Article

pubs.acs.org/accounts

Transition State Models for Understanding the Origin of Chiral

Induction in Asymmetric Catalysis
Published as part of the Accounts of Chemical Research special issue “Computational Catalysis for Organic
Synthesis”.
Raghavan B. Sunoj*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India

CONSPECTUS: In asymmetric catalysis, a chiral catalyst bearing chiral center(s) is employed to impart chirality to developing
stereogenic center(s). A rich and diverse set of chiral catalysts is now available in the repertoire of synthetic organic chemistry.
The most recent trends point to the emergence of axially chiral catalysts based on binaphthyl motifs, in particular, BINOL-
derived phosphoric acids and phosphoramidites. More fascinating ideas took shape in the form of cooperative multicatalysis
wherein organo- and transition-metal catalysts are made to work in concert. At the heart of all such manifestations of asymmetric
catalysis, classical or contemporary, is the stereodetermining transition state, which holds a perennial control over the
stereochemical outcome of the catalytic process. Delving one step deeper, one would find that the origin of the stereoselectivity is
delicately dependent on the relative stabilization of one transition state, responsible for the formation of the predominant
stereoisomer, over the other transition state for the minor stereoisomer. The most frequently used working hypothesis to
rationalize the experimentally observed stereoselectivity places an undue emphasis on steric factors and tends to regard the same as
the origin of facial discrimination between the prochiral faces of the reacting partners. In light of the increasing number of
asymmetric catalysts that rely on hydrogen bonding as well as other weak non-covalent interactions, it is important to take
cognizance of the involvement of such interactions in the sterocontrolling transition states. Modern density functional theories offer
a pragmatic and effective way to capture non-covalent interactions in transition states. Aided by the availability of such improved
computational tools, it is quite timely that the molecular origin of stereoselectivity is subjected to more intelligible analysis.
In this Account, we describe interesting molecular insights into the stereocontrolling transition states of five reaction types, three of
which provide access to chiral quaternary carbon atoms. While each reaction has its own utility and interest, the focus of our
research has been on the mechanism and the origin of the enantio- and diastereoselectivity. In all of the examples, such as
asymmetric diamination, sulfoxidation, allylation, and Wacker-type ring expansion, the role played by non-covalent interactions in
the stereocontrolling transition states has been identified as crucial. The transfer of the chiral information from the chiral catalyst to
the product is identified as taking place through a series of non-covalent interactions between the catalyst and a given position/
orientation of the substrate in the chiral environment offered by the axially chiral catalyst. The molecular insights enunciated herein
allude to abundant opportunities for rational modifications of the present generation of catalysts and the choice of substrates in
these as well as related families of reactions. It is our intent to propose that the domain of asymmetric catalysis could enjoy
additional benefits by having knowledge of the vital stereoelectronic interactions in the stereocontrolling transition states.

1. INTRODUCTION and molecular biology, routinely makes reference to TSs, albeit

The importance of transition states (TSs) in chemical catalysis with varying connotations. In experimental organic chemistry,
has long been recognized. A catalyzed process follows a lower- structural and electronic features of TSs are often invoked to
energy pathway due to the involvement of lower-energy TSs
compared with the corresponding uncatalyzed pathway, resulting Received: January 31, 2016
in rate enhancements.1 The literature, spanning both chemistry

© XXXX American Chemical Society A DOI: 10.1021/acs.accounts.6b00053

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rationalize rate enhancement as well as product selectivity in highly likely that the preferences for the addition to the si and re
reactions.2 What is intriguing is that although the transitory TSs prochiral faces are not equal. In fact, the difference in the Gibbs
remain elusive to experimental observation, they enjoy ubiquitous free energies of the TSs for the si and re face additions, denoted as
acceptance in the rationalization of experimental observations. ΔG⧧, is a desirable feature for enhanced stereocontrol (Figure 2).
In particular, concepts such as kinetic and thermodynamic control
of product distributions are omnipresent. One of the didactic
examples of TSs that makes its earliest appearance in organic
chemistry textbooks is when one tries to rationalize endo/exo
product selectivity in a Diels−Alder reaction. While there have
been alternative views on the origins of endo selectivity, the most
widely used interpretation relies on additional stabilization due to
secondary orbital interactions in the endo TS.
In this Account, the importance of transition state models in
asymmetric catalysis is highlighted by using a select set of recent
examples from our laboratory. It is implicitly proposed that the
overemphasis on steric arguments in interpreting observed Figure 2. Illustration of ΔG⧧ and the Boltzmann distribution for the
stereochemical outcomes be subjected to a timely refinement. calculation of enantiomeric excess (% ee). ΔG⧧R/S denotes the free
With the advent of affordable density functional theory (DFT) energy difference between the pro-R and pro-S transition states.
methods that can capture dispersive and long-range interactions,3
computational tools have become increasingly more reliable in The stereochemical relationship between these two TSs is
addressing real-life problems in asymmetric catalysis. Many of diastereomeric. The Boltzmann distribution of these competing
the chosen examples are from the domain of rapidly emerging diastereomeric TSs would determine the extent of enantiose-
multicatalytic protocols in asymmetric synthesis. The discussions lectivity. The larger the value of the free energy difference
revolve around the stereocontrolling TSs and are intended to between the pro-R and pro-S transition states (ΔG⧧R/S), the
shed light on the origins of stereoselectivity and illustrate how greater is the enantioselectivity, and thus, this is regarded as one
such insights could help further developments in the design of of the most important control elements in asymmetric catalysis.
asymmetric catalysts. Computational methods offer an effective tool to locate such
stereocontrolling TSs on the respective free energy surfaces.
2. ASYMMETRIC INDUCTION
The process of transfer of chiral information from the catalyst 3. COMPUTATIONAL PROTOCOLS IN THE STUDY OF
to the product is termed asymmetric induction. The chiral catalyst STEREOSELECTIVITY
usually forms a catalyst−substrate complex via either a covalent The identification of the energetically most preferred TS is vital
or non-covalent activation mode. Two such examples of catalyst− to the development of a robust stereoelectronic model. A detailed
substrate complexes are given in Figure 1. The catalyst proline search through a plethora of mechanistic possibilities might be
required, first to identify the lower-energy pathway. Within the
lower-energy pathway, far more careful analyses of the conforma-
tional features of the TSs are equally important. Such rigor can
engender a greater degree of confidence in the computation of a
delicate quantity such as ΔG⧧. An immediately accompanying
question on the stereocontrolling TSs pertains to the very origin
of this energy difference. There are a few contemporary recipes
for unraveling the origin of the vital energy difference ΔG⧧. In one
such method, known as the activation−strain model (synonymous
to the distortion−interaction model), the activation energy is
Figure 1. Examples of (a) covalent activation and (b) non-covalent partitioned as the difference between the attractive interaction
activation of substrates by chiral catalysts. between the distorted reactants in the TS and the sum of
distortions in each reactant when they go from the reactant
combines with a ketone to provide a more reactive nucleophilic geometry to the TS geometry.6
enamine through covalent bond formation in the first example4 Analysis of weak interactions in the TSs also offers more
(Figure 1a), whereas hydrogen-bond activation of the electrophile insights into the origin of the energy difference. The electron
takes place prior to the reaction in the second case (Figure 1b).5 density distributions in the TSs can be examined by using topo-
In several instances, a chiral catalyst can exhibit a modest logical analysis within the Atoms-in-Molecules framework.7
preference for the formation of an interaction complex with one Identification of bond paths between the interacting atoms as
of the possible orientations of the prochiral substrate, rendering well as the electron densities at the corresponding bond critical
one of its prochiral faces more amenable to the incoming reacting points (ρbcp) provides useful indicators of intramolecular inter-
partner. An early inception of chiral induction can be regarded as actions in a TS. ρbcp is proportional to the strength of the
occurring in the initial “chiral recognition” complex, which gets interaction, while the Laplacian as well as the total energy density
modulated at the TS. at a bcp (H) can ascertain whether the interaction is covalent or
Certain basic premises involved in the computational study ionic.8 A similar recent approach, known as the non-covalent
of asymmetric catalysis deserve mention here. The actual chiral interaction index (NCI), is based on the reduced density
induction takes place in the stereocontrolling TS. When a gradient and electron density.9 NCI can provide a qualitative
nucleophile adds to the prochiral faces of an electrophile in the picture of the regions of attractive non-covalent interactions,
presence of a chiral catalyst (or other source of chirality), it is hydrogen bonding, and repulsive steric interactions in a TS.
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These topological methods should be considered suitable for followed by the C1−N8 bond formation, which is the stereo-
the purpose of comparison of the intramolecular interactions controlling event wherein the chirality at the developing
between two diastereomeric TSs, although they might not offer stereogenic carbon is decided. The addition of the aziridinone
quantitative accuracies. nitrogen to the re face of the diene is 3.3 kcal/mol more preferred
In the following sections, some representative recent examples than that to the si face. The preference for cis or trans diastereo-
of asymmetric catalysis are employed to delineate the process of selectivity of the final product would depend on the second
chiral induction in stereocontrolling TSs. The source of chirality C2−N6 bond formation through the reductive elimination step.
in these examples is axially chiral phosphoramidite(s) as ligand(s) The formation of the trans product is noted as energetically more
bound to a suitable transition metal or an axially chiral BINOL favorable, which is in line with the experimentally observed
phosphoric acid. diastereomer.
The enantiocontrolling C−N bond formation TS structures
4. CHIRAL INDUCTION BY AXIALLY CHIRAL suggest that the facial discrimination between the si and re faces
PHOSPHORAMIDITES of the incoming diene does not appear to emanate from steric
A large number of organic reactions make use of axially chiral differential (Figure 3). However, the non-covalent interactions
compounds as a source of chirality. In one such recent example in the si and re face approaches exhibit notable differences.
from the domain of palladium catalysis, an interesting strategy The number of C−H···π, C−H···O, and anagostic interactions is
for introducing two nitrogen atoms across a double bond is much more pronounced when the re face of the diene approaches
reported. This approach, which came to be known as asymmetric the nitrogen of the palladated diaziridinone. The key interactions
diamination, stands out as an exclusive example in comparison such as C−H···O and C−H···π can be noted as missing in the
with a gamut of other double-bond functionalization reactions.10 TS for the si face addition, resulting in some destabilization
In another study, Shi and co-workers reported a palladium- compared with the corresponding re face addition.
catalyzed asymmetric diamination of butadiene derivatives The insights into the process of stereoinduction as described
(Scheme 1a).11 We examined the mechanism and origin of the above could in principle be exploited as a tool for predicting new
catalysts or substrates for the same and related class of reactions.
Scheme 1. (a) Pd−Phosphoramidite-Catalyzed Asymmetric On an optimistic ground, the idea of in silico catalyst design
Diamination; (b) Mechanism of Diamination of a Conjugated appears to hold promise.14 However, the challenges in the experi-
Diene by Di-tert-butyldiaziridinone mental verification of such predictions could be formidable.
There have been efforts to design newer catalysts for different
types of reactions.15
We have employed DFT computations to design of a series of
phosphoramidites by way of fine-tuning the vital interactions in
the TSs.16 Among the designed ligands shown in Figure 4, the
first two were earlier reported to yield good enantioselectivities
whereas the remaining ones are yet to be tested experimentally.11
A comparison of the computed ee values for 1 and 2 indicates
good agreement with the experimental enantioselectivities. Two
hot spots for modifications are the BINOL 3,3′-positions and the
substituents on the amido nitrogen. It can be noted that the
position of the gem-dimethyl group is important (1 vs 5),
although the nature of the chiral center on the amido substituent
does not seem to have a large impact (2−4). Suitable
decorations, such as the introduction of an aryl group, can be
beneficial as well (8). Stereoinversion without altering the axial
chirality of the BINOL backbone is also likely by installation
of an extended aromatic arm (7). A balance of the natures of
the substituents on the amido and the BINOL is suggested as a
potentially good strategy for catalyst design for the asymmetric
diamination reaction.

5. CHIRAL INDUCTION BY AXIALLY CHIRAL

PHOSPHORIC ACIDS
The use of BINOL-derived axially chiral phosphoric acids is one
of the prototypical examples of Brønsted acid catalysis.17 A range
of substituents that can be introduced at the 3,3′-positions of
the BINOL framework enhance the diversity of BINOL
stereoselectivity to gain insights into the chiral induction phosphoric acids.18 While the catalytic ability of such phosphoric
provided by the axially chiral ligands. It can be noticed that the acids can readily be attributed to the Brønsted acidity, deeper
source of chirality in this reaction is the phosphoramidite ligand, understanding of the origin of the stereoselectivity requires
which is used in a gamut of recent reactions.12 knowledge of the TSs. In recent years we have examined a
The mechanism can be broadly viewed as involving activation number of interesting reactions wherein the source of chirality
of the diaziridinone by oxidative addition of palladium, leading to stems from the axially chiral BINOL phosphoric acid or its
a palladacycle intermediate.13 Uptake of the diene would then be variants.
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Figure 3. Stereocontrolling C−N bond formation transition states for the addition of diene to the palladated diaziridinone obtained at the
M06/6-31G*,LANL2DZ(Pd) level of theory. The numbers in parentheses are the relative Gibbs free energies (in kcal/mol).

Figure 4. Computationally designed phosphoramidites and the corresponding enantioselectivities (calculated at the M06/6-31G**//B3LYP/6-31G*
level of theory) for asymmetric diamination. Numbers in parentheses refer to experimental % ee, wherever available.

5.1. Asymmetric Sulfoxidation The two arms of the thioanisole through which it can interact
Motivated by the importance of chiral sulfur-atom-containing with the catalyst are the aryl ring and the S-Me group. Evidently,
compounds as pharmaceuticals, we examined an asymmetric these groups are not capable of engaging in stronger interactions
sulfoxidation reaction wherein chirality transfer from an axially with the catalyst framework. In other words, the incipient chiral
chiral phosphoric acid to a center of chirality in the product recognition of the prochiral substrate and the developing
occurs (Scheme 2a). It can be noticed that catalyst II is quite chirality in the TSs are expected to be very similar for both the
effective in imparting high enantiocontrol whereas catalyst I yields si and re face approaches of the thioanisole to the chiral pocket
surprisingly poor enantioselectivity.19 However, in reactions of the H2O2−catalyst complex. More interesting features became
other than asymmetric sulfoxidation, catalyst I generally offers evident in the case of catalyst II, which has more aromatic
high enantioselectivity.20 Knowledge of the enantiocontrolling decorations at the 3,3′-positions. With a larger π face, the
TS helped us decipher the origin of these contrasting abilities of substrate can develop more C−H···π interactions with the
BINOL phosphoric acids in asymmetric sulfoxidation. catalyst. Each such weak contact is likely to improve the chirality
The reaction involves Brønsted acid activation of H2O2 and transfer, as the cumulative effect could be in just the right
oxygenation of the sulfur center of the incoming thioanisole proportion for high levels of stereoinduction. The differential in
(a representative substrate here), which is then followed by the such multipoint contacts holds the key to stereoinduction.
release of a molecule of water to yield the sulfoxidated product The action of one chiral catalyst in a given reaction has been
(Scheme 2b). In the stereocontrolling event, the oxygen of the the focus of discussions until now. Perusal of the recent literature
activated H2O2 adds to the sulfur center. It can be noticed from conveys an increasingly widespread use of multiple catalysts
Figure 5 that the oxygenation of the re face is only marginally under one-pot reaction conditions.22 As with many other
more favorable than that to the si face in the case of catalyst I.21 developmental strides in synthetic methodologies, mechanistic
The weak interactions that help hold the thioanisole in a clarity in multicatalytic reactions continues to remain vague.
desirable orientation for the oxygen transfer in these two TSs are Taking cognizance of these lacunae, we have examined the
quite similar, leading only to a modest energy differential between mechanistic intricacies of a number of cooperative asymmetric
the diastereomeric TSs. multicatalytic reactions.23 In the following sections, the origin of
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Scheme 2. Phosphoric Acid-Catalyzed Asymmetric chiral induction in some of the most recent multicatalytic
Sulfoxidation and the Mechanism reactions is described.
5.2. Asymmetric Allylation
A well-known challenge in asymmetric catalysis is to construct
quaternary carbon centers. Some elegant solutions have recently
emerged that could effectively address this issue.24 Similar to the
earlier examples involving axially chiral phosphoric acids, we have
probed the mechanism of a Tsuji−Trost asymmetric allylation
(Scheme 3). Jiang and List25 showed that a combination of three
catalysts such as benzhydrylamine, Pd(PPh3)4, and (S)-TRIP can
provide access to quaternary chiral carbon atoms.
The mechanism has been identified to involve an enamine
nucleophile (derived from the secondary amine and the
aldehyde) and a Pd−π-allyl electrophile (generated by the
action of the phosphoric acid on the palladium-bound allyl
alcohol).26 The bulkier triphenyl groups on the palladium
precursor Pd(PPh3)4 should make way for the incoming
reactants. The computed energies of the Pd−π-allyl intermedi-
ates with two or one PPh3 on the metal did not offer much clarity
as to what could potentially be the active electrophile. Hence, we
addressed this problem in greater detail to compare two
fundamentally distinct modes of chiral induction by the chiral
(S)-TRIP phosphate.
Two modes of participation of the chiral phosphate, either as a
ligand directly bound to the palladium (Figure 6a) or as a
counterion that remains in the outer sphere (Figure 6b), were
considered. Both of these TS models offered the correct sense of
the enantioselectivity, in line with the experimentally observed
major stereoisomer. Akin to the other examples in this Account,

Figure 5. Transition state geometries for S−O bond formation obtained at the M06-2X/6-31G** level of theory. The numbers in parentheses are the
relative Gibbs free energies (in kcal/mol).

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Scheme 3. (a) A Triple-Catalytic Tsuji−Trost Asymmetric Allylation; (b) Two Types of Transition State Models for the
Stereocontrolling C−C Bond Formation

Figure 6. Stereocontrolling C−C bond formation transition states when the chiral phosphate acts as (a) a ligand or (b) a counterion, obtained at the
M06/6-31G**,LANLD2Z(Pd) level of theory. The numbers in parentheses are the relative Gibbs free energies (in kcal/mol) in the SMD(toluene)
solvation model at the same level of theory with thermal and entropic corrections from the gas phase.

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we note that the differential C−H···π interaction and ionic the palladium-bound acetate and dislodge it in the form of acetic
N−H···O hydrogen bonding contribute to the energy differences acid while itself occupying the coordination site as a phosphate
between the additions to the re and si faces of the enamine. ligand.28
The most important aspect of these two modes of C−C bond The computed energetics conveyed that two phosphate
formation is that the TS for the counterion mode of stereo- ligands, a molecule of water, and the substrate are the most
induction is about 8 kcal/mol lower in energy than the TS for the preferred ligands for the initial Wacker-type ring expansion, as
ligand mode. shown in Figure 7. An alternative model, with the native acetate
5.3. Asymmetric Wacker-Type Ring Expansion Reaction ligands on palladium and the chiral phosphoric acid bound
Methods for the generation of spirocyclic ring systems have been through hydrogen bonding (with the acetate and the OH group
in recent focus in asymmetric catalysis. In particular, spiroox- of the substrate), was found to be of much higher energy.
indoles and spiroindenes received considerable attention because Interestingly, this prediction is in contrast to the earlier example
of their potential biological applications. The mode of chirality of the (S)-TRIP−Pd-catalyzed asymmetric Tsuji−Trost allyla-
transfer becomes an intriguing question when the source of tion, wherein the chiral phosphate was found to be a counterion
chirality is not from the native ligands on the transition metal. in the enantiocontrolling TS. In the formation of the spirocyclic
In the example shown in Scheme 4, the acetate ligands would ring junction, the stereocontrolling event is a semipinacol-type
rearrangement. Depending on the prochiral face to which the
Scheme 4. Cooperative Dual Catalysis Leading toward a cyclobutanol carbon atom migrates, two configurations at the
Spirocyclic Ring with a Quaternary Ring Junction spiro ring junction can be created, as depicted in Figure 7.29
In the ring expansion TSs, two chiral phosphates are nearly
orthogonal in the lower-energy TS-si, whereas a coplanar orienta-
tion is noticed in the higher energy TS-re (Figure 7). The BINOL
3,3′ substituents exhibit a pronounced spatial spread and provide
a chiral environment for the substrate. A larger number of
relatively shorter C−H···π interactions can be identified in TS-si
compared with the higher-energy diastereomeric TS. It is
have to be displaced by the chiral phosphate derived from important to note that C−H···π interactions between the sub-
(S)-TRIP.27 In our recent study, dynamic ligand exchange was strate and the catalyst arm (denoted as c, d, e, and f) are more
considered as a viable possibility, first by computing the energetic prominent in TS-si compared with TS-re (only c). In this chiral
feasibility of the exchange of the native acetate ligands with environment, the substrate is positioned in such a way that the
various ligands potentially available under the reaction con- ring expansion to the si face of the palladated indenyl framework is
ditions. For instance, the stronger phosphoric acid can protonate noted as more favored. A nearly square-planar geometry around

Figure 7. Stereocontrolling transition states for the ring expansion, obtained at the M06/6-31G**,LANL2DZ(Pd) level of theory. The numbers in
parentheses are relative Gibbs free energies (in kcal/mol) in the SMD(toluene) solvation model at the same level of theory using the thermal and
entropic corrections from the gas phase.

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palladium (as indicated by the distortion coordinates θ1−θ4 and Ir−π-allyl intermediate [Ir(Cl)(π-allyl)(PR)2] with the bis-(R)-
the dihedral angles ϕ1 and ϕ2) indicated less distortion in TS-si. phosphoramidite as the chiral ligand are provided in Figure 8.32
Although the predicted sense of the selectivity is in agreement The lowest-energy TS involves the addition of the re face of the
with the experimentally observed stereoisomer, the extent of enamine to the si face of the Ir-π-allyl intermediate, which would
selectivity at the M06 level is overestimated.30 We believe the result in the (2R,3R) product. The TSs for the si−si and si−re
source of additional stabilization of the lower-energy TS, which modes of addition are respectively about 3.3 and 7.6 kcal/mol
exhibits a greater number of C−H···π contacts, stems from an higher in energy, indicating very high enantio- and diaster-
inherent geometric feature noted for the M06 functional wherein eoselectivity. These predictions are in agreement with the
such interactions tend to be stickier. The example presented here experimentally observed high enantio- and diastereoselectivity.
constitutes an interesting illustration of how the axial chirality The lowest-energy TS is richly dominated by weak non-covalent
emanating from the BINOL framework gets effectively trans- interactions such as π−π stacking, C−H···π, lone pair···π, N···H,
mitted through the aryl substituents. and Cl···H. In the higher-energy TS, the number and strength
of these interactions are found to be lower. Among these
6. ASYMMETRIC ALLYLATION USING TWO CHIRAL interactions, the π stacking between the quinoline arm of the
CATALYSTS UNDER ONE-POT CONDITIONS cinchona and the phenyl ring of the allylic substrate (denoted as
In the general practice of multicatalytic one-pot reactions, only a, b, and c in Figure 8) is found to be the most important control
one of the catalysts is chiral. As a natural progression, it is of element. Similarly, a couple of crucial C−H···π contacts between
inherent interest to ask how the chirality transfer would be the olefinic C−H of the azepine and the phenyl ring of the
accomplished when both catalysts are chiral. The Carreira group enamine (e and f) can be identified as well. It is noted that
recently reported an exemplary dual-catalytic reaction with chiral the orientations of the quinoline ring in the higher-energy si−si
iridium phosphoramidites and the cinchona family of chiral and si−re TSs are not conducive for this π stacking. Again, these
amines.31 The reaction makes use of an Ir−π-allyl complex (derived molecular insights, as with the other examples described, could
from an allyl alcohol by the action of trichloroacetic acid in the be further exploited in making suitable modifications to the chiral
presence of a chiral phosphoramidite ligand) and an enamine ligands and in the choice of the substrates.
(obtained from the aldehyde and the cinchona primary amine
catalyst, again in the presence of trichloroacetic acid) (Scheme 5). 7. CONCLUSIONS AND OUTLOOK
An interesting feature of this reaction is that the configura- Transition state models for the stereocontrolling bond formation
tion at each chiral center could be altered by employing a step developed by using modern DFT computations have helped
catalyst with the opposite configuration. For instance, when us gain valuable molecular insights into the process of chiral
the (R)-phosphoramidite is used in conjunction with the induction. The most recent examples from the domain of asym-
(R,R)-cinchona, the product has the 2R,3R configuration. The metric catalysis encompassing (a) axially chiral phosphoramidites,
configuration at the α stereocenter can be inverted by using (b) BINOL-derived phosphates as ligands on transition metals,
the (S,S)-cinchona to produce the 2S,3R product. Similarly, and (c) Brønsted acid catalysis by BINOL phosphoric acids have
the configuration at the β stereocenter could be inverted by been detailed in order to shed light on the control elements in
using the (S)-phosphoramidite ligand on the Ir−π-allyl species. chirality transfer. The central theme fortifying these examples has
The stereocontrolling C−C bond formation TSs were located been the significance of non-covalent interactions in asymmetric
and helped us establish the origin of this stereodivergence for induction. How the cumulative effect of weak non-covalent
different combinations of chiral catalysts. interactions dictates the relative energies of transition states that
The optimized geometries of the TSs for the C−C bond differ in the prochiral faces involved in the stereodetermining bond
formation between the (8R,9R)-cinchona enamine and the formation step has been delineated through this Account.

Scheme 5. Cooperative Dual-Catalytic Asymmetric α-Allylation of an Aldehyde Leading to Two New Chiral Centers, Including a
Quaternary α-Carbon

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Indian Institute of Technology Bombay. He was promoted to full

professor in 2012. He is an elected member of the board of the World
Association of Theoretical and Computational Chemists (WATOC).
His research interests are in the domain of computational studies of
transition states in asymmetric catalysis, mechanisms of multicatalytic
reactions, and catalyst design.

■ ACKNOWLEDGMENTS
I acknowledge the present and past members of the RBS group at
IIT Bombay. Special thanks are extended to Dr. Garima Jindal
(University of Southern California) and Bangaru Bhaskararao
(IIT Bombay) for their efforts in pursuing increasingly complex
problems in transition state modeling and chiral induction.

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J DOI: 10.1021/acs.accounts.6b00053
Acc. Chem. Res. XXXX, XXX, XXX−XXX