Chemoenzymatic synthesis of enantiomerically pure tricyclic benzomorphan analogues

The key step in the synthesis of enantiomerically pure benzomorphan analogous tricyclic amines 2 is the kinetic resolution of secondary alcohol 7 using the lipase from Pseudomonas fluorescence. The (S)-configured alcohol (S)-7 and the (R)-configured ester (R)-8 were obtained in good yield (40% and 46%, respectively) and excellent enantiomeric excess (99% ee and 98.4% ee, respectively). A diastereoselective oxa-Pictet-Spengler reaction of (S)-7 with ethyl glyoxalate (OHC–CO2Et) followed by a Dieckmann cyclization provided the tricyclic ring system 11, which allowed the diastereoselective introduction of an amino group at the 6-position. The absolute configuration of alcohol (S)-7 was determined with the tricyclic alcohol 13. The quantum mechanically calculated specific optical rotation of (S,S,S)-configured alcohol 13 is in accordance with the measured specific rotation of the synthesized compound. Moreover, X-ray crystal structure analysis of the synthesized compound, determined with the three-beam interference method, proved the (S,S,S)-configuration of 13. The enantiomerically pure dimethylamine 12 showed moderate affinity toward σ2 receptors.

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(S)-(−)-4-Hydroxy-N,N-dimethyl-5-phenylpentanamideC13H19NO2Ee = 99%[α]D = −9.7Source of chirality: lipase catalyzed kinetic resolution (Pseudomonas fluorescence)Absolute configuration: (S)

(+)-[(R)-4-(N,N-Dimethylcarbamoyl)-1-phenylbutan-2-yl] acetateC15H21NO3Ee = 98.4%[α]D = +3.4Source of chirality: lipase catalyzed kinetic resolution (Pseudomonas fluorescence)Absolute configuration: (R)

(+)-Ethyl (1S,3S)-3-(2-ethoxycarbonylethyl)-3,4-dihydro-1H-2-benzopyran-1-carboxylateC17H22O5Ee = 99%[α]D = +9.1Source of chirality: lipase catalyzed kinetic resolutionAbsolute configuration: (1S,3S)

(5S,9S)-(−)-7,8,9,10-Tetrahydro-5,9-epoxybenzocycloocten-6(5H)-oneC12H12O2Ee = 99%[α]D = −221Source of chirality: lipase catalyzed kinetic resolutionAbsolute configuration: (5S,9S)

(5S,6S,9S)-(−)-N,N-Dimethyl-5,6,7,8,9,10-hexahydro-5,9-epoxybenzocycloocten-6-amineC14H19NOEe = 99%[α]D = −40.4 (HCl)Source of chirality: lipase catalyzed kinetic resolutionAbsolute configuration: (5S,6S,9S)

(5S,6S,9S)-(−)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocycloocten-6-olC12H14O2Ee = 99%[α]D = −71.8Source of chirality: lipase catalyzed kinetic resolutionAbsolute configuration: (5S,6S,9S)