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Organic Chemistry Highlights

Total Synthesis

Monday, September 5, 2005
Douglass Taber
University of Delaware

Enantioselective Synthesis of (-)-Epoxomycin

For many classes of physiologically-important natural products, total synthesis requires the construction of an extended array of acyclic stereogenic centers, with control of relative and absolute configuration. In the course of a synthesis (J. Am. Chem. Soc. 2004, 126, 15348. DOI: 10.1021/ja044563c) of the proteasome inhibitor (-)-epoxomycin (3), Lawrence J. Williams of Rutgers University has developed an elegant and potentially powerful solution to this problem. It was apparent that the preparation of 3 reduced to the stereocontrolled synthesis of 2, since the balance of the natural product is made up of readily-available amino acids. The oxygenated quaternary center of 2 appeared to be a particular challenge. The key insight of the synthesis was that both centers could be established in a single step by selective nucelophilic opening of the enantiomerically-enriched spiro bis epoxide 1.

The left hand fragment of epoxymycin 3 was assembled from the previously-described amino acid derivatives 4, 5, and 7, using standard coupling techniques.

The preparation of the allene bis-epoxide 1 started with isovaleraldehyde 9. Addition of the protected propargyl alcohol 10 under the Carreira conditions led to 11 in > 95% ee. Mesylation followed by displacement with methyl cuprate provided the allene without loss of enantiomeric excess. Oxidation of the allene 12 with dimethyldioxirane could have led to any of the four diastereomers of the spiro bis epoxide. In the event, only two diastereomers were observed, as a 3:1 mixture. That 1 was the major diastereomer followed from its conversion to 3. The configuration of the minor diastereromer was not noted. Exposure of 1 to nucleophilic azide then gave the easily-purified 2.

The spirodiepoxide 1 is an intriguing new approach to relative and absolute stereocontrol. It will be interesting to see what other nucleophiles can be used in the opening. It is possible that a chiral oxygen transfer reagent, such as the dioxirane prepared by the Shi protocol, would convert 12 to 1 with improved diastereoselectivity (double diastereoselection).

D. F. Taber, Org. Chem. Highlights 2005, September 5.