Quantum mechanical predictions of the stereoselectivities of proline-catalyzed asymmetric intermolecular aldol reactions

Article abstract of DOI:10.1021/ja028812d

Quantum mechanical calculations were employed to predict the ratio of four stereoisomeric products expected from two complex reactions involving the aldol reactions of cyclohexanone with benzaldehyde or with isobutyraldehyde catalyzed by (S)-proline. Expe

Full text of DOI:10.1021/ja028812d

Published on Web 02/08/2003
Quantum Mechanical Predictions of the Stereoselectivities of
Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions
S. Bahmanyar,† K. N. Houk,*,† Harry J. Martin,‡ and Benjamin List*,‡
Contribution from the Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, California 90095-1569, Department of Molecular Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received October 4, 2002
Abstract: Quantum mechanical calculations were employed to predict the ratio of four stereoisomeric
products expected from two complex reactions involving the aldol reactions of cyclohexanone with
benzaldehyde or with isobutyraldehyde catalyzed by (S)-proline. Experimental tests of these predictions
provide an assessment of the state-of-the-art in quantum mechanical prediction of products of complex
organic reactions in solution.
Scheme 1
I. Introduction
Although Dirac once noted that the Schro¨dinger equation
“leads to equations much too complicated to be soluble,”1
quantum mechanics has had an enormous impact on chemistry.
Although computers and algorithms bring us closer to accurate
approximations to exact solutions, quantitative predictions are
rare. We report quantum mechanical predictions of stereose-
lectivities of a synthetically useful reaction: the ratios of four
possible stereoisomeric aldol products of the reactions of
cyclohexanone and two aldehydes, catalyzed by proline, were
predicted using quantum mechanical hybrid density functional
theory,2 and then the experimentally determined product yields
were compared to theoretical predictions. These results provide
an assessment of the current state of computational methods
for the prediction of the products of complicated organic
processes.
Proline has long been known as an effective asymmetric
catalyst for the intramolecular aldol reaction.3 Recently, it was
discovered that this amino acid could also catalyze inter-
molecular aldol reactions between ketones and aldehydes.4-9
These reactions proceed through an enamine-mediated mech-
anism10-12 and provide a prototype for the burgeoning area of
organocatalysis.13,14
R ) Ph: 62% yield, 60% ee; R ) 4-O2NC6H5: 68% yield, 76% ee; R
) i-Pr: 97% yield, 96% ee; R ) tert-butyl: 81% yield, >99% ee.
The stereoselectivities of intermolecular proline-catalyzed
direct aldol reactions of acetone with a variety of aldehydes
have been rationalized with a Zimmerman-Traxler six-
membered ring chair-like model15 (shown at the top of Scheme
1).4,5,8,9
The minor product could arise from a switch to an axial
R, or via the alternative Zimmerman-Traxler transition state
shown at the bottom of Scheme 1.
Aldol reactions of cyclohexanone enamines with aldehydes
can produce four stereoisomers that are syn- and anti-diaster-
eomeric pairs of enantiomers (Scheme 2). Because the aldehyde
and enamine may adopt three staggered arrangements about the
forming bond, and because the cyclohexene of the enamine can
adopt two-half-chair conformations, there are 24 reasonable
transition states for this reaction.
† Department of Chemistry and Biochemistry, University of California.
‡ Department of Molecular Biology, The Scripps Research Institute.
(1) Dirac, P. A. M. Proc. R. Soc. 1929 123, 714-733.
(2) Gill, P. M. W. Aust. J. Chem. 2001, 54, 661-662.
(3) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1973, 38, 3239-3243. (b)
Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621. (c) Eder,
U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496-
497. (d) Experiments demonstrating that both the carboxylic acid group
and pyrrolidine ring of proline are essential for effective asymmetric
induction were carried out by Hiroi, K.; Yamada, S. I. Chem. Pharm. Bull.
1975, 23, 1103-1109. (e) List, B. Tetrahedron 2002, 58, 5573-5590.
(4) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122,
2395-2396.
(10) (a) Brown, K. L.; Damm, L.; Dunitz, J. D.; Eschenmoser, A.; Hobi, R.;
Kratky, C. HelV. Chim. Acta 1978, 298, 3108-3135. (b) Jung, M. E.
Tetrahedron 1976, 32, 3-31.
(11) Agami, C. Bull. Soc. Chim. Fr. 1988, 3, 499-507.
(12) Agami, C.; Levialles, J.; Sevestre, H. Bull. Soc. Chim. Fr. 1987, 2, 358-
360.
(5) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386-7387.
(6) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573-575.
(7) List, B. Synlett 2001, 11, 1675-1686.
(13) (a) Gro¨ger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529-532. (b)
Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481-2495.
(14) MacMillan, D. W. C.; Northrup, A. B. J. Am. Chem. Soc. 2002, 124, 6798-
6799.
(8) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001,
123, 5260-5267.
(9) Coˆrdova, A.; Notz, W.; Barbas, C. F., III J. Org. Chem. 2002, 67, 301-
303.
(15) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920-
1923.
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A R T I C L E S
Bahmanyar et al.
Scheme 2. Possible Products from Cyclohexanone Enamine Reactions with Aldehydes
Scheme 3. Various Rotamers Involving the Carbonyl Group of the
Aldehyde with Dihedral Angles of (60° and 180° Relative to the
CdC Bond of the Enamine. Only Those Transition States with
Dihedral Angles of (60° Can Involve Intramolecular Acid Catalysis
Previous theoretical studies show that proton transfer from
the amine or carboxylic acid group of proline to the forming
alkoxide is essential for charge stabilization and to facilitate
C-C bond formation in the transition state.16,17 The carboxylic
acid can be syn or can be anti and hydrogen bond to the enamine
nitrogen in the starting enamine, but becomes strongly associated
with the developing alkoxide in the transition state for the aldol
reaction. Consequently, only transition states that involve
hydrogen bonding between the carboxylate and the aldehyde
were considered here. In addition, only transition states involving
the carbonyl group of the aldehyde with dihedral angles of (60°
relative to the CdC bond of the enamine can involve intra-
molecular acid catalysis, so all other rotamers were excluded
from consideration (Scheme 3).
Transition states of simple systems with a dihedral angle -60°
were found to be 5-10 kcal/mol higher in energy than those
with +60° in simple models, and so the higher energy
conformers are excluded as well (Figure 1). This leaves eight
possible transition states for four possible stereoisomeric
products in each reaction.
basis set as implemented in Gaussian 98.20 Enthalpies, ∆H298
,
and free energies, ∆G298, were computed for the gas phase, and
the solvation energies, ∆G298(ꢀ)47), for reactants and for transition
states were computed using a polarizable continuum model with
a permittivity of 47, the value for DMSO, the solvent used in
the experiments. These calculations involve the solvation model
CPCM21 as implemented in Gaussian 98.
II. Computational Methods
Stationary points (reactant and transition state geometries)
were optimized and characterized by frequency analysis using
hybrid density functional theory (B3LYP)18 and the 6-31G*19
(16) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 12911-12912.
(17) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11 273-11 283.
(18) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 1372-1377. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
(19) (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54,
724-728. (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys.
1972, 56, 2257-2261. (c) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta
1973, 28, 213-222.
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Asymmetric Intermolecular Aldol Reactions
A R T I C L E S
Figure 1. Relative energies of transition states for the reaction of the proline-enamine of acetone (3a-3h, R ) CH3, R′ ) CH3) and cyclohexanone (4a-4d,
R ) CH3) with acetaldehyde. After optimization, intramolecular hydrogen bonding changes the ideal arrangement for staggering substituents ((60° and
180°) to more eclipsed arrangements (∼(5°-80°). This change is most dramatic in transition states 3e-3h. Newman projections along the forming C-C
bond are shown.
III. Results and Discussion
than the transition states for si attack on the syn-enamine (TS
5c,d and TS 6c,d) as shown in Figure 2. Transition states for
reaction of the anti-enamine with aldehydes have the NCC-
CO atoms in a half-chair conformation (5a, 5b R ) Ph; 6a, 6b
R ) i-Pr). The H of the carboxylic acid group of proline is
being transferred to the forming alkoxide. Favorable hydrogen
bonding interaction between the partial positive hydrogens of
the carbon adjacent to the proline nitrogen to the forming
alkoxide (δ+NCH-Oδ- distances: 2.36-2.47 Å) contribute to
further electrostatic stabilization of TS 5a,b and TS 6a,b.23
The lowest energy transition states leading to the four
products from the reactions of the proline enamine of cyclo-
hexanone with benzaldehyde and isobutyraldehyde are shown
in Figure 2.22 The transition states involving the re attack on
the anti-enamine (TS 5a,b and TS 6a,b) are lower in energy
(20) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.
R.; Gomperts, R.; Martin, L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M. P.; Gill, M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.9,
Gaussian, Inc.; Pittsburgh, PA, 1998.
(21) Barone, B.; Cossi, M.; Tomasi, J. J. Comput. Chem. 1998, 19, 404-417.
(22) After the experimental verification of our predictions, several papers (see
ref 3e) reported these and related experimental results. Relevant compu-
tational work was published by Rankin, K. N.; Gauld, J. W.; Boyd, R. J.
J. Phys. Chem. A. 2002, 106, 5155-5159, and Arno, M.; Domingo, L. R.
Theor. Chem. Acc. 2002, 108, 232-239.
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Bahmanyar et al.
Figure 2. Transition state geometries for the reaction of syn- and anti-enamine with benzaldehyde (5a-5d) and isobutyraldehyde (6a-6d). Newman
projections along the forming C-C bond are shown.
Table 1. Comparison of Computed Energies versus Known
Experimental Results
Transition state 5b is slightly destabilized due to additional
interactions of the pseudoaxial phenyl ring of the aldehyde with
the cyclohexane enamine, whereas transition state 6b is highly
destabilized. The phenyl group can easily adopt a relatively
sterically unhindered arrangement in 5b, whereas 6b suffers
from the large steric repulsion involving the isopropyl tertiary
hydrogen. Transition states involving the syn-enamine force the
substituents at the forming C-C bond to be nearly eclipsed,
and the δ+NCH-Oδ- distances (3.12-3.18 Å) are longer and
therefore the electrostatic stabilization of these transition states
is diminished. The computed transition state geometries reveal
that the carboxylic acid proton and enamine nitrogen (N-H
distance ∼2.5 Å) are not arranged to form an ideal Zimmerman-
Traxler six-membered ring as shown in Scheme 1.
To gauge the inaccuracies involved in our prediction of
product ratios, the average absolute errors in calculations for
a Reaction carried out at 323 K; %ee extrapolated for 298 K. *Calculated
known proline-catalyzed aldol reactions were determined. For
by CPCM solvation model (∆G298(ꢀ)47)).
three reactions studied earlier, the calculated gas-phase enthal-
pies of activation have the smallest error (standard deviation (
0.4 kcal/mol) when compared with the experimental enantio-
of cyclohexanone with isobutyraldehyde is predicted to be
substantially more stereoselective.
selectivities as shown in Table 1.24 Table 2 gives the predicted
The experiments were conducted using standard conditions
product ratios.25 From ∆H298 values, the proline-catalyzed
(20 vol % cyclohexanone/DMSO, 30 mol % of (S)-proline).
reaction of cyclohexanone with benzaldehyde should give syn-2
The experiments were conducted in triplicate, and control
and anti-2 products involving attack on the enamine in
experiments show that anti and syn isomers do not equilibrate
comparable amounts (between 50:50 and 80:20). The reaction
under reaction conditions. In the reaction of cyclohexanone with
benzaldehyde, anti-2 and syn-2 were formed in equal amounts
in 85 ( 5% ee and 76 ( 5% ee, respectively. Absolute and
relative configurations of the products were assigned based on
literature optical rotation values and 1H NMR data and product
ratios were determined by HPLC. In the reaction of cyclohex-
anone with isobutyraldehyde, a single diastereomer, anti-2, was
formed in 97 ( 3% ee. In this case, absolute and relative
(23) These types of favorable CH-O bonds have been observed in other systems.
Cannizzaro, C. E.; Houk, K. N. J. Am. Chem. Soc. 2002, 124, 7163-7169.
(24) Absolute average errors were computed for the three intermolecular aldol
reactions in Table 1) by averaging the absolute differences between ∆G298expt
and either ∆H298theory, ∆G298theory, or ∆G298(ꢀ)47).
(25) Product ratios for the experiments (%ee) were determined by HPLC (see
the Supporting Information). Product ratios for the predictions were
determined by converting calculated gas-phase enthalpies of activation
∆H298 ( 0.4 kcal/mol to %ee using absolute rate theory: ln(k1/k2) ) -∆∆G/
RT.
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A R T I C L E S
Table 2. Predicted and Experimental Product Ratios for the Reaction of Cyclohexanone with Benzaldehyde and Isobutyraldehyde
configurations were determined based on the X-ray structure
of the corresponding tosylhydrazone.
Acknowledgment. We are grateful to the National Institute
of General Medical Sciences, National Institutes of Health
(GM36700 to K.N.H. and GM63914 to B.L.) for financial
support of this research. We thank William Biller, Chris
Castello, and Raj K. Chadha for technical assistance.
The predictions are compared with experimental results in
Table 2. There is excellent agreement between the quantum
mechanical prediction and the experimental results for these
synthetically useful reactions. The only difference between
theory and experiment involves the unexpected formation of
5-7% of ent-syn-2. This may be due to a background pathway
of different or lower selectivity that uses an alternative reaction
mechanism such as general acid or base-catalyzed aldolization.
Quantum mechanical calculations can successfully predict the
product ratios of a synthetically useful reaction with a complex
stereochemical outcome. With the increasing speed and ef-
ficiency of computers, quantum mechanical calculations of this
type will soon become a common predictive tool.
Supporting Information Available: Cartesian coordinates of
all reported structures, the total electronic and zero point
vibrational energies, and experimental details (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA028812D
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