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Reducing Alkenes Like Nature Does

Enantioselective organocatalytic hydride reductions of ∝ ,β-unsaturated aldehydes achieved

by Stu Borman
January 24, 2005 | A version of this story appeared in Volume 83, Issue 4

An enantioselective approach for reducing olefins with amine catalysts has been developed independently by two research groups. The technique could ease the synthesis of drugs, fine chemicals, and natural products, although additional refinements may be needed for it to be broadly useful in industry.

The reaction--in which hydrogen is transferred enantioselectively from a "Hantzsch ester" to an ,-unsaturated aldehyde to produce a saturated aldehyde--was inspired by the way hydride reductions are carried out in biological systems. The approach is part of a recent renaissance in the development of small organic compounds as catalysts for asymmetric reactions (C&EN, Sept. 6, 2004, page 41).

In chemical syntheses of pharmaceuticals and fine chemicals, transition-metal or organometallic complexes are often used to catalyze two types of hydride reductions: hydrogenations, in which molecular hydrogen is used as the hydrogen atom source, and hydride transfers, in which hydrogen comes from other hydrogen-donating reagents. In biological systems, enzymes catalyze hydride reductions, and the hydrogen source is always an enzyme cofactor such as reduced nicotinamide adenine dinucleotide (NADH).

Two groups have now emulated such biological processes by developing a class of hydride transfers that don't require metal-containing catalysts and use an NADH-type hydrogen source. In these reactions, ,-unsaturated aldehydes are reduced enantioselectively by using chiral imidazolidinones as catalysts and Hantzsch dihydropyridine esters--which are structurally similar to NADH--as hydrogen sources.

The achievement was reported virtually simultaneously by professor of chemistry and chemical engineering David W. C. MacMillan and coworkers at California Institute of Technology [J. Am. Chem. Soc., 127, 32 (2005)] and by associate professor of chemistry Benjamin List and coworkers at Max Planck Institute for Coal Research, Mülheim an der Ruhr, Germany [Angew. Chem. Int. Ed., 44, 108 (2005)]. In both studies, products were obtained in high yields and with enantiomeric excesses generally exceeding 90%. List's group had also previously reported a nonasymmetric variant of the reaction [Angew. Chem. Int. Ed., 43, 6660 (2004)].


The MacMillan and List groups find that imidazolidinones and Hantzsch dihydropyridines can be used to reduce ∝ ,β,-unsaturated aldehydes to saturated aldehydes enantioselectively.
The MacMillan and List groups find that imidazolidinones and Hantzsch dihydropyridines can be used to reduce ∝ ,β,-unsaturated aldehydes to saturated aldehydes enantioselectively.

THE MECHANISM of the asymmetric reaction seems to involve transient conversion of the chiral organocatalyst into an iminium ion, which activates the ,-unsaturated aldehyde substrate to accept hydrogen enantioselectively from the Hantzsch dihydropyridine. The technique is enantioconvergent, which means that only a single-enantiomer product is generated when a mixture of E and Z ,-unsaturated aldehyde isomers is reduced by hydride transfer. (The other enantiomer can be obtained by using a catalyst of opposite chirality.)

Professor of chemistry and biochemistry Bruce H. Lipshutz of the University of California, Santa Barbara, whose research interests include organometallic catalysis, comments that the new technique is "conceptually very attractive and of potentially wide-ranging influence. There is little doubt that the notion of doing asymmetric catalysis without metals holds great promise for selected situations."

However, the approach "is still very early in its development," Lipshutz says. He notes that a relatively large proportion of catalyst (5 to 10%) is needed, stoichiometric amounts of reducing agent are required, and both catalyst and oxidized Hantzsch reagent must be separated out to isolate a useful reaction product. In addition, Lipshutz says, the enantiomeric excesses "are good but not fabulous, so some enrichment will be needed after purification to get to 99+% levels [of product purity], and the rates of these reactions are very slow, requiring up to three days to get 90% [enantiopurity]."

Another researcher in the field, who requested anonymity, agrees with Lipshutz that the efficiencies of the reactions "are far from optimal, given the competition in the hydrogenation area, where catalyst-to-substrate ratios of 1:1,000,000 are not unusual and the reactions are very fast. Turnover numbers [reaction efficiencies] are important not only for reasons of economics but also for the environment," he explains.

"Those who believe turnover numbers are the central component for asymmetric catalysis are really missing the point," MacMillan replies. "Convenience, substrate generality, cost, and ease of operation are, if anything, far more meaningful."

MacMillan says he can foresee the new reaction being used by medicinal chemists at the benchtop but not necessarily by process chemists. He notes that he and his coworkers "have already found new conditions that enable nearly all of the reactions we have tested to reach completion in less than eight hours."

In collaboration with the MacMillan group, Materia Inc. will soon produce a powder called MacH that chemists can use to carry out metal-free catalytic asymmetric hydride reductions. "MacH is a 1:6 blend of the tert-butyl-imidazolidinone catalyst we use in the JACS paper and a Hantzsch ester," says MacMillan, who serves on the scientific advisory board of Materia. "This bench-stable solid can be added directly to ,-disubstituted-,-unsaturated aldehydes in chloroform to enable enantioselective catalytic hydride transfer in a rapid and operationally simple fashion. Upon completion of the asymmetric reduction, the reaction mixture is simply passed through a plug of silica and concentrated to afford the -stereogenic aldehyde with high levels of enantiocontrol and high levels of product purity." The product will be marketed commercially by Sigma-Aldrich.




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