Evaluation of catalyst acidity and substrate electronic effects in a hydrogen bond-catalyzed enantioselective reaction

Article abstract of DOI:10.1021/jo1013806

A modular catalyst structure was applied to evaluate the effects of catalyst acidity in a hydrogen bond-catalyzed hetero Diels-Alder reaction. Linear free energy relationships between catalyst acidity and both rate and enantioselectivity were observed, wh

Full text of DOI:10.1021/jo1013806

pubs.acs.org/joc
Evaluation of Catalyst Acidity and Substrate Electronic Effects
in a Hydrogen Bond-Catalyzed Enantioselective Reaction
Katrina H. Jensen and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City,
Utah 84112, United States
sigman@chem.utah.edu
Received July 15, 2010
A modular catalyst structure was applied to evaluate the effects of catalyst acidity in a hydrogen
bond-catalyzed hetero Diels-Alder reaction. Linear free energy relationships between catalyst
acidity and both rate and enantioselectivity were observed, where greater catalyst acidity leads to
increased activity and enantioselectivity. A relationship between reactant electronic nature and rate
was also observed, although there is no such correlation to enantioselectivity, indicating the system is
under catalyst control.
Introduction
influence of catalyst acidity upon reaction outcome, both in
terms of rate8,9 and enantioselectivity, remains underinves-
tigated.10-12 This lack of understanding is likely due to the
fact that significant structural differences often make the
direct comparison of catalysts with different acidity unin-
formative.
A hydrogen bond catalyst design was developed in our
laboratory and consists of an oxazoline core and two pen-
dant arms with sites capable of hydrogen bond donation
(Scheme 1).13 This catalyst employs amino acid derivatives
as the chiral building blocks, allowing for the incorporation
of a variety of substituents into the catalyst structure. A key
A crucial function of hydrogen bonding in nature is
transition state stabilization during enzyme catalysis. Syn-
thetic chemists have applied this mode of activation to
asymmetric catalysis, where hydrogen bond donors are used
in small chiral molecules to impart facial selectivity during
catalysis. Recent advancement in this field has been rapid,
and a plethora of structurally distinct catalysts, covering a
range of approximately 20 pKa units, have been successfully
employed.1-3 Despite the surge of reports, mechanistic
understanding of how subtle changes to catalyst structure
affect selectivity is still relatively scarce.4-7 Moreover, the
(8) Hine, J.; Linden, S. M.; Kanagasabapathy, V. M. J. Am. Chem. Soc.
1985, 107, 1082.
(9) Hine, J.; Linden, S. M.; Kanagasabapathy, V. M. J. Org. Chem. 1985,
50, 5096.
(10) Jensen, K. H.; Sigman, M. S. Angew. Chem., Int. Ed. 2007, 46, 4748.
(11) Li, X.; Deng, H.; Zhang, B.; Li, J.; Zhang, L.; Luo, S.; Cheng, J.-P.
Chem.;Eur. J. 2010, 16, 450.
(12) Du, J.; Li, Z.; Du, D.-M.; Xu, J. ARKIVOC 2008, 145.
(13) Rajaram, S.; Sigman, M. S. Org. Lett. 2005, 7, 5473.
(1) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
(2) Akiyama, T. Chem. Rev. 2007, 107, 5744.
(3) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
(4) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
(5) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 15872.
(6) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 15358.
(7) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science
2010, 327, 986.
7194 J. Org. Chem. 2010, 75, 7194–7201
Published on Web 10/04/2010
DOI: 10.1021/jo1013806
r
2010 American Chemical Society

Jensen and Sigman
JOCArticle
SCHEME 1. Modular Hydrogen Bond Catalyst Design
advantage of the design is its modularity, facilitating opti-
mization of catalyst structure for a given reaction, as well as
allowing systematic changes to be incorporated to advance
understanding of the relationship between structure and
selectivity.14,15
The viability of this general motif as a hydrogen bond
catalyst was demonstrated using a model reaction, the
hetero-Diels-Alder reaction16 of the activated diene 117-20
with aromatic aldehydes, initially reported by Rawal and co-
workers (Figure 1).21,22 The modular nature of the catalyst
design allowed for the evaluation of a variety of catalyst
structures, and catalyst 2 was found to provide the dihydro-
pyranone products in high enantiomeric excess.13
FIGURE 1. Hetero Diels-Alder reaction and modular hydrogen
bond catalysts.
TABLE 1. Oxazoline-Amide Catalyzed Hetero Diels-Alder Reaction
Following the successful demonstration of the efficacy of
the catalyst design, the focus of the project turned to utilizing
the catalyst’s modularity to contribute to the mechanistic
understanding of enantioselective hydrogen bond catalysis.
Specifically, we hoped to systematically evaluate the influ-
ence of catalyst acidity.10 We hypothesized that a more acidic
catalyst may lead to a stronger hydrogen bond between
catalyst and aldehyde, and consequently greater substrate
activation, ultimately leading to a more active catalyst. Our
catalyst was seen as an ideal template with which to test this
hypothesis, as its modularity allows for systematic changes
to one portion of the catalyst, while keeping the remainder of
the catalyst unchanged. A series of halogenated acetamide
derivative catalysts 3-7 (Figure 1) was chosen, as they
provide a significant range of N-H acidity (approximately
5 pKa units as measured in DMSO)23,24 and all could be
synthesized from a common precursor (see Experimental Sec-
tion for details). We initially reported the observation of a direct
correlation between catalyst acidity and enantioselectivity in
2007.10 Herein we report a more detailed investigation of this
reaction, including an examination of both catalyst and sub-
strate electronic effects on rate and enantioselectivity, and
provide a plausible origin of these observations.
entry
catalyst
R
% yield
% ee
er
1
2
3
4
5
3
4
5
6
7
CF3
CCl3
CHCl2
CH2F
CH2Cl
67
61
53
17
32
91
81
75
62
52
95.3:4.7
90.6:9.4
87.5:12.5
81.1:18.9
75.8:24.2
TABLE 2. Scope of Hetero Diels-Alder Reaction Catalyzed by 3
Results and Discussion
entry
R
time (h) temp (°C) % yield % ee
er
Catalysts 3-7 were synthesized from a common oxazoline
amine intermediate, obtained via coupling of an amino
alcohol with an N-protected amino acid, followed by oxazoline
1
2
3
4
5
6
7
8
Ph
60
48
48
48
72
48
72
48
-65
-65
-55
-55
-40
-65
-40
-40
72
70
74
74
59
65
14
32
93
81
96
83
88
90
47
30
96:4
4-O2NC6H4
1-naphthyl
4-ClC6H4
4-MeOC6H4
PhCHdCH
PhCH2CH2
CH3(CH2)4
90:10
98:2
92:8
94:6
95:5
(14) Miller, J. J.; Sigman, M. S. Angew. Chem., Int. Ed. 2008, 47, 771.
(15) Sigman, M. S.; Miller, J. J. J. Org. Chem. 2009, 74, 7633.
(16) Pellissier, H. Tetrahedron 2009, 65, 2839.
73:27
65:35
(17) Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321.
(18) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662.
(19) Kozmin, S. A.; Janey, J. M.; Rawal, V. H. J. Org. Chem. 1999, 64,
3039.
(20) Kozmin, S. A.; He, S.; Rawal, V. H. Org. Synth. 2002, 78, 152.
(21) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003,
424, 146.
(22) Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am.
Chem. Soc. 2005, 127, 1336.
(23) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(24) Bordwell, F. G.; Fried, H. E.; Hughes, D. L.; Lynch, T. Y.; Satish,
A. V.; Whang, Y. E. J. Org. Chem. 1990, 55, 3330.
cyclization (see Experimental Section for details). The series
of catalysts was evaluated in the hetero-Diels-Alder reaction
between Rawal’s diene 1and benzaldehyde 8(Table1). Isolated
yields of the dihydropyranone product 9 were taken as
the first indication that catalyst acidity may indeed affect
catalytic activity, as more acidic catalysts generally gave
higher product yields (Table 1). Interestingly, a trend in
enantioselectivity was also observed, with the most acidic
J. Org. Chem. Vol. 75, No. 21, 2010 7195

Jensen and Sigman
JOCArticle
SCHEME 2. Proposed Mechanism for the Hetero Diels-Alder
Reaction Catalyzed by 3
Thus, while the series of catalysts was initially developed as a
mechanistic probe, 3 was found to be a viable catalyst. This is
encouraging because 3 is significantly simpler, having fewer
stereocenters and a lower molecular weight, than the camphor
sulfonamide catalyst 2.
Mechanistic Investigation
To gain a better understanding of how the observed trends
in yield and enantioselectivity based on catalyst acidity may
reflect the mechanism of the reaction, kinetic measurements
were acquired using in situ IR spectroscopy, and the reaction
rate dependence on each reaction component was deter-
mined (Figure 2, note: rate measured by monitoring the
change in IR absorbance of 1, which is correlated to [1], as
a function of time; rates reported in M/s). A first order
dependence on [catalyst] provides evidence against a dimer
or higher order species as the active catalyst (Figure 2A).
Initially, kinetic measurements were performed at room
temperature for practicality, but based on the observation
of a nonzero intercept, indicating a background reaction, all
further measurements were performed at reduced tempera-
ture (either 0 or -45 °C). Saturation in [aldehyde] was
observed (Figure 2B), as well as a first order dependence
on [diene] at high [aldehyde] (Figure 2 C). These results led to
the proposal of the mechanism shown in Scheme 2, where the
catalyst and aldehyde bind reversibly to form an activated
complex C:A, which reacts with diene in the turnover limiting
step to form the product.
Upon the basis of the proposed mechanism, rate law
derivation was performed following the Michaelis-Menten
kinetic model. Assuming the second step is the turnover
determining step, the rate of product formation is propor-
tional to the product of the concentration of the two inter-
mediates involved in this step, where C:A is the activated
catalyst-aldehyde complex (eq 1). As the catalyst exists in
two different states in this mechanism, we define [C]T as the
total catalyst concentration (eq 2). Using the steady state
approximation (eq 3) allows us to solve for [C:A] (eq 4).
Substitution into eq 1 results in the derived rate law (eq 5).
FIGURE 2. Reaction component dependencies with catalyst 3
measured by in situ IR spectroscopy. (A) First order dependence
on [catalyst 3], conditions: [benzaldehyde] = 0.37 M, [diene] = 0.18
M, rt. (B) Saturation in [aldehyde], conditions: [3] = 0.018 M,
[diene] = 0.18 M, 0 °C. (C) First order dependence on [diene],
conditions: [3] = 0.018 M, [benzaldehyde] = 1.0 M, 0 °C.
catalyst leading to the highest enantiomeric excess. This result
was initially unexpected, as it was assumed that substituent size
had the most significant effect on facial selectivity, and our
assumption was that halogen substitution would have a minor
effect upon the steric nature of the catalyst.
Because 3 was discovered to catalyze the hetero-Diels-
Alder reaction with high enantioselectivity, the scope of the
hetero-Diels-Alder reaction with this catalyst was exam-
ined (Table 2). In general, high enantioselectivity was obtained
with aromatic aldehyde substrates (entries 1-5), highlighted
by a 96% ee for 1-naphthaldehyde. An R,β-unsaturated alde-
hyde, cinnamaldehyde, also gives the product in high enantio-
meric excess (entry 6). Enantioselectivity is diminished for
hydrocinnamaldehyde and hexanaldehyde (entries 7 and 8),
but this marks an improvement as prior experimentation
had shown catalyst 2 to be ineffective in the catalysis of the
hetero Diels-Alder reaction with aliphatic aldehydes.
d½Pꢀ
¼ k2½C : Aꢀ½Dꢀ
ð1Þ
ð2Þ
dt
½Cꢀ ¼ ½CTꢀ - ½C : Aꢀ
d½C : Aꢀ
¼ k1ð½CTꢀ - ½C : AꢀÞ½Aꢀ - k- 1½C : Aꢀ
- k2½C : Aꢀ½Dꢀ ¼ 0
dt
ð3Þ
7196 J. Org. Chem. Vol. 75, No. 21, 2010

Jensen and Sigman
JOCArticle
FIGURE 3. Conversion of diene vs time for hydrogen bond cata-
lyst 3-7, conditions: [benzaldehyde] = 0.78 M, [diene] = 0.18 M,
[catalyst] = 0.036 M, -45 °C.
FIGURE 4. Linear free energy relationship between rate and pKa of
the corresponding acetic acid derivative, conditions: [benzaldehyde] =
0.78 M, [diene] = 0.18 M, [catalyst] = 0.036 M, -45 °C.
use the pKa values of acetic acid derivatives measured in
water as the reference, with the key assumption being that the
electron-withdrawing ability of the R substituent affects the
acidity of our catalyst and the acidity of the corresponding
acetic acid derivative similarly.
k1½CTꢀ½Aꢀ
½C : Aꢀ ¼
ð4Þ
ð5Þ
k1½Aꢀ þ k- 1 þ k2½Dꢀ
d½Pꢀ
¼
k1k2½CTꢀ½Aꢀ½Dꢀ
dt
k1½Aꢀ þ k- 1 þ k2½Dꢀ
logðkÞ ¼ - RðpKaÞ þ C
ð8Þ
Importantly, the derived rate law is consistent with the
empirical observations. Specifically, when [aldehyde] is low
the rate law can be simplified to eq 6 which is consistent with
a first order dependence of rate on [aldehyde], and when
[aldehyde] is high the rate law can be simplified to eq 7
which is consistent with zero order dependence of rate on
[aldehyde], and first order dependence on [catalyst] and
[diene].
To evaluate the effect of catalyst acidity upon substrate
binding, the saturation curves for the most and least acidic
catalysts, 3 and 7, respectively, were examined (Figure 5,
note y-axis scales are different). Comparing the curvature of
these two plots, saturation is reached at much lower [alde-
hyde] for the more acidic catalyst (Figure 5A) than for the
least acidic catalyst (Figure 5B), indicating that binding
equilibrium is also perturbed by catalyst acidity.
With the understanding that catalyst acidity has a direct
effect on both substrate binding and rate of reaction with
diene, we were interested in whether the observed trends in
enantioselectivity could also be directly correlated to catalyst
acidity. Considering that enantiomeric ratio is a measure-
ment of the relative rate of formation of each enantiomer
(er = kS/kR), a Brønsted-type plot was constructed by plotting
log(er) vs pKa (Figure 6). A linear free energy relationship was
observed between enantioselectivity and acidity, a unique
example of such a direct correlation in a hydrogen bond
catalyzed reaction. This indicates that enantioselectivity can
be directly perturbed by the hydrogen bond donating ability.
d½Pꢀ
k1k2½CTꢀ½Aꢀ½Dꢀ
k- 1 þ k2½Dꢀ
¼
ð6Þ
ð7Þ
dt
d½Pꢀ
¼ k2½CTꢀ½Dꢀ
dt
Catalyst Acidity Effects
In light of the proposed mechanism, the question re-
mained whether catalyst acidity is affecting the binding equili-
bria of catalyst with substrate (k1/k-1), the rate of reaction of
the activated aldehyde C:A with diene (k2), or both. To
determine the influence upon the second step, the reaction
rate was measured for the complete series of catalysts 3-7
under saturation conditions. A clear trend was observed,
with the most acidic catalyst leading to the highest rate
(Figure 3).
To determine whether this trend in reaction could be
directly correlated to the electronic nature of the catalyst, a
Brønsted-type plot was constructed (Figure 4). The Brønsted
equation (eq 8)25 relates the rate of an acid-catalyzed reac-
tion to the pKa of the corresponding acid. The resulting
linear free energy relationship is similar to the more common
Hammett relationship, where pKa’s of benzoic acids are used
as the reference measurement for the effect of electronic
perturbations on rate or equilibrium. In our case, we chose to
Substrate Electronic Effects
In an attempt to further understand the subtleties of the
system, we chose to evaluate the influence of substrate electronic
perturbations. We hypothesized that the electronic nature of the
substrate could potentially affect both the rate at which the
aldehyde reacts with the diene, as well as the Lewis basicity and
thus the binding of substrate to catalyst. Therefore, a series of
benzaldehyde derivatives with either electron-donating or
electron-withdrawing substituents in the para position were
examined. In situ IR was used to monitor the rate of the reaction.
We first examined the two most electronically disparate cases
within the series, p-anisaldehyde 10 and p-trifluoromethylben-
zaldehyde 11. Initial reaction rates were measured over a range
of [aldehyde]. Similar rates were observed at low [aldehyde],
(25) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chem-
istry; University Science Books: Sausalito, CA, 2006; p 466.
J. Org. Chem. Vol. 75, No. 21, 2010 7197

Jensen and Sigman
JOCArticle
FIGURE 5. Comparison of saturation in [aldehyde] for catalysts 3 and 7. Conditions: [diene] = 0.075 M, [catalyst] = 0.018 M, -45 °C. Fit to
y = ax/(b + x). (A) a = 5.47 ꢁ 10-5 ( 3.1 ꢁ 10-6, b = 0.074 ( 0.017, R2 = 0.97; (B) a = 1.45 ꢁ 10-5 ( 6.4 ꢁ 10-7, b = 0.209 ( 0.029, R2 = 0.99.
FIGURE 6. Linear free energy relationship between enantiomeric
ratio and pKa of the corresponding acetic acid derivative, condi-
tions: [benzaldehyde] = 0.36 M, [diene] = 0.18 M, [catalyst] =
0.036 M, -40 °C.
however, significant differences can be observed in the saturation
curves for the two substrates. p-Anisaldehyde reaches saturation
at a lower [aldehyde] (Figure 7A), as would be expected with a
more electron rich aldehyde which is a stronger Brønsted base
and thus binds to the catalyst more effectively. On the other
hand, p-trifluoromethylbenzaldehyde achieves a much higher
rate of reaction at saturation (Figure 7B), which is consistent with
this being the more electron-poor, and thus more electrophilic
aldehyde.
The rate of the hydrogen bond-catalyzed hetero-Diels-
Alder reaction was measured at both high and low [aldehyde]
with a series of benzaldehyde derivatives bearing electron-
donating or electron-withdrawing substituents (Table 3).
A Hammett plot was constructed by plotting log(rate) vs
σ+ (Figure 8). When [aldehyde] = 1.0 M (conditions where
FIGURE 7. [aldehyde] saturation curves for benzaldehyde derivi-
tives bearing (A) an electron-donating group and (B) an electron-
withdrawing group. Conditions: [catalyst 3] = 0.016 M, [diene] =
0.16 M, -45 °C.
saturation is assumed) a linear free energy correlation is
observed, with F+ = 1.61 ( 0.16 (Figure 8A).26 A positive
F value indicates that there is a build up of negative charge, or
diminution of positive charge, during the transition state.
Additionally, the better fit obtained with σ+ than with σ
indicates significant resonance contribution from electron
donating groups. This is consistent with the proposed
mechanism in which a hydrogen bond is formed between
aldehyde and catalyst, which would lead to a build up of
positive charge on the carbonyl carbon of the aldehyde.
Stabilization of this positive charge by electron donation
would lead to a lower energy C:A intermediate, as demon-
strated by the difference in saturation curves in Figure 7. A
lower energy for the C:A intermediate would contribute to a
(26) Rate data for 4-Cl-benzaldehyde and 4-Br-benzaldehyde were not
obtained at high [aldehyde] due to poor solubility of these substrates at
reduced temperature.
7198 J. Org. Chem. Vol. 75, No. 21, 2010

Jensen and Sigman
JOCArticle
TABLE 3. Rate of Hetero Diels-Alder Reaction Catalyzed by 3a
TABLE 4. Enantiomeric Excess of Hetero Diels-Alder Adducts with
Benzaldehyde Derivatives
[aldehyde] = 1.0 M
average rate
[aldehyde] = 0.025 M
average
entry
R
% ee
er
R
σþ
(M/s)
6.78 ꢁ 10-4
log(rate)
rate (M/s)
log(rate)
1
2
3
4
5
6
CF3
Cl
91
86
84
91
83
90
95.4:4.6
93.0:7.0
91.8:8.2
95.5:4.5
91.5:8.5
95.2:4.8
CF3
Br
Cl
H
F
Me
0.53
0.15
0.11
0
-0.07
-0.31
-3.17
-
-
6.35 ꢁ 10-7
1.87 ꢁ 10-5
1.54 ꢁ 10-5
6.03 ꢁ 10-6
6.51 ꢁ 10-6
2.90 ꢁ 10-6
8.21 ꢁ 10-7
-6.20
-4.73
-4.83
-5.22
-5.19
-5.54
-6.09
F
-
H
Me
OMe
-
4.64 ꢁ 10-5
2.93 ꢁ 10-5
2.61 ꢁ 10-5
2.93 ꢁ 10-6
-4.43
-4.53
-4.58
-5.53
OMe -0.78
in mechanism as this aldehyde substrate is such a poor Brønsted
base that k1 is turnover limiting.
aConditions: [catalyst] = 0.016 M, [diene] = 0.16 M, -45 °C.
The observed Hammett correlation under saturation con-
ditions is consistent with previous LFERs observed for other
Diels-Alder reactions.27-35 In general positive F values are
observed with respect to electronic perturbations to the
dienophile, whereas negative F values are observed when
derivatives of the diene are examined. This is in agreement
with the generally accepted view of a polar, asynchronous
[4 þ 2] cycloaddition pathway in which the diene and the
dienophile can be considered the nucleophile and the elec-
trophile, respectively.
Inspection of the enantiomeric excess of the products
formed following workup with acetyl chloride shows no
effect of the electronic nature of the aldehyde upon enantio-
selectivity (Table 4). Plotting log(er) vs either σ or σþ shows no
LFER (Figure 9). This indicates that the enantioselectivity of
the reaction is solely under catalyst control (vide infra).
Origin of Catalyst Acidity Effect on Enantioselectivity
The observation of such direct effects of catalyst acidity on
both rate and enantioselectivity should prove beneficial in
the future design of hydrogen bond catalysts for asymmetric
catalysis. While the effect upon rate was expected, the direct
effect on enantioselectivity was not. Several explanations to
account for such an effect can be proposed.
One explanation might be that a background, or uncata-
lyzed reaction, is occurring concurrent to the catalyzed
reaction. This uncatalyzed reaction would result in racemic
product, and thus the overall enantiomeric excess of product
would be diminished. As kcat decreases, the effect of a back-
ground reaction would certainly be more significant. In the
case of our system, however, the background reaction at
-45 °C is not significant with no product formation observed
after 48 h at this temperature. Furthermore, this explanation is
FIGURE 8. Hammett plots relating aldehyde electronic nature and
reaction rate. Conditions: [catalyst 3] = 0.016 M, [diene] = 0.16 M,
-45 °C. (A) [aldehyde] = 1.0 M, (B) [aldehyde] = 0.025 M.
higher activation energy for electron rich benzaldehyde
derivatives, as evidenced by the decrease in k2.
(27) Doyle, M. P.; Valenzuela, M.; Huang, P. Proc. Natl. Acad. Sci. U.S.
A. 2004, 101, 5391.
When [aldehyde] = 0.025 M, again a linear free energy
relationship is observed using σþ values with a F value of 1.47.
However, a break in the Hammett plot is observed when
evaluating the most electron poor aldehdye (Figure 8B). On
the left-hand side, F is positive as the substrates are electron rich
enough to be in a situation where k2 is turnover limiting. In
contrast, with a very electron withdrawing substituent, it is
likely that there is a change in turnover limiting step or change
(28) Benghait, I.; Becker, E. I. J. Org. Chem. 1958, 23, 885.
(29) Lotfi, M.; Roberts, R. M. G. Tetrahedron 1979, 35, 2131.
(30) Okamoto, Y.; Brown, H. C. J. Org. Chem. 1957, 22, 485.
(31) DeWitt, E. J.; Lester, C. T.; Ropp, G. A. J. Am. Chem. Soc. 1956, 78,
2101.
(32) Inukai, T.; Kojima, T. J. Chem. Soc. D 1969, 1334.
(33) Salakhov, M. S.; Musaeva, N. F.; Suleimanov, S. N. Org. React.
(Tartu) 1979, 16, 54.
(34) Domingo, L. R.; Saez, J. A. Org. Biomol. Chem 2009, 7, 3576.
(35) Charton, M. J. Org. Chem. 1966, 31, 3745.
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Jensen and Sigman
JOCArticle
acidic catalyst. Furthermore, this disparity likely decreases
in the transition state, as negative charge builds on the
carbonyl oxygen. The formation of a stronger hydrogen
bond in the transition state may lead to greater rigidity,
and thus account for the higher enantioselectivity observed
with more acidic catalysts. In contrast, there is a lack of
correlation between substrate electronic nature and enan-
tioselectivity (Table 4). When considering a possible transi-
tion state structure, the substrate portion, with negative
charge on the oxygen atom stabilized by hydrogen bond
formation to the catalyst, is analogousto the conjugatebaseof
benzyl alcohol (Figure 10). The pKa range of para-substituted
benzylic alcohols is quite small (approximately 0.6 pKa units, a
4-fold difference in Ka),39 and thus has less of an impact on the
strength of hydrogen bond formed in the transition state than
the catalyst, where the range is significant (approximately 5 pKa
units, a 105-fold difference in Ka).23,24
Conclusion
We have presented a detailed examination of the effect
of catalyst acidity in an enantioselective hydrogen bond-
catalyzed reaction. This systematic study investigates the effects
of electronic perturbations to both the catalyst and substrate.
A process where catalyst acidity controls enantioselectivity is
revealed. Since our initial report of a direct correlation
between catalyst acidity and enantioselectivity,10 examples
of similar trends in other hydrogen bond-catalyzed reactions
have emerged,11,12 implying this effect is not unique to our
system. However, ideal catalyst acidity is likely to differ
depending on the specific reaction of interest, as the role of
the catalyst is to stabilize the transition state more than the
bound substrate intermediate, therefore it should not be
assumed that a more acidic catalyst will always lead to
improved enantioselectivity.40 Optimal matching of the pKa’s
of catalyst and transition state structure should lead to
improved catalyst performance in other systems as well,
and the understanding gained in this study may aid in future
catalyst design.
FIGURE 9. Hammett plots show no linear free energy relationship
for enantioselectivity, conditions: [benzaldehyde] = 0.36 M, [diene] =
0.18 M, [catalyst] = 0.036 M, -45 °C.
Experimental Section
Preparation of Catalyst 3 (2,2,2-Trifluoro-N-((R)-1-((S)-
4-(hydroxydiphenylmethyl)-4,5-dihydrooxazol-2-yl)-2-phenylethyl)-
acetamide). The synthesis of the Cbz oxazoline intermediate (benzyl
(R)-1-((S)-4-(hydroxydiphenylmethyl)-4,5-dihydrooxazol-2-yl)-2-
phenylethylcarbamate) 12 has been previously reported.13 A 100
mL round-bottom flask was charged with 44 mg of 10% Pd/C and
the flask was flushed with nitrogen. In a separate 100 mL flask,
442.3 mg of oxazoline 12 (0.873 mmol) was dissolved in 6 mL of dry
MeOH, and this solution was transferred via cannula into the flask
containing Pd/C (on occasions when this is difficult, gentle warm-
ing or addition of excess MeOH is helpful and has no discernible
effect on overall yield). A further 4 mL of MeOH (2 ꢁ 2 mL) was
used for rinsing. The flask was then evacuated under water
aspirator pressure and filled with H2 from a balloon. The cycle
was repeated thrice more, and the reaction mixture was stirred
under a H2 balloon atmosphere. On completion of reaction (7-8 h,
by disappearance of oxazoline 12 on TLC, Rf = 0.6 with 1:1
EtOAc/hexanes), the reaction mixture was filtered through a pad
FIGURE 10. Effect of substituents on acidity of hydrogen bond
donor and acceptor in proposed the transition state.
inconsistent with the lack of a correlation between substrate
electronic nature and enantioselectivity.
A reasonable explanation is that a stronger hydrogen
bond between the catalyst and the substrate at the transition
state is formed with the more acidic catalyst, leading to
increased rigidity in the transition state. It has been reported
that if the pKa of the hydrogen bond donor and that of the
protonated hydrogen bond acceptor are closely matched, a
shorter and stronger hydrogen bond is formed.36-38 While
the pKa difference between catalyst and protonated substrate
is substantial, they are more closely matched with a more
(36) Perrin, C. L. Science 1994, 266, 1665.
(39) Based on calculated pKa values reported on Scifinder (Calculated
using Advanced Chemistry Development Software V8.14).
(40) Davis, T. A.; Wilt, J. C.; Johnston, J. N. J. Am. Chem. Soc. 2010, 132,
2880.
(37) Cleland, W. W.; Kreevoy, M. M. Science 1994, 264, 1887.
(38) Schwartz, B.; Drueckhammer, D. G.; Usher, K. C.; Remington, S. J.
Biochemistry 1995, 34, 15459.
7200 J. Org. Chem. Vol. 75, No. 21, 2010

Jensen and Sigman
JOCArticle
of Celite. The filtrate was concentrated under reduced pressure, and
the resulting residue was dissolved in benzene and concentrated
under reduced pressure to remove exogenous water (2 ꢁ 30 mL
benzene), then dried overnight under high vacuum and used with-
out further purification. The residue from deprotection was dis-
solved in 5 mL of dry CH2Cl2 under nitrogen along with 10.7 mg of
DMAP (0.087 mmol, 0.10 equiv). To this solution, 490 μL of
freshly distilled Et3N (3.49 mmol, 4 equiv) was added. The reaction
mixture was cooled to 0 °C in an ice bath. In a separate flask, 123 μL
of trifluoroacetic anhydride (95% pure, 0.873 mmol, 1 equiv) was
dissolved in 3 mL of CH2Cl2. This solution was transferred via
cannula into the reaction flask. An additional 2 mL of CH2Cl2 was
used for rinsing. The reaction mixture was stirred for 4 h, then
diluted with 30 mL of CH2Cl2 and washed with 30 mL of saturated
aqueous NaHCO3 followed by 30 mL of brine. The organic phase
was dried over Na2SO4, filtered, and concentrated. The crude
mixture in a minimum amount of CH2Cl2 was purified by flash
silica-gel column chromatography with 20 to 25 to 30% Et2O/
hexanes as the solvent to give 178.8 mg of 3 (yield: 43%). Rf = 0.7
with 1:1 EtOAc/hexanes; white solid; mp: 50-52 °C; [R]D20 = -20
(c = 0.28, CHCl3);1HNMR(300, MHzCD2Cl2) δ=2.50(s, 1H),
3.10 (dd, J = 6.6, 14.0 Hz, 1 H), 3.23 (dd, J = 6.0, 14.0 Hz, 1 H),
4.26 (d, J = 8.9 Hz, 1 H), 4.27 (d, J = 8.9 Hz, 1 H), 4.81 (ddd, J =
6.0, 6.5, 6.5 Hz, 1 H), 5.25 (dd, J = 8.9, 8.9 Hz, 1 H), 6.79 (br d, J =
6.0 Hz, 1 H), 7.13-7.37 (m, 11 H), 7.41-7.46 (m, 4 H). 13C NMR
(75 MHz, CD2Cl2) δ = 37.5, 50.0, 70.8, 73.2, 78.6, 115.8 (q, J =
288 Hz), 126.0, 126.5, 127.3, 127.5, 127.8, 128.4, 128.7, 129.1, 129.6,
135.3, 144.2, 145.9, 157.0 (q, J = 38 Hz), 167.1. IR: (KBr) 3482,
3393, 3062, 3030, 2360, 2343, 1721, 1668, 1543, 1496, 1449, 1210,
1173, 749, 700 cm-1. HRMS C26H23F3N2O3 m/z (MþNa)þ calcd
491.1558, obsvd 491.1557.
the reaction vial. An additional 200 μL of toluene was used for
rinsing. After stirring for 48 h at -40 °C, the reaction mixture
was cooled to -78 °C, diluted with 2 mL of CH2Cl2, and 31 μL
of acetyl chloride (0.44 mmol, 2 equiv) was added. After
stirring for 30 min, the contents were directly transferred to a
silica column for purification using 5-15% EtOAc/hexanes as
eluent to give 26.1 mg of 9. Yield: 67%; yellow oil. The 1H NMR
of the pyranone products were compared to those reported
previously.22,41,42
Standard in situ FTIR Procedure. The ASI React IR 1000 or
the Mettler Toledo React IR ic10 was used to analyze reaction
progress in situ. For each reaction, the probe was cleaned and a
background spectrum was taken. Disappearance of diene 1 was
observed by recording the absorbance at maximum peak height
(1648.2 cm-1 for ASI React IR 1000 or 1649.6 cm-1 Metler
Toledo React IR ic10). The absorbance measurements were
converted to concentration units dividing by the constant (ε =
1.0885 or ε = 0.769) relating absorbance to concentration
determined by constructing calibration curves of the starting
materials (Beer’s Law). The apparatus used was a 50 mL
Schlenk flask with a sidearm and a 24/40 ground glass joint
for probe insertion. An ice water bath was used for reactions
performed at 0 °C. A dry ice/MeCN bath was used for reactions
performed at -45 °C. Standard solutions of catalyst, aldehyde,
and diene were used. Each kinetic experiment was conducted
similar to this example procedure: the probe was equipped with
a 50 mL Schlenk flask fitted with a stirbar, and the flask was
flushed with nitrogen. To the apparatus are added 241 μL of
0.076 M solution of 3 (0.018 mmol), 400 μL of 2.50 M solution of
benzaldehyde 8 (1.00 mmol), and 192 μL of toluene. The
reaction flask was placed in an ice bath and allowed to stir for
approximately 20 min. The IR instrument was programmed to
collect spectra every 15 or 30 s. Following commencement of data
collection, 167 μL of 1.10 M solution of diene 1 (0.183 mmol) was
added and data collection was continued for 1-6 h. Initial rates
where determined after 5% conversion of diene.
Synthesis of catalyst 4-7 follows an analogous procedure to
that described above for 3. See Supporting Information for full
characterization data.
Standard Procedure for the Hetero Diels-Alder Reaction. All
pyranone products were prepared according to the following
representative procedure: to an oven-dried 4 mL vial with a
septum cap containing 20.6 mg of 3 (0.0440 mmol, 0.200 equiv)
under nitrogen, 500 μL of dry toluene was added followed by
45 μL of benzaldehyde (0.44 mmol, 2 equiv). The vial was
cooled to -40 °C and 50 mg of diene 1 (0.22 mmol, 1 equiv)
dissolved in 500 μL of toluene was transferred via cannula into
Acknowledgment. This work was supported by the National
Science Foundation (CHE-0749506). MSS thanks the Dreyfus
Foundation (Teacher-Scholar) and Pfizer for their support.
Supporting Information Available: Experimental proce-
dures, kinetic data, and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(41) Ji, B.; Yuan, Y.; Ding, K.; Meng, J. Chem.;Eur. J. 2003, 9, 5989.
(42) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998,
63, 403.
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