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Organic Chemistry Highlights

Total Synthesis

Monday, July 7, 2014
Douglass F. Taber
University of Delaware

The Baran Synthesis of Ingenol

The early promise for the biological activity of the derivatives of Ingenol (3) has been borne out by the clinical efficacy of the derived angelate, recently approved by the FDA for the treatment of actinic keratosis. Phil S. Baran of Scripps La Jolla envisioned (Science 2013, 341, 878. DOI: 10.1126/science.1241606) a route to 3 based on a rearrangement of 2, available by the Pauson-Khand cyclization of the allenyl alkyne 1.

One of the partners for the preparation of 1 was available following the Sugai (Synlett 1997, 1297. DOI: 10.1055/s-1997-1034) procedure, by the Claisen rearrangement of triethyl orthopropionate 5 with the propargyl alcohol 4. Reduction delivered a racemic mixture of alcohols. On exposure of the mixture to vinyl acetate and Pseudomonas cepacia lipase, the undesired enantiomer was selectively acetylated, leaving residual 8 of high ee. IBX was found by the Scripps group to be effective at oxidizing 8 without racemization.

The other component of 1 was prepared from the inexpensive (+)-3-carene (10). Chlorination followed by ozonolysis delivered 11, that was reduced to the enolate, then alkylated with methyl iodide. Exposure to LiHMDS gave a new enolate, that was added to the aldehyde 9 to give 12. Addition of ethynyl magnesium bromide to the now more open face of 12 proceeded with high diastereoselectivity. Selective silylation of the secondary alcohol followed by silylation of the tertiary alcohol set the stage for the Pauson-Khand cyclization.

Following the Brummond protocol, 1 was cyclized to 2. Methyl magnesium bromide was added, again to the more open face of the ketone, to give a new tertiary alcohol. Exposure to stoichiometric OsO4 converted the more available alkene to the cis diol, that was protected as its cyclic carbonate 13.

A central challenge in the total synthesis of the ingenanes is the construction of the "inside-outside" skeleton. This was achieved by the pinacol rearrangement of 13 with BF3•OEt2, to give 14.

All that remained to complete the synthesis was selective oxidation. Allylic oxidation with stoichiometric SeO2 installed the secondary alcohol, that was acetylated. The other secondary alcohol was then freed, and dehydrated with the Martin sulfurane, to give 16. A last allylic oxidation completed the synthesis of Ingenol (3).

It is informative to compare the concise approach to Ingenol (3) achieved in this work to the complementary total syntheses outlined in other Highlights (Total Synthesis of Ingenol 2004, March 1; Natural Product Synthesis Using Grubbs Metathesis: Lasubine II, Ingenol, and Ophirin B 2005, April 25). The three syntheses are quite different one from another.

D. F. Taber, Org. Chem. Highlights 2014, July 7.