A very short asymmetric synthesis of enantiomerically pure methyl substituted tetrahydro-3-benzazepines

An efficient synthesis of both enantiomers of methyltetrahydro-3-benzazepines 10 and 15 has been elaborated following a very short reaction sequence. The two diastereomeric oxazolo[3]benzazepinones 6 and 7 were prepared by condensation of keto acid 4 with (R)-phenylglycinol 5. Benzylation of 6 and 7 was controlled by the newly established N/O-acetalic stereogenic center leading to products 11 and 12. Reduction of the diastereomeric pairs 6, 7 and 11, 12 with LiAlH4/AlCl3 (3:1) occurred under retention of configuration yielding tetrahydro-3-benzazepines 8 and 9 with de >98%, as well as 13 and 14 with complete diastereoselectivity. Hydrogenolytic cleavage of the N-substituent led to the enantiomerically pure 2-methyltetrahydro-3-benzazepines (R)-10 and (S)-10 and 1-benzyl-4-methyltetrahydro-3-benzazepines (R,R)-15 and (S,S)-15. The relative and absolute configuration of the formed products were deduced from X-ray crystal structure analysis of the 3-benzazepine 14·HCl still bearing the original stereochemical information in the N-substituent.