Leonidas Zervas

Über eine neue Phosphorylierungsmethode 1-Glucosyl-phosphat

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NEW METHODS IN PEPTIDE SYNTHESIS

Publisher Summary This chapter discusses new methods in peptide synthesis. The N- o -nitrophenylsulfenyl-derivatives of amino-acids and peptides are yellow substances that crystallize easily. The cleavage of the o -nitrophenylsulfenyl group proceeds rapidly with hydrogen chloride. The coupling of N- o -nitrophenylsulfenyl-amino-acids with amino-acid esters is accomplished very easily through the mixed carboxylic–carbonic anhydride, and, in much better yields, through the dicyclohexylcarbodi-imide or the diphenylphosphoryl method. The tritylsulfenyl and N- o -nitrophenylsulfenyl protecting groups are cleaved more easily than the benzyloxycarbonyl group and, in many cases, more easily than the trityl group. A peptide chain can be lengthened at its amino end by coupling with N- o -nitrophenylsulfenyl-protected amino-acid or peptide. The protection of the carboxyl group during peptide synthesis is usually performed by esterification either with methanol or ethanol, either with benzyl alcohol or by esterification with t-butyl alcohol.

New methods in peptide synthesis. Part III. Protection of carboxyl group

For the protection of the carboxyl group of amino-acids during peptide synthesis, the acid-labile diphenylmethyl ester group was used. N-Trityl-(i.e., triphenylmethyl), N-formyl-, or N-o-nitrophenylsulphenyl-amino-acid diphenylmethyl esters were converted by known methods into the corresponding ester hydrochlorides. The deblocking of the carboxyl group was accomplished either by the action of dilute solutions of hydrogen chloride or hydrogen bromide in nitromethane, by trifluoroacetic acid, or by catalytic hydrogenolysis.The acid-stable phenacyl ester group permitted the preparation of the corresponding amino-acid ester hydrobromides by treating N-benzyloxycarbonylamino-acid phenacyl esters with hydrogen bromide in acetic acid. Easy alkyl–oxygen ester fission was brought about by sodium thiophenoxide.

On cysteine and cystine peptides. Part V. S-trityl- and S-diphenylmethyl-cysteine and -cysteine peptides

A new method for the preparation of S-trityl-(i.e. triphenylmethyl) and S-diphenylmethyl-cysteines or -cysteine peptides involves treatment of cysteine or cysteine peptides with aralkylcarbinols in the presence of trifluoroacetic acid or hydrogen halides in acetic acid solution. The optimal conditions for the removal of these S-protecting aralkyl groups by trifluoroacetic acid or hydrogen halides in acetic acid solution under various conditions have been determined.

New methods in peptide synthesis. Part V. On α- and γ-diphenylmethyl and phenacyl esters of L-glutamic acid

Several diphenylmethyl and phenacyl esters of monocarboxylic acids (L-proline, S-trityl-L-cysteine, L-glutamine, and L-asparagine) as well as α- and γ-esters of L-glutamic acid are described. The structures of the α-and γ-esters have been established by conversion of the α-esters into derivatives of L-glutamine. All these esters should prove to be useful in peptide synthesis, since the carboxy protecting groups can be selectively removed; the diphenylmethyl group by hydrogen chloride in certain non-polar solvents, and the phenacyl group by the action of sodium phenyl sulphide. Furthermore, both protecting groups can be removed by hydrogenolysis. An explanation for the unexpected hydrogenolysis of the phenacyl esters is presented.

Lanthionine chemistry. Part 4. Synthesis of diastereoisomeric cyclolanthionyl derivatives

The direct synthesis of monomeric cyclo-L-lanthionyl (2a) and cyclo-(D→L)-lanthionyl (2b) derivatives has been achieved using derivatives of L- or meso-lanthionine differentially protected at the amino and the carboxyl groups, e.g. Nα-benzyloxycarbanyl-Nα′-trityl-L-(or D→L)-lanthionine α′-methyl ester (6a, b). The specific rotation of L-lanthionine in acidic or alkaline solutions is markedly temperature-dependent; it increases in the former and decreases in the latter as the temperature increases. Previous investigations on the reversibility of the specific rotation change in acidic solutions have been confirmed and expanded. After heating acidic solutions of L-lanthionine above 96 °C, or at this temperature for >5 h, an irreversible change of the specific rotation was observed. Racemization calculated from the observed decrease of the specific rotation includes transformation to both DL- and meso lanthionine. The meso-stereoisomer was determined by Moore and Stein amino-acid analysis. After acidic hydrolysis the cyclo-L-lanthionyl compound (2a) exhibited a similar temperature- and time-dependent formation of DL-and meso-lanthionine. A change of the configuration was also observed when either meso-lanthionine or cyclo(D→L)-lanthionyl derivative (2b) were treated under acidic conditions.

New methods in peptide synthesis. Part IV. N → S transfer of N-o-nitrophenylsulphenyl groups in cysteine peptides

When the N-o-nitrophenylsulphenyl group is removed from cysteine peptides by means of hydrogen chloride in methanol or non-polar solvents, or by means of acids in aqueous methanol or acetone, an N → S transfer of the o-nitrophenylsulphenyl-group takes place, to give the corresponding S-o-nitrophenylsulphenyl derivative. Even in alkaline solution transfer of the o-nitrophenylsulphenyl group from the α-amino-group to the thiol can occur to some extent.

THE SYNTHESIS OF AN OXYTOCIN-TYPE FRAGMENT OF INSULIN

Publisher Summary This chapter discusses the synthesis of an oxytocin-type fragment of insulin. S-trityl, S-diphenylmethyl, and S-acyl cysteine derivatives are intermediates for incorporation of cysteine residues in a peptide chain. These S-protecting groups do not hinder the further lengthening of the peptide chain, provided that, in each case, the amino acid to be incorporated, has been properly N-protected. S-protecting groups can be selectively removed without affecting the sensitive parts of the molecule, especially any already existing -S-S-bridge. When N-benzyloxycarbonylglycine is not coupled with S-benzoyl-L-cysteine methyl ester hydrochloride through the relatively slowly reacting carbodi-imide but through the much faster reacting mixed anhydrides, then the N-peptide, N-(N-benzyloxycarbonylglycyl)-S-benzoyl- L-cysteine methyl ester can be obtained in moderate yield instead of the S-peptide. Treatment of the fully protected heptapeptide with mercuric chloride in acetic acid or silver nitrate-pyridine in dimethylformamide yields the corresponding dimercaptides.

Lanthionine chemistry. Part 5. Synthesis of cyclic non-symmetrical lanthionyl peptides

The synthesis of a protected fragment of the antibiotic nisin, specifically Nα-benzyloxycarbonyl-D-hemilanthionyl-L-isoleucyldehydroalanyl-L-leucyl-L-hemilanthionine α′-methyl ester (B) and of its analogue Nα-benzyloxycarbonyl-L-hemilanthionyl-L-isoleucyl-L-seryl-L-leucyl-L-hemilanthionine α′-methyl ester (A) is described. For the synthesis of these unusual peptidic compounds, unsymmetrically substituted derivatives of L- or mesolanthionine were used. For the synthesis of compound (B), the O-diphenylphosphorylserine portion of the peptide (26) was transformed by a β-elimination reaction to the dehydroalanine group in peptide (27), which after partial deprotection was subjected to cyclization. Compound (A) is a precursor of the dehydroalanine-containing cyclo-L-lanthionyl peptide. The monomeric structures of the cyclo-peptides (A) and (B) were proved by molecular-weight determination and the presence of the amino-acrylic acid grouping in the molecule of (B) was ascertained by amino-acid analysis and its i.r, spectrum.