Enantiomers of 2-methyl- and 2,4-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid: Preparation by resolution, determination of absolute configuration, and Curtius rearrangement

The First Phenyl-N-pyridinylcarbamate Structures: Structural and Conformational Analysis of Nine Methoxyphenyl-N-pyridinylcarbamates

“…Most isomers (CppOMe, CpoOMe, CmpOMe, CmoOMe, and CopOMe) were synthesized by using condensation reactions of aminopyridines with commercially available p - and o -methoxyphenyl chloroformates in the presence of triethylamine base (Et 3 N) and CH 2 Cl 2 solvent. − The CopOMe isomer was synthesized under solventless conditions (without base) in order to minimize formation of double carbamates where both amino H atoms are substituted by phenyl chloroformates (in an analogous reaction to that used in the synthesis of the trezimide and tennimide macrocycles). , The remainder (CpmOMe, CmmOMe, ComOMe, and CooOMe) were synthesized using the Curtius rearrangement, − performed as a two-step (one pot) reaction with isonicotinic or nicotinic acids as starting materials, diphenylphosphoryl azide as converting agent, and Et 3 N in anhydrous acetonitrile at 70 °C. On formation of the pyridinyl isocyanate, addition of m - or o -methoxyphenol initiates the final condensation to a methoxyphenyl- N -pyridinylcarbamate. − For CooOMe, the reaction was performed at 110 °C in toluene instead of acetonitrile . Full synthetic procedures are provided in the Supporting Information (SI) (Section 1).…”

The First Phenyl-N-pyridinylcarbamate Structures: Structural and Conformational Analysis of Nine Methoxyphenyl-N-pyridinylcarbamates

“…Most isomers (CppOMe, CpoOMe, CmpOMe, CmoOMe, and CopOMe) were synthesized by using condensation reactions of aminopyridines with commercially available p - and o -methoxyphenyl chloroformates in the presence of triethylamine base (Et 3 N) and CH 2 Cl 2 solvent. − The CopOMe isomer was synthesized under solventless conditions (without base) in order to minimize formation of double carbamates where both amino H atoms are substituted by phenyl chloroformates (in an analogous reaction to that used in the synthesis of the trezimide and tennimide macrocycles). , The remainder (CpmOMe, CmmOMe, ComOMe, and CooOMe) were synthesized using the Curtius rearrangement, − performed as a two-step (one pot) reaction with isonicotinic or nicotinic acids as starting materials, diphenylphosphoryl azide as converting agent, and Et 3 N in anhydrous acetonitrile at 70 °C. On formation of the pyridinyl isocyanate, addition of m - or o -methoxyphenol initiates the final condensation to a methoxyphenyl- N -pyridinylcarbamate. − For CooOMe, the reaction was performed at 110 °C in toluene instead of acetonitrile . Full synthetic procedures are provided in the Supporting Information (SI) (Section 1).…”

Synthesis of the retro-inverso peptide analogues of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP)

“…by hydrogenolysis afforded the gem-diamine derivatives 11a and 11b which were coupled immediately with pure enantiomers of 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (12) prepared by us previously 15 to give 3a and 3b in the form of diastereomeric mixtures each containing four diastereomers as evidenced by proton NMR spectra, indicating racemization at C-2 of the morpholinone ring during the coupling reaction. Racemization at C-2 could be deduced from identical 1 H-NMR spectra of 3a obtained either from (R)-12 or (S)-12; similarly, also 1 H-NMR spectra of 3b obtained either from (R)-12 or (S)-12 were identical and displayed the presence of 4 diastereomers.…”

“…Racemization at C-2 had been previously observed also in 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-amines. 15 However, a mechanism of racenization at C-2 of the heterocyle has not yet been clarified. An attempt to separate the diastereomers of 3b by HPLC gave two pure distereomers (3bI and 3bII) as well as an equimolar mixture of enantiomers 3bIII and 3bIV which were inactive in the immunorestoration test in mice 16, thus supporting a hypothesis that a retro-inverso modified peptide bond between L-alanine and D-glutamate moieties in this carbocyclic series of MDP analogues is not beneficial for immunostimulating activity.…”

The First Phenyl-N-pyridinylcarbamate Structures: Structural and Conformational Analysis of Nine Methoxyphenyl-N-pyridinylcarbamates

“…Most isomers (CppOMe, CpoOMe, CmpOMe, CmoOMe, and CopOMe) were synthesized by using condensation reactions of aminopyridines with commercially available p - and o -methoxyphenyl chloroformates in the presence of triethylamine base (Et 3 N) and CH 2 Cl 2 solvent. − The CopOMe isomer was synthesized under solventless conditions (without base) in order to minimize formation of double carbamates where both amino H atoms are substituted by phenyl chloroformates (in an analogous reaction to that used in the synthesis of the trezimide and tennimide macrocycles). , The remainder (CpmOMe, CmmOMe, ComOMe, and CooOMe) were synthesized using the Curtius rearrangement, − performed as a two-step (one pot) reaction with isonicotinic or nicotinic acids as starting materials, diphenylphosphoryl azide as converting agent, and Et 3 N in anhydrous acetonitrile at 70 °C. On formation of the pyridinyl isocyanate, addition of m - or o -methoxyphenol initiates the final condensation to a methoxyphenyl- N -pyridinylcarbamate. − For CooOMe, the reaction was performed at 110 °C in toluene instead of acetonitrile . Full synthetic procedures are provided in the Supporting Information (SI) (Section 1).…”

Synthesis of the retro-inverso peptide analogues of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP)

“…by hydrogenolysis afforded the gem-diamine derivatives 11a and 11b which were coupled immediately with pure enantiomers of 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (12) prepared by us previously 15 to give 3a and 3b in the form of diastereomeric mixtures each containing four diastereomers as evidenced by proton NMR spectra, indicating racemization at C-2 of the morpholinone ring during the coupling reaction. Racemization at C-2 could be deduced from identical 1 H-NMR spectra of 3a obtained either from (R)-12 or (S)-12; similarly, also 1 H-NMR spectra of 3b obtained either from (R)-12 or (S)-12 were identical and displayed the presence of 4 diastereomers.…”

“…Racemization at C-2 had been previously observed also in 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-amines. 15 However, a mechanism of racenization at C-2 of the heterocyle has not yet been clarified. An attempt to separate the diastereomers of 3b by HPLC gave two pure distereomers (3bI and 3bII) as well as an equimolar mixture of enantiomers 3bIII and 3bIV which were inactive in the immunorestoration test in mice 16, thus supporting a hypothesis that a retro-inverso modified peptide bond between L-alanine and D-glutamate moieties in this carbocyclic series of MDP analogues is not beneficial for immunostimulating activity.…”

The First Phenyl-N-pyridinylcarbamate Structures: Structural and Conformational Analysis of Nine Methoxyphenyl-N-pyridinylcarbamates

“…Most isomers (CppOMe, CpoOMe, CmpOMe, CmoOMe, and CopOMe) were synthesized by using condensation reactions of aminopyridines with commercially available p - and o -methoxyphenyl chloroformates in the presence of triethylamine base (Et 3 N) and CH 2 Cl 2 solvent. − The CopOMe isomer was synthesized under solventless conditions (without base) in order to minimize formation of double carbamates where both amino H atoms are substituted by phenyl chloroformates (in an analogous reaction to that used in the synthesis of the trezimide and tennimide macrocycles). , The remainder (CpmOMe, CmmOMe, ComOMe, and CooOMe) were synthesized using the Curtius rearrangement, − performed as a two-step (one pot) reaction with isonicotinic or nicotinic acids as starting materials, diphenylphosphoryl azide as converting agent, and Et 3 N in anhydrous acetonitrile at 70 °C. On formation of the pyridinyl isocyanate, addition of m - or o -methoxyphenol initiates the final condensation to a methoxyphenyl- N -pyridinylcarbamate. − For CooOMe, the reaction was performed at 110 °C in toluene instead of acetonitrile . Full synthetic procedures are provided in the Supporting Information (SI) (Section 1).…”

Synthesis of the retro-inverso peptide analogues of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP)

“…by hydrogenolysis afforded the gem-diamine derivatives 11a and 11b which were coupled immediately with pure enantiomers of 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (12) prepared by us previously 15 to give 3a and 3b in the form of diastereomeric mixtures each containing four diastereomers as evidenced by proton NMR spectra, indicating racemization at C-2 of the morpholinone ring during the coupling reaction. Racemization at C-2 could be deduced from identical 1 H-NMR spectra of 3a obtained either from (R)-12 or (S)-12; similarly, also 1 H-NMR spectra of 3b obtained either from (R)-12 or (S)-12 were identical and displayed the presence of 4 diastereomers.…”

“…Racemization at C-2 had been previously observed also in 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-amines. 15 However, a mechanism of racenization at C-2 of the heterocyle has not yet been clarified. An attempt to separate the diastereomers of 3b by HPLC gave two pure distereomers (3bI and 3bII) as well as an equimolar mixture of enantiomers 3bIII and 3bIV which were inactive in the immunorestoration test in mice 16, thus supporting a hypothesis that a retro-inverso modified peptide bond between L-alanine and D-glutamate moieties in this carbocyclic series of MDP analogues is not beneficial for immunostimulating activity.…”