Concise Synthesis of Cyclothialidine Analogues with Ring Sizes from 12 to 15: Novel Macrocyclization Protocol Involving Reductive Thiolation

Abstract

The DNA gyrase inhibitor cyclothialidine was shown to be an interesting lead structure for the search of new antibacterials. During extensive work elucidating the structure-activity relations, it was demonstrated that variation of the lactone ring size of its bicyclic core was tolerated. Indeed, even ‘seco’ analogues exhibited DNA gyrase inhibitory activity. These derivatives were subsequently found to be conveniently accessible by a reductive thiolation approach. Application of this methodology to cyclic systems established an alternative, concise, and flexible synthetic access to congeners of cyclothialidine of varying ring size which so far had been prepared by Mitsunobu lactonization of the corresponding seco acids.

Key words

cyclothialidine - DNA gyrase inhibitor - antibacterials - reductive thiolation - macrocyclization

References

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1

Present address: Ciba Spezialitaetenchemie Grenzach GmbH, Postfach 1266, 79630 Grenzach-Wyhlen, Germany.

5

Angehrn, P.; Buchmann, S.; Goetschi, E.; Gmuender, H.; Hebeisen, P.; Kostrewa, D.; Link, H.; Luebbers, T.; Masciadri, R.; Nielsen, J.; Reindl, P.; Ricklin, F.; Schmitt-Hoffmann, A., Theil, F.-P. J. Med. Chem., in press.