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Organic Chemistry Highlights

Total Synthesis

Monday, March 7, 2005
Douglass Taber
University of Delaware

Synthesis of (-)-Hamigeran B

Of all the ring-forming reactions of organic synthesis, diastereoselective intramolecular Diels-Alder reactions are among the most powerful. Often, as illustrated by the cyclization of 1 to 2, a single stereogenic center can set the relative and absolute configuration of two rings. The cyclization of 1 to 2 is the key step in the total synthesis of (-)-hamigeran B recently reported (J. Am. Chem. Soc. 2004, 126, 613. DOI: 10.1021/ja030498f) by K.C. Nicolaou of the Scripps Research Institute.

The preparation of 1 started with the addition of lithiated 4 to the enantiomerically-pure epoxide 5, which was prepared from the racemate using the Jacobsen protocol. Reduction followed by selective protection of the primary alcohol gave the monosilyl ether, which was further protected with MOM chloride to give 7. Pd-mediated oxidation to the methyl ketone followed by condensation with the Horner-Emmons reagent gave the unsaturated ester 8 as an inconsequential mixture of geometric isomers. Oxidation then set the stage for the crucial cyclization.

On irradiation, the aldehyde 1 underwent photoenolization to give the quinone methide 9. Intramolecular Diels-Alder cyclization then proceeded with high diastereocontrol to give 2 as a mixture of epimeric esters.

The ester 2 has a trans 6-5 ring fusion, whereas in the desired 3 the ring fusion is cis. This was easily corrected, as the 6-5 ring fusion is more stable cis. Acid-mediated dehydration to give the alkene proceeded with concomitant removal of the MOM protection. Osmylation followed by acetonide formation and subsequent oxidation gave the ketone, which was readily epimerized to 10. The acetonide was designed to block H addition to the bottom side, so hydrogenation of 11 would give the isopropyl group endo. In fact, hydrogenation led to the undesired exo isopropyl, but hydroboration proceeded from the exo face, leading to the desired 12.

Hydrolysis of the acetonide followed by oxidation and bromination provided the ketone 13, which is itself a natural product, hamigeran A. Hydrolysis under aerobic conditions led first to decarboxylation, then to autooxidation, to give (-)-hamigeran B 3.

D. F. Taber, Org. Chem. Highlights 2005, March 7.