The Synthesis of Cyclopamine by Giannis et al.

          The synthesis of cyclopamine by the laboratory of Giannis begins with the remote stereoselective C-H functionalization of the steroidal C12 position according to a modification of the protocol of Schonecker. It seems initially surprising that the attack of the oxygen occurs on the hindered (by the pseudoaxial 13beta-methyl) beta-side of the steroid. This indicates that in the active copper complex (shown), the copper and oxygen atoms must lie in the same plane as the 12beta-hydrogen such that the oxygen can abstract the 12betaH more readily than the axial 12alphaH. In this way, hydroxylation of the readily available dehydroepiandrosterone secures the corresponding 12beta-hydroxy steroid derivative in a very good yield, when one considers the relative challenges associated a total synthesis approach to this type of functionalization.

          After a straight-forward installation of the C17 spiro-lactone, the steroid skeletal framework was rearranged to the C-nor-D-homo system of cyclopamine. A very interesting cationic ring contraction/expansion was developed for this purpose. The reaction involves triflation under thermal conditions and the detailed mechanism has not been described. Interestingly, the 12beta-triflate does not seem to be an intermediate in the formation of the rearrangement products of the reaction, which contain an exocyclic double bond (major) along with an endo isomer (minor). Clearly, a cationic mechanism involving C14 bond migration is operative in the rearrangement process. The reaction is effective on a variety of different steroidal systems including 17-keto steroids (separate methodology paper: JACS 2010).

          Subsequently, a tandem Horner-Wadsworth-Emmons (HWE) olefination/intramolecular oxy-Michael addition was successfully conducted on an advanced azidolactol intermediate. Diastereoselectivity in the case is probably derived from the relative thermodynamic stability of the equatorially disposed furan substituent in the observed stereoisomer. Next, the piperidine is constructed in four steps as shown above. Given the presence of three double bonds (two exocyclic) in the advance piperidine intermediate, regioselective olefin functionalization was required to complete the synthesis of cyclopamine. First, regio- and stereoselective hydrogenation of the C25-27 olefin was achieved with Wilkinson’s rhodium(I) catalyst. The C13-18 exocyclic double bond was then selectively functionalized by execution of an intramolecular ene reaction which generated an N-sulfinylated intermediate that was desulfurized with Raney nickel. Consecutive reductive deprotections completed a concise (20 steps) and efficient synthesis of the biomedically useful modified steroid, cyclopamine.