Mechanistic studies inform design of improved Ti(salen) catalysts for enantioselective [3 + 2] cycloaddition

Article abstract of DOI:10.1021/jacs.0c07128

Ti(salen) complexes catalyze the asymmetric [3 + 2] cycloaddition of cyclopropyl ketones with alkenes. While high enantioselectivities are achieved with electron-rich alkenes, electron-deficient alkenes are less selective. Herein, we describe mechanistic studies to understand the origins of catalyst and substrate trends in an effort to identify a more general catalyst. Density functional theory (DFT) calculations of the selectivity determining transition state revealed the origin of stereochemical control to be catalyst distortion, which is largely influenced by the chiral backbone and adamantyl groups on the salicylaldehyde moieties. While substitution of the adamantyl groups was detrimental to the enantioselectivity, mechanistic information guided the development of a set of eight new Ti(salen) catalysts with modified diamine backbones. These catalysts were evaluated with four electron-deficient alkenes to develop a three-parameter statistical model relating enantioselectivity to physical organic parameters. This statistical model is capable of quantitative prediction of enantioselectivity with structurally diverse alkenes. These mechanistic insights assisted the discovery of a new Ti(salen) catalyst, which substantially expanded the reaction scope and significantly improved the enantioselectivity of synthetically interesting building blocks.

Full text of DOI:10.1021/jacs.0c07128

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Mechanistic Studies Inform Design of Improved Ti(salen) Catalysts
for Enantioselective [3 + 2] Cycloaddition
Sophia G. Robinson,† Xiangyu Wu,† Binyang Jiang, Matthew S. Sigman,* and Song Lin*
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ABSTRACT: Ti(salen) complexes catalyze the asymmetric [3 +
2] cycloaddition of cyclopropyl ketones with alkenes. While high
enantioselectivities are achieved with electron-rich alkenes,
electron-deficient alkenes are less selective. Herein, we describe
mechanistic studies to understand the origins of catalyst and
substrate trends in an effort to identify a more general catalyst.
Density functional theory (DFT) calculations of the selectivity
determining transition state revealed the origin of stereochemical control to be catalyst distortion, which is largely influenced by the
chiral backbone and adamantyl groups on the salicylaldehyde moieties. While substitution of the adamantyl groups was detrimental
to the enantioselectivity, mechanistic information guided the development of a set of eight new Ti(salen) catalysts with modified
diamine backbones. These catalysts were evaluated with four electron-deficient alkenes to develop a three-parameter statistical model
relating enantioselectivity to physical organic parameters. This statistical model is capable of quantitative prediction of
enantioselectivity with structurally diverse alkenes. These mechanistic insights assisted the discovery of a new Ti(salen) catalyst,
which substantially expanded the reaction scope and significantly improved the enantioselectivity of synthetically interesting building
blocks.
enantioselective reactions will have significant implications in
this burgeoning area of research.4b
INTRODUCTION
■
Stereoselective catalysis of radical-based organic transforma-
tions remains a challenge in modern synthetic chemistry in
part because of the high reactivity and relatively limited
knowledge about reaction pathways involving radical inter-
mediates.1 Recent advances have made possible a plethora of
highly enantioselective reactions mediated by radical inter-
mediates.2 In contrast to the rapid developments in this area,
mechanistic understanding of catalytic radical-based reactivities
lags behind.3 Better understanding will lead to rational design
and optimization of next-generation catalysts with broader
scope and improved synthetic applications.
In this context, we have recently developed a new catalytic
strategy that harnesses the single-electron redox activity of Ti
complexes for the formal [3 + 2] cycloaddition of cyclopropyl
ketones and alkenes (Figure 1).4 Notably, the use of a chiral
Ti(salen) complex ((R,R)-4a) renders this transformation
diastereo- and enantioselective, producing polysubstituted
cyclopentanes from alkenes and cyclopropyl ketones. This
development is interesting for several reasons. Synthetically,
cyclopentanes are common structures in complex bioactive
compounds.5 In particular, cyclopentylcarboxylic acids (cf. 3e
and 3f) have been studied as structural analogs for prolines in
the discovery and evaluation of peptidyl drugs.6 On a
fundamental level, enantioselective radical reactions catalyzed
by Ti predominantly rely on chiral cyclopentadienyl ligands,7
which are typically cumbersome to synthesize. The successful
use of salen compounds, a class of modular chiral ligands, in
In the initial discovery, we found that Ti catalysts such as
(R,R)-4a generally promoted the reaction in excellent diastero-
and enantioselectivity for styrene-type substrates with electron-
rich and -neutral substituents (e.g., (S,S)-3a−c). Nonetheless,
reactions with electron-deficient alkenes led to much poorer
stereocontrol, and the application of lower reaction temper-
atures was necessary to achieve reasonable levels of
enantioselectivity at the expense of longer reaction times and
lower efficiency. Specifically, acrylates, methacrylates, phenyl
vinyl sulfone, and vinyl pinacolboronate ester gave rise to
products in high diastereoselectivity but low enantioselectivity
(Figure 1, (S,S)-3e−h). Reactions using such Michael
acceptors often afford more synthetically useful products. For
example, acrylate-derived products (S,S)-3e and (S,S)-3f can
be used as amino acid analogues in peptide synthesis,6 whereas
vinyl pinacolboronate ester 2h provides product (S,S)-3h with
a stereogenic C−B bond that could be further elaborated into
other synthetically useful compounds.8
Received: July 2, 2020
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on the salicylaldehyde of the catalyst. Ultimately, the
mechanistic understanding informed the design of a new
catalyst, which significantly expanded and improved the scope
of the reaction.
RESULTS AND DISCUSSION
■
A. Experimental and Computational Studies of
Reaction Mechanism. The proposed mechanism for this
reaction begins with the generation of an active Ti(III) catalyst
via single electron reduction by Mn (Figure 2A). Subsequently,
Figure 1. Reported Ti(salen)-catalyzed [3 + 2] cycloaddition.
Electron-deficient alkenes yield products with lower enantioselectiv-
ities.
We sought to address this significant limitation of our
reaction system and improve the Ti(salen) catalyst by means
of probing the mechanism of stereochemical induction. Metal-
salen complexes have been widely used in enantioselective
catalysis in the context of small molecule9 and polymer
synthesis.10 Empirically, several structural factors including the
nature of the metal center,11 the interplay of steric and
electronic factors garnered by the salicylaldehyde groups,12 and
the conformation of the complex13 can profoundly influence
the reaction enantioselectivity. In contrast to the extensive use
of metal-salen complexes in asymmetric catalysis, mechanistic
understanding of the high enantioselectivity imparted by these
chiral catalysts remains largely underexplored with the
exception of the extensive, elegant studies of the hydrolytic
kinetic resolution of epoxides by Jacobsen.14 Against this
backdrop, we aimed to gain further insights into the
mechanism of stereochemical induction in the context of the
Ti-catalyzed [3 + 2] cycloaddition reaction with the primary
goal of providing general guidelines for new catalyst design to
improve currently challenging substrate classes, namely
electron poor alkenes. Given the rigidity of metal salen
complexes, we hope that these guidelines can be translated to
other enantioselective transformations catalyzed by these
privileged chiral catalysts.
Figure 2. (A) Proposed mechanism for the Ti(salen)-catalyzed [3 +
2] cycloaddition of cyclopropylketones with alkenes. (B) Spin
trapping experiment supports a single electron mechanism.
reductive ring opening of the cyclopropyl substrate occurs
regioselectively under the action of the Ti(III) catalyst to yield
a tertiary carbon-centered radical I. Addition to a radical
acceptor alkene then proceeds to form intermediate II, which
cyclizes to generate the final product. This stepwise, single-
electron mechanism is supported by a spin trapping experi-
ment (Figure 2B).4a Nonlinear effect and diffusion NMR
experiments (see Experimental SI Section 6) were conducted
to rule out cooperative reactivity between multiple catalysts,
which has been reported for other metal-salen systems.15
Diffusion NMR experiments revealed that the catalyst is
monomeric in the ground state. This information, taken
together with the lack of a nonlinear effect of the catalytic
reaction, suggests that this system operates through a
monomeric catalyst. With experimental evidence to support a
radical mechanism and a monomeric catalyst, computational
analysis was carried out to assess the energetic feasibility of the
mechanism.
The proposed catalytic cycle was computed using
Gaussian0916 with a model Ti catalyst with only the salen
core and p-chlorostyrene 2b as the substrate to reduce the
computational expense (Figure 3). Alternative mechanisms,
such as a concerted reductive ring opening and radical
addition, were considered but such TSs were not located. As
proposed, the reaction first proceeds through a TS
corresponding to reductive ring opening (TS1) to yield radical
Thus, we report herein a combination of experimental and
computational tools to interrogate the mechanism of this
Ti(salen)-catalyzed [3 + 2] cycloaddition. Both the structural
features of catalysts and substrates were systematically
modified to probe structure-selectivity relationships. By
combining theory and statistical mathematical modeling, a
stereochemical model was developed that features the role of
catalyst distortion as well as intermediate positioning provided
by both the chiral diamine backbone and the ortho-substituents
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Figure 3. Catalytic cycle for the Ti(salen) catalyzed [3 + 2] cycloaddition calculated with a model catalyst. Energies are reported in kcal/mol.
Computational method: IEFPCM(EtOAc)-M06/def2-TZVP//M06/6-31G(d)-LANL2DZ level of theory.
intermediate I, which occurs with a free energy of activation of
26.9 kcal/mol relative to the catalyst-ketone complex (preTS1)
and the styrene at infinite separation. The addition of this
radical to the olefin (TS2) is irreversible and the rate-
determining step (RDS). The subsequent radical cyclization
(TS3) establishes the stereogenic centers and thus is the
enantio- and diastereoselectivity-determining step. With this
truncated model catalyst system, the cis cyclization pathway is
slightly lower in energy than that of the trans pathway.
The achiral model catalyst allowed us to interpret the
feasibility of reaction steps in the proposed mechanism, but
does not explain the observed selectivities. Therefore, to
interpret the origins of selectivity, we next performed
computational analysis of TS3, the selectivity-determining
step, with the full optimal catalyst.17
B. Computational Analysis of the Selectivity Deter-
mining Transition States with the Full Catalyst System.
For the diastereo- and enantio-determining radical cyclization
step, four possible TSs are considered: trans-Re, trans-Si, cis-
Re, and cis-Si, each of which leads to a stereoisomer of the
cyclopentane product. Conformers in each of these TS
categories were also explored and generated by performing a
conformational search (see Computational SI Section IV for
details). These conformers were then used as candidate
structures for TS optimization using Gaussian09 with the
IEFPCM(EtOAc)-M06/6-31+G(d,p)//M06/6-31G(d)-SDD
level of theory.16 From this process, the lowest-energy
structure for each of the four stereochemical pathways was
interpreted further. The lowest-energy pathway was calculated
to be trans-Re TS3 (hereon referred to as major TS3), which is
lower in energy by 0.8 kcal/mol relative to cis-Si TS3 and 1.5
kcal/mol relative to trans-Si TS3 (hereon referred to as minor
TS3). The cis-Re TS3 pathway was significantly higher in
energy and thus was excluded from further analysis (4.2 kcal/
mol higher in energy than major TS3). These results are
consistent with the experimentally observed enantio- and
diastereoselectivity (Figure 4A). This method provided values
in agreement with experiment for two additional styrene
substrates (see Computational SI Section IV for details),
further validating the DFT method.
Visual inspection of all three TSs shows that a well-defined
chiral pocket is created by the backbone and constrained by
the large adamantyl groups. Conformational analysis of the
catalyst core in the key TSs shows the general positions of the
adamantyl groups are similar in the minor TS3 and cis-Si TSs
but inverted for the favored major TS3. Thus, viewing the
catalyst along the C2 axis allows for the creation of a quadrant
diagram based on the general positions of the adamantyl and
backbone phenyl substituents. In this diagram, two quadrants
are categorized as “full” with the catalyst adamantyl and phenyl
substituents positioned toward the intermediate and the other
two quadrants are “empty” with the adamantyl and phenyl
substituents positioned away (Figure 4B). The large steric
profile of the adamantyl groups directs the intermediate to
adopt a position that places aromatic substituents on the
intermediate in proximity to the salen core. Therefore, the
distinct catalyst conformations in each TS result in disparate
contacts between catalyst and intermediate. Specifically, the
qualitative model shows that the intermediate substituents are
arranged in the TS that leads to competing enantiomers to
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Figure 4. (A) Major TS3 scenarios to consider for analysis of reaction of 2a with (R,R)-4a, including calculated and experimental ΔΔG‡ values.
Computational method: IEFPCM(EtOAc)-M06/6-31+G(d,p)//M06/6-31G(d)-SDD level of theory. (B) Qualitative model developed for
rationalizing selectivity outcomes based on intermediate positioning and catalyst distortion and (C) overlay of each catalyst TS with the lowest-
energy ground state catalyst (gray) to visualize catalyst distortion in each TS3. Distortion/interaction analysis was performed using single point
energies calculated with the M06/6-31+G(d,p)-SDD level of theory.
occupy two empty and one full quadrants. As such, the impact
of minimizing energetically repulsive contacts in one TS over
another is not clear. Intriguingly, we noticed that the catalyst in
the major TS3 adopts a similar planar conformation to that of
the ground state of the catalyst (Figure 4C, left), whereas the
catalyst is significantly distorted to a stepped conformation to
form the minor or cis-Si TSs (Figure 4C, center and right). The
differences in catalyst-intermediate arrangement and catalyst
conformation prompted further assessment using distortion/
interaction and noncovalent interaction (NCI) analyses to
determine the stereocontrolling factors.
interaction energies that are established for the TS to favorably
form despite the distortion. Single-point calculations in the
gas-phase at the M06/6-31+G(d,p)-SDD level were employed
to evaluate the relative roles of distortion and interaction on
the overall energy differences for the diastereomeric TSs (see
Computational SI Section VI). Using this method, the overall
energy differences for the TSs forming enantiomeric products
(ΔΔE‡
= ΔE‡
− ΔE‡Major‑TS3) and TSs forming
Minor‑TS3
enant.
diastereomeric products (ΔΔE‡
= ΔE‡
−
cis‑Si‑TS3
diaster.
ΔE‡Major‑TS3) are 0.7 and 2.9 kcal/mol, respectively.19 The
calculated distortion energy differences reveal that cis-Re (3.1
kcal/mol) and minor (3.2 kcal/mol) TSs exhibit similar levels
of distortion in reference to the major TS. Analysis of the
contributions from the catalyst and intermediate fragments for
each enantiomer suggests that the differences in distortion
A distortion/interaction analysis was performed to inves-
tigate the nature and energetic cost of catalyst distortion.18
This analysis quantifies the energy required for the catalyst and
intermediate to distort into the TS conformation and the
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energy arise from catalyst distortion (3.09 kcal/mol)) rather
than intermediate distortion (0.08 kcal/mol). Yet, the
interaction energies reveal a significant difference in interaction
energies for the minor TS3 relative to major TS3 (−2.5 kcal/
mol), but not cis-Si TS3 relative to major TS3 (0.2 kcal/mol).
This suggests that the interactions between catalyst and
intermediate are more favorable in the minor TS3 than major
TS3.
Natural energy decomposition analysis (NEDA) was
performed to analyze the specific contribution of different
interactions to the differences in total interaction energy for
the TSs (see Computational SI Section VII). Although the
minor TS3 has a greater level of repulsive interactions from
steric crowding relative to the major TS3, minor TS3 also
features more stabilizing attractive NCIs, ultimately resulting in
an overall more negative total interaction energy. Furthermore,
the values from this analysis imply that the gem-dimethyl
contacts with the salen backbone in minor TS3 are more
energetically costly than the interactions with the 4-
chlorophenyl in major TS3. NCI plots were generated,
demonstrating that a network of attractive interactions
between the arenes on the intermediate and salen core occur
in the TSs, further confirming our analysis (see Computational
SI Section VIII).20 Although the interaction energy for the
minor TS3 is more stabilizing, the energetic penalty for
distortion outweighs the stabilizing interactions. On the basis
of these analyses, we propose that catalyst distortion is the
major contributor to the observed stereoselectivities with the
p-chlorostyrene substrate 2b. The notion of a preferred
conformation of a metal-salen in dictating selectivity was first
invoked for rationalizing selectivity in Mn(salen)-catalyzed
epoxidations, but it is plausible that catalyst distortion plays a
significant role in these reactions as well.9e,21
To determine if catalyst distortion was a stereocontrolling
factor among a wider range of substrates, we next performed
TS analysis with 2-vinylpyridine (2l). This substrate reacted to
yield products in low enantioselectivity (39% ee). Since
enantioselectivity, and not diastereoselecivity, was the limiting
aspect of this reaction with many substrates, we focused only
on TSs that form enantiomeric products. TS analysis with
substrate 2l was conducted to assess if catalyst distortion was
also the primary enantiocontrolling factor with poorly
performing substrates. The relevant TSs (trans-Re = major
TS3 and trans-Si = minor TS3) were located using the same
computational method as for the p-chlorostyrene TSs. The
lowest energy major TS3 pathway was calculated to be 0.8
kcal/mol lower than the minor TS3 (Figure 5, top). This
corresponds well with the lower levels of enantioselectivity
obtained with this substrate. Distortion/interaction analysis of
the TSs revealed that unlike the p-chlorostyrene substrate 2b,
catalyst (2.7 kcal/mol) and substrate distortion (1.0 kcal/mol)
both contribute to the relative difference in distortion energy
between the TSs. Since the distortion contribution (+3.7 kcal/
mol) is much larger than the energy difference between the
major and minor TSs, other factors must be contributing to the
enantioselectivity outcome. Most notably, NEDA demonstra-
ted that minor TS3 has a larger attractive energy term than
major TS3. Although these attractive interactions between
catalyst and intermediate lower the enantioselectivity, the
overall sense of stereoinduction can be explained by catalyst
distortion.
Figure 5. TS analysis for reaction of catalyst (R,R)-4a with 2-
vinylpyridine 2l as substrate (top). Distortion/interaction analysis for
these TSs (bottom).
distortion and/or reducing the stabilizing interactions in the
minor TS3. We reasoned that modifying the catalyst structure
to increase steric bulk would increase catalyst distortion.
Our stereochemical models revealed that both adamantyl
groups and chiral diamine backbone substituents play critical
organizational roles in the selectivity-determining TS, resulting
in disparate catalyst distortion. The critical role of the
adamantyl groups is supported by results from a screen of a
training set of Ti(salen) catalysts with variations of the
salicylaldehyde portion to probe the steric influence of the
ortho substituents and electronic tuning of the metal center by
the para substituent. The data set revealed large ortho
substituents (t-butyl (t-Bu) or adamantyl (Ad)) on the catalyst
are required to access enantioenriched products. Specifically,
ortho-t-Bu catalysts yielded products with moderate enantio-
selectivities and ortho-Ad catalysts formed products in excellent
enantio- and diastereoselectivity regardless of the para
substituent on the catalyst (see Experimental SI Section 4
for details). Notably, tuning the electronics of the catalyst
through the para substituent had a minimal effect on
selectivity. Attempts to further increase the enantioselectivity
by improving the size of the ortho-substituents beyond Ad
proved unfruitful. Overall, this clearly demonstrated that
varying the ortho and para substituents on the salicylaldehyde
are not effective approaches for improving the catalyst, and
that alternative structural modifications to the catalyst (e.g.,
varying the diamine backbone) needed to be considered.
C. Catalyst Backbone SAR and Statistical Modeling.
After our studies of structural modifications on the
salicylaldehyde moiety reinforced the critical role of the
adamantyl groups, we next explored introducing substituents
on the diamine backbone of Ti(salen) to create a more
compact stereochemical environment for the cyclization
transition state to induce a higher degree of catalyst distortion
in the minor TS. We note that such modifications are largely
underexplored in the area of asymmetric catalysis by metal-
salen complexes, despite the fact that the structure of the
This analysis indicated that improving enantioselectivity
with poorly performing substrates requires increasing catalyst
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diamine backbone has been shown to affect enantioselectivity
in certain reaction systems.22
As a first experimental support for the stereochemical
hypothesis, we subjected a modified catalyst to the reaction in
which the phenyl groups on the diamine backbone were
replaced with pentafluorophenyl groups ((S,S)-4aa) (Figure
6).23 This modification perturbs the steric and electronic
Figure 6. Modification of the chiral backbone substituents results in
diminishing of stereoselectivity.24
environment of the active site. Indeed, reaction with this
catalyst resulted in a significant reduction of diastereo- and
enantioselectivity (2:1 dr, 77% ee) relative to the parent
catalyst (S,S)-4aa (14:1 dr, 90% ee; Figure 6). In the original
optimization of this reaction with styrene, it was also observed
that both diastereo- and enantioselectivity diminished when
the phenyl diamine backbone was replaced with a cyclohexane-
1,2-diamine backbone (from >19:1 to 14:1 dr, 97 to 69% ee).4a
These results provide support that structural variation of the
catalyst diamine backbone can have significant implications for
stereoselectivity outcomes. Given these initial explorations did
not result in a more selective catalyst, we reasoned that more
subtle changes to the catalyst diamine backbone may be
necessary to effectively increase catalyst distortion and reduce
favorable interactions in minor TS without significantly
changing the reaction pathway.
Accordingly, we designed a series of eight Ti(salen) catalysts
that incorporate different chiral diamine backbones ((S,S)-4a−
h). This series of catalysts bear an ortho substituent on each of
the aryl groups on the backbone, which based on the
computational models are perfectly positioned into the chiral
pocket where the intermediate assembly is bound. We first
evaluated these catalysts in the reaction with 1 and p-
chlorostyrene 2b and observed slightly increased enantiose-
lectivities (from −90% to between −93% and −96% ee; Figure
7). This result suggests that the catalyst modification did not
lead to a detrimental effect on enantioinduction. Nevertheless,
the enantioselectivities are comparable across the series of
catalysts. We propose that the general lack of sensitivity to
these catalyst modifications for the styrene substrate is a
consequence of similar influences on the major and minor TS
3s. Essentially, comparable differences in the interplay of
catalyst distortion and interaction energy result in no
additional differentiation in the relative energies of these two
TSs, and subsequently little influence on enantioselectivity.
Figure 7. Graphical representation of substrate structure−selectivity
trends as a function of catalyst backbone B5 Sterimol value. Each
trend line represents a different olefin substrate.
In contrast, when this set of eight new Ti(salen) catalysts
were explored in reactions with four electron-deficient alkene
reactants, all of which performed poorly with the original
optimal (S,S)-4a catalyst (Figure 7), significant enhancements
were observed in enantioselectivity. Increasing the backbone
steric profile results in a more confined Ti active site, thus
introducing a greater degree of catalyst distortion for dictating
enantioselectivity outcomes with these substrates. Initial
analysis of the enantioselectivity data of the new catalyst series
revealed a trend between the B5 Sterimol value of the
backbone arene substituent and enantioselectivity. The size of
the backbone substituent was not simply related to their
efficacy, as the most selective one was neither too large nor too
small. In fact, a goldilocks effect was observed in which the
optimal catalyst for all four alkenes possesses the medium-sized
o-trifluoromethylphenyl backbone substituents. Although the
specific catalyst trends vary for the alkenes, catalysts with aryl
backbones smaller or larger than this group yield inferior
enantioselectivity outcomes (Figure 7). This suggests that
smaller backbones result in inadequate levels of catalyst
distortion for the minor TS3.25 Yet, beyond a certain size, the
steric interactions and subsequent distortion begin to impact
both the minor and major TSs, resulting in lower levels of
enantioselectivity. Catalyst (S,S)-4e provides the optimal
backbone to enhance catalyst distortion in the minor TS3,
but not the major TS3. The results with p-chlorostyrene 2b are
also plotted, demonstrating the general lack of sensitivity to
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Figure 8. MLR statistical models I and II developed with 8 catalyst X 4 substrate matrix (32 data points for training set, top). Both models suggest
there is significant catalyst control in enantioselectivity outcomes. Predictions for novel substrates with improved catalyst (S,S)-1e (Ar = o-CF3Ph)
are labeled. All other predictions are for product (R,R)-3h with the catalyst series.
these structural modifications of the backbone substituent.
Overall, these data provided a ΔΔG‡ range of 1.5 kcal/mol,
which constitutes a sufficient statistical spread to employ
multivariate linear regression (MLR) statistical modeling.26
MLR statistical modeling was then used to interrogate the
catalyst and substrate effects specific to these alkenes. This
approach relates molecular descriptor sets for the alkenes and
catalysts to enantioselectivity outcomes.26 Because the
inherent enantioselectivity of the new catalysts is masked by
the styrene subset in which the ee variation is small, only the
substrates exhibiting variable selectivity as a function of catalyst
structure were further investigated. To appropriately capture
the relevant substrate features in the selectivity-determining
step, we acquired parameters such as NBO charges, spin
densities, and SOMO energy computationally using truncated
intermediate II with a surrogate TiCl3 in place of the full
Ti(salen) catalyst. This was a simple yet crucial means of
describing the molecular features most relevant to the enantio-
determining step. Parameters such as Sterimol values and
dihedral angles were collected from the optimized catalyst
(S,S)-1a−h structures. Backbone specific parameters, such as
polarizability, quadrupole moment, and molecular surface area,
were obtained from the relevant arene structures and employed
as additional catalyst descriptors for aiding model develop-
ment. Using forward stepwise linear regression in MATLAB, a
three-parameter statistical model was developed, consisting of
two catalyst terms, namely, polarizability and B5 Sterimol value
of the arene on the diamine backbone, and one intermediate
parameter, namely, the NBO charge at the carbon-centered
radical in intermediate II (Figure 8, plot I). Notably, the
catalyst descriptors have larger coefficients in the model than
the intermediate parameter, demonstrating the critical role of
the catalyst backbone in enantioselectivity outcomes and
implying significant catalyst control in this reaction. This is
consistent with the proposal that catalyst distortion, as
opposed to catalyst−intermediate interactions, is the primary
factor in dictating enantioselectivity outcomes.
Cross-validation and external validation in which the results
of all eight catalysts with a vinyl pinacolboronate ester
substrate (Figure 9, 2h) were predicted (see Figure 8 for
predictions), suggesting the model is robust. Furthermore, the
model effectively predicted the results of three structurally
diverse substrates (Figure 9, 2i, 2j, 2k) with new catalyst (S,S)-
4e. The prediction for the acrylonitrile-derived product
((R,R)-3i) is less accurate, which we attribute to its
substantially smaller steric profile relative to the other
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Figure 9. Improved performance of catalyst (S,S)-4e with previously challenging substrates.
substrates that are more effectively modeled. All attempts at
predicting results for styrene-type substrates (e.g., 2b, 2d, 2m)
with the model were unsuccessful and it was not possible to
develop robust models when styrene substrates were included
in the training set. This is consistent with our hypothesis that
the factors controlling enantioselectivity differ in the styrenyl
substrate class.
The catalyst descriptors, polarizability and B5 Sterimol value
of the aryl groups on the backbone, presumably capture the
role of backbone substituents in influencing the degree of
catalyst distortion (Figure 8). The two parameters are required
to encapsulate the goldilocks effect of the backbone size.
Intriguingly, a single parameter was sufficient at describing the
diverse substrates. This is in part due to the substantial range in
these NBO charge values (−0.55 up to 0.21). Yet,
interpretation of this parameter in the enantio-determining
TS was unclear. Thus, our efforts focused toward developing a
mechanistically interpretable model.
A correlation matrix was generated for the parameters in
order to identify more digestible parameters related to the
NBOC2 parameter. Specifically, the spin density at the carbon
centered radical (spinC2) and the Ti−O bond distance were
determined as correlative with NBOC2 of the intermediate II
structures (R2 = 0.65). Using these additional parameters, a
four-parameter model was developed by manually altering the
model to include these parameters in place of NBO (Figure 8,
plot II). These two substrate parameters are interpreted as
capturing the position of the TS along the reaction coordinate
in the context of the Hammond postulate, in which more
stabilized TSs represent more product-like TSs and result in
higher levels of enantioselectivity. Although this model is more
interpretable, it is less accurate in predicting out-of-sample
compared to the three-parameter model. The value of these
models is the ability to quickly, computationally assess how
novel substrates will perform in this reaction without requiring
exhaustive TS analysis.
Yet we remained curious how the new, improved catalyst
provided such marked improvements in enantioselectivity.
Thus, a final set of TS analysis was performed with the 2-
vinylpyridine substrate 2l and the best catalyst (R,R)-4e. The
lowest energy major TS3 pathway was calculated to be 5.0
kcal/mol lower in energy than the minor TS3 pathway (Figure
10). Although the energy difference is overestimated, the
reproduction of experimental enantioselectivity trends, specif-
ically that this new catalyst (S,S)-4e should promote the
reaction with 2-vinylpyridine with higher levels of enantiose-
lectivity than catalysts (S,S)-4a, demonstrates the strength of
the computational analysis. Distortion/interaction analysis was
performed with single-point energy calculations in gas phase
with M06/6-31+G(d,p)-SDD level. This revealed that the
distortion energy difference between the TS 3s was increased
(6.0 kcal/mol), whereas the relative interaction energy
difference was reduced (−1.6 kcal/mol). This suggests that
the backbone modification was an effective avenue for both
increasing catalyst distortion and reducing the stabilizing
interaction energy in the minor TS3.
D. Substrate Scope Expansion Using New-Generation
Ti(salen). The catalyst modification informed by computa-
tional analysis led us to identify an improved Ti(salen) catalyst
(S,S)-4e for the [3 + 2] cycloaddition reaction. Thus, the
scope with the new Ti(salen) catalyst (S,S)-4e was
substantially expanded to include various previously challeng-
ing, electron-deficient alkenes (Figure 9). Although the MLR
statistical model and TS analysis suggests that the enantio-
determining factors likely differ for styrene-type substrates
from Michael acceptors, enantioselectivity was retained or
improved for styrene-type substrates using the new catalyst
((R,R)-3a, (R,R)-3b, (R,R)-3d, and (R,R)-3m). In other
H
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CONCLUSIONS
■
The ability to control organic radical reactivity in a selective
manner remains a synthetic challenge, but could provide access
to unique useful structural scaffolds. In the Ti-catalyzed [3 + 2]
cycloaddition reaction, through a suite of computational and
experimental mechanistic studies, catalyst distortion was
elucidated to dictate stereochemical outcomes. The mecha-
nistic insights aided in our search for an improved catalyst,
which substantially expanded the reaction scope and provided
a collection of synthetically interesting products in high
diastereo- and enantioselectivity. A catalyst−substrate matrix
based on the new catalysts allowed for the development of an
MLR statistical model that could predict the performance of
each catalyst with a novel substrate. The predictive power of
this model was demonstrated through accurate prediction of
enantioselectivity outcomes for various substrates in reactions
with the improved catalyst. This work demonstrates the utility
of mechanistic studies in guiding catalyst optimization toward
a more broadly applicable transformation. Furthermore, this
development represents a rare example of metal-salen
asymmetric catalysis in which the modification of the chiral
diamine backbone was systematically studied to understand
and improve reaction stereoselectivity. Given the broad use of
metal-salen complexes in enantioselective synthesis, we
anticipate that our discovery will have broader implications
in transformations catalyzed by these privileged catalysts. Our
future directions will focus on using the information gleaned
from TS analysis to expand reactivity with different substrate
classes.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c07128.
■
sı
Experimental procedures, and characterization data
(PDF)
Computational details (PDF)
Figure 10. TS analysis for reaction of catalyst (R,R)-4e with 2-
vinylpyridine 2l as substrate (top). Distortion/interaction analysis for
these TS 3s (bottom).
AUTHOR INFORMATION
Corresponding Authors
■
words, the new catalyst constitutes a more general catalyst for a
broader range of reaction partners without compromise to the
original results, a particularly challenging feat in asymmetric
catalysis.
Song Lin − Department of Chemistry and Chemical Biology,
Cornell University, Ithaca, New York 14853, United States;
orcid.org/0000-0002-8880-6476; Email: songlin@
cornell.edu
Matthew S. Sigman − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States; orcid.org/
0000-0002-5746-8830; Email: sigman@chem.utah.edu
With respect to electron-deficient alkenes, the precise
improvement in diastereo- and enantioselectivity varied for
each substrate, with the most significant improvement being
for 2-vinylpyridine 2l, which constituted a 1.4 kcal/mol
increase in differential free energy of activation. Notably, this
improved Ti(salen) catalyst provides access to a diverse suite
of synthetically useful products in high diastereo- and
enantioselectivity. For example, proline analogues ((R,R)-
3e−f) and a quaternary α-amino acid ((R,R)-3j) can be
accessed from acrylates. Reactions with phenyl vinyl sulfone
and vinyl pinacolboronate ester give rise to carbocycles with
stereogenic C−S and C−B bonds (e.g., (R,R)-3g−h) that can
be further transformed into other useful products. Finally,
several products with quaternary stereogenic centers, including
a spiro-bicyclic structure ((R,R)-3k), could be readily formed
from the corresponding 1,1-disubstituted alkenes with
excellent stereoselectivity.
Authors
Sophia G. Robinson − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States
Xiangyu Wu − Department of Chemistry and Chemical Biology,
Cornell University, Ithaca, New York 14853, United States;
orcid.org/0000-0003-1169-1997
Binyang Jiang − Department of Chemistry and Chemical
Biology, Cornell University, Ithaca, New York 14853, United
States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c07128
Author Contributions
†S.G.R. and X.W. contributed equally to this work.
I
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Lin, S. Recent Advances in Titanium Radical Redox Catalysis. J. Org.
Chem. 2019, 84, 14369−14380.
Notes
The authors declare no competing financial interest.
(5) (a) Hudlicky, T.; Price, J. D. Anionic approaches to the
construction of cyclopentanoids. Chem. Rev. 1989, 89, 1467−1486.
(b) Heasley, B. Stereocontrolled preparation of fully substituted
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ACKNOWLEDGMENTS
■
This work is dedicated to the occasion of Prof. Eric Jacobsen’s
60th birthday and the 30th anniversary of his initial publication
on Mn(salen)-catalyzed asymmetric epoxidation (commonly
known as the Jacobsen epoxidation; J. Am. Chem. Soc. 1990,
112, 2801−2803). Financial support is provided by the
National Science Foundation (CHE-1763436 (M.S.S)) and
the National Institute of Health (GM134088 (S.L.)).
Computational resources were provided from the Center for
High Performance Computing (CHPC) at the University of
Utah and the Extreme Science and Engineering Discovery
Environment (XSEDE), which is supported by the National
Science Foundation grant number ACI-1548562. SGR
acknowledges the National Science Foundation for a graduate
research fellowship. SGR thanks Dr. Jolene P. Reid for
computational training and helpful discussions in regard to
MLR modeling and TS analysis.
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(19) A variety of levels of theory were employed for identifying the
optimal method for single-point energy calculations (details tabulated
in the Supporting Information). Electronic energies consistently
underestimate the barrier for enantioselectivity and overestimate the
energy barriers for diastereoselectivity regardless of the level of theory
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or inclusion of solvation model. Free energies for the TSs were all in
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calculated dE values are not as accurate as the computed dG, the
general trends for the substrate−catalyst combinations are analyzed to
provide insight into this system, rather than focusing on the exact
values.
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(24) Please note that the catalysts in the original method report (J.
Am. Chem. Soc. 2018, 140, 3514−3517) possess (R, R) diamine
backbones, whereas catalysts with modified diamine backbones in this
study were prepared with (S, S) diamine backbones. Thus, the (S, S)
products formed with the (R, R) catalyst have positive (+) % ee,
whereas performing the reaction with the (S, S) catalysts yields (R, R)
products reported with negative (−) % ee values. All TS analysis was
performed with (R, R) catalysts.
(25) Note that for the training set series the catalyst all have the (S,
S) backbone, whereas the original report of this method and all TS
analysis employed the (R, R) backbone. Thus, for these reactions the
major TS3 is trans-Si and the minor TS3 is trans-Re.
(26) For recent reviews of MLR statistical modeling see the
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