Peptide isocyanates

Scheme 4 Formation of a Peptide Isocyanate Using Phosgene or Triphosgene and its Reaction with an Aniline Derivative to Produce a Ureine Peptide[1S1...

Amino acid ester isocyanates are produced cleanly by this method and can often be used without purification. If desired, volatile amino acid ester isocyanates, such as the title compound, can be purified to analytical purity by Kugelrohr distillation. The amino acid ester isocyanates generated by this method are formed without detectable racemization (>99.5% ee) the er antiomeric purity of the isocyanates can be checked by trapping with (S)-l-phenylethylamine, followed by 1H NMR analysis of the resulting urea adducts.2 If this method is used to generate isocyanates of peptides, then efficient stirring is necessary to prevent epimerization of the peptide isocyanates.3 4... 

Peptide isocyanates 454 have been prepared using triphosgene (0.7 mmol/mmol peptide hydrochloride) 453 under milder reaction conditions, so as to minimize the formation of hydantoins 455 and other side products [313]. 

For the preparation of many other peptide isocyanates, phosgene, either neat or in toluene solution, rather than triphosgene was preferred. 

Mass spectral fragmentation patterns of alkyl and phenyl hydantoins have been investigated by means of labeling techniques (28—30), and similar studies have also been carried out for thiohydantoins (31,32). In all cases, breakdown of the hydantoin ring occurs by a-ftssion at C-4 with concomitant loss of carbon monoxide and an isocyanate molecule. In the case of aryl derivatives, the ease of formation of Ar—NCO is related to the electronic properties of the aryl ring substituents (33). Mass spectrometry has been used for identification of the phenylthiohydantoin derivatives formed from amino acids during peptide sequence determination by the Edman method (34). 

Substitution of alkaline cyanates by isocyanates allows the preparation of 3-substituted hydantoias, both from amino acids (64) and amino nitriles (65). The related reaction between a-amino acids and phenyl isothiocyanate to yield 5-substituted 3-phenyl-2-thiohydantoiQS has been used for the analytical characterization of amino acids, and is the basis of the Edman method for the sequential degradation of peptides with concomitant identification of the /V-terminal amino acid. 

The structures of these ylide polymers were determined and confirmed by IR and NMR spectra. These were the first stable sulfonium ylide polymers reported in the literature. They are very important for such industrial uses as ion-exchange resins, polymer supports, peptide synthesis, polymeric reagent, and polyelectrolytes. Also in 1977, Hass and Moreau [60] found that when poly(4-vinylpyridine) was quaternized with bromomalonamide, two polymeric quaternary salts resulted. These polyelectrolyte products were subjected to thermal decyana-tion at 7200°C to give isocyanic acid or its isomer, cyanic acid. The addition of base to the solution of polyelectro-lyte in water gave a yellow polymeric ylide. 

In another report, aspects for automating preparative chemistry are described [130]. A comprehensive description of the Ugi reaction is given in [132] and the vision of a micro multi-component reaction as automated parallel micro-channel synthesis is sketched. An interesting point is to convert aldehydes, chiral primary amines, carboxylic adds and isocyanates into corresponding a-amino acids and peptides (U-4CR). 

Carbonyldiimidazole has been used for the preparation of such compounds as esters, anhydrides, amides, peptides, ketones, ethers, and isocyanates.2 The present procedure provides a convenient method for its preparation in good yield. 

Reaction of an isocyanate with an amino acid or peptide hydrazide affords products with a central azaamino acid residue 3,10,19 20 (Scheme 3). 

Goodman and Chorev 75 found that the required a-aminoacyl azides 14 are best prepared by reaction of the mixed anhydride of the amino acid with sodium azide. This method led to slightly better yields than the nitrosylation of TV-formylaminoacyl hydrazide. Curtius rearrangement of the a-aminoacyl azide 14 yielded the isocyanate 16, which was subsequently trapped as 17 or 18 as shown in Scheme 2. Comparable yields were obtained by nitrosylation with tert-butyl nitrite. 76 Other methods of acyl azide formation have rarely been employed for PMRI-peptide synthesis. Only Fincham et al. 11 reported the use of trimethylsilyl azide to synthesize an acyl azide en route to a PMRI-peptide. 

Scheme 3 Addition of an Available Isocyanate to an N -Free Peptide to Produce a Ureine Peptide I10 ...

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