Stille–Heck Coupling Sequences Applied in a Versatile New Access to Steroid Skeletons

A variety of enantiomerically pure steroidal compounds was synthesized utilizing a sequence of Stille and Heck cross‐coupling reactions and subsequent thermal 6π‐electrocyclizations. Highly chemoselective Stille couplings on the triflate moiety of several 2‐bromocyclohex‐1‐enyl triflates with cis ‐ and trans ‐fused bicyclo[4.3.0]nonenylstannanes furnished the corresponding tricyclic bromobutadienes in good to excellent yields (70–97 %). These were subjected to Heck reactions with tert ‐butyl acrylate to provide pentasubstituted tricyclic 1,3,5‐hexatrienes. A significant increase in efficiency could be achieved by applying a novel protocol with a precatalyst on the basis of the palladacycle prepared from Pd(OAc) 2 and P( o ‐Tol) 3 with added triarylphosphines as co‐ligands (73–90 % yield). Upon heating to 205–215 °C in decalin or to 140 °C in toluene (for certain cases), these hexatrienes yielded (78–90 %) various unsaturated steroid analogues as single diastereomers. A particular oxohexatriene, obtained after deprotection of an adjacent carbonyl group, underwent 6π‐electrocyclization at the unusually low temperature of 140 °C to yield (75 %) an interesting 7‐carboxyl‐substituted steroidal dienone. Attempts to remove the remaining protecting groups from some of the other new steroidal compounds under acidic conditions furnished a novel 3‐oxo‐7‐carboxyl steroid analogue and a 3‐hydroxy‐substituted steroidal diene. A novel estradiol derivative could be obtained in 69 % yield from the synthesized steroidal dienone. Deprotection furnished the corresponding unprotected 7‐carboxylestradiol in 81 % yield.