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Addition Against The Grain

ACS Meeting News: Defying classic rules, reaction makes new chiral centers

by Carmen Drahl
March 29, 2010 | A version of this story appeared in Volume 88, Issue 13

Aldehydes with bulky protected hydroxyls usually obey the Felkin-Anh model (top). Stanton's new method gives the opposite outcome (bottom).
Aldehydes with bulky protected hydroxyls usually obey the Felkin-Anh model (top). Stanton's new method gives the opposite outcome (bottom).

With the help of zinc reagents, chemists have found a loophole in rules that govern additions to chiral carbonyl compounds, a fundamental reaction in organic synthesis. The work, presented on March 24 at the ACS national meeting in San Francisco, could lead to more efficient syntheses of pharmaceuticals.

In compounds in which a carbonyl group is close to a hydroxyl stereocenter that has a protecting group, time-honored models predict the chirality of the new stereocenter that arises after adding a carbon nucleophile to the carbonyl, converting it to a second hydroxyl. If the protecting group is small, the Cram chelation model predicts that the product will be a syn-diol (both hydroxyls on the same side). Bulky protecting groups, in contrast, obstruct chelation, leading to an anti-diol (hydroxyls on opposite sides) per the Felkin-Anh model.

Using these predictive models has a drawback—chemists sometimes choose protecting groups that suit the carbonyl addition reaction but aren't optimal for their overall strategy, said chemist Patrick Walsh of the University of Pennsylvania.

Most workaround strategies employ large amounts of chiral additives or have poor yields. Walsh, graduate student Gretchen R. Stanton, and undergraduate Corinne N. Johnson have now developed an alternative approach with two achiral zinc reagents—a dialkyl zinc nucleophile and an alkylzinc halide Lewis acid (J. Am. Chem. Soc., DOI: 10.1021/ja910717p).

During a symposium in the Division of Organic Chemistry, Stanton described how the method bucks the rules by unexpectedly yielding syn-diol products in addition reactions of aldehyde compounds with bulky silicon-protected groups. The team's NMR studies suggest that the alkylzinc Lewis acid chelates both the carbonyl and hydroxyl oxygens in the aldehyde. The team is now exploring this reactivity with different carbonyl compounds.

The Cram chelation and Felkin-Anh models are among the first concepts introduced to organic chemistry graduate students, Stanton told C&EN. "To be working on something that could affect what's in textbooks is very exciting," she said.

Organozinc compounds are readily available and are gentle on complex functional groups, so this strategy is highly compatible with natural product synthesis, said organic chemist Oliver Reiser of the University of Regensburg, in Germany.

"Given the ubiquity of silyl groups as protecting groups in complex molecule synthesis, these observations will add significantly to the organic chemist's toolbox," adds Richmond Sarpong of the University of California, Berkeley.

"I can predict that this addition reaction will find numerous applications in the synthesis of complex organic molecules and natural products," adds organometallic chemist Paul Knochel of the University of Munich, in Germany.



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