Progress in the preparation of peptide aldehydes via polymer supported IBX oxidation and scavenging by threonyl resin

Abstract

Peptide aldehydes are of interest due to their inhibitory properties toward numerous classes of proteolytic enzymes such as caspases or the proteasome. A novel access to peptide aldehydes is described using a combination of solid phase peptide synthesis with polymer-assisted solution phase synthesis based on the oxidation of peptide alcohols with a mild and selective polymer-bound IBX derivative. The oxidation is followed by selective purification via scavenging the peptide aldehyde in a capture-release procedure using threonine attached to an aminomethyl resin. Peptide aldehydes are obtained in excellent purity and satisfying yield. The optical integrity of the C-terminal residue is conserved in a high degree. The procedures are compatible with the use of common side-chain protecting groups. The potential for using the method in parallel approaches is very advantageous. A small collection of new and known peptide aldehydes has been tested for inhibitory activity against caspases 1 and 3.

An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS‐CoV Mpro) Inhibitors

“…In particular it would be desirable to have a method that yielded pure peptide aldehydes directly by cleavage from the resin without tedious isolation procedures, such as crystallization or chromatography. [31] Ede and Bray have described the first step for this by introducing a threonine-based oxazolidine linker on "Synphase Crowns", that is, polyethylene carriers grafted to a copolymer of methacrylic acid and dimethylacrylamide. [19] Recently, this linker has been employed with polystyrene in a catch-andrelease protocol to purify peptide aldehydes that were first prepared by polymer-supported IBX in solution.…”

“…Great efforts have been made to optimize these approaches in solution, [23][24][25] in the solid phase, [20,[26][27][28][29] and by the use of polymer reagents. [30,31] For the efficient preparation of peptide aldehyde libraries, it would be advantageous to enhance the efficiency of solid-phase peptide synthesis. In particular it would be desirable to have a method that yielded pure peptide aldehydes directly by cleavage from the resin without tedious isolation procedures, such as crystallization or chromatography.…”

“…Additionally, in the case of both 1UK4 protomers, the terminal valine of the CMK inhibitor has no visible density. and to S4 in mode II) was varied by using F, D, E, H, and Q, thereby testing the FlexX predictions for S4 (31)(32)(33)(34)(35). Finally two compounds were synthesized with substitutions at multiple positions (36,37).…”

Novel Polymer and Linker Reagents for the Preparation of Protease‐Inhibitor Libraries

“…A polymer-supported approach employing oxidizing IBX-resin could be a valuable contribution to solving the task [29]. Thus, a collection of 24 C-terminal peptide alcohols was synthesized on trityl resin.…”

Synthesis of β‐Amino Alcohols Using Ethyl 2‐Cyano‐2‐(2‐nitrobenzenesulfonyloxyimino)acetate (o‐NosylOXY)

“…These alcohols are the key intermediates for the synthesis of β ‐amino acids, long chain diamines and tetramines, several insecticides, ligands and chiral auxiliaries in asymmetric synthesis . Besides, aldehydes resulted from the oxidation of β ‐amino alcohols serve as inhibitors of HIV‐protease or are used for the synthesis of stereochemical methylene‐oxy dipeptides . Moreover, β ‐Amino alcohols have a broad range of applications in medicinal chemistry.…”