Ethyl-5-phenylisoxazolium-3/-sulfonate

A. Carbobenzoxy-L-asparaginyl-L-lewine Methyl Ester. A mixture of 2.024 g. (0.0080 mole) of A -ethyl 5 phenylisoxazolium-3 -sulfonate [Isoxazolium, 2-ethyl-5-(3-sulfophenyl)-, hydroxide, inner salt] (Note 1) and 20 ml. of nitromethane (Note 2) is prepared in a 50-ml., glass-stoppered Erlenmeyer flask at room temperature and stirred vigorously... 

These procedures illustrate the use of N-ethyl-5-phenylisoxazolium-3 -sulfonate as a reagent for peptide synthesis.2-3 Procedure A is recommended for peptides that are not soluble in either organic solvents or in water. Procedure B illustrates the formation of a peptide that is soluble both in organic solvents and in water. Por peptides that are soluble in organic solvents and insoluble in water, the submitters recommend the use of Procedure B, except that the peptide product may be recovered directly from its solution in ethyl acetate after this organic solution has been washed successively with aqueous 5% sodium bicarbonate, water, aqueous 1 M hydrochloric acid, and water. Table I summarizes the preparation of various peptides by these procedures. Some more complex examples from other laboratories are listed elsewhere.2b... 

Ethyl-l -phenyl-6,7-dimethoxy-3,4-dihydroisoquinolinium iodide, 56, 7 A -Ethyl-5-phenylisoxazolium-3 -sulfonate, 56, 99... 

Woodward s Reagent K See 7V-ethyl-5-phenylisoxazolium-3 -sulfonate. wud-wordz... 

N-Ethyl-5-phenylisoxazolium-3 -sulfonate (1). Mol. wt. 253.28. Suppliers Aldrich, Pilot Chemicals. Preparation and use in peptide synthesis. " It is recommended that the commercial salt be dissolved in excess 1N hydrochloric acid and precipitated with acetone to give a fluffy product. ... 

Peptide synthesis. The compound is useful as a coupling agent because the corresponding urea derivative is soluble in dilute acid and hence readily separated from the peptide. Squibb workers found it far superior to DCC for the final cycliza-tion step in the synthesis of a peptide lactone related to the antibiotic vemamycin B methylene chloride was found to be an excellent solvent. The polar character of the urea formed facilitated its separation from the product. Of all other coupling agents tested, only N,N -carbonyldiimidazole and N-ethyl-5-phenylisoxazolium 3 -sulfonate permitted isolation of the cyclized peptide, if in much lower yield. 

Peptide synthesis /-Amyl chloroformate. Bis-(2,4-dinitrophenyl)carbonate. Bis-o-phenylene pyrophosphite. i-Butyl chloroformate. sec-Butyl chloroformate. /-Butyl chloroformate. /-Butyl 2,4,5-trichlorophenyl carbonate. CopoIy(ethylene-N-hydroxymaleimide). N,N-Diethyl-I-propynylamine. Di-(p-nitrophenyl)sulfate. Ethoxyacetylene. N-Ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline. N-Ethylbenzisoxazolium fluoroborate. Ethyl chloroformate. N-Ethyl-5-phenylisoxazolium-3 -sulfonate. N-Hydroxysuccinimide trifluoroacetate. Methyl-morpholine. 4-Methylthiophenol. p-Nitrophenol. Oxalylchloride. Pentachlorophenol. Pentamethylbenzyl chloride. /-Pentyl chloroformate. Phenacyl bromide. Polyhexamethylene carbodiimide. Tetraethyl pyrophosphite. 1,2,4-Triazole. 

Peptide synthesis. Izumiya and Muraoka1 examined the extent of isomerization with commonly used coupling reagents (isobutyl chloroformate, DCC, N-ethyl-5-phenylisoxazolium-3 -sulfonate, and EEDQ) and of these found that EEDQ caused the least racemization (0.2%) in the particular test chosen. The next most satisfactory was N-ethyl-5-phenylisoxazolium-3 -sulfonate (Woodward s Reagent K, 1.7-1.8%). 

Peptide synthesis mediated by N-ethyl-5-phenylisoxazolium-3 -sulfonate 3 (see 1st edition). 

Isoxazolium method, peptide bond formation using N-ethyl-5-phenylisoxazolium-3 -sulfonate (Woodward reagent K) forming an end ester with N-protected amino acids and peptides which reacts in situ with the amino component providing the desired product beside a water-soluble aryl sulfonate as a byproduct that is easy to separate [R. B. Woodward, R. A. Olofson. J. Am. Chem. Soc. 1961, 83,1010]. 

PEPTIDES N-Ethyl-5-phenylisoxazolium 3 -sulfonate. 3-Hydroxy-5-methyl-hydantoin. 4-(4 -Methyl-T-piperazinyl)-... 

Selective reduction. A soln. of borane in tetrahydrofuran added dropwise at -18 during 19 min. to a mixture of adipic acid monoethyl ester and tetrahydrofuran, stirred and allowed to warm to room temp, during 16 hrs. -> ethyl 6-hydroxy-hexanoate. Y 75-88%. - Other functional groups such as cyano, halogeno, keto, or nitro, are likewise retained during this highly convenient reduction. F. e., also reduction of sterically hindered acids, s. N. M. Yoon, H. C. Brown et al., J. Org. Chem. 38, 2786 (1973) 2-aminoalcohols from a-aminocarboxylic acids s. M. L. Anhoury et al., Soc. Perkin 11974,191 via reduction with aq. NaBH of enolesters obtained from the acids and N-ethyl-5-phenylisoxazolium 3 -sulfonate (s. Synth. Meth. 16, 448) s. P. L. Hall and R. B. Perfetti, J. Org. Chem. 39, 111 (1974). 

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