Asymmetric Catalysis DOI: 10.1002/anie.

200((will be filled in by the editorial staff))

Asymmetric Ion-Pairing Catalysis

Katrien Brak and Eric N. Jacobsen*

Keywords: Dedicated to the memory and legacy

anion-binding catalysis • asymmetric catalysis of W.S. Knowles
• chiral anions • ion pairs • phase-transfer
catalysis

1
Charged intermediates and reagents are ubiquitous in organic
transformations. The interaction of these ionic species with chiral
neutral, anionic, or cationic small molecules has emerged as a
powerful strategy for catalytic, enantioselective synthesis. This review
describes developments in the burgeoning field of asymmetric ion-
pairing catalysis with an emphasis on the insights that have been
gleaned into the structural and mechanistic features that contribute to
high asymmetric induction.

1. Introduction

All chemical reactions involve some degree of charge

polarization, and many archetypal organic transformations proceed Solvation effects are crucially important in understanding the
via the intermediacy of at least one discrete, charged species. behavior of ion pairs, which can be classified into three different
Controlling the stereochemical outcome of reactions of charged types based on the extent to which the ions are solvated (Figure 2).
reagents and intermediates is a long-standing goal in organic An ion pair with a common solvation shell and no solvent molecules
synthesis, and the identification of efficient, catalytic methods to do between the two ions is termed a contact ion pair. When the ions are
so represents a current frontier of the field. This review focuses on separated by a shared solvation shell, or when they each have their
two general approaches that have emerged for asymmetric catalysis own solvation shell, they are termed solvent-shared and solvent-
of reactions proceeding via charged intermediates or reagents: (i) separated ion pairs, respectively. Contact ion pairs are energetically
ion-pairing with a charged, chiral catalyst and (ii) noncovalent favorable in nonpolar solvents of low dielectric constant, whereas
binding to the intermediate ion pair by a chiral, neutral catalyst the solvent-shared and solvent-separated ion pair types are more
(Figure 1). prevalent in solvents of higher dielectric constant. [3] The ions of
contact pairs have a stronger influence on the environment around
each other; therefore, for reactions in which selectivity is controlled
largely by an ion-pairing interaction, higher selectivity is generally
observed in nonpolar solvents.

Figure 1. Types of asymmetric ion-pairing catalysis.

Figure 2. Types of ion pairs.

In order to frame the challenges that exist in designing

enantioselective catalysts that operate by ion-pairing mechanisms, a The goal in asymmetric ion-pairing catalysis is to identify
brief description of the physical principles underlying ion pairs is synthetic, chiral molecules that can induce high enantioselectivity in
appropriate. The concept of ion pairs as distinct chemical entities reactions of discrete ionic species. Small-molecule catalysts, by their
was introduced in 1926 by Bjerrum. [1] Anslyn and Dougherty very nature, rely on a limited number of interactions to control
provide a modern physical-organic textbook definition: stereoselectivity. In such systems, the level of transition structure
organization that is necessary for high stereoinduction is often
“An ion pair is defined to exist when a cation and anion are achieved through highly directional catalyst-substrate interactions.
close enough in space that the energy associated with their For example, covalent iminium catalysis and Lewis acid catalysis –
electrostatic attraction is larger than the thermal energy (RT) two approaches that rely chiefly on strong, directional interactions –
available to separate them. This means that the ions stay associated are broadly successful approaches to enantioselective activation of
longer than the time required for Brownian motion to separate non- carbonyl derivatives (Figure 3). Hydrogen-bond donor catalysts rely
interacting species.”[2] on interactions that are generally weaker and less directional in
nature, yet a growing number of highly effective chiral catalysts of
Coulomb’s law [Eq. (1)] describes the attractive potential this type have also been reported.[4]
energy (E) between two ions of opposite charge (q1 and q2). The
magnitude of the electrostatic interaction is inversely related to the
distance between the ions (r) and the dielectric constant of the
medium (ε). Strong ion-pairing interactions are thus favored at short
distances and in nonpolar solvents.
 While covalent, Lewis acid, and H-bond donor catalysts have scientists on the use of a chiral quaternary ammonium salt as a
clear utility in enantioselective synthesis, their application to highly efficient and enantioselective phase-transfer catalyst for the
reactions of charged intermediates is often not straightforward, and C-methylation of indanones (Scheme 1).[5i] This result revealed for
it is in this context that ion-pairing catalysis emerges as a most the first time that high enantioselectivity can be achieved solely
attractive strategy. The fact that ion-pairing interactions are through electrostatic and other noncovalent interactions of a charged
inherently less directional than covalent or hydrogen-bonding intermediate with a chiral, ionic catalyst. Since that seminal
interactions underlies the challenge in designing stereoselective discovery, a remarkable number of methods that utilize chiral
catalysts that operate by this principle. Yet, as outlined in this quaternary ammonium and phosphonium ion catalysts have been
review, a variety of highly enantioselective small-molecule catalysts identified. These catalysts have been shown to induce high levels of
have been identified that proceed through the basic mechanisms enantioselectivity in a wide range of reactions, including enolate
outlined in Figure 1. The success of these systems can be ascribed to alkylation, Michael, Aldol, Mannich, and Darzens reactions, as well
the fact that the catalysts incorporate secondary structural elements as epoxidations and aziridinations. The large number of excellent
capable of inducing specific attractive or repulsive interactions in reviews on chiral cation-directed catalysis is a testament to this
the stereoselectivity-determining transition structures, in a manner field’s success.[5a-h]
reminiscent of their far more complex, enzymatic counterparts.

Figure 3. Comparative directionality of catalyst-substrate interactions

of common asymmetric catalysis strategies (Ln* = chiral ligand; B*H = Scheme 1. First reported enantioselective phase-transfer-catalyzed
chiral Brønsted acid; X* = chiral counterion) alkylation of indanone derivatives.

Here we provide an analysis of the four classes of asymmetric Because extensive secondary literature exists on asymmetric
ion-pairing catalysis defined in Figure 1, with emphasis placed on catalysis with onium ions, this review will focus only on selected
the conceptual and mechanistic underpinnings of key illustrative systems that have yielded mechanistic and conceptual insight into
reactions. This field has a relatively long history in phase-transfer the basis for enantioselectivity.
catalysis with chiral cationic or cation-binding catalysts. [5] In
contrast, ion-pairing catalysis with chiral anionic [6] and anion-
binding[7] catalysts is a much newer field of endeavor, but research 2.1. Quaternary Ammonium Cations
in this area has progressed at a particularly rapid pace in the last five
years. The aim of this review is to tie together these different Quaternary ammonium salts are the largest and most well-
activation modes to help shed light on the common features that studied class of chiral phase-transfer catalysts (Figure 4). Building
enable highly enantioselective transformations of reactive, charged on the pioneering work by the Merck research group, [5i] O’Donnell
species with small-molecule chiral catalysts, with the ultimate goal and co-workers reported a similar cinchona alkaloid-derived
of providing design principles for future discovery efforts. ammonium salt for the enantioselective synthesis of α-amino acids
under phase-transfer conditions.[8] N-benzyl cinchonidinium chloride
(1b) was found to effect the alkylation of the benzophenone imine
2. Chiral Cation-Directed Catalysis of glycine tert-butyl ester (4) with moderate levels of
enantioselectivity (Scheme 2a). This synthetically useful alkylation
The history of ion-pairing catalysis as an important approach in of 4 has served as a benchmark reaction for the development of new
asymmetric synthesis can be traced to the 1984 report by Merck enantioselective phase-transfer catalysts.

Katrien Brak was born in Leuven, Belgium Eric N. Jacobsen was born and raised in
in 1983. She obtained her B.S. degree in New York City. He earned his B.S.
chemistry in 2000 from MIT, and completed degree from New York University in 1982
her Ph.D. studies at UC Berkeley working and his Ph.D. degree at the UC Berkeley
under the supervision of Prof. Jonathan A. in 1986, working under the direction of
Ellman. Her graduate work focused on the Robert Bergman. He carried out
design of nonpeptidic cruzain inhibitors and postdoctoral studies with Barry
Sharpless at MIT. In 1988, he began his
the development of methods for the
independent career at the University of
asymmetric synthesis of α-branched allylic Illinois at Urbana–Champaign. He moved
[] Dr. K. Brak, Prof. E. N.amines. She is currently an NIH
Jacobsen to Harvard University in 1993, where he
Department of Chemistrypostdoctoral fellowBiology
and Chemical in the laboratories of is currently the Sheldon Emory Professor
Harvard University Prof. Eric N. Jacobsen. Her research of Organic Chemistry and Department
12 Oxford St, Cambridgeinvolves the development
MA 02138 (USA) of Chair. His research interests lie in the
enantioselective catalytic reactions of cationic intermediates by anion-
Fax: (+1) 617-496-1880 discovery, mechanistic elucidation, and application of new catalytic
binding catalysis.
E-mail: Jacobsen@chemistry.harvard.edu processes.
 the highly efficient and enantioselective catalysts 1c-d (Scheme 2a).
Subsequently, Park and Jew took advantage of the positive influence
of sterically bulky N(1)-substituents to develop dimeric and trimeric
cinchona alkaloid-derived catalysts linked via the quinuclidinium
nitrogen. These multimeric catalysts provide dramatically improved
levels of asymmetric induction in alkylations of 4 compared to less
sterically congested, monomeric catalysts such as 1b.[5e]
The basis for enantioselectivity in the alkylation of glycine
derivative 4 catalyzed by N-anthracenylmethyl ammonium salts 1c
and 1d has been probed by several research groups. The quaternary
ammonium ion of these catalysts can be envisioned at the center of a
tetrahedron composed of the four carbon atoms adjacent to the
Figure 4. Structures of chiral ammonium phase-transfer catalysts.
bridgehead nitrogen (Figure 5a). [12] Based on an X-ray crystal
structure of the p-nitrophenoxide salt of 1d, Corey and co-workers
propose that three of the faces of this tetrahedron are blocked by the
Two general mechanistic descriptions have been proposed for quinuclidine, quinoline, and anthracenyl groups. The remaining
phase-transfer-catalyzed reactions using aqueous bases, differing in face, however, is sufficiently open to allow for close contact
the location of the substrate in the deprotonation event – either at the between the enolate anion and ammonium cation. 26 Pochapsky and
interface of the aqueous and organic phases (interfacial mechanism), co-workers provided experimental support for preferred anion
or in the organic phase (extraction mechanism). [9] For enolate occupancy at this face of the ammonium ion with the observation of
alkylation reactions, experimental support for the interfacial specific interionic NOE correlations of a cinchona alkaloid-derived
mechanism was provided by Merck scientists (Scheme 2b). [10] ammonium• borohydride ion pair in solution.[14] The higher
Specifically, the alkylation of glycine ester 4 was shown to proceed selectivity observed with the N-anthracenylmethyl catalysts 1c-d
via α-deprotonation of the ester at the aqueous/organic interface by versus N-benzyl catalyst 1b is attributed to more effective
metal hydroxide. The resulting metal enolate remains at the interface differentiation of the tetrahedron faces.
until ion exchange with the chiral catalyst cation (Q* +) generates Studies by the Reetz and Houk research groups have provided
key lipophilic ion pair intermediate 5. After diffusion into the insight into the noncovalent interactions that result in highly
organic phase, this chiral ion pair reacts with an alkyl halide, structured enolate•ammonium catalyst contact ion pairs. Reetz and
affording the optically active monoalkylated product and co-workers used molecular orbital calculations to determine that the
regenerating the catalyst. positive charge of tetraalkylammonium cations is delocalized to a
significant extent onto the α-carbon atoms. [15] This charge
distribution is consistent with the stabilizing R 3N+–C–H•••–O–C=C
hydrogen bonds identified in several X-ray structures of
tetrabutylammonium•enolate ion pairs.[16] Using MP2 calculations
with a large basis set, Houk and Cannizzaro evaluated the
geometries and interaction energies of such hydrogen bonds using
[Me3NH•CH2COOMe] as a model ion pair (Figure 5b).[17] The most
stable complex identified has the plane containing the enolate
parallel to the tetrahedral face of the trimethylammonium cation
defined by the hydrogens of three parallel C-H bonds α to the
quaternary nitrogen. Based on this computational model, Houk
proposes a mechanism for the alkylation reaction in which the Z-
enolate of 4[18] binds in a parallel fashion to the open face of the
cinchonidinium, leaving the si face exposed for electrophilic attack
(Figure 5a).[19] This arrangement also allows for π-stacking between
the electron-rich phenyl substituents of the enolate substrate and the
electron-deficient anthracenyl unit of the catalyst. The high
enantioselectivity observed in the alkylation of glycine derivative 4,
catalyzed by cinchonidinium salts 1c-d, is thus ascribed to a highly
ordered catalyst-enolate complex stabilized primarily by N +–C–
Scheme 2. (a) Enantioselective alkylation of glycine ester 4
H•••X hydrogen-bonding and π-stacking interactions. This complex
catalyzed by various quaternary ammonium ions and (b) the
interfacial mechanism for phase-transfer catalysis. leaves only one face of the nucleophile exposed to alkylation.

Through the study of catalyst structure-activity/selectivity

relationships, several highly selective N-alkyl cinchona alkaloid-
derived phase-transfer catalysts (1) have been identified for the
glycinate Schiff base alkylation methodology. A particularly strong
dependence of catalyst performance on the identity of the N(1)-
arylmethyl substituent has been noted.[11] In 1997, Corey[12] and
Lygo[13] independently reported that replacement of the N-benzyl
Figure 5. (a) Tetrahedron stereoselectivity model for cinchona
group of 1b with a bulky N-9-anthracenylmethyl group resulted in
alkaloid-derived catalysts and the proposed enolate approach based
on (b) the optimal geometry for attractive R3N+–C–H•••X bonds in the
[Me3NH•CH2COOMe] complex at the MP2/6-311++G** level of theory.

The effect on enantioselectivity of varying the electronic

properties of the quinuclidinium N(1)-arylmethyl substituents has
been investigated. Park and co-workers prepared several fluorinated
N-benzylcinchonidinium salts and identified 2’,3’,4’-trifluorophenyl
analog 1e as a highly enantioselective catalyst for the alkylation of
glycine ester 4 (Figure 6).[20] The fluorine substituent in the 2’-
position of the benzyl group was found to be of particular
Figure 7. X-ray crystal structure of N-spiro binaphthyl catalyst
importance for achieving high enantioselectivity. The authors (2)•PF6– (adapted from reference 27).
propose that the 2’-F substituent is involved in internal hydrogen
bonding via a water molecule, which results in a more rigid catalyst
conformation (Figure 6). This model was corroborated by the To gain insight into the interactions that produce organized
success of catalysts containing 2’-N-oxopyridine (1g) or 2’- binding of tartrate-derived diammonium catalyst 3 to the enolate of
cyanophenyl (1h) moieties;[21] these groups have previously been 4, Shibasaki and co-workers carried out a computational analysis of
established, through a series of X-ray crystal structures, to form the complex.[24a] The optimized structure suggests that the Z-enolate
internal hydrogen-bonding networks similar to those of fluorophenyl is associated to the catalyst through a network of hydrogen bonds
substituents.[22] between the methylene groups adjacent to the ammonium nitrogens
and the enolate (Figure 8). Thus, N +–C–H•••X hydrogen bonds are
proposed to serve as the primary organizational interactions of
enolate ion-pair complexes formed with both cinchona alkaloid-
derived catalysts 1a-1h and catalyst 3.

Figure 6. Proposed internal hydrogen-bonding via a water molecule

for catalysts 1e-h and enantioselectivity in the benzylation of 4.

Even though cinchona alkaloid derivatives have been applied

with great success as asymmetric phase-transfer catalysts, these
natural product-derived molecular frameworks are amenable to only
limited structural modification. This restriction has provided an Figure 8. Optimized structure of a tartrate-derived diammonium
impetus for the development of fully synthetic catalyst structures catalyst (3)•enolate ion pair at the B3LYP/6-31G(d) level of theory.
that are easier to modify and diversify. Towards this goal, the
research groups of Maruoka[23] and Shibasaki[24] have developed N-
spiro C2-symmetric quaternary ammonium catalysts (2) and two- 2.2. Quaternary Phosphonium Cations
centered tartrate-derived diammonium salts (3), respectively (Figure
4).[25] Carefully optimized derivatives of these catalysts promote the In recent years, chiral quaternary phosphonium salts have been
alkylation of glycine ester 4, as well as other transformations, in a identified as a new type of onium salt for asymmetric ion-pairing
highly enantioselective fashion (Scheme 2a). [26] Maruoka and co- catalysis (Figure 9). Maruoka and co-workers have shown that C 2-
workers found that the steric and electronic nature of the 3,3’- symmetric tetraalkyl phosphonium salt 6 is an effective phase-
binaphthyl substituents (Ar) of 2 had a dramatic effect on reactivity transfer catalyst for catalytic enantioselective amination, [29] Michael,
[30]
and enantioselectivity in the alkylation of 4.[26b, 27] In particular, the and Mannich reactions.[30] Ooi and co-workers accomplished the
catalyst bearing 3,4,5-trifluorophenyl groups determined to be enantioselective alkylation of azlactones with N-benzylated D2-
optimal; the beneficial effect of electron-deficient aromatic symmetric P-spiro tetraaminophosphonium salt 7 under phase-
substituents could be a consequence of an attractive π-π interaction transfer conditions.[31]
between the catalyst and phenyl groups of substrate 4. X-ray
crystallographic analysis of the PF 6– salt of 2 revealed that the two
3,4,5-trifluorophenyl groups create a well-defined pocket by
blocking two sides of the central ammonium cation (Figure 7).
While the usual caution must be exercised in deriving mechanistic
interpretation of selectivity effects based solely on solid state
catalyst structures,[28] Maruoka and co-workers advance the
intriguing proposal that it is this pocket that restricts binding of the
E-enolate of 4 to conformations where the si-face is shielded by the Figure 9. Representative chiral phosphonium phase-transfer catalyst
binaphthyl and trifluorophenyl moieties. This binding orientation structures.
leaves the re-face accessible to alkyl halides, in agreement with the
observed sense of enantioinduction in alkylations of 4.
 Chiral phosphonium salts have been successfully employed not
only as phase-transfer catalysts, but also as organic base catalysts. [32]
In one of the most impressive examples, Ooi and co-workers
designed P-spiro tetraaminophosphonium phenoxide salt 8 and
demonstrated its utility in the enantioselective addition of azlactones Figure 10. Cation binding by chiral polyether catalysts.
to α,β-unsaturated acylbenzotriazoles (Scheme 3). [32d] This
transformation is proposed to proceed via deprotonation of the
azlactone by the phenoxide counterion of the catalyst, followed by To date, greatest success with this approach has been achieved
ion-pairing of the resultant enolate nucleophile to a supramolecular using chiral crown ethers as asymmetric phase-transfer catalysts for
assembly of the chiral, cationic catalyst and two phenol molecules Michael addition reactions. The first highly enantioselective
(Scheme 3). An X-ray crystal structure analysis of the catalyst salt Michael addition under phase-transfer catalysis was accomplished
revealed that the supramolecular assembly of the by Cram and Sogah in 1981. The potassium enolate of a β-keto ester
aminophosphonium cation, two phenols, and a phenoxide ion is was added to methyl vinyl ketone with very high enantioselectivity
structured by a 10-membered, cyclic, network of hydrogen-bonding by employing a 1,1’-bi-2-naphthol (BINOL)-based chiral crown
interactions, and strong experimental evidence was obtained that the ether (Scheme 4a).[34] More recently, chiral crown ether catalyst
same supramolecular assembly is generated under the conditions of structural motifs have been derived from naturally-abundant
reaction. Furthermore, the structure of the achiral phenolic carbohydrates. For example, Akiyama and co-workers prepared a
component was shown to affect the enantioselectivity. The chiral ion chiro-inositol-derived crown ether that enabled the highly
pair 9, stabilized by a well-defined array of hydrogen bonds, was enantioselective Michael addition of the potassium enolate of
proposed to account for the observed highly enantioselective glycine Schiff base 4 to alkyl vinyl ketones (Scheme 4b).[35]
addition to α,β-unsaturated acylbenzotriazoles.

Scheme 3. Tetraaminophosphonium salt 8 as a supramolecular chiral

organic base catalyst for conjugate additions to acylbenzotriazoles.

Asymmetric catalysis by onium salts has been explored for

three decades. Yet, activity in this field is currently at its highest
level with new discoveries being reported at a remarkably rapid
pace. The intense interest in this research area can be attributed to
the broad applicability of the approach, the discovery of new classes
of chiral onium ions, and, the identification of mechanistic
Scheme 4. Chiral crown ethers as phase-transfer cation-binding
principles that govern successful catalyst scaffolds. catalysts for enantioselective Michael addition reactions.

3. Cation-Binding Catalysis Song and co-workers recently evaluated the reactivity and
selectivity of a BINOL-based bis(hydroxy) polyether catalyst/KF
By capitalizing on the well-established cation-binding property complex in the desilylative kinetic resolution of silyl ethers (Scheme
of polyethers, researchers have long sought to devise effective 5).[36] The polyether catalyst was designed such that simultaneous
enantioselective catalysts that operate through binding of a chiral binding could take place to (i) the potassium cation, through
polyether to the cationic counterion of the reacting anion (Figure chelation with the ether groups, and (ii) the fluoride anion and the
10). Phase-transfer catalysis with polyether compounds differs from silyl ether, through hydrogen bonding with the terminal hydroxy
catalysis with onium salts (Section 2) in that the entire reacting ion groups. Computational support was provided for the proposed
pair, not just the anion, is transferred into the organic phase. [33] cooperative mechanism.[37] An additional catalyst–ion-pair
interaction was suggested by the observation that only catalysts
having halogen substituents at the 3,3’-positions of the BINOL units
exhibit catalytic activity, and that the reaction outcome is
dramatically affected by the identity of the halogen atom. An X-ray
crystal structure analysis of a bromo-substituted polyether using chiral phosphoric acid derivatives, and has been discussed in
catalyst/KF complex suggests that this effect is the result of a strong several recent reviews on asymmetric catalysis with hydrogen-bond
interaction between the halogen substituent and the potassium ion. donors.[4b-d]

Figure 11. Types of ion-pairing interactions.

The following discussion will focus on asymmetric catalytic

systems operating through strict ion pair interactions of chiral
Scheme 5. Bis(hydroxy) polyether-catalyzed desilylative kinetic anionic catalysts and cationic intermediates or reagents. When the
resolution of silyl-protected secondary alcohols. information is available, attention will be drawn to the specific
noncovalent interactions that serve to organize the contact ion pairs,
enabling discrimination of the enantiotopic faces of the charged
These reports and others[33] demonstrate the conceptual validity prochiral intermediates.
of cation-binding catalysis using chiral crown ethers. It should be
noted, however, that the scope of this approach to catalysis has thus
far been limited, perhaps because of the difficulty associated with 4.1. Borate Anions
creating a highly organized chiral environment around a reacting
anion by simply binding a chiral catalyst to the associated cation. In The first report of asymmetric catalysis via ion pairing with a
more broadly successful asymmetric ion-pairing catalysis strategies chiral anion was provided by Arndtsen and co-workers in 2000.
such as those described in the other sections of this review, explicit Achiral cationic copper complexes with D2-symmetric BINOL-
secondary interactions have been shown to be essential for attaining based chiral borate counterion 12 were applied as catalysts in a
high enantioselectivity. It may, therefore, prove useful to design series of aziridination and cyclopropanation reactions (Scheme 6a).
cation-binding catalysts that bear ancillary components capable of
[39]
Ion pairing between Cu(I)-intermediates and borate counterion
creating specific steric and/or attractive secondary interactions. As 12 was proposed to be the source of enantioselectivity, rather than a
discussed above, Song and co-workers nicely illustrate the potential covalent interaction with borate 1 acting as an anionic ligand.
validity of this hypothesis in their design of bis(hydroxy) polyether Support for such an electrostatic interaction was provided by the fact
catalyst 11. It will be interesting to see if future work in this field that the enantioselectivity was sensitive to changes in solvent in a
follows along similar lines, or whether other concepts arise for manner consistent with the known inverse relationship between ion-
achieving high enantioselectivity in cation-binding catalysis. pairing energy and solvent dielectric constant: benzene (ε = 2.3;
7% ee), methylene chloride (ε = 9.1; 4% ee), and acetonitrile (ε =
38.8; <1% ee). Analysis of a copper complex that was crystallized in
4. Chiral Anion-Directed Catalysis the presence of 2,2’-bipyridine and styrene, to mimic the catalytic
conditions, revealed a [(bipy)Cu(H2C=CHC6H5)+][12] structure.
While asymmetric catalysis of reactions proceeding via anionic This result implies that borate anions do not interfere with the
intermediates through ion-pairing with chiral cationic catalysts has a binding of olefin substrates and diimine ligands to the copper center,
relatively long history (Section 2), reports of analogous charge- and strongly supports their role as counterions. While the initial
inverted processes did not emerge until recently. The successful experiments with borate 12 provided products with ≤ 10% ee, this
implementation of chiral anion-directed ion-pairing catalysis is work served, nevertheless, as an important proof-of-concept.
potentially very powerful; this strategy provides a platform for Subsequent studies on the cyclopropanation of styrene using
absolute stereocontrol in reactions that proceed via cationic copper catalysts with borate counterions prepared from tartaric acid
intermediates or that utilize cationic reagents or catalysts. The and α-amino acid residues (13) demonstrated improved
following section, organized by type of anionic counterion, details enantioselectivities of up to 34% ee (Scheme 6b). [40] When a borate
the impressive advances that have been reported to date. anion derived from achiral glycine methyl esters (13 with R = H)
Reactions catalyzed by strong Brønsted acids that proceed via was used, racemic product was obtained, indicating that the α-amino
ion pairs containing a hydrogen-bonding interaction directly acid residues, and not the tartrate backbone, are critical for chiral
involved in the activation of the reactive intermediate will not be induction in this case. 1H NMR and IR analyses of [Cu+][13] salts
included in this discussion (Figure 11). As an example, a recent revealed only a single set of signals for the tartrate and amino acid
NMR spectroscopy-based study established that significant portions of the catalyst, further bolstering the idea that the borate
hydrogen bonding still exists in the ion pair resulting from anions act as counterions and not as ligands. These studies with
protonation of N-aryl imines by diphenyl phosphoric acid. [38] Such copper borate salts provided the earliest support for the concept of
hydrogen bonds provide directionality to the electrostatic interaction inducing asymmetry in metal-catalyzed reactions through ion-
between chiral catalysts and reactive electrophiles, thereby pairing cationic metal intermediates to chiral anions.
contributing significantly to the molecular organization necessary to
favor one of the diastereomeric transition states. This type of
asymmetric Brønsted acid catalysis has been particularly successful
 Figure 12. BINOL-derived phosphate anions 14.

4.2.1. Reactions of Iminium Ions

In 2006, List and Mayer published a landmark paper describing

the first highly enantioselective transformation that relies solely on
the chirality of an anionic counterion to induce asymmetry. [45] The
Scheme 6. Proof-of-concept studies using chiral borate anions. discovery was based on the biomimetic transfer hydrogenation of
enals using a Hantzsch dihydropyridine as the reductant and a chiral
secondary amine as the catalyst, which was reported independently
In the field of organocatalysis, the principle of stereochemical the previous year by the List and MacMillan groups (Scheme 8a). [46]
communication between chiral anions and prochiral cationic That reaction proceeds through a now-classical aminocatalytic
intermediates was first demonstrated by Nelson and co-workers in mechanism, with LUMO-lowering activation of the α,β–unsaturated
the context of the asymmetric ring-opening of meso-aziridinium aldehyde via the reversible formation of iminium ions. Because the
cations (Scheme 7).[41] By using ammonium salts of borate 12, structure of the counterion of the iminium intermediate was found to
enantioselectivity of up to 15% was achieved. In line with an ion- have a strong effect on the yield and enantioselectivity of the
pairing interaction, 1H NMR spectroscopy studies revealed proton reaction, List and Mayer hypothesized that the source of asymmetry
and carbon shifts of the aziridinium to vary linearly with the amount in the catalyst system could be relocated to the counterion (Scheme
of borate present. In this same study, the authors did not observe any 8b). The successful demonstration of this strategy was achieved with
splitting of the enantiotopic protons of the aziridinium salt, the morpholine salt of sterically hindered chiral phosphate 14a.
indicating that no specific interaction exists between the meso cation Using this catalyst, β,β-aryl,methyl-disubstituted enals were reduced
and the chiral anionic catalyst; this observation is consistent with the with up to 99% ee.[45, 47] It is particularly noteworthy that higher
low levels of enantioselectivity attained. The aziridinium-opening enantioselectivity was observed for all of the reported substrates
reaction was later rendered highly enantioselective by employing a with the ion-pairing approach compared to the prior covalent chiral
chiral phosphate-containing catalyst (vide infra). [42] iminium strategy. Studies on the basis for enantioselectivity were
not reported. However, an organizational hydrogen-bond between
the Hantzsch ester N-H and the Lewis basic oxygen of the
phosphoryl group is likely based on detailed theoretical studies that
support the presence of this interaction in the closely-related
BINOL-phosphoric acid-catalyzed reductions of imines with
Hantzsch dihydropyridines (Scheme 8b).[48]

Scheme 7. Chiral borate anion-directed aziridinium opening reaction.

Even though only low levels of enantioselectivity were

achieved, the pioneering studies with borate salts set the stage for
further studies in the area of chiral anion-directed ion-pairing
catalysis.

4.2. Phosphate Anions

Since their discovery by Akiyama[43] and Terada[44], BINOL-

derived monophosphoric acids have proven to be an attractive and
widely useful class of enantioselective Brønsted acid catalysts for
hydrogen-bond catalysis.[4c] Furthermore, the conjugate bases of
acids with this privileged structure have emerged as powerful
counterions in the development of highly enantioselective reactions
proceeding via strict ion pairs (Figure 12).
Scheme 8. Comparison of enantioselective transfer hydrogenations Scheme 9. (a) Scope and (b) mechanism for the epoxidation of enals
of enals via iminium catalysis by (a) chiral ammonium- or (b) chiral catalyzed by chiral secondary ammonium•phosphate salts.
anion-based salts.

Both the transfer hydrogenation and epoxidation methodologies

List and Wang have subsequently applied this new mode of developed by List have been successfully extended to ketone
chiral anion-directed asymmetric iminium activation to the substrates.[51] The epoxidation of α–branched enals has also been
epoxidation of α,β–unsaturated aldehydes (Scheme 9a). [49] The best achieved.[52] Due to the increased steric requirements of the ketone
catalyst for the conjugate reduction, the morpholine salt of 14a, was and α–branched substrates, phosphoric acid salts of primary amines
found to be only moderately enantioselective (54% ee) for the proved to be uniquely effective. While the reactions catalyzed by
epoxidation reaction. By screening different amines, a new catalyst salts of secondary amines proceed via strict quaternary iminium-
salt, derived from a trifluoromethyl-substituted dibenzylamine and phosphate ion pair intermediates, salts of primary amines proceed
phosphate 14a, was identified that catalyzes the epoxidation of β– via hydrogen-bonded protioiminium-phosphate ion pairs (Figure
aryl substituted enals in high yield (60-95%), diastereoselectivity 11). For reasons discussed above, this reaction manifold is best
(97:3 to >99:1), and enantioselectivity (84-96%). Notably, this described as hydrogen-bond catalysis and falls beyond the scope of
secondary ammonium salt catalyst system is also effective for the the review.
epoxidation of β,β–disubstituted enals, a substrate class for which N-Acyl iminium ions are highly reactive electrophiles that have
achieving high enantioselectivity has proven elusive with other been utilized extensively in the construction of various N-
asymmetric epoxidation methodologies.[50] heterocyclic frameworks.[53] Due to the weak Lewis basicity of N-
The fact that excellent enantioselectivity was achieved with acyl iminium ions, the development of asymmetric transformations
symmetric β,β–disubstituted enals provides valuable clues to the of this functional group by traditional Lewis acid catalysis
mechanism of stereoinduction in these epoxidation reactions. The approaches is not straightforward. In contrast, the advent of chiral
intermediate (15) resulting from the conjugate addition of tert-butyl anion-directed catalysis has enabled the discovery of several highly
hydroperoxide to this class of substrates is achiral, and a stereogenic enantioselective counterion-controlled reactions of N-acyliminium
center is only formed in the subsequent cyclization step (Scheme ions promoted by either chiral phosphoric acids (vide infra) or
9b). As such, enantioselectivity is only possible if either 15 is thioureas (Section 5).
generated in a chiral conformation through the influence of 14a and Dixon and co-workers reported an enantioselective N-
undergoes rapid cyclization before bond rotation to an achiral acyliminium ion cyclization cascade that generated polycyclic
conformation is reached, or if the second cyclization step is tetrahydro-β-carboline products in 68-99% ee through a chiral
enantioselectivity-determining. In the latter case, the chiral phosphoric acid-catalyzed condensation of tryptamines and enol
phosphate must be involved in this second C-O bond-forming event. lactones[54] or keto acid derivatives [55] (Scheme 10a). The formation
Since the intermediate poised to undergo cyclization (15) is neutral, of cyclization products in high enantioselectivity and syn-
stereochemical communication with the catalyst cannot occur via diastereoselectivity was suggested to be the result of a dynamic
ion-pairing, but must take place instead via hydrogen-bonding. The kinetic resolution of the chiral iminium ion intermediates. The
basis for stereoinduction with unsymmetric β,β–disubstituted enals proposed mechanism involves fast and reversible formation of the
or enals with a single β–substituent is also ambiguous, since the ion- diastereomeric N-acyliminium phosphate salts 17 and 18 via
pairing interaction of iminium ion intermediates with the chiral prochiral cyclic enamide intermediate 16, followed by rate-
phosphates is only relevant to the observed asymmetric induction if determining cyclization (Scheme 10b). In support of this
the addition of tert-butyl hydroperoxide is irreversible. Thus, while mechanism, enamide intermediate 16 (R1, R2 = –(CH2)4–) could be
this methodology represents an important synthetic advance by isolated during the early stages of the reaction. Furthermore,
expanding the scope of asymmetric epoxidations, the implications it subjecting enamide 16 to the reaction conditions afforded product in
carries for ion-pairing catalysis must await further mechanistic nearly identical yield and enantiomeric excess to that obtained from
analysis. the reaction of the tryptamine and keto acid starting materials.

Scheme 10. (a) Enantioselective phosphoric acid-catalyzed N-

acyliminium ion cyclization cascade and (b) the proposed mechanism.
 Huang and co-workers developed a (thio)phosphoric acid-
catalyzed enantioselective N-alkylation of indoles with N-
acyliminium ions.[56] Chiral N-acyliminium•phosphate ion pairs were
proposed to form in situ upon treatment of α,β-unsaturated γ-lactams
with (thio)phosphoric acid catalysts (Scheme 11). Subsequent
addition of indole resulted in the enantioselective formation of N-
pyrrolidine indole derivatives. Reactions catalyzed by
thiophosphoric acid 19-H were shown to proceed with higher
enantioselectivity, but lower yield, than those catalyzed by the
analogous phosphoric acid. Substitution was tolerated at the C2 and
C3 positions of the indole, and a range of 2,3-fused indoles reacted
in high yield and enantioselectivity when using thiophosphoric acid
19-H.
Huang and co-workers carried out preliminary mechanistic Scheme 12. Phosphoric acid-catalyzed Pictet-Spengler reaction
studies to better understand the reaction pathway and the role of the proceeding via (a) sulfenyliminium ions or (b) dialkyl iminium ions.
Brønsted acid. The observed absence of catalyst nonlinear effects
provided evidence for a monomeric catalyst in both the resting and
transition states. On the basis of deuterium labelling studies, it was 4.2.2. Reactions of Carbocations
found that: (i) formation of the N-acyliminium ion is reversible, (ii)
the Brønsted acid is the proton source for generation of the N- Several methods for the enantioselective synthesis of 3-
acyliminium ion, (iii) N-acyliminium ion formation occurs prior to substituted indoles, a structural motif prevalent in therapeutic agents
alkylation, and (iv) indole addition is not the rate-determining step. and natural products, have been developed by applying asymmetric
The stoichiometric reaction of phosphoric acid 14a-H and lactam 20 ion-pairing catalysis strategies. These methods generally rely on the
was followed by in situ FTIR and analyzed by HRMS. The mass formation of carbocationic intermediates through phosphoric acid-
spectrometry analysis clearly indicated that ion pair 21 is formed, mediated dehydration of indolyl alcohols. [60] The resultant chiral
and the FTIR data were most consistent with the enol tautomer indolyl carbocation•phosphate ion pairs can be intercepted by a
dominating in the ground state. However, the identity of the reactive variety of nucleophiles. Within this mechanistic framework, You
tautomer could not be established by this analysis. and co-workers[61] discovered an intramolecular Friedel-Crafts
reaction for the enantioselective synthesis of fluorene derivatives
and Gong and co-workers[62] developed an intermolecular
enantioselective enamide alkylation reaction. Another impressive
application of this ion-pairing concept, developed by Antilla and co-
workers, involves the first reported catalytic asymmetric pinacol
rearrangement (Scheme 13).[63] Consistently high enantioselectivity
was observed upon variation of the indole N-substituent or the
identity of the migrating aryl group (91-96% ee, 14 examples).
Lower enantioselectivity was observed, however, in reactions
involving migration of non-aryl groups. The authors proposed that
the chiral phosphate binds to the cationic intermediate through a
combination of hydrogen-bonding and electrostatic interactions
(Scheme 13).
Scheme 11. (Thio)phosphoric acid-catalyzed enantioselective N-
alkylation of indoles with cyclic N-acyliminium ion intermediates.

Expanding upon the types of iminium ions that are amenable to

asymmetric ion-pairing catalysis, Hiemstra and co-workers
described phosphoric acid-catalyzed enantioselective Pictet-
Spengler reactions that proceed through N-sulfenyliminium ions
(Scheme 12a).[57] The highest levels of enantioselectivity were
obtained with substrates bearing bulky substituents on the sulfenyl
moiety, with trityl (Tr) substitution being optimal. The labile N-
tritylsulfenyl group could be removed easily, and a one-pot
cyclization/deprotection method provided access to tetrahydro-β-
carboline products derived from both alkyl- and arylaldehydes in up
to 87% ee enantiomeric excess. In later reports, Hiemstra and co- Scheme 13. Enantioselective phosphoric acid-catalyzed pinacol
workers also expanded the Pictet-Spengler methodology to N,N- rearrangement.
dialkylamine substrates (Scheme 12b). [58] Condensation and
cyclization of N-benzyltryptamine with a series of aldehydes
proceeded in good yield and up to 87% ee. The methodology was By integrating dienamine and Brønsted acid catalysis,
applied successfully to the concise synthesis of the tetracyclic indole Melchiorre and co-workers developed a remarkable system for the
alkaloid (–)-arboricine.[59] enantioselective δ-alkylation of α,β-disubstituted enals (Scheme 14).
[64]
A quinidine-derived primary amine catalyst was employed for pathway or by a concerted S N2-type displacement of one of the
the activation of enals as the corresponding nucleophilic diastereotopic ethoxy groups (Scheme 15).
dienamines. These intermediates were shown to undergo δ-
alkylation with the benzyhydryl carbocation derived from acid-
catalyzed ionization of bis(4-dimethylaminophenyl)methanol. In this
dual-catalyst system, the enantioselectivity was found to be
significantly higher when chiral phosphoric acid 14d-H (93% ee)
was used in place of trifluoroacetic acid (60% ee). The matched and
mismatched amine/acid catalyst combinations provided dramatically
different results (93% yield,95% ee vs. 30% yield,21% ee), with the
sense of absolute stereochemistry in the product determined by that
of the phosphoric acid. The kinetic order in Brønsted acid was not
established, however, a 1:2 amine/acid catalyst ratio was found to be
optimal. Alcohols that are precursors to less stable carbocations
were found not to be compatible substrates for the δ-alkylation,
consistent with the proposed SN1-type pathway. Based on these
experimental observations, a complex reaction assembly was
proposed wherein phosphate 14d serves as the counterion for the
basic quinuclidine moiety and another molecule of 14d serves as the Scheme 15. Phosphoric acid-catalyzed enantioselective
transacetalization reactions.
counterion to the in situ-formed benzyhydryl cation. A stabilizing
hydrogen-bond between the 6’-OH of the quinidine-derived catalyst
and phosphate 14d was suggested based on the importance of this
substituent in achieving high levels of reactivity and Oxocarbenium ion intermediates can also be generated through
stereoselectivity. the protonation of vinyl ethers. Terada and co-workers utilized this
strategy in the development of an enantioselective direct aldol-type
reaction of azlactones with oxocarbenium ions. Activation of vinyl
ether substrates was accomplished with phosphoric acid 14a-H to
generate β-hydroxy-α-amino acid derivatives bearing a quaternary
stereogenic center at the α-carbon atom in high enantio- and
diastereoselectivity (Scheme 16a).[67] Experimental support for the
intermediacy of an oxocarbenium ion was provided: (i) identical
reaction outcomes were observed when using either (E)- or (Z)-vinyl
ethers, and (ii) treatment of tert-butyl vinyl ether with a catalytic
amount of phosphoric acid 14a-H in the presence of methanol
resulted in the formation of tert-butyl methyl acetal.
Terada and co-workers found that variation of the electronic
properties of the C2-aryl substituent of the azlactone significantly
affected the stereochemical outcome of the aldol-type reaction, with
electron-donating methoxy substituents at the 3- and 5-positions
providing the highest enantio- and diastereoselectivity. Interactions
of the C2-aryl group with catalyst 14a were therefore suggested as
an organizational element in the enantiodetermining transition
Scheme 14. Cooperative dienamine and ion-pairing catalysis for the structure. The authors further proposed that C–H•••O hydrogen-
δ-alkylation of α–branched enals. bonding interactions between the acidic protons of the
oxocarbenium ion and the negative charge-bearing sites of the
phosphate counterion restrict the conformational flexibility of the
4.2.3. Reactions of Oxocarbenium Ions oxocarbenium•phosphate ion pair (Scheme 16a). DFT
computational analysis of the oxocarbenium ion charge by a natural
Several groups have reported efficient enantioselective population analysis was shown to support the reasonable expectation
transformations that are proposed to proceed via that the oxocarbenium ion’s α-hydrogens are the most acidic. Lower
oxocarbenium•phosphate ion pairs. Based on the premise that enantioselectivity was observed with analogues in which the
Brønsted acids catalyze the breakdown of O,O-acetals to hydrogen atom directly attached to the carbenium carbon was
oxocarbenium intermediates, List and co-workers have developed a replaced with a methyl group or a deuterium atom. These results
series of highly enantioselective intramolecular chiral phosphoric suggest that direct interactions with this hydrogen atom may be
acid-catalyzed transacetalization reactions. Catalyst 14a-H was important as well.
found to be optimal for the enantioselective transacetalization of Tu and co-workers developed an enantioselective ring
achiral homoaldol starting materials (23, R1 = R2) (Scheme 15).[65] expansion-type semipinacol rearrangement that provides access to
However, the highly selective kinetic resolution of chiral derivatives spiroethers in up to 98% ee (Scheme 16b). [68] The authors also
(23, R1 ≠ R2) required the development of a new 1,1’-spirobiindane designed this reaction on the premise that protonation of vinyl ether
phosphoric acid catalyst 24-H.[66] The kinetic resolution reactions starting materials by a chiral phosphoric acid should result in the
were carried out with as little as 0.1 mol% 24-H. At this stage, it has formation of chiral oxocarbenium•phosphate ion pair intermediates.
not been established whether the cyclization proceeds through a By employing the silver salt of 14a as a precatalyst, mild conditions
discrete oxocarbenium ion by an S N1-type ion-pairing catalysis were identified that are optimal for most substrates. The authors
propose that a phosphoric acid catalyst forms in situ by silver-proton
exchange between the silver phosphate precatalyst and the alcohol
moiety of the vinyl ether substrate.

Scheme 17. (a) Desymmetrization of meso-aziridinium ions by chiral

phosphate-directed PTC and (b) the proposed catalytic cycle for this
application of chiral anion PTC compared to chiral cation PTC (X =
halide, B = basic anion, A* = chiral anion, Q* = chiral cation, M = alkali
metal).

More recently, a second application of chiral anion PTC was

reported by Toste and co-workers. A strategy was described for
Scheme 16. a) Aldol-type reaction and (b) semipinacol asymmetric electrophilic fluorination that utilizes an achiral,
rearrangement of oxocarbenium ions formed in situ by the protonation insoluble cationic fluorinating agent and a chiral phosphate phase-
of vinyl ethers. transfer catalyst. The methodology was developed on the premise
that ion exchange of lipophilic chiral phosphate anions with the
tetrafluoroborate anions of Selectfluor would result in the formation
4.2.4. Chiral Anion Phase-Transfer Catalysis of a more soluble, chiral electrophilic fluorinating agent (Scheme
18). Unlike the majority of previously reported enantioselective
Although chiral cation phase-transfer catalysis (PTC) was electrophilic fluorination methodologies,[69] this method allows for
discovered more than 25 years ago, the first example of chiral anion catalytic generation of the chiral fluorinating reagent.
PTC was reported only in 2008 by Toste and co-workers. [42] In The enantioselective fluorocyclization of olefins [70] and
analogy to chiral cation PTC (Section 2), the authors envisioned that fluorination of enamides[71] have been accomplished using the anion
a lipophilic chiral anionic catalyst could extract a cationic reagent PTC approach (Scheme 18). In enamide fluorinations, the presence
from an aqueous or solid phase into the organic phase. Ion-pairing of an N-benzoyl group was shown to be important, as significantly
of the cation with the chiral anionic catalyst would then provide a lower enantioselectivity was observed with aliphatic acyl groups
chiral environment for the desired enantioselective reaction with the (e.g. acetyl, 3% ee). In agreement with the proposed role of the
substrate. catalyst as a phase-transfer agent, the hydrophobic alkyl chains on
The first successful application of chiral anion PTC led to a new the backbone of catalyst 14e-H were found to be beneficial for
method for the asymmetric synthesis of β-alkoxy amines (Scheme achieving high enantioselectivity. Additionally, the authors observed
17a).[42] This reaction is proposed to involve extraction of Ag(I) a nonlinear relationship between catalyst ee and product ee,
from solid Ag2CO3 to the liquid phase by a chiral phosphoric acid consistent with the reaction proceeding via a pathway in which both
catalyst, with the resulting silver phosphate salt abstracting chloride tetrafluoroborate anions are exchanged for chiral phosphates. The
from a β-chloro tertiary amine substrate to generate a meso- discovery of two distinct applications of anion PTC within a short
aziridinium ion (Scheme 17b). Influenced by the chiral phosphate time frame suggests that this strategy may find broad utility in the
counterion, the aziridinium ion then undergoes ring opening by development of enantioselective reactions that utilize positively
alcohols in an enantioselective manner. Indeed, under the optimized charged reagents or proceed via cationic intermediates.
conditions, addition of sterically hindered alcohols proceeds with
very high enantioselectivity (90-99% ee). Nucleophilic addition and
proton transfer result in regeneration of the phosphoric acid catalyst.
Control experiments established that both the phosphoric acid
catalyst and Ag2CO3 are necessary for the reaction to proceed. The
fact that Ag2CO3 does not promote the reaction by itself is consistent
with the notion that the phosphate anion acts as a phase transfer
agent. Furthermore, addition of more soluble silver salts such as
AgOTs leads to significantly lower enantioselectivity. The observed
diastereoselectivity strongly supports a double inversion
mechanism, and rules out a pathway proceeding via direct S N2
substitution of the organochloride starting material.
 Scheme 19. Chiral phosphate-directed desymmetrization of (a)
meso-episulfonium and (b) meso-halonium ions.

Scheme 18. Enantioselective fluorocyclization of olefins and

fluorination of enamides by chiral anion PTC.
4.2.6. Transition-Metal Catalyzed Reactions

In 2007, Toste and co-workers reported the first highly

4.2.5. Desymmetrization Reactions of Episulfonium and
enantioselective chiral anion-directed transition metal-catalyzed
Halonium Ions
reaction.[74] It had long been recognized that the development of
enantioselective Au(I)-catalyzed additions to systems using
Toste and co-workers have also extended the chiral anion
traditional chiral ligand approaches was rendered very difficult due
concept to the desymmetrization of episulfonium ions (Scheme
to the fact that the linear coordination geometry of gold positions the
19a).[42] To avoid potential issues arising from sequestration of Ag(I)
chiral ligand far from the reaction site. In testing the hypothesis that
by the sulfide products, an alternative to the silver-halide abstraction
asymmetric induction from a chiral counterion could provide a
method that proved successful for the formation of aziridinium ions
solution to this problem, the authors found that significantly higher
(vide supra) was devised. Trichloroacetimidate was chosen instead
levels of stereoinduction could be achieved in the cyclization of
as the leaving group, allowing for generation of
allenol substrates with cationic gold complexes bearing a chiral
episulfonium•phosphate ion pair intermediates through direct
phosphate counterion than with neutral complexes bearing chiral
activation by chiral phosphoric acid catalysts. This putative meso
phosphine ligands (Scheme 20). The chiral counterion strategy
electrophilic intermediate can be intercepted by alcohol nucleophiles
proved highly effective for an impressive array of electronically and
to provide β-alkoxy sulfide products in 90-98% yield and 87-92%
sterically diverse nucleophiles, which is remarkable because of the
ee. Enantioselectivity is likely achieved via ion-pairing between the
likely presence of a secondary stabilizing H-bonding interaction
meso episulfonium ion and the anionic catalyst in the
between the phosphate anion and the nucleophile. [74-75] For
stereoselectivity-determining ring-opening step.
particularly challenging substrates such as allene-carboxylates, high
Frӧhlich and co-workers have demonstrated that meso-
enantioinduction was achieved by the combination of chiral ligands
haloniums represent another class of charged intermediates that are
and chiral counterions. The additive effect of the two chiral
amenable to asymmetric ion-pairing catalysis. Using the sodium salt
components was evidenced by the dramatically different
of phosphate catalyst 1b and N-haloamides as a halogen source, the
enantioselectivity observed with the matched (82% ee) and
enantioselective haloetherification of ene-diol substrates was
mismatched (3% ee) combinations.
achieved via the desymmetrization of meso-halonium ions (Scheme
Consistent with an ion-pairing mechanism, a strong solvent
19b).[72] The same enantioselectivity was observed regardless of
effect was observed for the Au(I)-catalyzed transformations, with
whether the 1b•Na salt was preformed or generated in situ from the
the highest enantioselectivity attained in nonpolar solvents such as
phosphoric acid catalyst and sodium carbonate. Small changes in
benzene. Furthermore, because the only two available coordination
enantioselectivity were observed with different metal counterions
sites on the Au(I) catalyst are occupied by the substrate and
(Li, 56% ee; Na, 62% ee; K, 46% ee). Bromo- and iodo-
phosphine ligand, the role of the phosphate as a counterion is
etherification products were formed in up to 67% and 71% ee,
unambiguous. This work represented an important breakthrough in
respectively.[73] However, the iodolactonization of a diacid substrate
asymmetric ion-pairing catalysis, demonstrating that chiral anions
resulted in only racemic product. The desymmetrization reactions
could be applied to enantioselective transition-metal catalyzed
developed by Toste and Frӧhlich represent elegant applications of
transformations in a synthetically useful manner.
ion-pairing catalysis to the enantioselective desymmetrization of
meso cationic reactive intermediates. Such transformations are not
readily accomplished by traditional Lewis acid catalysis.
 Figure 13. Acidity of phosphoric acid versus N-triflylphosphoramide
catalysts.[84-85]

Rueping and co-workers reported the asymmetric addition of

indoles to N-methylindolium[86] and N-acyliminium ions[87] generated
in situ using N-triflylphosphoramide catalysts 25-H (Scheme 21). In
both cases, no product formation was observed with weaker
Scheme 20. Chiral phosphate-directed Au(I)-catalyzed
enantioselective hydrofunctionalization of allenes. phosphoric acid catalysts 14-H. Addition to an indolium•N-
triflylphosphoramidate ion pair, formed upon 25a-H–catalyzed
elimination of a tertiary indolyl alcohol, resulted in the formation of
In view of the vast number of reactions catalyzed by ionic a bisindole with axial chirality in 56% ee (Scheme 21a). This
complexes of palladium, rhodium, iridium, and other metals, there is serendipitous discovery inspired the development of an alkylation
tremendous potential for the chiral counterion strategy in the field of reaction of γ-hydroxy lactams (Scheme 21b). Highly electrophilic
asymmetric transition-metal catalysis. [76] Most transition metals, N-acyl iminium ion intermediates, generated by N-
however, have more available coordination sites than Au(I). As a triflylphosphoramide-catalyzed ionization of the γ-hydroxy lactams,
result, it is often difficult to distinguish whether chiral anions are underwent nucleophilic addition by indole to provide disubstituted
functioning as counterions or as anionic ligands. Due to this lactams in good yields and moderate enantioselectivity (up to 84%
ambiguity, the significant number of recent reports of asymmetric ee).
catalysis with transition metals associated with chiral phosphates are
cited here, but will not be discussed further. [77] Cooperative catalysis
by transition-metal complexes and chiral phosphoric acid Brønsted
acids has served as the basis for significant recent contributions to
the field of asymmetric catalysis. [78] This body of work, which is
properly described as hydrogen-bonding catalysis, has recently been
reviewed.[4c, 79] In particular, Rueping and co-workers have provided
a detailed analysis of both chiral phosphate-transition metal
complexes in catalysis and chiral phosphoric acid-transition metal
co-catalysis.[80]
Ion pairing has also been applied successfully as a strategy for
ligand design in asymmetric transition-metal catalysis. [81] Ooi and
co-workers developed a new strategy for the supramolecular
assembly of chiral ligands based on an electrostatic intramolecular
interaction.[82] Achiral ammonium-phosphine ligands were paired
with chiral binaphtholate anions for asymmetric palladium catalysis. Scheme 21. N-triflylphosphoramide-catalyzed nucleophilic addition to
This ion-pairing approach to ligand design allows for rapid access to (a) N-alkylindolium and (b) N-acyliminium ions.
a large number of chiral catalysts, and holds promise as an important
tool in the development of metal-catalyzed stereoselective
transformations. More recently, Rueping and co-workers developed an
organocatalytic asymmetric allylic alkylation reaction that provides
access to biologically-relevant chromenes (Scheme 22). [88] Again, N-
4.3. N-Triflylphosphoramidate Anions triflylphosphoramide catalysts were found to be more reactive and
enantioselective than phosphoric acid catalysts. The transformation
Motivated by the desire to develop more acidic catalysts than was proposed to proceed via chiral contact ion-pair catalysis:
phosphoric acids for the activation of a wider range of substrates, protonolysis of the allylic alcohol by the Brønsted acid catalyst
Yamamoto and Nakashima introduced the strongly electron- followed by intramolecular attack on the resulting chiral allyl
withdrawing triflylamide group into the BINOL phosphate cation•phosphoramidate ion pair. Evidence for this S N1-type
framework (Figure 13).[83] This strategy has proven successful, as mechanism was provided by the observation that racemic product is
the N-triflyl phosphoramide catalysts (14-H) have been applied formed in the reaction of optically pure allylic alcohol with an
successfully to the activation of weakly basic electrophiles that are unspecified achiral catalyst. However, an alternative dynamic
unreactive towards phosphoric acids.[84] kinetic resolution mechanism consisting of an enantioselective S N2’
substitution pathway coupled to rapid racemization of the allylic
alcohol cannot be ruled out on the basis of this experiment. In
addition to hydrogen-bonding with the phenol, a cation-π interaction 4.4. Noncovalent Interactions between Cationic
between the allylic cation intermediate and the catalyst was Intermediates and BINOL-derived Phosphates and
proposed to play a role in organizing the ion pair. Phosphoramidates

The transformations described in section 4.2 and 4.3

demonstrate the ability of chiral BINOL-derived phosphate and
related anions to promote highly enantioselective reactions of
positively charged intermediates or reagents. A common theme
among the most enantioselective anions of this type is the
requirement for bulky 3,3’-substituents on the BINOL framework.
Subtle variations of the electronic and steric properties of these
Scheme 22. Organocatalytic enantioselective allylic alkylation
groups often have pronounced effects on the enantioselectivity. On
reaction. the basis of computational studies [91] and crystal structures of
hydrogen-bonded protioiminium•BINOL-derived phosphate ion
pairs[91-92], it has been suggested that the importance of the 3,3’-
Enantioselective protonation of prochiral enol silanes represents substituents stems from their role in creating a specific substrate
an attractive method for the synthesis of chiral, α-branched ketones. recognition site. In these systems, hydrogen-bonding interactions [93]
In an effort to develop an organocatalytic process, Yamamoto and with the bifunctional phosphoric acid moiety, as well as steric
Cheon focused on the design of new, highly acidic chiral Brønsted shielding[94] and stabilizing π-π interactions [95] with the 3,3’-
acids (Scheme 23).[89] In the presence of the appropriate achiral, substituents of the catalyst are proposed to provide the
stoichiometric proton source (phenol), N-triflylphosphoramide and conformational constraints required for high stereoinduction. In the
N-triflylthiophosphoramide derivatives were found to catalyze the strict ion pair systems described in sections 4.2 and 4.3, the
transformation efficiently and with high enantioselectivity, whereas hydrogen-bond interaction between the phosphate and the cationic
phosphoric and thiophosphoric acids were shown to be unreactive. electrophile is replaced by an electrostatic interaction, and the same
The highest enantioselectivity was achieved with the more acidic N- secondary noncovalent interactions are likely also important for
triflyl thiophosphoramide catalysts. Catalyst loadings as low as 0.1 organizing the substrate-catalyst interaction in the
mol% were used without deleterious effects on yield or enantiodetermining transition structures (Figure 14). Detailed
enantioselectivity. studies aimed at further elucidating the interactions that enable high
On the basis of preliminary mechanistic studies, Yamamoto and levels of asymmetric induction in these systems are warranted and
Cheon suggests that the protonation reaction proceeds through a should enable the design of new catalysts and transformations.
two-step process, with initial protonation of the silyl enol ether by
catalyst 26b-H followed by desilylation of the intermediary chiral
ion pair by phenol (Scheme 23). No reaction was observed in the
absence of the phenol, even when a stoichiometric amount of the N-
triflyl thiophosphoramide catalyst was used. Additionally, the
structure of both the phenol and the silyl group were found to affect
the enantioselectivity. These results do not distinguish between two
possible mechanistic scenarios: (i) the protonation is rate- and ee-
determining and takes place via a [PhOH2]+•26b complex that is
generated by rapid proton transfer between 26b-H and PhOH, or (ii)
the protonation is reversible and the desilylation is rate- and ee- Figure 14. Substrate recognition site created by the 3,3’-substituents
determining. The latter scenario, which would represent a clear (G) of chiral BINOL-derived anions (Y = O, S; X = O, NTf).
example of asymmetric ion-pairing catalysis, appears more likely. [90]

4.5. Disulfonimide Anion

List and co-workers discovered the binaphthyl-derived

disulfonimide catalyst 27-H while exploring new chiral Brønsted
acid motifs for the activation of simple aldehydes. The authors were
initially drawn to this C2-symmetric class of catalysts because the
acidic proton appears to reside more deeply within the asymmetric
environment than in the corresponding BINOL-derived phosphoric
acid and phosphoramide catalysts. In fact, catalysis of the
Mukaiyama aldol reaction of 2-naphthaldehyde with an isobutyrate-
derived ketene acetal was found to proceed only with disulfonimide
catalyst 27-H among several chiral Brønsted acid catalysts
examined. The catalyst was shown to be quite broad in scope,
Scheme 23. N-triflyl thiophosphoramide-catalyzed enantioselective providing aldol products from isobutyrate- and acetate-derived
protonation of silyl enol ethers. ketene acetals in high yields and enantioselectivity (Scheme 24a). [96]
Analysis of these reactions by NMR spectroscopy revealed that
catalyst 27-H undergoes rapid silylation by ketene acetals (Scheme
24b). The resulting 27-SiMe3 species was shown to be the active
catalyst in the aldol reaction, with the reaction proceeding even in
the presence of a hindered base known to suppress Brønsted acid
catalysis. Aldehyde activation is therefore proposed to take place
through O-silylation, with reactions occurring via
disulfonimide•oxocarbenium ion pair 28. Catalyst 27-SiMe3 shows
extraordinary promise for inducing enantioselectivity in the wide
range of reactions susceptible to catalysis by SiR 3NTf2-type Lewis
acids.

Scheme 25. Enantioselective spiroacetalization catalyzed by an

exceptionally bulky imidodiphosphoric acid.

5. Anion-Binding Catalysis

Asymmetric catalysis by chiral dual hydrogen-bond donors has

enabled the development of a remarkable number of highly
enantioselective transformations.[4b] Discoveries in this field were
initially centered on the direct activation of neutral electrophiles by
hydrogen bonding (Figure 15). In recent years, the chemistry has
been expanded to reactions proceeding via ion-pair intermediates by
Scheme 24. (a) Enantioselective disulfonimide-catalyzed Mukaiyama taking advantage of the well-established anion-binding properties of
aldol reaction and (b) the proposed in situ silylation of the catalyst. ureas and thioureas.[7, 98] This approach to asymmetric ion-pairing
catalysis relies on the binding of neutral hydrogen-bond donor
catalysts to the unreactive or reactive counterion of cationic
4.6. Imidodiphosphate Anion intermediates in the enantiodetermining transition-structures (Figure
15). To date, successful implementations of the anion-binding
Despite the impressive successes achieved with chiral anionic approach have been documented only with (thio)urea catalysts.
catalysts, the scope of many of the enantioselective transformations However, it is very likely that other hydrogen-bond donor catalysts
described in the preceding sections is limited by the presence of that are proficient anion-binders will soon find application in this
sterically demanding substituents or specific ancillary functionality arena.[99] Two distinct types of anion-binding catalysis have been
on the substrate required to achieve the requisite organization in the uncovered thus far: (i) (thio)urea-assisted ionization of ion-pair
enantiodetermining transition structure. For example, many of the precursors through anion-abstraction and (ii) (thio)urea-controlled
cationic intermediates subjected successfully to chiral anion-directed reactivity of ion-pair intermediates through anion-binding. The work
catalysis bear aromatic groups that may be engaged in crucial π-π covered in this section, organized by type of (thio)urea-bound anion,
interactions with the catalysts. In an important recent study, List and demonstrates the generality of these concepts.
Coric reported a highly enantioselective spiroacetalization of simple
hydroxyenol ethers (Scheme 25). [97] The new, C2-symmetric
imidodiphosphate catalyst 29 was proposed to confine the reaction
within a rigid, highly restricted environment. Interestingly, 29 has
the same binaphthyl-based dimer backbone as quaternary
ammonium phase-transfer catalyst 2, and these two catalysts thus
can be viewed as charge inverted analogs of each other.
Broad scope was observed in enantioselective
spiroacetalizations to form 5- and 6-membered rings from 5-, 6-, and
7-membered cyclic enol ethers. An X-ray crystal structure of 29-H
confirmed that the imidodiphosphate moiety resides in a confined Figure 15. Modes of electrophile activation by dual hydrogen-bond
space created by the interlocking BINOL subunits. It remains to be donors.
seen whether the proposed confined-space catalyst concept will
prove useful for other catalytic asymmetric reactions of small,
structurally and functionally-unbiased substrates. 5.1. Alkoxide Anions

In 2006, Schreiner and Kotke discovered a highly efficient

achiral thiourea-catalyzed acetalization of aliphatic and aromatic
carbonyl compounds (Scheme 26). [100] Broad scope was observed in
the addition of ethanol and 1,2-ethanediol to a variety of aldehydes
and ketones. The reactions reached completion at room temperature
with catalyst loadings as low as 0.01–1 mol%. The rate accelerations
provided by the thiourea were significant, as the uncatalyzed
reactions generally provided <1% product under otherwise identical
conditions. Mechanistic insight was gleaned from attempted
thioacetalization reactions, which resulted in the formation of
diethyl acetals as opposed to thioacetals in the presence of the
HC(OEt)3 orthoester. If the reaction were to proceed by direct
carbonyl electrophile activation (Scheme 26), thioacetal formation
would be expected even in the presence of the orthoester because of
the greater nucleophilicity of thiols compared to alcohols. Thus, an
alternative mechanism was proposed that involves generation of an
alkoxide nucleophile by thiourea-assisted heterolysis of the
orthoester through stabilization of the incipient anion. This is akin to
well-established enzymatic reaction mechanisms in which
stabilization of high-energy alkoxide intermediates is achieved
through hydrogen-bonding.[101]

Scheme 27. (a) Thiourea-catalyzed tetrahydropyranylation of

alcohols by anion-binding and (b) a comparison of transition
structures for the uncatalyzed and thiourea-catalyzed addition of
methanol to dihydropyran at the B3LYP/6-31G(d,p) level of theory
(adapted from reference 102).

5.2. Cyanide Anion

α-Amino acid derivatives are important building blocks for the

synthesis of complex, biologically active molecules and chiral
catalysts. The addition of hydrogen cyanide to imines, also known
Scheme 26. Acetalization by thiourea-assisted orthoester hydrolysis as the Strecker reaction, is one of the most valuable and widely used
through anion-binding. approaches to the α-amino acid motif. As such, the development of
asymmetric variants of this transformation has received much
attention. In the earliest applications of urea and thiourea derivatives
The anion-binding concept was subsequently applied by in asymmetric catalysis, Jacobsen and co-workers discovered that
Schreiner and Kotke to the development of an acid-free, thiourea- these hydrogen-bond donors can promote the hydrocyanation of a
catalyzed tetrahydropyranylation of alcohols. [102] Thiourea 30 was variety of imine substrates with high enantioselectivity. [103] After
found to catalyze the acetalization of primary, secondary, and several iterations of catalyst refinement and optimization, thiourea
tertiary alcohols, as well as many acid-sensitive substrates such as 31 was identified as a practical and broadly applicable catalyst for
cyanohydrins and oximes, with remarkable efficiency (Scheme 27a). the hydrocyanation of imines using trimethylsilyl cyanide or
A mechanism was proposed wherein protonation of the potassium cyanide as the cyanide source (Scheme 28a). [104]
dihydropyran olefin is followed by alkoxide addition in a formally
concerted, but highly asynchronous manner. DFT computation
analyses predict that thiourea 30 lowers the activation barrier for the
addition step by about 20 kcal mol –1 (Scheme 27b). The observed
increase in length of the newly-forming C–O bond in the transition
structure of the thiourea-catalyzed compared to the uncatalyzed
reaction (2.587 Ǻ versus 2.187 Ǻ) supports the notion that the
thiourea assists in generation of the alkoxide nucleophile by
stabilizing the developing negative charge. While the acetalization
reactions reported by Schreiner involved only achiral catalysts and
were therefore not enantioselective, they provided key proof-of-
concept for the applicability of the anion-binding properties of
thioureas in catalysis.
 protioiminium ion N-H from the cyanide anion and amide carbonyl
(d3 + d4). This observation indicates that the enantioselectivity can
be ascribed to the differential stabilization of the iminium cation in
the diastereomeric transition states of the ion pair rearrangement.
List and Pan developed an enantioselective thiourea-catalyzed
Strecker reaction using acetyl cyanide as the cyanide source; this
reagent offers practical advantages over HCN or TMSCN (Scheme
29).[106] Two mechanisms were proposed for the acylcyanation: (i)
formation of an N-acyliminium intermediate, followed by the
addition of cyanide or (ii) cyanation with traces of HCN formed in
the reaction mixture, followed by acetylation. In an experiment in
which acetyl cyanide was added after hydrocyanation of the imine
with HCN, the acylated product was obtained in nearly identical
enantioselectivity as in the one-pot procedure. This result provides
support for the reaction proceeding through addition of HCN, as
established in the closely-related Strecker reactions developed by
Jacobsen and co-workers (vide supra).[105]

Scheme 28. (a) Thiourea-catalyzed enantioselective Strecker

reaction, (b) potential activation mechanisms, and (c) correlation of
selected, calculated transition structure hydrogen-bond lengths with Scheme 29. Thiourea-catalyzed acylcyanation of imines.
enantioselectivity for the hydrocyanation of N-benzhydryl pivaldimine.
for eight structurally distinct thiourea catalysts.

5.3. Halide Anions

A detailed investigation into the mechanism of hydrocyanations
Ureas and thioureas are potent halide-anion binders. [107] Over the
catalyzed by 31 established that this transformation proceeds via
past few years, a wide variety of enantioselective reactions
anion-binding catalysis, and also elucidated the noncovalent
proceeding via reactive cationic intermediates have been developed
interactions that are the basis for enantioselectivity. [105] Hammett,
by halide-binding thiourea catalysis.
catalyst structure/activity relationships, isotope labelling, and
The Pictet-Spengler reaction, the cyclization of electron-rich
computational studies pointed to a reaction mechanism involving a
aryl groups onto iminium electrophiles, is a powerful method for the
catalyst-bound cyanide•iminium ion pair (Scheme 28b). In the
synthesis of alkaloids.[108] The first catalytic asymmetric variant of
proposed pathway, proton transfer from thiourea-bound HCN (or
this reaction was developed by Jacobsen and Taylor with the
HNC) to imine generates a catalyst-bound cyanide•iminium ion pair.
discovery that chiral thioureas catalyze the cyclization of indoles
Rate- and enantio-determining rearrangement of this ion pair leads
onto N-acyliminium ions generated in situ by the acylation of imines
to separation of the charged species, and results in a subsequent
(Scheme 30a).[109] The efficient total synthesis of (+)-yohimbine was
stereospecific collapse to the α-aminonitrile product. The key ion
subsequently achieved by employing this thiourea-catalyzed acyl-
pair rearrangement is proposed to occur through transferring the
Pictet-Spengler reaction.[110] The enantiodifferentiation of prochiral
hydrogen-bonding interaction of the protioiminium ion N-H from
N-acyliminium ion intermediates by chiral thioureas was also
the bound cyanide to the carbonyl of the catalyst amide. Additional
applied successfully in acyl-Mannich reactions of isoquinolines
support for the accuracy of the proposed mechanism was the strong
(Scheme 30b).[111] The enantioselectivity of both of these reactions
correlation (P « 0.01) between experimental and calculated
was shown to depend strongly on the polarity of the reaction solvent
enantioselectivity for eight different thiourea catalysts.
and structure of the acylating agent.
To elucidate the basis for enantioselectivity, the relationship
between enantioselectivity and various calculated transition
structure hydrogen-bond lengths was evaluated. No trend was
observed when plotting the sum of the thiourea-cyanide bond
lengths (d1 + d2) versus enantioselectivity (Scheme 28c). Thus,
differences in the observed enantioselectivity cannot be traced to the
degree of stabilization of the cyanide nucleophile. There was,
however, a positive correlation between enantioselectivity and the
calculated lengths of the stabilizing hydrogen bonds to the
 Scheme 31. Pictet-Spengler-type cyclization of hydroxylactams and
the proposed anion-binding mechanism.

Scheme 30. Thiourea-catalyzed (a) acyl-Pictet-Spengler and (b) acyl- The hydroxylactam-based acyl-Pictet-Spengler methodology has
Mannich reactions proceeding via N-acyliminium ions. been extended successfully to the regio- and enantioselective
cyclization of pyrrole nucleophiles using the same thiourea catalyst
32.[113] In agreement with the proposed S N1-type mechanism, rate
In an effort to further broaden the scope of thiourea-catalyzed acceleration due to increased substitution at the electrophilic center
reactions of N-acyliminium ions and obtain insight into the nature of was observed again. An intermolecular addition of indoles to N-acyl
the substrate-catalyst interactions, an acyl-Pictet-Spengler-type iminium ions derived from hydroxylactams was also achieved upon
cyclization of tryptamine derivatives was developed wherein the N- fine tuning the catalyst structure. [114] In this case, replacing the
acyl iminium ions are generated in situ by the dehydration of pyrrole moiety on the thiourea catalyst with a Schiff base was
hydroxylactams (Scheme 31).[112] 1H-NMR studies of a necessary for achieving high enantioselectivity. These variants of
hydroxylactam substrate in the presence of the TMSCl dehydrating the hydroxylactam-based acyl-Pictet-Spengler methodology, [113-114]
reagent indicated that formation of the corresponding chlorolactam in addition to the acylative acyl-Pictet-Spengler [109] and acyl-
is fast and irreversible. The experimentally observed increase in Mannich[111] reactions described above, were proposed to proceed
reactivity with hydroxylactam derivatives generated by imide via an anion-binding mechanism by analogy.
alkylation (R = Me) versus by imide reduction (R = H) pointed to an The first catalytic asymmetric Petasis reaction was reported by
SN1-type mechanism. While these experiments established that the Takemoto and co-workers in 2007.[115] The authors designed a chiral
reaction proceeds via an N-acyliminium ion, the mode of the bifunctional thiourea that promotes the enantioselective addition of
catalyst interaction in the enantiodetermining transition state was not vinyl boronic acids to in situ generated N-acylquinolinium salts
yet apparent. (Scheme 32). The 1,2-amino alcohol and thiourea moieties of the
DFT computational analyses failed to converge for all structures catalyst were both shown to be important for achieving high
of the thiourea bound to the N-acyliminium ion carbonyl, but a reactivity and enantioselectivity. The 1,2-amino alcohol was
productive interaction was identified between the thiourea and the α- proposed to chelate the boronic acid and form a reactive “ate”
chloroamide via the α–chloro substituent. Enantioselective complex, whereas the thiourea was presumed to control the cis/trans
cyclization of the indole was therefore proposed to occur via a chiral isomer distribution of the N-acylquinolinium amide bond by
thiourea-bound N-acyliminium•chloride ion pair resulting from hydrogen bonding to the carbonyl. However, in light of the
thiourea-induced dissociation of the chloride. Further support for the mechanistic studies outlined above, [112] it is worth considering
anion-binding model includes the pronounced halide counterion whether the thiourea moiety is in fact interacting with the N-
effects (Cl, 97% ee; Br, 68% ee; I, <5% ee) and solvent effects acylquinolinium salt via the chloride anion in an ion-pairing
(TBME, 97% ee; CH2Cl2, <5% ee) on enantioselectivity. catalysis mechanism (Scheme 32).
Additionally, treatment of the thiourea catalyst with a chloride
source resulted in a 0.56 ppm downfield shift of the thiourea N-H
protons, consistent with strong binding to the chloride anion.

Scheme 32. Thiourea-catalyzed enantioselective Petasis-type

reaction of quinolines proceeding via N-acylquinolinium ions.
 Jacobsen and co-workers recently reported the development of a the reaction. Racemization of the chloroether starting materials is
new thiourea catalyst for the enantioselective bicyclization of believed to occur via the in situ generation of oxocarbenium ions by
hydroxylactams. A marked correlation between the size of the thiourea-assisted chloride dissociation. Support for chloride-binding
aromatic group of 2-arylpyrrolidine catalysts 33-36 and catalytic catalysis is provided by the fact that addition of 10 mol% n-Bu4NCl
performance was observed, with larger arenes providing improved resulted in complete inhibition of the reaction. The presence and
reactivity and selectivity (Scheme 33a). Pyrenyl-substituted thiourea configuration of an aryl group in the amide component of the
derivative 36 was found to catalyze the bicyclization of substrates catalyst had a large impact on the reaction rate and
with various aromatic terminating nucleophiles in 89-95% ee. [116] enantioselectivity, which could be indicative of this group’s
Given the cationic nature of the substrate and the dependence of involvement in stabilizing interactions in the rate-determining
enantioselectivity on the expanse of the catalyst arene, experiments transition state (Scheme 34).
were undertaken to establish whether stabilizing cation-π
interactions are directing the stereochemical course of the reaction
in a manner akin to the biosynthetic proposal for cyclase enzymes.
[117]

It has been proposed that the energetic benefit of noncovalent

binding interactions are generally manifested enthalpically. [118] An
Eyring analysis revealed that enantioselectivity is indeed
enthalpically controlled for catalysts 34-36, and that the degree of
the differential enthalpy increases for the more extended arenes.
Additionally, there is a positive linear free energy relationship
between the quadrupole moment and polarizability of the arenes and
the degree of asymmetric induction. Taken together, these data
provide strong support for a cation-π interaction being responsible
for the differential stabilization of the diastereomeric transition
states (Scheme 33b). This work provides a clear illustration of how Scheme 34. Enantioselective thiourea-catalyzed addition of silyl
asymmetric induction can be achieved through stabilization of the ketene acetals to oxocarbenium ions.
major transition state through attractive interactions, as opposed to
destabilization of the minor transition state through steric repulsion.
Asymmetric anion-binding catalysis has also been applied to
reactions proceeding via carbocations that are not stabilized by a
heteroatom. A primary aminothiourea was found to catalyze the
enantioselective α-alkylation of α-branched aldehydes with
symmetrical diarylbromomethanes (Scheme 35). [120] Several
experiments were performed to elucidate the mechanism of this
reaction. A normal secondary kinetic isotope effect was observed for
the benzhydryl proton, indicating that the electrophilic carbon
undergoes rehybridization from sp3 to sp2 in the rate-determining
transition state. A Hammett study was also consistent with the
development of positive charge at the benzhydryl carbon in the
transition state (ρ = –1.95). Additionally, a competition experiment
established that, under the catalytic conditions, only alkylation of
bromodiphenylmethane was observed in the presence of an
equimolar amount of benzyl bromide. The results of these three
experiments suggest strongly that the alkylation proceeds through a
discrete, catalyst-associated benzhydryl cation by an S N1-like
substitution mechanism (Scheme 35). Interestingly, the reaction of
enantioenriched diarylchloromethanes was found to be 95%
stereospecific. When considered along with the previous
experiments, this finding implies that addition of the catalyst-
Scheme 33. (a) Effect of thiourea catalyst aromatic group on the associated enamine to the ion-pair intermediate is faster than ion-
efficiency and enantioselectivity of the bicyclization of hydroxylactam pair racemization.
37 and (b) the proposed stabilizing cation–π interaction in the
dominant transition state.

The principle of asymmetric hydrogen-bond catalysis by anion

binding has been applied successfully to transformations involving
various cationic species aside from iminium ions. For example, the
asymmetric thiourea-catalyzed addition of silyl ketene acetals to 1-
chloroisochromans was achieved in 70-95% yield and 74-95%
enantioselectivity (Scheme 34).[119] The addition reaction proceeds
by a dynamic kinetic resolution because the products are isolated in
>50% yield and the enantioselectivity remains constant throughout
Scheme 35. Enantioselective, catalytic SN1-type alkylation of
aldehydes with benzhydryl cations.

Asymmetric chloride-binding hydrogen-bond catalysis has been

applied successfully to several different classes of electrophiles. Scheme 36. Thiourea-catalyzed enantioselective protio-Pictet-
Combined with recent advances with bromide- [120] and fluoride- Spengler reaction with rate-determining rearomatization.
binding systems[121] (vide infra), there is clearly broad potential in
asymmetric ion-pairing catalysis using halide counterions.
A dual catalyst system consisting of a chiral primary
aminothiourea and achiral thiourea 30 was found to promote
5.4. Carboxylate Anions enantioselective intramolecular oxidopyrylium-based [5+2]
cycloadditions, thereby providing access to valuable chiral 8-
Urea- and thiourea-based compounds are excellent synthetic oxabicyclo[3.2.1]octane architectures (Scheme 37). [128] A
receptors for Y-shaped, coplanar anions such as carboxylates. [122] remarkable cooperative effect was observed between the thiourea
The topology of this class of anions allows for hydrogen-bonding in catalysts, with significant improvement in both reactivity and
a bidentate fashion. It is perhaps because of this constrained enantioselectivity in the presence of achiral thiourea 30 (32% yield,
geometry that carboxylate-binding by chiral thiourea catalysts has 72% ee vs. 72% yield, 91% ee). To elucidate the roles of the
been applied with particular success in asymmetric catalysis. different components in the thiourea catalyst system, a series of
Using a chiral thiourea/benzoic acid dual catalyst system, [123] catalyst structure–activity–relationship studies were carried out. A
Jacobsen and co-workers developed mild and operationally simple chiral amino catalyst lacking the thiourea moiety could effect the
protocols for enantioselective Pictet-Spengler[124] and iso-Pictet- reaction in good yield and up to 87% enantioselectivity, but only in
Spengler[125] reactions (Scheme 36). The one-pot method affords the presence of thiourea 30. A tertiary aminothiourea, in contrast,
unprotected tetrahydro-β-carboline and tetrahydro-γ-carboline was unreactive regardless of whether thiourea 30 was present. Based
products directly from tryptamine and aldehyde derivatives. on these experiments, an enamine catalysis mechanism was
Formation of a benzoate•iminium ion salt was proposed to be proposed. Additional support for an aminopyrilium, and not an
facilitated by the thiourea catalyst through hydrogen-bonding oxido- or amido-pyrilium, intermediate was provided by the
(Scheme 36). Cyclization followed by rearomatization of the correlation of computational frontier molecular orbital predictions
thiourea-bound benzoate•indolyl cation ion pair then affords the with observed experimental trends. Thus, the suggested mechanism
tetrahydrocarboline products. Notably, rearomatization was found to involves condensation of the primary aminothiourea with the ketone
be rate-determining based on the observed primary kinetic isotope of the pyranone substrate to form a dienamine after tautomerization,
effect (KIE = 2.9-3.3) with a 2-deuterotryptamine derivative. [126] As followed by benzoate abstraction by achiral thiourea 30 to generate
such, catalysis by the thiourea was proposed to involve stabilization the reactive aminopyrylium•benzoate ion pair 39 that is poised to
of the key ion-pair intermediates and association to the benzoate in undergo the cycloaddition.
the enantioselectivity-determining final deprotonation step. This
appears to represent a new manifold for asymmetric ion-pairing
catalysis, wherein the chiral catalyst-anion complex acts as a
Brønsted base in the key step. Other recently-developed
enantioselective catalytic Pictet-Spengler reactions, [127] currently
proposed to proceed via H-bonding catalysis mechanisms, might
also proceed via rate-limiting rearomatization, in which case ion-
pairing interactions would play a key role in achieving
enantioselectivity in those systems as well.

Scheme 37. Enantioselective oxidopyrilium-based [5+2] cycloaddition

via anion-binding/enamine co-catalysis.
 Catalytic asymmetric acyl transfer reactions generally rely on significantly more reactive and selective than benzoic anhydride.
the use of chiral variants of nucleophilic catalysts such as This reaction represents the first example of anion-binding catalysis
derivatives of 4-(dimethylamino)pyridine (DMAP).[129] Seidel and with fluoride. The excellent hydrogen-bond acceptor properties and
co-workers have designed an alternative approach by taking silicon affinity of fluoride likely play important roles in enabling
advantage of the anion-binding properties of thioureas. They this transformation. Key insight into the mechanism was gained
reasoned that an achiral acylpyridinium salt, formed in situ from a from experiments that varied the silyl group of the silyl ketene
dialkylaminopyridine catalyst and an acylating agent, could be acetal. The size of the silyl group considerably affected the rate of
rendered chiral upon binding of a chiral thiourea catalyst to the the reaction, but did not influence the enantioselectivity. A
associated anion (Scheme 38). The authors anticipated that catalysis mechanism consistent with this observation was proposed involving
could be achieved due to the higher reactivity and/or higher formation of a thiourea-bound acylpyridinium•fluoride ion pair,
concentration of the catalyst-bound ion pair relative to the unbound followed by rate-determining desilylation of the silyl ketene acetal,
ion pair. and then enantio-determining acylation via a thiourea-bound
Amines are notoriously challenging substrates for asymmetric acylpyridinium•enolate ion pair (Scheme 39).
nucleophilic catalysis due to their inherent nucleophilicity. Seidel’s
chiral thiourea–dialkylaminopyridine co-catalysis approach,
however, enabled the acylative kinetic resolution of benzylic, [130]
propargylic,[130b] and allylic[131] amines with selectivity factors of up
to 67 (Scheme 38). The desymmetrization of meso-diamines by
enantioselective monoacylation was also achieved. [132] Remarkably,
all of these variations can be accomplished under nearly identical
reaction conditions with the same thiourea catalyst. As might be
anticipated, the nature of the carboxylate anion was found to be
important, with benzoate giving the best results. Control
experiments established that both the dialkylaminopyridine
nucleophilic catalyst and the thiourea anion-binding co-catalyst
were required for good conversion and enantioselectivity. Under the
standard reaction conditions, no conversion was observed with the
dialkylaminopyridine alone. However, some acylation was observed
with only the thiourea catalyst. It is interesting to note that the
reaction promoted by the thiourea alone, which presumably occurs
via direct activation of the anhydride acylating reagent through
hydrogen-bonding, was found to afford only racemic products. Scheme 39. Enantioselective acylation of silyl ketene acetals by an
anion-binding approach to nucleophilic catalysis.

The dual catalysis approach was also extended by Seidel and co-
workers to reactions proceeding via thiourea-bound
acylpyridinium•enolate ion pair intermediates (Scheme 40). [133] A
chiral thiourea–DMAP co-catalyzed asymmetric Steglich reaction,
the rearrangement of O-acylated azlactones to the corresponding C-
acylated products, affords α,α-disubstituted amino acid derivatives
in 49-65% yield and 87-91% ee. By replacing the DMAP
nucleophilic co-catalyst with isoquinoline, Seidel and co-workers
achieved incorporation of the nucleophile framework into the
product; the azlactone-derived enolates were found to add to the 1-
position of the isoquinoline ring as opposed to the acyl group of the
acylisoquinolinium ion. This transformation resulted in the efficient
synthesis of α,β–diamino acid derivatives in 81-95% yield with high
levels of enantio- and diastereocontrol (Scheme 40). The optimal
Scheme 38. Acylative kinetic resolution of primary amines by an thiourea catalyst (42) for both the azlactone addition and
anion-binding approach to nucleophilic catalysis.
rearrangement reactions, is structurally similar to the optimal
catalyst (41) identified by Jacobsen and co-workers for a reaction
that is also proposed to proceed via a thiourea-bound enolate. It is
5.5. Enolate Anions
worth noting that the facial selectivity of the azlactone addition to
isoquinolines is opposite to that of the azlactone rearrangement
Asymmetric anion-binding/nucleophilic co-catalysis has been
reaction, suggesting that significantly different secondary
applied successfully by Jacobsen and co-workers to the C-acylation
interactions must be at play in the corresponding thiourea-bound ion
of enolate equivalents. By using chiral arylpyrrolidine-based
pair intermediates. The reports by the Seidel [130-133] and Jacobsen[121]
thiourea catalyst 41 in combination with 4-pyrrolidinopyridine, the
groups demonstrate the power of anion-binding in asymmetric
enantioselective acylation of silyl ketene acetals with acyl fluorides
nucleophilic catalysis, and suggest that this strategy may be broadly
was developed to generate valuable α,α-disubstituted butyrolactone
applicable.
products (Scheme 39).[121] A marked dependency on the nature of the
acylating agent was observed, with benzoyl fluoride being
 Jacobsen and co-workers demonstrated that anion-binding
catalysis can be used as a strategy for inducing enantioselectivity in
reactions proceeding via specific acid mechanisms. [135] The
combination of an achiral sulfonic acid and chiral bifunctional
sulfinamidourea 44 was found to be optimal for promoting a highly
enantioselective [4+2] cycloaddition of N-aryl imines and electron-
rich olefins, also known as the Povarov reaction (Scheme 42a).
Structure–reactivity/enantioselectivity studies established the
importance of both the urea and sulfinamide groups of the catalyst.
Kinetic analysis of the reaction revealed a first-order dependence on
triflic acid (TfOH) and a zeroth-order dependence on imine 45,
consistent with quantitative protonation of imine 45 by triflic acid
(TfOH) under the reaction conditions and protioiminium triflate
45•HOTf as the resting state of the sulfonic acid catalyst. A large
binding constant (K = 9 x 103 M–1) was determined for the
interaction of the urea catalyst 44 with salt 45•HOTf.
Computational and 1H NMR spectroscopic analysis of the ternary
complex (44•45•HOTf) shed light on the nature of the binding
Scheme 40. Dual catalysis approach to the enantioselective Steglich interaction. A dynamic structure was elucidated, consisting of the
rearrangement and addition of O-acylated azlactones to urea-sulfonate anion complex associated to the protioiminium ion
isoquinolines. through a combination of electrostatic and hydrogen-bonding
interactions (Scheme 42b).
A comparison of the kinetics of the HOTf/urea 44 co-catalyzed
5.6. Imidate Anions reaction relative to the reaction catalyzed by HOTf alone revealed
that the urea induces a several-fold decrease in the reaction rate. It
The development of catalytic, enantioselective was concluded that 44 serves to stabilize the protoiminium ion
iodolactonizations has proven challenging due to the inherent triflate ground state more than the cycloaddition transition state.
difficulty in controlling the stereoselectivity in the formation and However, the racemic pathway was shown to be suppressed, and
reaction of iodonium ions. Inspired by the success of (thio)urea high enantioselectivity was still achieved because the high
catalysts in effecting enantioselective reactions of a diverse array of association equilibrium of the urea catalyst and the protioiminium
cationic intermediates, Jacobsen and Veitch developed a tertiary intermediate ensures that the iminium ion undergoes cycloaddition
aminourea-catalyzed enantioselective iodolactonization (Scheme only in association with the chiral urea. Additional investigations led
41).[134] 1H-NMR studies of the aminourea catalyst in the presence of to the proposed basis for enantioselectivity: a stabilizing π-π
the iodinating agents suggested an N-iodo derivative of the catalyst interaction between the (bis)trifluoromethylphenyl group of the
is formed in situ. This species was proposed to undergo reaction catalyst and the aniline arene of the imine. This attractive interaction
with the hexanoic acid substrate to form thiourea-bound is apparent in the computed transition structure leading to the major
imidate•iodonium ion pair intermediate 43. Based on the difference enantiomer, but absent in the competing diastereomeric transition
in reactivity observed with substrates forming 5-, 6-, or 7-membered state (Scheme 42c). Careful study of the urea-catalyzed Povarov
lactone products (5 > 6 >> 7), the subsequent cyclization step was reaction thus revealed that a network of weak, noncovalent
proposed to be rate- and enantio-determining. The level of interactions can function cooperatively to attenuate the reactivity of
enantioinduction was shown to be sensitive to the structure of the a highly reactive intermediate as well as effect a highly
imidate, indicating that it is directly involved in the enantioselective transformation.
enantiodetermining step. Preliminary computational studies of
putative intermediate 43 support a tertiary amino-iodonium
interaction and deprotonation of the carboxylic acid by the urea-
bound phthalimide in the enantiodetermining cyclization event.

Scheme 41. Urea-catalyzed enantioselective iodolactonization.

5.7. Sulfonate Anions

 states. We anticipate that future catalyst designs will also capitalize
on other known attractive noncovalent interactions, such as halogen-
bonding or anion-π interactions.[138]
Highly enantioselective phase-transfer catalysis with chiral
cationic and cation-binding catalysts was first demonstrated in the
1980’s, and important advances in this area continue to be made at
an impressive pace. Much more recently, charge-inverted strategies
involving anionic and anion-binding catalysts have emerged, and
these areas are the focus of an explosion of current research activity.
At this stage, enantioselective catalytic reactions that engage a wide
variety of cationic intermediates have been developed primarily
using catalysts from one of only two structural classes: binaphthol-
derived phosphates and related P V-based anions in chiral anion-
directed catalysis, and chiral urea and thiourea catalysts in anion-
binding catalysis. Continued exploration of these and closely related
systems will undoubtedly lead to the discovery of interesting and
useful new enantioselective transformations and concepts in
stereoselective catalysis, especially if novel catalyst structures are
identified.
The different classes of asymmetric ion-pairing catalysts
described in this review all rely on networks of noncovalent
interactions to achieve energetic differentiation of selectivity-
determining transition structures. Due to the often weak and non-
directional nature of such noncovalent interactions, determining the
basis for catalysis and enantioselectivity is generally extremely
challenging. The increasing power of computational methods is
Scheme 42. (a) Urea/strong Brønsted acid co-catalyzed
enantioselective Povarov reaction (NBSA = o-nitrobenzenesulfonic
enabling the study of noncovalent interactions in such catalytic
acid), and energy and geometry-minimized structures of (b) the reactions with increasing accuracy. [139] In combination with
ground state catalyst-substrate interactions (Ar = 3,5-(CF3)2C6H3) and experimental investigations, such analyses will facilitate elucidation
(c) the cycloaddition transition structure leading to the major of the factors controlling enantioselectivity. Increased understanding
enantiomer of product at the B3LYP/6-31G(d) level of theory. of asymmetric ion-pairing mechanisms will open up new
opportunities for this important mode of catalysis.

Detailed mechanistic studies such as this one have provided This work was supported by the NIH (GM43214) and through a
valuable insight into how the stereochemical outcome of reactions postdoctoral fellowship to K.B. (GM090477).
can be controlled solely through noncovalent interactions between a
neutral catalyst and an ion-pair intermediate. In several cases of
anion-binding catalysis mechanisms, it has been established that Received: ((will be filled in by the editorial staff))
high levels of enantioselectivity are attained via stabilization of the Published online on ((will be filled in by the editorial staff))
dominant transition state through attractive noncovalent interactions.
[136]
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Entry for the Table of Contents

Asymmetric Catalysis Framing the field, this review provides

an overview of four ion-pairing
strategies that have emerged for
K. Brak, E. N. Jacobsen* __________ asymmetric catalysis of transformations
Page – Page proceeding via charged intermediates or
reagents (see picture). Particular
emphasis is placed on the mechanistic
Asymmetric Ion-Pairing Catalysis features that enable high asymmetric
induction in these systems.