induced macrocyclisation of phthalimide‐containing peptides composed of proteinogenic amino acids.[ ¹⁰⁷ , ¹⁰⁸ ]

Figure 20

PET‐initiated cyclisation of N‐adamantyl phthalimides to C‐terminal phenylalanine derivatives. The stereochemistry of the resultant products was dictated by ring size. ^[111]

Figure 21

Mechanism of PET‐initiated macrocyclisation of N‐adamantyl phthalimides to C‐terminal phenylalanine derivatives. Phenylalanine‐based substrates undergo an analogous PET process to that outlined in Figure 17. In contrast, mono‐ and di‐methoxy‐substituted phenylalanines undergo an intermediate generation of an aryl radical cation. ^[111]

Figure 22

Peptide macrocyclisation via PET from C‐terminal N‐trimethylsilylmethyl amides to an excited‐state phthalimide.[ ¹¹⁰ , ¹¹⁴ ]

Figure 23

Possible catalytic quenching cycles of a photoexcited photoredox catalyst PC*.

Figure 24

Mechanism of photoredox formation of disulfide bonds via a reductive quenching cycle.

Figure 25

Photoredox‐mediated peptide macrocyclisation to form a disulfide linkage, catalysed by A) eosin Y ^[132] and B) TiO₂. ^[133]

Figure 26

Mechanism of photoredox‐catalysed macrocyclisation via the Giese reaction.

Figure 27

First example of a photoredox‐mediated Giese reaction for peptide macrocyclisation. [a] 10 mol % 2,4,6‐triisopropylthiophenol added. [b] Pra=propargylglycine. [c] N‐Me‐Ala=N‐methyl alanine. ^[135]

Figure 28

Alternative C‐ and N‐terminal functionalities for the Giese macrocyclisation of peptide substrates. [a] N‐Me‐Leu=N‐methyl leucine. [b] Reaction performed in DMSO. [c] ACC=1‐Aminocyclopropane‐1‐carboxylic acid. [d] AC5=Cycloleucine. [e] Yield over two steps, following removal of protecting groups with TFA/PhOH/H₂O/iPr₃SiH (88:5:5:2) at 0 °C for 2 h. ^[135]

Figure 29

Mechanism of dual photoredox–nickel catalysis for the macrocyclic etherification of alcohols with aryl bromides.

Figure 30

Dual photoredox–nickel catalysis for peptide macrocyclisation. ^[145]