SYNTHESIS OF (PLUS-OR-MINUS)-4-DEOXYPODOPHYLLOTOXIN, (PLUS-OR-MINUS)-PODOPHYLLOTOXIN AND (PLUS-OR-MINUS)-EPIPODOPHYLLOTOXIN

6,7-Methylenedioxy-1-(3',4',5'-trimethoxyphenyl)-2-benzopyran-3-one 1 and dimethyl fumarate in acetonitrile give mostly the C-2 exo-CO2Me adduct 4 which is transformed in four steps into epipodophyllotoxin 10a. Attempted addition of dimethyl maleate to 1 proceeds with decarboxylation of the putative endo-adduct 11 to a transient o-quinodimethane which undergoes a highly regioselective 1,5-hydrogen shift to the dihydronaphthalene 14. The alternative 1,5-shifts are shown for the model o-quinodimethane 22 [22 and 22a (arrows)] it being suggested that the shift in 22a is disfavoured by the steric clash shown therein. The product 14 is converted into 4-deoxypodophyllotoxin in an efficient sequence of reactions having as a key step a high-yield epimerisation of the aldehyde 26 to 27. The dihydronaphthalene 14 is also converted into podophyllotoxin 10b (seven steps, 24% overall yield); novel steps include the epimerisation of 35 to 36 and selective oxidation of 34 to 35 using (Bu3Sn)2O-I2.