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Organic Chemistry Highlights

Total Synthesis

Monday, September 5, 2011
Douglass F. Taber
University of Delaware

The Overman Synthesis of (-)-Actinophyllic Acid

(-)-Actinophyllic Acid (3), isolated from Alstonia actinophylla, is a promising inhibitor of TAFIa/hippicuricase (0.84 Ám). Larry E. Overman of UC Irvine envisioned (J. Am. Chem. Soc. 2010, 132, 4894. DOI: 10.1021/ja100178u) a bold route to 3 based on the aza-Cope/intramolecular Mannich reorganization of 1 to 3.

The absolute configuration of 1 and thus of 3 was set by Noyori hydrogenation of the enone 4. Ozonolysis followed by acetylation delivered the pyridone 6 as an inconsequential mixture of diastereomers.

The ketone 9 was assembled by condensation of dimethyl malonate 8 with the acid chloride 7. Cyclization then followed directly on reduction of the nitro group to the amine, to give the crystalline indole 10. Under Lewis acid catalysis, 10 coupled smoothly with the diacetate 6, to give 11. Selective reduction of the acetate was followed by oxidation, leading to 12.

The ketone 12 has only a single acidic stereogenic center. It was not clear that it could be cyclized without epimerization. A preliminary study with material resolved by enantioselective chromatography, however, showed that this in fact worked well. The LDA kinetically deprotonated the ketone away from the N, at the same time deprotonating the malonate, to give a dianion that underwent smooth oxidative coupling to 13.

With 13 in hand, it remained to differentiate the two esters derived from the malonate. This was succinctly accomplished by the addition of vinyl magnesium bromide. Selective reduction of the spontaneously formed lactone 14 cleanly delivered 1.

The topological connection between 1 and 3 is not necessarily obvious. Exposure of 1 to HCl gave the amine hydrochloride. Condensation with formaldehyde then gave 15, poised for aza-Cope rearrangement to 2. The enol 2, then, proceeded via intramolecular Mannich condensation directly to (-)-Actinophyllic Acid (3).

D. F. Taber, Org. Chem. Highlights 2011, September 5.