Synthesis of an enantiopure isoxazolidine monomer for β3-aspartic acid in chemoselective β-oligopeptide synthesis

Abstract

The synthesis of an enantiopure isoxazolidine monomer for the incorporation of β 3 -apartic acid residues into β 3 -oligopeptides via chemoselective α-ketoacid-hydroxylamine amide formation. This route involves nitrone cycloaddition of 3-thiophenylpropanal and circumvents limitations of other potential starting materialsWe have recently reported a highly chemoselective amide-bond forming reaction between α-ketoacids and hydroxylamines. i In addition to its potential for the fragment coupling of unprotected α-peptide fragments, we have explored its application to the iterative, aqueous synthesis of oligo-β 3 -peptides, ii an exciting class of peptidomimetics of contemporary interest in medicinal and bioorganic chemistry. iii Our novel approach to the synthesis of these oligopeptides takes advantage of the chemoselective coupling of a growing β-peptide chain with chiral isoxazolidines. The amide formation results in N-O bond cleavage and the formation of an α-ketoester. Following hydrolysis, the chain is poised for iterative elongation (Scheme 1). The key amide forming reaction requires no reagents, produces only carbon dioxide and methanol as byproducts (Scheme 2), and operates in the presence of unprotected functional groups including amines and carboxylic acids. As such, it offers great potential as an alternative route to the preparation of β-oligopeptides that circumvents challenges of the established methods including difficult couplings and deprotections in longer β-peptide chains and improved access to the requisite β-peptide monomers.The major challenge to the widespread adoption of this method for β 3 -peptide synthesis is the need to prepare the isoxazolidine monomers as single enantiomers. We have reported the use of Vasella's mannose-derived nitrones iv as chiral auxiliaries for their asymmetric synthesis via 1,3-dipolar cycloaddition with 2-methoxymethacrylate (Scheme 3). Following purification of the cycloadducts and removal of the auxiliary, the desired isoxazolidine monomers are obtained, in most cases, in enantiomerically pure form. This approach has proven successful for the synthesis of isoxazolidine monomers bearing most of the common amino acid sidechains, including those found in leucine, valine, phenylalanine, lysine, glutamic acid, glycine, and numerous others. Unfortunately, this procedure fails for the most logical synthetic *Corresponding author. Tel.: +1-215-573-1953; e-mail: bode@sas.upenn.edu. Supplementary MaterialExperimental procedures, characterization data, and 1 H and 13 C NMR spectra for all new compounds.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply...

KAHA Ligations That Form Aspartyl Aldehyde Residues as Synthetic Handles for Protein Modification and Purification

“…16 As part of ongoing efforts to design new stable hydroxylamines that afford other unnatural or natural residues at the ligation site, we considered the possibility of using KAHA ligation to reveal an aldehyde upon N−O bond cleavage. In the context of the synthesis of short β 3 -peptides, we have described isoxazolidine monomers that form ketones upon ligation, 17 but it was not clear if a corresponding design for an aldehydeforming substrate would be sufficiently stable to peptide cleavage, HPLC purification, and ligation. Furthermore, the increased steric hindrance could interfere with the ligation of longer peptides.…”

Organocatalytic Selective [3 + 2] Cycloadditions: Synthesis of Functionalized 5-Arylthiomethyl-1,2,3-triazoles and 4-Arylthio-1,2,3-triazoles

“…All solvents and commercially available chemicals were used as received without further purification unless otherwise stated. Starting materials 1a – 1h , 6a , 10a – 10c , 13a , and 17a – 17c , were synthesized based on the previous literature methods.…”