The tetracycline molecule has offered a splendid challenge to a synthetic organic chemist,
a mojor obstacle in its total synthesis being the stereospecific
introduction of many functional groups into the basic carbon nucleus. Of even greater
concern is the extreme chemical sensitivity of this molecule, particularly its lability
in acidic and basic media .
The following synthesis was reported by Shemyatkin et al. . The precursor had been prepared in six stages from juglone (a naturally occurring quinone, the active staining principle of black walnut hulls) , and the product was obtained by degradation of the naturally occurring tetracycline according to the procedure of Green and Boothe . Since the latter is a degradation product of tetracycline, and has been reconverted by 12a-hydroxylation followed by photo-addition etc., according to the Scott procedure , into tetracycline, a formal total synthesis of the latter had been accomplished .
The next synthesis of a tetracycline-like structure by Woodward was reported in 1968 :
Muxfeldt et al. presented a simple route to tetracycline system, using brilliant condensation and oxazolone moiety cleavage to produce a sensitive group in A ring :
The improved method of the latter, with a controlled introduction of stereocenter at C4a, has been presented by Stork et al. :