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Organic Chemistry Highlights

Total Synthesis

Monday, September 1, 2008
Douglass F. Taber
University of Delaware

The Toste Synthesis of (+)-Fawcettimine

The tetracyclic Lycopodium alkaloid fawcettimine (3) and its derivatives are of interest as inhibitors of acetylcholine esterase. F. Dean Toste of the University of California, Berkeley recently reported (Angew. Chem. Int. Ed. 2007, 46, 7671. DOI: 10.1002/anie.200702695) the first enantioselective synthesis of 3. The key to the synthesis was the rapid assembly of the enantiomerically-enriched hydrindane (2).

The preparation of 2 began with the enantioselective Robinson annulation of the β-keto ester 4 with crotonaldehyde (5), mediated by the organocatalyst 6. In this protocol, originally developed by Karl Anker Jørgensen, the single stereogenic center was established by conjugate addition, presumably to the chiral iminium salt generated by the condensation of 5 with 6. Subsequent aldol (or more likely Mannich) cyclization followed by elimination gave 7. Hydrolysis and decarboxylation by heating with p-TsOH converted 7 to 1. This procedure was robust enough to allow preparation of a ten gram batch of 1. This Jørgensen annulation is the current method of choice for the enantioselective preparation of 2,5-dialkyl cyclohexenones.

Conjugate addition of the propargyl anion equivalent 8 to 1 proceeded with the expected > 95:5 axial diastereoselectivity, to give the silyl enol ether 9. Exposure of the derived iodide 10 to catalytic [Ph3PAu]Cl and AgBF4 induced smooth cyclization to the cis hydrindane 2.

Before constructing the nine-membered ring amine of fawcettimine (3), it was first necessary to protect the ketone as the ketal. Pd-mediated coupling of the alkenyl iodide with the organoborane derived from 11 then proceeded smoothly, as did the subsequent hydroboration of the terminal alkene.

Neither the mesylate nor the tosylate derived from 12 could be induced to cyclize. In contrast, intramolecular displacement of the iodide proceeded well, to give 13. Hydroboration followed by oxidation then gave 15, which on deprotection cyclized to (+)-fawcettimine (3).

Several aspects of this synthesis are attractive. While the stereochemical outcome of the hydroboration of 14 could not necessarily be predicted with confidence, in fact it did not matter, as the stereogenic center adjacent to the ketone could be epimerized under the trifluoroacetic acid deprotection conditions, and only the desired diastereomer would be able to add in an intramolecular fashion to the cyclohexanone. The construction of 2 from 10 underscores the importance of the Au-catalyzed cyclizations developed by Professor Toste.

The most important news from this synthesis is the validation in a second research group of the enantioselective Robinson annulation previously described by Professor Jørgensen. In the assembly of polycarbocycles, the central challenge is the enantioselective construction of the first ring. The Jørgensen annulation is a powerful solution to that problem.

D. F. Taber, Org. Chem. Highlights 2008, September 1.