Mechanistic insights into the BINOL-derived phosphoric acid-catalyzed asymmetric allylboration of aldehydes

Article abstract of DOI:10.1021/ja210200d

BINOL-derived phosphoric acids catalyze the asymmetric allylboration of aldehydes. DFT and QM/MM hybrid calculations showed that the reaction proceeds via a transition state involving both a hydrogen-bonding interaction from the catalyst hydroxyl group to

Full text of DOI:10.1021/ja210200d

Article
pubs.acs.org/JACS
Mechanistic Insights into the BINOL-Derived Phosphoric
Acid-Catalyzed Asymmetric Allylboration of Aldehydes
Matthew N. Grayson,† Silvina C. Pellegrinet,‡ and Jonathan M. Goodman*,†
†Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge CB2 1EW, United Kingdom
‡Instituto de Química Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmaceu
́
ticas, Universidad Nacional de Rosario,
Suipacha 531, Rosario (2000), Argentina
S
* Supporting Information
ABSTRACT: BINOL-derived phosphoric acids catalyze the asymmet-
ric allylboration of aldehydes. DFT and QM/MM hybrid calculations
showed that the reaction proceeds via a transition state involving both a
hydrogen-bonding interaction from the catalyst hydroxyl group to the
pseudoaxial oxygen of the cyclic boronate and a stabilizing interaction
from the phosphoryl oxygen of the catalyst to the formyl hydrogen of
the aldehyde. These interactions lower the energy of the transition
structure and provide extra rigidity to the system. This mechanistic
pathway is consistent with the experimentally observed enantioselectivity except in one case. We have used our model’s
predictions to guide our own experimental work. The conflict is resolved in favor of our calculations.
catalyst induces such strong enantioselectivity. Antilla suggested a
six-membered ring chairlike transition state with activation of the
pseudoequatorial oxygen of the cyclic boronate via protonation by
the chiral phosphoric acid catalyst to explain the reactivity
(Antilla’s model, Scheme 1). Such a model, in which the catalyst
binds to the reactants through its Brønsted acidic site only, seems
too flexible to account for the high experimental enantiomeric
ratios. Furthermore, our previous investigations into similar
BINOL-derived phosphoric acid-catalyzed reactions have shown
that single-point binding from the catalyst to the substrate cannot
explain the observed enantioselectivity, whereas double coordina-
tion from both the PO and the P−O−H groups leads to good
enantioselectivity.10,11
Herein, we report the results of DFT and QM/MM hybrid
calculations, which suggest that the reaction involves both a
hydrogen-bonding interaction from the catalyst hydroxyl group
to the pseudoaxial oxygen of the cyclic boronate and a
stabilizing interaction from the phosphoryl oxygen of the
catalyst to the formyl hydrogen of the aldehyde. These
interactions lower the energy of the transition structure and
provide extra rigidity to the system.
1. INTRODUCTION
Allylboration has become an important reaction for the
stereoselective formation of carbon−carbon bonds.1,2 These
reactions proceed via cyclic, six-membered ring chairlike transi-
tion states (TSs) involving the activation of the carbonyl by
the boron atom.3,4 As a result, they are highly stereoselective.
Brown developed highly enantioselective allylboration reac-
tions using pinene-derived reagents,5,6 and more recently
catalytic methods have emerged such as work by Hall7 and
Shibasaki.8
In 2010, Antilla et al. reported the use of a chiral BINOL-
derived phosphoric acid as an efficient catalyst for the
allylboration of aldehydes, which gave the corresponding
homoallylic alcohols in excellent yields and enantioselectivities
(Scheme 1).9 However, it is not altogether clear how the chiral
Scheme 1. Asymmetric Allylboration of Aldehydes9
2. COMPUTATIONAL DETAILS
To gain mechanistic insight into the origins of the enantioselectivity
observed in the BINOL-derived phosphoric acid-catalyzed allylbora-
tion of aldehydes, we performed a thorough theoretical study using
three different approaches.
The preferred reaction pathway was first investigated using buta-1,3-
diene-1,4-diol-phosphoric acid as a model for the catalyst,11 before
Received: October 30, 2011
Published: January 2, 2012
© 2012 American Chemical Society
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taking a single-point energy using M06-2X/6-31G**, ΔG⧧ was
lowered to 14.0 kcal mol−1.
studying the full molecular system. Quantum mechanical calculations
were performed using the Jaguar program (version 7.6).12 The B3LYP
density functional,13,14 and split-valence polarized 6-31G** basis
set,15,16 were used for all geometry optimizations. Single-point energies
were taken using the M06-2X density functional17 and 6-31G** basis
set.15,16 This energy was used to correct the gas-phase energy obtained
from the B3LYP calculations.18 Activation free energies are quoted
relative to infinitely separated reagents.
To further validate the results obtained with the model system, we
also performed full B3LYP/6-31G* calculations using the phosphoric
acid derived from (R)-3,3′-bis(2,4,6-trimethylphenyl)-1,1′-bi-2-phenol
as a model,19 implemented in Gaussian 03 (revision C.02).20
For the QM/MM hybrid calculations on the full catalyst, transition
states were located using the ONIOM method implemented in
Gaussian 03 (revision E.01).20 B3LYP/6-31G** was used for the high-
layer, and the force field UFF21 was used for the low-layer. The
reactants and the phosphoric acid moiety of the catalyst were included
in the high-layer, and the remaining regions of the catalyst were treated
as the low-layer. The combination of DFT and UFF has previously
been shown to give excellent results when used to describe reactions
catalyzed by chiral phosphoric acids.10,22 The position of the partition
within the catalyst was chosen as the phosphoric acid binds directly to
the reagents, whereas the rest of the catalyst acts as steric bulk and can
be adequately described by molecular mechanics.10 M06-2X/6-31G**
single-point energy calculations were performed on the resulting
structures using the Jaguar program (version 7.6) and used to correct
the gas-phase energy derived from the ONIOM calculations.18
Free energies in solution were derived from structures optimized in the
gas phase at the B3LYP/6-31G** level of theory by means of a single-
point calculation using M06-2X/6-31G** with the polarizable continuum
model (PCM) as implemented in the Jaguar program (version 7.6) using
toluene (probe radius = 2.76 Å) as the solvent.23 These values were used
to correct the Gibbs free energy derived from the ONIOM calculations.
Investigation of the TS originally proposed by Antilla using
buta-1,3-diene-1,4-diol-phosphoric acid as our simplest model
catalyst reveals the value of ΔG⧧ to be 20.5 kcal mol−1 for TS-2
when evaluated using B3LYP/6-31G** (Figure 2). This is
significantly lower than the uncatalyzed activation barrier. It is
possible, however, that there are even lower energy pathways.
Other possible modes of activation involve protonation of
the carbonyl oxygen by the phosphoric acid (TS-3) and the
formation of a 10-membered ring TS (TS-4). After the first
reaction via TS-4, the catalyst would be regenerated as the
boron-based species, which would lead to TS-5. However, all of
these possibilities are disfavored relative to TS-2.
If the phosphoric acid hydrogen interacts with the pseudoaxial
oxygen of the boronate, the phosphoryl oxygen can act as a Lewis
basic site and establish a hydrogen bond to the formyl hydrogen.
This stabilizing interaction provides rigidity in the transition state
that could be responsible for the high levels of enantioselectivity
observed (TS-6). TS-6 is the lowest energy TS and also the
tightest of the six-membered TSs with the shortest oxygen−
hydrogen, carbon−carbon, and boron−oxygen distances (1.47,
2.11, and 1.50 Å, respectively). The formyl hydrogen bond has
previously been identified as playing a crucial role in many
asymmetric transformations.24,25 Terada et al. also suggested that
the formyl hydrogen bond was a key component in the BINOL-
derived phosphoric acid-catalyzed enantioselective aza-ene-type
reaction between glyoxylate and enecarbamate.26 The lowest
energy ground-state complex between aldehyde and catalyst was
located, which involved both protonation of the oxygen of the
aldehyde and an interaction from the phosphoryl oxygen of the
catalyst to the formyl proton of the aldehyde.
3. RESULTS AND DISCUSSION
Investigation of the uncatalyzed reaction identified four unique
TSs corresponding to the chair and boat conformations with
the phenyl group of the aldehyde either pseudoequatorial or
pseudoaxial. The values of ΔG⧧ suggest the most favorable TS
to be the chair conformation with the phenyl group equatorial
(TS-1eq, Figure 1). The corresponding axial TS is destabilized
Investigation of the potential energy surface using (R)-3,3′-
bis(2,4,6-trimethylphenyl)-1,1′-bi-2-phenol as our second
model catalyst suggested the lowest energy pathways to
correspond to the six-membered TSs in which the phosphoric
acid simultaneously interacts with the pseudoaxial oxygen of the
boronate and with the formyl proton of the aldehyde through the
Brønsted acid (proton) and Lewis basic (phosphoryl oxygen) sites,
respectively (TS-7Re and TS-7Si, Figure 3). In line with the buta-
1,3-diene-1,4-diol-phosphoric acid model results, the 10-mem-
bered TSs were calculated to be less stable than the six-membered
TSs (TS-8Re and TS-8Si). Also, the free energy barrier for the
catalyzed reaction through the most favorable Re six-membered
TS reaction was ca. 6 kcal mol−1 lower than the barrier cor-
responding to the background reaction. The computed
enantioselectivity arising from these calculations was found to be
high and in agreement with the experimental value. We also
located TSs similar to TS-7Re and TS-7Si, which lack the
interaction from the catalyst to the formyl proton (TS-9Re and
TS-9Si). These TSs involved single-point binding from the
catalyst to the substrate, like Antilla’s proposed mode of activation,
and were higher in energy than TS-7Re and TS-7Si.
Figure 1. Preferred uncatalyzed transition structure. Geometry
B3LYP/6-31G**, single-point energy M06-2X/6-31G**.
by steric interactions between the phenyl group of the aldehyde
and the cyclic boronate (5.4 kcal mol−1 higher than TS-1eq).
Similarly, higher energies were observed for both boat TSs.
Therefore, only TS-1eq needs to be considered when examining
the uncatalyzed pathway. The activation free energy of the
uncatalyzed reaction was calculated to be 26.6 kcal mol−1 when
evaluated using B3LYP/6-31G**. A similar study of the
uncatalyzed reaction by Sakata et al. calculated ΔG⧧ to be
30.1 kcal mol−1 using B3LYP/6-311G** relative to the infinitely
separated reagents.3 When the Gibbs energy was corrected by
Comparison of TS-7Si and TS-9Si provided an estimate of
the strength of the formyl hydrogen bond. Superposition of the
allylboronic acid pinacol ester and benzaldehyde from both TSs
leads to an rmsd of 0.0568 between the two structures. This
suggests that the primary reason for a difference in energy can
be attributed to the formyl hydrogen bond. The difference in
free energy was found to be 2.7 kcal mol−1, in close agreement
with the strength suggested by Weber et al., who estimated the
average strength of the formyl hydrogen bond falls in the range
of 2.4−3.6 kcal mol−1.27
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Figure 2. Competing transition structures for the reaction of benzaldehyde catalyzed by buta-1,3-diene-1,4-diol-phosphoric acid. Geometry B3LYP/
6-31G**, single-point energy M06-2X/6-31G**.
Figure 3. Competing transition structures for the reaction of benzaldehyde using the (R)-3,3′-bis(2,4,6-trimethylphenyl)-1,1′-bi-2-phenol model
system. Optimized transition structure geometries B3LYP/6-31G*.
Transition states for the full catalyst were located using
ONIOM for several of the possible reaction pathways, and
these confirmed that the same trends in activation energies
were present as for the model catalyst systems. These results
show that ONIOM calculations are effective for this system.
The 10-membered ring TSs (TS-10 and TS-11, Figure 4)
were strongly disfavored relative to the six-membered ring TSs,
a result expected on the basis of the outcome of the model
studies. For Antilla’s proposed mode of activation, 24 unique
transition structures were located due to the conformational
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Figure 4. Competing transition states for the reaction of benzaldehyde. ONIOM(B3LYP/6-31G**:UFF), single-point energy M06-2X/6-31G**.
Grayed-out regions were treated with UFF, and the full-color regions were treated with B3LYP/6-31G**.
flexibility associated with rotation about the single hydrogen-
bonding interaction to the substrate. Of these TSs, TS-12Re
and Si were the lowest energy structures. TS-12Si was found to
be disfavored relative to TS-12Re by 1.3 kcal mol−1.
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However, TS-13Re was found to be the most favorable and
also the tightest of the six-membered TSs with the shortest
oxygen−hydrogen, carbon−carbon, and boron−oxygen dis-
tances, consistent with the findings of the buta-1,3-diene-1,4-
diol-phosphoric acid model study (Figure 4 and Table 1).
agreement with the observed experimental outcome. Reasons
for such strong selectivity toward the (R)-homoallylic alcohol
originate from the unfavorable steric clash between the pinacol
ester methyl groups and the large aromatic group of the catalyst,
which disfavors TS-13Si relative to TS-13Re. Because of the
concerted and apolar nature of the transition structures, solvent
⧧
Table 1. Interatomic Distances for Key ONIOM TSs
effects were shown to have minimal effect on the values of ΔΔGsol
(Figure 4).
interatomic distance (Å)
Although the activation modes of TS-13 and Antilla’s proposed
TS (TS-12) are similar, the former is substantially more
energetically preferable. To rationalize this, TSs were located for
the latter activation mode in conformations that closely resembled
that of TS-13Re and TS-13Si, but lacked a phosphoryl oxygen−
formyl proton interaction (TS-14Re and TS-14Si, Figure 5).
These TSs were disfavored relative to TS-13Re and TS-13Si.
Approximately 2.7 kcal mol−1 of the energy difference can be
attributed to the absence of the formyl hydrogen bond. TS-14Re
is destabilized relative to TS-13Re because the pinacol group must
O−H
CH−O
(boronate protonation) C−C B−O
(formyl hydrogen)
TS-12Re
TS-12Si
TS-13Si
TS-13Re
1.59
1.62
1.59
1.45
2.21
2.22
2.13
2.09
1.51
1.52
1.50
1.49
2.19
2.15
TS-13Re is favored over TS-13Si by 6.7 kcal mol−1. Using the
calculated Boltzmann ratios of both TSs at 243 K, the expected
enantiomeric excess (ee) from this pathway is >99.9% in close
Figure 5. Optimized transition structure geometries for the reaction of benzaldehyde. ONIOM(B3LYP/6-31G**:UFF), single-point energy
M06-2X/6-31G**. Grayed-out regions were treated with UFF, and the full-color regions were treated with B3LYP/6-31G**.
Figure 6. Optimized transition structure geometries for the reaction of cyclohexanecarbaldehyde. ONIOM(B3LYP/6-31G**:UFF), single-point
energy M06-2X/6-31G**. Grayed-out regions were treated with UFF, and the full-color regions were treated with B3LYP/6-31G**.
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Figure 7. Competing transition structures for the reaction of thiophene-2-carbaldehyde. ONIOM(B3LYP/6-31G**:UFF), single-point energy
M06-2X/6-31G**. Grayed-out regions were treated with UFF, and the full-color regions were treated with B3LYP/6-31G**.
now be orientated toward the bulky pocket of the catalyst. TS-
14Si places the pinacol group in the empty pocket of the catalyst
but is destabilized relative to TS-13Si because the aldehyde
substituent must now be accommodated in the sterically
demanding pocket of the catalyst. Because of the flexible nature
of this monocoordination activation mode, lower energy TSs (TS-
12Re and TS-12Si) were located, which avoid these unfavorable
steric interactions. However, the strength of the hydrogen bond to
the cyclic boronate is compromised in these sterically more
accessible conformations. The angle of the hydrogen bond
deviates away from near linear (178°) in the case of TS-14Re to
164° in TS-12Re and lengthens from 1.56 to 1.59 Å. In the case of
TS-12Si, the linear hydrogen-bonding arrangement is present, but
the length of this interaction was found to be longer in TS-12Si
(1.62 Å) than in TS-14Si (1.53 Å). Therefore, the reason for the
large energetic preference for TS-13Re and TS-13Si is a
combination of both steric and electronic factors as well as the
presence of the formyl hydrogen bond.
The biphenol derived model system indicates that the energy
difference between TS-13Re and TS-13Si is overestimated by
the ONIOM method. This is due to the UFF component of the
optimization, which overestimates short-range repulsion
effects.28 Although the absolute values are larger as compared
to our DFT optimized structures, the method still accurately
predicts changes in levels of enantioselectivity. The lowest
experimentally observed enantioselectivity was 73% in the case
of cyclohexanecarbaldehyde. TS-15Re and TS-15Si (Figure 6)
were located, and the energy difference (3.8 kcal mol−1) was found
to be significantly lower than for the corresponding TSs involving
benzaldehyde (6.7 kcal mol−1). While the energy difference is still
overestimated, the reproduction of experimental enantioselectivity
trends illustrates the strength of the formyl proton hydrogen-
bonded transition state model. Therefore, the model can be used
to predict approximate enantioselectivities of novel aldehydes,
relative to benzaldehyde.
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Although the clash of the pinacol ester methyl groups with
the catalyst’s bulky aromatic substituent controls the absolute
stereochemistry, the aldehyde substituent can destabilize the Re
relative to the Si TS. This is due to minimization of the
unfavorable pinacol interaction with the catalyst increasing the
aldehyde clash. The pinacol group fits into the empty pocket of
the catalyst; however, this means that the aldehyde substituent
must be accommodated in the sterically demanding pocket
(Figure 4, R = cyclohexyl). The cyclohexane ring clashes with
the catalyst more strongly than in the case of the flat phenyl
group of benzaldehyde. This stabilizes Si relative to Re, but the
overriding effect is still the clash of the pinacol group and the
preference for Re-face attack is maintained.
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete list of authors in the Gaussian 03 reference;
Cartesian coordinates, energies, and number of imaginary
frequencies of all stationary points and values of imaginary
frequencies of all transition structures; and full experimental
details. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jmg11@cam.ac.uk
■
Experimental Test of the Model. Antilla’s results suggest
Re-face attack in every example except for attack on thiophene-
2-carbaldehyde. (2-(Benzyloxy)acetaldehyde was reported to
yield the (S)-enantiomer, corresponding to Si-face attack, by
analysis of the optical rotation. However, after reviewing the
Supporting Information, the data suggest that the R product is
formed.29) This leads to the R product in most cases. For
3-phenylpropanal, the low priority of the unbranched side chain
results in the S product from Re-face attack. In the case of
thiophene-2-carbaldehyde, our calculations suggest that Re-face
attack should also be expected. ONIOM calculations were
performed in the same manner as those reported for the
reaction of benzaldehyde. According to our calculations, TS-
16Re is favored over TS-16Si by 6.6 kcal mol−1, a value very
similar to that calculated for the reaction of benzaldehyde
(Figure 7). The orientation of the thiophene moiety was found
to be important with TS-17Re and TS-17Si disfavored by
approximately 1.4 kcal mol−1 relative to TS-16Re and TS-16Si,
respectively.
Therefore, to test our mechanistic hypothesis, the reaction of
allylboronic acid pinacol ester and thiophene-2-carbaldehyde
was repeated under the same conditions as described by Antilla
(see the Supporting Information). Chiral HPLC analysis
indicated that the ee generated by the reaction was 96%. The
product displayed the opposite sense of optical rotation to that
reported in the original paper. The absolute stereochemistry of
the product was determined by analysis of both diastereomeric
Mosher esters (see the Supporting Information). The results
indicated that the product formed was the (R)-homoallylic
alcohol, in full agreement with our calculations.
ACKNOWLEDGMENTS
M.N.G. and J.M.G. thank the EPSRC for funding and Unilever.
S.C.P. thanks CONICET, UNR, and ANPCyT.
■
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4. CONCLUDING REMARKS
DFT and QM/MM hybrid calculations suggest that the
phosphoric acid-catalyzed allylboration of aldehydes involves
a highly ordered transition structure in which there is a
hydrogen-bonding interaction from the catalyst hydroxyl group
to the pseudoaxial oxygen of the cyclic boronate. An additional
stabilizing interaction from the phosphoryl oxygen of the cata-
lyst to the formyl hydrogen of the aldehyde lowers the energy
of the transition state and provides extra rigidity to the system.
This transition structure is lower in energy than the one
proposed in the original paper.9 The role of the formyl hydro-
gen bond as a key element that controls the enantioselectivity
of a reaction catalyzed by a BINOL-derived phosphoric acid
proposed herein should promote future developments in the
field. Our calculations suggest a qualitative model (Figure 4)
that accurately reproduces the experimentally observed enantio-
selectivity in all cases. The model highlights and leads to the
correction of a misassignment of absolute configuration in the
original data.
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