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Organic Chemistry Highlights

Total Synthesis

Monday, May 3, 2004
Douglass Taber
University of Delaware

Synthesis of (+)-Phomactin A

The diterpene (+)-Phomactin A 4 is an antagonist of platelet activating factor. The preparation of 4 recently reported (J. Am. Chem. Soc. 2003, 125, 1712. DOI: 10.1021/ja0296531) by Randall Halcomb of the University of Colorado elegantly illustrates the use of readily-available natural products as starting materials for natural product synthesis.

The synthetic plan called for a late-stage intramolecular reductive coupling of the iododiene 3 to establish the macrocyclic ring of 4. The iododiene 3 was to be assembled by condensation of the highly-substituted cyclohexene 1 with the aldehyde 2.

The aldehyde 2 was prepared from the inexpensive geraniol ether 5. Selective ozonolysis followed by Wittig homologation gave the bromodiene, which was converted via dehydrobromination and alkylation to the alkyne 6. Regioselective hydridozirconation followed by iodination of the C-Zr bond gave the alkenyl iodide 7 with high geometric control. The two stereogenic centers of 2 were then established by Sharpless asymmetric epoxidation.

The preparation of the cyclohexene 1 began with pulegone 8, available commercially in high enantiomeric purity. Methylation followed by retro aldol condensation to remove the unwanted isopropylidene group gave 2,3-dimethylcyclohexanone, which on bromination-dehydrobromination gave 9. Vinylation followed by alkylative enone transposition gave 11, which was brominated over several steps to give 12. Conditions to reduce the ketone 11 directly to the axial alcohol were unavailing, so the dominant pseudoequatorial alcohol from NaBH4 reduction was inverted, to give 1.

Condensation of 1 with 2 led to 3, setting the stage for the key macro ring closure. Happily, conditions could be developed to effect this important transformation, a B-alkyl Suzuki coupling. The ligand dppf is 1,1'-bisdiphenylphosphinoferrocene. The use of AsPh3, rather than a phosphine, as the supporting ligand was important, as was the use of the thallium base.

D. F. Taber, Org. Chem. Highlights 2004, May 3.