Issue Date: March 3, 2011
A new reaction expands the use of organocatalysis to the production, in a single step, of β-functionalized aldehydes, an important class of compounds that normally cannot be made so quickly and easily. By providing a new catalytic route to these compounds, the work adds to the armamentarium of synthetic organic chemistry.
In the rapidly expanding field of organocatalysis, non-metal-containing small organic compounds are used as catalysts to produce a broad array of molecular products, including aldehydes bearing a functional group at the α-position, the carbon atom adjacent to the aldehyde's carbonyl carbon.
β-Functionalized aldehydes—which bear a functional group at the next carbon over—are just as useful synthetically. Now, they also can be produced organocatalytically with the approach devised by Jian Li of Shanghai-based East China University of Science & Technology; Wei Wang of the Shanghai Institute of Materia Medica and the University of New Mexico, Albuquerque; and coworkers (Nat. Commun., DOI: 10.1038/ncomms1214).
The new approach was inspired by earlier techniques that use secondary amine organocatalysts to α-functionalize aldehyde substrates by forming iminium ions that convert to enamine intermediates. These, in turn, react with electrophiles and are hydrolyzed to form useful α-substituted products.
Li, Wang, and coworkers found a way to make β-functionalized aldehydes from a similar reaction, which they call "oxidative enamine catalysis." They too react an aldehyde substrate with a secondary amine organocatalyst. But in their case, the reaction initially forms an enamine intermediate, which is oxidized to an unsaturated iminium ion, which in turn reacts with a nucleophile to form β-substituted products.
The researchers write that a method "for direct β-functionalization of simple aldehydes rather than enals [α,β-unsaturated aldehydes] in a catalytic enantioselective manner" has not previously been reported. They use the technique not only to β-functionalize simple aldehydes enantioselectively but also in enantioselective double, triple, and quadruple cascade reactions to carry out one-pot conversions of aldehydes to more-complex chiral structures.
Leading investigators in the field of organocatalysis call the new technique a significant advance. "In providing for an efficient and compatible oxidation of enamines to iminium ions, the reaction provides new opportunities in reaction connectivity, allowing new catalytic asymmetric assembly reactions to be constructed," Carlos F. Barbas III of Scripps Research Institute says. Benjamin List of the Max Planck Institute for Coal Research, in Mülheim, Germany, says the new β-functionalization reaction "is an extremely useful transformation that had previously been rather elusive." And David W. C. MacMillan of Princeton University adds that the Chinese team's cascade sequences are "elegant, practical, and really useful."
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