Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, September 3, 2012
Douglass F. Taber
University of Delaware

The Carreira Synthesis of (+)-Daphmanidin E

(+)-Daphmanidin E (3), isolated from the leaves of Daphniphyllum teijsmanni, shows moderate vasorelaxant activity on the rat aorta. Considering the curiously compact structure of 3, Erick M. Carreira of ETH Zürich chose (Angew. Chem. Int. Ed. 2011, 50, 11501. DOI: 10.1002/anie.201104681) to start the synthesis from the enantiomerically-pure bicyclic diketone 2.

The mono enolate of 2 was readily prepared, but the steric bulk of the ketal of 4 was needed to direct the subsequent hydroboration. Indeed, the alkene of 5 was so congested that excess BH3 at elevated temperature was required. Under those conditions, the esters were also partially reduced, so the reduction was completed with Dibal to deliver the crystalline triol 6. After protection of the alcohols, the remaining carbon atoms of 3 were added by sequential Claisen rearrangements. O-Alkylation with 7 delivered 8, which rearranged with 10:1 diastereoselectivity. After O-allylation, the second Claisen rearrangement led to 9 as the only isolable product.

Selective hydroboration of 9 led to 10, which was deprotected, then dehydrated following the Grieco protocol. Functional group manipulation of 11 led to the aldehyde 12, that was condensed with nitromethane to give 13. Direct conjugate addition to 13 gave at best a 1:3 preference for the wrong diastereomer. With a chiral Cu catalyst, this was improved to 5:1 in favor of the desired diastereomer.

Ozonolysis of 14 followed by selective reduction of the aldehyde gave the primary alcohol, that was carried on to the iodide. Elimination with DBU then delivered 15, setting the stage for the key intramolecular bond connection. After extensive exploration, it was found that irradiation of 15 in the presence of a catalytic amount of a cobaloxime catalyst and a stoichiometric amount of Hünig’s base gave clean cyclization to 16.

The last carbocyclic ring of (+)-Daphmanidin E (3) was closed by intramolecular aldol addition of the aldehyde of 17 to the ketone, followed by dehydration. The seemingly simple intramolecular imine formation to prepare the natural product, initially elusive, was effected by heating the ammonium salt in ethanol.

The Co-catalyzed cyclization of 15 to 16 is particularly striking. In concurrent work, the Carreira group further explored (Angew. Chem. Int. Ed. 2011, 50, 11125. DOI: 10.1002/anie.201105235) the scope of this transformation.

D. F. Taber, Org. Chem. Highlights 2012, September 3.