HPLC enantioseparation of phenylalanine analogs by application of (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester as a new chiral derivatizing agent

Abstract

Key WordsColumn liquid chromatography Chiral derivatization Indirect enantiomeric separation (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester, (S)-NIFE Phenylalanine analogs SummaryThe indirect stereochemicaJ resolution of the enantiomers of phenylalanine analogs was studied by high-performance liquid chromatographic methods. The resolution was performed by applying pre-column derivatization with (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester, (S)-NIFE, as a new chiral derivatizing agent. Its applicability is demonstrated by the derivatization and separation of a series of ring-and s-methyl-substituted phenylalanines and phenylalanine amides, and especially by the derivatization of sterically hindered, less reactive s-methyl-substituted phenylalanine analogs. The diastereomeric derivatives produced were separated by reversed-phase high-performance liquid chromatography. The conditions of both derivatization and separation were optimized. The method described offers good enantioselectivity for various chiral amino compounds derived from chemo-enzymatic processes.

Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

“…In accordance with the results reported by Jew and co-workers, the aldimine 9 a, RbOH and O(9)-allyl-N-1-cyanobenzylhydrocinchonidinium bromide (24) [39] catalyst were used in the alkylation reaction, but only a moderate ee of 60 % was obtained ( [a] Enantiomeric purity was determined by HPLC analysis after hydrolysis of 11 a,b to 12 and (S)-NIFE derivatization. [40] Switching to the O(9)-allyl-N-2',3',4'-trifluorobenzylhydrocinchonidinium bromide catalyst (23), [37,38] under the same reaction conditions, did not improve the enantioselectivity (entry 4, 54 % ee). Lowering the temperature to À78 8C (entry 5, 13 % ee), switching to CsOH as a base (entry 6, 68 % ee) by using the 2-naphthyl aldimine 9 b (entry 7, 34 % ee) or/and another catalyst (entry 8, 58 % ee) did not improve the enantioselectivity dramatically in comparison with entry 3.…”

“…Deprotonation of the substituted bis-lactim ether chiral auxiliary 17 with tBuLi, followed by an alkylation of the resulting anion with o-cyanobenzyl bromide (10) provided compound 18 with a yield of 72 % after purification by flash column chromatography. Hydrolysis of 18 by using TFA at room temperature, and subsequent hydrolysis of the methyl ester in HCl (6 n) at 658C, yielded (S)-a-Me-o-CN-Phe·HCl (12) with an ee of 88 %, as determined by HPLC analysis after (S)-NIFE derivatization [40] (S)-a-Me-o-CN-Phe·HCl was methyloxycarbonyl (Moc)protected to 13 by means of MocCl, as previously described for the racemic compound. [21] Reduction of the nitrile in 13 with H 2 /Pd on C provided the aminomethyl derivative, which underwent intramolecular cyclization to 14 after activation of the carboxylic acid by using N-(3-methylaminopropyl)-N-ethylcarbodiimide (EDC).…”

Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

“…In accordance with the results reported by Jew and co-workers, the aldimine 9 a, RbOH and O(9)-allyl-N-1-cyanobenzylhydrocinchonidinium bromide (24) [39] catalyst were used in the alkylation reaction, but only a moderate ee of 60 % was obtained ( [a] Enantiomeric purity was determined by HPLC analysis after hydrolysis of 11 a,b to 12 and (S)-NIFE derivatization. [40] Switching to the O(9)-allyl-N-2',3',4'-trifluorobenzylhydrocinchonidinium bromide catalyst (23), [37,38] under the same reaction conditions, did not improve the enantioselectivity (entry 4, 54 % ee). Lowering the temperature to À78 8C (entry 5, 13 % ee), switching to CsOH as a base (entry 6, 68 % ee) by using the 2-naphthyl aldimine 9 b (entry 7, 34 % ee) or/and another catalyst (entry 8, 58 % ee) did not improve the enantioselectivity dramatically in comparison with entry 3.…”

“…Deprotonation of the substituted bis-lactim ether chiral auxiliary 17 with tBuLi, followed by an alkylation of the resulting anion with o-cyanobenzyl bromide (10) provided compound 18 with a yield of 72 % after purification by flash column chromatography. Hydrolysis of 18 by using TFA at room temperature, and subsequent hydrolysis of the methyl ester in HCl (6 n) at 658C, yielded (S)-a-Me-o-CN-Phe·HCl (12) with an ee of 88 %, as determined by HPLC analysis after (S)-NIFE derivatization [40] (S)-a-Me-o-CN-Phe·HCl was methyloxycarbonyl (Moc)protected to 13 by means of MocCl, as previously described for the racemic compound. [21] Reduction of the nitrile in 13 with H 2 /Pd on C provided the aminomethyl derivative, which underwent intramolecular cyclization to 14 after activation of the carboxylic acid by using N-(3-methylaminopropyl)-N-ethylcarbodiimide (EDC).…”

HPLC Separation of Enantiomers of α‐Substituted Proline Analogues by the Application of (S)‐N‐(4‐Nitrophenoxy‐carbonyl)phenylalanine Methoxyethyl Ester as Chiral Derivatizing Agent

“……”

High‐performance liquid chromatographic enantioseparation of (R,S)‐fluoxetine using Marfey's reagent and (S)‐N‐(4‐nitrophenoxycarbonyl) phenylalanine methoxyethyl ester as chiral derivatizing reagents along with direct thin‐layer chromatographic resolution and isolation of enantiomers using l‐tartaric acid as mobile phase additive

“…, 2000) and analogs of phenyl alanine (Olajos et al. , 2001), β ‐alkyl‐substituted analogs of tyrosine, phenylalanine, 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid and tryptophan (Vékes et al. , 2002), and unusual β ‐amino acids like N‐ MeThr, allo ‐ N‐ MeThr and 3‐amino‐4‐methylpentanoic acid (Árki et al.…”

Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

“…In accordance with the results reported by Jew and co-workers, the aldimine 9 a, RbOH and O(9)-allyl-N-1-cyanobenzylhydrocinchonidinium bromide (24) [39] catalyst were used in the alkylation reaction, but only a moderate ee of 60 % was obtained ( [a] Enantiomeric purity was determined by HPLC analysis after hydrolysis of 11 a,b to 12 and (S)-NIFE derivatization. [40] Switching to the O(9)-allyl-N-2',3',4'-trifluorobenzylhydrocinchonidinium bromide catalyst (23), [37,38] under the same reaction conditions, did not improve the enantioselectivity (entry 4, 54 % ee). Lowering the temperature to À78 8C (entry 5, 13 % ee), switching to CsOH as a base (entry 6, 68 % ee) by using the 2-naphthyl aldimine 9 b (entry 7, 34 % ee) or/and another catalyst (entry 8, 58 % ee) did not improve the enantioselectivity dramatically in comparison with entry 3.…”

“…Deprotonation of the substituted bis-lactim ether chiral auxiliary 17 with tBuLi, followed by an alkylation of the resulting anion with o-cyanobenzyl bromide (10) provided compound 18 with a yield of 72 % after purification by flash column chromatography. Hydrolysis of 18 by using TFA at room temperature, and subsequent hydrolysis of the methyl ester in HCl (6 n) at 658C, yielded (S)-a-Me-o-CN-Phe·HCl (12) with an ee of 88 %, as determined by HPLC analysis after (S)-NIFE derivatization [40] (S)-a-Me-o-CN-Phe·HCl was methyloxycarbonyl (Moc)protected to 13 by means of MocCl, as previously described for the racemic compound. [21] Reduction of the nitrile in 13 with H 2 /Pd on C provided the aminomethyl derivative, which underwent intramolecular cyclization to 14 after activation of the carboxylic acid by using N-(3-methylaminopropyl)-N-ethylcarbodiimide (EDC).…”

HPLC Separation of Enantiomers of α‐Substituted Proline Analogues by the Application of (S)‐N‐(4‐Nitrophenoxy‐carbonyl)phenylalanine Methoxyethyl Ester as Chiral Derivatizing Agent

“……”

High‐performance liquid chromatographic enantioseparation of (R,S)‐fluoxetine using Marfey's reagent and (S)‐N‐(4‐nitrophenoxycarbonyl) phenylalanine methoxyethyl ester as chiral derivatizing reagents along with direct thin‐layer chromatographic resolution and isolation of enantiomers using l‐tartaric acid as mobile phase additive

“…, 2000) and analogs of phenyl alanine (Olajos et al. , 2001), β ‐alkyl‐substituted analogs of tyrosine, phenylalanine, 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid and tryptophan (Vékes et al. , 2002), and unusual β ‐amino acids like N‐ MeThr, allo ‐ N‐ MeThr and 3‐amino‐4‐methylpentanoic acid (Árki et al.…”

Asymmetric Synthesis and Conformational Analysis by NMR Spectroscopy and MD of Aba‐ and α‐MeAba‐Containing Dermorphin Analogues

“…In accordance with the results reported by Jew and co-workers, the aldimine 9 a, RbOH and O(9)-allyl-N-1-cyanobenzylhydrocinchonidinium bromide (24) [39] catalyst were used in the alkylation reaction, but only a moderate ee of 60 % was obtained ( [a] Enantiomeric purity was determined by HPLC analysis after hydrolysis of 11 a,b to 12 and (S)-NIFE derivatization. [40] Switching to the O(9)-allyl-N-2',3',4'-trifluorobenzylhydrocinchonidinium bromide catalyst (23), [37,38] under the same reaction conditions, did not improve the enantioselectivity (entry 4, 54 % ee). Lowering the temperature to À78 8C (entry 5, 13 % ee), switching to CsOH as a base (entry 6, 68 % ee) by using the 2-naphthyl aldimine 9 b (entry 7, 34 % ee) or/and another catalyst (entry 8, 58 % ee) did not improve the enantioselectivity dramatically in comparison with entry 3.…”

“…Deprotonation of the substituted bis-lactim ether chiral auxiliary 17 with tBuLi, followed by an alkylation of the resulting anion with o-cyanobenzyl bromide (10) provided compound 18 with a yield of 72 % after purification by flash column chromatography. Hydrolysis of 18 by using TFA at room temperature, and subsequent hydrolysis of the methyl ester in HCl (6 n) at 658C, yielded (S)-a-Me-o-CN-Phe·HCl (12) with an ee of 88 %, as determined by HPLC analysis after (S)-NIFE derivatization [40] (S)-a-Me-o-CN-Phe·HCl was methyloxycarbonyl (Moc)protected to 13 by means of MocCl, as previously described for the racemic compound. [21] Reduction of the nitrile in 13 with H 2 /Pd on C provided the aminomethyl derivative, which underwent intramolecular cyclization to 14 after activation of the carboxylic acid by using N-(3-methylaminopropyl)-N-ethylcarbodiimide (EDC).…”

HPLC Separation of Enantiomers of α‐Substituted Proline Analogues by the Application of (S)‐N‐(4‐Nitrophenoxy‐carbonyl)phenylalanine Methoxyethyl Ester as Chiral Derivatizing Agent

“……”

High‐performance liquid chromatographic enantioseparation of (R,S)‐fluoxetine using Marfey's reagent and (S)‐N‐(4‐nitrophenoxycarbonyl) phenylalanine methoxyethyl ester as chiral derivatizing reagents along with direct thin‐layer chromatographic resolution and isolation of enantiomers using l‐tartaric acid as mobile phase additive

“…, 2000) and analogs of phenyl alanine (Olajos et al. , 2001), β ‐alkyl‐substituted analogs of tyrosine, phenylalanine, 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid and tryptophan (Vékes et al. , 2002), and unusual β ‐amino acids like N‐ MeThr, allo ‐ N‐ MeThr and 3‐amino‐4‐methylpentanoic acid (Árki et al.…”