Total Synthesis Highlights

The elegantly concise strategy displayed here for the enantioselective and diastereoselective
construction of the tricyclic enone 3, by two-directional tandem methathesis of the Diels-Alder
derived diketone 1, should have some generality
67. 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.) 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