The Yang Synthesis of Principinol B

The toxicity of rhododendrons has been known since the time of Xenophon. Principinol B (3) was isolated from Rhododendron principis Bur. Et Franch, a small evergreen growing in south and southeast Tibet. Ming Yang of Lanzhou University assembled 3 via the carbonyl-olefin metathesis cyclization of 1 to 2 (Angew. Chem. Int. Ed. 2024, 63, e202400956. DOI: 10.1002/anie.202400956).

The cyclopentane of 3 was prepared from commercial 2,2-dimethylcyclopentane-1,3-dione (4) following the literature protocol, Itsuno-Corey reduction followed by silylation.

The starting cyclohexenone for the assembly of 1 was the Corey chiron 7. Axial conjugate addition of the Grignard reagent 8 followed by trapping with Mander's reagent and subsequent alkylation with the dibromide 9 delivered 10. Selective conversion of the allyl silane to the alcohol led to the lactone, that was further oxidized to the enone, then reduced under the Luche conditions to give the allylic alcohol 11 with high diastereocontrol. Free radical cyclization followed by alkene isomerization gave the cyclopentene, that was silylated, then reduced to the lactol 12. Addition of vinyl magnesium bromide followed by esterification gave a diacetate, that was selectively reduced by way of the π-allyl Pd complex. Deacetylation then led to the primary alcohol 14. Oxidation to the aldehyde followed by addition of the enolate of 6 and silylation completed the construction of 1.

On exposure to ten equivalents of Petasis reagent, followed by aqueous acid, the ketone 1 was smoothly converted to the cycloheptenol 2. The cyclization is thought to proceed via first conversion of the monosubstituted alkene to the titanacyclobutane, that then added to the target carbonyl to give the titanaoxirane 15. Chelotropic elimination then led to the alkene. While it was possible that the cyclization was proceeding via initial ketone methylenation followed by alkene metathesis, control experiments ruled this out.

The carbon skeleton was completed by oxidation of the secondary alcohol to the ketone, followed by methyl Grignard addition and dehydration, leading to the triene 16. As the cyclopentene was the most reactive of the three double bonds, this was first epoxidized. Osmylation then delivered the cis diol. Monomesylation followed by Mukaiyama hydration led not to the expected tertiary alcohol, but directly to the desired bridging ether. Reduction of the epoxide followed by desilylation then gave principinol B (3).