Synthesis of the Putative Active Metabolites of the Cyclopentaphenanthrenes. Synthesis of the trans-3,4-Dihydro 3,4-Diol and syn-3,4-Diol 1,2-Epoxide Derivatives of the Mutagen 15,16-Dihydrocyclopentaphenanthren-17-one

Article abstract of DOI:10.1021/jo00047a030

The first synthesis of the trans-dihydro diol and syn-diol epoxide derivatives of a biologically active cyclopentaphenanthrene is described.The cyclopentaphenanthrene skeleton is rapidly and efficiently assembled utilizing the Lewis acid-catalyzed Diels-Alder reaction of 1,2-dihydro-7-methoxy-4-vinylnaphthalene (5) with an α-heterosubstituted cyclopentenone, a "cyclopentynone" equivalent.It was found that the Diels-Alder reaction of α-(phenylselenenyl)- (6a) or α-bromocyclopentenone (6b) with 5 in the presence of 1.5 equiv of SnCl4 followed by elimination with hydrogen peroxide or DBU produced the key intermediate 15,16-dihydro-3-methoxycyclopentaphenanthren-17-one (10) in 28percent or 59percent overall yield, respectively.The synthesis of the A-ring metabolites features the use of a unique methoxime protecting group for the 17-ketone.The deprotection of the 17-methoxime group of the highly acid-sensitive 3,4-trans-dihydro 3,4-diol bis(TBDMS) ether 15b was achieved through the use of the low-valent titanium reagent produced upon reduction of TiCl3-3THF by DIBAL-H (51percent).Treatment of bis-(TBDMS) ether 16 with TBAF in THF provided the desired 3,4-trans-dihydro 3,4-diol (3) (83percent), thus achieving the synthesis of 3 in 10 steps in 9.6percent overall yield from 6b.In addition, the bay-region syn-3,4-diol 1,2-epoxide (4a) was also synthesized from 3 in two steps <(1) NBA in 1:5 H2O/DMSO, (2) NaOMe/THF> in 59percent overall yield.