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Organic Chemistry Highlights

Total Synthesis

Monday, January 2, 2023
Douglass F. Taber
University of Delaware

The Li Synthesis of Albolic Acid

Albolic acid (3) and ceroplastol II, the corresponding primary alcohol, are sesterterpenoids isolated from the wax secretion of Ceroplastes albolineatus, a scale insect. Chuang-Chuang Li of the Southern University of Science and Technology devised a route to 3 based on the Rh-catalyzed Pauson-Khand cyclization of the allene 1 to the tricyclic enone 2 (J. Am. Chem. Soc. 2022, 144, 10162. DOI: 10.1021/jacs.2c04633).

The synthesis started with the inexpensive limonene 4. Ozonolysis followed by aldol condensation led to 5, that was reduced, then carried on to the allylic bromide 6. Coupling with ethynyl magnesium bromide 7 led to the volatile alkyne 8. Diastereoselective hydroboration led after oxidation to the aldehyde 9. The addition of the propargyl borane 10 was also highly diastereoselective, completing the assembly of the yne-allene substrate 1.

The Pauson-Khand cyclization probably proceeds via initial complexation with the alkyne, followed by addition to the distal end of the allene, to give 11. Carbonylation would then give 2. In the course of this work, the authors demonstrated a high degree of functional group tolerance for this ring construction strategy.

The conformation of the medium ring directed the hydrogenation of 2, to give the enone 12. Conjugate addition to the congested system failed, so the requisite angular methyl group was introduced by reduction to the allylic alcohol followed by Simmons-Smith cyclopropanation, leading to 13. Oxidation followed by deprotection and dehydration led to the ketone 14. Aldol condensation with the aldehyde 15 gave, after dehydration, the expected more stable E-enone 16. Conjugate addition proceeded across the more open face of the enone, establishing the sidechain stereocenter of the ketone 17. Dissolving metal reduction followed by deoxygenation completed the assembly of the triene 18.

It would have been possible to achieve selective oxidation of the sidechain alkene of 18. It was more expedient to effect cross metathesis with methyl methacrylate (19), leading, after saponification, to albolic acid (3).

D. F. Taber, Org. Chem. Highlights 2023, January 2.