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‐8 and 14 with cyclohexenol triflates 17 and 18 and subsequent Diels–Alder reactions of the resulting dienes. The enantiomerically pure bicyclo[4.3.0]nonenylstannanes cis‐ and trans‐8 were 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 14 was obtained from the [2+2] cycloadduct 10 a produced from addition of dichloroketene to the enantiomerically pure and protected bishydroxycyclohexadiene 9 a (65 %). Treatment of 10 a with 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‐19 in good yields (73–77 %), whereas the tricyclic diene 20 was obtained in only 34 % yield at best. Diels–Alder reactions of trans‐19 with various reactive dienophiles yielded the novel steroidal compounds trans‐21 to trans‐26 with complete diastereoselectivity. Heating the dienes cis‐19 or 20 with 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‐19 to furnish several stereoisomeric forms of trans‐28 and trans‐29 in significantly lower yields (31–45 %). The selected steroid analogues trans‐22 and trans‐23 were deprotected in two steps by using acid catalysis to provide trans‐31 and trans‐33 (91 and 80 % over two steps). Cyclopropanation of trans‐30 yielded the cyclopropasteroid analogue 34 (74 %), treatment of which with trifluoroacetic acid furnished the cyclopropasteroid 35 and the 2‐methyl‐substituted steroid analogue 36 in 40 and 12 % yield, respectively. Aromatic B‐ring steroids 38 (69 %) and 39 (5 %) were accessed by dehydrogenation of trans‐24 with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone. Cross‐coupling: A range of diverse B‐ring‐substituted steroid analogues can easily be assembled by Diels–Alder reactions of tricyclic dienes that are accessible by Stille couplings of cyclohexenyl triflates and bicyclononenylstannanes (see scheme) in good overall yields.