ChemInform Abstract: SYNTHESEN IN DER TETRACYCLINREIHE 1. MITT. TOTALSYNTHESE VON D,L‐7‐CHLOR‐6‐DESOXYTETRACYCLINEN UND D,L‐7‐CHLOR‐6‐DESMETHYL‐6‐DESOXYTETRACYCLINEN DER NATUERLICHEN, DER 5A‐EPI‐ UND DER 6‐EPI‐REIHE

Abstract

Aus den Aldehyden (Ia) und (Ib) erhält man mit Hippursäure (II) die Oxazolone (III), die mit 3‐Oxo‐glutarsäuremonomethylester (IV) kondensiert werden.

The history of the tetracyclines

“…Their pathway chose a conjunctive approach, coupling a BA ring fragment with a DC ring fragment, and generating the tetracycline DCBA ring system and novel compounds of varying antibacterial activity. In the past and over several decades, the total synthesis efforts of Conover and Woodward, 75 then Drueckheimer, 76 among others, were successful in generating several compounds of which only one entered clinical trials, and it was soon abandoned presumably because of toxicity issues 77 . Currently, this pathway of tetracycline synthesis has been used by Tetraphase Pharmaceuticals of Watertown, Massachusetts, and has resulted in the generation of a C7‐fluorotetracycline derivative coded TP‐434, which is currently entering Phase II clinical trials against pathogens and indications related to intra‐abdominal infections 78…”

Chemical Modification of the Tetracyclines

“…This may explain the biologieal inactivity of the 4-epitetracyclines (STEZOWSKI 1976). Replacement of the dimethylamino group with a primary amino group does not alter the in vitro activity URBACH et al 1973). A methylamino group, on the other hand, causes a slight drop in activity, while a diethylamino group and longer-chained alkylamino groups lead to more pronounced loss of activity as the chain length increases, as shown in Table 3 ( ESSE et al 1964 b).…”

“…Synthesis was by the principle of Muxfe1dt (URBACH et al 1973). The racemic aldehyde (184) condenses with hippuric acid in tetrahydrofuran in the presence of basic lead acetate and acetic anhydride to give the oxazolinone (187) (Fig.…”