The Huang/Yang Synthesis of Penicibilaene A

Penicibilaene A (3), isolated from the marine fungus Penicillium bilaiae MA-267, showed potent activity against the plant pathogenic fungus Colletotrichum gloeosporioides. Jun Huang of the University of South China and Zhen Yang of Peking University Shenzhen Graduate School envisioned assembling the tricyclic precursor 2 by the double Conia cyclization of the diyne 1 (J. Am. Chem. Soc. 2024, 146, 4363. DOI: 10.1021/jacs.3c14614).

The enantioselective preparation of 1 began with the enone 4, from the combination of commericial cyclohexane-1,4-dione and the inexpensive enantiomerically-pure stilbene diol. Diastereoselective conjugate addition with the Grignard reagent 5 followed by enolate trapping led to the acetal 6. Selective hydrolysis of the acetal followed by the addition of the Grignard reagent 7 gave the alcohol 8. Methylmagnesium chloride addition to the open face of the ketone delivered the axial alcohol 9. Ketal hydrolysis followed by desilylation then completed the assembly of 1.

The cyclization of 1 following the Trauner protocol was very fast, taking just ten minutes at room temperature. DFT calculations suggested that there was a lower energy barrier to the formation of the five-membered ring, so it presumably formed first, followed by six-membered ring formation to give 1. Although this was not mentioned by the authors, there is the possibility that the second ring formation is proceeding via the allene 10.

To complete the synthesis, it was necessary to selectively add H₂ to what may be the more hindered face of the target alkene. The Crabtree catalyst was found to work particularly well, probably via complexation with the secondary alcohol. Wolff-Kishner reduction then led to 11. The synthesis was completed by the oxidation of the alcohol to the ketone, followed by reduction to penicibilaene A (3).

Note that with the Wolff-Kishner reduction, even a C-15 diol such as 11 can be volatile in steam. It is necessary to take appropriate precautions to avoid losing the product.

We often speak of "solvent polarity". Some considerations are dipole moment, H-bond acceptor, H-bond donor, perhaps water solubility. Christian Laurence of Université Rouen Normandie and Julien Legros of Université de Nantes have assembled a detailed analysis of parameters for 380 solvents (J. Org. Chem. 2024, 89, 9521. DOI: 10.1021/acs.joc.4c00858).