Reviews P. I. Dalko and L.

Moisan

Asymmetric Catalysis

In the Golden Age of Organocatalysis**

Peter I. Dalko* and Lionel Moisan

Keywords:
asymmetric catalysis · chiral auxiliaries ·
organocatalysis · synthetic
methods

Angewandte
Chemie
5138  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200400650 Angew. Chem. Int. Ed. 2004, 43, 5138 – 5175
 Angewandte
Organocatalysis Chemie

The term “organocatalysis” describes the acceleration of chemical From the Contents
reactions through the addition of a substoichiometric quantity of an
1. Introduction 5139
organic compound. The interest in this field has increased spectacu-
larly in the last few years as result of both the novelty of the concept 2. Reactions via Covalent
and, more importantly, the fact that the efficiency and selectivity of Transition Complexes 5140
many organocatalytic reactions meet the standards of established
organic reactions. Organocatalytic reactions are becoming powerful 3. Reactions via Noncovalent
Activation Complexes 5158
tools in the construction of complex molecular skeletons. The diverse
examples show that in recent years organocatalysis has developed 4. Enantioselective Phase-Transfer
within organic chemistry into its own subdiscipline, whose “Golden Reactions [195] 5164
Age” has already dawned.
5. Asymmetric Transformations in
a Chiral Cavity 5168

6. Summary and Outlook 5169

1. Introduction related reactions, such as aldol and Mannich reactions, the

similarities in the reaction profiles can be understood and
Organocatalysis is the acceleration of chemical reactions exploited. When a catalyst, such as l-proline, performs well in
with a substoichiometric amount of an organic compound one reaction, it can be expected to mediate all similar
which does not contain a metal atom.[1] reactions under optimized reaction conditions. However, less
Despite the very recent introduction of this type of closely related reactions may also be promoted by catalysts of
catalysis to synthetic chemistry, organocatalytic reactions the same class. For example, chiral thiourea derivatives and
look back on a venerable history. Evidence has been found their analogues catalyze the hydrocyanation of imines
that this type of catalysis played a determinant role in the (Strecker reaction) as well as asymmetric Mannich reactions.
formation of prebiotic key building blocks, such as sugars, and This finding is surprising, when one considers that the
thus allowed the introduction and spread of homochirality in Strecker and Mannich reactions have quite different reac-
living organisms.[2] According to this hypothesis, enantiomeri- tivity and stereoinduction profiles. Likewise, short-chain
cally enriched amino acids, such as l-alanine and l-isovaline, oligopeptides, which are established catalysts for asymmetric
which may be present with up to 15 % ee in carbonaceous acylation, can also mediate selective 1,4-addition reactions.
meteorites, catalyze the dimerization of glycal and an aldol- Cinchona alkaloids are another example of a privileged
type reaction between glycal and formaldehyde to afford catalyst class.[7] Their ability to mediate an astonishingly wide
sugar derivatives with significant enantiomeric excess. variety of enantioselective transformations is discussed in this
Although organic molecules have also been used since the Review.
beginnings of chemistry as catalysts, their application in Important progress has been made in the development of
enantioselective catalysis has only emerged as a major site-selective reactions with organic catalysts. These results
concept in organic chemistry in the last few years.[3, 4] As a have far-reaching consequences: From a philosophical point
result of both determined scientific interest, such as usually of view, the boundaries between enzyme- and small-molecule-
accompanies emerging fields, and the recognition of the huge mediated reactions are becoming blurred. From a practical
potential of this new area, organocatalysis has received
considerable attention.[3, 4]
The goal of this Review is to update and extend our
[*] Dr. P. I. Dalko
previous account on enantioselective organocatalysis.[3a] Thus,
Laboratoire de Recherches Organiques associ au CNRS
we focus herein on enantioselective reactions that have ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05 (France)
appeared in the last three years. We attempt to offer a Fax: (+ 33) 1-4079-4660
comprehensive overview of the field with emphasis on E-mail: [email protected]
practical aspects. When available, mechanistic models are L. Moisan
presented for the rationalization of the reaction process. CEA-SACLAY, Service de Marquage Mol culaire
Which are the newest and conceptually most challenging et de Chimie Bioorganique
ideas in organocatalysis? The pinpointing of “privileged” B=t 547, 91191 Gif-sur-Yvette Cedex (France)
catalyst classes showing general superiority for many reaction [**] The illustration on the frontispiece is taken from the codex The Book
types is undoubtedly one of the most intriguing aspects and of Chess, Dice, and Board Games, completed around 1280 by
Alfonso X of Castille. Alfonso’s heritage represents above all a great
may have a considerable impact on the development of new
cultural bridge between the Christian West and the Muslim East. In
catalytic systems.[5] Some organic and organometallic mole- a similar way, organocatalysis represents a link between two major
cules have the extraordinary capacity to mediate efficiently a forms of catalysis: metal-complex-mediated and enzymatic catal-
variety of mechanistically distinct reactions.[6] In closely ysis, and thus between synthetic and bioorganic chemistry.

Angew. Chem. Int. Ed. 2004, 43, 5138 – 5175 DOI: 10.1002/anie.200400650  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5139
Reviews P. I. Dalko and L. Moisan

point of view, this type of reaction may allow the use of These compounds activate both the donor and the acceptor,
nonprotected substrates in synthesis.[8, 9] thus resulting in a considerable acceleration of the reaction
Our understanding of the mechanistic details of individual rate.
reaction pathways is improving. Organocatalytic reactions The vast majority of organocatalytic reactions are amine-
proceed either by a much “tighter” or a much “looser” based reactions.[18] In this asymmetric aminocatalysis amino
transition state than those mediated by chiral metal com- acids, peptides, alkaloids, and synthetic nitrogen-containing
plexes. The former class of organocatalysts includes com- molecules are used as chiral catalysts. Most of these reactions
pounds that act as covalently bonded reagents. The latter class proceed by the generalized enamine cycle or as charge-
induces a high level of enantioselectivity mainly through such accelerated reactions through the formation of imonium
interactions as hydrogen bonding or ion pairing. The enor- intermediates. These two types of activation are often
mous potential of hydrogen bonding as an activating inter- complementary and can therefore sometimes be used as
action has been recognized only recently.[10, 11] alternatives in the same transformation. The donor molecule
The scope of organocatalytic reactions has been expanded can be activated through the formation of an enamine, which
considerably. Typical transition-metal-mediated coupling leads to an increase in the electron density at the reactive
reactions, such as Suzuki,[12] Sonogashira,[13] Ullmann,[14] and center or centers; the acceptor molecule can be activated
Heck-type coupling reactions,[15] as well as the Tsuji–Trost through the formation of an onium salt, which leads to a
reaction,[16] can now be performed under metal-free condi- decrease in the electron density at the reactive center or
tions. The development of catalysts with a higher molecular centers (Figure 1).
weight and increased complexity often leads to a sharp
improvement not only in the selectivity of the catalyst, but
also in its kinetic profile. In an increasing number of
asymmetric reactions these catalysts can meet the high
standards of modern synthetic methods.
Whereas many metal centers are good Lewis acids, Figure 1. Electrophilic or nucleophilic activation of a carbonyl group by
organic catalysts tend to react as heteroatom-centered a secondary amine.
(mainly N(O)-, P(O)-, and S(O)-centered) Lewis bases.
However, novel, previously unexplored catalyst classes are
emerging. For example, asymmetric catalysis by Brønsted 2.1.1. The Generalized Enamine Catalytic Cycle[19]
acids is a recent addition to the field of organic catalysis.
Moreover, the design and use of synergic systems and Chiral secondary amine catalysts can form imonium ions
bifunctional catalysts, which have two distinct functionalities with ketones or aldehydes. These intermediates react by
(e.g. a Lewis base and a Brønsted acid) within the same imine–enamine tautomerism or a related mechanism to form
molecule, is becoming more and more common.[17] a nucleophilic enamine species, which can be trapped
Organocatalytic methods have great practical potential in conveniently by an activated p electrophile, for example, an
devising multicomponent and tandem sequences. In the aldehyde, ketone, or azodicarboxylate.
future all these reactions will also find use outside the Until now the most successful catalyst for enamine-type
academic environment for the synthesis of complex molecular reactions has undoubtedly been l-proline. Although the
structures. natural l form is usually used, both enantiomers of proline
are available,[20] which is an advantage over enzymatic
methods.[21] It is remarkable the variety of reactions that
2. Reactions via Covalent Transition Complexes may be mediated with this simple amino acid, whose
simplicity contrasts with the complex machinery of the
2.1. Nucleophilic Catalysis: Activation of the Donor natural enzymes (class I aldolases) capable of performing
similar transformations (Figure 2).[19]
Most organocatalysts used currently are bifunctional, What are the main features that make proline such a good
commonly with a Brønsted acid and a Lewis base center.[4e] catalyst? Proline is the only natural amino acid with a

Peter I. Dalko was born in 1960 in Budapest Lionel Moisan was born in Annemasse
(Hungary). He studied chemistry at the (France) in 1975. He studied chemistry at
Budapest Technical University (Hungary) the Ecole Sup-rieure de Physique et de
and obtained his doctorate with Dr. S. D. Chimie Industrielles (ESPCI, Paris) and
G-ro in Gif-sur-Yvette (France). After under- obtained his Dipl=me d’Etudes Approfondies
taking postdoctoral research with Sir in organic and bioorganic chemistry at the
Derek H. Barton at Texas A&M University Pierre et Marie Curie University (Paris) in
(USA) and Prof. Yoshito Kishi at Harvard 2000. He is currently carrying out research
University he joined Prof. Janine Cossy’s towards his PhD in organic chemistry at the
research group at the ESPCI in Paris. His Commissariat ? L’Energie Atomique
current main research interest is the develop- (Saclay), in the research group of Dr. C.
ment of novel asymmetric reactions. Mioskowski under the supervision of Dr. B.
Rousseau.

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 Angewandte
Organocatalysis Chemie

Figure 2. The l-proline-mediated enamine catalytic cycle.

secondary amine functionality and thus has a higher pKa value

and enhanced nucleophilicity relative to other amino acids.
Proline can therefore react as a nucleophile with carbonyl
groups or Michael acceptors to form iminium ions or
enamines. As the carboxylic acid functionality of the amino
acid acts as a Brønsted acid in these reactions, proline can be
regarded as a bifunctional catalyst.
The high, often exceptional enantioselectivity of proline-
mediated reactions can be rationalized by the capacity of this
molecule to promote the formation of highly organized
transition states with extensive hydrogen-bonding networks.
In all proline-mediated reactions the proton transfer from the
amine or the carboxylic acid group of proline to the forming
alkoxide or imide is essential for charge stabilization and C C
bond formation in the transition state.[22] Although most, if
not all, partial steps in amine-catalyzed reactions are equili-
brium reactions, enhanced nucleophilicity of the catalyst can
lead to a number of equilibrated reactions with electrophiles
present in the medium, resulting in a low turnover number. Figure 3. Some proline analogues used as organocatalysts.
This drawback can be remedied by using a higher catalyst
loading if the catalyst is inexpensive.
Proline is not the only organic molecule able to promote synthesis of erythromycin by Woodward et al., [27] appeared as
enamine reactions, and not all enamine reactions can be isolated examples. Remarkably, in this synthesis the racemic
mediated by l-proline.[23, 24] Furthermore, synthetic shortcom- keto aldehyde 26 could be used in an aldol reaction in the
ings persist; for example, in the dimerization or oligomeriza- presence of d-proline (2) as the catalyst. All of the asym-
tion of a-unbranched aldehydes it is difficult to avoid metric centers of the erythronolide backbone were derived
competing reactions. Reactions with acetaldehyde or aceto- directly or indirectly from this rather poor reaction, which
phenone generally lead to low yields and low selectivity. gave the product 27 with only 36 % ee. However, enantiomeri-
Although proline continues to play a central role in amino- cally pure 27 could be obtained by simple recrystallization,
catalysis, its supremacy is being challanged by new synthetic which made the process eminently practical (Scheme 1).
analogues and by more-complex oligopeptides. Chiral imida-
zolidinone catalysts also offer better rates and selectivity in a
number of reactions (Figure 3).

2.1.1.1. Aldol Condensations[25]

In the last 25 years the l-proline-mediated Robinson

annulation has not attracted particular interest, although it
offers a practical and enantioselective route to the Wieland– Scheme 1. The proline-mediated epimerization and intramolecular
Miescher ketone, which is an important building block for aldol reaction in the synthesis of erythromycin by Woodward and co-
total synthesis.[26] Applications in total synthesis, such as in the workers. Bn = benzyl.

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Reviews P. I. Dalko and L. Moisan

Renewed interest in this reaction was awakened by the

observation that proline is able to catalyze not only intra-
molecular[28] but also intermolecular reactions with high
selectivity and in high yield (Scheme 2).[29] Early cross-aldol
reactions were developed in which acetone derivatives
reacted as donors with aromatic aldehydes or a-hydroxyalde-
hydes in the presence of a high concentration of the catalyst
( 20 %). To increase the relative concentration of the
reagents and thus accelerate the reaction, an aqueous micellar Scheme 3. Intermolecular proline-catalyzed cross-aldol reaction.
version of the aldol reaction (of ketones) was also devel-
oped.[29b] Usually a polar solvent is employed for this trans-
formation, such as dimethyl sulfoxide (DMSO), N,N-dimeth-
ylformamide (DMF), water, or an ionic liquid;[30] it has been
shown that the use of high pressure may increase the
efficiency of the transformation.[31]
The development of intermolecular aldol reactions has
been hindered by the self-condensation of the aldehyde or
ketone donors in the presence of acceptors that react slowly.
However, these self-condensations can be exploited for the
synthesis of cyclic dimers and trimers (Scheme 2).[33]

Scheme 4. Aldol reaction of aldehydes with activated carbonyl

compounds. EWG = electron-withdrawing group.

Although proline has been used extensively in nucleo-

philic organocatalytic aldol reactions, systems based on
cinchona alkaloids and oligopepetides were also developed
in parallel. The asymmetric intramolecular aldol reaction of
Scheme 2. The proline-catalyzed aldol reaction of propionaldehyde.
31 was catalyzed by the O-acylated cinchona alkaloid 32; the
aldol product underwent cyclization in situ to form the
bicyclic b-lactone 33 (Scheme 5).[38] A variety of esters,
The first intermolecular cross-aldol reactions were devel- carbamates, and carbonates of the parent cinchona alkaloid
oped between aldehydes as acceptors and ketones as donors, lead to similar enantioselectivities.
and this research area remains active.[32] As the enamine Oligopeptides such as 34 with N-terminal proline residues
intermediates generated from aldehydes are less reactive than have been used instead of l-proline as catalysts
those generated from ketones, intermolecular cross-coupling (Scheme 6).[39] The advantage of this catalyst system is its
reactions between unmodified aldehydes are troublesome.
Until now, aldehydes could only be used as nucleophiles in
their unmodified form for catalytic asymmetric synthesis
through organocatalysis.[34] Both the reaction conditions and
the nature of the acceptor are crucial to the success of the
reaction: To avoid the self-condensation reaction, the temper-
ature of the reaction should kept at 4 8C. The small differences
in reactivity of the aldehyde components with the catalyst can
be amplified by the slow addition of the most reactive
(nucleophilic) component.[35] Remarkably, under these con-
ditions only a single regioisomer of the cross-aldol product is
obtained when both the aldol donor and acceptor contain Scheme 5. Cinchona-alkaloid-catalyzed intramolecular aldol reaction
enolizable a-methylene hydrogen atoms (Scheme 3). Lower with lactone formation.
catalyst loadings (10 mol %) can be used without a decrease in
the efficiency of the reaction.
The cross-aldol reaction of aldehydes can also be facili-
tated by the use of activated, non-enolizable acceptors, such
as diethyl ketomalonate (28, EWG = CO2Et; Scheme 4).[36]
When hydroxylamines are added to the mixture at the end of
the reaction, b-hydroxynitrones, which are otherwise difficult
to access, can be obtained.[37] Scheme 6. Oligopeptide-catalyzed asymmetric aldol reaction.

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 Angewandte
Organocatalysis Chemie

modular structure: The catalyst can be optimized for the the use of a syringe pump was not necessary and a lower
substrate and reaction conditions. catalyst loading was possible.
The reaction is ideally suited for tandem processes, and an
2.1.1.2. Mannich Reactions[40] astonishing variety and complexity of transformations have
been devised. Scheme 9 shows a tandem Mannich–Michael
The proper choice of reaction conditions and reaction
partners is key to the success of organocatalytic Mannich
reactions. Nevertheless, the reaction tolerates a wide range of
acceptors, donors, and amine reagents, and can be carried out
in a large variety of polar solvents. The reaction also tolerates
a certain amount of water, although the presence of water
may result in diminished reaction rates.
Organocatalytic Mannich reactions can be carried out
either as three-component one-pot reactions or as reactions of
preformed (protected) imines with aldol donors. Proline was
Scheme 9. Asymmetric tandem Mannich–Michael reaction catalyzed
found to catalyze both reaction variants, usually in good yield by l-proline. Ts = p-toluenesulfonyl.
and with high selectivity. In the former case the highest
ee values were observed with aromatic aldehydes.
The one-pot three-component Mannich reaction of a reaction. The l-proline-catalyzed asymmetric addition of
ketone, an aldehyde, and p-anisidine offers practical access in methyl vinyl ketone to the b-carboline 36 gave the tetracyclic
the presence of l-proline to a number of enantiomerically precursor 37 to yohimbine and deserpidine.[45] In some cases,
enriched b-amino carbonyl compounds.[41] The use of pre- the addition of a small amount of water (50–100 equiv)
formed imines, such as N-PMP-protected a-imino ethyl improved the selectivity of the reaction. However, the
glyoxylate (35), is a more recent development (Scheme 7). addition of more water resulted in a decrease in the reaction
rate.
Interestingly, the proline-catalyzed Mannich reaction
occurs with the opposite diastereo- and enantioselectivity to
the related aldol reactions:[22a] The syn adducts are usually
obtained as the major isomers. In contrast, anti addition was
observed in reactions of N-PMP-protected a-imino ethyl
glyoxylate (35) with aldehydes in the presence of the catalyst
(S)-2-(methoxymethyl)pyrrolidine (SMP, 5; Scheme 10).[46]

Scheme 7. Proline-catalyzed Mannich reaction of aldehydes with

N-PMP-protected a-imino ethyl glyoxylate. PMP = p-methoxyphenyl.

The advantage of this modification is that potential side

reactions are minimized under these conditions, and both
ketones and aldehydes can be used as aldol donors.[34]
Surprisingly, when unmodified aldehydes are used as Scheme 10. Synthesis of the anti product in an SMP-catalyzed Mannich
donors, the cross-Mannich reaction can proceed faster than reaction in the ionic liquid [bmim]BF4. bmim = 1-butyl-3-methylimida-
the competing cross-aldol reaction (Scheme 8).[42–44] The zolium.
three-component cross-Mannich reaction exhibits higher
stereo- and chemoselectivity (kMannich > kaldol) at temperatures
below 0 8C. With electron-rich aromatic acceptor aldehydes Aldol and Mannich reactions have similar reaction
profiles. Several models have been proposed to explain the
stereoselectivity of these transformations. According to
kinetic and stereochemical evidence, for both intra- and
intermolecular aldol reactions only one proline molecule
participates in the transition state.[22c] Although early models
focused principally on the formation of a Zimmerman–
Traxler six-membered-ring chairlike transition state, it has
since been found that this six-membered-ring conformation is
not an absolute criterion: In the preferred transition state for
the aldol reaction the carboxylic acid group should be anti to
Scheme 8. Proline-catalyzed asymmetric Mannich reaction with the forming C C bond, whereas a pseudoequatorial orienta-
aldehydes as a three-component one-pot reaction. tion of the substituent on the aldehyde should facilitate the

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Reviews P. I. Dalko and L. Moisan

stereodetermining proton transfer from the carboxylic acid of Efforts have also been made to convert Mannich products
proline to the forming alkoxide (Figures 2 and 4).[22] In the into synthetically more useful intermediates. Scheme 12
aldol reaction the aldehyde substituent occupies a pseudo- shows a short sequence with a Baeyer–Villiger oxidation,
equatorial position, whereas in the Mannich reaction the during which essentially no racemization occurs. The poly-
substituent is forced into a pseudoaxial orientation, since the functional acyloxy oxazolidinone products are formed with
high optical purity and can be converted readily into 4-alkyl 2-
oxazolidinones or protected b-amino alcohols.[53]

Scheme 12. Transformation of Mannich adducts into 5-acetoxyoxazoli-

din-2-ones.

2.1.1.3. a Amination[54]

The electrophilic addition of substituted azodicarboxy-

lates to reactive enamines, generated in situ from alde-
Figure 4. Proposed transition states (top) and products (bottom) for
the intermolecular aldol and Mannich reactions. hydes[55a,b] or ketones[55c] and a catalytic amount of a chiral
secondary amine, yields chiral a-hydrazino carbonyl com-
pounds (Scheme 13).[55] This reaction offers access to a-amino
E imine is more stable than the Z imine. These differences acids and a-amino alcohols. Unsymmetrical ketones react
explain the opposite stereoselectivities observed for the regioselectively to afford the products of amination at the
proline-catalyzed Mannich and aldol reactions. more substituted a position.
A detailed study demonstrated that proline-derived
catalysts containing heteroatoms or lacking the carboxylic
acid functionality are less efficient in this transformation than
proline itself.[47]
The lengthy reaction times, which are a disadvantage of
both proline- and SMP-catalyzed Mannich reactions, can be
considerably decreased (by a factor of 4 to 50) by replacing
standard organic solvents by ionic liquids, such as [bmim]BF4
or [bmim]PF6.[48, 49] With this modification as little as 1 mol %
of the catalyst may be used with reasonable reaction times
(approximately 2 h). The products are usually formed in Scheme 13. l-Proline-catalyzed a amination of aldehydes and ketones.
higher yields than in organic solvents, and similar enantiose-
lectivities are observed. The enhanced reaction rates may
result from activation of the imine electrophile by the ionic The reaction can be extended to the preparation of
liquid. enantiomerically enriched tertiary amines when a-substituted
A number of domino reactions were developed in which aldehydes are used as donors.[56] Both l-proline (1) and
the Mannich reaction was combined with hydrocyanation,[50] structurally similar l-azetidinecarboxylic acid (8) catalyze
allylation,[51] or conjugate addition,[52] allowing access to this transformation, although the use of the former catalyst
complex structures with defined stereogenic centers from led to higher enantioselectivities.
simple starting materials (Scheme 11).
2.1.1.4. a-Aminooxylation of Aldehydes and Ketones

As discussed in Section 2.1.1.1, aldehydes are usually

unsuitable donors in enamine reactions because they undergo
competing self-condensation. In a hydroxylations this unde-
sired reaction can be minimized when nitrosobenzene is used
as the acceptor (Scheme 14).[57] The superior reactivity of
nitrosobenzene causes a dramatic decrease in self-aldoliza-
tion and enables the use of a nearly equimolar amount of the
aldehyde. These reactions are anomalously rapid relative to
Scheme 11. One-pot Mannich reaction/allylation in the asymmetric other proline-catalyzed reactions. Another interesting facet of
synthesis of substituted amino acids. the transformation is the O-selective attack of the enamine; in

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Scheme 16. (S)-2(morpholinomethyl)pyrrolidine-catalyzed Michael

addition of aldehydes to nitroalkenes.

Scheme 14. l-Proline-catalyzed a aminooxylation of aldehydes.

the diastereoselectivity with a-hydroxyacetone can be ascri-

contrast, nitroso-aldol reactions proceed through selective bed to the putative formation of a Z enamine intermediate,
attack at the N atom.[58] The nitrosoaldehyde can be trapped which is favored through the formation of hydrogen bonds
in a domino sequence through an indium-promoted allylation between the OH group of a-hydroxyacetone and the tertiary
to afford syn or anti 1,2-diols in high yields and with excellent nitrogen atom of the catalyst (Scheme 17).[66]
enantioselectivities.[59]
Excellent chemo-, regio-, and enantioselectivities
(> 99 % ee) were observed in the direct a aminooxylation of
cyclic and acyclic ketones.[60] Although double aminooxyla-
tion can take place with ketones that have two enol forms, the
double attack could be circumvented by the slow addition of
the nitroso electrophile (Scheme 15). Improved yields and

Scheme 17. Asymmetric addition of a hydroxyketone to nitrostyrenes

catalyzed by (S,S)-N-(2-propyl)-2,2’-bipyrrolidine (iPBP).

For comparative purposes Scheme 18 shows conjugate

addition involving electrophilic activation with the structur-
ally related imidazolidine-2-carboxylic acid 15 (see Sec-
tion 2.2.1.1). With suitable substrates an intramolecular
Scheme 15. l-Proline-catalyzed a aminooxylation of ketones.

selectivities were observed upon the slow addition of the

nitrosobenzene to a solution of the ketone in DMF.[61] In this
way the homodimerization of PhNO and the double amino-
oxylation of the ketone reagent could be avoided, and the
desired product was formed with up to > 99 % ee in nearly
quantitative yield.
A similar enamine mechanism to that for aldol and
Mannich reactions (see Section 2.1.1.2) provides an ideal
model to rationalize the stereoselectivity of the reaction.[22, 64d]

2.1.1.5. Asymmetric Conjugate Addition[62, 63]

In contrast to aldol-type reactions, the proline-mediated

conjugate addition of various enolizable carbonyl compounds Scheme 18. Domino Michael–aldol reaction of b-ketoesters with a,b-
to activated olefins occurs with only modest enantioselectiv- unsaturated ketones.
ity.[64] Higher enantioselectivity was observed with structur-
ally similar (S)-2-(morpholinomethyl)pyrrolidine (22), which
was tested in the syn-selective addition of ketones and aldol reaction mediated by the same catalyst (with nucleo-
aldehydes to trans-b-nitrostyrene (Scheme 16).[65] philic activation) may follow the Michael addition step.[67]
Interestingly, N-isopropyl-2,2’-bipyrrolidine (iPBP, 24) This domino reaction sequence affords cyclohexanones with
mediates an anti-selective Michael addition. The reversal of three or four contiguous stereogenic centers with high

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Reviews P. I. Dalko and L. Moisan

enantio- and diastereoselectivities. The transformation can Similarly, enamine catalysis can be used to generate the
also be applied to b-aroyl and b-heteroaroyl b-ketoesters, diene component in situ from a,b-unsaturated ketones for
which can be converted readily upon treatment with a,b- reaction with nitroalkenes[70] or as one of three components in
unsaturated ketones into valuable building blocks for the a Knoevenagel/Diels–Alder sequence (Scheme 21).[71] This
synthesis of complex molecules. domino reaction affords highly substituted spiro[5.5]unde-
cane-1,5,9-triones with high enantio- and diastereoselectivity.
2.1.1.6. SN2 Alkylation

An efficient intramolecular alkylation of iodoaldehydes

catalyzed by proline derivatives was described recently.[68]
Best results were obtained with (S)-a-methylproline (4),
which led to both a higher reaction rate and higher
enantioselectivity than observed with l-proline
(Scheme 19). Although the mechanism of the enantiodiffer-

Scheme 21. Asymmetric three-component domino Knoevenagel/Diels–

Alder reaction.
Scheme 19. Direct asymmetric intramolecular a alkylation of
aldehydes: effect of b-geminal substitution.

entiation step has not been fully elucidated, the selectivity of 2.1.2. [2+2] Cycloaddition
the most effective catalyst was rationalized as an effect of
a disubstitution, whereby the equilibrium is shifted toward The mechanism of [2+2] cycloaddition reactions cata-
the anti form of the enamine to minimize 1,3-allylic strain. lyzed by chiral tertiary amines is similar to that of ammonium
ylide reactions (Section 2.1.5).[3a]
2.1.1.7. [4+2] Addition The most efficient chiral catalysts for the dimerization of
ketenes and related cycloadditions between ketenes and
Asymmetric organocatalytic [4+2] addition reactions with compounds with a C=O or C=N bond are cinchona alkaloids.
inverse electron demand have a similar reaction profile to For the formation of ketenes from acyl chlorides not only are
conjugate addition reactions mediated by chiral organocata- homogeneous bases, such as a proton sponge and 2-tert-
lysts. However, although the latter reactions proceed with low butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaza-
selectivity, both the yields and enantioselectivities of [4+2] phosphorine (BEMP), available, but also heterogeneous
additions are usually high (up to 94 % ee). Chiral secondary bases, such as K2CO3,[72] NaH,[73] NaHCO3,[74] and a resin-
amines react with aldehydes to form electron-rich enamines, bound variant of BEMP.[75] However, side reactions that do
which then react as dienophiles with enones (Scheme 20).[69] not involve [2+2] cycloaddition may predominate, in partic-
To make a catalytic cycle possible, a small amount of silica is ular when a stoichiometric amount of a proton sponge or the
required to transform the hemiaminal into an acetal and thus HKnig base is used.[76] The dimerization reaction can be
release the catalyst. performed without epimerization of the newly formed stereo-
centers when nonpyrolytic methods are used for the prepa-
ration of the ketene reagent, or when O-functionalized
quinine or quinidine derivatives, such as O-Bz, O-nPr, and
O-TMS (trimethylsilyl) analogues, are used (Scheme 22).[77]
Aldehydes react with ketenes to form the corresponding
b-lactones with high selectivity and in high yield.[78] This
reaction was also extended to the addition of ketenes to
imines to afford b-lactams,[78c] and applied in a one-pot
preparation of b-substituted aspartic acid derivatives through
a [2+2] enantioselective cycloaddition catalyzed by a cin-
chona alkaloid (Scheme 22). In this procedure the chiral
nucleophilic catalyst benzoylquinine plays four distinct roles:
1) catalytic dehydrohalogenation of the acid chloride to form
Scheme 20. Hetero-Diels–Alder reaction with inverse electron demand. the ketene, 2) dehydrohalogenation of the a-chloroamine to
PCC = pyridinium chlorochromate. form the corresponding imine, 3) catalyzation of the cyclo-

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Scheme 22. Benzoylquinine-catalyzed one-pot asymmetric synthesis of

b-amino acids. Bz = benzoyl.
Scheme 23. Synergistic effect of a peptide-based catalyst and l-proline
in the enantioselective Baylis–Hillman reaction.

addition to produce the b-lactam intermediate, and finally

4) ring opening to form the aspartic acid derivative. All of philic catalyst and the cocatalyst were evoked to explain the
these steps rely on the exchange of protons between the synergistic effect.
nucleophilic catalyst and a nonnucleophilic proton sponge, Alternatively, chiral Brønsted acids, such as 41, can be
and of course on the nucleophilicity of the quinine derivatives. used with achiral trialkyl phosphines to catalyze the enantio-
A reactor system was developed for a continuous-flow selective addition of aldehydes to cyclic enones
variant of the b-lactam synthesis.[79] Each of a sequence of (Scheme 24).[86] The Brønsted acid may serve to promote
columns contains the solid-phase-bound reagents for one step
of the synthesis. Thus, the formation of the reactive ketene,
the formation of the imine, and the cycloaddition were linked
in sequence and followed by the removal of unwanted by-
products to afford the pure b-lactam.

2.1.3. The Morita–Baylis–Hillman Reaction[80]

Nucleophilic amines or phosphines are known to catalyze

the addition of aldehydes to electron-deficient alkenes.[81] The
functionalized allylic alcohol products are valuable building
blocks for synthesis. Organocatalytic variants of the reaction
Scheme 24. In the presence of a chiral Brønsted acid the asymmetric
are often considered to be less efficient in terms of enantio-
Morita–Baylis–Hillman reaction with achiral phosphine catalysts leads
selectivity and reaction rate than the metal-complex-medi- to a chiral product.
ated alternatives. With few exceptions, the products are
obtained with less than 50 % ee, thus leaving plenty of room
for improvement.[82] Cinchona alkaloids are the chiral orga-
nocatalysts that have been used the most. A direct correlation the conjugate addition step of the reaction and remains
has been found between the pKa value and the activity of the hydrogen bonded to the resulting enolate in the enantiose-
quinuclidine-based catalysts: the higher the pKa value, the lectivity-determining addition of the enolate to the aldehyde.
faster the rate.[83] The presence of proton donors as additives, The asymmetric Morita–Baylis–Hillman reaction was
such as methanol, triethanolamine, formamide, and water, led used in the synthesis of ( )-mycestericin,[87] a potent immu-
to additional rate acceleration. nosuppressor, and epopromycin B,[88] an inhibitor of cell-wall
Although cinchona alkaloids continue to play a major role synthesis in plants (Scheme 25). Both syntheses rely on the
as catalysts in the asymmetric Morita–Baylis–Hillman reac- same b-isocupreidine organocatalyst 42, as well as the use of
tion, peptide-based catalysts are emerging as alternatives. hexafluoroacrylate, which had proved considerably more
One exciting advance is the use of a nucleophilic catalyst reactive than the corresponding methyl ester in previous
(cinchona alkaloid or peptide 40) in combination with a studies.
suitable acid as a cocatalyst, such as proline or a proline- Activated amines can also be used as acceptors in the
containing oligopeptide, in a Morita–Baylis–Hillman reaction Morita–Baylis–Hillman reaction catalyzed by b-isocupreidine
with methyl vinyl ketone (Scheme 23).[84, 85] Although the (42; Scheme 26).[89] b-Isocupreidine was shown to be a much
cocatalyst accelerates the reaction and improves the enantio- more efficient catalyst than the related quinidine derivative.
selectivity, the influence of the configuration of the additive is In the reaction described the major product is the S adduct;
minimal.[84b, 85] Noncovalent interactions between the nucleo- with aldehydes the R product is formed.[89a]

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Reviews P. I. Dalko and L. Moisan

structure of the catalyst and the presence of a sterically

demanding tert-butyl group account for the high enantiose-
lectivity of the reaction (53–95 % ee).
The asymmetric benzoin condensation can also be medi-
ated by the rotaxane-based catalyst 44 (Scheme 28).[92] The
distinctive characteristic of this system is the cooperation of
the “axle”, which contains the catalytic site, and the “wheel”,
a ring on which the chiral template is located. Although this
cooperation is relatively inefficient, the originality of the
system may inspire further studies.

Scheme 25. Asymmetric synthesis of ( )-mycestericin E.

Scheme 28. Asymmetric benzoin condensation with a rotaxane

catalyst. Ar = 3,5-di-tert-butylphenyl.

2.1.4.2. The Stetter Reaction

The intramolecular 1,4-addition of an aldehyde-derived

Scheme 26. The b-isocupreidine-catalyzed Morita–Baylis–Hillman
reaction of an activated imine with an acrylate. nucleophile to a conventional Michael acceptor (the Stetter
reaction) could be catalyzed by the structurally similar chiral
triazolium salt 45 (Scheme 29).[93] The indanoyl moiety of the
most efficient catalyst is reminiscent of the aminoindanol
2.1.4. Asymmetric Synthesis with Carbene Catalysts recently developed by Merck for chiral derivatization and
2.1.4.1. The Benzoin Condensation[90] resolution, and as a ligand in asymmetric reactions. The
reaction was applied to the synthesis of chromanes (up to
Heteroazolium salts in the presence of a base are the most 97 % ee).[93] The electronic properties of the catalyst were
frequently used nucleophiles for the umpolung of an aldehyde optimized by functionalization of the N-phenyl substituent.
for an asymmetric addition to another aldehyde or an imine. KHMDS was found to be the most suitable base and xylene
The asymmetric benzoin condensation of various aryl the most suitable solvent for the reaction.
aldehydes was carried out with the Wanzlick carbene catalyst
derived from 43 (Scheme 27).[91] The rigidity of the bicyclic

Scheme 27. Benzoin condensation catalyzed by the chiral triazolium Scheme 29. Asymmetric Stetter reaction with the tetrazolium
salt 43. compound 45 as the catalyst. HMDS = hexamethyldisilazide.

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2.1.5. Asymmetric Reactions with Ylide Intermediates

Ylides can be prepared either by the alkylation of chiral

dialkyl sulfides or trialkyl amines by using reactive organic
halides, such as benzyl bromide, or by carbene-transfer
reactions. To ensure efficient catalytic turnover phase-trans-
fer conditions can be used, in which case the chiral catalyst is
not the phase-transfer agent.
Scheme 31. Asymmetric epoxidation of aldehydes catalyzed by the
2.1.5.1. Epoxidation tartrate-derived C2-symmetric phenylsulfanyl-substituted catalyst 48.
TBS = tert-butyldimethylsilyl.
Sulfur ylides react with aldehydes to form epoxides,
predominantly as the trans isomer. Although the stoichio-
metric asymmetric sulfur ylide mediated epoxidation reac- Although the main features of the epoxidation process are
tions have become useful tools in organic chemistry,[94] the known (addition of the ylide to the carbonyl group followed
catalytic version presents difficulties: Not only is substrate by elimination of the sulfide yields the epoxide), details of this
incompatibility a problem, but also the control of the relative reaction remain unclear. Computational studies have been
and absolute configuration, which show opposite trends in carried out on the formation of the betaine.[98]
these systems. These trends can be explained by the stability
of the ylide intermediate:[95] High trans diastereoselectivity 2.1.5.2. Aziridination
but low enantioselectivity were observed in reactions in which
the betaine intermediates were formed reversibly. In contrast, Phenyldiazomethane as well as the more stable diazo-
nonreversible betaine formation resulted in low diastereose- esters and diazoacetamides were tested as aziridinating agents
lectivity and high enantioselectivity. The solvent and counter- for activated aryl aldimines in the presence of different sulfide
ion have an important effect on the stereoselectivity of the catalysts (46, 49–51; Scheme 32).[99] An inversion of diaster-
reactions: An increase in enantioselectivity was observed eoselectivity was observed: Diazoesters gave predominantly
when protic solvent mixtures and lithium salts were used. This the cis aziridine, whereas phenyldiazomethane gave the trans
observation is explained by the nonreversible formation of isomer as the major product.
the anti betaine, whose charge is better stabilized in a protic
medium through solvation. Conversely, diastereoselectivity
can be improved through the use of an aprotic solvent and the
avoidance of species capable of solvating an alkoxide.
With a chiral sulfonium ion derived from a C2-symmetric
thiolane, such as 46 or 47, and benzyl bromide, aryl aldehydes
can be converted into oxiranes (Scheme 30).[96] The reaction

Scheme 32. Sulfide catalysts in the aziridination of activated

benzaldimines with phenyldiazomethane.

Scheme 30. Asymmetric epoxidation of aryl aldehydes with the C2-sym-

metric sulfonium catalyst. A catalytic amount of the camphor-derived sulfide 52
mediates the asymmetric aziridination of cinnamylidene-N-
tosylamine and benzyl bromide with K2CO3 as a solid base.[100]
at room temperature under optimized conditions with Heating at reflux in acetonitrile does not lead to a significant
10 mol % of the chiral sulfide 46 and an aldehyde concen- loss of enantioselectivity (Scheme 33).
tration of 0.5 m was complete within 4 days in 82 % yield, with The sulfur ylide catalyzed asymmetric synthesis of trans
85 % ee and d.r. 92:8. The use of the diethyl thiolane catalyst aziridines from imines and tosylhydrazines[101] was applied to
47 led to higher selectivities but slower reaction rates. the synthesis of the side chain of taxol.[102] The reaction
The C2-symmetric chiral sulfide 48 (Scheme 31) can be sequence is based on the regio- and stereoselective conver-
synthesized on a large scale from tartaric acid.[97] The TBS- sion of a trans aziridine into a trans oxazoline, the ring
protected catalyst with aryl substituents was the most opening of which then gives the side chain. N-Trimethylsilyl-
effective, and the best result was obtained with trans- ethylsulfonyl (SES) imines, which were more stable under the
cinnamaldehyde (75 % yield, 75 % ee, d.r. 80:20). conditions of the catalytic aziridination than N-carbonyl

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Reviews P. I. Dalko and L. Moisan

tion the catalytic cycle is inefficient, and a stoichiometric

amount of the catalyst is required for the cyclopropanation of
tert-butyl acrylate with phenacyl bromide. The reaction is
truly catalytic, however, under intramolecular conditions.

2.1.6. Acyl-Transfer Reactions: Desymmetrization and Kinetic

Resolution[104]

The nature of the interaction (covalent bond or ion pair)

Scheme 33. Enantioselective aziridination of cinnamylidene-N-tosyla-
between the catalyst and the transferring acyl group in the
mine with benzyl bromide. The chiral sulfide catalyst is derived from
camphor. activated complex remains a subject of controversy. It is
possible that the type of interaction depends on the individual
system.[104a]
imines, were treated with the tosylhydrazone salt in the Both the desymmetrization of cyclic anhydrides by
presence of a phase-transfer catalyst, [Rh2(OAc)4], and the selective ring opening with alcohols, amines, or other
chiral sulfide 53 (20 mol %). In the example shown in nucleophiles and the kinetic resolution of secondary alcohols
Scheme 34 the aziridine was obtained in 57 % yield in a have been at the center of much interest. Although there may
be differences in the mechanistic details of these transforma-
tions, high-performing catalysts mediate both types of reac-
tion efficiently.
A number of chiral nucleophilic catalysts derived from 4-
dimethylaminopyridine (DMAP), proline, oligopeptides, and
phosphines have been designed both for kinetic resolution
through acylation and asymmetric desymmetrization (Fig-
ures 5 and 6 and Scheme 43). In these transformations organic
catalysts have advantages over chiral metal-derived Lewis
acid catalysts, which may promote racemization.[105]

Scheme 34. Asymmetric aziridination with a sulfur ylide as the catalyst

in the synthesis of the side chain of taxol.
SES = 2-(trimethylsilyl)ethanesulfonyl.

trans/cis diastereomeric ratio of 8:1 (with 98 % ee for the trans

isomer). The high selectivity of the aziridination is probably a
consequence of the favorable combination of several key
factors: the formation of a single diastereomer of the
sulfonium ylide, the high level of control of both the ylide
conformation and the facial selectivity of the reaction, and the
irreversible formation of the betaine intermediate.

2.1.5.3. Cyclopropanation

A further application of organocatalysts is an asymmetric

cyclopropanation via an ammonium ylide.[103] With the
cinchona-alkaloid catalyst 54 the trans product is obtained Figure 5. Selected nitrogen-containing chiral acyl-transfer catalysts.
diastereoselectively (Scheme 35). In the intermolecular reac- Boc = tert-butoxycarbonyl.

2.1.6.1. Cinchona-Alkaloid Catalysts

The first systems for catalytic asymmetric acylation were

based on naturally occurring cinchona alkaloids, which allow
a remarkably high degree of desymmetrization of meso
anhydrides. More complex catalysts with two cinchona-
alkaloid units, such as (DHQD)2AQN (61 b) and
(DHQ)2AQN (62 b; Figure 6), which were developed origi-
Scheme 35. Asymmetric intermolecular cyclopropanation with an nally as ligands for asymmetric dihydroxylation, exhibit high
intermediate ammonium ylide formed from the catalyst 54 and the activity and selectivity in desymmetrization reactions
alkyl bromide. (Figure 6).[106] In contrast to reactions with other catalysts, a

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Scheme 37. Parallel kinetic resolution of 2-alkyl succinic anhydrides.

dipole moment rather than hydrogen-bonding interactions

account for the selectivity of the catalyst.
In the synthesis of (+)-biotin a catalytic enantioselective
desymmetrization of a meso cyclic anhydride served as a key
step (Scheme 38).[107] The best result for this transformation
was obtained with DHQD-PHN (61 e).

Scheme 38. Asymmetric synthesis of (+)-biotin through the

Figure 6. C2-Symmetric cinchona-alkaloid derivatives as acyl-transfer desymmetrization of a meso anhydride with the cinchona-alkaloid
catalysts. catalyst DHDQ-PHN (61 e).

stoichiometric amount of a base is not required, thus The different functional groups of the chiral phosphinite
suggesting that the protonated form of the catalyst is equally 63 derived from a cinchona alkaloid act cooperatively in the
active in the acyl-transfer reaction. acylation reaction to activate the acylating reagent and trap a
The highly enantioselective dynamic kinetic resolution of proton (Scheme 39).[108] The catalyst mediates the asymmetric
dioxolanediones,[106b] succinic anhydride derivatives,[106d] and desymmetrization of diols: With benzoyl chloride as the
N-protected cyclic anhydrides of a-amino acids[106a,c] by 61 b acylating agent, the monoacylated hydrobenzoin was
has been reported. (DHQD)2AQN (61 b, 10–20 mol %) obtained in almost quantitative yield and with 91 % ee.
mediates the alcoholysis of the cyclic anhydride in diethyl
ether at 10 8C (Scheme 36). The catalyst plays a dual role by

Scheme 36. Dynamic kinetic resolution of Cbz-protected a-amino acid

N-carboxyanhydrides. Cbz = benzyloxycarbonyl.
Scheme 39. Asymmetric desymmetrization of a meso 1,2-diol by the
chiral phosphinite catalyst 63 derived from a cinchona alkaloid.
catalyzing both the racemization and the enantioselective
alcoholytic ring opening.[106a,b] Yields are greater than 50 % if
the racemization is faster than the alcoholysis step: kracemiza- 2.1.6.2. DMAP Derivatives[109]
tion @ kalcoholysis.
Cinchona alkaloids were known previously to catalyze the The substitution pattern of the chiral DMAP (4-dimethyl-
desymmetrization of cyclic anhydrides into chiral hemiesters aminopyridine) derivative is a key factor in both the stereo-
with moderate enantioselectivity (up to 76 % ee). Biscinchona selectivity and the reactivity of the catalyst.[110–115] Although 2-
alkaloids, such as 61 b, were more efficient in this trans- substituted DMAP derivatives enable remarkable stereo-
formation.[106e] With this catalyst hemiesters were obtained in chemical induction, the presence of a substituent at the 2-
yields ranging from 72 to 90 % and with up to 98 % ee position inhibits catalytic turnover. Chiral atropisomeric
(Scheme 37).[106d] Ab initio calculations suggest that the biaryl DMAP derivatives[110] and variously substituted

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Reviews P. I. Dalko and L. Moisan

DMAP analogues containing chiral amino or acyloxy groups 57 (Figure 5), the efficient kinetic resolution of ethanolamine
have been developed as catalytically active analogues.[110–115] derivatives is possible,[113] whereas proline-derived diamines,
The preparation and resolution of these catalysts gener- such as 60, only catalyze benzoylation reactions.
ally requires multistep synthesis. A notable exception is the
axially chiral, atropisomeric biaryl 4-aminopyridine 55, which 2.1.6.4. Oligopeptides[116]
can be prepared in three steps by synthesis and resolution.[110a]
The chirality transfer from the acyl pyridinium species Oligopeptides such as 64 with N-terminal histidine
derived from the catalyst to the substrate is ascribed to residues were shown early on to catalyze asymmetric acyl-
steric and p–p interactions between the substrate and the transfer reactions. A recent application of this class of
catalyst (Scheme 40). catalysts in the synthesis of a mitosane core structure
illustrates the scope and the power of these catalysts in
kinetic resolution (Scheme 42).[116f]

Scheme 40. Kinetic resolution of secondary alcohols mediated by an

atropisomeric pyridine catalyst. RS = smaller substituent, RL = larger
substituent.

In the case of a new class of chiral pyridine derivatives

(e.g. 58), the reactive acyl pyridinium intermediate has Scheme 42. Kinetic resolution of a mitosane core structure.
restricted conformational freedom.[115] In the presence of
the catalyst 58 the Steglich rearrangement of enol carbonates
leads to the corresponding azlactones with quaternary carbon 2.1.6.5. Phosphorus-Based Catalysts[117]
atoms in excellent yields and with high ee values (Scheme 41).
Phosphane catalysts are efficient enzyme substitutes in
acyl-transfer reactions of benzylic and allylic alcohols.[118] A
study showed that the bicyclic phospholanes 68–70 were more
reactive as acyl-transfer catalysts than the monocyclic ana-
logues 71–73 by about two orders of magnitude (Scheme
43).[118e,f] This increased reactivity can be attributed to
destabilization of the ground state of the bicyclic compounds
by the P-phenyl group, which also forces these compounds to
adopt a conformation that is closer to that of the transition
state.
Scheme 41. Asymmetric Steglich rearrangement with the nucleophilic
pyridine catalyst 58.
2.1.6.6. Asymmetric Phosphorylation[119]

Asymmetric phosphorylation with the catalyst 74 derived

2.1.6.3. Proline Derivatives from a short-chain peptide not only allowed the kinetic
differentiation of two enantiotopic stereocenters of a myo-
In contrast to most pyridine-based catalysts, the prepara- inositol derivative, but also the regioselective transformation
tion of proline-derived catalysts is straightforward.[113, 114] of the substrate (Scheme 44).[120] Such “artificial kinase”
During the last steps of the synthesis of these catalysts a catalysts were obtained through the screening of a library of
wide range of substituents can be introduced. This class of 39 synthetic peptides. Depending on the peptide structure,
catalysts seems, however, to have limited substrate generality. either stereoisomer of inositol could be prepared selectively.
With N-4-aminopyridyl-a-methylproline derivatives, such as This result underlines the fact that peptides that are not

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cyanohydrin carbonates (Scheme 45).[121] The enantioselec-

tivity of these transformations is particularly noteworthy:
With some cyclic ketones the products were formed with
greater than 90 % ee.

Scheme 45. Asymmetric cyanation of ketones with the modified

cinchona alkaloid 61 e as the catalyst.

2.2. Electrophilic Catalysis: Activation of the Acceptor

Lewis acid activation in organocatalytic reactions is

possible through the formation of either an iminium ion or
ion pairs (see below). In the former case the condensation of a
carbonyl compound with a secondary amine leads to the
Scheme 43. A comparison of monocyclic and bicyclic phospholanes as formation of an iminium ion, whose LUMO is lowered in
acyl-transfer catalysts.
energy through conjugation with a p system, such as an alkene
or an aromatic ring. This activation effect is similar to that
typically associated with reactions involving metal-derived
Lewis acids and may be exploited in a number of trans-
formations, such as cycloaddition or alkylation reactions in
the presence of electron-rich aromatic rings or stabilized
carbanions of malonates or nitro compounds. As the chiral
amine catalyst is often used in these reactions in the form of a
salt, asymmetric catalysis through proton transfer, whereby
the chiral amine acts as a ligand, can not be excluded as an
alternative mechanism.

2.2.1. 1,4-Addition
2.2.1.1. Reactions with Enolates or Enolate Equivalents

Chiral imidazolidinone salts, such as 17H+ formed from 17

and a stoichiometric amount of 2,4-dinitrobenzoic acid,
catalyze the addition of silyl enol ethers to a,b-unsaturated
aldehydes (Scheme 46).[146] The chemoselectivity of the trans-
Scheme 44. Asymmetric phosphorylation with the short-chain formation is remarkable: The products of 1,4-addition are
oligopeptide 74 as the catalyst. The absolute configuration of the formed, whereas metal-containing Lewis acid catalysts medi-
product was not established. ate 1,2-addition preferentially. This reaction can be used to
prepare enantiomerically enriched butenolides under cata-
lytic conditions. The treatment of a 2-silyloxy furan with
enantiomerically pure may afford a high degree of enantio- unsaturated aldehydes afforded the desired adducts with
selectivity in the sense of enantiodivergence.[21] The incorpo-
ration of histidine derivatives with restrictions in the dihedral
angle was important for the optimization of the catalyst. As
little as 2 mol % of the peptide effects the asymmetric
phosphorylation of one of the hydroxy groups of myoinositol
to give myoinositol-1-phosphate with > 98 % ee and in 65 %
yield in a very direct manner (Scheme 44).

2.1.6.7. Cyanation: Lewis Base Activation

Modified cinchona alkaloids, such as DHQD-PHN (61 e)

and (DHQD)2AQN (61 b, Figure 6), catalyze the addition of Scheme 46. Addition of silyl enol ethers to a,b-unsaturated aldehydes
ethyl cyanoformate to carbonyl groups to form tertiary in the presence of chiral imidazolidinone catalysts.

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Reviews P. I. Dalko and L. Moisan

good syn selectivity and 84–99 % ee (Scheme 46). The anti

isomer can be obtained simply by changing the solvent and
the acid cocatalyst. High yields were only observed when a
protic cosolvent, such as water or an alcohol, was added to the
reaction mixture. The effect of the additive on the yield was
attributed to its ability to quench the putative silyl cation
formed, which inhibits the catalytic cycle through the
formation of (TMS)2O. This transformation was used in the
synthesis of spiculisporic acid.[146]
Scheme 49. Enantioselective Michael addition of malonates to enones
The lowering of the energy of the LUMO through the in the presence of chiral imidazolidine catalysts.
formation of an onium ion conjugated with a double bond can
be exploited for the alkylation of a,b-unsaturated aldehydes
with electron-rich nuceophiles, such as pyrroles, indoles, and To ensure optimum reaction rates, solvent-free conditions
benzene derivatives (Scheme 47).[147] Formally, the reaction is were used (reaction times ranged from 150 to 288 h). The
substitution pattern of the malonate ester significantly
influences both the yield and the selectivity of the reaction.
Best results were obtained with dibenzyl malonate, which was
then used to screen a wide range of unsaturated cyclic and
acyclic ketones. The best yields and enantioselectivities (up to
99 % ee) were observed with enones that were not sterically
hindered. The conjugate addition of nitroalkanes to unsatu-
rated enones follows a similar reaction course.[150]
The chiral imidazolidine 25 derived from diphenylethy-
lene diamine was also shown to be efficient in catalyzing the
Michael addition of cyclic 1,3-dicarbonyl compounds to a,b-
unsaturated ketones. One elegant application is the synthesis
of the anticoagulant warfarin (coumadin) and analogues
(Scheme 50).[151] This reaction also proceeds on a kilogram

Scheme 47. Enantioselective 1,4-addition of electron-rich nucleophiles

to a,b-unsaturated aldehydes in the presence of chiral imidazolidinone
catalysts.

a conjugate 1,4-addition of the aromatic or heteroaromatic

ring to the a,b-unsaturated aldehyde. This strategy was used
in tandem with a ruthenium-catalyzed cross-metathesis Scheme 50. Enantioselective one-step synthesis of warfarin.
reaction in the synthesis of ( )-ketorolac (99 % ee), a non-
steroidal anti-inflammatory drug (Scheme 48).[148]
The 1,4-addition of malonates to a,b-unsaturated carbon- scale without a decrease in yield or enantioselectivity.
yl compounds was performed with the imidazolidine catalyst Although the reaction affords the product with just 82 % ee,
15, which has a carboxylic acid functionality (Scheme 49).[149] a single recrystallization from a water/acetone mixture
provides the enantiomerically pure product (> 99.9 % ee).
Remarkably, the use of l-proline as the catalyst in this
reaction leads to a racemic mixture of the product.
The reaction may proceed either via the previously
discussed iminium intermediates (Section 2.1.1.1), or alter-
natively via aminal intermediates. Although no intermediates
have been structurally characterized, the results of computa-
tional studies suggest the latter pathway is more likely
because this structure accounts for better shielding of the
substrate.

2.2.1.2. Heteroatom-Centered 1,4-Addition

Scheme 48. Tandem olefin metathesis/asymmetric Michael addition in The asymmetric addition of 2-thionaphthol to a wide
the synthesis of ( )-ketorolac. DCA = dichloroacetic acid. range of cyclic enones is catalyzed by just 1 mol % of

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(DHQD)2PYRE (61 c) to afford the desired products with

greater than 90 % ee (Scheme 51).[152]
Short-chain peptides such as 75, with a His or modified
His residue and a well-defined b-turn structure, catalyze with
a l-Pro-d-tert-Leu sequence (proline contribution) the con-

Scheme 51. Asymmetric 1,4-addition of 2-thionaphthol to cyclic enones

under the catalysis of the biscinchona alkaloid (DHQD)2PYR (61 c).
Nph = b-naphthyl. Scheme 53. Asymmetric [4+2] cycloaddition of a,b-unsaturated
aldehydes and ketones with cyclopentanone in the presence of chiral
imidazolidinone catalysts.
jugate addition of an azide ion to a,b-unsaturated carbonyl
compounds.[153] These oligopeptides were tested earlier in
asymmetric acylation reactions.[154] Both the secondary struc- Polymer-[158a] and silica-supported[158b] catalysts were also
ture and the amine base are necessary for the activity of the developed as alternatives for use in the asymmetric [4+2]
catalyst, whose imidazole ring acts as the catalytic center. cycloaddition. A tyrosine-derived imidazolidin-4-one was
Conformational restriction through functionalization of the immobilized on a modified poly(ethylene glycol) matrix and
b position of the His residue (restriction of the dihedral angle) converted in situ into a soluble catalyst. This polymer was
resulted in improved selectivity in the azidation (Scheme 52). shown to be an efficient catalyst for the asymmetric [4+2]
cycloaddition of acrolein to 1,3-cyclohexadiene and 2,3-
dimethyl-1,3-butadiene.[158a] Catalyst recycling (up to four
cycles) led to only a small decrease in chemical efficiency and
enantioselectivity.

2.2.2.2. [3+2] Cycloaddition

The scope of the chiral organocatalyst 77 in 1,3-dipolar

cycloadditions was extended to the condensation of acyclic
nitrones with cyclic aldehydes (Scheme 54).[159] Maximum
yields were between 70 and 80 % (d.r. up to 97:3 and up to
93 % ee).
Scheme 52. Asymmetric 1,4-addition of azide to an enone catalyzed by
the short-chain oligopeptide 75. Nph = a-naphthyl.

2.2.2. Cycloaddition
2.2.2.1. [4+2] Cycloaddition

Chiral secondary amines also catalyze [4+2] cycloaddi-

tions through the reversible formation of iminium intermedi-
ates from an unsaturated aldehyde and the catalyst. The
acceleration of the rate of the cycloaddition is a consequence
of the lowering of the energy of the HOMO of the iminium
ion through conjugation with the double bond.[155] The most Scheme 54. 1,3-Dipolar cycloaddition of an acyclic nitrone with an
efficient catalysts for this transformation are usually the aldehyde in the presence of a chiral organocatalyst.
ammonium salts of chiral imidazolidines and pyrrolidines.
The previously described [4+2] cycloaddition of a,b-
unsaturated aldehydes was extended recently to a,b-unsatu- 2.2.2.3. [4+3] Cycloaddition
rated ketones.[156, 157] The chiral salt derived from the amine 16
led to poor yields and no enantioselectivity in these cases. A The chiral imidazolidine 17 catalyzes the addition of
structural analogue, 76, however, mediated the cycloaddition silyloxy pentadienals to substituted furans (Scheme 55). A
reaction of a wide range of cyclic or acyclic enones to give the seven-membered-ring cycloadduct forms as the product of the
products in yields between 24 and 89 % and with up to 92 % ee reaction with endo selectivity (up to 90 % ee).[160] Although
(Scheme 53). the finer details of the reaction mechanism have not yet been

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Reviews P. I. Dalko and L. Moisan

the fused ketal of 78 by more strongly electron withdrawing

groups, such as the acetate groups in 79 (Figure 8).[163] This
modification allows the epoxidation of E cinnamates,
although 79 is unsuitable as a catalyst for the oxidation of
E aliphatic a,b-unsaturated esters.[164]
Further improvement resulted from the replacement of
the spiroketal appendage of 78 with N-aryl substituted
oxazolidinones.[165] The use of the catalyst 80 for the
Scheme 55. The asymmetric [4+3] cycloaddition of silyloxypentadienals epoxidation of Z olefins and styrenes leads to encouragingly
with substituted furans. R1 = SiR3, R2 = alkyl, R3 = H, TFA = trifluoroace- high enantioselectivities.[166] The substituents on the nitrogen
tic acid. atom of the ketone catalyst have a significant effect on the
enantioselectivity of the epoxidation reaction.[166] This influ-
ence is believed to be electronic rather than steric in nature
elucidated, it is conceivable that an iminium ion is formed that when styrene is used as the substrate. The attractive
is in resonance with an allylic cation, thus leading to charge interaction between the aryl group of the substrate and the
acceleration. N-aryl group of the catalyst can be enhanced by introducing
electron-withdrawing groups on the N-aryl group.
2.2.3 Oxidation A variety of ketones of natural and fully synthetic origin
2.2.3.1. Epoxidation were tested as alternative catalysts to the fructose derivatives
2.2.3.1.1. Chiral Dioxiranes[161, 162] for asymmetric epoxidation. Binaphthyl ketones, tropinone
derivatives,[167] dehydrocholic acid, and the synthetic bicyclic
Dioxiranes generated in situ from chiral ketones through ketone 81 were also shown to react with high enantioselec-
oxidation with oxone have been shown to be highly enantio- tivity and high conversion rates (Scheme 56).[167–169]
selective for the asymmetric epoxidation of a variety of
olefins (Figure 7).

Scheme 56. Asymmetric epoxidation of stilbene with the chiral

organocatalyst 81.

Figure 7. The catalytic cycle of oxidation with oxone in the presence of

a ketone.
The synthesis of diltiazem, a potent calcium antagonist,
illustrates the scope of the reaction.[170] A key intermediate
was prepared in high yield, although with moderate enantio-
The fructose-derived ketones 78–80 have emerged as selectivity, by using the binaphthyl catalyst 82, which was
particularly effective catalysts for the epoxidization of E- found to be the most efficient catalyst for the asymmetric
configured and trisubstituted olefins (Figure 8).[163] If the epoxidation (Scheme 57). Recrystallization provided the key
epoxidation is slow, however, the decomposition of the intermediate in enantiomerically pure form.
catalyst, presumably by Baeyer–Villiger oxidation, is often a Chiral fluoroketones, such as 83 and 84, were investigated
competing process. The stability and reactivity of the catalyst as catalysts for asymmetric epoxidation with oxone as the
can be increased by decreasing the electron density in the bulk oxidant (Figure 9).[171] The presence of a-fluoro sub-
proximity of the carbonyl group; for example, by replacing stituents considerably increases the reactivity of the carbonyl
group. The tropinone derivative 83 showed excellent reac-
tivity but only modest enantioselectivity. The biphenyl ketone
84 exhibited modest reactivity, but higher enantioselectivity
relative to 83 in most cases. Better results were obtained with
the chiral fluoro-substituted binaphthyl ketone 85
(Scheme 58).[172]

2.2.3.1.2. Chiral Oxaziridines

Figure 8. Sugar-derived ketones for the asymmetric epoxidation of Oxaziridinium salts have been utilized in oxidation
alkenes. reactions far less than chiral ketones. The intermediate

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Figure 10. Iminium catalysts for the asymmetric epoxidation of

alkenes.

method allows greater flexibility in modulating the structure

of the catalyst.
Scheme 57. Asymmetric epoxidation of an a,b-unsaturated ester with
2.2.3.2. Asymmetric Baeyer–Villiger Reaction
the chiral organocatalyst 82 in the synthesis of diltiazem.

Chiral ketones are not suitable catalysts for the asym-

metric Baeyer–Villiger oxidation as a result of competing
decomposition under the reaction conditions. As an alter-
native, the planar-chiral bisflavin catalyst 90 was developed.
This compound catalyzes the oxidation of cyclobutanones to
the corresponding lactones in 17–67 % yield and with up to
74 % ee (Scheme 59).[175] The solvent has a considerable
influence on the enantioselectivity: Best results were
Figure 9. a-Fluoroketone catalysts for the asymmetric epoxidation of obtained with protic solvents.
alkenes. Tf = trifluoromethanesulfonyl.

Scheme 59. Asymmetric Baeyer–Villiger oxidation of 3-aryl cyclobuta-

nones with a flavin catalyst.
Scheme 58. Asymmetric epoxidation of trans-b-methylstyrene mediated
by the chiral fluorinated binaphthyl ketone catalyst 85.
2.2.3.2.1. Amine Catalysts

Alkenes can be epoxidized under phase-transfer condi-

oxaziridines, which are formed from the iminium salt upon tions with a chirale amine catalyst and oxone in a pyridine–
reaction with oxone, typically in aqueous acetonitrile, are acetonitrile/water–sodium bicarbonate biphasic system.[176]
efficient oxygen-transfer reagents. They generally enable the The oxidation of 1-phenyl cyclohexene gave the correspond-
epoxides to be obtained in 60–70 % yield, but not with higher ing epoxide with 46 % ee with the catalyst (S)-2-(diphenyl-
than 60 % ee. In the most effective catalysts 86–89 (Figure 10) methyl)pyrrolidine (20; Scheme 60). Although the reaction
the asymmetric centers are located close to the reaction mechanism has not been fully elucidated, the finding that
site.[173] A complicating feature of this process is the potential secondary ammonium salts are considerably more active than
for the formation of diastereomeric oxaziridinium salts from tertiary, which in turn are more active than quaternary
the iminium species. Each diastereomer can transfer the ammonium salts, shows that the protonated amine does not
oxygen atom to one of the prochiral faces of the alkene only act as a phase-transfer catalyst. The active oxidant is
substrate with a different degree of enantioselectivity. believed to be the peroxysulfate of the chiral amine: The
The iminium salts can also be generated in situ through ammonium ion activates the peroxymonosulfate through
the condensation of a chiral amine with an aldehyde.[174] This hydrogen bonding, thus generating a more electrophilic

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Reviews P. I. Dalko and L. Moisan

selective nature of proton catalysis relative to that of other

Lewis acids suggested that any possible catalysis by a chiral
proton complex would be suppressed by competing achiral
catalysis by a protonated solvent molecule.
Although the approach to the design of each of these
types of chiral proton catalyst is quite different, the reactions
of both types of catalyst proceed via noncovalently activated
complexes and will therefore be discussed together in this
Scheme 60. Amine-catalyzed epoxidation of 1-phenylcyclohexene with section.
oxone under PTC conditions.
3.1.1. Catalytic Enantioselective Protonation[178]

species. The problems with reproducibility encountered Despite the apparently simple concept behind the enan-
previously were solved when the protonated amine catalyst tioselective protonation of a prostereogenic enol derivative,
20–HCl was used. In this way the catalyst is protected from the mechanism of this transformation is not fully understood.
oxidation under the reaction conditions. We believe, however, that the majority of the catalytic
processes are more like organometallic reactions in which
2.2.3.2.2. Peptides[177] the chiral organic molecule serves as a ligand. Therefore, they
are out of the scope of this Review.
The mechanism of the oxidation of enones with free or The enantioselective decarboxylation and reprotonation
supported polyamino acids as catalysts (the so-called JuliO– of a malonate precursor is a further example of a metal-free
Colonna reaction) is not yet well understood. The group asymmetric protonation. This transformation in the presence
nearest to the N terminus seems to play an important role in of enzymes or microorganisms has been known for some
the stereoselectivity of the reaction. Polypeptides derived time; however, it has received little attention in synthetic
from b-amino acids (instead of a-amino acids) were also chemistry.[179] Although a stoichiometric variant with cin-
tested, and it was found that poly-b-leucines are effective chona alkaloids, such as 91, as chiral protonating agents gave
catalysts for the epoxidation of chalcones and their analogues good results, the catalytic reaction proceeded with only
(up to 70 % ee). modest enantioselectivity (Scheme 61).[180]

3. Reactions via Noncovalent Activation Complexes

A growing number of asymmetric organocatalytic reac-

tions are accelerated by weak Lewis acid/Lewis base inter-
actions. These weak interactions were seldom exploited to
promote chemical reactions in the past. The rationalization of
the mechanism of these reactions is often difficult, and our
current understanding of the key structural elements that
determine the selectivity of the reactions is poor.
Scheme 61. Enantioselective decarboxylation–reprotonation of
a-aminomalonate derivatives.
3.1. Asymmetric Proton Catalysis

The proton is arguably the most common Lewis acid 3.1.2. Catalytic Enantioselective Deprotonation[181]
found in nature. It forms hydrogen bonds, which can be
divided into two classes according to the nature of the Chiral Brønsted bases used as catalysts in asymmetric
interaction: polar covalent (RX H) and polar ionic synthesis are mainly metal-containing compounds, such as
(RX+H···Y ). In the former case the conjugate base carries chiral lithium amides and magnesium bisamides. Metal-free
the chiral information, whereas in the latter case the anion is superbases were recently developed as alternatives. In the
achiral and the proton is complexed with a chiral ligand presence of a catalytic amount of the modified guanidine 92
(usually an amine base). Polar covalent proton catalysis is (20 mol %) asymmetric Michael reactions proceed with high
developing rapidly as an important method in asymmetric enantioselectivity (Scheme 62).[182]
synthesis. Polar ionic catalysis is a more recent and also a
more elusive strategy. Until recently, it seemed to make no 3.1.3. 1,4-Addition to Activated Alkenes
chemical sense to design an asymmetric catalytic reaction
with an ionic hydrogen bond as the catalyst, for at least two The bifunctional thiourea-derived catalyst 93 mediates
main reasons: Because of the spherical symmetry of the the enantioselective Michael addition of malonates to nitro-
empty 1 s orbital of the proton, no stereoisomerically discrete alkenes (Scheme 63).[183] The basic, nucleophilic tertiary
coordination complexes should exist. Furthermore, the non- amine activating group in the catalyst and the thiourea

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 Angewandte
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Scheme 62. Asymmetric Michael reaction of a glycine imine with an

acrylate in the presence of a modified guanidine catalyst. Scheme 65. Asymmetric proton-catalyzed aza-Henry reaction.

observed when substituted nitromethane derivatives were

used as nucleophiles.

3.1.5. [4+2] Cycloaddition

A catalytic amount of taddol (95; 10 mol %) promotes the

hetero-Diels–Alder reaction of a variety of aldehydes and
dienes (Scheme 66).[186] The cycloadduct is formed as a single
Scheme 63. Enantioselective 1,4-addition of diethyl malonate to
diastereoisomer in > 98 % ee. Aryl aldehydes are particularly
b-nitrostyrene mediated by the bifunctional thiourea catalyst 93. effective dienophiles in this hetero-Diels–Alder reaction.

reaction center act in a synergistic manner. The tertiary amine

functionality has a significant effect on the reaction rate, but
only a slight effect on the enantioselectivity. Its precise
mechanistic role is not clear.

3.1.4. The Aza-Henry Reaction

The bifunctional thiourea derivative 93 also catalyzes the

reaction of nitroalkanes with activated imines to afford the
corresponding b-nitroamines (Scheme 64).[184] Noteworthy is

Scheme 66. Taddol-catalyzed asymmetric hetero-Diels–Alder reaction.

3.1.6. Hydrocyanation
3.1.6.1. The Asymmetric Strecker Reaction

Chiral peptidelike urea catalysts have been studied in

considerable detail.[187] Surprisingly, the same class of catalyst
can be used both in asymmetric cyanation reactions of
Scheme 64. Aza-Henry reaction with the bifunctional organocatalyst aldimines and methyl ketimines and in asymmetric Mannich
93. reactions of N-Boc aldimines with silyl ketene acetals.[188]
Oligopeptide-like catalysts were prepared and tested in
the hydrocyanation of N-benzyl and N-allyl aldimines and
that the thiourea and amine only have a synergistic effect in ketimines by a parallel-library approach.[189] Optimization of
this reaction if they are tethered. the structure of the catalyst led to the derivative 96 with a
The chiral Brønsted acid 94, formed from a 1:1 mixture of single amino acid unit (Scheme 67). This catalyst promotes
the quinoline bisamidine ligand and HOTf, accelerates the asymmetric addition of a silyl ketene acetal to N-Boc
considerably the addition of nitroalkanes to Boc-activated benzaldimine with 94 % ee.[188b]
aldimines at 20 8C (Scheme 65).[185] The enantioselectivity The reaction has remarkably broad generality: the same
and yield of the transformation are best for EWG-activated catalyst afforded the products in greater than 95 % ee for all
aldimine derivatives. High diastereoselectivities were aldimines examined, including substrates with aromatic sub-

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Reviews P. I. Dalko and L. Moisan

Scheme 67. The oligopeptide-like thiourea catalyst 96 for the

asymmetric Strecker reaction. The absolute configuration of the prod-
uct was not determined.

stituents and those with bulky (e.g. tert-butyl) or small (e.g. n- Scheme 68. The asymmetric vinylogous Mukaiyama aldol reaction.
pentyl) aliphatic substituents. Ketimines can also be used.
This degree of generality is still unusual in asymmetric
catalysis.
The mode of action of the catalysts in the Strecker
reaction has been investigated.[189a] A mechanism was pro-
posed based on the results of screening a library of catalysts
prepared by parallel synthesis. According to this model, an
imine–catalyst complex forms reversibly through the forma-
tion of a hydrogen bond between the nitrogen atom of the Z-
configured imine and the acidic protons of the urea. This
hypothesis is supported by the Michaelis–Menten kinetics of
the transformation, with a first order dependence on both the
catalyst and HCN, and saturation kinetics with respect to the
imine substrate. The interaction between the imine and the
catalyst in the complex was found to be stronger than the
classical hydrogen bond in catalyst–product complexes, thus
explaining the efficient catalyst turnover. An investigation of
the structure of the transition state showed which factors were
responsible for the high enantioselectivity of the reaction: Scheme 69. Asymmetric nitroaldol reaction of silyl nitronates with
The steric demands of the substituents flanking the imine aromatic aldehydes.
group should be markedly different, the substituent on the
nitrogen atom should favor the formation of the Z isomer of
the imine, and the additon of HCN should take place from the 3.2.3. Trifluoromethylation of Ketones
diaminocyclohexane side of the catalyst.
The cinchonine catalyst 99 was used in the enantioselec-
tive addition of a trifluoromethyl anion to aryl ketones
3.2. Ammonium Ions as Chiral Templates in Homogeneous (Scheme 70).[192] Although the reaction parameters are rem-
Catalytic Reactions iniscent of those of a phase-transfer reaction, the reaction
3.2.1. The Mukaiyama Aldol Reaction takes place under homogeneous conditions. The trifluoro-

Chiral ammonium fluorides, such as 97 (X = F), catalyze

the asymmetric vinylogous Mukaiyama aldol reaction with
modest efficiency (Scheme 68).[190] Surprisingly, the ammoni-
um hydroxide 97 (X = OH) was also found to mediate the
reaction in quantitative yield, albeit with less than 30 % ee.

3.2.2. Nitroaldol Reaction of Silyl Nitronates

The chiral ammonium fluoride salt 98 was engineered for

the asymmetric nitroaldol reaction of silyl nitronates with aryl
aldehydes.[191] High enantioselectivity and anti diastereose-
lectivity were observed when a 3,3’-substituted catalyst with Scheme 70. Enantioselective nucleophilic addition of a trifluoromethyl
bulky aryl substituents was used (Scheme 69). anion to a ketone mediated by the cinchonine catalyst 99.

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methyl anion is formed from CF3TMS by activation by the thesis.[124] The complementary activation with chiral Lewis
fluoride counter ion of the catalyst. Catalysts such as 99 with a bases is less common. The substrates in this reaction are
free hydroxy function afford products in near-quantitative halosilane derivatives; enantiomerically pure phosphora-
yield in the reaction shown in Scheme 70. The protection of mides, tartrates, 2-pyridinyloxazolines, formamides, urea
the free OH group of the cinchonine catalyst resulted in a derivatives, and axially chiral bis(heteroallyl) N,N’-dioxides
drastic decrease in reactivity. act as catalysts.

3.3.1.1. Chiral Phosphoramides

3.3. Activation of Lewis Acids by Lewis Bases[122]
Whereas chiral HMPA derivatives can activate allyl or
The concept of the activation of a Lewis acid by a Lewis propargyl tin compounds,[125] allyltrimethylsilane is unreac-
base may appear to contradict general chemical intuition, as tive. Allyltrichlorosilane, however, can be used for the
the reaction between a donor and an acceptor entity is allylation of aromatic and heteroaromatic aldehydes. Recent
expected to lead to the averaged rather than the polarized efforts have been directed towards the extension of the
electron density of the molecule. There are, however, well- reaction to aliphatic aldehydes. In these reactions chiral
defined circumstances under which charge separation may bidentate phosphoramides gave variable results; among
operate and lead to decreased electron density at a particular them, imidodiphosphoric tetramides were found to be
central atom. In these cases, electron transfer does not take suitable catalysts for the allylation of aryl aldehydes.[126]
place towards the central atom of the Lewis acid, but towards A systematic investigation of bisphosphoramides revealed
its peripheral ligands. Once the ligand is ionized the positive that the catalysts with a pentamethylene bridge between the
charge can be assigned to the central atom, thus translating two phosphoramide units were the most enantioselective.[127]
into enhanced Lewis acidity at this center. This phenomenon The optimization of the catalyst led to the bis(phosphora-
can also be considered as ligand-accelerated catalysis, mide) 100, with two 2,2’-bispyrrolidine substituents, which
whereby the acidity of the active center is considerably catalyzes the addition of allyltrichlorosilane, as well as (E)-
enhanced after complexation with the Lewis base.[123] and (Z)-2-butenyltrichlorosilane, to unsaturated aldehydes
with excellent diastereo- and enantioselectivities
(Scheme 71).[128] This method was also applied to the synthesis

This principle operates during activation by silicon halides

in the presence of catalytic amounts of chiral bases, such as
hexamethyl phosphoramide (HMPA) or pyridine N-oxide
derivatives, trialkylamines, and sulfoxides. Weak Lewis acids, Scheme 71. Asymmetric allylation of aryl aldehydes with the tethered
such as SiCl4 and RSiCl3, coordinate to these bases to give phosphoramide catalyst 100.
hypervalent silyl cations, which act as strong Lewis acids in a
chiral environment. An important advantage of this process is of compounds with quaternary stereocenters (R1,R2 = alkyl,
that the use of an excess of the weak, achiral Lewis acid does aryl).[128, 129] To illustrate its preparative value, it was also used
not compromise the enantioselectivity of the transformation in the synthesis of the serotonin antagonist LY426965.[129]
by participating in competing nonstereoselective background
reactions. This dual activation (the binding of the Lewis base 3.3.1.2. Chiral Pyridine N-Oxides
to the nucleophile and the formation of a reactive hyper-
coordinate silicon center, which coordinates to the electro- Amine N-oxides are good electron-pair donors, and this
phile) leads to high reaction rates and excellent transfer of property has been exploited in organocatalytic reactions in a
stereochemical information, because of the tight transition- chiral environment. In particular, chiral 2,2’-bipyridine N-
state structure. The catalytic cycle is made possible through oxides and N,N’-dioxides catalyze a broad range of asym-
the noncovalent interactions between the chiral Lewis base metric reactions.
and the chlorosilane substrate. The high degree of enantioselectivity observed in allyla-
tions with allyl silanes can be attributed to steric and p–p
3.3.1. Allylation and Propargylation Reactions interactions between the substrate and the bipyridine N-oxide
catalyst 101 or 102.[130] The best results were obtained with
The allylation of aldehydes with allyltrialkyl silanes in the pyridine N-oxide catalysts derived from ( )-b-pinene
presence of a chiral Lewis acid (the Sakurai–Hosomi reac- (pindox, dimethylpindox) or ( )-pinocarvone (iso-pindox;
tion) has had a considerable impact on asymmetric syn- Scheme 72).[131] The products were obtained in 10–85 % yield

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Reviews P. I. Dalko and L. Moisan

were observed in the allylation of N-acyl hydrazones when the

chiral sulfoxide catalyst 104 was used with allyltrichlorosilane
(Scheme 74).[134, 135]
Sulfoxides of oxazolines, such as 105, have been used as
bidentate ligands for metal catalysts in enantioselective

Scheme 72. Asymmetric allylation of aromatic aldehydes with chiral

2,2’-bipyridine-N-monoxide catalysts.

Scheme 74. Allylation of hydrazones in the presence of a chiral sufox-

and with up to 98 % ee. With both types of catalyst good ide catalyst.
diastereo- and enantioselectivities were observed in crotyla-
tion reactions with (E)- and (Z)-crotyltrichlorosilane,
although the use of iso-pindox led to better yields. Mecha- cyanohydrin synthesis.[136] In the absence of a metal, these
nistic analysis suggests that the N-oxide activates the tri- molecules are also able to mediate the enantioselective
chlorosilyl functionality and the other nitrogen atom stabil- allylation of aldehydes with allyltrichlorosilane with moder-
izes the complex by chelation, thus leading to a closed, chair- ate enantioselectivity (Scheme 75).[137] However, the catalytic
like transition state.[130a, d] Depending on the structure of the turnover is low, and a stoichiometric amount of the catalyst is
catalyst and the substrate, p–p or C H–p interactions were required.
also used to explain stabilization effects and the formation of
the compact transition state. The solvent has a major effect on
the reaction rate.
The symmetrical bidentate 2,2’-bipyridine N,N’-dioxide
103 has also been reported in the catalytic asymmetric
allylation of various activated electron-rich aromatic alde-
hydes (up to 98 % ee; Scheme 73).[132, 133] The selectivity of the

Scheme 75. Enantioselective allylation of benzaldehyde with allyltri-

chlorosilane in the presence of the chiral sulfoxide catalyst 105.

3.3.2. Aldol Reactions[25]

Bisphosphoramides also mediate the selective cross-

aldolization of aldehydes.[138] The geometrically defined
trichlorosilyl enolates of aldehydes undergo reaction with a
Scheme 73. Asymmetric allylation of aromatic aldehydes with the chiral variety of aromatic or a,b-unsaturated aldehydes to afford the
2,2’-bipyridine N,N’-dioxide 103 as the catalyst. cross-aldol products with high diastereo- and enantioselectiv-
ities. The mechanism of the transformation is similar to that
for allylation with the formation of a closed, chairlike
catalyst can be tuned by varying the substitution pattern of transition state centered around a hexacoordinated silicon
the pyridyl group. The best selectivity was observed with the atom (Scheme 76).
phenyl-substituted derivative 103. This result was explained With chiral phosphoramides as catalysts, a-oxygenated
by a p-stacking interaction between the substrate and the chiral ketone enolates react to give the 1,4-syn products in a
catalyst in the transition state of the stereodiscriminating step. highly diastereoselective manner.[139] The selectivity is dic-
tated by the substrate: Both internal and relative stereo-
3.3.1.3. Chiral Sulfoxides control is high even with the achiral HMPA analogue 107. The
diastereoselectivity can be only slightly improved by using the
Unlike P(O) or N(O) Lewis bases, which are excellent matched chiral catalyst 108 (Scheme 77).
catalysts in a number of reactions, chiral sulfoxides have The effect of the stereogenic center bearing the silyloxy
seldom been used. The catalytic turnover is generally low: substituent fades with increasing distance from the reaction
Synthetically useful yields were only observed when excess center. In the case of substrates with a b-silyloxy substituent,
sulfoxide was used. High diastereo- and enantioselectivities the chiral catalyst governs the diastereoselectivity in the

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 Angewandte
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Scheme 78. The effect of a remote substituent on the diastereoselectiv-

ity of the phosphoramide-catalyzed asymmetric aldol reaction of silyl
enolates.

Scheme 76. Enantioselective aldol reaction of silyl enolates catalyzed

by the chiral bisphosphoramide 106.

Scheme 79. Enantioselective aldol reaction of benzaldehyde with an

exo TMS enolate in the presence of a chiral bis(phosphoramide)
catalyst.

As in aminocatalysis, the enantioselective aldol addition

Scheme 77. The effect of the structure of the substrate on the of preformed enolates to ketone acceptors with phosphor-
diastereoselectivity of the phosphoramide-catalyzed asymmetric aldol
amide catalysts remains elusive. The difficulty in devising
reaction of silyl enolates.
such a reaction arises both from the attenuated reactivity of
the ketone and the smaller differences between the flanking
addition of a chiral enolate to an aldehyde (Scheme 78).[140] In substituents, making stereodifferentiation more difficult. The
these reactions the effect of the remote stereogenic center is addition of trichlorosilyl acetals of ketenes to ketones in the
low, and the internal diastereoselectivity is mainly controlled presence of the chiral bis-N-oxide catalyst 110 was described
by the catalyst. This result can be compared to aldol reactions recently (Scheme 80).[143] Good enantioselectivities were
of boron enolates in which 1,5-anti stereoinduction is observed with aromatic ketones (80–86 % ee), but the prod-
observed. ucts were only obtained with 20–41 % ee from aliphatic
Complementary studies on substrates with a small, non- ketones.
chelating substituent, such as a methyl group, in the proximity
of the reacting silyl enol ether showed that the configuration
of the newly formed stereogenic is determined principally by
the catalyst.[141]
High selectivities were observed in the addition of various
exo trimethylsilyl enolates to aromatic aldehydes in the
presence of the bisphosphoramide catalyst 106
(Scheme 79).[142] The protonolysis of the TMS enol ether,
which results in diminished conversion, was suppressed by the
addition of a small amount (10 %) of an amine base. Under
these conditions the reaction affords the desired b-hydroxy-
ketones in nearly quantitative yield with remarkable selec- Scheme 80. Asymmetric addition of a trichlorosilyl methyl ketene
tivity. Aliphatic aldehydes are unreactive under these con- acetal to aryl ketones in the presence of the chiral 2,2’-bipyridine N,N’-
ditions. dioxide derivative 110.

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Reviews P. I. Dalko and L. Moisan

3.3.3. Nucleophilic Catalysts for the Hydrocyanation of Imines

The axially chiral biquinoline N,N’-dioxide 111 was used

to promote the asymmetric Strecker reaction between aryl or
heteroaryl aldimines and trimethylsilyl cyanide
(Scheme 81).[144] The presence of electron-withdrawing sub-

Scheme 82. Intramolecular [2+2] photocycloaddition of an enone–

alkene catalyzed by the chiral molecular receptor 112.

phase systems, most commonly in vigorously stirred aqueous/

apolar solvent mixtures. An inorganic base, such as K2CO3 or
Cs2CO3, is used to form the reactive enolate. The role of the
Scheme 81. Enantioselective Strecker reaction between aldimines and catalyst is primarily that of an ion shuttle. Chiral nonracemic
trimethylsilyl cyanide mediated by the chiral 2,2’-bipyridine N,N’-diox- catalysts also act as templates to direct the approach of the
ide catalyst 111. reagent.
Phase-transfer reactions were initially carried out with
cinchona alkaloids. Recently, the enantioselectivities were
stituents on the aryl ring resulted in an increase in both the improved significantly by optimizing the catalyst structures,
yield and the enantioselectivity of the reaction. According to the reagent types, and the reaction conditions. Despite
the proposed transition-state model, a hypervalent silicon significant progress, however, low reactivity, in particular at
center forms through coordination of the biquinoline N,N’- low temperatures, as well as substrate incompatibility, are
dioxide catalyst to TMSCN. The hexacoordination at silicon commonly encountered problems. These disadvantages con-
results in enhanced nucleophilicity of the cyano group, which tinue to motivate the search for new efficient catalysts. Other
reacts with the aldimine in such way that the nitrogen atom of catalysts (usually C2 symmetric), both derived from natural
the aldimine coordinates simultaneously to the silicon atom. products and fully synthetic, are being developed. The ready
accessibility of phase-transfer catalysts and the mild exper-
imental conditions make asymmetric phase-transfer reactions
3.4. Chiral Sensitizing Receptors as Catalysts appealing both for academic research and for industrial
applications.
Until now preparative applications of enantioselective
transformations in photochemistry have been restricted to
photoreactions in which the chirality transfer is assured by a 4.1. Cinchona Alkaloids as Phase-Transfer Catalysts
stoichiometric amount of a chiral auxiliary or host,[193] such as
a chlathrate or chirally modified zeolite. Recently, it was Cinchona alkaloids were the first efficient phase-transfer
shown that even a substoichiometric amount (up to 25 mol %) catalysts for asymmetric catalysis, and the majority of the
of the photosensitizing receptor 112 mediated a photocy- most recent work is also dedicated to this class of catalysts.
cloaddition in quantitative yield and with 19 % ee Somewhat surprisingly, neither the electronic nor the steric
(Scheme 82).[194] In this system the synthetic receptor both factors that determine the enantioselectivity of this class of
assures a well-defined chiral environment upon binding to the catalysts are yet fully understood. Although the elucidation of
template and offers a highly selective energy transfer to the the structure of some salts of cinchona alkaloids in solution
substrate via a triplet exciplex. This transfer is efficient when was an important step toward the rational design of such
the lifetime of the exciplex is comparable to the rate of catalysts,[196] the development of the catalysts has been based
cyclization. mainly on empirical observations. It was recognized early that
the substituents on both the oxygen and the nitrogen atom of
the quinuclidine moiety of the cinchona alkaloids play a key
4. Enantioselective Phase-Transfer Reactions [195] role in the enantioselectivity.[197, 198] Whereas the influence of
the substitution pattern of the secondary alcohol is a matter of
Phase-transfer catalysis (PTC) is an attractive alternative controversy, it is clearly established that a bulky substituent at
for organic reactions in which charged intermediates are the quaternary nitrogen atom increases the enantioselectivity
involved. Reactions are usually carried out in two- or three- of the catalyst.

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 Angewandte
Organocatalysis Chemie

This observation initiated the synthesis of a number of N-

benzyl and N-antracenylmethyl derivatives, referred to gen-
erally as second- and third-generation catalysts. In alkylation
reactions O-allyl-N-anthracenylmethyl (third-generation)
catalysts are usually the most efficient cinchona-alkaloid
catalysts.[199, 200] These molecules can be prepared either by
multistep synthesis or, more conveniently, in situ.[201] The one-
pot procedure is particularly suitable for automated catalyst
screening. The catalysts perform well in alkylation reactions
with glycine-derived Schiff bases as substrates and in con-
jugate addition reactions with nitroalkanes and malonates.[201]
The selectivity of the catalyst can be improved by replacing
the vinyl side chain with an ethyl group. The substitution
pattern of the glycine derivative also has a major impact on
the stereoselectivity of the alkylation. Recent studies dem-
onstrated that the tert-butyl ester of the glycine reagent can be
advantageously replaced by a diphenylmethyl ester when the
catalyst 126 (Figure 14) is used.[202]
Phase-transfer alkylations are being used increasingly in
multistep synthesis. A key intermediate in the synthesis of the Scheme 84. Asymmetric synthesis of protected hydroxyornithine as an
ent-fragment of the potential antitumor agent belactosin A example of a substrate-controlled stereoselective alkylation.
was prepared through asymmetric phase-transfer catalysis.[203]
Whereas the (aminocyclopropyl)alanine enantiomer shown
was prepared by using the cinchonidinium bromide catalyst triscinchona[207] derivatives were prepared and tested (Fig-
113 (66 % yield, d.r. 97:3; Scheme 83). A similar strategy was ure 11).[7b, 208]
devised to prepare the caprolactam subunit of the antitumor The deprotonation of compounds with acidic hydrogen
agent bengamide.[204] atoms followed by an asymmetric transformation in the
presence of a cinchona alkaloid under phase-transfer con-

Figure 11. Bis- and triscinchonine derivatives as phase-transfer

catalysts. CD = cinchonidinium, HCD = hydrocinchonidinium.

ditions has been used in a number of related reactions, such as

Scheme 83. Synthesis of belactosin A through the asymmetric asymmetric deuteration, hydroxylation,[209] electrophilic fluo-
alkylation of a glycine derivative under phase-transfer conditions. rination,[210] isomerization of alkynes to chiral allenes,[212] and
the Darzens reaction,[211] to afford products with moderate to
good ee values. Asymmetric alkylation reactions in
It is often difficult to control the selectivity of the micelles[213] and on a solid support have also been reported.[214]
alkylation when one of the reagents possesses a stereocenter. The rate of alkylation reactions, Michael additions, and the
For example, in the synthesis of a protected hydroxyornithine epoxidation of enones under phase-transfer conditions could
derivative the selectivity of the alkylation was dictated by the be increased by ultrasonic irradiation.[215]
substrate rather than by the chiral catalyst, regardless of the Ammonium salts of cinchona alkaloids catalyze the
structure and the configuration of the latter (Scheme 84).[205] asymmetric epoxidation of activated olefins in the so-called
When achiral tetrabutylammonium bromide was used as the Weitz–Scheffer reaction. A range of enones were transformed
catalyst, roughly the same diastereoselectivity was observed into oxiranes under these conditions with either inorganic
as with the cinchonidine and cinchonine catalysts 113 and 114, oxidants, such as H2O2,[216] hypochlorite salts,[217] trichloroiso-
respectively. To enhance the catalyst activity, bis-[206] and cyanuric acid,[218] or chlorates,[219] or with organic perox-

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Reviews P. I. Dalko and L. Moisan

ides.[220] When the 1-phenyl hydroperoxide 120 was used as that their structure can be modified easily, thus allowing rapid
the oxidant in the asymmetric epoxidation of the isoflavon access to a variety of analogues.
117, the reaction also allowed the kinetic resolution of the The N-spiro biaryl catalysts are more active and often
oxidizing agent, albeit with modest enantioselectivity more selective than cinchona alkaloids in the alkylation of
(Scheme 85).[220] This relatively inefficient enantiodifferentia- glycine-derived Schiff bases; the fluorinated derivatives 122 c
tion is probably the consequence of a weak interaction and 122 d afforded excellent results (up to 99 % ee)
between the phase-transfer catalyst 118 and the hydroper- (Figure 12).[223] Good to excellent results were also obtained
oxide. with the symmetrical 4,4’,6,6’-binaphthyl-substituted catalyst
123 (up to 97 % ee).[224] Interestingly, not only glycine-derived
Schiff bases but also N-terminal oligopeptides can be
alkylated in a highly selective manner.[225]
Simplified catalysts, such as 124, with one of the two chiral
binaphthyl units replaced by a flexible achiral biphenyl
moiety, were also prepared (Figure 13). The catalyst design

Figure 13. The hetero- and homochiral conformations of N-spiroammo-

Scheme 85. Asymmetric epoxidation of the isoflavon 117 with a nium catalysts are in equilibrium.
parallel kinetic resolution of the hydroperoxide oxidizing agent 120.

relies on the concept of “induced atropisomerism”:[226] The

chirality of the binaphthyl group is magnified by the fact that
4.2. C2-Symmetric Phase-Transfer Catalysts the biphenyl group can adopt two interconverting conforma-
tions, which are either homo- or heterochiral relative to the
A considerable amount of work has been devoted to the conformation of the catalyst. The enantioselectivity of the
development of ammonium catalysts from either natural catalyst can be improved by increasing the steric hinderance
compounds, such as tartaric acid, or purely synthetic com- in the achiral biphenyl moiety near the quaternary nitrogen
pounds, such as 1,1’-(2,2’-binaphthol), for use in asymmetric atom.
phase-transfer reactions.[221–228] Among these catalysts, N- As an extension to this work, symmetrically 4,6-disubsti-
spiro biaryl derivatives, such as 122 and 123, lead to tuted atropisomeric N-spiro catalysts, such as 125, were also
remarkable selectivity and reactivity in a variety of reactions prepared (Scheme 86).[227] These catalysts mediate the alkyl-
(Figure 12).[222] A considerable advantage of this class of ation of glycine-derived Schiff bases with sterically less
compounds over other synthetic phase-transfer catalysts is

Scheme 86. Enantioselective alkylation of the Schiff base of tert-butyl

glycinate and benzophenone with the N-spiro biphenyl phase-transfer
catalyst 125. R2 = 1,1-dimethylbenzyl.

demanding electrophiles, such as allylic and propargylic

bromides, with high enantioselectivity (up to 97 % ee).
The non-atropisomeric biaryl catalyst 126 was also
Figure 12. Some N-spiro biaryl ammonium phase-transfer catalysts. prepared and tested in the alkylation of the glycine Schiff

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 Angewandte
Organocatalysis Chemie

base with alkyl halides (up to 97 % ee; Figure 14).[228] In this

system the additional chiral centers may enhance the
selectivity of the catalyst and can be modified for optimal
efficiency.

Scheme 87. Asymmetric Michael reaction catalyzed by the l-tartrate-

derived N-spiroammonium catalyst 129.

Figure 14. An asymmetric phase-transfer catalyst with a methylnaph-

thylammonium unit.

Tartrate-derived catalysts were also shown to be efficient

in mediating phase-transfer reactions. A series of phase-
transfer catalysts, such as 127 and 128, with two reactive
quaternary nitrogen centers were prepared and tested in
asymmetric alkylation and Michael addition reactions
(Figure 15).[229] The best results for the asymmetric alkylation
Scheme 88. Asymmetric alkylation with the guanidine derivative 130 as
a phase-transfer catalyst.

also be used for asymmetric PTC alkylation with a variety of

electrophiles (yields between 61 and 85 %, up to 90 % ee).[232]

4.3. Chiral Selectors and Phase-Transfer Agents

Figure 15. Tartrate-derived diammonium phase-transfer catalysts.
The design of chiral selectors is a novel concept for the
kinetic resolution of racemic molecules.[233] The phase-trans-
of the glycine Schiff base were obtained with the unsym- fer catalyst tetrahexylammonium bromide (THAB, 132)
metrical catalyst 127, whereas a C2-symmetric catalyst 128
was found to be more efficient in mediating Michael-type
additions. Surprisingly, the opposite stereoselectivity was
observed in the asymmetric alkylation to that observed in
the Michael addition. It was suggested that the catalyst
functions as a bifunctional catalyst and activates both the
nucleophile and the electrophile in the Michael addition. The
catalyst 127 was used in the synthesis of the serine protease
inhibitor aeruginosin 298-A.[230]
The spiroammonium catalyst 129 derived from l-tartrate
was tested in the Michael addition of a glycine Schiff base and
tert-butyl acrylate under phase-transfer conditions
(Scheme 87).[231] Diethyl ether and tert-butyl methyl ether
were found to be the best solvents for this reaction. The
product was formed in 73 % yield and with 77 % ee with the
trifluoromethylbenzyl-substituted catalyst (Scheme 87).
The structure of the C2-symmetric chiral pentacyclic
guanidine catalyst 130 was inspired by the marine natural
product ptilomycalin A (Scheme 88). The compound medi- Scheme 89. Enantioselective esterification of an N-acyl amino acid.
ates efficiently the enantioselective 1,4-addition of anions The phase-transfer catalyst is a system comprising the two compo-
derived from glycine esters to acrylates. The same catalyst can nents 131 and 132.

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Reviews P. I. Dalko and L. Moisan

transports both enantiomers of a polar molecule (for example,

a carboxylate anion) into the apolar phase, where it is
converted in the presence of a chiral selector (typically a
proline derivative, such as the N-acylated l-proline anilide
131) in an asymmetric transformation (such as esterification)
into an enantiomerically enriched product (Scheme 89). In
contrast to traditional phase-transfer catalysis the chiral
information is not present in the phase-transfer agent, but
in a separate compound, the chiral selector.
The concept has been used for acylation, nucleophilic
aromatic substitution, and the enantioselective hydrolysis of Scheme 90. Asymmetric epoxidation of trans-stilbene with oxone
catalyzed by the cyclodextrin ketoester 133.
esters. In the last two cases the basic principle is the same: The
chiral selector shields one of the two enantiomers from the
reaction through noncovalent interactions.
133 up to 40 % ee was observed. It was demonstrated by NMR
spectroscopic studies that the reaction proceeds via inclusion
5. Asymmetric Transformations in a Chiral Cavity complexes, at least for the substrates investigated.[236]

The selective recognition of substrates based on their

molecular structure by using engineered molecular cavities in 5.2. Molecular Imprinting[238, 239]
which a chemical transformation then takes place is a
technique modeled on the principle of enzyme catalysis. Molecular imprinting involves the formation of a struc-
The developing understanding of the mechanisms of enzyme ture, most often a polymer, around a molecular template.
catalysis, in particular the theory of transition-state stabiliza- When the template is removed by extraction a catalytic cavity
tion, has also served as a major source of inspiration for remains, which is characterized by both its shape and the
devising new structures and functions. This concept, however, arrangement of functional groups. This site can have a variety
emulates enzyme functions only partially. We now know that of properties engineered into it, ranging from the selective
other factors are also important for the acceleration of binding of specific molecules (molecular recognition) to
reactions by enzymes: Electrostatic effects, quantum- enzymelike catalysis. In addition to traditional applications
mechanical tunneling, coupled protein motion, low-barrier in chromatography, new applications in sensors and catalysis
hydrogen bonds, and near attack conformations enable are emerging.
enzymes to enhance reaction rates by a factor of up to Early efforts led to successful catalytic ester hydrolysis,
1020.[234] On the other hand, the mimicking of enzymes by and this area is still significant. By analogy with proteolytic
catalytically active polymers has a number of disadvantages biopolymers, the “catalytic triad” motif of serine, histidine,
related to the microstructure of the catalyst, such as and aspartic acid (as the carboxylate anion) present in the
accessibility, local solvation, and homogeneity of the catalytic serine protease enzyme family served as a model for catalyst
centers, and to the rigidity of the structure. When the design. l-Arginine with a guanidinium group also plays an
structure of the starting material is similar to that of the important role in catalyzing the basic hydrolysis of esters.
product the host–guest complex formed is often too stable, Recently, a wider range of reactions have been addressed,
thus resulting in product inhibition. Whereas enzyme cata- including C C bond-forming reactions. This progress was
lysts are capable of undergoing conformational changes to made possible by new and improved techniques, which have
release the product, the rigidity of artificial catalysts does not enhanced the quality of molecularly imprinted substances. In
allow efficient catalytic turnover. The development of systems parallel, innovative approaches to the design of receptors
for the dynamic release of products after the reaction is based on dynamic combinatorial libraries are emerging.[240]
therefore a promising area of further reasearch. Although shape-selective transformation also infers enantio-
discrimination, truly asymmetric transformations with
imprinted polymers remain scarce.[241]
5.1. Cyclodextrins and Calixarenes in Catalytic Asymmetric To mimic the catalytic triad of the active site of
Synthesis chymotrypsin, imidazole rings, phenolic hydroxy groups, and
carboxy groups were used as catalytically active groups.
Cyclodextrins and calixarenes can form inclusion com- Enantiomerically pure phosphonic acid monoesters, such as
plexes with a variety of guests, depending on size, structure, 135, were prepared as stable transition-state analogues and
and polarity. Nevertheless, little is known about the enzyme- used as templates (Scheme 91).[242] They were connected by
like catalytic activity of these substrates.[235] defined noncovalent interactions with the amidinium unit of
Scheme 90 shows, as an example, the asymmetric epox- the binding site. After polymerization and removal of the
idation of alkenes with the cyclodextrin-substituted ketoester template, the polymer 136 obtained mediated the hydrolysis
133.[236] Convalently modified cyclodextrins mimic cyto- of the nonactivated phenyl amino acid ester 137 with
chrome P450 in catalytic oxidations.[237] In the enantioselec- remarkable enantio- and substrate selectivity. The hydrolysis
tive epoxidation of styrene derivatives with 20–100 mol % of proceeded 80 times faster than with a control polymer

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 Angewandte
Organocatalysis Chemie

We thank Prof. Carlos F. Barbas

III, Prof. Eric N. Jacobsen, Prof.
Pavel Kočovský, Prof. Ben List,
Prof. Keiji Maruoka, Prof. Scott
Miller, and Prof. Alan C. Spivey
for the critical reading of the
manuscript and Dr. Michael
Gray for his help in the editing.

Received: January 19, 2004

[1] a) In many cases it is difficult to

define the boundary between
organometallic and purely
organic asymmetric catalysis.
Organometallic reactions, in
which a catalytic amount of an
organic ligand participates, are
not considered as organocata-
lytic reactions. The elements
that can be contained in
“organic” compounds can also
be decided arbitrarily, in par-
ticular for metalloid elements.
Scheme 91. Substrate-selective and enantioselective hydrolysis of a phenyl amino acid ester mediated by For example, according to gen-
a molecularly imprinted catalyst. eral consensus, silicon is not
considered to be a metal, but
boron is. On the other hand,
the absence of a metal is not an
absolute criterion: Thus, in phase-transfer reactions a metal ion
containing the same functionalities but prepared without the
(e.g. Na+, K+, Cs+) may play an indirect role through
template. Even more interesting was the relatively high association with the base. For this reason, in organocatalytic
enantioselectivity (a consequence of both selective binding reactions the “absence of metals” is more correctly considered
and selective formation of the transition state) observed in the within the context of the postulated “primary” catalytic cycle.
comparison of l and d substrates (catalytic efficiency = 1.65). b) This overview covers enantioselective reactions that were
described since our preceding account,[3a] between 2001 and
2004.
[2] S. Pizzarello, A. L. Weber, Science 2004, 303, 1151.
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631.
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[4] For reviews on enantioselective catalysis dealing partly with
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2004, 43, 4566 – 4583; f) “Special Feature: Asymmetric Catal-
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Angew. Chem. Int. Ed. 2004, 43, 5138 – 5175 www.angewandte.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5175