Stereoselective synthesis of novel centrally active benzomorphan-type tricycles with 2-phenylethylamine substructure

Article abstract of DOI:10.1002/ardp.19933260208

Addition of the LDA-deprotonated glycine ester 6 to the homophthalaldehyde monoacetal 5 yields the β-hydroxyester 7 which is cyclized after reduction to give the racemic 2,6-epoxy-3-benzoxocin-5-amines (+/-)-12 and (+/-)-13. The key intermediates for the synthesis of 12 and 13 in enantiometrically pure form are the hydroxyacetals (R,S,R)-22 and (R,S,S)-23: (R,S,R)-22 is stereoselectively prepared by addition of the aryllithium-compound 21b or the aryltitan-compound 21c to the new serinal equivalent (R,S)-20; reduction of the ketone (R,S)-24 with LiAlH₄ at -78°C affords the diastereomeric hydroxyacetal (R,S,S)-23 predominantly (>95%). With acid (R,S,R)-22 and (R,S,S)-23 are transformed into the tricyclic ure-thanes (S,S,R)-25 and (R,S,S)-30, which are reduced and methylated to yield the dimethylamines (S,S,R)-12 and (R,S,S)-13 (ee > 97%), respectively. Analogously the enantiomeric amines (R,R,S)-12 and (S,R,R)-13 are prepared starting from (R)-serine. The relative configuration of (R,S,R)-22 is confirmed by molecular dynamics calculations (Sybyl 5.4) combined with NOE-measurement. Symptoms typical for sedation are observed after application of both enantiomers of 12, 13, 27, and 32 to mice. In the acetic acid writhing test (mouse) (S,S,R)-12, (S,R,R)-13, (R,S,S)-13, (S,S,R)-27, (R,R,S)-27, and (R,S,S)-32 exhibit strong analgesic effects with ED₅₀-values in the range of the ED₅₀-value of tramadol-HCl.