Hydantoin-Free Synthesis of Peptide Ester Isocyanates, Isothiocyanates, and Dipeptidyl Ureas: The Application of Zinc Dust in a Carbonylation Procedure without Base

Abstract

Non-Schotten-Baumann conditions are described for the hydantoin-free synthesis of peptide ester isocyanates using activated zinc dust as a non-basic HCl scavenger. Also, the procedure gives no N-acylated products in the case of the conversion of amino acid and peptide amides into isocyanates.

Key words

zinc dust - peptide ester isocyanates - isothiocyanates - base-free synthesis - peptidyl ureas - thioureas

References

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• 12a

  An authentic sample of hydantoin was prepared from isocyanate 2a. To confirm the present protocol is free from hydantoin formation (see Supporting Information).

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9

Phosgene in toluene can be used in stoichiometric amounts, forms no byproducts and the unreacted portion, if any, can be completely removed simply through evaporation. On the other hand, other carbonylating agents including triphosgene and the byproducts they form have to be separated from isocyanates either through extraction with aqueous solvents or column chromatography, conditions that tend to reduce the yields of peptide ester isocyanate. Also, in case of phosgene the co-product of acylation, HCl, can be neutralized using non-basic reagent zinc without raising the pH of the medium. Consequently, we chose this reagent in spite of its known safety concerns.

11

HPLC was carried out on Agilent 1100 using an Agilent EcilpseXDB-C18 G1311A column (4.6 × 150 mm, 5 µm) and a gradient of 0.1% TFA in H₂O-MeCN 30-90% in 30 min with spectrometric monitoring at λ = 215 nm. HPLC profile of the crude 3a showed a sharp single peak at
t _R = 20.045 min with a purity of 95%.