Enantiomerically Pure β-Amino Acids: A Convenient Access to Both Enantiomers of trans-2-Aminocyclohexanecarboxylic Acid

Abstract

Enantiomerically pure trans-2-aminocyclohexanecarboxylic acid is an important building block for helical β-peptides. We report here that this amino acid can be obtained from transcyclohexane-1,2-dicarboxylic acid in good yield by a simple one-pot procedure comprising cyclization to the anhydride, amide formation with ammonia, and a subsequent Hofmanntype degradation with phenyliodine(III) bis(trifluoroacetate) (PIFA) as the oxidant. The N-Fmoc-and N-BOC-protected derivatives were obtained by treatment of the amino acid with Fmoc-OSu and BOC 2 O, respectively. The N-BOC derivative could be prepared in even better overall yield by a onepot procedure leading directly from trans-cyclohexane-1,2-

Synthesis of Enantiopure cis- and trans-Fused Octahydroisoindole-1-Phosphonic Acids from Octahydroisoindolones

“…High-resolution mass spectra (HRMS) were obtained in positive ion mode (FAB + and CI + ) using a JEOL MStation MS-700. Analytical and spectroscopic data for compounds (±)-10, 15 (3R,5aS,9aR,9bS)-8, 15 (1′R,3aR,7aS)-11, 15 (3aR,7aS)-7, 15 (3R,5aR,9aR,9bS)-9 15 and (3aR,7aR)-18 17 were identical to those described in the literature.…”

“…Additionally, the trans-hydroxymethyl ester (1R,2R)-17 could be obtained from chiral 1,2-cyclohexanedicarboxylic anhydride (3aR,7aR)-18 (Scheme 6). 10a As depicted in the retrosynthetic analysis in Scheme 6, the synthesis started with C2-symmetric chiral 1,2-cyclohexanedicarboxylic anhydride (3aR,7aR)-18, 17 which was first subjected to methanolysis under reflux conditions, yielding the acid ester (1R,2R)-19 in quantitative yield. The reduction of the carboxylic acid was achieved via an intermediate mixed anhydride, prepared by treating (1R,2R)-19 with isobutyl chloroformate (IBCF) in the presence of Et 3 N. The resulting mixed anhydride was then reduced with NaBH 4 in water, producing the hydroxymethyl ester (1R,2R)-17 in 37% yield.…”

Synthesis of Enantiopure cis- and trans-Fused Octahydroisoindole-1-Phosphonic Acids from Octahydroisoindolones

“…High-resolution mass spectra (HRMS) were obtained in positive ion mode (FAB + and CI + ) using a JEOL MStation MS-700. Analytical and spectroscopic data for compounds (±)-10, 15 (3R,5aS,9aR,9bS)-8, 15 (1′R,3aR,7aS)-11, 15 (3aR,7aS)-7, 15 (3R,5aR,9aR,9bS)-9 15 and (3aR,7aR)-18 17 were identical to those described in the literature.…”

“…Additionally, the trans-hydroxymethyl ester (1R,2R)-17 could be obtained from chiral 1,2-cyclohexanedicarboxylic anhydride (3aR,7aR)-18 (Scheme 6). 10a As depicted in the retrosynthetic analysis in Scheme 6, the synthesis started with C2-symmetric chiral 1,2-cyclohexanedicarboxylic anhydride (3aR,7aR)-18, 17 which was first subjected to methanolysis under reflux conditions, yielding the acid ester (1R,2R)-19 in quantitative yield. The reduction of the carboxylic acid was achieved via an intermediate mixed anhydride, prepared by treating (1R,2R)-19 with isobutyl chloroformate (IBCF) in the presence of Et 3 N. The resulting mixed anhydride was then reduced with NaBH 4 in water, producing the hydroxymethyl ester (1R,2R)-17 in 37% yield.…”

Resolution of trans‐1,2‐cyclohexanedicarboxylic acid containing two carboxylic groups by forming diastereomeric salts based on feeding molar ratio control

“…They detected that the optical purity of (RR)-CHDA exceeded 99 e.e.%. 5 Similarly, Kimura confirmed that the resolution product obtained was (RR)-CHDA if using (R)-phenethylamine as the resolving agent. 6 Since then, (R)-phenylethylamine has been the major resolving agent for CHDA resolution because of its low cost and readily availability.…”

“…Berkessel et al corrected this by determining the structure of the product by X‐ray diffraction. They detected that the optical purity of ( RR )‐CHDA exceeded 99 e.e.% 5 . Similarly, Kimura confirmed that the resolution product obtained was ( RR )‐CHDA if using ( R )‐phenethylamine as the resolving agent 6 .…”

Asymmetric Synthesis of a New Helix‐Forming β‐Amino Acid: trans‐4‐Aminopiperidine‐3‐carboxylic Acid

“…In addition, we have extended this route to generate a practical synthesis of enantiomerically pure ACHC. (After our work was completed Berkessel et al reported an alternative and very practical synthesis of ACHC, in either enantiomeric form 12…”

Synthesis of Enantiopure cis- and trans-Fused Octahydroisoindole-1-Phosphonic Acids from Octahydroisoindolones

“…High-resolution mass spectra (HRMS) were obtained in positive ion mode (FAB + and CI + ) using a JEOL MStation MS-700. Analytical and spectroscopic data for compounds (±)-10, 15 (3R,5aS,9aR,9bS)-8, 15 (1′R,3aR,7aS)-11, 15 (3aR,7aS)-7, 15 (3R,5aR,9aR,9bS)-9 15 and (3aR,7aR)-18 17 were identical to those described in the literature.…”

“…Additionally, the trans-hydroxymethyl ester (1R,2R)-17 could be obtained from chiral 1,2-cyclohexanedicarboxylic anhydride (3aR,7aR)-18 (Scheme 6). 10a As depicted in the retrosynthetic analysis in Scheme 6, the synthesis started with C2-symmetric chiral 1,2-cyclohexanedicarboxylic anhydride (3aR,7aR)-18, 17 which was first subjected to methanolysis under reflux conditions, yielding the acid ester (1R,2R)-19 in quantitative yield. The reduction of the carboxylic acid was achieved via an intermediate mixed anhydride, prepared by treating (1R,2R)-19 with isobutyl chloroformate (IBCF) in the presence of Et 3 N. The resulting mixed anhydride was then reduced with NaBH 4 in water, producing the hydroxymethyl ester (1R,2R)-17 in 37% yield.…”

Resolution of trans‐1,2‐cyclohexanedicarboxylic acid containing two carboxylic groups by forming diastereomeric salts based on feeding molar ratio control

“…They detected that the optical purity of (RR)-CHDA exceeded 99 e.e.%. 5 Similarly, Kimura confirmed that the resolution product obtained was (RR)-CHDA if using (R)-phenethylamine as the resolving agent. 6 Since then, (R)-phenylethylamine has been the major resolving agent for CHDA resolution because of its low cost and readily availability.…”

“…Berkessel et al corrected this by determining the structure of the product by X‐ray diffraction. They detected that the optical purity of ( RR )‐CHDA exceeded 99 e.e.% 5 . Similarly, Kimura confirmed that the resolution product obtained was ( RR )‐CHDA if using ( R )‐phenethylamine as the resolving agent 6 .…”

Asymmetric Synthesis of a New Helix‐Forming β‐Amino Acid: trans‐4‐Aminopiperidine‐3‐carboxylic Acid

“…In addition, we have extended this route to generate a practical synthesis of enantiomerically pure ACHC. (After our work was completed Berkessel et al reported an alternative and very practical synthesis of ACHC, in either enantiomeric form 12…”

Synthesis of Enantiopure cis- and trans-Fused Octahydroisoindole-1-Phosphonic Acids from Octahydroisoindolones

“…High-resolution mass spectra (HRMS) were obtained in positive ion mode (FAB + and CI + ) using a JEOL MStation MS-700. Analytical and spectroscopic data for compounds (±)-10, 15 (3R,5aS,9aR,9bS)-8, 15 (1′R,3aR,7aS)-11, 15 (3aR,7aS)-7, 15 (3R,5aR,9aR,9bS)-9 15 and (3aR,7aR)-18 17 were identical to those described in the literature.…”

“…Additionally, the trans-hydroxymethyl ester (1R,2R)-17 could be obtained from chiral 1,2-cyclohexanedicarboxylic anhydride (3aR,7aR)-18 (Scheme 6). 10a As depicted in the retrosynthetic analysis in Scheme 6, the synthesis started with C2-symmetric chiral 1,2-cyclohexanedicarboxylic anhydride (3aR,7aR)-18, 17 which was first subjected to methanolysis under reflux conditions, yielding the acid ester (1R,2R)-19 in quantitative yield. The reduction of the carboxylic acid was achieved via an intermediate mixed anhydride, prepared by treating (1R,2R)-19 with isobutyl chloroformate (IBCF) in the presence of Et 3 N. The resulting mixed anhydride was then reduced with NaBH 4 in water, producing the hydroxymethyl ester (1R,2R)-17 in 37% yield.…”

Resolution of trans‐1,2‐cyclohexanedicarboxylic acid containing two carboxylic groups by forming diastereomeric salts based on feeding molar ratio control

“…They detected that the optical purity of (RR)-CHDA exceeded 99 e.e.%. 5 Similarly, Kimura confirmed that the resolution product obtained was (RR)-CHDA if using (R)-phenethylamine as the resolving agent. 6 Since then, (R)-phenylethylamine has been the major resolving agent for CHDA resolution because of its low cost and readily availability.…”

“…Berkessel et al corrected this by determining the structure of the product by X‐ray diffraction. They detected that the optical purity of ( RR )‐CHDA exceeded 99 e.e.% 5 . Similarly, Kimura confirmed that the resolution product obtained was ( RR )‐CHDA if using ( R )‐phenethylamine as the resolving agent 6 .…”

Asymmetric Synthesis of a New Helix‐Forming β‐Amino Acid: trans‐4‐Aminopiperidine‐3‐carboxylic Acid

“…In addition, we have extended this route to generate a practical synthesis of enantiomerically pure ACHC. (After our work was completed Berkessel et al reported an alternative and very practical synthesis of ACHC, in either enantiomeric form 12…”