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Organic Chemistry Highlights

Total Synthesis

Monday, December 1, 2014
Douglass F. Taber
University of Delaware

The Fukuyama Synthesis of (-)-Lepenine

The denudatine alkaloids, exemplified by (-)-Lepenine (3), have been converted chemically into the physiologically-active aconitine alkaloids. Tohru Fukuyama of Nagoya University envisioned (J. Am. Chem. Soc. 2014, 136, 6598. DOI: 10.1021/ja503023h) an intramolecular Mannich condensation, the conversion of 1 to 2, that in a single step would assemble two of the six rings of 3.

The starting material for the synthesis was the ether 4, prepared by Mitsunobu coupling of the phenol with L-lactic acid methyl ester. Reduction of the ester to the aldehyde followed by the addition of vinylmagnesium chloride led to the secondary allylic alcohol. Claisen rearrangement with triethyl orthoacetate delivered not the ether, but rather 5, the desired product of an additional Claisen rearrangement. The phenol of 5 was protected as the mesylate, that was then subjected to ozonolysis with a reductive workup to give the primary alcohol. This was protected as the pivalate, which was selectively saponified. The resulting carboxylic acid was cyclized to 6 using trifluoroacetic anhydride.

The triene 7 was prepared from 6 by the addition of vinylmagnesium chloride followed by dehydration. Prospective intramolecular Diels-Alder cycloadditions that would form five- or six-membered ring lactones often fail. In the event, the cyclization of 7 to the seven-membered ring lactone 8 proceeded smoothly. The tetracyclic 8 could be brought to high ee by recrystallization. Hydroboration followed by reduction then delivered the diol aldehyde 9, that was converted to 1 by reductive amination followed by protection and oxidation.

On deprotection, 1 cyclized to the iminium salt 10. Intramolecular Mannich addition of the enol form of the ketone then proceeded, to give 2.

It is possible to protect tertiary amines, inter alia by formation of the adduct with a borane. In this case, transient protection as the hydrochloride was sufficient to allow oxidation of the alcohol derived from 2 to the diene 11. This was reactive enough to undergo the Diels-Alder addition of ethylene, from the more open face, leading to 12. The now-extraneous methoxy groups were then removed reductively, and the last stereogenic center of 3 was installed by hydroboration of the alkene. Methylenation of 14 followed by Luche reduction then completed the synthesis of (-)-Lepenine (3).

D. F. Taber, Org. Chem. Highlights 2014, December 1.