Insoluble 1‐hydroxybenzotriazole‐bound polystyrene was prepared through a series of chemical modifications of commercially available polystyrene. Reaction of 3‐nitro‐4‐chlorobenzyl alcohol or of 3‐nitro‐4‐chlorobenzyl bromide with polystyrene in the presence of aluminium trichloride yielded (3‐nitro‐4‐chloro)benzylated polystyrene. Upon reaction with hydrazine it was converted to (3‐nitro‐4‐hydrazine)benzylated polystyrene which was cyclized, by acidolysis, to yield 1‐hydroxybenzotriazole‐bound polystyrene. This was coupled, using N,N'‐dicyclohexylcarbodiimide as the coupling agent, to many N‐blocked amino acid derivatives, yielding polymeric polystyrene‐bound active esters. Such derivatives are highly reactive and their efficacy in the synthesis of several peptides, including that of the tetrapeptide Boc‐l‐Leu‐l‐Leu‐l‐Val‐OBzl‐l‐Tyr‐OBzl and of thyrotropin‐releasing hormone was demonstrated.
Insoluble (4-hydroxy-3-nitr0)benzylated polystyrene (PHNB) was prepared by reacting 4-hydroxy-3-nitrobenzyl chloride with copolystyrene-2°/,-divinylbenzene in the presence of aluminium trichloride. PHNB-active esters of many N-blocked amino acids were prepared using dicyclohexylcarbodiimide as a coupling agent, and used for the preparation of di, tri and tetra-peptides. The synthesis of the tetra-peptide Boc-L-Leu-L-Leu-L-Val-OBzl-L-Tyr-OBzl, was effected by means of the polymeric active esters of Boc-L-Val and Boc-L-Leu. The synthesis was initiated by reacting 0-benzyl-L-tyrosine benzyl ester with Boc-Val-PHNB in dichloromethane to yield N-tert-butyloxycarbonyl-L-valyl-O-benzyl-L-tyrosine benzyl ester. Removal of the tert-butyloxycarbonyl group yielded a dipeptide ester which was coupled with the corresponding polymeric active ester to yield an N-blocked tripeptide ester. Repetition of this set of reactions led to the formation of the pure blocked tetrapeptide in 82O/, over-all yield.Peptide synthesis by means of polymeric reagents was introduced recently as a new approach to the preparation of peptides with a predetermined sequence [l--51. This process is based on the coupling of amino acids or peptide esters, possessing a free &-amino group, with high-molecular-weight insoluble active esters of N-blocked amino acids and crosslinked hydroxy polymers. The N-and C-blocked peptides obtained in such a reaction could be separated readily from the insoluble reagent and elongated after removal of the N-blocking group and coupling with an insoluble polyfunctional active ester of a desired N-blocked amino acid.The successful use of active ester derivatives of cross-linked poly-4-hydroxy-3-nitrostyrene in the synthesis of several peptides including the naturally occurring nonapeptide bradykinin has been described [I, 61. However, the following drawbacks were encountered during the course of peptide synthesis by means of these active esters. (a) The polymeric reagents tend to disintegrate during reactions and the products are sometimes contaminated with superfine particles of the polymer. (b) The acylation of amines with the polymeric active esters is strongly dependent on steric factors; it was observed, for example, that insoluble active esters in which the amino group of the amino acid was protected by carbobenzoxy group were more efficient acylating reagents than similar polymeric reagents containing the more bulky t-butyloxycarbonyl group 171. (c) The swelling properties of these active esters are such that only dimethylformamide could be employed as a solvent in the synthesis. (d) As a result of (c) continuous synthesis in columns is troublesome. Part of these difficulties might be due to the fact that the polymer was an amorphous powder and tends to change its physical properties during the reactions employed. I n order to overcome the above-mentioned difficulties we are describing a new type of polymeric carrier in which the active ester function was farther from the polymeric backbone than in the polymer origina...
The Fries rearrangement of acetoxy and benzyloxy esters of 4-hydroxy-3-nitrobenzylated polystyrene (14, gel type, and 15, macroreticular type) and 5-polystyrylmethyl-8-quinolinol (16, macroreticular type), and of a model compound (4-acetoxy-3-nitro)benzylated toluene (17b) was investigated in 1.8 M aluminum chloride in nitrobenzene. It was found that with 14b, 15b, and 17b the acylium ion is transferred exclusively to the nonphenolic aromatic ring. The evidence for this is provided from mass spectra (of 19b), IR spectroscopy, and copper complexation studies. Interpolymeric reactions, performed in the presence of a polymeric acceptor, proved that an oxocarbonium ion is an intermediate in the Fries rearrangement. Polymeric reagents are finding use in a variety of synthetic applications.'$* So far, little attention has been given to the use of insoluble polymers in mechanistic studies and for the determination of reaction intermediates. Blackburn et al.,3 studying the role of metaphosphate 1 and cyclic trimethylphosphate 2 in phosphorylation reactions in the presence of cyclohexylcarbodiimide, made use of polybenzyl alcohol 3 and its phosphorylated derivative 4. 0 0 4 RO-% OR
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