Preparation of Peptide Aldehyde Collections

Peptide aldehydes are important biochemical tools for specific and reversible inhibition of serine, cysteine, and aspartate proteases in-vitro and in-vivo. Whereas several methods for the preparation of peptide aldehydes have been described [26-28], their reliable parallel synthesis remained a tedious endeavor. Peptide aldehydes suffer from configurational lability in the a-carbonyl position and from high chemical reactivity.

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 pep-tide alcohols was synthesized on trityl resin. Cleavage of the fully protected alcohols could be effected by treatment with hexafluoroisopropanol. The lyophilized pure products were then treated with 2 equiv. IBX-resin for 2 h. Conversions could be followed by NMR spectroscopy (Figure 3.6.6). A single aldehyde signal indicated conversion to the peptide aldehydes without racemization. Prolonged storage in

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Fig. 3.6.6. Smooth and racemization-free polymer-assisted preparation of peptide aldehydes with oxidizing polymer 5. Racemization of the peptide aldehydes was effected by acid treatment and monitored by 1H-NMR at 9.3-9.5 ppm.

Fig. 3.6.6. Smooth and racemization-free polymer-assisted preparation of peptide aldehydes with oxidizing polymer 5. Racemization of the peptide aldehydes was effected by acid treatment and monitored by 1H-NMR at 9.3-9.5 ppm.

CDCl3 solution led to the slow formation of a second diastereomer. Heating in dilute acetic acid (60 °C) effected rapid racemization.

Prolonged storage and release of pure peptide aldehydes could be realized by a threonine-scavenging resin. Peptide aldehydes were scavenged directly from the oxidation solution after washing, drying, and storage of the peptide aldehyde as C-terminal 1,3-oxazolidine derivative. Release of pure peptide aldehydes was effected by treatment with 1% AcOH at room temperature (Figure 3.6.7).

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