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Organic Chemistry Highlights

Total Synthesis

Monday, April 6, 2020
Douglass F. Taber
University of Delaware

The Sarlah Synthesis of Stelletin E

The stellettins, represented by stelletin E (3), with its challenging trans-syn-trans skeleton, are of interest to the National Cancer Institute because they have the same antineoplastic pattern as the schweinfurthins and the cephalostatins. David Sarlah of the University of Illinois established a route to 3 based on the reductive cyclization of 1 to 2 (J. Am. Chem. Soc. 2019, 141, 14131. DOI: 10.1021/jacs.9b08487).

The starting point for the preparation of 1 was commercial geranylacetone (4). Exposure to TosMIC gave the nitrile, that was selectively epoxidized via the bromohydrin, leading to 1. To effect cyclization, a solution created by reducing three equivalents of titanocene dichloride with six equivalents of zinc was added dropwise to a solution of 1 over eight hours at room temperature. The crude cyclization product was carried on to the crystalline ether 2.

The ketone 2 has the expected chair-chair conformation. In the course of constructing the third ring of 3, that would have to flip to the high energy twist boat of the natural product. To this end, the ketone was carried on to the unsaturated aldehyde 5. Addition of lithium acetylide (6) proceeded with high diastereocontrol, leading to the pivalate 7. Gold-catalyzed rearrangement then delivered the fluoro ketone 8, with the key cyclic quaternary center established.

The ketone 8 was converted to the corresponding tosylhydrazone. Although fluoride is not usually a good leaving group, the nonbonding electrons of the hydrazone supported methanolysis. Reduction under Kabalka conditions then delivered the requisite trans fused 9.

The authors turned again to early transition metal chemistry, reducing 9 with stoichiometric Negishi reagent, then coupling the resulting Zr allyl with acetyl chloride, leading to 10 as the dominant regioisomer. Hydroboration with subsequent removal of the silyl protecting group, then oxidation, led to the triketone 11, that was converted to the vinylogous acid bromide 12. Coupling with 13 followed by saponification and irradiation then completed the synthesis of stelletin E (3).

Methods have been developed for the preparation of epoxides such as 1 in high enantiomeric purity. Presumably, beginning this route with such an epoxide would deliver 3 also in high ee.

D. F. Taber, Org. Chem. Highlights 2020, April 6.