C O MMU N I C A T I O N S
out at the present time, there is no remaining experimental evidence
supporting this mechanism. Significantly, our results, along with
recent theoretical studies,8,9,16 suggest a unified mechanism of
proline-catalyzed inter- and intramolecular aldol reactions.
Acknowledgment. Support by the NIH (GM63914 to B.L. and
GM36700 to K.N.H.) is most gratefully acknowledged. We thank
Chris Castello for kinetic experiments.
Supporting Information Available: Computational, experimental,
and HPLC data (PDF). This material is available free of charge via the
References
(1) (a) Hajos, Z. G.; Parrish, D. R. German Patent DE 2102623, 1971. (b)
Eder, U.; Sauer, G.; Wiechert, R. German Patent DE 2014757, 1971. (c)
Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10,
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(2) For example Taxol: Danishefsky, S. J.; Masters, J. J.; Young, W. B.;
Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung, D. K.; Isaacs, R. C. A.;
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Chem., Int. Ed. 2001, 40, 529-532. (b) Jarvo, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481-2495. (c) List, B. Tetrahedron 2002, 58,
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575. For the first proline-catalyzed asymmetric intermolecular Mannich-,
Michael-, and R-amination reactions, see: (d) List, B. J. Am. Chem. Soc.
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108, 2353-2357. (d) Agami, C.; Puchot, C. J. Mol. Catal. 1986, 38, 341-
343. (e) Agami, C. Bull. Soc. Chim Fr. 1987, 3, 499-507.
(6) Jung, M. E. Tetrahedron 1976, 32, 3-31.
(7) Brown, K. L.; Damm, L.; Dunitz, J. D.; Eschenmoser, A.; Hobi, R.; Kratky,
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(8) (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 9922-
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11273-11283. (c) For quantitative stereoselectivity predictions of proline-
catalyzed intermolecular aldol reactions, see: Bahmanyar, S.; Houk, K.
N., Martin, H. J., List, B. Manuscript submitted.
(9) Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. A. 2002, 106,
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(10) For related enantiogroup-differentiating aldol cyclodehydrations, see:
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Figure 1. (a) retro-Aldolization kinetics of aldol 7. (b) Absence of nonlinear
effects in the Hajos-Parrish-Eder-Sauer-Wiechert reaction. (c) Absence
of dilution effects on the enantioselectivity.
which can be precisely determined using reverse chiral phase HPLC
measurements. Plotting the ee of proline versus that of 3b showed
an excellent linear correlation (Figure 1b). Furthermore, the reaction
of triketone 1a to give aldol 2a and, after in situ acid-catalyzed
dehydration, enone 3a, also showed no significant deviation from
linearity (Figure 1b). As in the case of ketone 3b, ee’s of enone 3a
were accurately determined using reverse chiral phase HPLC. Both
experiments were repeated twice and studied in DMSO as well as
in DMF without significant deviations. Our results are consistent
with the one-proline mechanism.
Finally, we investigated whether there are concentration effects
on the enantioselectivity of the aldolizations of triketones 1a and
1b (Figure 1c). An observed decreased enantioselectivity upon
diluting the reaction mixture has been interpreted as evidence for
the two-proline-mechanism.5d However, no such effects were
observed, again consistent with the one-proline mechanism.15
In summary, kinetic, stereochemical, and dilution experiments
support a one-proline-mechanism of proline-catalyzed aldolizations.
Although the two-proline mechanism cannot be completely ruled
(11) (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas C. F., III. J. Am. Chem. Soc.
2001, 123, 5260-5267. (b) Co´rdova, A.; Notz, W.; Barbas, C. F., III. J.
Org. Chem. 2002, 67, 301-303.
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Zhuang, W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790-
1793.
(14) Spencer, T. A.; Neel, H. S.; Fletcher, T. W.; Zayle, R. A. Tetrahedron
Lett. 1965, 3889-3897.
(15) One of the reviewers correctly pointed out that prevailing models for
nonlinear effects do not allow for concentration dependence of ee unless
the chiral entity is an auxiliary and not a catalyst. Also see: Blackmond,
D. G. Acc. Chem. Res. 2000, 33, 402-411.
(16) Additional detailed B3LYP/6-31G* calculations do not support a second
proline molecule in the proton-transfer step (see Supporting Information).
While previous calculations (ref 8) showed that intramolecular proton
transfer from the proline carboxylic acid to the developing alkoxide gives
a
good accounting for the observed stereoselectivity, inclusion of
dimethylamine as a proton-transfer mediator, produces transition states
with higher activation energies and predicts that both enantiomers would
be formed with nearly equal facility. Neither calculated activation energies
nor stereoselectivies are consistent with a two-proline mechanism.
JA028634O
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