New mechanistic studies on the proline-catalyzed
aldol reaction
Benjamin List*, Linh Hoang, and Harry J. Martin
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Edited by Barry M. Trost, Stanford University, Stanford, CA, and approved February 4, 2004 (received for review December 4, 2003)
The mechanism of the proline-catalyzed aldol reaction has stimu-
lated considerable debate, and despite limited experimental data,
at least five different mechanisms have been proposed. Comple-
mentary to recent theoretical studies we have initiated an exper-
imental program with the goal of clarifying some of the basic
mechanistic questions concerning the proline-catalyzed aldol re-
action. Here we summarize our discoveries in this area and provide
further evidence for the involvement of enamine intermediates.
iscovered in the early 1970s, the Hajos Parrish Eder
DSauer Wiechert reaction (1, 2), a proline-catalyzed in-
tramolecular aldol reaction, represents not only the first asym-
metric aldol reaction invented by chemists but also the first
highly enantioselective organocatalytic transformation [1(4) 3
2(5) 3 3(6)] (Eq. 1 of Scheme 1) (3 6). Inspired by Nature s
phenomenal enzymes, which catalyze direct asymmetric aldol-
izations of unmodified carbonyl compounds (7, 8), we have
recently extended the Hajos Parrish Eder Sauer Wiechert re-
action to the first intermolecular variant (7 8 3 9) (Eq. 2 of
Scheme 1) (9), and to several other reactions including proline-
Scheme 1. Proline-catalyzed aldolizations (Eqs. 1 3) and proposed mecha-
catalyzed asymmetric Mannich (10), Michael (11), -amination
nisms (transition states).
(12), and intramolecular enolexo aldolization reactions (10 3
11) (13) (Eq. 3 of Scheme 1) (14 18).
Similar to the aldolase enzymes, proline catalyzes direct
We have recently reported evidence for the involvement of
asymmetric aldol reactions between two different carbonyl
only one proline molecule in the transition state of the C C-bond
compounds to provide aldol products in excellent yields and
forming step of both proline-catalyzed inter- and intramolecular
enantioselectivities. Early on it has been speculated that in
aldol reactions (26). Here we build on these findings and provide
addition to operating on related substrates, both class I aldolases
evidence for enamine intermediates. We show that if the Hajos
and proline may also share a similar enamine mechanism (19,
Parrish Eder Sauer Wiechert reaction is conducted in the pres-
20). However, there has been some debate over several mech- 18
ence of O-enriched water, the side-chain carbonyl group is
anistic aspects of the reaction, and a number of alternative
indeed labeled, a requirement of the proposed enamine mech-
models have been proposed. For example, Hajos (1) suggested
anism. In addition, covalent intermediates formed in reversible
a mechanism that involves the activation of one of the
reactions of ketones with proline have been detected and
enantiotopic acceptor carbonyl groups as a carbinol amine (A of 1
characterized by H NMR, and equilibrium constants of their
Scheme 1). At least the stereochemistry of this model was
formation have been estimated.
questioned by Jung (19) soon after its initial proposal. An
Our studies on the mechanism of the proline-catalyzed aldol
enamine mechanism was suggested by various groups already in
reaction began when we found that whereas Agami had dem-
the 1970s and 1980s (19 21). Nonlinearity studies by Agami and
onstrated that the intramolecular Hajos Parrish Eder Sauer
colleagues (21) have led to the proposal of a side-chain enamine
Wiechert reaction apparently showed a nonlinear effect in the
mechanism that involves two proline molecules in the C C-bond-
asymmetric catalysis, our intermolecular variant did not. Addi-
forming transition state, one engaged in enamine formation and
tional evidence that only one proline molecule may be involved
the other as a proton transfer mediator (B of Scheme 1).
in the transition state of the intermolecular aldol variant came
Swaminathan et al. (22) favor a heterogeneous aldolization
from kinetic studies. We determined retroaldolization kinetics
mechanism on the surface of crystalline proline (C of Scheme 1),
of a fluorogenic substrate and found these to be first order in
despite the fact that many proline-catalyzed aldolizations
proline. Intrigued by the apparent mechanistic discrepancy
are completely homogenous. Agami s widely accepted two-
between inter- and intramolecular proline catalyzed aldoliza-
proline mechanism was recently challenged when we proposed
tions, we set up experiments to confirm the nonlinear effects
a homogenous one-proline enamine mechanism for the inter-
earlier reported for the intramolecular reaction. However, in this
molecular variant in which the various proton transfers are
carefully conducted study no such effects could be observed. In
mediated by proline s carboxylic acid functionality (9). On the
addition, previously reported dilution effects on the enantiose-
basis of density functional theory calculations, Houk et al.
lectivity could not be reproduced. An explanation for the
(23 25) subsequently proposed a very similar mechanism for the
intramolecular variant (D of Scheme 1). Surprisingly, despite the
This paper was submitted directly (Track II) to the PNAS office.
apparent interest, very limited experimental data in support of
either of the several mechanistic proposals has been accumu- *To whom correspondence should be addressed. E-mail: list@mpi-muelheim.mpg.de.
lated. © 2004 by The National Academy of Sciences of the USA
www.pnas.org cgi doi 10.1073 pnas.0307979101 PNAS April 20, 2004 vol. 101 no. 16 5839 5842
SPECIAL FEATURE
CHEMISTRY
observed differences may be that Agami and colleagues (21)
had used optical rotation measurement for the ee determina-
tions, whereas we had used a more accurate HPLC-based assay.
Another strong piece of evidence for our one-proline mechanism
came from studies with polymer-supported proline as the cata-
lyst for asymmetric inter- and intramolecular aldolizations and
for our previously discovered asymmetric Mannich reaction
(10, 27 29). It was shown that rates and enantioselectivities
of the supported catalysts are comparable with proline itself.
Because a two-proline mechanism on the polymer is unlikely,
these studies as well as our own experiments effectively removed
the remaining evidence for the previously widely accepted
Agami mechanism and clearly supported the proposed one-
proline mechanism. What remained to be shown was that the
reaction indeed proceeds via enamine intermediates, because
alternative noncovalent mechanisms or even the unusual Hajos
mechanism could not be entirely ruled out.
Scheme 2. Seebach oxazolidinones are formed reversibly from simple ke-
Materials and Methods
tones and (S)-proline.
NMR Study. For the preparation of a 2 mg ml stock solution, dried
(P4O10) and finely powdered proline was stirred in dry DMSO-d6
1
Using H NMR, we found that under standard reaction
for 12 h under argon. Different 0.6-ml samples of this solution
conditions (1 20 vol % ketone donor DMSO) but in the absence
in an NMR tube were treated with varying amounts of the freshly
dried and distilled ketone (acetone, cyclopentanone, and cyclo- of aldehydes, proline indeed reacts with ketones to give the
hexanone). The concentrations of proline, ketone, oxazolidi- expected oxazolidinones along with 1 eq of water in a concen-
none, and water were determined by integration of characteristic tration-dependent, reversible manner. We estimated equilibrium
NMR signals, and equilibrium constants were determined ac- constants at various ketone concentrations. For example, ace-
cordingly at varying ketone concentrations. tone gave oxazolidinone 12 with an observed estimated equilib-
rium constant of K 0.12 (Scheme 2). Similarly, cyclopen-
GC-MS Study. A 0.2 M stock solution of dried triketone 4 (39.2 mg, tanone and cyclohexanone underwent the same transformation
0.2 mmol) in dry DMSO (1 ml) was prepared under argon. Each under these conditions to furnish oxazolidinones 13 (K 0.5)
500 l of this solution were successively treated with 470 l of and 14 (K 0.68), respectively. Thus, under standard condi-
18
dry DMSO, 30 l of water [regular or O-enriched (95%, tions but in the absence of aldehyde, proline is almost quanti-
Aldrich)], and dried (S)-proline (2.9 mg, 0.025 mmol, 25 mol %).
tatively engaged in unproductive oxazolidinone formation with
The mixtures were stirred for 4 days under argon. Samples were
simple ketones. We have not been able to detect enamine or
1
submitted to GC-MS (Agilent Technologies, Palo Alto, CA).
iminium ion intermediates under these conditions by H NMR.
However, ketone self-aldolization or aldolization with added
Results and Discussion
aldehyde proceeds over time. Thus, the observed oxazolidinone
Seebach Oxazolidinones Are Formed in Parasitic Equilibria Between
formation demonstrates that in addition to the reaction of
Ketones and Proline. Although chiral enamines prepared from
aldehydes, the initial covalent reaction of ketones with proline is
proline derivatives have been used in stoichiometric asymmetric
a facile process.
synthesis (30), enamines of unactivated carbonyl compound
derived from proline itself have never been isolated or charac- 18
O-Incorporation Studies. Although we have so far been unable to
terized. In fact, although vinylogous amides or carbamates from
detect proline enamines of simple aldehydes or ketones, we have
proline and -keto esters or -diketones can be prepared
obtained further indirect evidence for their formation in proline
efficiently, unactivated carbonyl compounds do not provide the
catalyzed aldolizations.
corresponding enamines in easily detectable quantities, but
provide alternative products instead. The reaction of proline
with aldehydes has been studied already in the 1980s, and it was
found that rather than enamines, oxazolidinones are formed
reversibly from -branched and -trisubstituted aldehydes (31). In
1
a H NMR study, we found that in the proline-catalyzed reaction
of acetone with isobutyraldehyde or pivaldehyde in d6-DMSO,
proline is initially quantitatively engaged in oxazolidinone for-
mation. Seebach had previously used these oxazolidinones in an
elegant overall asymmetric -alkylation reaction of proline (32).
The formation of oxazolidinones in the proline-catalyzed inter-
molecular aldol reaction, however, can best be characterized in
terms of a parasitic equilibrium that, whereas unwanted and
rate-diminishing, would still allow for turnover. At the same
time, rapid oxazolidinone formation is indicative for the ease of
covalent interactions between proline and aldehydes. Carbino-
lamines, iminium ions, and enamines may also be formed in these
reactions but at much lower concentrations. However, Seebach
oxazolidinones or other covalent adducts have never been de-
scribed before in the reaction of proline with unactivated ketones
Scheme 3. The proposed enamine catalysis cycle of the Hajos Parrish Eder
18
such as those typically used in proline-catalyzed aldolizations,
Sauer Wiechert reaction requires O incorporation when the reaction is
18
e.g., acetone, cyclopentanone, or cyclohexanone. performed in the presence of O-enriched water.
5840 www.pnas.org cgi doi 10.1073 pnas.0307979101 List et al.
18
Scheme 4. O-incorporation experiment.
16 18
The typically used substrate concentration in the Hajos presence of proline (25 mol %) and O- or O-enriched water
Parrish Eder Sauer Wiechert cyclization (0.1 0.5 M) is gener- (3 vol %) gave after 4 days reaction time 40% of the aldol
addition product 5, 50% of the aldol condensation product
ally smaller compared to the ketone concentration used in the
intermolecular reaction (2 4 M). From our estimated equilib- 6, and 10% of dieneamine 16 as detected by GC (Scheme 4).
16
If run in the presence of O water, the corresponding M " at
rium constants only a small oxazolidinone concentration is
196 (5), 178 (6), and 231 (16 CO2) can be identified. However,
expected to be formed under typical Hajos Parrish Eder
18
in the presence of O-enriched water, both the M " of the
Sauer Wiechert conditions. Indeed NMR spectra in this case
aldol addition and aldol condensation products appear at two
hardly provide evidence for oxazolidinone formation and typi-
18
mass units higher at 198 (5) and 0 (6), respectively, clearly
cally only show mixtures of starting material and product along
18
demonstrating efficient ( 90%) O incorporation. Because
with the proline catalyst.
18
both products incorporate exactly one O atom, incorpora-
However, an alternative way to prove a dehydrative covalent
tion could not have occurred at the alcohol moiety. That
interaction between proline and the ketone substrate could
18
18 dieneamine 16 did not incorporate O indicates that the
involve an O-incorporation study. If the proposed enamine
18
site of incorporation of the single O oxygen atom must be
mechanism was indeed operative and the reaction were to be
at the carbonyl group expected from the proposed enamine
18
run in the presence of O-enriched water, incorporation of
mechanism. Similar results were obtained when triketone 1
18
O at the initially acyclic carbonyl group would be expected
18
was used as the substrate to give both O-labeled aldol 2 and
because of the final hydrolysis step in the enamine catalysis cycle
traces of enone 3.
(Scheme 3).
In summary, our studies provide further evidence for covalent
Surprisingly, Hajos had reported that in contrast to what
catalysis in the proline-catalyzed aldol reaction. We show that
would be expected from considering the enamine mechanism,
initial covalent adduct formation between ketones and proline is
18
O incorporation did not occur, although important details of
a fast and facile reaction and that, in the presence of [18O]water,
these experiments have never been published (1).
18
O labeling does indeed occur at the expected position. These
We have studied the Hajos Parrish Eder Sauer Wiechert
studies, together with our previous experimental investigations
cyclization of ketones 1 and 4 to give the corresponding aldol
and Houk s DFT calculation, may further help to bring light into
addition (2 and 5) or condensation products (3 and 6) in
the vast mechanistic darkness of what is believed to be enamine
18 18
the presence of O-enriched water (95% O, Aldrich), using
catalysis.
carefully controlled conditions. When the reactions were
performed under completely air- and moisture-free conditions
We thank the Departments of Mass Spectrometry and NMR Spectros-
(except of course for the purposely added water), and when
copy of The Scripps Research Institute (La Jolla, CA) for technical
both the substrate and proline catalyst had been carefully dried
assistance, the Max-Planck-Institut für Kohlenforschung, and Dr. Sabine
azeotropically, and when dried solvent (DMSO) was used, high
Behnsen for encouragement. This work was supported by National
18
O incorporation was indeed observed. Triketone 4 in the Institutes of Health Grant RO1 GM-63914 (to B.L.).
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