Total Synthesis of Kellermanoldione, 3-Deoxyconferdione, and Progress towards the Total Synthesis of epi-Conferdione

1) Total Synthesis of Kellermanoldione. The total synthesis of the natural product Kellermanoldione is described. This labdane diterpene has been synthesized via a stepwise [4+2] cycloaddition, namely an initial [2+2] cycloaddition between a monosubstituted allenoate and a highly substituted silyloxydiene followed by a purely thermal [3,3]-sigmatropic shift to give a [4+2] exo ester. This exo cycloadduct was converted into kellermanoldione in 6 steps via a Horner-Wadsworth-Emmons olefination with a furyl substituted phosphonate and a non conjugative hydrolysis of a gamma-methylene silyl enol ether, to afford the desired natural product in a total of 17 steps. We were also able to synthesize a less oxidized kellermanoldione analogue, following a very similar synthetic route, namely a stepwise [4+2] cycloaddition between the same monosubstituted allenoate used in the synthesis of kellermanoldione and a less oxidized silyloxydiene.;2) Progress towards the Total Synthesis of epi-Conferdione and Total Synthesis of 3- Deoxyconferdione. In the efforts to synthesize the antiviral natural product epi-conferdione, we were able to obtain three very close analogues to epi-conferdione: 3-deoxyconferdione, a sesquiterpene isolated in 1985, along with two other analogues. Their syntheses were achieved via a synthetic route which involves two key steps: 1) a stepwise [4+2] cycloaddition between a highly hindered silyloxydiene and a monosubstituted allenoate, and b) a microwave-assisted Mitsunobu etherification reaction, a process that allowed us to couple a 7-hydroxycoumarin unit with a trans-decalin alcohol. We also explored the possibility of forming the ether linkage using other strategies, such as: 1,6-Michael addition, SN2 nucleophilic substitution, nucleophilic aromatic substitution, and metal-catalyzed cross coupling processes. However, the microwave-assisted Mitsunobu etherification exhibited the best results in terms of reaction times and yields. In addition, we were also able to synthesize the natural product fetidone, via acid hydrolysis of a cyclohexanedienone intermediate that was obtained in some of the reactions attempted towards the synthesis of epi-conferdione and analogues.