SYNTHESIS OF THE TETRACYCLIC CARBON CORE OF MENOGARIL UTILIZING THE BENZANNULATION REACTION OF A FISCHER CARBENE COMPLEX AND AN ALKYNE

The synthesis of the 2-bromoanthracyclinone 3 containing the tetracycl ic core of menogaril is achieved with a strategy that is formulated ar ound the benzannulation reaction of a Fischer carbene complex and an a lkyne. This benzannulation requires a 2,5-dimethoxyphenyl carbene comp lex that bears an additional functional group at the 4-position that i s the nascent 2-bromo substituent in 3. The evaluation of 4-bromo- and 4-trimethysilyl-substituted complexes with 1-pentyne revealed that th e benzannulation was more efficient with the silyl complex. The synthe sis of 3 is achieved with methoxy and acetoxy substituents at the C-9 position, which begins with the methoxy- and benzyloxy-substituted alk ynes 14 and 30 that contain the A ring of the menogaril core. The clos ure of the last ring is accomplished by a Friedel-Crafts reaction on a n in situ generated acid chloride. Adjustment of the oxidation states of the B and C rings failed according to procedures that had been deve loped in model studies. This was accomplished in an unexpected fashion with novel bromination reactions that occurred at a benzylic position with the C-9 methoxyl derivative and alpha to a ketone in the C-9 ace toxy derivative.