Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, October 4, 2010
Douglass F. Taber
University of Delaware

The Overman Synthesis of Briarellin F

Briarellin F (4) is an elegant representative of the complex polycyclic ethers produced by soft corals such as Briareum abestinum. Larry E. Overman of the University of California, Irvine developed (J. Org. Chem. 2009, 74, 5458. DOI: 10.1021/jo9010156) a triply-convergent approach to 4, the central feature of which was the Prins-pinacol combination of 1 with 2 to give 3.

The aldehyde 2 was assembled by Wittig homologation of the aldehyde 5 with the phosphorane 6, followed by metalation and formylation. The aldehyde 10 was prepared by opening the enantiomerically-pure epoxide 8 with the acetylide 9.

Hydroboration of carvone 11 could not be effected with sufficient diastereocontrol. As an alternative, the mixture of diols was oxidized to the lactone 12. Kinetic quench of the derived silyl ketene acetal followed by reduction led to the diastereomerically-pure crystalline diol 13. This key intermediate will have many other applications in target-directed synthesis.

The ketone 14 was converted to the alkenyl iodide 15 by stannylation of the enol triflate, followed by exposure of the stannane to N-iodosuccinimide. Addition of the alkenyl iodide 15 to the aldehyde 10 gave the diol 1 as an inconsequential 3:1 mixture of diastereomers. This mixture was combined with the aldehyde 2 to give, via Lewis acid-mediated rearrangement of the initially-prepared acetal, the aldehyde 3.

The aldehyde 3 was readily decarbonylated by irradiation in dioxane. Face-selective Al-mediated epoxidation of the derived homoallylic alcohol proceeded with 10:1 selectivity, and subsequent MCPBA epoxidation of the cyclohexene was also secured with 10:1 facial control. This set the stage for the triflic anhydride-mediated closure of the six-membered ring ether. The Nozaki-Hiyama-Kishi cyclization of 18 proceeded with remarkable selectivity, delivering Briarellin E (19) as a single diastereomer. Dess-Martin oxidation converted 19 into Briarellin F (4).

D. F. Taber, Org. Chem. Highlights 2010, October 4.