Use of (S)-(trifloxymethyl)oxirane in the synthesis of a chiral .beta.-adrenoceptor antagonist, (R)- and (S)-9-[[3-(tert-butylamino)-2-hydroxypropyl]oximino]fluorene

Authors:
  • JBJohn J. Baldwin
    John J. Baldwin
  • DMDavid E. McClure
    David E. McClure
  • DGDennis M. Gross
    Dennis M. Gross
  • MWMichael Williams
    Michael Williams
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Abstract
Two synthetic approaches were used to prepare, in chirally pure form, the .beta.-adrenoceptor antagonist 9-[[3-(tert-butylamino)-2-hydroxypropyl]oximino]fluorene (1a). One of these employed the oxazolidine (S)-6 generated from D-mannitol, while the other utilized (S)-[[(trifluoromethanesulfonyl)oxy]methyl]oxirane (4) as the chiral 3-C fragment. This latter synthesis was designed to incorporate the amino function in the last step. In vitro, a .beta.2 selectivity of only 2.2 was observed for 1a. The example, (S)-9-[[3-(tert-amylamino)-2-hydroxypropyl]oximino]fluorene (1b), was prepared and was selective for the .beta.1 receptor by a factor of 2.5. In contrast to other .beta.-adrenoceptor antagonists, the enantiomers of 1a exhibited no chiral preference; i.e., (S)-1a and (R)-1a possessed a similar order of .beta.-adrenoceptor antagonistic activity. [Activity was tested in guinea pigs.].