Diversity‐Oriented Synthesis of Enantiomerically Pure Steroidal Tetracycles Employing Stille/Diels–Alder Reaction Sequences

Various steroid analogues were synthesized by Stille coupling of bicyclo[4.3.0]nonenylstannanes cis‐/trans‐8and 14with cyclohexenol triflates 17and 18and subsequent Diels–Alder reactions of the resulting dienes. The enantiomerically pure bicyclo[4.3.0]nonenylstannanes cis‐ and trans‐8were prepared in good yields via the enol triflates cis‐ and trans‐7, obtained from the bicyclo[4.3.0]non‐2‐en‐3‐one 5. The alkenylstannane 14was obtained from the [2+2] cycloadduct 10 aproduced from addition of dichloroketene to the enantiomerically pure and protected bishydroxycyclohexadiene 9 a(65 %). Treatment of 10 awith diazomethane, reduction of the dichloromethylene group, and trapping with tributyltin chloride after lithium‐for‐bromine exchange, yielded the bicyclo[4.3.0]nonenylstannane 14(23 % over four steps). Stille couplings provided the tricyclic dienes cis‐/trans‐19in good yields (73–77 %), whereas the tricyclic diene 20was obtained in only 34 % yield at best. Diels–Alder reactions of trans‐19with various reactive dienophiles yielded the novel steroidal compounds trans‐21to trans‐26with complete diastereoselectivity. Heating the dienes cis‐19or 20with maleic acid derivatives provided the corresponding tetracycles cis‐23α,β and 27α,β with a cis‐C,D ring junction, each as mixtures of two diastereomers. Less reactive dienophiles required higher temperatures to promote the relevant cycloaddition with trans‐19to furnish several stereoisomeric forms of trans‐28and trans‐29in significantly lower yields (31–45 %). The selected steroid analogues trans‐22and trans‐23were deprotected in two steps by using acid catalysis to provide trans‐31and trans‐33(91 and 80 % over two steps). Cyclopropanation of trans‐30yielded the cyclopropasteroid analogue 34(74 %), treatment of which with trifluoroacetic acid furnished the cyclopropasteroid 35and the 2‐methyl‐substituted steroid analogue 36in 40 and 12 % yield, respectively. Aromatic B‐ring steroids 38(69 %) and 39(5 %) were accessed by dehydrogenation of trans‐24with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone.