Total Synthesis Highlights
Total Synthesis Highlights
Total Synthesis Highlights
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The elegantly concise strategy displayed here for the enantioselective and diastereoselective<br />
construction of the tricyclic enone 3, by two-directional tandem methathesis of the Diels-Alder<br />
derived diketone 1, should have some generality<br />
67. Enantioselective <strong>Synthesis</strong> of (-)-Epoxomycin<br />
For many classes of physiologically-important natural products, total synthesis requires the<br />
construction of an extended array of acyclic stereogenic centers, with control of relative and<br />
absolute configuration. In the course of a synthesis (J. Am. Chem. Soc. 2004, 126, 15348.) of the<br />
proteasome inhibitor (-)-epoxomycin (3), Lawrence J. Williams of Rutgers University has<br />
developed an elegant and potentially powerful solution to this problem. It was apparent that the<br />
preparation of 3 reduced to the stereocontrolled synthesis of 2, since the balance of the natural<br />
product is made up of readily-available amino acids. The oxygenated quaternary center of 2<br />
appeared to be a particular challenge. The key insight of the synthesis was that both centers could<br />
be established in a single step by selective nucelophilic opening of the enantiomerically-enriched<br />
spiro bis epoxide 1.<br />
The left hand fragment of epoxymycin 3 was assembled from the previously-described amino acid<br />
derivatives 4, 5, and 7, using standard coupling techniques.<br />
The preparation of the allene bis-epoxide 1 started with isovaleraldehyde 9. Addition of the<br />
protected propargyl alcohol 10 under the Carreira conditions led to 11 in > 95% ee. Mesylation<br />
followed by displacement with methyl cuprate provided the allene without loss of enantiomeric<br />
excess. Oxidation of the allene 12 with dimethyldioxirane could have led to any of the four<br />
diastereomers of the spiro bis epoxide. In the event, only two diastereomers were observed, as a