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Organic Chemistry Highlights

Total Synthesis

Monday, July 6, 2015
Douglass F. Taber
University of Delaware

The Trauner Synthesis of (-)-Nitidasin

The sesterterpene (-)-Nitidasin (4) is a component of the Peruvian infusion "hercampuri", prepared from the shrubs Gentianella nitida and Gentianella alborosea, that was used traditionally to treat hepatitis, diabetes and hypertension. Dirk Trauner of Ludwig-Maximilians-Universität München envisioned (Angew. Chem. Int. Ed. 2014, 53, 8513. DOI: 10.1002/anie.201403605) the assembly of 4 by the convergent coupling of 1 with 2.

For this strategy to be effective, both 1 and 2 had to be prepared in enantiomerically-enriched form. The skeleton of 1 was found in the enone 5, prepared by asymmetric Robinson annulation, that had already been carried on to the trans-fused ketone 6. Following their earlier work (J. Org. Chem. 2012, 77, 5838. DOI: 10.1021/jo300726z), conjugate addition to the enone 8 gave 10. Hydrogenation of 10 had to be carried out with a Pt catalyst to avoid the undesired equilibration of the pendant group. Regioselectivity and diastereoselectivity in the hydroboration of the alkene 11 was optimized with the enantiomerically-pure borane. Allylation of the derived ketone was best effected by way of the enol borinate. Reduction with K-Selectride gave the cis alcohol, that was processed to the lactone. Kinetic alkylation then established the secondary methyl group.

The lactone 13 was reduced to the diol, and protected as the bis TES ether. Selective oxidation of the primary TES ether generated the aldehyde, that could be methylenated without epimerization. Desilylation and oxidation then completed the synthesis of 1.

The preparation of 2 began with commercial enantiomerically-enriched citronellene (14). Oxidative cleavage of the more substituted alkene of 2 gave an aldehyde that was carried by the Corey-Fuchs protocol to the volatile enyne 15. This was cyclized with the Negishi reagent to an intermediate zirconacycle, that was oxidized to the diiodide. Elimination gave a diene, that was hydroborated with good kinetic control to give the alcohol 16. Oxidation followed by methylenation then completed the preparation of 2.

The addition of an excess of the alkenyl lithium derived from 2, a 4:1 mixture of enantiomers, to the ketone 1 proceeded with remarkable diastereoselectivity. The tetrasubstituted alkene of 17 intercepted the Grubbs intermediate, so epoxidation, that also proceeded with remarkable diastereoselectivity, was carried out before ring-closing metathesis. The final steps were unusually delicate, but conditions were found for deprotection, hydrogenation and oxidation to complete the synthesis of (-)-Nitidasin (4).

D. F. Taber, Org. Chem. Highlights 2015, July 6.