Understanding the mechanism of the asymmetric propargylation of aldehydes promoted by 1,1′-Bi-2-naphthol-derived catalysts

Article abstract of DOI:10.1021/ja3122137

1,1'-Bi-2-naphthol (BINOL)-derived phosphoric acids catalyze the asymmetric propargylation of aldehydes. Density functional theory (DFT) calculations showed that the reaction proceeds via a six-membered transition structure (TS) in which the catalyst Bron

Full text of DOI:10.1021/ja3122137

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Article
Understanding the Mechanism of the Asymmetric Propargylation
of Aldehydes Promoted by BINOL-Derived Catalysts
Matthew Neil Grayson, and Jonathan M. Goodman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja3122137 • Publication Date (Web): 22 Mar 2013
Downloaded from http://pubs.acs.org on March 22, 2013
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Understanding the Mechanism of the Asymmetric
Propargylation of Aldehydes Promoted by BINOL-Derived
Catalysts
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Matthew N. Grayson and Jonathan M. Goodman*
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Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of
Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
ABSTRACT:
BINOL-derived phosphoric acids catalyze the asymmetric propargylation of aldehydes. DFT
calculations showed that the reaction proceeds via a six-membered TS in which the catalyst
Brønsted acidic site interacts with the pseudoaxial cyclic boronate oxygen and the phosphoryl
oxygen interacts with the formyl proton. This model accurately predicts the stereochemical
outcome observed experimentally. Replacement of the phosphoric acid hydroxyl group with
an N-triflyl moiety has been included in the model by calculation, and a broader
understanding achieved by qualitative assessment of similar reactions. We present a
qualitative guide to rationalizing the experimental outcome and use this to make a prediction
which was confirmed experimentally.
1. INTRODUCTION
Propargylation has become a key reaction for the construction of carbon-carbon bonds.1-3
Propargylation of carbonyls, and the resulting homopropargylic alcohols, have been applied
to the total synthesis of a wide range of natural products including zincophorin,4 (-)-
histrionicotoxin5 and bafilomycin.6 Whilst these versatile compounds are synthetically very
useful, their preparation remains challenging relative to the synthesis of enantiomerically
pure homoallylic alcohols. Selectivity issues can arise from propargylic reagent
rearrangement to the allenic analogues to afford a mixture of the β-acetylenic and α-allenic
carbinols.7,8 Early asymmetric propargylation reactions made use of chiral allenyl reagents,
notably those reported by Yamamoto,9 Corey,10 and Soderquist.11 Recently, catalytic methods
have emerged such as work by Denmark,12 Yamamoto,13 and Shibasaki.14
In 2012, Antilla et al. and Reddy independently reported the use of a chiral BINOL-derived
phosphoric acid as an efficient catalyst for aldehyde propargylation (Scheme 1).15,16 The
reaction gives the corresponding homopropargylic alcohols in excellent yields and
enantioselectivities for both aromatic and aliphatic aldehydes (Scheme 1), and employs an
easily prepared allenylboronate which offers complete regioselective control.
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Scheme 1 Asymmetric Propargylation of Aldehydes.15,16
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However, the origins of enantioselectivity are unclear which would make the products of
reactions involving novel substrates difficult to predict. Based on DFT calculations, Antilla et
al. proposed that the reaction proceeds with protonation of the cyclic boronate
pseudoequatorial oxygen by the chiral phosphoric acid and orientation of the phosphoryl
oxygen towards the ortho-hydrogen of the equatorial phenyl group (Scheme 1). However, our
previous work has indicated that single-point binding from the catalyst to the substrate cannot
explain the observed enantioselectivity in similar reactions catalyzed by BINOL-derived
phosphoric acids.17-19 Reddy proposed that the catalyst hydroxyl group interacts with the
aldehyde oxygen and the phosphoryl oxygen interacts with the aldehyde formyl proton
(Scheme 1). However, this arrangement places the aldehyde phenyl group axial rather than
equatorial, an arrangement found to be disfavored for aldehyde allylboration.18
Herein, we report the results of DFT calculations which provide mechanistic insight into this
important propargylation reaction. Our calculations indicate that the reaction proceeds via a
cyclic six-membered ring transition structure (TS) involving both a hydrogen bonding
interaction from the catalyst hydroxyl group to the cyclic boronate pseudoaxial oxygen and
an additional interaction from the catalyst phosphoryl oxygen to the aldehyde formyl proton.
This mechanistic pathway is lower in energy than that proposed in the original papers and
predicts the correct sense of enantioselectivity. We present a qualitative guide to rationalizing
the experimental outcome which is consistent with the model derived from our study of
aldehyde allylboration.18
2. COMPUTATIONAL DETAILS
The preferred reaction pathway for aldehyde propargylation was investigated using buta-1,3-
diene-1,4-diol-phosphoric acid as a model for the catalyst,19 implemented in Gaussian03
(Revision E.01),20 using the B3LYP density functional,21,22 and split-valence polarized 6-
31G* basis set.23,24 Single-point energies were taken using the M06-2X density functional,25
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and the 6-31G* basis set using the Jaguar program (version 7.6).26 These energies were used
to correct the gas phase energies obtained from the B3LYP calculations.27 All activation free
energies are quoted relative to infinitely separated reagents.
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To further validate the results obtained with the model system and to explore the origins of
enantioselectivity, we also performed B3LYP/6-31G* calculations using the phosphoric acid
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derived from (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-bi-2-phenol as
a
model,15
implemented in Gaussian03 (Revision E.01).20 This model was selected instead of the full
catalyst to reduce computational time and to ensure results were directly comparable to those
reported by Antilla et al. M06-2X/6-31G* single-point energy calculations were performed
on the resulting structures using the Jaguar program (version 7.6),26 and used to correct the
gas phase energies.27 All activation free energies are quoted relative to infinitely separated
reagents.
Free energies in solution were derived from gas phase optimized structures (B3LYP/6-31G*)
by means of a single-point calculation using M06-2X/6-31G* with the polarizable continuum
model (PCM),28 as implemented in the Jaguar program (version 7.6). These values were used
to correct the Gibbs free energy derived from the B3LYP calculations.
3. RESULTS AND DISCUSSION
Investigation of uncatalyzed aldehyde propargylation identified 2 unique TSs with the
benzaldehyde phenyl group either pseudoequatorial or pseudoaxial. The most favorable TS
was found to be TS-1, with TS-2 destabilized by the steric interaction between the cyclic
boronate and the benzaldehyde phenyl group (Figure 1). The activation free energy of TS-1
was calculated to be 32.9 kcal mol-1 when evaluated using B3LYP/6-31G*. The Gibbs free
energy was corrected by taking a single-point energy using M06-2X/6-31G* which lowered
the value of the activation free energy to 20.0 kcal mol-1.
Figure 1 Competing TSs for the reaction of benzaldehyde and allenylboronic acid pinacol ester.
Geometries B3LYP/6-31G*, single-point energies M06-2X/6-31G*. Non-critical hydrogen atoms
omitted for clarity.
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Investigation of the catalyzed reaction using our model catalyst derived from buta-1,3-diene-
1,4-diol-phosphoric acid, revealed the value of ꢀG‡ for the Antilla-Houk model (TS-3, Figure
2) to be approximately 5 kcal mol-1 lower in energy than the uncatalyzed activation barrier
when evaluated using B3LYP/6-31G*. Alternative mechanisms include the Reddy model
(TS-4), protonation of the aldehyde oxygen by the phosphoric acid (TS-5) and a ten-
membered ring TS (TS-6). However, these mechanisms were found to be disfavored relative
to TS-3. Interestingly, the aldehyde phenyl group in TS-5 occupies the pseudoaxial position
and was found to be lower in energy than the alternative pseudoequatorial TS. This is the
result of increased steric interactions between the phosphoric acid and the phenyl group in the
latter TS relative to TSs which involve protonation of the cyclic boronate pseudoequatorial
oxygen in which there was a strong preference for the aldehyde substituent to be
pseudoequatorial. This steric interaction can be avoided if the phenyl group is placed
pseudoaxially.
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Figure 2 Competing TSs for the reaction of benzaldehyde and allenylboronic acid pinacol ester
catalyzed by buta-1,3-diene-1,4-diol-phosphoric acid. Geometries B3LYP/6-31G*, single-point
energies M06-2X/6-31G*. Non-critical hydrogen atoms omitted for clarity.
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Thorough exploration of the potential energy surface yielded a total of 64 unique TSs (see
supporting information). The lowest energy TS was found to involve protonation of the cyclic
boronate pseudoaxial oxygen by the phosphoric acid and a hydrogen bonding interaction
between the phosphoryl oxygen and the formyl proton, a similar mechanism to our findings
from the study of aldehyde allylboration (TS-7, Figure 2).18 TS-8 was found to involve
protonation of the axial oxygen with no secondary interaction to the formyl proton, and was
found to be disfavored relative to TS-7. Superposition of the 6 reacting ring atoms, axial
oxygen and catalyst hydroxyl group of TS-7 and TS-8 allowed calculation of an RMSD value
of 0.26 Å suggesting minimal geometric change between the 2 TSs. Therefore, the difference
in energy between the two structures can be attributed to the enthalpic benefit of the formyl
hydrogen bond. ꢀEM06-2X between the structures was found to be 3.6 kcal mol-1, in close
agreement with the value previously reported for the strength of the formyl hydrogen bond
for aldehyde allylboration.18
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The origins of enantioselectivity were investigated using (R)-3,3'-bis(2,4,6-
triisopropylphenyl)-1,1'-bi-2-phenol as a catalyst model to ensure that our results were
comparable to those reported by Antilla et al. Examination of the B3LYP free energies
indicates that TS-9Re is the lowest energy TS which proceeds via protonation of the cyclic
boronate pseudoaxial oxygen by the phosphoric acid with an additional stabilizing interaction
to the aldehyde formyl proton from the phosphoryl oxygen (Figure 3). The free energy
barrier for this pathway was found to be 5.5 kcal mol-1 lower than that corresponding to the
background reaction, when evaluated at the B3LYP level of theory.
However, the B3LYP energies also indicated a flat potential energy surface with regard to the
lowest Si TS. 3 TSs, all conformationally very different, were found to be separated by less
than 0.7 kcal mol-1 (TS-9Si, TS-10Si and TS-11Si, Figure 3). These B3LYP studies weakly
suggested the Antilla-Houk model to be the preferred pathway to the minor product. A
clearer understanding of the potential energy surface would better allow rationalization of the
enantioselective origins. The shortcomings of the B3LYP functional at describing TS
energies have been well documented.29-33 Whilst B3LYP has been found to give reliable TS
geometries, the corresponding energies fail to accurately sum the many complex van der
Waals interactions which lead to the overall catalytic effect. Therefore, M06-2X single-point
energies should be taken, representing only a small additional calculation but providing a
significant increase in precision when compared to experiments.27 This new potential energy
surface allowed a less ambiguous identification of the lowest energy Si TS (TS-9Si). In TS-
9Si, the formyl hydrogen bond was found to be lengthened by 0.19 Å relative to TS-12Si.
This distortion serves to reduce the steric clash between the large catalyst aromatic
substituent and the pinacol ester methyl groups. Despite this stabilization the pathway
remains energetically disfavored, by 2.1 kcal mol-1, relative to TS-9Re.
Therefore, the enantioselectivity can be rationalized using the formyl hydrogen bonded
pathway. The computed enantioselectivity arising from TS-9Re and TS-9Si was found to be
97 % at 253 K, close to that seen experimentally. The origins of such strong selectivity for
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the (R)-homopropargylic alcohol are due to the unfavorable steric clash between the pinacol
ester methyl groups and the bulky catalyst aromatic group in TS-9Si. This mechanistic
understanding of aldehyde propargylation is consistent with our findings for aldehyde
allylboration, both of which employ an M06-2X energy correction to compensate for the
shortfalls of the B3LYP functional.
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Figure 3 Competing TSs for the reaction of benzaldehyde and allenylboronic acid pinacol ester
catalyzed by (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-bi-2-phenol-phosphoric acid. Geometries
B3LYP/6-31G*, single-point energies M06-2X/6-31G*. B3LYP/6-31G* free energies in parentheses.
Non-critical hydrogen atoms omitted for clarity.
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TS-10Re and TS-10Si, corresponding to the Antilla-Houk model, were found to be higher in
energy than both TS-9Re, TS-9Si and TS-12Si (Figure 3). Moreover, the predicted sense of
enantioselectivity by this model is opposite to that observed experimentally. In TS-10Re, the
pinacol ester methyl groups must be placed in the sterically demanding pocket of the catalyst
and whilst the absence of the formyl proton hydrogen bond means that this clash is reduced,
TS-10Si still benefits from this less sterically demanding arrangement.
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A total of 17 unique TS were located using this catalyst model (see supporting information),
of which TS-13Re was found to be the lowest energy of the mono substrate-catalyst
interaction model. To confirm that the results obtained using the biphenyl model accurately
reflect the reaction conditions, TS-9Re and TS-9Si were optimized using the full catalyst
system at the B3LYP/6-31G* level of theory (see supporting information). M06-2X/6-31G*
single-point energy calculations were performed on the resulting structures and used to
correct the B3LYP gas phase energies. The dihedral angle defined by both naphthyl groups
(described by carbons 2,1,1’ and 2’, where 2 and 2’ are the oxygen bearing carbons) in the
new TSs was found to be 54.9° on average, in contrast to 43.2° in the biphenyl derived TSs.
The relative free energies between the TSs increased by 0.6 kcal mol-1. This indicates that the
dihedral modification has a minor effect on the predicted selectivity and therefore confirms
the validity of the biphenyl model catalyst.
Toluene (Antilla’s conditions) and cyclohexane (Reddy’s conditions) solvent effects were
shown to have minimal impact on the relative free energies of the competing TSs due to their
concerted and apolar nature, in full agreement with our findings for aldehyde allylboration.18
Solvation of TS-9Re and TS-9Si led to an increase in relative free energy of just 0.4 kcal
mol-1 in both solvents. The small size of these changes show that gas phase calculations are a
reasonable approximation for aldehyde propargylation reaction conditions.
When the solvent was dichloromethane (DCM), however, the experiments show a drop in
selectivity. Using the PCM method, solvation of TS-9Re and TS-9Si in DCM reduced the
relative free energy from 2.1 to 1.0 kcal mol-1, in agreement with the trend observed in the
experimental data. TS-9Si has a weaker and longer formyl hydrogen bond than TS-9Re, and
this is one of the factors that favors Re attack over Si attack in non-polar solvents. In polar
solvents, such as DCM, this favorable interaction stabilizing Re attack may be replaced by a
favorable interaction between P=O and the polar solvent molecules for Si attack. In order to
test this idea, complexes between DCM and buta-1,3-diene-1,4-diol-phosphoric acid were
located and structures in which the P=O-solvent interaction was present and absent were
compared. The free energy associated with this solvent-catalyst interaction was calculated to
be 3.1 kcal mol-1, which is comparable to the strength of the formyl hydrogen bond (see
supporting information). A similar strength of interaction has been observed between the
C=O of acetone and chloroform.34 These calculations suggest that the lower
enantioselectivity observed in polar solvents than non-polar solvents arises because the key
formyl hydrogen bond is not strongly favored over interactions with polar solvent molecules.
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To further test our mechanistic hypothesis, the effect of changing the catalyst was
investigated. Experimentally, Antilla found that changing the 3 and 3’ groups from 2,4,6-
triisopropylphenyl to 3,5-bis(trifluoromethyl)phenyl reduced the ee from 74 % to 4 %. TS-
14Re and TS-14Si were found to be closer in energy than TS-9Re and TS-9Si (Figure 4).
This can be understood in terms of the reduced steric demands of the CF3 groups relative to
the isopropyl groups, resulting in lower levels of enantioselectivity. The lack of formyl
hydrogen bond distortion in TS-14Si, in contrast to TS-9Si, is due to the absence of large
sterically demanding 2,4,6-triisopropylphenyl groups. This absence allows maximum TS
stabilization from the favorable formyl hydrogen bonding interaction.
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Figure 4 Competing TSs for the reaction of benzaldehyde and allenylboronic acid pinacol ester
catalyzed by (R)-3,3'-bis(3,5-bis(trifluoromethyl)phenyl)-1,1'-bi-2-phenol-phosphoric acid.
Geometries B3LYP/6-31G*, single-point energies M06-2X/6-31G*. Non-critical hydrogen atoms
omitted for clarity.
Figure 5 Competing TSs for the reaction of benzaldehyde and allenylboronic acid pinacol ester
catalyzed by a BINOL-derived N-triflyl phosphoramide. Geometries B3LYP/6-31G*, single-point
energies M06-2X/6-31G*. Measured dihedrals highlighted in green. Non-critical hydrogen atoms
omitted for clarity.
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The use of a BINOL-derived N-triflyl phosphoramide bearing the same 3 and 3’ groups as
TRIP-PA resulted in a decrease in ee from 74 to 16 %, experimentally. This result was non-
intuitive, given that the bulky aromatic substituents that usually control the enantioselectivity
levels remained identical. 9 TSs were located for this reaction, of which TS-15Re and TS-
15Si were the lowest in energy (Figure 5). Our calculations predict a dramatic fall in ee and
suggest the reasons for this are the increased steric demands of the phosphoramide
phosphorous centre relative to the phosphoric acid. To the best of our knowledge, this is the
first report of mechanistic investigations into N-triflyl phosphoramides of this nautre.
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The CF3 group of the triflyl moiety was found to be preferentially orientated towards the less
sterically demanding pocket of the catalyst, in a similar way to the pinacol ester methyl
groups. This modifies the dihedral of the BINOL-derived scaffold and the aromatic
substituent, towards which the CF3 group is orientated, from 72.9° in TS-9Re to 84.7° in TS-
15Re (Figure 5). The oxygens of the triflyl moiety also modify the dihedral of the substituent
towards which they are orientated from 113.1° in TS-9Si to 121.6° in TS-15Si (Figure 5).
Therefore, these catalyst backbone distortions create a larger cone of empty space around the
protic hydrogen, reducing the impact of the pinacol ester methyl group clash with the catalyst
3 and 3’ groups, lowering the energy of TS-15Si relative to TS-15Re. This led to a lower ee
relative to the reaction catalyzed by TRIP-PA. Furthermore, the pocket to the rear of the
catalyst which accommodates the benzaldehyde phenyl group in the Re TS becomes more
sterically demanding, because of the CF3 distortion, than in the corresponding TRIP-PA TS.
However, in the Si TS, this pocket only accommodates the allenylboronate hydrogens and so
is less destabilized than the Re TS.
This implies that if the strong steric demands of the substrate are bound to the catalyst
Brønsted acidic moiety, the ee should be higher in a reaction catalyzed by the phosphoric acid
than by the phosphoramide, providing both are effective catalysts for the reaction. Therefore,
in examples where the phosphoramide gives high ee, it is expected that the sterically
demanding substrate is bound to the phosphoryl oxygen. Table 1 contains examples in which
the general trend outlined above is observed. Without detailed mechanistic investigation, only
a correlation can be established. However, combining these data with the results of our
calculations, supported the hypothesis.
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Table 1 Examples of reactions catalzyed by chiral phosphoric acids and N-triflyl phosphoramides.
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Reaction
Mode of
Activation
Asymmetric
Nuc. at P=O
Asymmetric
Nuc. at P=O
Asymmetric
Strong Steric
Demands
ee with PA
ee with N-triflyl
phosphoramide / %
/ %
Indole 1,4-additon35
-
-
80-92 (10 examples)
84-94 (7 examples)
P=O
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Friedel-Crafts
Alkylation36
P=O
Propargylation of
Aldehydes15
Nuc. at Brønsted Brønsted Acidic Site
Acidic Site
74
46
16
Asymmetric
Reduction of
Ketones37
Symmetric Nuc.
Brønsted Acidic Site
at P=O
-17
Symmetric Nuc.
Brønsted Acidic Site
at P=O
Reductive
91
89
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Amination38
An additional test of the model was performed by investigating the effects of aldehyde
substitution upon ee. The aldehyde that gave the lowest ee under the optimized conditions
was cyclohexanecarboxaldehyde. TSs were located based around the formyl proton hydrogen
bonding model (TS-16Re and TS-16Si, Figure 6) which show a reduction in the relative free
energy between Re and Si compared to TS-9Re and TS-9Si, in agreement with experimental
results. The cyclohexyl substituent involves more severe clashing with the bulky aromatic
group at the rear of the catalyst than in the case of the flat benzaldehyde phenyl group in the
Re TS. In the case of the Si TS, the aldehyde substituent occupies the empty pocket and so is
stabilized relative to the Re TS. Whilst this effect lowers the ee observed experimentally, the
overall sense of enantioselectivity is determined by the unfavorable interactions between the
pinacol ester methyl groups and the bulky catalyst aromatic substituent.
TS-16Re
G‡ = 0 kcal mol-1
TS-16Si
G‡ = +1.2 kcal mol-1
Figure 6 Competing TSs for the reaction of cyclohexanecarboxaldehyde and allenylboronic acid
pinacol ester catalyzed by (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-bi-2-phenol-phosphoric acid.
Geometries B3LYP/6-31G*, single-point energies M06-2X/6-31G*. Non-critical hydrogen atoms
omitted for clarity.
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Experimental test of the model
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To assess the utility of our qualitative model we hypothesised that the combination of
cyclohexanecarboxaldehyde and the BINOL-derived N-triflyl phosphoramide described
above could lead to a large reduction in ee for this reaction. The modified catalyst creates a
larger cone of empty space about the protic hydrogen bond and therefore reduces the effect of
the pinacol ester methyl groups. This, in combination with the sterically demanding
cyclohexanecarboxaldehyde which prefers to be placed in the empty pocket to the rear of the
catalyst, should lead to a reduction in the energetic preference for the Re TS.
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To test this prediction, firstly the N-triflyl phosphoramide (1) was synthesised (see supporting
information).
The
reaction
of
allenylboronic
acid
pinacol
ester
and
cyclohexanecarboxaldehyde was then conducted in the presence of 1 under the same
conditions described by Antilla et al. (Figure 7). The product displayed the same sense of
optical rotation as that reported in the original paper when catalyzed by (R)-TRIP-PA. The
absolute stereochemistry and ee were determined by analysis of both diastereomeric Mosher
esters (see supporting information). The results showed the product formed was the (R)-
enantiomer in 39 % ee. This illustrated that by understanding the qualitative model presented
here, experimental predictions can be made without the need for further calculations and
demonstrated its power for application in the design of asymmetric methodology.
Figure 7 Reaction of cyclohexanecarboxaldehyde and allenylboronic acid pinacol ester catalyzed by
1.
CONCLUDING REMARKS
In conclusion, DFT calculations have suggested that asymmetric aldehyde propargylation
proceeds via a six-membered TS in which the catalyst Brønsted acidic site interacts with the
cyclic boronate pseudoaxial oxygen and the phosphoryl oxygen interacts with the formyl
proton. This mode of activation is energetically preferred to the models proposed in the
original papers.15,16 This model accurately predicts the experimental stereochemical outcome
and reproduces the observed trends in enantioselectivity when the aldehyde substituent is
changed, allowing approximate trends in ee to be determined for novel substrates. We present
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a qualitative guide to rationalizing the experimental outcome (Figure 3) that is consistent with
the results from our study of aldehyde allylboration which demonstrates the generality of this
reaction model.18
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Furthermore, replacement of the phosphoric acid hydroxyl group with an N-triflyl moiety has
been included in the model by calculation, and a broader understanding achieved by
qualitative assessment of similar reactions. This exchange leads to an erosion of the reaction
ee when highly sterically demanding groups bind to the OH/NH site. The opposite is true,
leading to higher ee, when the sterically demanding groups occupy the phosphoryl pocket of
the catalyst. This qualitative guide was used to make a prediction which was confirmed
experimentally.
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The model presented here for aldehyde propargylation gives a clear mechanistic insight into
this reaction and should serve to promote further development of synthetic methodology
involving this mode of activation.
ASSOCIATED CONTENT
Supporting Information. Complete list of authors in the Gaussian03 reference; Cartesian
coordinates, energies and number of imaginary frequencies of all stationary points and values
of imaginary frequencies of all transition structures; 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
ACKNOWLEDGMENT
We thank the EPSRC for funding and Unilever.
REFERENCES
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
Tsuji, J.; Mandai, T. Angew. Chem. Int. Edit. 1996, 34, 2589.
Ding, C.-H.; Hou, X.-L. Chem. Rev. 2011, 111, 1914.
Ljungdahl, N.; Kann, N. Angew. Chem. Int. Edit. 2009, 48, 642.
Marshall, J. A.; Palovich, M. R. J. Org. Chem. 1998, 63, 3701.
Adachi, Y.; Kamei, N.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2011, 13, 4446.
Marshall, J. A.; Adams, N. D. Org. Lett. 2000, 2, 2897.
Wotiz, J. H. J. Am. Chem. Soc. 1950, 72, 1639.
Favre, E.; Gaudemar, M. J. Organomet. Chem. 1975, 92, 17.
Ikeda, N.; Arai, I.; Yamamoto, H. J. Am. Chem. Soc. 1986, 108, 483.
Corey, E. J.; Yu, C. M.; Lee, D. H. J. Am. Chem. Soc. 1990, 112, 878.
Lai, C.; Soderquist, J. A. Org. Lett. 2005, 7, 799.
ACS Paragon Plus Environment

Page 13 of 13
Journal of the American Chemical Society
1
2
(12)
(13)
(14)
6638.
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
(26)
(27)
(28)
(29)
(30)
(31)
(32)
(33)
(34)
(35)
593.
(36)
Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199.
Usanov, D. L.; Yamamoto, H. Angew. Chem. Int. Edit. 2010, 49, 8169.
Shi, S.-L.; Xu, L.-W.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132,
3
4
5
6
7
8
9
Jain, P.; Wang, H.; Houk, K. N.; Antilla, J. C. Angew. Chem. Int. Edit. 2012, 51, 1391.
Reddy, L. R. Org. Lett. 2012, 14, 1142.
Simón, L.; Goodman, J. M. J. Am. Chem. Soc. 2008, 130, 8741.
Grayson, M. N.; Pellegrinet, S. C.; Goodman, J. M. J. Am. Chem. Soc. 2012, 134, 2716.
Simón, L.; Goodman, J. M. J. Am. Chem. Soc. 2009, 131, 4070.
Frisch, M. J.; et al., Gaussian 03; Gaussian, Inc., Wallingford CT, 2004.
Becke, A. D. Phys. Rev. A 1988, 38, 3098.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
Krishnan R.; Binkley J. S.; Seeger R.; Pople J. A. J. Chem. Phys. 1980, 72, 650.
Gill, P. M. W.; Johnson, B. G.; Pople, J. A.; Frisch, M. J. Chem. Phys. Lett. 1992, 197, 499.
Zhao, Y.; Truhlar, D. Theor. Chem. Acc. 2008, 120, 215.
Jaguar, version 7.6, Schrodinger, LLC, New York, NY, 2009.
Simón, L.; Goodman, J. M. Org. Biomol. Chem. 2011, 9, 689.
Mennucci B.; Tomasi J. J. Chem. Phys. 1997, 106, 5151.
Zhao, Y.; Truhlar, D. G. Org. Lett. 2006, 8, 5753.
Wodrich, M. D.; Corminboeuf, C.; Schleyer, P. v. R. Org. Lett. 2006, 8, 3631.
Zhao, Y.; Schultz, N. E.; Truhlar, D. G. J. Chem. Theory Comput. 2006, 2, 364.
Zhao, Y.; Truhlar, D. G. J. Phys. Chem. A 2006, 110, 10478.
Anderson, C. D.; Dudding, T.; Gordillo, R.; Houk, K. N. Org. Lett. 2008, 10, 2749.
Singh, S.; Murthy, A. S. N.; Rao, C. N. R. Trans. Faraday Soc. 1966, 62, 1056.
Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem. Int. Edit. 2008, 47,
Wang, S.-G.; Han, L.; Zeng, M.; Sun, F.-L.; Zhang, W.; You, S.-L. Org. Biomol. Chem. 2012,
10, 3202.
(37)
(38)
Zhang, Z.; Jain, P.; Antilla, J. C. Angew. Chem. Int. Edit. 2011, 50, 10961.
Enders, D.; Liebich, J. X.; Raabe, G. Chem-Eur. J. 2010, 16, 9763.
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