Enantioselective Synthesis of a 2,2-Disubstituted Tetrahydro-3-benzazepine as Novel NMDA Receptor Antagonist

Husain SM, Frohlich R, Schepmann D, Wünsch B

Abstract

The tricyclic oxazolidines trans-4 and cis-4 were interconverted upon treatment with allyltrimethylsilane/TiCl4. The oxazolidine trans-4 was diastereoselectively reacted with PhMgBr to yield the 4,4-disubstituted 3-benzazepinone 6, along with two side products. An X-ray crystal structure analysis of 6 proved the (R)-configuration of the stereogenic center C-4 and thus the retention of configuration. Reduction of 6 with AlCl3/LiAlH4 (1/3) followed by hydrogenolysis with H-2, Pd/C resulted in the formation of enantiomerically pure 2-methyl-2-phenyl-tetrahydro-3-benzazepine 11 which has a moderate affinity (K-i = 496 nM) to the PCP binding site of the NMDA receptor.