Solid-Phase Photochemical Peptide Homologation Cyclization

Abstract

Forging new C(sp 3 )−C(sp 3 ) bonds to central positions within a peptide backbone is critical for the development of new therapeutics and chemical probes. Currently, there are no methods for decarboxylating Asp and Glu side chains solid-phase photochemically or using such radicals to form peptide macrocycles. Herein, electron-donor-acceptor complexes between Hantzsch ester and on-resin peptide N-hydroxyphthalimide radical precursors are used to access these radicals, demonstrated with two-carbon homologations and homologation cyclizations of Atosiban and RGDf.

Side-Selective Solid-Phase Metallaphotoredox N(in)-Arylation of Peptides

“…In this regard, Molander’s and Chenoweth’s groups have demonstrated the on-resin photochemical decarboxylative hydroalkylation, for the homologation and cyclization of peptides through a Giese radical type-addition, using redox-active ester (RAE) derivatives as radical precursors. , Besides, Hart’s group described the photochemical deaminative hydroalkylation of lysine-derived Katritzky salt-containing peptides in solid phase . However, both methodologies require the previous peptide elaboration as acrylic, RAE, and pyridinium salt derivatives.…”

On-resin Photochemical Decarboxylative Arylation of Peptides

“…25,26 Solid-phase activation of Asp and Glu side chain carboxylic acids with NHPI has previously been performed using excesses of a dicarbodiimide or hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) and various bases. 27,28 However, in these reports, this was performed with proline as the neighbouring amino acid which eliminates the possibility for aspartimide formation but limits the applicability to peptide sequences with an Asp-Pro pair. Instead, we wanted to create a general protocol that avoids this side reaction irrespective of the nature of the next amino acid.…”

On-Resin Photochemical Decarboxylative Arylation of Peptides

“…Briefly, the N -terminally acetylated tripeptide was synthesized on a Rink amide polystyrene (PS) resin, followed by removal of the allyl side-chain protecting group of Asp by treatment with Pd­(PPh 3 ) 4 and phenylsilane (Scheme S1). Next, N -hydroxypthalimide (NHPI) was to be coupled to the free acid to obtain the RAE, but this was complicated by aspartimide formation. , Solid-phase activation of Asp and Glu side-chain carboxylic acids with NHPI has previously been performed using excesses of carbodiimide or hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) and various bases. , However, in these reports, proline was always used as the neighboring amino acid, eliminating the possibility for aspartimide formation but restricting the applicability to peptide sequences with an Asp-Pro pair. Instead, we looked for a general protocol that avoids this side reaction, irrespective of the nature of the next amino acid.…”

“… 26 , 27 Solid-phase activation of Asp and Glu side-chain carboxylic acids with NHPI has previously been performed using excesses of carbodiimide or hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) and various bases. 28 , 29 However, in these reports, proline was always used as the neighboring amino acid, eliminating the possibility for aspartimide formation but restricting the applicability to peptide sequences with an Asp-Pro pair. Instead, we looked for a general protocol that avoids this side reaction, irrespective of the nature of the next amino acid.…”