Cascade radical synthesis of heteroarenes via iminyl radicals

Abstract

A novel cascade cyclisation protocol has been developed which ‘zips up’ two rings to form new tetracycles. In the protocol, treatment of vinyl bromides and iodides with hexamethylditin (Me3Sn˙) yields intermediate vinyl radicals which undergo 5-exo cyclisation onto nitrile groups to yield intermediate iminyl radicals. The iminyl radicals can undergo 6-endo cyclisation (or 5-exo followed by neophyl rearrangement) to yield tetracyclic π-radicals which lose hydrogen (H˙) in an H-abstraction step. Methyl radicals, generated from the breakdown of trimethylstannyl radicals (Me3Sn˙), are proposed as a possible H-abstractor for this final oxidative step. The protocol has been used to synthesise the tetracyclic rings A–D (tetracycle indolizino[1,2-b]quinolin-9(11H)-one) of the anticancer alkaloids camptothecin, mappicine, nothapodytine B and nothapodytine A. The protocol has also been applied to the synthesis of analogues of camptothecin in which ring A has been replaced by thiophene (8,10-dihydrothieno[2′,3′:5,6]pyrido[2,3-a]indolizin-8-one) and ring D by pyrrole (10H-pyrrolizino[1,2-b]quinoline) and benzene (11H-indeno[1,2-b]quinolin-11-one).