[103-72-0] · C7H5NS · Phenyl Isothiocyanate · (MW 135.20)
(Edman degradation of peptides; synthesis of heterocyclic systems)
Physical Data: bp 221 °C; mp -21 °C; d 1.1288 g cm-3.
Solubility: insol H2O; sol alcohol, ether.
Form Supplied in: liquid; widely available.
Handling, Storage, and Precautions: use in a fume hood.
Identification of terminal amino acid residues of peptides can readily be accomplished by an Edman degradation.1 Treatment of the peptide with phenyl isothiocyanate in pyridine-water (1:1) produces a phenylthiocarbamoyl derivative which, upon exposure to anhydrous Hydrogen Chloride in nitromethane, rapidly cleaves to form a 3-phenyl-2-thiohydantoin and a peptide with one less amino acid residue. If needed, the free amino acid can be isolated by hydrolysis of the thiohydantoin with Barium Hydroxide (eq 1).
The procedure, which is amenable to complex peptides containing a variety of sensitive functionalities, has been applied to the vancomycin group of antibiotics,2-4 and was instrumental in the structure elucidation of avoparcin (1).5,6 In this case, the thiohydantoin of the deoxysugar amino acid fragment forms in the first step without a need for acid-catalyzed cyclization.
An interesting method for the resolution of amines involves preparing its amide with L-phenylalanine. Chromatographic separation of the corresponding diastereomers followed by an Edman degradation furnishes either pure enantiomer (eq 2).7 In this manner, dibenzo[a,d]cycloalkenimines (2)8 and 3-amino-1-hydroxypyrrolidin-2-one (3)9 have been resolved and evaluated for their N-methyl-D-aspartate and glycine antagonist activities, respectively.
The elements of phenyl isothiocyanate can be incorporated into cyclization motifs to form a variety of heterocyclic systems. For example, treatment of 2-amino-5-chlorobenzhydrol with phenyl isothiocyanate, followed by cyclization of the intermediate thiourea with dilute HCl, produces 6-chloro-3,4-diphenyl-2-thioxo-1,2,3,4-tetrahydroquinazoline in 60% yield (eq 3).10
The core of the penem heterocyclic system can readily be assembled using phenyl isothiocyanate to supply the sulfur and one carbon atom for its five-membered ring. Treatment of a suitable azetidinone with Lithium Hexamethyldisilazide at -40 °C, followed by phenyl isothiocyanate and acetic anhydride, affords a ketene derivative. Deprotection, chlorinolysis, and hydrolysis produce the 2-phenylaminopenem (eq 4).11
N-Benzoylanthranilic acid, when heated with phenyl isothiocyanate at 160-170 °C in the presence of Pyridine as a catalyst, gives 2-phenyl-3,1-benzoxazin-4-one in 30% yield (eq 5).12 Analogously, oxazolones are produced by a phenyl isothiocyanate-mediated cyclodehydration of N-acylglycines at 160-170 °C.13,14 When the reaction is performed in the presence of a salicylaldehyde, 3-N-acylaminocoumarins are isolated in yields of 20-68% (eq 6).15
Gary M. Coppola
Sandoz Research Institute, East Hanover, NJ, USA