Evaluating the use of chiral anthracene templates to access pyroglutamic acids

An approach for the asymmetric synthesis of pyroglutamic acid derivatives is described based on an anthracene chiral auxiliary. The introduction of a furan ring as a masked carboxylic acid moiety proceeded with excellent levels of diastereo-selectivity, followed by conversion into a carboxylate ester. The ensuing retro-Diels–Alder procedure using flash vacuum pyrolysis (FVP) followed by reduction gave pyroglutamate esters in good yield but poor enantioselectivity, the latter of which was found to be dependant on the electronic nature of the N-protecting group.

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(3aS,9aS)-3a,4,9,9a-Tetrahydro-4-[(1S)-1-methoxyethyl]-2-(N-4′-methoxyphenylmethyl)-4,9-[1′,2′]benzeno-1H-benzo[f]isoindole-1,3-(2H)-dioneC29H27NO4[α]D = −42 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3aR,9aR) (1R)

(3aS,9aS)-3a,4,9,9a-Tetrahydro-4-[(1S)-1-methoxyethyl]-2-(N-phenylmethyl)-4,9-[1′,2′]benzeno-1H-benzo[f]isoindole-1,3-(2H)-dioneC28H25NO3[α]D = −36 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3aR,9aR) (1R)

(3S,3aS,9aS)-9-[(1S)-1-Methoxyethyl]-2,3,3a,4,9,9a-hexahydro-3-hydroxy-2-methyl-4,9 [1′,2′]-benzeno-1H-benz[f]isoindol-1-oneC22H23NO3[α]D = −24 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,3aR,9aR) (1R)

(3S,3aS,9aS)-9-[(1S)-1-Methoxyethyl]-2,3,3a,4,9,9a-hexahydro-3-hydroxy-2-[N-4′-methoxyphenyl]-4,9 [1′,2′]-benzeno-1H-benz[f]isoindol-1-oneC22H23NO3[α]D = −44 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,3aR,9aR) (1R)

(3S,3aS,9aS)-9-[(1S)-1-Methoxyethyl]-2,3,3a,4,9,9a-hexahydro-3-hydroxy-2-[N-4′-methoxyphenylmethyl]-4,9 [1′,2′]-benzeno-1H-benz[f]isoindol-1-oneC29H29NO4[α]D = +8 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,3aR,9aR) (1R)

(3S,3aS,9aS)-9-[(1S)-1-Methoxyethyl]-2,3,3a,4,9,9a-hexahydro-3-hydroxy-2-[N-phenylmethyl]-4,9 [1′,2′]-benzeno-1H-benz[f]isoindol-1-oneC28H27NO3[α]D = +9 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,3aR,9aR) (1R)

(3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxyethyl]-3-(2-furanyl)-2-methyl-4,9-[1′,2′]benzeno-1H-benz[f]isoindol-1-oneC26H25NO3[α]D = +59 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3aR,9aR,3R) (1R)

(3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro 4-[(1S)-1-methoxyethyl]-3-(2-furanyl)-2-(N-4′-methoxyphenyl)-4,9[1′,2′]benzeno-1H-benz[f]isoindol-1-oneC32H29NO4[α]D = +8 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3aR,9aR,3R) (1R)

(3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro 4-[(1S)-1-methoxyethyl]-3-(2-furanyl)-2-(N-4′-methoxyphenylmethyl)-4,9[1′,2′]benzeno-1H-benz[f]isoindol-1-oneC33H31NO4[α]D = +8 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3aR,9aR,3R) (1R)

(3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxyethyl]-2-(N-phenylmethyl)-3-(2-furanyl)-2-methyl-4,9[1′,2′]benzeno-1H-benz[f]isoindol-1-oneC32H29NO3[α]D = +21 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3aR,9aR,3R) (1R)

(3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxyethyl]-2-methyl-4,9-[1′,2′]benzeno-1H-benz[f]isoindol-1-one-3-carboxylic acid methyl esterC24H25NO4[α]D = +21 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3aR,9aR,3R) (1R)

(3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxyethyl]-2-(N-4′-methoxyphenyl)-4,9-[1′,2′]benzeno-1H-benz[f]isoindol-1-one-3-carboxylic acid methyl esterC30H29NO5[α]D = +13 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3aR,9aR,3R) (1R)

(3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxyethyl]-2-(N-4′-methoxyphenylmethyl)-4,9-[1′,2′]benzeno-1H-benz[f]isoindol-1-one-3-carboxylic acid methyl esterC31H31NO5[α]D = +10 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3aR,9aR,3R) (1R)

(3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxyethyl]-2-(N-phenylmethyl)-4,9-[1′,2′]benzeno-1H-benz[f]isoindol-1-one-3-carboxylic acid methyl esterC30H29NO4[α]D = +2 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3aR,9aR,3R) (1R)

(S)-1-(4-Methoxyphenyl)-5-oxo-proline methyl esterC13H15NO4Ee 23%[α]D = −6 (c 0.8, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)