SYNTHESIS OF THE PUTATIVE ACTIVE METABOLITES OF THE CYCLOPENTA[A]PHENANTHRENES - SYNTHESIS OF THE TRANS-3,4-DIHYDRO 3,4-DIOL AND SYN-3,4-DIOL 1,2-EPOXIDE DERIVATIVES OF THE MUTAGEN 15,16-DIHYDROCYCLOPENTA[A]PHENANTHREN-17-ONE

The first synthesis of the trans-dihydro diol and syn-diol epoxide derivatives of a biologically active cyclopenta[a]phenanthrene is described. The cyclopenta[a]phenanthrene 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 alpha-heterosubstituted cyclopentenone, a "cyclopentynone" equivalent. It was found that the Diels-Alder reaction of alpha-(phenylselenenyl)- (6a) or alpha-bromocyclopentenone (6b) with 5 in the presence of 1.5 euqiv of SnCl4 followed by elimination with hydrogen peroxide or DBU produced the key intermediate 15,16-dihydro-3-methoxycyclopenta[a]phenanthren-17-one (10) in 28% or 59% 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 (51%). Treatment of bis-(TBDMS) ether 16 with TBAF in THF provided the desired 3,4-trans-dihydro 3,4-diol (3) (83%), thus achieving the synthesis of 3 in 10 steps in 9.6% 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 59% overall yield.