Photocyclization of Tetra- and Pentapeptides Containing Adamantylphthalimide and Phenylalanines: Reaction Efficiency and Diastereoselectivity

Abstract

A series of tetrapeptides and pentapeptides was synthesized bearing a phthalimide chromophore at the N-terminus. The C-terminus of the peptides was strategically substituted with an amino acid, Phe, Phe­(OMe), or Phe­(OMe)2 characterized by different oxidation potentials. The photochemical reactivity of the peptides was investigated by preparative irradiation and isolation of photoproducts, as well as with laser flash photolysis. Upon photoexcitation, the peptides undergo photoinduced electron transfer (PET) and decarboxylation, followed by diastereoselective cyclization with the retention of configuration for tetrapeptides or inversion of configuration for pentapeptides. Molecular dynamics (MD) simulations and NOE experiments enabled assignment of the stereochemistry of the cyclic peptides. MD simulations of the linear peptides disclosed conformational reasons for the observed diastereoselectivity, being due to the peptide backbone spatial orientation imposed by the Phe amino acids. The photochemical efficiency for the decarboxylation and cyclization is not dependent on the peptide length, but it depends on the oxidation potential of the amino acid at the C-terminus. The results described herein are particularly important for the rational design of efficient photochemical reactions for the preparation of cyclic peptides with the desired selectivity.

Photochemical Methods for Peptide Macrocyclisation

“…Vazdar, Basarić, and co‐workers subsequently applied PET‐mediated decarboxylative cyclisation to tetra‐ and pentapeptides 60 bearing N‐terminal adamantyl phthalimides and C‐terminal phenylalanines, or methoxylated analogues thereof (Figure 20). [111] Products 61 were found to reside as open chain amides, rather than the amidol structures observed in previous reports, and hence are fully peptidic albeit containing an unusual, and potentially metabolically vulnerable, phenyl ketone unit [112] . Interestingly, the macrocycles were formed as single diastereomers (with the exception of 61 d ), with the newly formed chiral centre found to be inverted between 17‐ or 20‐membered ring sizes.…”

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

“…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] …”

“…The stereochemistry of the resultantp roducts was dictatedbyr ing size. [111] Figure 21. Mechanism of PET-initiatedm acrocyclisationofN-adamantyl phthalimides to C-terminal phenylalanine derivatives.…”

[3 + 2] Cycloaddition with photogenerated azomethine ylides in β-cyclodextrin

“…We found out that H-abstraction reactions were about ten times more efficient in the β-CD complexes than in the isotropic solution, and the macrocyclic host affected the stereochemistry of the reaction. Moreover, we studied photodecarboxylation reactions initiated by the phthalimide chromophore [17][18][19] and applied them in cyclizations with memory of chirality [20] and diastereoselective peptide cyclizations [21]. Photodecarboxylations were also intensively investigated in a series of nonsteroidal anti-inflammatory drugs [22][23][24] such as ketoprofen [25][26][27][28][29][30][31][32][33][34], due to photoallergic responses initiated by photodecarboxylation of these drugs [35].…”