Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling

Article abstract of DOI:10.1002/anie.202006237

The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experi

Full text of DOI:10.1002/anie.202006237

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Angewandte
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Accepted Article
Title: Enantioselective Intramolecular Allylic Substitution via Synergistic
Palladium/Chiral Phosphoric Acid Catalysis: Insight into
Stereoinduction through Statistical Modeling.
Authors: F. Dean Toste, Cheng-Che Tsai, Christopher Sandford, Tao
Wu, Buyun Chen, and Matthew Sigman
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10.1002/anie.202006237
Angewandte Chemie International Edition
RESEARCH ARTICLE
Enantioselective Intramolecular Allylic Substitution via
Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight
into Stereoinduction through Statistical Modeling
Cheng-Che Tsai,‡[a] Christopher Sandford,‡[b] Tao Wu,[a] Buyun Chen,[a] Matthew S. Sigman,*[b] and
F. Dean Toste*[a]
Abstract: The mode of asymmetric induction in an enantioselective
intramolecular allylic substitution reaction catalyzed by a combination
of palladium and a chiral phosphoric acid was investigated by a
combined experimental and statistical modeling approach.
Experiments to probe nonlinear effects, the reactivity of deuterium-
labeled substrates, and control experiments revealed that nucleophilic
attack to the π-allylpalladium intermediate is the enantio-determining
allylation of branched aldehydes (Scheme 1a),[6a] wherein the
CPA is the sole source of chiral information responsible for
enantioinduction. In contrast, CPAs have also been leveraged to
enhance the enantioselectivity of an allylic substitution reaction in
which the primary source of asymmetric induction is a chiral
phosphoramidite ligand for Pd, as demonstrated by the groups of
Gong[6c] and Beller[6d] (Scheme 1b and 1c, respectively). Despite
step, in which the chiral phosphate anion is involved in stereoinduction. the rapid development in this field, insights into the origin of
Using multivariable linear regression analysis, we identified that
multiple noncovalent interactions with the chiral environment of the
phosphate anion are integral to enantiocontrol in the transition state.
The synthetic protocol to form chiral pyrrolidines was further applied
to the asymmetric construction of C−O bonds at fully-substituted
carbon centers in the synthesis of chiral 2,2-disubstituted
benzomorpholines.
asymmetric induction by CPAs in these complicated reaction
processes remains challenging.[7]
In this context, we report herein our investigation into the origin of
asymmetric induction in Pd/CPA catalyzed enantioselective allylic
substitutions using a combination of experimental studies and
statistical modeling (Scheme 1d).[8,9] In doing so, we are able to
identify noncovalent interactions (NCIs) between the substrate
and chiral phosphate anion that differentiate the energy of the
transition states leading to the stereoisomeric products. The
knowledge gained from these mechanistic studies allows for
expansion of synthetic scope to the formation of chiral
benzomorpholines, a compound class containing fully-substituted
carbon centers.
Introduction
Chiral phosphoric acids (CPAs) serve as versatile catalysts in
organocatalyzed asymmetric transformations, and as effective
co-catalysts in transition metal-catalyzed reactions.[1] The
combination of CPAs with transition metal catalysts imparts new
reactivity (and selectivity) manifolds that are not accessible by
their
individual
catalytic
components.[2,3]
Specifically,
enantioselective allylic substitution reactions of non-derivatized
(unactivated) allylic alcohols are desirable as a step-economic
approach to the formation of key carbon–carbon and carbon–
heteroatom bonds.[4] The synergy between two distinct catalysts
allows for unique reactivity of these substrates, often with
enhanced enantio- and diastereocontrol.[5]
As an example, CPAs were found to be effective co-catalysts for
asymmetric induction in Pd-catalyzed enantioselective allylic
substitutions (Scheme 1).[6] List and co-workers reported the
combination of Pd and CPA catalysts in the enantioselective
[a]
Dr. C.-C. Tsai,‡ Dr. T. Wu, Mr. B. Chen, Prof. Dr. F. D. Toste
Department of Chemistry
University of California, Berkeley,
Berkeley, California 94720 (USA)
E-mail: fdtoste@berkeley.edu
Dr. C.-C. Tsai
Present Address: Department of Chemistry, Tunghai University,
Taichung City 40704 (Taiwan)
[b]
‡
Dr. C. Sandford,‡ Prof. Dr. M. S. Sigman
Department of Chemistry
University of Utah
315 South 1400 East, Salt Lake City, Utah 84112 (USA)
E-mail: sigman@chem.utah.edu
These authors contributed equally to this work
Supporting information for this article is given via a link at the end of the
document
Scheme 1. (a-c) Literature examples of synergistic Pd/CPA-catalyzed
enantioselective allylic substitutions of unactivated alcohols. (d) Intramolecular
reactions studied herein.
1
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RESEARCH ARTICLE
Results and Discussion
To probe the origin(s) of enantiocontrol, nonlinear effect (NLE)[11]
studies of both the synergistic Pd/CPA and SN2' reactions were
performed (Figure 1). Both reactions exhibited linear correlations
(R2 > 0.99) between the product and catalyst ee, consistent with
models reported by Takasu[10a] and Beller,[6d] which propose that
a single CPA is involved in the enantio-determining transition
state.
Initial Results. We commenced our study with the Pd-catalyzed
enantioselective intramolecular allylic amination of allylic alcohol
1a with privileged CPA, (R)-TCYP 3, as a co-catalyst (Table 1).
For comparative purposes, we also investigated the same
reaction in the absence of Pd, according to work reported by the
Takasu group in which a CPA catalyzes the allylic substitution
when the alcohol is replaced by an activated trichloroacetimidate
leaving group, substrate 1a'.[10]
In the initial study, the substitution of allylic alcohol 1a was carried
out in the presence of 10 mol% of both (R)-TCYP 3 and
Pd(PPh3)4, resulting in pyrrolidine product (S)-2a in full conversion
with 84% ee (entry 1). In contrast, the reaction of 1a' with (R)-
TCYP
3 under metal-free conditions gave the opposite
enantiomer of the product, (R)-2a, in 78% ee (entry 2). Given that
the Takasu group has demonstrated that the reaction in the
absence of Pd likely proceeds by nucleophilic attack on the π-
system antiperiplanar to the activated leaving group (an SN2'-type
mechanism),[10a] the enantio-divergence in the presence of Pd
provides evidence of a distinct mechanism. To gain insight into
the origins of this enantio-divergence, control experiments were
performed: the reaction of 1a without Pd gave no product (entry
3), while the Pd/CPA-catalyzed reaction of activated substrate 1a'
gave (S)-2a in only 9% ee (entry 4), as a consequence of
background reactivity (entry 5).
Figure 1. Nonlinear effect studies comparing the ee of (R)-TCYP 3 with the ee
of the product (R/S)-2a, both (a) in the presence of Pd(PPh3)4 with substrate 1a,
and (b) in the absence of Pd(PPh3)4 with substrate 1a'. Conditions as Table 1,
entries 1 and 2, respectively.[12]
To enhance the enantioselectivity of the reaction, we turned our
attention towards examining alternative CPA scaffolds. We
recently developed a new class of CPA catalysts, doubly-axially
chiral phosphoric acids (DAPs), which possess a larger chiral
pocket derived from two homo-coupled BINOL scaffolds.[13] The
use of DAPCy catalyst 4a resulted in an increase in
enantioselectivity for both the synergistic Pd/CPA and SN2'
reactions to 95% and 90% ee, respectively (Table 1, entries 6 and
7).
Table 1. Initial results and control experiments for intramolecular substitutions[a]
During optimization, we observed that the identity of both the DAP
catalyst and the sulfonamide protecting group on the nucleophilic
nitrogen of the substrate play an important role in the
enantioselectivity of the reaction, with different trends associated
with the two strategies. The dependency of these two modular
components of the reaction presented an ideal case study for
utilizing statistical modeling tools to probe the origins of enantio-
divergence between the two processes.
Statistical Modeling of the Substrate Variation. In our
statistical modeling approach to investigating molecular
interactions in transition states,[8] parameter sets describing
molecular properties of the substrate and/or catalyst are related
to the enantioselectivity of the reaction, expressed as ΔΔG‡. The
combination of multiple parameters in the mathematical
expression defining ΔΔG‡ provides insight into the overlapping
factors contributing to stereocontrol.
To formulate such an equation, it is first necessary to define a set
of parameters that describes electronic and steric properties of
the molecular structure. In this case, we opted to simulate trends
in structural variation of the sulfonamide protecting group by
truncating the substrate to an ArSO2NH2 group (see Supporting
Information). DFT properties of these truncated structures were
collated, and, through an iterative multivariable linear regression
modeling process, models describing the effect of sulfonamide
variation on the enantioselectivity were obtained. Both leave-one-
out (Q2) and external validation (R2valid.) statistics were used,
where appropriate, to identify a statistically robust model.
Entry
Substrate
Catalysts
conv. (%)[b]
ee (%)[c]
1
2
3
4
5
6
7
1a
1a'
1a
Pd(PPh3)4 / 3
100
100
84
−78
n.d.
9
3
3
0
1a'
1a'
1a
Pd(PPh3)4 / 3
Pd(PPh3)4
Pd(PPh3)4 / 4a
4a
100
70
0
100 (85)
86 (77)
95
1a'
−90
[a] The reaction was carried out with 10 mol% of Pd(PPh3)4 and/or CPA 3/4a in
toluene at ambient temperature. [b] conv. represents conversion measured by
crude 1H NMR, isolated yields in parentheses. [c] ee of product 2a, determined
using HPLC equipped with a chiral column, wherein a positive ee corresponds
to (S)-2a, and a negative ee to (R)-2a, as the major configuration. n.d. = not
determined.
2
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A combination of the asymmetric IR stretching frequency of the
NH2 group (νNH2,asym) with the partial charge according to NBO on
the sulfur (NBOS) was necessary to describe the impact of the
variation of the protecting group in the enantiocontrol of the SN2'
reaction (Figure 2a and 2b). These parameters can be compared
directly with transition states computed by Takasu and co-
workers,[10a] in which the asymmetric IR stretching frequency
defines the propensity of the amine N–H to undergo hydrogen-
bonding to the phosphoric acid P=O motif in the transition state.
The partial charge according to NBO on the sulfur atom
(S,E)-isomer could be generated directly from a slightly less
favorable syn-ionization of (S,E)-5a,[18] whereby formation of the
Pd(II)-allyl intermediate is enantio-determining. To examine these
possibilities, we repeated the reaction with half the palladium
predominantly describes
a
correctional factor for ortho-
substituents, a steric property that results in a change in
conjugation with the aromatic ring.
With agreement between our modeling and transition states
computed by Takasu and co-workers in the absence of palladium,
we next turned to using statistical modeling to probe the dual
catalysis manifold. According to the workflow described above,
we obtained a model (Figure 2c) for the protecting group variance
in which the dominant parameter is the asymmetric IR stretching
frequency of the SO2 group (νSO2,asym). Interestingly, this key
parameter corresponds to a hydrogen-bond (or other noncovalent
interaction) to the protecting group oxygen in the transition state;
however, this interaction is opposite in directionality to the
hydrogen-bond of the SN2' mechanism identified above.
At this stage, we identified two possibilities for the origin of this
discrepancy: (1) the amine is deprotonated prior to the enantio-
determining step, whereby the phosphoric acid O–H binds to the
SO2 group as part of an inner-sphere Tsuji-Trost mechanism,[14]
or (2) the vibrational stretching frequency is signifying a molecular
interaction between the sulfonamide oxygens and an alternative
hydrogen (or Lewis acid). In order to differentiate these
possibilities, it was necessary to gain further insight into the
mechanism of the enantio-determining step in the reaction.
To determine whether an inner- or outer-sphere Tsuji-Trost
mechanism is in operation, we synthesized deuterium-labeled,
enantiomerically enriched (er = 3.4/1) allylic alcohol (S,E)-5a
along with its corresponding trichloroacetimidate derivative (S,E)-
5a' (Figure 3a). In this experiment, an inner-sphere process
should afford the E-isomer of the deuterated olefin, and the Z-
isomer results from an outer-sphere process.[15] The absolute
configuration of 5a and 5a' was determined by Mosher ester
analysis, in comparison with 1H NMR spectra of analogues
reported in the literature (see Supporting Information).[15c,d] In the
SN2' reaction, the cyclized product (R)-6a was obtained in 93% ee
with 3.4:1 Z:E selectivity, consistent with a transition state in which
the nucleophile attacks the π-system on the opposite face to the
departing leaving group.
In the presence of palladium, cyclized product (S)-6a was
obtained with 95% ee and 2.0:1 Z:E selectivity, indicative of an
outer-sphere mechanism. It is notable that the minor E-isomer of
the product is also formed in high enantio-enrichment with the
same absolute configuration as the Z-isomer. We propose that
this may result from a second order process in Pd, in which a
second Pd(0) molecule attacks the Pd(II)-allyl intermediate,
leading to a switch in the facial position of the palladium (Figure
3b).[16] Rapid π-σ-π isomerization must then occur to form the
observed isomers of deuterated product. In this scenario, the
reaction operates under Curtin–Hammett control, in which outer-
sphere attack of the nitrogen nucleophile is enantio-
determining.[17] Alternatively, the π-allylpalladium precursor to the
Figure 2. (a) Variance of the nitrogen protecting group. (b) Model describing the
protecting group variance in the absence of Pd, in which (R)-2 is formed as the
major enantiomer. (c) Model describing the protecting group variance in the
presence of Pd, in which (S)-2 is formed as the major enantiomer.
3
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Figure 3. (a) Deuterium labeling experiment to probe outer- or inner-sphere Tsuji-Trost mechanism. PG = SO2-1-naphthyl. (b) Rationale for major and minor isomers
in the presence of palladium. (c) Model for protecting group variance in the presence of palladium using parameters derived from SAPT computations. Outlier 2h
was generated from 1h, which was not fully soluble in the reaction mixture, and is not included in the correlation statistics (also an outlier in Figure 2c).
loading, and observed an increase in selectivity to 2.6:1 Z:E, in
agreement with slowing the second order Pd process of the first
scenario. From these experiments, an inner-sphere Tsuji-Trost
mechanism can be excluded, and the enantio-determining attack
of the nucleophile occurs through a transition state in which the
DAP catalyst is a phosphate anion (having previously protonated
the OH leaving group). This leads to the conclusion that the
asymmetric SO2 vibrational stretching frequency corresponds to
a noncovalent interaction (NCI) other than a hydrogen-bond from
the phosphoric acid O–H.
enantiomer of (Ra,Ra,Ra)-DAPPhtBu 4e. We observed a reduced
enantioenrichment of product (R)-2a of 84%, when compared to
the ee of (S)-2a of 93% with 4e.[20] While the reduced
enantioselectivity may result from manipulations in the catalyst
pocket from the additional methyl substituents, it also suggested
the possibility that the higher energy (Ra,Sa,Ra)-configuration of
the DAP anion may be catalytically active. We modeled both
configurations separately,[21] and obtained more interpretable
multivariable linear regression models with the (Ra,Sa,Ra)-
configuration. With these data in agreement, it suggests that the
higher energy configuration of the catalyst may be operational.
Consequently, we believe that configurational flexibility is
important in successful catalysis, and we proceed to discuss
molecular interactions associated with the (Ra,Sa,Ra)-
configuration of the catalyst.
Parameters associated with the variation of the DAP catalysts
(Figure 4a) were obtained from truncated DFT structures (see
Supporting Information). With molecular descriptors in hand, we
obtained a bivariable model (Figure 4b) to describe enantiocontrol
in the synergistic Pd/CPA catalytic reaction, using the
combination of the partial charge according to NBO on the
reactive phosphate oxygen (NBOO) with the dihedral angle about
the naphthyl-naphthyl bond (DihedNap-Nap). We ascribe the
dihedral angle parameter to a classification for the partial charge,
where the angle alters the delocalization across the conjugated
ring system. The sign of the NBOO term leads to the conclusion
that the more negative the phosphate oxygen, the lower the
degree of enantiocontrol. This is consistent with the statistical
modeling of the protecting groups, since it showcases the
opposite trend to one expected if deprotonation of the amine
represents the key defining molecular interaction. Indeed, it
suggests that the major factor that controls stereochemistry is an
NCI from the phosphate oxygen that stabilizes the minor transition
state and leads to reduced enantioselectivity.
With this in mind, we turned to symmetry-adapted perturbation
theory (SAPT) computations to probe the energetics of an NCI to
the sulfonamide oxygens.[13a,19] In this approach, the hydrogen of
a benzene probe was used to determine the maximum magnitude
interaction energy and corresponding equilibrium binding
distance to the protecting group. The magnitude of the interaction
energy was also separated into constituent energies
corresponding to electrostatics, exchange interactions, induction
and dispersion. With these new parameters, an improved
statistical model (Figure 3c) was afforded with the equilibrium
binding distance (Dmin), alongside a cross-term of the dispersion
energy of the interaction (Edisp). The negative coefficient of Dmin
defines the benefit of an interaction with a smaller equilibrium
distance (stronger interaction) for improved stereocontrol, while
the cross-term compensates for the additional dispersion
obtained with a protecting group bearing an ortho-substituent on
the aromatic ring. Analyzing these results, the statistical modeling
suggests that an NCI with the sulfonamide oxygens is the most
important molecular interaction responsible for differentiating the
major and minor transition states in the presence of palladium.
Statistical Modeling of the Variation in DAP Catalyst. To gain
insight into the molecular interactions with the chiral phosphate
anion which govern selectivity, it was necessary to consider the
flexibility of the catalyst. Given the configurational flexibility of the
central axis of the DAP scaffold,[13a] we subjected TAPPhtBu
(triply-axially chiral phosphate) catalyst 4m, where configurational
flexibility is prevented, to our reaction conditions in the presence
of Pd (Figure 4a), providing a direct comparison with the
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It is interesting to compare these predicted NCIs with transition
states calculated by Jindal and Sunoj[7f] for the Pd/CPA reaction
developed by List and co-workers (Scheme 1a).[6a] While
statistical modeling does not enable the identification of the
precise molecular interactions involved, it does highlight both an
NCI from the sulfonamide oxygen that stabilizes the major
transition state, and an NCI from the phosphate oxygen that
stabilizes the minor transition state. In the transition states
computed by Jindal and Sunoj, the greatest change in bond
distances between the major and minor transition states is for an
NCI between the phosphate oxygen and a hydrogen of the PPh3
ligand, in which the bond distance is shorter (stronger NCI) in the
minor transition state.[7f] While the exact nature of the system is
different in this study to the work of Jindal and Sunoj, it is possible
that the statistical model is describing a similar NCI.
Moving to the analysis of catalyst effects without Pd, a univariate
correlation with the dihedral angle of the varied substituent was
observed for DAP catalysts with a dihedral angle > 60° (Figure
4c). However, no statistically robust models were obtained to
define the variance in catalysts with a dihedral angle < 60°, which
is likely a consequence of the modest spread of enantioselectivity
(between 2.1 and 2.4 kcal mol−1). Nonetheless, we propose that
the threshold effect of the dihedral angle defines the size of the
catalyst pocket, whereby a larger dihedral angle leads to an
increase in the pocket size and greater flexibility in substrate
binding, leading to the observed reduction in enantioselectivity.
Formation
of
Fully-Substituted
Stereocenters
in
Benzomorpholine Motifs. Having established evidence for the
proposed mechanism, we reasoned that the combination of the
configurational and conformational flexibility of the DAP catalyst
may allow dynamics to alleviate the constraints of a more
sterically-crowded transition state.[22] Consequently, we sought to
apply our synergistic reaction conditions to a more demanding
bond-formation reaction, and, to test our hypothesis, we targeted
the formation of 2,2-disubstituted benzomorpholines.
Chiral benzoxazines, including benzomorpholines, are important
precursors in the synthesis of many bio-active natural products
and pharmaceuticals.[23] In particular, 2,2-disubstituted
benzoxazines are core structures in renin inhibitors developed by
Pfizer.[24] However, stereocontrol in the formation of a C−O bond
at a fully-substituted carbon center remains challenging.[25]
Although fully-substituted chiral chromans have been
successfully synthesized through allylic substitution,[17,26] there
are no reports, to the best of our knowledge, of the formation of
2,2-disubstituted benzomorpholines via a Tsuji-Trost reaction.
To initiate this part of the study, the enantioselective
intramolecular allylic substitution of allylic alcohol 7a was carried
out with 10 mol% of Pd(PPh3)4 and DAPCy 4a, according to the
previous conditions for pyrrolidine formation, affording cyclized
product (R)-8a in only 25% conversion and 5% ee (Table 2, entry
1). Addition of water was found to improve the conversion of the
reaction (entry 2),[27] and replacement of the cyclohexyl group on
the DAP catalyst with an aromatic substituent (R = Ph and 4-tBu-
C6H4) led to a significant improvement in enantioselectivity (50%
and 86% ee, entries 3 and 4). Since several DAP catalysts were
ineffective in the transformation, full analysis of the catalyst
variance could not be made, but models of further data presented
in the Supporting Information suggest that sterics may be more
significant for catalyst selection in this reaction than for pyrrolidine
formation, which is in agreement with the formation of a more
sterically encumbered fully-substituted stereocenter. Lastly,
Figure 4. (a) Variance of DAP and TAP catalysts. (b) Model describing the DAP
catalyst variance in the presence of Pd, in which (S)-2a is formed as the major
enantiomer. (c) Model describing the DAP catalyst variance in the absence of
Pd, in which (R)-2a is formed as the major enantiomer.
5
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10.1002/anie.202006237
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RESEARCH ARTICLE
the flexibility of the DAP catalyst family enables the phosphate
anion to afford reactivity and selectivity in both settings.
Table 2. Optimization of benzomorpholine formation[a]
Finally, to test the limitation of the substrate scope, the methyl
group in allylic alcohol 7a was replaced by alternative
substituents. Changing to either a hydrogen atom or ethyl
substituent did not inhibit cyclization, affording products 8r and 8t
in 86% yield with 83% ee, and 68% yield with 84% ee,
respectively. However, allylic alcohols 7u and 7v, with benzyl- or
phenyl-substituents, were unreactive under the standard reaction
conditions, representing the limits of our current approach.
Conclusion
We report herein mechanistic studies on the asymmetric induction
of Pd/CPA catalyzed enantioselective allylic substitutions.
Several notable observations and conclusions can be drawn from
these studies: (1) CPAs catalyze both palladium- and Brønsted
acid-catalyzed allylic substitution reactions with high
enantioselectivity; (2) deuterium-labeling experiments are
consistent with an outer-sphere nucleophilic addition to a π-
allylpalladium intermediate, in which the CPA acts as a chiral
anion in the enantio-determining step. In contrast, the CPA
directly participates in the Brønsted acid-catalyzed SN2'-type
substitution. Overall, these divergent mechanistic paradigms
allow for the preparation of both enantiomers of the product using
a single enantiomer of the CPA catalyst; (3) the origin of this
enantio-divergence was investigated by statistical modeling,
providing correlations to understand the noncovalent interactions
for both reaction pathways. Remarkably, catalyst flexibility allows
the CPA to adapt to leverage these NCIs, despite the different
requirements for enantioselectivity in each; (4) finally, the
Pd/CPA-catalyzed reaction allowed for the asymmetric
construction of C−O bonds at fully-substituted carbon centers,
giving challenging chiral 2,2-disubstituted benzomorpholine
motifs. In combination, these results highlight that chiral
phosphoric acid catalysis with DAPs, in both palladium- and direct
phosphate catalysis, enables unique reactivity in accessing both
Entry
Substrate
Catalysts
conv. (%)[b]
ee (%)[c]
1[d]
2
7a
7a
7a
7a
7a
7a
7a’
Pd(PPh3)4 / 4a
Pd(PPh3)4 / 4a
Pd(PPh3)4 / 4c
Pd(PPh3)4 / 4e
Pd(PPh3)4 / 4e
Pd(PPh3)4 / 3
4e
25
72
5
9
3
100
50
86
93
n.d.
−15
4
59
5[e]
6
100 (89)
trace
24
7[d]
[a] The reaction was carried out with 10 mol% of Pd(PPh3)4 and/or CPA 3/4 in
toluene/H2O (10/1 v/v) at ambient temperature. [b] conv. represents conversion
measured by crude 1H NMR, isolated yields in parentheses. [c] ee of product
8a, determined using HPLC equipped with a chiral column, wherein a positive
ee corresponds to (R)-8a, and
configuration. n.d. = not determined. [d] Toluene was used as solvent. [e]
a negative ee to (S)-8a, as the major
PhCF3/H2O (10/1 v/v) was used as solvent, reaction duration 48 h.
optimization of the solvent enabled product 8a to be isolated in
89% yield with 93% ee (entry 5, see SI for details). In contrast,
using privileged CPA 3 in the synergistic catalysis gave only trace
product (entry 6), while the SN2’ reaction of 7a’ with DAPPhtBu 4e
gave the opposite enantiomer, (S)-8a, in 24% conversion and only
15% ee (entry 7). These comparative results demonstrate the
power of the DAP family of catalysts to expand the synthetic
applications of CPA catalysis beyond those of existing scaffolds.
We next investigated the scope of the reaction (Figure 5a), and
determined that the protecting group on the amine was again
important for enantiocontrol (8b–e), even though variation is distal
to the bond-forming centers. Additionally, manipulations of the
phenol substituents were found to be significant for
enantioselectivity (8a–b, 8f–p); the introduction of para-electron-
withdrawing groups led to significant erosion of enantioselectivity
(3% ee for 8n). Correlating the result of variance in both the
phenol substitution and protecting group, we found a strong
correlation between ΔΔG‡ and the HOMO energy, indicative of
divergent enantioselectivity with
a
single catalyst and
unprecedented access to tertiary ether stereocenters.
Acknowledgements
F.D.T. thanks the National Institutes of Health (R35 GM118190)
and M.S.S. thanks the National Institutes of Health (GM121383)
for support of this work. C.-C.T. thanks the Ministry of Science
and Technology, Taiwan, for a postdoctoral fellowship (106-2917-
I-564-056). C.S. thanks the EU for Horizon 2020 Marie
Skłodowska-Curie Fellowship (grant no. 789399). Resources
from the Center for High Performance Computing at the University
of Utah, and the Extreme Science and Engineering Discovery
Environment (XSEDE, supported by the NSF (ACI-1548562) and
provided through allocation TG-CHE190060), are gratefully
acknowledged. We thank Dr. Javier Arenas and Dr. Suhong Kim
(Berkeley), Dr. Tobias Gensch (Utah), Ms. Soumi Trebedi and
Prof. Raghaven Sunoj (IIT Bombay), for useful discussions.
the requirement for
a highly nucleophilic phenoxide for
enantiocontrol (Figure 5b). This suggests that the protecting
group can be used to modulate the enantioselectivity of the
reaction through orbital control, rather than through the adoption
of noncovalent interactions, as observed in the above study of
pyrrolidine formation. Despite the different demands on the
transition states imposed by the two substrate classes studied,
Keywords: catalyst control • chiral anions • noncovalent
interactions • palladium • statistical modelling
6
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Figure 5. (a) Scope of benzomorpholine synthesis. The reaction was carried out with 10 mol% of Pd(PPh3)4 and DAPPhtBu 4e in PhCF3/H2O (10/1 v/v) at ambient
temperature. Duration of reaction was 48 h, except 8e, 8m, 8n, 8p, and 8t, for which the duration was 72 h. Yields reported are isolated yields, ee was determined
using HPLC equipped with a chiral column. [a]PhCF3 was used as solvent. [b]Toluene was used as solvent. [c]Toluene/H2O (10/1 v/v) was used as solvent.
(b) Correlation of enantioselectivity with the HOMO energy for substrates 8a-o. 8p was excluded as the only example with significantly altered steric properties.
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8
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Entry for the Table of Contents
The mechanism through which a palladium catalyst and a chiral phosphoric acid act synergistically to induce enantiocontrol in
intramolecular allylic substitution reactions is investigated, with statistical modeling identifying multiple noncovalent interactions.
These studies led to an expansion of synthetic scope to the formation of challenging tertiary ether stereocenters.
9
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