SCIENCE & TECHNOLOGY FROM
THE
ACS
MEETING
CONSERVATION OF HELICAL ASYMMETRY Electronic theory for chiral interactions has powerful consequences for asymmetric catalysis A. MAUREEN ROUHI, C&EN
C
WASHINGTON
HIRAL RECOGNITION AND ASYM-
metric induction are based on conservation of helical asym metry, according to a new theo ry developed by David Zhigang Wang, a graduate student at Columbia Uni versity The theory assumes that interac tions between chiral molecules of similar helicity (homohelical) are favored over those between molecules of opposite he licity (heterohelical). If the theory holds, the helicities of chiral molecules can be used to predict the course of chiral recog nition and asymmetric induction events. Wang described the theory earlier this month at the American Chemical Society national meeting in New York City Ac cording to his research adviser, chemistry professor ThomasJ. Katz, Wang developed this theory on his own. According to the theory a chiral catalyst will electronically prefer forming the chiral product that allows the catalyst to preserve its helicity in the transition state. There fore, it is possible to match prochiral sub strates to chiral catalysts for maximum enantioselectivity based on their helicities. Helicity refers to the path followed by electrons in a molecule, Wang said. Ac cording to quantum chemical theory, he explained, optical activity arises when the electrons of a molecule are constrained to a helical path. For example, for the gener al chiral molecule abCde, the helical path comes about because the polarizabilities of the carbon substituents a, b, d, and e are different The differences cause the sym metry of bonding electron clouds to be perturbed by neighboring electron clouds, forcing a pair of bonds to deviate from perfect coplanarity The consequence is a net helicity, right handed or left handed. Using these principles, Wang has ana lyzed hundreds ofpublished results of cat alytic asymmetric reactions from the point ofview of homohelical interactions. With out exception, he said, the theory correctly predicts the results. More important, the theory accommodates results that cur rently accepted theories do not. 34
C&EN / SEPTEMBER 29, 2003
"Steric arguments usually are used to ex plain the results of asymmetric catalytic reactions," Wang said. That is, chiral in duction is held to be the consequence of steric interactions. One enantiomer is pre dominantly formed because it arises from
P O L A R I Z A B I L I T Y
a transition state in which the substrate fits the chiral catalyst's reactive pocket just right. However, Wang said, many results contradict this argument. Among the results that intrigued Wang were those from catalytic asymmetric re duction of ketones with the chiral oxazaborolidine called the Corey-Bakshi-Shibata catalyst [Angew. Chem. Int. Ed., 37, 1986 (1998)}. According to Wang, the re action's transition state had been estab lished through mechanistic studies, and the course of the reaction was explained us ing steric arguments: The catalyst has a bulky group, and when the ketone ap proaches with its own bulky group away from that of the catalyst, the reaction ρΓΟτ ceeds favorably But for some results, such as that for cy-
RULES
Homohelical Interactions Are Favored Ar = aromatic, Het = heteroaromatic, R = alkyl, PL = large polarizability group (blue), Ps = small polarizability group (red), ee = enantiomeric excess
OH
0
Right-handed Noyori hydrogénation catalyst A Homohelical induction PL PS"
OH
OH
(T°
H2
99% ee 1
24% ee 2
OH Ar'
OH
OH
> 90% ee
66% ee 6
> 90% ee 5
OH
OH
-e
CN
HoCO
*3 ?5% ee 7
η the basis of homohelical analy sis, the right-handed catalyst will react more favorably with sub strates that form right-handed transi tion states. A ketone substituted as shown will yield an alcohol of the con figuration shown. Steric arguments and homohelical analysis predict the same outcomes for substrates yielding com pounds 1 and 2. For substrates leading to compounds 3 and 4, steric arguments are difficult to apply because the substituents can vary greatly in size. Compounds 5 and 6,
0!
^
Het"
> 90% ee 3
OH
OH
47% e< 8
95% ee 9
however, are nearly isosteric, but con trary to the steric theory, the reactions yield significant enantiomeric excesses. By contrast, the homohelical theory consistently predicts the results for compounds 3-6. For compounds 7-9, the steric argument fails. The products formed are the mirror images of what steric analysis predicts, but homohelical analysis gives the correct results. More over, for substrates with substituents that differ only slightly in polarizability, homohelical analysis correctly predicts the low enantiomeric excesses.
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clopropyl isopropyl ketone, "that explanation seems to fail," Wang said. The isopropyl group is larger, but the reaction favors the product that goes through a transition state in which the isopropyl group butts against the catalyst's bulky group, he said. Furthermore, according to the steric explanation, the reaction with ketones bearing substituents of similar size (isosteric) should give low enantiomeric excess. In fact, he pointed out, some ketones with isosteric groups yield products with high enantiomeric excess. "The catalyst has a strong preference for one orientation, but the basis may not be size," Wang said. W h a t he finds remarkable is that the results, when analyzed on the basis of homohelical interactions, are highly predictable. In this case, the catalyst has a right-handed helicity, as analyzed from the polarizabilities of the substituents around the chiral centers. Thus, substrates that form right-handed transition states yield products with high enantiomeric excess. Moreover, the greater the difference is between the polarizabilities of the substituents around the complexed substrate, the more enantioselectively the reaction proceeds. ANALYZING RESULTS for asymmetric carbonyl reductions with a Noyori catalyst [Angew. Chem. Int. Ed., 4 0 , 4 0 (2001)], Wang reaches a similar conclusion: Highly enantioselective reductions are better predicted by polarizability differences than by size differences. For the analyses he has done so far, Wang said all he needed was the reaction mechanism, the relative polarizabilities of relevant groups, pen, paper, and a few minutes. "Ifou can apply the rules even ifyou don't understand the underlying quantum theory" "The theory could be very useful to predict the stereochemical outcome of asymmetric reactions," says Cheng Chen, a senior investigator at Merck Research Laboratories, Rahway, N.J. Chen had been working on asymmetric reduction of an aromatic-heteroaromatic ketone. Wang predicted the favored product in Chen's experiments, Chen tells C&EN. Chen thinks the theory can be used to match substrates to catalysts, especially if a comprehensive database of polarizabilities can be compiled. Conversely, it would also be possible to design catalysts specifically for particular high-value substrates. Despite the theory's accuracy Wang is still struggling with one fundamental question. The theory assumes that homohelical interactions are favored. Wang will be far more satisfied once he figures out why • HTTP://WWW.CEN-ONLINE.ORG
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