Stereoselectivities of histidine-catalyzed asymmetric aldol additions and contrasts with proline catalysis: A quantum mechanical analysis

Article abstract of DOI:10.1021/ja2118392

Quantum mechanical calculations reveal the origin of diastereo- and enantioselectivities of aldol reactions between aldehydes catalyzed by histidine, and differences between related reactions catalyzed by proline. A stereochemical model that explains both the sense and the high levels of the experimentally observed stereoselectivity is proposed. The computations suggest that both the imidazolium and the carboxylic acid functionalities of histidine are viable hydrogen-bond donors that can stabilize the cyclic aldolization transition state. The stereoselectivity is proposed to arise from minimization of gauche interactions around the forming C-C bond.

Full text of DOI:10.1021/ja2118392

Article
pubs.acs.org/JACS
Stereoselectivities of Histidine-Catalyzed Asymmetric Aldol
Additions and Contrasts with Proline Catalysis: A Quantum
Mechanical Analysis
Yu-hong Lam,† K. N. Houk,*,† Ulf Scheffler,‡ and Rainer Mahrwald*,‡
†Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
‡Institute of Chemistry, Humboldt University, Brook-Taylor Strasse 2, 12489 Berlin, Germany
S
* Supporting Information
ABSTRACT: Quantum mechanical calculations reveal the origin
of diastereo- and enantioselectivities of aldol reactions between
aldehydes catalyzed by histidine, and differences between related
reactions catalyzed by proline. A stereochemical model that explains
both the sense and the high levels of the experimentally observed
stereoselectivity is proposed. The computations suggest that both
the imidazolium and the carboxylic acid functionalities of histidine are
viable hydrogen-bond donors that can stabilize the cyclic aldolization
transition state. The stereoselectivity is proposed to arise from
minimization of gauche interactions around the forming C−C bond.
reactions of isobutyraldehyde and other α,α-dialkyl aldehydes
as donors, although only nonenolizable, aromatic aldehydes
were used as acceptors. We found,31 however, that in the
presence of histidine as catalyst, α-branched aldehydes react
as donor components with a variety of enolizable aldehydes
such as 1a−g, including electron-deficient aldehydes, forging
quaternary stereogenic centers with defined configurations in
the aldol products with remarkable ease (Scheme 1). The
enantioselectivities in the isolated β-hydroxyaldehydes 2a−g
were good to excellent. Moreover, with the α-chiral aldehydes
1f and 1g as the electrophilic components, the aldol products 2f
and 2g were obtained with exclusive syn diastereoselectivity
(Scheme 1). These transformations also pose interesting
mechanistic problems due to the presence of both an imidazole
and a carboxylic acid in the amino acid. Although catalytic
motifs containing imidazole or imidazolium ions have been
extensively studied in relation to natural and artificial
enzymes,33 much less has been explored about their potential
involvement in small-molecule catalysis.34 We now present
further experimental and computational results that uncover the
origin of the asymmetric induction in these histidine-catalyzed
aldehyde−aldehyde cross-aldol reactions.
INTRODUCTION
■
Aldol reactions1 constitute an important class of carbon−
carbon bond formation reactions amenable to enantioselective
organocatalysis.2−10 Intramolecular aldol reactions were found
to be catalyzed by proline in the 1970s.11,12 Proline was also
used in the first examples of intermolecular organocatalyzed
aldol reactions, starting from acetone and a variety of
aldehydes.13,14 Since then, the use of nonenolizable aldehydes
and ketones as the acceptor and the donor components in
enamine catalysis, respectively, has been amply demonstrated.
On the other hand, it was recognized early on that the use of
enolizable aldehydes as acceptor components was challenging
due to competing side reactions, especially aldehyde self-
condensation.14 The search for general, efficient methods for
the metal- or organocatalyzed aldol reactions between two
different, readily enolizable aldehydes remains an intensively
investigated topic.15−17 Proline18−28 and its derivatives, as well
as chiral imidazolidinones,29 also catalyze the aldol reactions
between two enolizable aldehydes with high enantioselectiv-
ities, although the lack of differentiation of reaction roles in the
case of two dissimilar aldehydes necessitates either the use of
careful and cumbersome syringe pump techniques19 or a large
excess of one of the aldehyde reactants.30
Our studies on direct amine-catalyzed aldol additions showed
that tertiary amines are effective catalysts,35 giving yields and
reaction rates comparable to a variety of secondary and primary
amines in some cases,36 for which the participation of enamine
intermediates in the catalytic cycle is conceivable. In light of
these results, we felt it important to establish whether enamine
formation from histidine is involved in the aldol additions
We recently reported31 that the readily available histidine is a
superior catalyst to facilitate the one-pot, cross-aldol reaction of
two dissimilar enolizable aldehydes, without the need for any
specialized experimental setup. As reviewed recently by List,8
α-branched aldehydes such as isobutyraldehyde are typically
used as electrophiles in asymmetric enamine catalysis including
organocatalyzed aldol reactions. A diamine containing two
pyrrolidine moieties, in conjunction with an acid cocatalyst, was
identified by Barbas32 to promote highly enantioselective aldol
Received: December 19, 2011
Published: March 29, 2012
© 2012 American Chemical Society
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that both the imidazole ring and the carboxylic acid are
important in catalyzing product formation. Importantly, no
reaction was observed in the presence of Boc-L-histidine (3d,
entry 5), suggesting that the aldol addition is likely to proceed
with enamine formation at the primary amine of histidine.
The mechanism and origin of the stereochemical induction
in proline-catalyzed aldol reactions are well established.37,38
Proline serves as a bifunctional catalyst as the amine functionality
forms an enamine with the donor carbonyl component while the
carboxylic acid maintains a hydrogen bond with the oxygen atom
of the acceptor carbonyl.39 Thus, the stereochemistry-determin-
ing, carbon−carbon bond formation step involves a partial
Zimmerman−Traxler-like transition state,40 featuring a chairlike
arrangement of the enamine and the carbonyl atoms (Figure
1A). The nucleophilic addition of the enamine proceeds with
Scheme 1. Asymmetric (S)-Histidine-Catalyzed Aldol Addition
Reactions of Isobutyraldehyde as Donor Component to
Enolizable Aldehydes as Acceptor Components
a
Aldehydes 2d and 2e were isolated as their corresponding 1,3-
dioxolanes.
studied here. Thus, using the aldol addition of 1c and
isobutyraldehyde (Table 1), we additionally tested various
derivatives of histidine 3a−d for their catalytic performance.
While histidine gave rise to the aldol product in 70% yield with
77% ee (entry 1), the methyl ester (3a) gave a substantially
lower yield and enantioselectivity (entry 2). Replacing histidine
by either of the two analogues N-methylated on the imidazole
ring (3b and 3c, entries 3 and 4) also resulted in lower yields
with further eroded enantioselectivities. These results suggest
Figure 1. Stereochemical models for the aldol reaction of cyclo-
hexanone and benzaldehyde catalyzed by (A) (S)-proline, (B) (S)-
alanine, and (C) (S)-tryptophan. (D) Stereochemical model for the
Hajos−Parrish reaction.
proton transfer from the carboxylic acid functional group to the
developing alkoxide. This so-called List−Houk stereochemical
model, featuring a (+)-synclinal arrangement of the carbonyl
Table 1. Aldol Additions of 1c and Isobutyraldehyde in the Presence of Histidine Derivatives
a
b
c
1
Isolated yield. Determined by H NMR after derivatization of 2c to the Mosher’s ester. No reaction.
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Figure 2. Relative free energies (kcal/mol) of the carboxylic acid-hydrogen-bonded transition structures 4a−4d for the addition of histidine-enamine
of isobutyraldehyde and formaldehyde. The Newman projections along the forming C−C bond (inset) show that the disposition of the carbonyl and
enamine groups in 4a and 4d is analogous to that of the carbonyl and the enolate in the Zimmerman−Traxler transition state.
group and enamine double bond (when the configuration of the
proline is S), has seen widespread use in understanding the origin
of asymmetric induction observed with different proline-derived
organocatalysts. The intermediacy of the proline-enamine in
aldol additions has also been demonstrated crystallographically41
and spectroscopically.42−44
While proline and its derivatives have dominated research on
asymmetric organocatalysis, relatively little is known about other
proteinogenic amino acids with regard to their efficiency and
mechanism of asymmetric induction in the catalysis of aldol
reactions. Alanine45 (Figure 1B) and tryptophan46 (Figure 1C)
have been studied by Himo and Cordova, and Lu, respectively,
with regard to their catalysis of the aldol reaction of cyclohexanone
and benzaldehyde, whereas our group previously computed the
stereoselectivities of intramolecular aldol cyclizations catalyzed by
proline, glycine, and phenylalanine (Figure 1D).47
Histidine differs from proline in three respects. First, the
enamine formed from the acyclic histidine can rotate about the
Cα−N bond, in contrast to proline-enamines, which contain a
pyrrolidine ring. In this regard, the cyclic transition structures
computed for the aldol additions catalyzed by the primary
amino acids alanine45 and tryptophan46 were found to feature
arrays of reacting atoms analogous to those in the proline-
catalyzed aldolizations.39 Second, the enamine formed from a
primary amino acid possesses an N−H bond, which could be
donated to the developing alkoxide in lieu of the carboxylic
acid. Although our early computations on the addition reaction
of N-methylvinylamine and acetaldehyde reveal the stabilizing
role of hydrogen-bond donation from the N−H bond to the
developing alkoxide,48 previous results on the Hajos−Parrish
transition states47 established that this proton transfer is
energetically unfavorable as compared to that from the carboxylic
acid. Most importantly, in water, histidine is protonated at the
imidazolium group, and can, therefore, potentially act as the
hydrogen-bond donor during the aldol additions. The role of a
functionalized side chain in primary amino acid organocatalysts
in influencing stereoselectivities has seldom been investigated,
although in the case of tryptophan, an N−H···π interaction
between the primary enamine and the indole ring on the side
chain was suggested46 to stabilize the aldolization transition states.
For histidine, using quantum mechanical calculations, we
have evaluated the relative importance of the imidazolium
ring and the carboxylic acid in stabilizing the aldol addition
transition state through hydrogen bonding. This allows us to
propose a model to rationalize the stereoselectivity of the series
of histidine-catalyzed aldehyde−aldehyde cross-aldol reactions.
COMPUTATIONAL METHODS
■
The stationary points (reactant and transition structure geometries)
were optimized and characterized by frequency computations at the
M06-2X/6-31+G(d,p) level of theory, in the presence of the SMD
continuum solvation model49,50 with water as the solvent. Truhlar’s
M06-2X functional51,52 was developed for computations involving
main-group thermochemistry, kinetics, and noncovalent interactions,
and has been found53 to give good energetics for the types of reactions
studied here. All of the computations were performed using
Gaussian 09.54
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Figure 3. Relative free energies (kcal/mol) of the imidazolium-hydrogen-bonded transition structures 4e−4h for the addition of histidine-enamine of
isobutyraldehyde and formaldehyde. The Newman projections along the Cα−Cβ of the histidine moiety (blue) and along the forming C−C bond
(red) are shown in the inset.
original Zimmerman−Traxler conformation,40 although here
RESULTS AND DISCUSSION
■
the enamine N−H does not coordinate with the developing
In view of the importance of hydrogen bonding in the List−
Houk model and the conformational flexibility of histidine, we
first studied the C−C bond forming transition structures using
formaldehyde and the histidine-enamine of isobutyraldehyde, as
model reactants. The transition structures with either the
carboxylic acid or the imidazolium group as the hydrogen-bond
donor were computed. Only transition structures in which the
alkoxide, in contrast to the metal in a Zimmerman−Traxler
transition state. Both the imidazolium N−H bond and the
carboxylic acid O−H bond are better hydrogen-bond donors
than the enamine N−H bond due to their higher acidities.
Structure 4d, the second most stable, is 1.7 kcal/mol higher in
energy than 4a and contains a (−)-synclinal disposition of the
reacting double bonds. The geometry of 4a also corresponds to
enamine adopts an s-trans conformation about the Cα−N bond
that of the transition structure in proline-catalyzed aldol
were considered, as it has been shown that the s-cis analogues
reactions. Its (−)-synclinal rotamer analogue, 4b, is 6.6 kcal/mol
higher in energy. After optimization, the hydrogen bond from
the carboxylic acid changes the ideal staggered substituents to
more eclipsed arrangements. The (+)-synclinal rotamer, 4c, is
the least stable in this series. 4b and 4c are non-Zimmerman−
Traxler structures, in which the enamine N−H and the
carbonyl CO bond, pointing approximately anti as shown by
the inset in Figure 2, are positioned too far to interact with each
other.
In the series of transition structures featuring the
imidazolium group as the hydrogen-bond donor (4e−4h,
Figure 3), the most stable rotamer was found to be 4e, in which
the acceptor carbonyl group is positioned (−)-synclinal to the
enamine double bond, again corresponding to a Zimmerman−
Traxler-like arrangement. Importantly, 4e is isoenergetic to
(+)-synclinal 4a, in which the carboxylic acid functions as the
hydrogen-bond donor. The (+)-synclinal analogue in the
are at least 3 kcal/mol higher in energy in the transition states
of aldol and other electrophilic additions catalyzed by proline39
and alanine.45 For the developing alkoxide to be associated
with a hydrogen-bonding group of histidine during the aldol
addition, the acceptor carbonyl group must be placed at
dihedral angles within 60° relative to the enamine CC
bond, and only these transition structures were considered.
With each hydrogen-bond donor, two arrangements differing
in the conformation of the Zimmerman−Traxler ring and,
therefore, the face of the enamine exposed for electrophilic
attack were investigated. The computed transition structures
with the carboxylic acid (4a−4d) and the imidazolium group
(4e−4h) as the hydrogen-bond donor are illustrated in
Figures 2 and 3, respectively.
Among the carboxylic-acid-bonded transition structures,
structure 4a, in which the carbonyl group is (+)-synclinal to
the CC double bond, has the lowest energy. This is the
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imidazolium-hydrogen-bonding 4f, is 4.3 kcal/mol higher in
free energy. The alternative (−)- and (+)-synclinal rotamers, 4g
and 4h, are 2.0 and 6.1 kcal/mol less stable, respectively.
Structures 4e−4h possess a 10-membered ring including the
hydrogen bond and the partially formed C−C bond. In contrast
to the nine-membered ring involving the carboxylic acid
functionality in 4a−4d, the larger ring size in 4e−4h can
accommodate a hydrogen bond from the imidazolium N−H to
the developing alkoxide without much distortion of the largely
staggered arrangement of substituents on the partial C−C
bond, as shown in the red inset. A staggered arrangement is
also maintained about the Cα−Cβ bond in the side chain of
histidine (blue inset). Nevertheless, the relative free energies
show that only 4e is significant among the imidazolium-
hydrogen-bonded transition structures.
It is noteworthy that the lower-energy transition structures
are consistent with Seebach’s topological rule55 in describing
the gross structures of transition states for a variety of carbon−
carbon bond formation reactions (Figure 4). One feature of this
Figure 5. Transition structures for the aldolization reaction of the
histidine-enamine of isobutyraldehyde and chloroacetaldehyde, in
which a hydrogen bond is donated by the imidazolium ring (5a, 5b) or
the carboxylic acid (5c, 5d). 5a and 5d lead to the major, (R)-
enantiomer, while 5b and 5c give rise to the (S)-isomer.
Figure 4. (A) Seebach’s topological rule for C−C bond forming
reactions. A = electron acceptor. D = electron donor. (B) Seebach’s
rule applied to TSs 4a−4h.
rule is that all of the bonds around the newly formed bond are
staggered. Indeed, as discussed above, the carboxylic acid-
bonded TSs 4a and 4d are more stable than the eclipsed
structures 4b and 4c (Figure 2). This staggered arrangement is
found in all of the imidazolium-bonded TSs 4e−4h (Figure 3).
However, 4e and 4g are lower in energy due to a synclinal
disposition of the donor CN and the acceptor CO bonds
rather than an anticlinal arrangement in 4f and 4h, consistent
with Seebach’s rule.55 Furthermore, the geometries of 4e and
4g position the donor nitrogen and the acceptor oxygen close
together, minimizing the charge separation. The role of
electrostatic stabilization in addition transition structures has
also been shown by our recent computations on the asymmetric
Stetter reaction between an NHC−enol intermediate and a
nitroalkene.56
The systematic survey of transition structure conformers
above established that both the imidazolium ring and the
carboxylic acid are plausible alternatives in stabilizing the aldol
transition states through hydrogen-bond donation. On the basis
of this, we computed the relative free energies of the transition
structures for the experimental aldolization reactions to explain
the enantioselectivities observed. The aldol addition of
isobutyraldehyde to chloroacetaldehyde (1a) was found to
give product (R)-2a in 90% ee (Scheme 1). The four transition
structures 5a−5d, featuring a hydrogen bond from either the
imidazolium group or the carboxylic acid and leading to either
enantiomer for this reaction, are shown in Figure 5. Transition
structure 5a, which involves the addition of the enamine to the
Re face of chloroacetaldehyde associated by a hydrogen bond to
the imidazolium ring, is the lowest in energy. The lowest-
energy transition structure in which the electrophilic aldehyde
reacts from the Si face is the carboxylic-acid-bonded 5c,
which contains a pseudoequatorial chloromethyl group and is
0.8 kcal/mol less stable than 5a. This energy difference
corresponds to an enantiomeric excess of 75% in favor of the
(R)-enantiomer. Transition structures 5b and 5d also lead to
the (S)- and the (R)-enantiomers, respectively, but they are at
least 2.5 kcal/mol higher in energy and are negligible.
The aldol addition transition structures for several other
aldehydes reacting as the electrophilic component with the
histidine-enamine of isobutyraldehyde were also computed
(Table 2). As shown in Figure 6 for the self-aldolization
reaction involving isobutyraldehyde to give (S)-2e, the
geometries of the transition structures resemble those found
for chloroacetaldehyde. The preferred transition structures are
invariably the imidazolium-hydrogen-bonded transition struc-
tures involving attack of the Re face of the electrophilic
aldehyde (4a, 6a), while the carboxylic acid-hydrogen-bonded
structures involving attack of the Si face of the electrophile (4c,
6c), which lead to the minor enantiomer, are also significant. In
all of the examples studied, the sense of enantioselectivities was
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The energy differences of the transition structures for a
given reaction can be understood by a closer analysis of their
geometries. The imidazolium-bonded transition structures of
type a, in which the substituent of the acceptor aldehyde is
pseudoaxial, are at least 1.7 kcal/mol more stable than those of
type b with the substituent pseudoequatorial. Similarly, type c
transition structures with pseudoaxial aldehydic substituents are
more stable than those of type d. The pseudoaxial preference of
the aldehyde substituent is contrary to the Houk−List model
of proline-catalyzed aldol reactions,38 in which the aldehydic
group prefers to be pseudoequatorial.
Table 2. Relative Free Energies (in kcal/mol) of Transition
Structures with Imidazolium or Carboxylic Acid Group as
Hydrogen-Bond Donor
Most proline-catalyzed aldol reactions employ α-unbranched
ketones as the donor components,48 forming predominantly
the (E)-enamines43 as the key intermediates. Thus, the
Zimmerman−Traxler-like ring will be monosubstituted at C2
and C3, as illustrated in Figure 1A. Whether the substituent on
the electrophilic aldehyde is pseudoaxial or pseudoequatorial, it
will suffer one gauche interaction with the enamine substituent
at C2. The pseudoequatorial preference of the aldehydic group
can then be understood as a result of minimization of its 1,3-
diaxial interactions with the C3-substituent. In the current
ΔΔG⧧ ΔΔG⧧ ΔΔG⧧ ΔΔG⧧
ee
ee
entry
R
(a)
(b)
(c)
(d) computed found
1
2
3
4
5
CH2Cl (1a)
0
0
0
0
0
2.5
0.8
0.6
1.3
0.6
0.7
2.8 75% (R) 90% (R)
CH(OMe)2 (1b)
3.9
3.4 47% (R) 84% (R)
a
a
a
CO2Et (1c)
−
−
80% (R) 77% (R)
1.0 47% (R) 71% (R)
1.3 54% (S) 56% (S)
b
CH2SBn (1d)
1.7
CH2i-Pr (1e)
2.0
a
Methyl glyoxylate (R = CO2Me) was used as a model reactant.
b
Transition structures of types b and c could not be located. 2-
(Methylthio)acetaldehyde (R = CH2SMe) was used as a model
reactant.
Figure 6. Transition structures for the aldolization reaction of the
histidine-enamine of isobutyraldehyde and isovaleraldehyde, in which a
hydrogen bond is donated by the imidazolium ring (6a, 6b) or the
carboxylic acid (6c, 6d). 6a and 6d lead to the major (S)-enantiomer,
while 6b and 6c give rise to the (R)-isomer.
Figure 7. Newman projections along the forming C−C bond, and
transition structures 5a−5d showing the Zimmerman−Traxler-like
cyclic arrangement of the reacting enamine, carbonyl, and hydrogen-
bonding group. Close hydrogen−hydrogen distances are annotated.
successfully reproduced, although the levels were under-
estimated in some cases.
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Figure 8. Reported examples of influence of gauche interactions on reaction diastereoselectivities. The unfavorable gauche interactions are indicated
by the red double-headed curved arrows.
series of aldehyde−aldehyde aldol transition states, on the other
hand, the Zimmerman-Traxler-like rings are disubstituted at C2
and unsubstituted at C3. It is conceivable that the pseudoaxial
preference might arise from the minimization of the number
of gauche interactions between the aldehydic group (the
C1-substituent) and the terminal enamine substituents (the
C2-substituents). The transition structures for the pair of
imidazolium-bonded transition structures 5a and 5b are
illustrated in Figure 7, emphasizing the chairlike arrangement of
the reacting enamine, carbonyl, and the hydrogen-bonding
group, annotated with short H−H distances. These perspec-
tives show that in the disfavored TS 5b, the chloromethyl group
occupies a pseudoequatorial position, coming into two pairs of
gauche interactions with the terminal methyl groups of the
enamine. The pseudoaxial site is sterically less demanding,
as the chloromethyl group suffers from only one gauche
interaction and negligible 1,3-diaxial interaction from the C3-
hydrogen.
This pseudoaxial preference of the substituent of the
electrophilic aldehyde can be compared to the transition
structures for the allylation reactions of aldehydes by 3,3-
disubstituted allylzinc reagents, which give homoallylic alcohols
featuring a quaternary stereocenter with high levels of di-
astereoselectivity (Figure 8A).57 The computed zinc-containing
Zimmerman−Traxler TSs show that with gem-dimethyl groups
on the terminus of the nucleophilic CC bond, the bulky
isopropyl or an aryl group on the electrophilic aldehyde prefers
a pseudoaxial position to avoid unfavorable gauche interactions
with the terminal methyl groups. Only when the allylzinc
reagent carries an additional substituent at C2 will the
pseudoaxial site be disfavored due to increased 1,3-diaxial
strain. Previous work from our group also found58 that high exo
selectivity was observed in Diels−Alder reactions when the
termini of the acyclic diene and dienophile involved in the
shorter of the forming C−C bonds were both monoalkyl-
substituted (Figure 8B). In the exoselective reactions, the endo
TSs, but not the exo TSs, were shown to be destabilized
by significant gauche interactions around the partial bond
between the methyl groups on the reacting partners. A series
of highly diastereoselective, intramolecular cycloadditions
involving nitrones and nitrile oxides forming 6,5-fused
rings (Figure 8C) was also rationalized by a pseudoaxial
preference of the alkyl substituent on an incipient six-
membered ring.59−61 This arrangement was presumed to
reduce the gauche repulsive interaction with the neighbor-
ing N-substituent.
This model also explains the diastereocontrol observed with
chiral aldehydes used as acceptors. The aldol addition of
isobutyraldehyde to the chiral aldehyde (R)-1f as the acceptor
carbonyl occurs in 87% yield with exclusive stereoselectivity
for the (R,R)-diastereomer of 2f (Scheme 1). The transition
structures of types a (imidazolium-hydrogen-bonded) and c
(carboxylic acid-hydrogen-bonded) were computed (Figure 9),
using 7 as the model reactant. The α-methoxy group of 7
makes it necessary to take two rotameric states of this moiety
into account when locating the TSs. In the Felkin−Anh
rotamer, the optimized geometry is consistent with the
electronegative group being antiperiplanar to the incoming
nucleophile, while the chelated rotamer features a chelated
hydrogen bond formed by the developing alkoxide and the
α-oxygenated substituent on the acceptor aldehyde.62 The
computations show that only the chelated rotamer of the
imidazolium-bonded TS 8a is significant, while the Felkin−Anh
rotamer of TS 8a is 4.5 kcal/mol higher in free energy. Both
rotamers of 8b with the carboxylic acid as the hydrogen-bond
donor are 3 kcal/mol higher than 8a. These calculations are
consistent with the sense and the high level of selectivity for
the formation of the (R,R) diastereomer of 2f found
experimentally. Similarly, the stereoselectivity of the aldol
addition of isobutyraldehyde to isopropylideneglyceraldehyde
(R)-1g was also reproduced by the computed TSs illustrated in
Figure 10.
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Figure 9. Transition structures for the aldolization reaction of the histidine-enamine of isobutyraldehyde and 7, in which a hydrogen bond is donated
by the imidazolium group (8a) or the carboxylic acid (8c). Two rotamers of the C−Cα bond are shown for 8a and 8c. 8a leads to the experimentally
observed (R,R)-diastereomer, while 8c gives rise to the (S,R)-isomer.
CONCLUSION
■
In summary, we have computationally studied the origin of
stereocontrol of histidine-catalyzed aldehyde−aldehyde cross-
aldol reactions. The imidazolium and the carboxylic acid groups
can both stabilize the aldol addition through hydrogen bonding
in a Zimmerman−Traxler-type transition state. The computa-
tions also identified an infrequent pseudoaxial preference of
the substituent of the electrophilic aldehyde in the presence of
a terminal dimethyl-substituted histidine enamine. This is
rationalized by a minimization of the gauche interaction around
the forming C−C bond. We envisage that this work will inspire
future efforts in the design of organocatalysts that employ
hydrogen bonding from the imidazolium group as the catalytic
principle, a possibility that has been relatively overlooked to date.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR data for all of the synthesized compounds, full
characterization of novel compounds, Cartesian coordinates
and energies of the transition structures, and the full citation for
ref 54. This material is available free of charge via the Internet
at http://pubs.acs.org.
Figure 10. Transition structures for the aldolization reaction of the
histidine-enamine of isobutyraldehyde and (R)-1g, in which a
hydrogen bond is donated by the imidazolium group (9a) or the
carboxylic acid (9c). 9a leads to the experimentally observed (R,R)-
diastereomer, while 9c gives rise to the (S,R)-isomer.
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(27) Zhao, G.-L.; Liao, W.-W.; Cor
47, 4929−4932.
(28) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Cor
́
dova, A. Tetrahedron Lett. 2006,
AUTHOR INFORMATION
■
Corresponding Author
houk@chem.ucla.edu; rainer.mahrwald@chemie.hu-berlin.de
́
dova, A.
Angew. Chem., Int. Ed. 2005, 44, 1343−1345.
(29) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2004, 43, 6722−6724.
Notes
The authors declare no competing financial interest.
(30) Hayashi, Y.; Aratake, S.; Itoh, T.; Okano, T.; Sumiya, T.; Shoji,
M. Chem. Commun. 2007, 957−959.
ACKNOWLEDGMENTS
(31) (a) Markert, M.; Scheffler, U.; Mahrwald, R. J. Am. Chem. Soc.
2009, 131, 16642−16643. (b) Scheffler, U.; Mahrwald, R. J. Org.
Chem. 2012, 77, 2310−2330.
■
We are grateful to the National Institute of General Medical
Sciences, National Institutes of Health (GM36700), for
financial support of this research. We also thank UCLA
Institute for Digital Research and Education, and the Shared
Research Computing Services Pilot Project for the UC systems.
This work also used the Extreme Science and Engineering
Discovery Environment (XSEDE), which is supported by
National Science Foundation grant number OCI-1053575.
(32) Mase, N.; Tanaka, F.; Barbas, C. F. III. Angew. Chem., Int. Ed.
2004, 43, 2420−2423.
(33) Noujeim, N.; Leclercq, L.; Schmitzer, R. Curr. Org. Chem. 2010,
14, 1500−1516.
(34) Yang, H.; Wong, M. W. J. Org. Chem. 2011, 76, 7399−7405.
(35) Markert, M.; Mulzer, M.; Schetter, B.; Mahrwald, R. J. Am.
Chem. Soc. 2007, 129, 7258−7259.
(36) Rohr, K.; Mahrwald, R. Org. Lett. 2011, 13, 1878−1880.
̈
(37) Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; Çelebi-Olcu̧ m, N.;
̈
REFERENCES
■
Houk, K. N. Chem. Rev. 2011, 111, 5042−5137.
(1) Mahrwald, R., Ed. Modern Aldol Reactions; Wiley-VCH:
New York, 2004; Vols. 1 and 2.
(38) Allemann, C.; Gordillo, R.; Clemente, F.; Cheong, P.; Houk,
K. N. Acc. Chem. Res. 2004, 37, 558−569.
(39) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem.
Soc. 2003, 125, 2475−2479.
(2) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen,
S.; Jørgensen, K. A. Chem. Commun. 2010, 632−649.
(3) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600−1632.
(40) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920−1923.
(4) Pihko, P. M.; Majander, I.; Erkkila, A. Top. Curr. Chem. 2009,
̈
291, 29−74.
(41) Bock, D. A.; Lehmann, C. W.; List, B. Proc. Natl. Acad. Sci.
U.S.A. 2010, 107, 20636−20641.
(5) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem.,
Int. Ed. 2008, 47, 6138−6171.
(42) Marquez, C.; Metzger, J. O. Chem. Commun. 2006, 1539−
1541.
(6) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638−
4660.
(43) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. Angew. Chem., Int.
́ ́
(7) Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry
Ed. 2010, 49, 4997−5003.
2007, 18, 2249−2293.
(44) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. J. Org. Chem. 2011,
76, 3005−3015.
(8) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471−5569.
́
(45) Bassan, A.; Zou, W.; Reyes, E.; Himo, F.; Cordova, A. Angew.
(9) List, B.; Yang, J. W. Science 2006, 313, 1584−1586.
Chem., Int. Ed. 2005, 44, 7028−7032.
(10) Notz, W.; Tanaka, F.; Barbas, C. F. III. Acc. Chem. Res. 2004,
(46) Jiang, Z.; Yang, H.; Han, X.; Luo, J.; Wong, M. W.; Lu, Y. Org.
Biomol. Chem. 2010, 8, 1368−1377.
37, 580−591.
(11) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615−
(47) Clemente, F. R.; Houk, K. N. J. Am. Chem. Soc. 2005, 127,
11294−11302.
1621.
(12) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 10, 496−497.
(13) List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc. 2000,
(48) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
11273−11283.
(49) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378−6396.
122, 2395−2396.
(14) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573−
(50) Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G.
J. Phys. Chem. B 2011, 115, 14556−14562.
575.
(15) Scheffler, U.; Mahrwald, R. Synlett 2011, 1660−1667.
(16) Marigo, M.; Melchiorre, P. ChemCatChem 2010, 2, 621−
(51) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157−167.
(52) Zhao, Y.; Truhlar, D. Theor. Chem. Acc. 2008, 120, 215−241.
(53) Wheeler, S. E.; Moran, A.; Pieniazek, S. N.; Houk, K. N. J. Phys.
Chem. A 2009, 113, 10376−10384.
623.
(17) Alcaide, B.; Almendros, P. Angew. Chem., Int. Ed. 2003, 42, 858−
860.
(54) Frisch, M. J.; et al. Gaussian 09, revision A.02; Gaussian, Inc.:
Wallingford, CT, 2009.
(18) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 6798−6799.
(19) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2004, 43, 2152−2154.
(20) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752−
1755.
́
(55) Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413−1423.
(56) Um, J. M.; DiRocco, D. A.; Noey, E. L.; Rovis, T.; Houk, K. N.
J. Am. Chem. Soc. 2011, 133, 11249−11254.
(57) Gilboa, N.; Wang, H.; Houk, K. N.; Marek, I. Chem.-Eur. J.
2011, 8000−8004.
(21) Storer, R. I.; MacMillan, D. W. C. Tetrahedron 2004, 60, 7705−
7714.
(58) Lam, Y.-h.; Cheong, P. H.-Y.; Blasco Mata, J. M.; Stanway, S. J.;
Gouverneur, V.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 1947−
1957.
(22) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 3696−3697.
(59) Noguchi, M.; Tsukimoto, A.; Kadowaki, A.; Hikata, J.; Kakehi,
(23) Cor
Chem. Commun. 2005, 2047−2049.
(24) Cordova, A.; Ibrahem, I.; Casas, J.; Sunden
́
dova, A.; Engqvist, M.; Ibrahem, I.; Casas, J.; Sunden
́
, H.
A. Tetrahedron Lett. 2007, 48, 3539−3542.
(60) Kadowaki, A.; Nagata, Y.; Uno, H.; Kamimura, A. Tetrahedron
Lett. 2007, 48, 1823−1825.
́
́
, H.; Engqvist, M.;
Reyes, E. Chem.-Eur. J. 2005, 11, 4772−4784.
(61) Tanaka, M.; Hikata, J.; Yamamoto, H.; Noguchi, M. Heterocycles
2001, 55, 223−226.
(25) Smith, A. B. III; Tomioka, T.; Risatti, C. A.; Sperry, J. B.;
Sfouggatakis, C. Org. Lett. 2008, 10, 4359−4362.
(62) Barbas and co-workers studied the syn-selective aldol reactions
of unprotected hydroxyacetone and dihydroxyacetone catalyzed by
́
(26) Chowdari, N. S.; Ramachary, D. B.; Cordova, A.; Barbas, C. F.
III. Tetrahedron Lett. 2002, 43, 9591−9595.
6294
dx.doi.org/10.1021/ja2118392 | J. Am. Chem. Soc. 2012, 134, 6286−6295

Journal of the American Chemical Society
Article
tryptophan, serine, and threonine, and their derivatives. The high
degree of syn selectivity was proposed to arise from hydrogen bonding
between the oxygen on the donor component and the enamine N−H.
(a) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F. III.
J. Am. Chem. Soc. 2007, 129, 288−289. (b) Ramasastry, S. S. V.;
Albertshofer, K.; Utsumi, N.; Tanaka, F.; Barbas, C. F. III. Angew.
Chem., Int. Ed. 2007, 46, 5572−5575. (c) Ramasastry, S. S. V.;
Albertshofer, K.; Utsumi, N.; Barbas, C. F. III. Org. Lett. 2008, 10,
1621−1624.
6295
dx.doi.org/10.1021/ja2118392 | J. Am. Chem. Soc. 2012, 134, 6286−6295