Synthesis of podophyllotoxin derivatives by means of tributyltin hydride- or palladium-mediated cyclization of α-benzylidene-β-(o-bromobenzyl)-γ-lactones

Article abstract of DOI:10.1016/S0040-4020(01)85735-5

Synthesis of podophyllotoxin derivatives based on an aryl radical cyclization of α-benzylidene-β-(o-bromobenzyl)-γ-lactones 20 and 21 has been examined. Treatment of a mixture of the alcohols 18a and 18b (ca. 1:1), prepared from 6-bromopiperonal (10) in 7 steps, with methanesulfonyl chloride gave a ca. 3:1 mixture of the chlorides 19a and 19b, which was treated with DBU to give the (Z)-and (E)-α-benzylidene-γ-lactones 20 and 21 in 64 and 22% yields, respectively. Thermolysis of the mixture of the sulfoxides 23a and 23b, prepared from 18a,b, afforded the E-isomer 21 as a major product. The Z-benzylidenelactone 20 when treated with Bu₃SnH in the presence of AlBN gave the 6-endo-trig radical cyclization product, (±)-deoxyisopicropodophyllin (24), and the 5-exo-trig cyclization product 25 in 29 and 49% yields, respectively. The E-isomer 21, however, gave only the 5-exo cyclization product 25. On the other hand, treatment of 20 with PdCl₂(PPh₃)₃ gave (±)-γ-apopicropodophyllin (29) in 75% yield. Similar treatment of 21 afforded no cyclization product, but, in the presence of sodium formate (H^- source), gave the 5-exo cyclization product 25 in 84% yield.