Absolute Configuration of Tetracycline
During the past years, in approaching research in the area of tetracycline chemistry and obtaining reviews on manuscripts, some question has been raised as to the absolute configuration of tetracycline. This letter simply is a review of the primary literature in this area and, hopefully, will settle this controversy.
The structures of oxytetracyclinel and cN~rtetracycline~*~ were elucidated by chemical degradation early in the history of these antibiotics. The relative configurations at the asymmetric carbons were established chemically3-1Q; for 7-chlorotetracycline h y d r ~c h l o r i d e ~~-~~, oxytetracycline hydrochloride14J5, anhydrotetracycline hydrobromide16, and 2,5a-diacetylo~ytetracycline~~, the configurations were approached by X-ray crystallography. This work establishing the configuration of the asymmetric centers has led to considerable confusion in the literature as to the exact absolute configuration because tetracycline and its related derivatives have been variously drawn as stereoisomers.
II
Some crystallographers have favored 1'7 while others have favored I111-16. Since an anomalous scattering atom is not present in the tetracycline, the absolute configuration is indeterminate by X-ray crystallography. Furthermore, the apparent incongruities among the X-ray structures in the work done by NMR18J9 and circular d i c h r ~i s m ~" -~~ have led to confusion among researchers. The absolute configuration of the tetracyclines, however, was chemically determinedZ5 by degradation of chlortetracycline to a derivative that was comparable to a derivative prepared from atrolactinic acid, the absolute configuration of which is known. This work showed that I is, in fact, the correct absolute configuration of the tetracyclines.
It is hoped that this discussion will prevent further inconsistencies in the representation of the absolute configuration of the tetracyclines.