Organic Chemistry Portal
Organic Chemistry Highlights

Search Org. Chem. Highlights:

Match: or and


Total Synthesis

Monday, June 6, 2016
Douglass F. Taber
University of Delaware

The Inoue Synthesis of Crotophorbolone

Crotophorbolone (3), one of the family of tigliane and daphnane diterpenes, was isolated from the dried roots of Euphorbia fischeriana Steud, used in traditional Chinese medicine for the treatment of edema, ascites and cancer. Masayuki Inoue of the University of Tokyo envisioned (Angew. Chem. Int. Ed. 2015, 54, 14457. ) that the tricarbocyclic core of 2 and so of 3 could be established by the diastereocontrolled cyclization of the bridgehead radical from the reduction of 1.

The preparation of 1 began with commercial R-carvone 4. Regioselective enol ether formation followed by distal addition of the dimethoxy methyl cation delivered 5, that was condensed with formaldehyde to give 6. Dissolving metal reduction led to the all-equatorial alcohol. Oxidation to the ketone followed by the addition of the lithiated enol ether gave 8, that was cyclized to 9.

The bicyclic acetal was formed as a 1:1 mixture of diastereomers. These were conveniently separated at a later stage. Each was carried forward to 3, but only one will be illustrated. The preparation of 1 was completed by a π-allyl Stille coupling of 10 with an allylic alcohol derived from 9.

There are two competing diastereomeric transition states for the cyclization of 1. Computational analysis suggested that the methyl substituent would destabilize one of those two transition states by more than 4 kcal/mol. In the event, reduction of 1 in degassed refluxing toluene led cleanly to 2. Methylenation of 2 gave 11, that was equilibrated to the more stable 12 by brief exposure to RhCl3.nH2O in EtOH.

The cyclic acetal of 12 was unraveled with aqueous HCl, and the allylic alcohol was reprotected to give 13. Oxidation gave the acid, that was silylated and activated with 14 to give 15. Oxidative decarboxylation gave the secondary alcohol, that was protected to give 16. Hydroxylation by the Davis procedure led selectively to the diastereomer 17, that was carried on to Crotophorbolone (3).

D. F. Taber, Org. Chem. Highlights 2016, June 6.