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Organic Chemistry Highlights

Total Synthesis

Monday, January 2, 2012
Douglass F. Taber
University of Delaware

The Reisman Synthesis of (+)-Salvileucalin B

Salvileucalin B (3) exhibits modest cytotoxicity against A549 (human lung adenocarcinoma) and HT-29 (human colon adenocarcinoma) cell lines. The compelling interest of 3 is its complex, highly functionalized heptacyclic skeleton. Sarah E. Reisman of the California Institute of Technology envisioned (J. Am. Chem. Soc. 2011, 133, 774. DOI: 10.1021/ja110192b) that the intramolecular cyclization of the diazo ketone 1 could offer an efficient entry to 2 and thus to 3.

The key intermediate for the preparation of 1 was the acid 11. It was not possible to achieve communication between the two stereogenic centers of 11, so the decision was taken to establish these independently. This led to a strategy centered on the construction of the 1,2,3,4-tetrasubstituted aromatic ring.

The absolute configuration of the stereogenic center of 8 was set by enantioselective addition of 5 to the commercial aldehyde 4. The absolute configuration of the second center was set using the Myers protocol. Although 10 could not be hydrolyzed without epimerization, cyclization followed by hydrolysis was effective, delivering 11 as a 10:1 mixture of diastereomers. From the algebra of mutual resolution, the major diastereomer, separated at a later stage, was of high enantiomeric purity.

The acid 11 was homologated, first by the Arndt-Eistert procedure, then by condensation of the methyl ester so prepared with the anion of acetonitrile. Exposure of the derived diazo nitrile 1 to Cu catalysis under brief microwave irradiation led to smooth cyclization to the hexacyclic ketone 2.

Although the skeleton of 2 was readily assembled, it is highly strained. This was made clear on Dibal reduction of the derived enol triflate. The product was clearly not the desired aldehyde 2, but rather 12, the product of Claisen rearrangement.

Reasoning that the Claisen rearrangement is thermally reversible, and that the ether 12 would be stable to hydride, they carried forward with Dibal reduction – and were rewarded by the appearance of the desired primary alcohol, from the reduction of 2. Pd-mediated cyclocarbonylation delivered 13, that was selectively oxidized to (+)-Salvileucalin B (3).

D. F. Taber, Org. Chem. Highlights 2012, January 2.