Evaluation of Catalyst Acidity and Substrate Electronic Effects in A Hydrogen Bond-Catalyzed Enantioselective Reaction

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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-
A crucial function of hydrogen bonding in nature is
tigated.10-12 This lack of understanding is likely due to the
transition state stabilization during enzyme catalysis. Syn-
fact that significant structural differences often make the
thetic chemists have applied this mode of activation to
direct comparison of catalysts with different acidity unin-
asymmetric catalysis, where hydrogen bond donors are used
formative.
in small chiral molecules to impart facial selectivity during
A hydrogen bond catalyst design was developed in our
catalysis. Recent advancement in this field has been rapid,
laboratory and consists of an oxazoline core and two pen-
and a plethora of structurally distinct catalysts, covering a
dant arms with sites capable of hydrogen bond donation
range of approximately 20 pKa units, have been successfully
(Scheme 1).13 This catalyst employs amino acid derivatives
employed.1-3 Despite the surge of reports, mechanistic
as the chiral building blocks, allowing for the incorporation
understanding of how subtle changes to catalyst structure
of a variety of substituents into the catalyst structure. A key
affect selectivity is still relatively scarce.4-7 Moreover, the

(8) Hine, J.; Linden, S. M.; Kanagasabapathy, V. M. J. Am. Chem. Soc.


(1) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. 1985, 107, 1082.
(2) Akiyama, T. Chem. Rev. 2007, 107, 5744. (9) Hine, J.; Linden, S. M.; Kanagasabapathy, V. M. J. Org. Chem. 1985,
(3) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. 50, 5096.
(4) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012. (10) Jensen, K. H.; Sigman, M. S. Angew. Chem., Int. Ed. 2007, 46, 4748.
(5) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 15872. (11) Li, X.; Deng, H.; Zhang, B.; Li, J.; Zhang, L.; Luo, S.; Cheng, J.-P.
(6) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 15358. Chem.;Eur. J. 2010, 16, 450.
(7) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science (12) Du, J.; Li, Z.; Du, D.-M.; Xu, J. ARKIVOC 2008, 145.
2010, 327, 986. (13) Rajaram, S.; Sigman, M. S. Org. Lett. 2005, 7, 5473.

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
JOC Article
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- FIGURE 1. Hetero Diels-Alder reaction and modular hydrogen
bond catalysts.
workers (Figure 1).21,22 The modular nature of the catalyst
design allowed for the evaluation of a variety of catalyst
TABLE 1. Oxazoline-Amide Catalyzed Hetero Diels-Alder Reaction
structures, and catalyst 2 was found to provide the dihydro-
pyranone products in high enantiomeric excess.13
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 entry catalyst R % yield % ee er
hypothesis, as its modularity allows for systematic changes 1 3 CF3 67 91 95.3:4.7
to one portion of the catalyst, while keeping the remainder of 2 4 CCl3 61 81 90.6:9.4
the catalyst unchanged. A series of halogenated acetamide 3 5 CHCl2 53 75 87.5:12.5
derivative catalysts 3-7 (Figure 1) was chosen, as they 4 6 CH2F 17 62 81.1:18.9
5 7 CH2Cl 32 52 75.8:24.2
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-
TABLE 2. Scope of Hetero Diels-Alder Reaction Catalyzed by 3
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.

Results and Discussion entry R time (h) temp (°C) % yield % ee er


Catalysts 3-7 were synthesized from a common oxazoline 1 Ph 60 -65 72 93 96:4
amine intermediate, obtained via coupling of an amino 2 4-O2NC6H4 48 -65 70 81 90:10
alcohol with an N-protected amino acid, followed by oxazoline 3 1-naphthyl 48 -55 74 96 98:2
4 4-ClC6H4 48 -55 74 83 92:8
5 4-MeOC6H4 72 -40 59 88 94:6
6 PhCHdCH 48 -65 65 90 95:5
(14) Miller, J. J.; Sigman, M. S. Angew. Chem., Int. Ed. 2008, 47, 771. 7 PhCH2CH2 72 -40 14 47 73:27
(15) Sigman, M. S.; Miller, J. J. J. Org. Chem. 2009, 74, 7633. 8 CH3(CH2)4 48 -40 32 30 65:35
(16) Pellissier, H. Tetrahedron 2009, 65, 2839.
(17) Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321.
(18) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662. cyclization (see Experimental Section for details). The series
(19) Kozmin, S. A.; Janey, J. M.; Rawal, V. H. J. Org. Chem. 1999, 64,
3039. of catalysts was evaluated in the hetero-Diels-Alder reaction
(20) Kozmin, S. A.; He, S.; Rawal, V. H. Org. Synth. 2002, 78, 152. between Rawal’s diene 1 and benzaldehyde 8 (Table 1). Isolated
(21) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003,
424, 146.
yields of the dihydropyranone product 9 were taken as
(22) Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. the first indication that catalyst acidity may indeed affect
Chem. Soc. 2005, 127, 1336. catalytic activity, as more acidic catalysts generally gave
(23) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(24) Bordwell, F. G.; Fried, H. E.; Hughes, D. L.; Lynch, T. Y.; Satish, higher product yields (Table 1). Interestingly, a trend in
A. V.; Whang, Y. E. J. Org. Chem. 1990, 55, 3330. enantioselectivity was also observed, with the most acidic
J. Org. Chem. Vol. 75, No. 21, 2010 7195
JOC Article Jensen and Sigman

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
FIGURE 2. Reaction component dependencies with catalyst 3 complex C:A, which reacts with diene in the turnover limiting
measured by in situ IR spectroscopy. (A) First order dependence step to form the product.
on [catalyst 3], conditions: [benzaldehyde] = 0.37 M, [diene] = 0.18 Upon the basis of the proposed mechanism, rate law
M, rt. (B) Saturation in [aldehyde], conditions: [3] = 0.018 M, derivation was performed following the Michaelis-Menten
[diene] = 0.18 M, 0 °C. (C) First order dependence on [diene], kinetic model. Assuming the second step is the turnover
conditions: [3] = 0.018 M, [benzaldehyde] = 1.0 M, 0 °C.
determining step, the rate of product formation is propor-
catalyst leading to the highest enantiomeric excess. This result tional to the product of the concentration of the two inter-
was initially unexpected, as it was assumed that substituent size mediates involved in this step, where C:A is the activated
had the most significant effect on facial selectivity, and our catalyst-aldehyde complex (eq 1). As the catalyst exists in
assumption was that halogen substitution would have a minor two different states in this mechanism, we define [C]T as the
effect upon the steric nature of the catalyst. total catalyst concentration (eq 2). Using the steady state
Because 3 was discovered to catalyze the hetero-Diels- approximation (eq 3) allows us to solve for [C:A] (eq 4).
Alder reaction with high enantioselectivity, the scope of the Substitution into eq 1 results in the derived rate law (eq 5).
hetero-Diels-Alder reaction with this catalyst was exam-
ined (Table 2). In general, high enantioselectivity was obtained d½P
with aromatic aldehyde substrates (entries 1-5), highlighted ¼ k2 ½C : A½D ð1Þ
dt
by a 96% ee for 1-naphthaldehyde. An R,β-unsaturated alde-
hyde, cinnamaldehyde, also gives the product in high enantio-
½C ¼ ½CT  - ½C : A ð2Þ
meric excess (entry 6). Enantioselectivity is diminished for
hydrocinnamaldehyde and hexanaldehyde (entries 7 and 8),
d½C : A
but this marks an improvement as prior experimentation ¼ k1 ð½CT  - ½C : AÞ½A - k - 1 ½C : A
had shown catalyst 2 to be ineffective in the catalysis of the dt
hetero Diels-Alder reaction with aliphatic aldehydes. - k2 ½C : A½D ¼ 0 ð3Þ

7196 J. Org. Chem. Vol. 75, No. 21, 2010


Jensen and Sigman
JOC Article

FIGURE 3. Conversion of diene vs time for hydrogen bond cata- FIGURE 4. Linear free energy relationship between rate and pKa of
lyst 3-7, conditions: [benzaldehyde] = 0.78 M, [diene] = 0.18 M, the corresponding acetic acid derivative, conditions: [benzaldehyde] =
[catalyst] = 0.036 M, -45 °C. 0.78 M, [diene] = 0.18 M, [catalyst] = 0.036 M, -45 °C.

k1 ½CT ½A use the pKa values of acetic acid derivatives measured in
½C : A ¼ ð4Þ water as the reference, with the key assumption being that the
k1 ½A þ k - 1 þ k2 ½D
electron-withdrawing ability of the R substituent affects the
d½P k1 k2 ½CT ½A½D acidity of our catalyst and the acidity of the corresponding
¼ ð5Þ acetic acid derivative similarly.
dt k1 ½A þ k - 1 þ k2 ½D
Importantly, the derived rate law is consistent with the logðkÞ ¼ - RðpKa Þ þ C ð8Þ
empirical observations. Specifically, when [aldehyde] is low
the rate law can be simplified to eq 6 which is consistent with To evaluate the effect of catalyst acidity upon substrate
a first order dependence of rate on [aldehyde], and when binding, the saturation curves for the most and least acidic
[aldehyde] is high the rate law can be simplified to eq 7 catalysts, 3 and 7, respectively, were examined (Figure 5,
which is consistent with zero order dependence of rate on note y-axis scales are different). Comparing the curvature of
[aldehyde], and first order dependence on [catalyst] and these two plots, saturation is reached at much lower [alde-
[diene]. hyde] for the more acidic catalyst (Figure 5A) than for the
least acidic catalyst (Figure 5B), indicating that binding
d½P k1 k2 ½CT ½A½D equilibrium is also perturbed by catalyst acidity.
¼ ð6Þ
dt k - 1 þ k2 ½D With the understanding that catalyst acidity has a direct
effect on both substrate binding and rate of reaction with
d½P diene, we were interested in whether the observed trends in
¼ k2 ½CT ½D ð7Þ
dt 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
Catalyst Acidity Effects (er = kS/kR), a Brønsted-type plot was constructed by plotting
In light of the proposed mechanism, the question re- log(er) vs pKa (Figure 6). A linear free energy relationship was
mained whether catalyst acidity is affecting the binding equili- observed between enantioselectivity and acidity, a unique
bria of catalyst with substrate (k1/k-1), the rate of reaction of example of such a direct correlation in a hydrogen bond
the activated aldehyde C:A with diene (k2), or both. To catalyzed reaction. This indicates that enantioselectivity can
determine the influence upon the second step, the reaction be directly perturbed by the hydrogen bond donating ability.
rate was measured for the complete series of catalysts 3-7
under saturation conditions. A clear trend was observed,
Substrate Electronic Effects
with the most acidic catalyst leading to the highest rate
(Figure 3). In an attempt to further understand the subtleties of the
To determine whether this trend in reaction could be system, we chose to evaluate the influence of substrate electronic
directly correlated to the electronic nature of the catalyst, a perturbations. We hypothesized that the electronic nature of the
Brønsted-type plot was constructed (Figure 4). The Brønsted substrate could potentially affect both the rate at which the
equation (eq 8)25 relates the rate of an acid-catalyzed reac- aldehyde reacts with the diene, as well as the Lewis basicity and
tion to the pKa of the corresponding acid. The resulting thus the binding of substrate to catalyst. Therefore, a series of
linear free energy relationship is similar to the more common benzaldehyde derivatives with either electron-donating or
Hammett relationship, where pKa’s of benzoic acids are used electron-withdrawing substituents in the para position were
as the reference measurement for the effect of electronic examined. In situ IR was used to monitor the rate of the reaction.
perturbations on rate or equilibrium. In our case, we chose to We first examined the two most electronically disparate cases
within the series, p-anisaldehyde 10 and p-trifluoromethylben-
(25) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chem- zaldehyde 11. Initial reaction rates were measured over a range
istry; University Science Books: Sausalito, CA, 2006; p 466. of [aldehyde]. Similar rates were observed at low [aldehyde],
J. Org. Chem. Vol. 75, No. 21, 2010 7197
JOC Article Jensen and Sigman

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-
saturation is assumed) a linear free energy correlation is tives bearing (A) an electron-donating group and (B) an electron-
observed, with F+ = 1.61 ( 0.16 (Figure 8A).26 A positive withdrawing group. Conditions: [catalyst 3] = 0.016 M, [diene] =
F value indicates that there is a build up of negative charge, or 0.16 M, -45 °C.
diminution of positive charge, during the transition state.
Additionally, the better fit obtained with σ+ than with σ mechanism in which a hydrogen bond is formed between
indicates significant resonance contribution from electron aldehyde and catalyst, which would lead to a build up of
donating groups. This is consistent with the proposed 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-
(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 strated by the difference in saturation curves in Figure 7. A
reduced temperature. lower energy for the C:A intermediate would contribute to a
7198 J. Org. Chem. Vol. 75, No. 21, 2010
Jensen and Sigman
JOC Article
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 [aldehyde] = 0.025 M


entry R % ee er
average rate average
þ
R σ (M/s) log(rate) rate (M/s) log(rate) 1 CF3 91 95.4:4.6
2 Cl 86 93.0:7.0
CF3 0.53 6.78  10-4 -3.17 6.35  10-7 -6.20 3 F 84 91.8:8.2
Br 0.15 - - 1.87  10-5 -4.73 4 H 91 95.5:4.5
Cl 0.11 - - 1.54  10-5 -4.83 5 Me 83 91.5:8.5
H 0 4.64  10-5 -4.43 6.03  10-6 -5.22 6 OMe 90 95.2:4.8
F -0.07 2.93  10-5 -4.53 6.51  10-6 -5.19
Me -0.31 2.61  10-5 -4.58 2.90  10-6 -5.54
OMe -0.78 2.93  10-6 -5.53 8.21  10-7 -6.09 in mechanism as this aldehyde substrate is such a poor Brønsted
a
Conditions: [catalyst] = 0.016 M, [diene] = 0.16 M, -45 °C. base that k1 is turnover limiting.
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
FIGURE 8. Hammett plots relating aldehyde electronic nature and case of our system, however, the background reaction at
reaction rate. Conditions: [catalyst 3] = 0.016 M, [diene] = 0.16 M,
-45 °C. (A) [aldehyde] = 1.0 M, (B) [aldehyde] = 0.025 M.
-45 °C is not significant with no product formation observed
after 48 h at this temperature. Furthermore, this explanation is
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.
When [aldehyde] = 0.025 M, again a linear free energy A. 2004, 101, 5391.
(28) Benghait, I.; Becker, E. I. J. Org. Chem. 1958, 23, 885.
relationship is observed using σþ values with a F value of 1.47. (29) Lotfi, M.; Roberts, R. M. G. Tetrahedron 1979, 35, 2131.
However, a break in the Hammett plot is observed when (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,
evaluating the most electron poor aldehdye (Figure 8B). On 2101.
the left-hand side, F is positive as the substrates are electron rich (32) Inukai, T.; Kojima, T. J. Chem. Soc. D 1969, 1334.
enough to be in a situation where k2 is turnover limiting. In (33) Salakhov, M. S.; Musaeva, N. F.; Suleimanov, S. N. Org. React.
(Tartu) 1979, 16, 54.
contrast, with a very electron withdrawing substituent, it is (34) Domingo, L. R.; Saez, J. A. Org. Biomol. Chem 2009, 7, 3576.
likely that there is a change in turnover limiting step or change (35) Charton, M. J. Org. Chem. 1966, 31, 3745.

J. Org. Chem. Vol. 75, No. 21, 2010 7199


JOC Article Jensen and Sigman

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 analogous to the conjugate base of
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
FIGURE 9. Hammett plots show no linear free energy relationship of similar trends in other hydrogen bond-catalyzed reactions
for enantioselectivity, conditions: [benzaldehyde] = 0.36 M, [diene] = have emerged,11,12 implying this effect is not unique to our
0.18 M, [catalyst] = 0.036 M, -45 °C. 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.

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
FIGURE 10. Effect of substituents on acidity of hydrogen bond (R)-1-((S)-4-(hydroxydiphenylmethyl)-4,5-dihydrooxazol-2-yl)-2-
donor and acceptor in proposed the transition state. phenylethylcarbamate) 12 has been previously reported.13 A 100
mL round-bottom flask was charged with 44 mg of 10% Pd/C and
inconsistent with the lack of a correlation between substrate the flask was flushed with nitrogen. In a separate 100 mL flask,
electronic nature and enantioselectivity. 442.3 mg of oxazoline 12 (0.873 mmol) was dissolved in 6 mL of dry
A reasonable explanation is that a stronger hydrogen MeOH, and this solution was transferred via cannula into the flask
bond between the catalyst and the substrate at the transition containing Pd/C (on occasions when this is difficult, gentle warm-
ing or addition of excess MeOH is helpful and has no discernible
state is formed with the more acidic catalyst, leading to
effect on overall yield). A further 4 mL of MeOH (2  2 mL) was
increased rigidity in the transition state. It has been reported used for rinsing. The flask was then evacuated under water
that if the pKa of the hydrogen bond donor and that of the aspirator pressure and filled with H2 from a balloon. The cycle
protonated hydrogen bond acceptor are closely matched, a was repeated thrice more, and the reaction mixture was stirred
shorter and stronger hydrogen bond is formed.36-38 While under a H2 balloon atmosphere. On completion of reaction (7-8 h,
the pKa difference between catalyst and protonated substrate by disappearance of oxazoline 12 on TLC, Rf = 0.6 with 1:1
is substantial, they are more closely matched with a more EtOAc/hexanes), the reaction mixture was filtered through a pad

(36) Perrin, C. L. Science 1994, 266, 1665. (39) Based on calculated pKa values reported on Scifinder (Calculated
(37) Cleland, W. W.; Kreevoy, M. M. Science 1994, 264, 1887. using Advanced Chemistry Development Software V8.14).
(38) Schwartz, B.; Drueckhammer, D. G.; Usher, K. C.; Remington, S. J. (40) Davis, T. A.; Wilt, J. C.; Johnston, J. N. J. Am. Chem. Soc. 2010, 132,
Biochemistry 1995, 34, 15459. 2880.

7200 J. Org. Chem. Vol. 75, No. 21, 2010


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

J. Org. Chem. Vol. 75, No. 21, 2010 7201

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