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. 2024 Jan 8;30(2):e202302937.
doi: 10.1002/chem.202302937. Epub 2023 Nov 16.

2-Pyridone Formation: An Efficient Method for the Solid-Phase Synthesis of Homodimers

Skander A Abboud  1 , Thomas Kodadek  1
Affiliations

2-Pyridone Formation: An Efficient Method for the Solid-Phase Synthesis of Homodimers

Skander A Abboud et al. Chemistry. .

Abstract

This study presents an efficient method for on-resin dimer generation through self-condensation of 3,3-dimethoxypropionic acid-modified molecules, resulting in 2-pyridones. The approach demonstrated remarkable versatility by producing homodimers of peptides, peptoids, and non-peptidic ligands. Its ease of application, broad utility, and mild reaction conditions not only hold significance for peptide and peptoid research but also offer potential for the on-resin development of a wide range of bivalent ligands.

Keywords: Homodimer; Pyridone; Solid-phase synthesis; peptide.

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Figures

Figure 1.
Figure 1.
(A) Dimerization of model tripeptides. (B) HPLC chromatogram showing incomplete dimerization when Boc protection was used. (C) HPLC chromatogram showing complete dimerization when Alloc protection was used.
Figure 2.
Figure 2.
(A-B) On-resin dimerization of the model peptides 6 and 6-Spacer (C) HPLC chromatogram of the dimerization reaction after 15 h. (D) HPLC chromatogram of the dimerization reaction after 64 h. (E) HPLC chromatogram of the dimerization reaction on a HL TentaGel resin. (F) HPLC chromatogram of the dimerization reaction when an EG spacer was added before the acetal group.
Figure 3.
Figure 3.
(A) On-resin synthesis of WJ657, a HOMO bivalent VHL degrader. (B) HPLC chromatogram of the crude compound generated through on-resin synthesis (C) HPLC chromatogram of the crude compound generated through on-resin Microwave-Assisted synthesis. (D) MS spectrum of the crude WJ657.
Figure 4.
Figure 4.
(A) Synthesis of pyridone linked GU40C dimer 12. (B) HPLC chromatogram of the crude compound. (C) MS spectrum of crude 12.
Figure 5.
Figure 5.
(A) Synthesis of pyridone linked Anoplin dimer 14. (B-C) HPLC chromatograms of the crude and purified compound 14. (D) MS spectrum of purified 14.
Scheme 1.
Scheme 1.
Mechanism of the acid-catalysed homodimerization of b-formyl acetamides to form 2-pyridones.
Scheme 2.
Scheme 2.
Reaction for testing amino acid scope.
Scheme 3.
Scheme 3.
Influence of glycol linker introduction on dimerization reaction.
Scheme 4.
Scheme 4.
On-resin pyridone formation triggered by I2 in acetone.
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