Expedient Solution‐Phase Synthesis and NMR Studies of Arylopeptoids

Abstract

The development of a highly convenient and efficient protocol for iterative solution-phase synthesis of shorter oligomers of para-and meta-arylopeptoids is described. Peptide coupling methods for accessing longer oligomers were studied: use of the new coupling reagent COMU was found to be the most efficient for creation of the tertiary benzamide bonds.

Aromatic Oligoamides with a Rare ortho‐Connectivity: Synthesis and Study of ortho‐Arylopeptoids

“…We have previously undertaken the first conformational studies of meta ‐ and para ‐arylopeptoids by means of NMR spectroscopy 12a,12c. Intriguingly, we found that the tert ‐butyl and phenyl side chains represented particularly interesting cases because only single, sharp sets of signals were observed in the spectra of meta ‐ and para ‐arylopeptoids carrying these side chains.…”

“…at 0 °C to room temp. overnight 12c. We were satisfied to find that this method could be adapted directly to the synthesis of ortho ‐arylopeptoids 2a – 4a and 2b – 4b simply by using 2‐(bromomethyl)benzoyl bromide instead.…”

“…We initiated our work on ortho ‐arylopeptoids by studying the feasibility of solution‐phase submonomer synthesis (Scheme ). We opted for the use of tert ‐butyl 2‐(bromomethyl)benzoate ( 1 )18 as starting material because the tert ‐butyl group may eventually serve in selective postsynthesis removal and modification as we have previously demonstrated in both peptoids and arylopeptoids 12c,19. Three series were studied, originating from the use of three different simple aliphatic amines in the substitution steps: series a carrying the least bulky ethyl side chains, series b decorated with the moderately bulky isopropyl side chains, and series c , carrying the highly bulky tert ‐butyl side chains (Scheme and Table 1).…”

“…was needed for the reactions to proceed to completion. This was also necessary for the corresponding meta ‐ and para ‐arylopeptoids,12c and with this modification each residue was formed in comparably high yield (78–89 %). Solution‐phase synthesis is useful for accessing products on gram‐scale and, overall, the methods previously developed by us for solution‐phase synthesis of meta ‐ and para ‐arylopeptoids could be adapted directly to the synthesis of ortho ‐arylopeptoids.…”

“…Since then, we have begun to unveil the potential of this promising class of aromatic oligoamides by developing greatly improved synthetic methods and undertaking the first conformational studies. Thus, we have recently developed the first convenient solution‐phase synthesis of meta ‐ and para ‐arylopeptoids using bromomethyl benzoyl bromides in the coupling steps,12c and two solid‐phase methodologies based on the use of either COMU‐activated chloromethylbenzoic acids12b or chloromethylbenzoyl chlorides12a in the coupling steps. These methods all rely on “submonomer” approaches wherein the arylopeptoid residues are created in an iterative manner directly on the growing oligoamide chains using a unique acylation‐substitution cycle.…”