Enantioselective conjugate addition catalyzed by a copper phosphoramidite complex: Computational and experimental exploration of asymmetric induction

Article abstract of DOI:10.1021/acscatal.7b01453

The stereochemical role of the phosphoramidite ligand in the asymmetric conjugate addition of alkylzirconium species to cyclic enones has been established through experimental and computational studies. Systematic, synthetic variation of the modular ligand established that the configuration of the binaphthol backbone is responsible for absolute stereocontrol, whereas modulation of the amido substituents leads to dramatic variations in the level of asymmetric induction. Chiral amido substituents are not required for enantioselectivity, leading to the discovery of a new family of easily synthesized phosphoramidites based on achiral amines that deliver equal levels of selectivity to Feringa's ligand. A linear correlation between the length of the aromatic amido groups and experimentally determined enantioselectivity was uncovered for this class of ligand, which, following an optimization, led to highly selective ligands (up to 94% ee) with naphthyl rather than phenyl groups. An electronic effect of sterically similar aromatic substituents was investigated through NMR and DFT studies, showing that electron-rich aryl groups allow better Cu coordination. An interaction between the metal center and an aromatic group is responsible for this enhanced affinity and leads to a more tightly coordinated transition structure, leading to the major enantiomer. These studies illustrate the use of parametric quantitative structure-selectivity relationships to generate mechanistic models for asymmetric induction and catalyst structures that may be further probed by experiment and computation. This integrated approach leads to the rational modification of chiral ligands to achieve enhanced levels of selectivity.

Full text of DOI:10.1021/acscatal.7b01453

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Article
Enantioselective conjugate addition catalyzed by a
copper-phosphoramidite complex: Computational
and experimental exploration of asymmetric induction
Ruchuta Ardkhean, Philippe Marie Christophe Roth, Rebecca M. Maksymowicz,
Alex Curran, Qian Peng, Robert S. Paton, and Stephen P Fletcher
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b01453 • Publication Date (Web): 23 Aug 2017
Downloaded from http://pubs.acs.org on August 23, 2017
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Page 1 of 11
ACS Catalysis
Enantioselective conjugate addition catalyzed by a
copper-phosphoramidite complex: Computational and
experimental exploration of asymmetric induction
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Ruchuta Ardkhean,a⊥ Philippe M. C. Roth,a⊥ Rebecca M. Maksymowicz,a Alex Curran,a Qian
Peng,b* Robert S. Paton,a* and Stephen P. Fletchera*
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aChemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, U.K. State Key Laboratory of Elemento-
Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
email: qpeng@nankai.edu.cn; robert.paton@chem.ox.ac.uk; stephen.fletcher@chem.ox.ac.uk
ABSTRACT: The stereochemical role of the phosphoramidite ligand in the asymmetric conjugate addition of
alkylzirconium species to cyclic enones has been established through experimental and computational studies.
Systematic, synthetic variation of the modular ligand established that the configuration of the binaphthol backbone is
responsible for absolute stereocontrol, whereas modulation of the amido substituents leads to dramatic variations in the
level of asymmetric induction. Chiral amido substituents are not required for enantioselectivity, leading to the discovery
of a new family of easily synthesized phosphoramidites based on achiral amines that deliver equal levels of selectivity to
Feringa’s ligand. A linear correlation between the length of the aromatic amido groups and experimentally determined
enantioselectivity was uncovered for this class of ligand, which, following an optimisation, leading to the highly selective
ligands (up to 94% ee) with naphthyl rather than phenyl groups. An electronic effect of sterically similar aromatic
substituents was investigated through NMR and DFT studies, showing that electron rich aryl groups allow better Cu-
coordination. An interaction between the metal center and an aromatic group is responsible for this enhanced affinity
and leads to a more tightly-coordinated transition structure leading to the major enantiomer. These studies illustrate the
use of parametric quantitative structure-selectivity relationships to generate mechanistic models for asymmetric
induction and catalyst structures that may be further probed by experiment and computation. This integrated approach
leads to the rational modification of chiral ligands to achieve enhanced levels of selectivity.
KEYWORDS: Asymmetric catalysis, phosphoramidite ligand, copper, quantitative structure selectivity relationship, linear
free energy relationship, steric parameters, quantum chemical calculations, mechanism.
Introduction: The development of modular chiral
ligands has led to the discovery of transition metal:ligand
complexes that catalyze various reactions with impressive
theoretical, and most recently through the application of
free energy relationships, which relate the effects of
catalyst, ligand or substrate structural modifications to
enantioselectivity in a quantitative way.11 Linear free
energy relationships (LFERs) have been applied to studies
of selectivity in kinetically controlled reactions arising
from differences in activation free energies, ꢀꢀG‡.12 Such
correlations give important insight into the selectivity-
determining transition structures (TSs), which in turn can
be used to modify catalyst structures to enhance
selectivity. Where the mechanism is confidently known,
computations may be used to compare competing TSs of
the selectivity-determining step, for example using
levels
of
enantioselectivity.1
Among
others,
phosphoramidites are “privileged” ligands.1c,2 They are
modular, easy to synthesize and provide high levels of
stereocontrol in
a wide variety of processes. First
introduced by Feringa3 and Alexakis4 for work on copper
catalyzed asymmetric conjugate additions5 they have
become invaluable workhorse ligands that perform well in
processes catalyzed by copper,6 iridium,7 palladium,8
rhodium9 and gold.10 This modularity provides the
opportunity for systematic variation of ligand structure
and optimization of enantioselectivity.
quantum-guided-molecular
mechanics
(Q2MM)
The discovery of the appropriate chiral ligands for a
desired transformation remains a formidable task in
general, especially for reactions where detailed
transition state force fields which permit thorough
conformational sampling.13 However, it is also possible to
derive meaningful and predictive correlations between
computed properties and experimental selectivities in the
absence of a mechanistic or TS model, as has been
demonstrated by the use of functionality mapping
methods, grid based quantitative structure-selectivity
relationships (QSSR),14 three dimensional QSSR,15 and
multidimensional structure-selectivity models.16
mechanistic data are yet to be uncovered. As
a
consequence, chance, intuition, and systematic screening
all play an important role in the discovery and
development of enantioselective catalytic reactions.
Understanding the interactions that give rise to
asymmetric induction is key to the rational design and
improvement of chiral catalysts. This knowledge is
derived from mechanistic studies, both experimental and
The use of multidimensional Sterimol parameters,
originally developed for quantitative structure–activity
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relationships in medicinal chemistry,17 leads to more
detailed description of steric parameters and also provide
greater mechanistic insight into key elements of
asymmetric induction.18 Recently, Sigman19 and others20
have applied the use of multidimensional Sterimol
parameters as the steric descriptors for QSSR and applied
it to problems regarding enantioselectivity in catalytic
asymmetric reactions.
Page 2 of 11
O
O
Cp2ZrHCl, CH2Cl2;
1
2
3
4
5
6
7
+
10% Ligand
10% CuCl, 11% AgOTf
or 5% (CuOTf)2—PhH
CH2Cl2, rt
Ph
O
O
O
O
O
O
P
N
P
N
P N
P
N
O
O
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9
We recently reported catalytic asymmetric conjugate
addition of alkylzirconium species to cyclic enones and
other Michael acceptors, in which a phosphoramidite
ligand is responsible for enantioselectivity.21 Here we
report systematic, synthetic variation of the modular
phosphoramidite structure to explore how structural
elements of the phosphoramidite ligand affect catalyst
selectivity in conjugate additions. Elucidation of the
important interactions is achieved via a combination of
quantitative analysis of the effects of ligand-structural
(Sa,R,R)ꢀB 74% ee
(R,R)ꢀC 17% ee
(R,R)ꢀD 25% ee
(Sa,S,S)ꢀA 80% ee
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O
O
O
Br
Br
O
P
N
P
N
P
N
O
O
(Rs,R,R)ꢀE 64% ee
(Sa,R,R)ꢀF 68% ee
(Sa,R,R)ꢀG 67% ee
Br
R
O
P
O
P
Ph
Ph
O
P
N
N
N
O
O
O
variation
on
the
resulting
enantioselectivity,
spectroscopic examination of metal-ligand complexes,
and DFT calculations. Never before have the
enantiocontrolling factors been identified for chiral
phosphoramidite ligands in copper catalysed conjugate
addition reactions.5d,5e,22
Br
R
(Sa,R,R)ꢀJ (R=Ph) 32% ee
(Sa,R,R)ꢀK (R=Me) 65% ee
(Sa,R,R)ꢀH 74% ee
(Sa,R,R)ꢀI 28% ee
Scheme 1. Variation of the ligand backbone.
The BINOL unit is also important in that its
stereochemistry governs the absolute sense of
stereoinduction in the product: (Sa,S,S)-A and (Sa,R,R)-B
both catalyzed formation of the (S)-ketone product with
nearly equivalent levels of selectivity.
Results and Discussion: The hydrometallation
–
asymmetric conjugate addition of 4-phenyl-1-butene to
cyclohexenone is shown in Scheme 1. Hydrometallation
in DCM using the Schwartz reagent23 and addition of the
resulting alkylzirconocene to
a solution of A and
Variation of the amido substituents: Retaining the
BINOL backbone, we examined variations of the amido
moiety on the ligands (Table 1). For simple alkyl
substituents, there is a general trend of increasing
selectivity as methyl groups are replaced by larger,
branched groups, with cyclohexyl-substitution giving 56%
ee (ligand O). When the alkyl group is too large such as
an adamantyl group, there is erosion of selectivity (P, 17%
ee). As ligands bearing simple alkyl substituents gave
lower enantioselectivity (7-56% ee), we examined ligands
more closely related to A; Ligand Q, first used by
Alexakis7b and bearing methoxy groups on the aryl rings,
reduced selectivity (43% ee), R24 with 2-naphthyl instead
copper(I)-triflate benzene complex in DCM gave the
product with 80% ee. Conditions which generate CuOTf
in situ (CuCl/AgOTf) give identical results, are highly
reproducible even on small scales (±2% ee for all cases
examined, 0.2 mmol), and were used throughout this
work (see SI p. S11-12). First, Feringa’s ligand A was
subjected to the screening conditions and found to give
good enatioselectivity (80% ee). Subsequently, we made
structural variations to the binaphthol (BINOL) backbone
while maintaining the structure of the amido-moiety. The
enantioselectivities obtained using 10 modified ligands
including catechol, biphenol and spirobiindanediol
backbones, are summarized in Scheme 1. As no backbone
gave higher enantioselectivity (17-74 % ee) than binol
(80% ee), this feature was retained in all subsequent
studies.
of
phenyl
rings
resulted
in
slightly
lower
enantioselectivity (76% ee), and S which has identical
structure as A except for replacing one methyl group with
H gave 43% ee.
We also explored N-substitutions where the aromatic ring
was part of a bi- or tri-cycle (T-X). This led to ligands with
2,3-dihydroindenyl moiety (T, U, V) which give
enantioselectivities comparable to A (72-75% ee vs. 80%
ee). These ligands gave similar ee’s despite the remarkable
difference in the structures of the other N-substituents.
Increasing the size of the bicyclic ring to 1,2,3,4-
tetrahydro-1-naphthyl moiety in W resulted in lower
selectivity (67% ee), while fluorenyl containg X gave even
poorer selectivity (53% ee).
The above results show no obvious correlation between
steric or electronics elements of the amino-substituents
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and Z to AI, the substituent pattern of naphthyl rings (R1)
and the measured ee, but rather illustrate that
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enantioselectivity is extremely sensitive to these
substituents, and ranges from 7-76%. Applying transition
state theory at room temperature the experimental ꢀꢀG‡
values range from 0.4-4.8 kJ/mol. Subsequently, a second
generation of ligands was examined where structural
variation is limited to a single substituent while the other
amido group remains unchanged. The larger of the two
N-substituents is divided at α-C into 2 groups: R1 and R2
where R1 is larger than R2. The smaller N-substituent is
labeled as R3. Following this approach, we examined
ligands where R3 is varied while R1 and R2 are fixed as 2-
naphthyl and methyl respectively (Y-AG). Across the
series from Y to AB the enantioselectivity progressively
increased with R3-substituent size (methyl, ethyl,
isopropyl, cyclohexyl) from 15-73% ee (ꢀꢀG‡ = 0.8-4.5
kJ/mol). A conformationally locked cyclohexane (AC)
gave similar levels of enantioselectivity as unsubstituted
cyclohexane (AB). A larger, cycloheptane group gave
lower ee (AD, 48%) and using adamantyl (in AE) is
detrimental to selectivity (5% ee). Ligand AG with sp2-
hybridized R3 and ligand AF with a benzyl group also gave
poor enantioselectivities (17% and 38% ee respectively).
The same trend was observed in a pair of ligands where R1
and R2 are 1-naphtyl and methyl (AH and AI) so that a
branched alkyl group gave higher selectivity than methyl
(48% and 15% ee). Notably, comparing ligands Y to AH
effects selectivity only when R3 is larger than methyl,
suggesting that the effects of each substituents are
dependent on one another i.e. their effects on ee are not
additive.
To gain insight into whether the electronic character of
the aromatic substituents is important for selectivity, we
maintained R3 as an isopropyl group while employing α-
methyl-aryl amido groups with differing aromatic
substituents/positions (AJ-AR). A subtle, but measurable
effect was evident: aromatic substitution of the phenyl
ring in AJ with varying substituents (halides, methyl and
methoxy) and position (ortho-, meta or para-) results in
an increase in selectivity from 51% ee (experimental ꢀꢀG‡
= 2.8 kJ/mol), to ee values of 60-72% (experimental ꢀꢀG‡
= 3.4-4.5 kJ/mol).
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Ligands bearing achiral N-substituents are considerably
easier to access than the chiral substituents and we
explored achiral amido structures. While AS gave only
55% ee, we were delighted to find that AT gave
comparable selectivity to A (78% ee). Analogues of AT
where the isopropyl group (R3) was replaced by 5-, 6-, and
7-membered cycloalkanes only slightly affected ee, with
AV giving the best result (86% ee).
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Table 1. Enantioselectivity observed for ligands with BINOL backbones and variation on amine substituents.
1
2
3
4
5
R1
O
O
R2
Cp2ZrHCl, CH2Cl2;
R1 ≥ R2
O
O
+
P
N
CH(R1)(R2) ≥ R3
10% Ligand
10% CuCl, 11% AgOTf
or 5% (CuOTf)2—PhH
CH2Cl2, rt
Ph
R3
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7
8
9
Ligand substituents
R2 R3
Measured
Variation of amido substituents
Alkyl substituents
Ligand
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R1
ee(%)
Variation of single N substituent (R3)
Yb
Zb
Methyl
Ethyl
Isopropyl
15
26
68
73
N
AAb
N
N
N
N
Me
ABb
ACb
Cyclohexyl
R3
N
M 7% ee
N
a entꢀ59% ee
La entꢀ17% ee
Oa entꢀ56% ee
Pa entꢀ17% ee
70
Ligands similar to A
ADb
Cycloheptyl
48
5
R1 = 2-Naphthyl,
Adamantyl
AEb
OMe
OMe
R2 = Methyl
Benzyl
N
N
N
AFb
38
17
Q 43% ee
R 76% ee
S 43% ee
Bicyclic and tricyclic substituents
AGb
Phenyl
Me
AHb
AIb
Methyl
15
R3
N
N
N
N
N
N
Isopropyl
49
R1 =1-Naphthyl,
R2 = Methyl
T 75% ee
U 72% ee
V 76% ee
W 67% ee
Xa entꢀ53% ee
Achiral substituents
Variation of aromatic substituent (R1)
AJb
AKb
ALb
AMb
ANb
Phenyl
51
N
4-Me-C6H4
64
ASa entꢀ55% ee
4-FC6H4
Me
60
Ligand substituents
Measured
4-Cl-C6H4
67
65
Ligand
N
R1
R1
R2
R3
ee (%)
3-Cl-C6H4
R2 = Methyl,
R3 = Isopropyl
AT
Isopropyl
78
AOa,c
3-Br-C6H4
ent -67
AU
AV
Cyclopentyl
Cyclohexyl
78
86
APb
4-MeO-C6H4
3-MeO-C6H4
72
69
R3
AQb
N
AW
Cyclooctyl
77
ARb
2-MeO-C6H4
66
R1, R2 = Phenyl
aLigands with (R)-BINOL backbone (otherwise (S)-BINOL), b(S)-amine, c(R)-amine.
model we prepared a series of new ligands (testing sets)
where a branching amido group bears two identical aryl
units (R1 = R2) and R3 is fixed as a branched alkyl group
(isopropyl or cyclohexyl) (Scheme 2). This also served to
remove asymmetry issues from the amido unit and
facilitated the synthesis of the ligands AX-BF.
In contrast to results obsereved with AJ to AR, Ligands
bearing two identically substituted aryls (AX-BA; 62-70%
ee) all showed lower ee than unsubstituted ligand AS.
Ligands bearing electron withdrawing group showed even
lower ee (BB, BC; 20-55% ee). 2-Naphthyl bearing BD
gave comparable selectivity to AS whereas 1-Naphthyl BE
was found to give the highest enantioselectivity (85% ee).
To summarize, varying amido substituents demonstrated
that high ee could be obtained in ligands besides
privileged A. Clearly an optimal level of steric bulk is
important and aromatic groups, although not directly
bonded to N (R1/R2), benefits selectivity. Furthermore, a
chiral amido group is not essential for high
stereoinduction. Nonetheless, with the exception of
ligand AV, all ligands showed levels of stereoinduction
lower than A, and so we sought to establish a quantitative
relationship between structure and selectivity using a
computational approach, with which to design new
ligands afresh (see the correlation section below for
detail).
3rd generation phosphoramidites: A preliminary model
which correlates steric bulk of R1 and R2 to
enantioselectvity was established (Figure S2). To test the
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O
O
Cp2ZrHCl, CH2Cl2;
O
O
1
2
3
4
5
6
7
8
10% Ligand
+
Cp2ZrHCl, CH2Cl2;
5% (CuOTf)2—PhH
5 eq. TMSCl, Et2O
room temperature
Ph
(S,S,S)-A 90% ee
BE 94%ee
AV 86% ee
+
10% Ligand
10% CuCl, 11% AgOTf
or 5% (CuOTf)2—PhH
CH2Cl2, rt
Ph
"optimized" conditions
tBu
Scheme 3. Asymmetric conjugate addition with ligands A,
AV and BE under optimized conditions.
tBu
tBu
tBu
O
O
O
O
P
N
P N
P
N
O
O
NMR spectroscopy of Cu-ligand complexes and test
for non-linear effect: The effect of the size, but not
electronics, on copper : phosphoramidite
9
(R)ꢀAX entꢀ70% ee
(R)ꢀAY entꢀ69% ee
(R)ꢀAZ entꢀ62% ee
solution
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20
O
CF3
CF3
F3C
behaviour has been studied by Gschwind using NMR
spectroscopy and revealed mixed trigonal/tetrahedral
dimers and higher aggregation states.25 We were curious
as to why A and isomeric AT gave similar levels of
selectivity (80 and 78% ee respectively) yet tetra-
trifluoromethyl BC gave only 20% ee. We therefore
examined CuOTf:phosphoramidite complexes with
ligands A, AT, and BC by NMR spectroscopy. NOE and
NOESY NMR spectroscopy with CuOTf:L complexes
indicated that AT and BC exhibit a similar conformational
preference in solution (See SI), a notion supported by
dispersion-corrected DFT calculations (see below and SI).
During the NMR experiments it became clear that Cu:L
complexes did not form nearly as readily or cleanly using
electron deficient BC Figure 1a. Several attempts were
required to observe CuOTf:BC by NMR spectroscopy;
significant degradation was often observed, and when the
complex was formed, it was accompanied by AgOTf:BC.
Assignment as AgOTf:BC was made by a control reaction,
and 1,4-addition is not catalyzed by these silver
complexes. EXSY (exchange spectroscopy) experiments
demonstrate that AgOTf:BC and CuOTf:BC undergo
rapid metal/ligand exchange on the NMR timescale at
room temperature.
CF3
O
CF3
O
O
O
P
N
P
N
P
N
O
O
O
CF3
(S)ꢀBA 64% ee
(R)ꢀBC entꢀ20% ee
(R)ꢀBB entꢀ55% ee
O
O
P
N
O
P
N
O
P
N
O
O
(R)ꢀBD entꢀ76% ee
(R)ꢀBE entꢀ85% ee
(R)ꢀBF entꢀ80% ee
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Scheme 2. Phosphoramidites with achiral bis-aryl amido
substituents.
By subjecting ligands A, AV and BE to the previously
reported optimised conditons21a using copper(I)-triflate
benzene complex and 5 equiv. of TMSCl in Et2O, product
was obtained with 90% ee using A and 94% ee when
using BE. However, the enantioselectivity obtained using
ligand AV was not changed with these reaction conditions
(86% ee, Scheme 3). While it is difficult to rationalize why
some ligands would show an upward shift in ee values (A
and BE) under our previously reported conditions, and
some would not (AV), it is possible that there is some
variation in the mechanism of control under the two sets
of conditions.
DCM, 1 h RT;
AgOTf, 15 min;
Ligand:CuOTf
complex
Ligand:AgOTf
complex
Ligand
+ CuCl
+
a)
filter, concentrate;
NMR in CD2Cl2
[L:Cu] : [L:Ag] =
CF3
F3C
O
O
P
O
O
CF3
N
P
N
P
N
O
O
CF3
(Sa,S,S)ꢀA (80% ee)
(S)ꢀAT (78% ee)
(R)ꢀBC (entꢀ20% ee)
L:Cu only; L:Ag not detected
15.4 : 1
~1.4 : 1
Figure 1. a) NMR spectroscopic studies on ligand:CuOTf and ligand:AgOTf complexes, b) Computed structures and relative
free energies of AT:CuOTf and BC:CuOTf complexes (SMD-B97D/def2-TZVPP//B97D/6-31G(d)), c) Relative stabilities of
Ligand:CuOTf complexes, their Cu-C bond distances (Å) with corresponding second-order interaction energies in the NBO
basis.
DFT was used to gain insight into the structures and
stabilities of the Cu:L complexes in Figure 1b. Following a
conformational search (see the Supporting Information)
the most stable conformation for each CuOTf:L complex
was obtained. Structures were optimized at the B97D/6-
B97D/def2TZVPP single point energetics were evaluated
on these stationary points. Complexation free energies for
the free ligands to form AT:CuOTf and BC:CuOTf, ∆∆Gs
were computed to be less favorable than A:CuOTf by 6.0
kJ/mol and 9.4 kJ/mol, respectively. In each of the
calculated complexes (1 and 2), the i-Pr amido-substituent
31G(d)
level
in
dichloromethane
(SMD)
and
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is oriented distal to Cu, with the diphenyl group proximal.
Page 6 of 11
work, we discovered a correlation between Sterimol
parameters18
and the experimentally observed
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This preference results from the ability of one of the aryl
rings to form a favorable interaction with the metal center
and its π-face. The computed distance between Cu and
the nearest aromatic C atom is 3.04 Å and 3.16 Å in
AT:CuOTf, in close contact based on the sum of the two
van der Waals radii (vdW radii: C 1.70 Å , Cu 1.40 Å)26 and
indicative of an attractive interaction. Metal:arene
coordination has been observed previously in X-ray
structures of d8-metal-phosphoramidite complexes and 2-
dimethylamino-2 -diphenylphosphino-binaphthyl
enantioselectivities on the “training” data set (see SI,
Figure S2). Sterimol parameters account for the spatial
anisotropy of subtituents. The
L value denotes a
substituent’s length in the direction of its attachment.
The B1 value is the minimum width of the substituent
perpendicular to the direction of L. Both are quoted in Å.
According to Verloop’s original defition the atomic
surface is defined by CPK radii. The correlation between
enantioselectivity and this purely steric model for the
ligand’s substituents gave unsatisfactory statistical fit
using the “training” data, and 3rd generation ligands
prepared to test this model were not adequately
described. A model that only contains steric parameters,
(SI p.S258, Figure S2) has a lower correlation coefficient
(R2 0.48) compared to models where both electronic and
steric factors are considered (vida infra, Figures 2 and 3).
Since NMR and DFT studies suggest ligand electronics are
important, we refined our initial model to include
electronic parameters. Of those considered, the most
statistically significant (as judged by its impact on
correlation, R2) electronic parameter was found to be the
computed HOMO energy. This was computed for each
isolated substituent, the bond to nitrogen being capped
by a methyl group. We found that a non-linear model
containing the two Sterimol L parameters, one each for R1
and R2, and the HOMO energy as a single electronic
descriptor gave a good correlation with experimental
results for all 21 ligands considered. This expression,
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ligands.27 Tuning of the metal:arene interaction in
phosphoramidite complexes has been used to optimize
levels
of
stereoinduction
in
Rh-catalyzed
cycloisomerization.28
Ligands AT and A both form stable complexes with
copper and give high enantioselectivity with arene:Cu
interactions evident in optimized structures. In contrast,
for BC this interaction is weaker: the distance between
Cu and the aromatic C atoms in the most stable
conformation are 3.11 Å and 3.59 Å to ortho-C and ipso-C,
respectively. NBO calculations suggest that the electron
donation from the arene π-system to Cu dominates this
interaction (Figure 1c). Electron withdrawing groups in
ligand BC are predicted to reduce this interaction and
destabilize the ligand:CuOTf complex, consistent with the
NMR data. In the case of ligand M bearing dimethyl
substituents on the amido group, no such interacton can
occur. We hypothesize that this interaction between
ligand aromatic substituent and metal provides
conformational rigidity to the chiral environment
surrounding the metal center and contributes to
asymmetric induction.
These results are consistent with enantioselectivity
being dependent on the ability of the phosphoramidite to
readily form a stable CuOTf complex. Presumably, an
achiral copper complex (e.g. CuOTf) is able to catalyze
the racemic background reaction,29 leading to an erosion
of observed enantioselectivity. This is consisted with an
observed correlation of selectivity with ligand parameters
(see below and Figure 2, black circles): there is a
correlation between selectivity and steric parameters, but
there are clusters of several ligands with similar size but
different ꢀꢀG‡ values. These ligands differ by aromatic
substituents and it appears that electronic effects affect
the ability to form an effective catalyst complex.
‡
ꢀꢀGexpt = 3.80 + 1.00HOMOR1(1 + 2.31LR2) – 1.14LR1 × LR2,
contains four fitting parameters with root-mean-square
error (RMSE) of 0.44 kJ/mol. A validation of this model in
the form of leave-one-out cross-validation yielded a good
cross-validated correlation coffeicient, q2 = 0.79. The
graphical model, expressed as enantiomeric excess ratio,
is shown in Figure 2. In terms of physical meaning, the
model illustrates the importance of both the R1 and R2
substituent’s length as well as the electronics of both the
overall ligand and one of the two R-groups, this is in line
with the stuctural hypothesis detailed below, in which
one of the R-groups coordinates to the metal center
making it electronically more important than the other R
group.
A test for non-linear effects30 was carried out in order to
gain insight into the identity of catalytic species using
scalemic AT (see Figure S1, p. S7). We observed a linear
relationship between the ligand enatiomeric excess and
the enatiomeric excess of the product which is consistent
with 1:1 metal : ligand stoicheometry in the chiral catalyst
.
Correlation of selectivity with steric and electronic
parameters: By correlating structural and electronic
descriptors for each ligand with the observed
experimental enantioselectivity, we reasoned it would be
possible to gain insight into the importance of steric
and/or electronic factors upon stereoinduction. In this
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R1
R1
R
R22
O
O
R1
R1
P
N
R2
R2
R
R3
3
O
O
P
N
iPr
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ꢀꢀG‡ (kJ/mol) = ꢀ0.35 + 0.92HOMOR1(1 + 1.99LR2
)
ꢀ 1.04LR1 x LR2 + 5.86exp(ꢀ0.276(B1R3 ꢀ 1.18)2
R2 = 0.79, RMSE = 0.76 kJ/mol, q2 (LOOCV) = 0.77
ꢀꢀG‡ (kJ/mol) = 3.80 + 1.00HOMOR1(1 + 2.31LR2) ꢀ 1.14LR1 x LR2
Estimated enantiomeric excess (%)
R2 = 0.80, RMSE = 0.44 kJ/mol, q2 (LOOCV) = 0.79
Figure 3. Correlation of enantioselectivity and model
utilizing steric and electronic parameters for all subtituents
on amine. (black- previous training set, blue-previous testing
set, red – ligands with R3≠iPr)
Estimated enantiomeric excess (%)
Figure 2. Correlation of enantioselectivity and model
utilizing steric and electronic parameters. (black- previous
training set, blue-previous testing set)
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To further clarify the role of the phosphoramidite upon
reactivity and stereoinduction, we examined the
competing TSs for conjugate addition using DFT
calculations.31 Several conformations of the Cu complexes
in the stereodetermining carbocupration step were
considered of which the two most stable are presented
(see the Supporting Information for all conformers). In
the interest of computational tractability, the alkene was
modeled by ethylene, but the structures of enone, catalyst
and ligands are identical to those used experimentally.
The most stable conformations of the TSs in are shown in
Figure 4a. This is the stereodetermining step:
irreversibility is predicted from the large >30 kcal/mol
computed barriers in the reverse direction. Based on the
magnitude of experimental Cu(I):alkene association
constants (0.1 to 18 M-1), along with observations of
dynamic alkene exchange on the NMR timescale,32,33 we
do not expect the formation of the Cu(I):alkene complex
The model in Figure 2 was generated from ligands with
iPr group as R3. By examining of the conformations of the
calculated transition states, R3 is on the opposite side of
the ligand from R1 and R2, away from the enone starting
material. Direct steric interactions between R3 and enone
are not possible in this conformation. However,
experiment data clearly illustrate the importance of R3 to
the enantioselectivity of the Michael addition. To account
for the other ligands where R3 are not an iPr group, we
have generated a more general model with an additional
steric term for R3 in a form of Gaussian function while
retaining the steric and electronic terms for R1 and R2
from the previous model. This resulted in a new non-
‡
linear expression, ꢀꢀGexpt = – 0.35 + 0.92HOMOR1(1 +
1.99LR2) – 1.04LR1 × LR2 + 5.86exp(– 0.276(B1R3 – 1.18)2), with
5 parameters. The model shows good correlation (R2 =
0.79) on 38 ligands with RMSE of 0.76 kJ/mol. Leave-one-
out cross-validation of the final model resulted in a good
cross-validated correlation coffeicient of q2 = 0.77. Based on
F-statistics all parameters were shown to be statistically
significant at the p<0.05 level. This model, expressed as
enantiomeric excess ratio, is shown in Figure 3. The use of
a Gaussian plot can be explained by our rationalisation
that there is an optimal size of R3 that fits under the
BINOL ring such that R1 and R2 can adopt the
conformation that does not disrupt any favourble
interaction between the metal and R1. From our fitting,
the Gaussian curve centred around 1.18 which is equvalent
to B1 of 2.39 Å, an estimated ‘ideal’ width for R3. The small
slope around the maximum of the Gaussian curve means
that small deviation of B1 from this ideal value will not
drastically lower the enatioselectivity, allow for a range of
synthetically plausible groups that resulted in maximum
enantioselectivity achieved with respect to R3 e.g.
isopropyl, α-methylnaphthyl, and cyclohexyl substituents.
to
be
stereodetermining.
The
calculated
enantioselectivities34 are in the same sense as the
experimental data with ligand AT and BE with ZrCp2Cl
and TMSCl as Lewis acids (screening vs. optimised
reaction condition). These calculations provide a model
with which to understand the correlation established
above. In both cases, clear differences in the distance
between metal and the aryl group in the competing pair
of TSs indicate that a copper-arene interaction favors the
formation of the major enantiomer of the product. Fig 4b
shows that the energetic difference between competing
TSs is linked to the differential interaction strength in
each structure. This interaction was also found in the
copper salt-ligand complexes as shown previously
(Scheme 3). In the QSSR model, HOMO energy of the aryl
ring alone has positive contribution to the
enantioselectivity. A higher energy HOMO of the aryl
rings indicates
a
better electron donor, and
corresponding stronger interaction with copper,
increasing the enantioselectivity.
a
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Figure 4. a) Stereodetermining TSs with ligand AT and BE. SMD-B97D/def2-TZVPP ꢀꢀG‡ (298K); selected distances in Å. b)
Experimental ꢀꢀG‡ against Cu-arene distances (Å) for ligands BC, AT and BE with different Lewis acids.
complexes by NMR spectroscopy. Full details of all computed
parameters and details of model building. Cartesian
coordinates and absolute energies of all computed stationary
points. This material is available free of charge via the
Internet at http://pubs.acs.org.
Conclusions: The stereochemical role of the
phosphoramidite ligand in the asymmetric conjugate
addition of alkylzirconium species to cyclic enones has
been firmly established through experimental and
computational studies. Systematic, synthetic variation of
the modular ligand established that while the binaphthol
backbone configuration is responsible for absolute
stereocontrol, modulation of the amido substituents leads
to dramatic variations in the levels of asymmetric
induction. The chirality of these substituents is relatively
unimportant, to the extent that ligands of the type AT
have been developed from achiral amines, and show
equivalent levels of selectivity with Feringa’s ligand. A
linear correlation was uncovered between the HOMO
energy and the length of the aromatic groups and the
experimentally determined enantioselectivity for this
class of phosphoramidites. NMR and DFT studies
confirmed that ligands containing electron rich aryl
groups led to stronger coordination and to structurally
more well-defined complexes with Cu. An important
interaction between the metal center and one of these
aromatic groups is responsible for this enhanced affinity,
and is maintained in the favoured transition state
structure leading to the major enantiomer. A refined
model, containing both steric parameters and an
electronic description of the amido-substituents was
derived that was capable of fitting all 38 cases examined
where Ri are alkyl or aryl substituents. These studies
illustrate the ability of quantitative structure-selectivity
relationships to provide both models for asymmetric
induction and catalyst structural hypotheses that may be
further probed by experiment and computation.
Collectively, such an approach emphasizes the
importance of both ligand steric and electronic
properties, which were optimized to achieve enhanced
levels of selectivity of up to 85% ee under screening
conditions with naphthyl rather than phenyl groups, and
94% ee under optimized ACA conditions.
AUTHOR INFORMATION
Author Contributions
⊥
These authors contributed equally to this work.
Corresponding Authors
Computational: qpeng@nankai.edu.cn;
robert.paton@chem.ox.ac.uk; Experimental:
stephen.fletcher@chem.ox.ac.uk
ACKNOWLEDGMENT
We thank the EPSRC (Career Acceleration Fellowship to SPF
[EP/H003711/1]), the CSA Trust (Grant to RSP) for funding,
the European Community (FP7-PEOPLE-2012-IIF under
grant agreement 330364 to QP), and Dr B. Odell for
assistance with the NMR experiments. We also thank the
Development and Promotion of Science and Technology
Talents Project (DPST), Royal Thai Government and the
EPSRC Centre for Doctoral Training in Synthesis for Biology
and Medicine (EP/L015838/1) for a studentship to RA,
generously supported by AstraZeneca, Diamond Light
Source, Defense Science and Technology Laboratory, Evotec,
GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta,
Takeda, UCB and Vertex. We acknowledge the use of the
EPSRC UK National Service for Computational Chemistry
Software (CHEM870).
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