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Short Synthesis Of A Wildflower Alkaloid

Organocatalytic Michael addition-aldol reaction sequence provides a key intermediate and total synthesis of an anticancer prospect

by Stephen K. Ritter
July 7, 2014 | A version of this story appeared in Volume 92, Issue 27

Extracts of Amaryllidaceae wildflowers, a family that includes daffodils, were known by Hippocrates in the days of the ancient Greeks and later by the Roman physician Pliny the Elder for the treatment of warts and skin tumors. The alkaloids produced by the flowers are among the most potent anticancer and antiviral compounds known. But their densely functionalized aminocyclitol core makes synthesizing useful quantities of the compounds a challenge. Carlos Zepeda-Velázquez and James McNulty of McMaster University, in Ontario, have now devised a one-pot synthesis of a key Amaryllidaceae alkaloid intermediate and used it in an expedited synthesis of the anticancer prospect (+)-trans-dihydrolycoricidine (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201403065). The researchers first combined cinnamaldehyde with an α-azidoacetone in a [3+3] Michael addition-intramolecular aldol reaction sequence to prepare the cyclohexanone intermediate. The one-pot method mediated by a chiral secondary amine catalyst and base cocatalyst proceeds in 65% yield and better than 98% enantiomeric excess. The team subsequently used the intermediate to prepare (+)-trans-dihydrolycoricidine in a record-low eight steps. The new strategy should provide researchers quicker access to aminocyclitols, McNulty says, which his group is actively pursuing.


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