Synthesis of 4-thia-2-azapodophyllotoxin, a new analogue of the antitumour lignan podophyllotoxin

Abstract
An efficient synthesis of 4-thia-2-azapodophyllotoxin 6, a new analogue of podophyllotoxin, is described. The hydantoin 11, prepared from the benzenethiol 10, was condensed with 3,4,5-trimethoxybenzaldehyde in the presence of trifluoromethanesulfonic acid to produce the pentacyclic fused imidazolidinedione 12 stereospecifically. Compound 12 was protected and reductively converted into the alcohol 16. Dehydration of 16 under Mitsunobu conditions allowed for the predominant formation of the N-trityl cyclic isourea 17, which was converted into the oxazolone 6 in two steps. Cytotoxicity (KB cells) testing revealed that 6 is less toxic than podophyllotoxin 2 or the known analogue 4.

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