Total Synthesis of Cyclothialidine

A total synthesis of cyclothialidine ( 1 ), a new DNA gyrase inhibitor isolated from Streptomyces filipinensis , is described. The synthetic concept was tested by preparing the lactone 13 ( Scheme 2 ) which contains the characteristic bicyclic core entity of 1 . Key features of the synthesis of 1 are: preparation of 3,5‐dihydroxy‐2,6‐dimethylbenzoic acid ( 23 ) from 3,5‐dihydroxybenzoic acid ( 19 ) by two consecutive Mannich aminomethylation/hydrogenation sequences; benzylic N ‐bromosuccinimide bromination of an ester derivative 25 thereof and its subsequent coupling with Boc‐Ser‐Cys‐OMe ( 11 ); cyclization of the ω‐hydroxy acid 29 29 to the 12‐membered lactone 30 using preferably Mitsunobu conditions; completion of the peptidic side chains of 1 using Boc strategy ( Scheme 4 ). Optically pure cis‐N ‐( tert ‐butoxycarbonyl)‐3‐hydroxy‐ L ‐proline ((–)‐ 14 ) was obtained by resolution of the racemate via an efficient reaction sequence containing a lipase‐catalyzed enantiospecific acetate hydrolysis ( Scheme 3 ). The structure of natural 1 was confirmed by comparison with the synthetic material. The synthetic route described provides also easy access to analogues of 1 , e.g., via the intermediate 30 .