September 8, 2008

Volume 86, Number 36

p. 10

Synthesis

A Catalytic Merger

Marriage of photoredox catalysis and organocatalysis creates new enantioselective reaction

Bethany Halford

BY COMBINING two well-established ways of activating molecules—photoredox catalysis and organocatalysis—chemists at Princeton University have achieved the first enantioselective α-alkylation of aldehydes (Science, DOI: 10.1126/science.1161976).

Thanks to the new combined-catalysis concept, this once-elusive asymmetric reaction has become "operationally trivial," according to the researchers, chemistry professor David W. C. MacMillan and postdoc David A. Nicewicz. Furthermore, they say, the combined-catalyst strategy could provide routes to a number of other enantioselective transformations.

MacMillan and Nicewicz selected a ruthenium(II) bipyridine complex, Ru(bpy)₃²⁺, as their photoredox catalyst. Although this single-electron-transfer agent has been used in a number of areas, such as energy storage, it hasn't been popular in organic synthesis. The Princeton chemists reasoned they could use the complex to harvest energy from ambient light, such as the overhead lamp in a fume hood, and thereby introduce a single electron into the catalytic cycle. Single-electron mechanisms are common in nature, MacMillan points out, but "as synthetic chemists we don't typically consider one-electron pathways."

In the mechanism proposed by MacMillan and Nicewicz, the ruthenium complex generates an electron-deficient alkyl radical from an alkyl bromide. This radical combines with an enamine formed from the condensation of an aldehyde and a chiral amine catalyst. Subsequent hydrolysis generates an α-alkylated aldehyde. Because it only takes weak light, rather than high-energy ultraviolet light, to initiate the catalytic cycle, MacMillan thinks the process could be useful for manufacturing-scale syntheses.

"MacMillan has managed to effect a challenging transformation with an efficient, versatile, mild, and environmentally benign process," comments John M. Schwab, an organic chemist at the National Institute of General Medical Sciences, in Bethesda, Md.

"I believe this will provide a new paradigm for asymmetric catalysis and at the same time open up the doorway to many new reactions that are currently unknown," MacMillan says. To that end, his group has already applied the "photoredox organocatalysis concept" to a number of other transformations, including benzylation, trifluoromethylation, amination, and alkylcyanation of aldehydes.

Chemical & Engineering News

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