Synthesis and chemistry of cyclopentenoid antibiotics

A new and simple method has been developed for the preparation of -methylene cyclopentenones and presently provides the most convenient route to sarkomycin. The work has, in addition, led to a better understanding of the vinylogous Dieckmann condensation, the course of Michael addition to -methylene cyclopentenones and the behavior of cyclopentenoid endocyclic and exocyclic dienolates towards electrophi es. INTRODUCTION The chemistry of "cyclopentenoid antibiotics",1 a small class of compounds isolated from the culture broth of streptomyces species, has recently attracted much attention from chemists. 2 Despite the success of existing methods, there have been recent reports on various alternative approaches to the synthesis of the cyclopentenoid nucleus, reflecting strong interest in this significant unit which is also found in a variety of other biologically important naturally occurring compounds. The work about to be described is from part of an on-going program being carried out in our laboratory. A THREE-CARBON ANN ELATION ROUTE TO CYCLOPENTENONES A few years ago we came across a very simple and effective method for the construction of disubstituted cyclopentenones (e.g. 4 or 5) via a three-carbon annelation as outlined below 3 (Scheme 1). Scheme 1 R4 R3 R4 R3 R4 R3 R4 R2 1. LDA LDA "?" 1 S#)._( R1',rCOOEt 2 .BrfR4 (X.COOEt R'>< 1 2 orThF/NEDA 3 4 The mechanism of the above annelation is regarded as involving rapid cyclisation of the allyl anion 3. Various attempts to trap the anion 3 have failed, the reaction directly giving 4 and/or its thermodynamically more stable product 5. Recognizing its potential, we decided to use the above reaction for the synthesis of -methylene cyclopentenones 6, including methylenomycin B and "the deceptive" sarkomycin Now, up until that time all the syntheses of -methylene cyclopentenones have invariably involved two compulsory steps: construction of the five-membered ring and subsequent formation of the exo-methylene group via an elimination reaction (Figure A). In our study, however, the desired sequence was achieved by simply reacting the propene unit with a masked -methylene carbonyl function (Figure B, Scheme 2, and Table 1). 781