Total Synthesis Highlights

9. The Nicolaou Synthesis of (+)-Vannusal
The correct assignment of relative configuration for portions of a complex structure that are
remote one from another can present substantial difficulties. This was brought home in the course
of the synthesis of (+)-Vannusal (3) described (Angew. Chem. Int. Ed. 2009, 48, 5642,; 5648, ) by
K. C. Nicolau of Scripps/La Jolla. In fact, they prepared several alternative diastereomers,
including the originally assigned structure, before finally coming to 3, the spectra of which
matched those of the natural product.
Their synthetic strategy was based on the late-stage convergent coupling of the aldehyde 13 with
the iodide 19, leading to 1. The preparation of 13 began with conjugate addition of the 1-propenyl
Grignard reagent 5 to the cyclohexenone 4. Deprotection, oxidation and acetal formation led to 6,
that cyclized with high diastereocontrol to 7. Carbomethoxylation of the ketone followed by
Mn(OAc) 3 cyclization delivered the highly strained norbornane 8 as a single diastereomer.
Condensation of the derived ketone 9 with acetone (10) followed by reduction set the three
remaining ternary stereogenic centers of 13. O-Alkylation of the aldehyde 11 followed by Claisen
rearrangement established the alkylated quaternary center. Functional group manipulation then
converted 12 into 13.
The preparation of the iodide 19 began with the diene 14. Hydroboration followed by acetylation
provided the meso diol. Enzymatic hydrolysis proceeded with high enantioselectivity, to give 15.
Opening of the epoxide 16 with 2-propenyl lithium gave the trans alcohol, that was converted to
the requisite cis alcohol 17 by Mitsunobu esterification followed by hydrolysis. Shapiro iodination
of 18 then delivered 19.