Stereoselective Syntheses of (2)-( 10-Methoxy-4H-benzo[4,5~cyclohepta[ 1,2-b)thiophen-4-ylidene)acetic Acid
Two stereoselective syntheses for the antiinflammatory compound 1 ((Z)-isomer) are described. In the first approach (Strategy A , Scheme I ) the stereoselective synthesis of 1 was realized oiu the bicyclic compound 11 under thermodynamic conditions, followed by a thiophene annelation with retention of the double-bond geometry (Schemes 2-4). Optimized conditions were necessary to avoid (E/Z)-isomerization during annelation. In the second approach (Strategy B, Scheme I ) , diastereoisomer 17b was obtained selectively from a mixture of the diastereoisomers 17b and 18b by combining thermodynamic epimerization and solubility differences (Scheme 5 ) . Diastereoisomer 17b was converted into the tricyclic compound 23 using a novel thiophene annelation method which we described recently (Scheme 6 ) . In a final step, a stereospecific 'syn'-elimination transformed the sulfoxide 24 into the target compound 1 (Scheme 7). To avoid (E/Z)-isomerization, it was necessary to trap the sulfenic acid liberated during the reaction. The key reactions of both approaches are highly stereoselective ( > 97: 3).