A Post-Synthetic Modification Strategy for the Preparation of Homooligomers of 3-Amino-1-methylazetidine-3-carboxylic Acid

Abstract

Post-synthetic modification is a powerful technique allowing access to non-canonical peptide derivatives in a selective manner, but it has not so far been applied for the installation of multiple arrays of modified side chains. Here, we use this approach in solution phase to prepare short N- and C-capped homooligomers of 3-amino-1-methylazetidine-3-carboxylic acid with all the azetidine side chain functions in free amine form. The key step is the multiple reductive amination reaction of the corresponding post-synthetically deprotected secondary amines.

trans-3-Benzyloxycarbonylamino-1-methyl-3-(methylcarbamoyl)azetidine-1-oxide

“…We recently prepared 3-amino-1-methylazetidine-3-carboxylic acid, abbreviated as Aatc(Me), and short peptide derivatives thereof [15][16][17]. The derivative Cbz-Aatc(Me)-NHMe 4 appeared to offer a new opportunity to examine the potential stabilization effects of hydrogen bonding in its corresponding N-oxide, so we undertook its preparation and study.…”

“…Cbz-Aatc(Me)-NHMe 4 was prepared according to the literature [16]. Commercial m-CPBA was purified according to a standard procedure [18].…”

“…The relative stability of these compounds with respect to other azetidine N-oxides was rationalized by 6-membered ring intramolecular hydrogen bonds (Figure 1), which was supported by an X-ray diffraction study on a crystal of 1. We recently prepared 3-amino-1-methylazetidine-3-carboxylic acid, abbreviated as Aatc(Me), and short peptide derivatives thereof [15][16][17]. The derivative Cbz-Aatc(Me)- NHMe 4 appeared to offer a new opportunity to examine the potential stabilization effects of hydrogen bonding in its corresponding N-oxide, so we undertook its preparation and study.…”

Length-Dependent Transition from Extended to Folded Shapes in Short Oligomers of an Azetidine-Based α-Amino Acid: The Critical Role of NH···N H-Bonds

“…Samples of compounds 1 – 3 were prepared as described in the literature [ 40 , 60 ]. Their gas phase spectra were obtained according to a procedure described in detail previously [ 47 ].…”