Racemization-Free Chemoenzymatic Peptide Synthesis Enabled by the Ruthenium-Catalyzed Synthesis of Peptide Enol Esters via Alkyne-Addition and Subsequent Conversion Using Alcalase-Cross-Linked Enzyme Aggregates

The C‐terminal activation of peptides as prerequisite for the formation or ligation of peptide fragments is often associated with the problem of epimerization. We report that ruthenium‐catalyzed alkyne addition with (+)‐2,3‐O‐isopropylidene‐2,3‐dihydroxy‐1,4‐bis(diphenylphosphino)butane as ligand al...

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Bibliographic Details
Published in:Advanced synthesis & catalysis 2013-06, Vol.355 (9), p.1799-1807
Main Authors: Schröder, Hilmar, Strohmeier, Gernot A., Leypold, Mario, Nuijens, Timo, Quaedflieg, Peter J. L. M., Breinbauer, Rolf
Format: Article
Language:English
Subjects:
alcalase
Alkynes
Amino acids
biocatalysis
Chains
enol esters
Esters
Fragments
peptide synthesis
Peptides
ruthenium
Solvents
Synthesis
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Summary:The C‐terminal activation of peptides as prerequisite for the formation or ligation of peptide fragments is often associated with the problem of epimerization. We report that ruthenium‐catalyzed alkyne addition with (+)‐2,3‐O‐isopropylidene‐2,3‐dihydroxy‐1,4‐bis(diphenylphosphino)butane as ligand allows the racemization‐free synthesis of peptide enol esters tolerating a wide range of functional groups. The transformation can be performed in a variety of different solvents addressing the solubility issues imposed by peptides with varying amino acid side chain patterns. We show that peptide enol esters with an amide motif in the enol moiety are excellent acyl donors for the peptide condensation with other peptide fragments in organic solvents using serine endopeptidase subtilisin A as catalyst. The reported combination of transition metal catalysis with enzymatic peptide ligations adds an important tool for the racemization‐free synthesis and ligation of peptides which is compatible even with unprotected amino acid side chains.
ISSN:1615-4150
1615-4169
DOI:10.1002/adsc.201200423