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 (O=HC-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 sigma(2) receptors. (c) 2006 Elsevier Ltd. All rights reserved.