Synthesis of podophyllotoxin analogues: δ-lactone-containing picropodophyllin, podophyllotoxin and 4′-demethyl-epipodophyllotoxin derivatives

Non-epimerizable cis and trans δ-lactone analogues of podophyllotoxin have been prepared. Thus the synthesis of the cis isomer has been achieved in 8 steps and 4% overall yield from podophyllotoxin via the reduction of the γ lactone ring into the trans diol, selective protection of the 4-OH and 11-OH as a benzylidene acetal, and Wittig elongation at C-13 with inversion of configuration at C-2. Same elongation at C-13 but via the formation of a mesylate and introduction of a cyano group, led to the trans δ-lactone (7 steps from and 6% overall yied) with a small amount of its C-4 epimer . The synthesis of non-epimerizable δ-lactone analogues of 4′-demethyl-epipodophyllotoxin and of 4-demethyl podophyllotoxin are also reported. The synthesis of and was based upon the reduction of the γ-lactone ring of 4′-demethyl-4-epipodophyllotoxin followed by selective protection at C-11 and elongation at C-13. (8–15% and 4% overall yields). Compounds , and did not display relevant cytotoxicity in vitro against L1210 murine leukemia.