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Total Synthesis of Cyclothialidine
Author(s) -
Götschi Erwin,
Jenny ChristianJohannes,
Reindl Peter,
Ricklin Fabienne
Publication year - 1996
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19960790816
Subject(s) - chemistry , total synthesis , stereochemistry , lactone , hydrolysis , derivative (finance) , synthon , mitsunobu reaction , bicyclic molecule , halogenation , combinatorial chemistry , organic chemistry , economics , financial economics
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 .