Bis(o-phenylene) Pyrophosphite

[16421-86-6]  · C12H8O5P2  · Bis(o-phenylene) Pyrophosphite  · (MW 294.14)

(reagent for peptide synthesis1)

Physical Data: mp 72 °C; bp 156 °C/0.25 mmHg; n20D 1.5090 (supercooled liquid).

Preparative Method: reaction of Catechol with Phosphorus(III) Chloride gives o-phenylene phosphorochloridite, which upon hydrolysis affords bis(o-phenylene) pyrophosphite (1).2

Purification: purified by distillation at reduced pressure.

Handling, Storage, and Precautions: may be stored indefinitely in a stoppered bottle.

Peptide Synthesis.

The reagent (1) was introduced as a substitute in peptide synthesis for the widely used, but less easily prepared, Tetraethyl Pyrophosphate. Heating a mixture of an N-protected (Cbz or phthaloyl) amino acid and an amino acid or peptide ester with 1.1 equiv of (1) in pyridine effects amide bond formation (eq 1).1 The amino acid or peptide ester may be used as its hydrohalide or tosylate salt. The method is experimentally simple and has the additional advantage that the crude product is generally of sufficient purity for preparative purposes. Prereaction of (1) with either coupling partner to give the active ester or the phosphoramidite intermediate is possible but offers no advantage.

While no racemization was detected in couplings involving N-Cbz-protected amino acids, use of N-protected dipeptides as carboxyl components resulted in extensive racemization, presumably by the oxazolone mechanism. The method is also unsuitable for the synthesis of tyrosine peptides without prior protection of the phenolic hydroxy group, since O-phosphorylation may occur.

Synthesis of cyclic peptides using (1) was studied by Miller and Smith.3 Use of diethyl phosphite as solvent rather than pyridine was found to be necessary; the method gave better results than 1,3-Dicyclohexylcarbodiimide (DCC) for cyclization of penta- and hexapeptides, but was not suitable for cyclization of tripeptides.

1. Crofts, P. C.; Markes, J. H. H.; Rydon, H. M. JCS 1959, 3610.
2. Crofts, P. C.; Markes, J. H. H.; Rydon, H. M. JCS 1958, 4250.
3. Miller, A. W.; Smith, P. W. G. JCS(C) 1967, 2140.

Alan Armstrong

University of Bath, UK

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