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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Org Lett. Author manuscript; available in PMC 2010 October 1.
Published in final edited form as:
PMCID: PMC2751814

Origin of Stereoselectivity in the Imidazolidinone-Catalyzed Reductions of Cyclic α, β-Unsaturated Ketones


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The organocatalytic transfer hydrogenation reactions of 3-phenyl-2-cyclopentenone with imidazolidinone catalysts are evaluated using the hybrid density functional (B3LYP/6-31G(d)) theory. The origin of the preference for the E iminium transition state is determined, and the stereosectivity of hydride transfer is investigated.

Organocatalyzed asymmetric transfer hydrogenations have been successfully employed in reduction of C=O, C=N, and C=C containing organic compounds using Hantzsch1 esters as the hydride source.2 Recently, the groups of MacMillan3 and List4 reported the reduction of α,β-unsaturated cyclic ketones using the valine ester phosphate salts and the imidazolidinone salts as catalysts.

The furyl imidazolidinone catalyst 3, a catalyst that previously enabled Diels-Alder reactions with cyclic enones,5 gave excellent yields, 57–96%, with moderate enantiocontrol, 74–91%, in hydrogenations of a variety of β-substituted α,β-unsaturated cyclic enones (Figure 1). The amine catalysts 1 and 2, which were previously shown to be efficient in hydrogenations of aldehydes,6 yielded poor results, 0% and 5% yields, respectively, and exhibited low or no enantiocontrol with α,β-unsaturated cyclic ketones. The enantioselectivity was explained by the condensation of the enone 4 with 3 to form the (E) iminium ion intermediate rather than the (Z) intermediate (Scheme 1). Subsequent hydride attack by the Hantzsch ester 5 from the less hindered si (“bottom”) face leads to the observed major product.

Figure 1
Experimental results from the reaction of 3-phenyl-2-cyclopentenone with imidazolidinone catalysts and Hantzsch ester 5.4

We have undertaken a detailed DFT tudy to provide a more quantitative explanation of observed enantioselectivity. Quantum mechanical calculations were carried out with density functional theory, B3LYP,7 with 6–31G(d)8 basis set, implemented in Gaussian 03,9 which our group has shown to be effective in explaining stereoselectivities of various organic reactions.10

Organocatalyzed hydrogenation proceeds as shown in Scheme 2 by reversible formation of iminium ion intermediates, hydride transfer from Hantzsch’s ester to the highly reactive iminum intermediate, and hydrolysis.

Condensation between 3-phenyl-2-cyclopentenone and 2 leads to the reversible formation of 2-E and 2-Z iminium intermediates. Calculations show a 0.4 kcal/mol preference for 2-Z, which avoids a steric repulsion between the methylene group of the cyclopentenone ring and the t-butyl group of the catalyst (Scheme 3). A shorter distance, 2.20 Å, is observed between the t-butyl group and the methylene of the substrate’s ring in the 2-E iminium intermediate.11 While only one (E) and one (Z) iminium conformer was found from 2, several are expected to be formed from 3.12 A large number of possible conformers from furyl rotation about the Cα-Cfuryl bond and phenyl rotation about the Cα-Cphenyl bond were considered in the search for iminium ion intermediates formed from 3 (Figure 3). The eclipsed −120°, rather than staggered 180°conformer, was found as noted earlier. 10c, 12

Figure 3
Iminium conformers of 3-E and 3-Z iminium intermediates.

Both (E) and (Z) iminium ions prefer the staggered conformations, 3-E-f, 3-E-b, 3-Z-f, and 3-Z-b as shown in Table 1. These four conformers account for 86% of the total at 25 °C and 84% at 0 °C. The (in, −60°) conformations, 3-E-f and 3-Z-f, are found to be the most stable conformers. This conformational preference is hypothesized to be stabilzed by a weak CH•••O attractive interaction between the furyl oxygen and the CH2 of the benzyl group and by a CH•••π interaction13 between the electron-rich phenyl group and the α-methylene of the iminium, with CH-π distances of 3.14 and 2.91 Å (Figure 4). The highest energy iminium ions, 3-E-d and 3-Z-d, have the furyl oxygen and the phenyl ring facing each other causing an electrostatic repulsion between the oxygen and the phenyl ring leading to a destabilization of up to 3.7 kcal/mol. A Boltzmann distribution calculation using all conformers listed in Table 1 revealed a 3E:3Z ratio of 78:22 in the gas phase14, consistent with the higher, 74% ee, enantioselectivity observed by MacMillan et al. using amine 3.

Figure 4
Iminium intermediates via 3. Relative enthalpies of formation are in kcal/mol. Bond distances are in Ångstroms.
Table 1
Conformers of 3-E and 3-Z iminium ion intemediates formed from amine 3 and enone 4. Gas phase percentages of each structure are given at 25 °C and 0 °C.

Four possible modes of attack by Hantzsch ester 5 on the iminium ion intermediates were considered (Figure 5).15 In all the transition structures, steric effects dominate the mode of hydride attack. Hydride transfer on the iminium derived from 2 is energetically favored when 5 attacks anti from the less hindered (“bottom”) face, entries 1 and 5 in Table 2. The low energy implies that both pathways are accessible. Hydride attack on the more hindered top face of the Z intermediate, entry 8, is only 0.1 kcal/mol higher in energy than attack on the bottom face, entry 5. The accessibility of the top face is achieved by attacking anti to the iminium ion and thus avoiding steric hindrance with the t-butyl group. The (top-syn) attack, entries 3 and 7, is the most energetically disfavored, due to the close proximity of 5 to the tert-butyl group.

Figure 5
Proposed hydride attack transition structures
Table 2
Hydride attack transition structures on 2-E and 2-Z.

The low activation energy difference between the bottom and top face attacks will lead to the relatively equal populations of both R and S products. Low enantioselectivity, 15% ee, is found experimentally. Due to the expense of calculations, only the lowest energy mode of attack, (bottom, anti), was considered for transition state searching with 3-E and 3-Z.

Hantzsch ester (bottom, anti) attack on the E iminium, TS-3-E, is found to be favored by 1.1 kcal/mol over the attack on the Z iminium, TS-3-Z (Figure 6).16 The energy difference between the two iminium ions, 3-E-f and 3-Z-f, increased upon hydride attack from 0.5 to 1.1 kcal/mol. The small difference in activation energies suggests that both pathways are accessible and will yield both R and S products. However, the 1.1 kcal/mol preference for hydrogenation through the E iminium ion intermediate will yield a S:R of 76% ee at 0 °C, in agreement with experimental data, 74% ee.

Figure 6
Hydride attack transition structures by 5 into 3-E and 3-Z. Relative activation energies are in kcal/mol.

DFT calculations explain the stereoselectivity in hydrogenation of α,β-unsaturated cyclic ketones via MacMillan’s imidazolidinone catalysts. Only one face of each iminium intermediate is accessible to attack by the hydride donor. The transition state for attack on the E iminium is formed, in part, due to the inherently greater stability of the E iminium. Current efforts are underway to design a more enantioselective imidazolidinone catalyst.

Supplementary Material



We are grateful to the National Institute of General Medical Sciences, National Institutes of Health, Ronald S. Gabriel, M.D./Scrubs Unlimited SRF for funding of the research, and UCLA Institute for Digital Research and Education for computer time.


Supporting Information Available: Cartesian coordinates and energies of all reported structures and full reference of 9. This material is available free of charge via the Internet at http://pubs.acs.


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14. Single point calculations on iminium ion intermediates at the B3LYP/6-311++G(d,p) revealed similar E/Z ratio of 62:38. A similar ratio, 66:34, was calculated for the iminium ions formed from the reaction from 3 and 3-methyl-2-cyclopentenone at the B3LYP/6-31G(d).
15. Wu Y, Houk KN. J. Am. Chem. Soc. 1987;109:2226.
16. Calculated hydride attack transition state structures for the reaction with 3-methyl-2-cyclopentenone imininium intermediate and Hantzsch ester 5 revealed a 0.8 kcal/mol reference for hydride attack on the E iminium ion. This result is consistent with experimental data which shows a preference for the S product derived upon hydride attack by the t-butyl substituted Hantzsch ester into the E iminium ion.