Tetracyclic benzothiophenes

Tetracyclic Benzothiophenes and Benzanthracenes Lilly disclosed conformationally restricted raloxifene and benzopyrane analogs [181]. Both series yielded tetracyclic SERM-type estrogens that showed good affinity for ERa. Benzothiophene 144 and benzopyrane 14S effectively inhibited MCF-7 proliferation. Compound 14S (LY-357489) showed high efficacy on bone protection and cholesterol metabolism at doses as low at lOmg/kg/day. No development has been reported. 

In the second example carbon monoxide insertion into a benzothiophenylpalladium complex, and a subsequent C-H activation led to the transformation of 3-iodo-2-phenyl-benzothiophene to the tetracyclic compound shown in 5.9.9... 

Lilly also disclosed two series of conformationally restricted benzanthracene derivatives [185]. These tetracyclic compounds showed high ERa affinity, but subtype selectivity was modest. Thus, benzothiophene analog 149 expressed 5-fold preference for ERa and similar ERa selectivity was noted for benzanthracene analog 150. The latter compound showed high MCF-7 antagonistic activity, whereas analog 149 was 20-fold less active. 

A synthesis of (+)-estradiol from an alkyl 1,3-dihydrobenzo[c]thiophene-2,2-dioxide involving o-quinodimethane formation by thermal extrusion of SO2 and subsequent cycloaddition has been achieved in an overall yield of 50% (ref. 143). Thus a chiral cyclopentanone component (ref. 144) was used to alkylate the appropriate benzothiophene dioxide and the required tetracyclic stucture obtained directly with avoidance of the customary hydrogenation. It was found desirable at the alkylation stage to enhance deprotonation at Cl by having a cyano group in the benzenoid ring. The ( anotetracycle (R CN) was reacted... 

In a beautiful study for establishing an efficient approach to the diverse tetracyclic heteroazulene ring systems,Jana and coworkers developed a tandem C-3/C-2 annulation of benzothiophene along with... 

---