Synthesis of 6-thiatetracycline, a highly active analogue of the antibiotic tetracycline

The Erlenmeyer synthesis with a thioazlactone

“…It is noteworthy that the condensation (2b+3) occurs with a catalytic quantity of the exceedingly weak base, basic lead acetate (Pb(OAc) 2 .Pb(OH) 2 ). 5,8,9 This supports the case for the relatively enhanced aromaticity of Ib. The mild conditions are particularly suited for aliphatic aldehydes, several of which afford the expected products 5 in excellent yields ( Table 1).…”

“…[5][6][7] The reaction mixture was treated with an aldehyde (3) and a catalytic amount of basic lead acetate over 20 min. 5,8,9 Minimal work-up and chromatographic purification led to the isolation of the 4-alkylidene or 4-arylidene thioazlactone derivative 5, in generally excellent yields (Table 1). These results indicate that the thiazolin-5-one (2b) generated in situ with DCC, 7 has condensed with the aldehyde (3).…”

Chemical Modification of the Tetracyclines

“…There follows a short description of the synthesis of 6-thiatetracycline (327) (Fig.40), the simplest basic structure in this series, which is also exemplary for all other compounds (KIRCHLECHNER and ROGALSKI 1980). The synthesis starts from 2-chloro-4-aminothiophenol (313).…”

The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery

“…The Woodward, Shemyakin, and Muxfeldt groups reported remarkable advances for their time with their successful constructions of sancycline (25 synthetic steps, 0.002 % yield), tetracycline (yield not reported), and oxytetracycline (22 steps, 0.06 % yield), respectively, but these routes were lengthy and impractical to scale (though it should be noted that the Muxfeldt approach was for a time adapted by researchers at Merck in Germany for the preparation of fully synthetic 6-thiatetracycline, an antibiotic candidate that was abandoned during clinical development due to liver toxicity). [123] Interestingly, each group had employed a "left-to-right" or D!A mode of construction, which was not ideal from the standpoint of drug discovery, since substitution of the D ring proves to be remarkably fruitful for the development of novel antibiotics, especially those with improved activities against tetracyclineresistant microorganisms, whereas most substitutions of the A ring diminish or abolish antibiotic activity.…”