STUDIES ON TOTAL SYNTHESIS OF STEROIDAL ANTIBIOTICS .2. 2 CONVERGENT SCHEMES FOR SYNTHESIS OF TETRACYCLIC INTERMEDIATES

Two synthetic schemes are outlined for the construction of tetracyclic intermediates with the syn-trans-anti-trans backbone characteristic of the fusidic acid nucleus. Both entail the use of the .alpha.-methylene ketone 14 as the source of the C/D rings. One approach utilizes the conjugate addition of m-methoxybenzylmagnesium chloride as the means for the introduction of the remmants of the A/B ring system, and the placement of the C-8 angular methyl group. Modification of the aromatic ring through Birch reduction and then the Eschenmoser hydrazone cleavage of the derived epoxy ketone leads to the enone 13. A new, versatile annelation procedure is demonstrated by utilization of the .alpha.-methylene ketone 14 as a heterodienophile in the Diels-Alder condensation with acrylates. Reductive fragmentation of the phosphorodiamidate derived from the adducts allows for introduction of the C-8 angular methyl group and provides for the ultimate formation of the enone 13 through aldol-type closure of the B ring. Further transformations of the enone 13 toward 11-deoxyfusidic acid type intermediates and tricyclic substances that contain the 11.alpha.-hydroxy group are outlined. Means are also presented for the conversion of the A-ring enone in tricyclic model compounds to the desired trans-syn-trans structures characteristic of fusidic acid.