Solid Phase Synthesis of Aromatic Oligoamides: Application to Helical Water-Soluble Foldamers

Abstract

Synthetic helical aromatic amide foldamers and in particular those based on quinolines have recently attracted much interest due to their capacity to adopt bioinspired folded conformations that are highly stable and predictable. Additionally, the introduction of water-solubilizing side chains has allowed to evidence promising biological activities. It has also created the need for methods that may allow the parallel synthesis and screening of oligomers. Here, we describe the application of solid phase synthesis to speed up oligomer preparation and allow the introduction of various side chains. The synthesis of quinoline-based monomers bearing protected side chains is described along with conditions for activation, coupling, and deprotection on solid phase, followed by resin cleavage, side-chain deprotection, and HPLC purification. Oligomers having up to 8 units were thus synthesized. We found that solid phase synthesis is notably improved upon reducing resin loading and by applying microwave irradiation. We also demonstrate that the introduction of monomers bearing benzylic amines such as 6-aminomethyl-2-pyridinecarboxylic acid within the sequences of oligoquinolines make it possible to achieve couplings using a standard peptide coupling agent and constitute an interesting alternative to the use of acid chloride activation required by quinoline residues. The synthesis of a tetradecameric sequence was thus smoothly carried out. NMR solution structural studies show that these alternate aminomethyl-pyridine residues do not perturb the canonical helix folding of quinoline monomers in protic solvents, contrary to what was previously observed in nonprotic solvents.

Synthesis and characterization of new photoswitchable azobenzene-containing poly(ε-caprolactones)

“…The backbone azobenzene moiety of this photoswitchable polymer could be traced through its J-coupling. 52 In the H,H-COSY of polymer-1b, a long-range coupling by arrangement of protons is observed between the doublet at 7.77 ppm (2H, J ¼ 8.81 Hz) and the doublet at 6.66 ppm (2H, J ¼ 8.12 Hz). The upeld shied benzylic doublet is assigned to the protons orthoto the amide functionality (i.e., 2H, signal-e), whereas the low eld doublet is assigned to the protons ortho-to the amine group (i.e., 2H, signal-h).…”

Large-scale and chromatography-free synthesis of an octameric quinoline-based aromatic amide helical foldamer

“…Methanol was an effective crystallization solvent in all cases encountered so far 27,32 . Alternatively, side chains could be introduced using a Williamson alkylation with strong electrophiles such as benzyl bromide or bromo-acetate derivatives 33 .…”

“…When the side chains contain acid-labile functions, such as tertbutyl ester 30,33 or tert-butyl carbamate 27,30 , activation of the Cterminal acid function as an acid chloride should be carried out under neutral conditions. For this purpose, oxalyl chloride is not appropriate, as its reaction generates hydrochloric acid 34 .…”

“…For example, a variant of the helical octamer bearing ornithine-like ammonium side chains shows promise for several biological applications [27][28][29][30] , and a variant bearing oligoethylene oxide side chains was recently prepared to be endowed with solubility in a broad range of media 32 . Anionic, aspartate-like side chains have been introduced as well 30,33 . Third, these procedures can be relevant in multiple ways to many of the aromatic amide foldamers referred to above.…”

Solid Phase Synthesis of Helically Folded Aromatic Oligoamides

“…The synthesis of various Fmoc protected 8-amino-2-quinolinecarboxylic acid and 7-amino-8-fluoro-2-quinolinecarboxylic acid has been reported before (Baptiste et al 2010, Buratto et al 2014, Shang et al 2014)…”