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Organic Chemistry Highlights

Total Synthesis

Monday, August 2, 2010
Douglass F. Taber
University of Delaware

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, DOI: 10.1002/anie.200902028; 5648, DOI: 10.1002/anie.200902029) 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.

The iodide 19 was enantiomerically pure, but the aldehyde 13 was racemic, so coupling of the two led to 1 and its diastereomer. The cyclization of 1 with SmI2 proceeded with remarkable diastereocontrol, to give the desired 2 directly. Deprotection and oxidation then completed the synthesis of (+)-Vannusal B (3).

It is noteworthy that throughout this synthesis, the radicals AZADO (20) and 1-Me-AZADO (21), developed by Professor Iwabuchi (Best Synthetic Methods: Oxidation 2010, March 8), more efficient than the traditional TEMPO, were used to effect selective catalytic oxidation.

D. F. Taber, Org. Chem. Highlights 2010, August 2.