Catalysts

catalysts
Review
Review
Organocatalysis and Beyond: Activating Reactions
Organocatalysis
with andSpecies
Two Catalytic Beyond: Activating Reactions
with Two Catalytic Species
Arianna Sinibaldi 1, Valeria Nori 1, Andrea Baschieri 1, Francesco Fini 2, Antonio Arcadi 1 and
Armando Carlone 1,1*, Valeria Nori 1 , Andrea Baschieri 1 , Francesco Fini 2 , Antonio Arcadi 1
Arianna Sinibaldi
and Armando ofCarlone 1,
1 Department Physical *and Chemical Sciences, Università degli Studi dell’Aquila, via Vetoio,
1 67100 L’Aquila,
Department of Italy; arianna.sinibaldi@graduate.univaq.it
Physical and Chemical Sciences, Università(A.S.); valeria.nori@graduate.univaq.it
degli Studi dell’Aquila, via Vetoio, (V.N.);
andrea.baschieri@univaq.it (A.B.); antonio.arcadi@univaq.it (A.A.)
67100 L’Aquila, Italy; arianna.sinibaldi@graduate.univaq.it (A.S.); valeria.nori@graduate.univaq.it (V.N.);
2 Department of Life Sciences, Università degli Studi di Modena e Reggio Emilia, via G. Campi 103,
andrea.baschieri@univaq.it (A.B.); antonio.arcadi@univaq.it (A.A.)
2 41125 Modena,ofItaly;
Department francesco.fini@unimore.it
Life Sciences, Università degli Studi di Modena e Reggio Emilia, via G. Campi 103,
* Correspondence: armando.carlone@univaq.it;
41125 Modena, Italy; francesco.fini@unimore.it +39-0862-433-036
Correspondence:
*Received: armando.carlone@univaq.it;
18 October 2019; 2019;+39-0862-433-036
Accepted: 1 November Tel.: Published: date

Received: 18 October 2019; Accepted: 1 November 2019;organocatalysis
Published: 6 November 2019
Abstract: Since the beginning of the millennium, has been gaining a predominant
role in asymmetric synthesis and it is, nowadays, a foundation of catalysis. Synergistic catalysis,
Abstract: Since the beginning of the millennium, organocatalysis has been gaining a predominant
combining two or more different catalytic cycles acting in concert, exploits the vast knowledge
role in asymmetric synthesis and it is, nowadays, a foundation of catalysis. Synergistic catalysis,
acquired in organocatalysis and other fields to perform reactions that would be otherwise
combining two or more different catalytic cycles acting in concert, exploits the vast knowledge
impossible. Merging organocatalysis with photo-, metallo- and organocatalysis itself, researchers
acquired in organocatalysis and other fields to perform reactions that would be otherwise impossible.
have ingeniously devised a range of activations. This feature review, focusing on selected
Merging organocatalysis with photo-, metallo- and organocatalysis itself, researchers have ingeniously
synergistic catalytic approaches, aims to provide a flavor of the creativity and innovation in the area,
devised a range of activations. This feature review, focusing on selected synergistic catalytic approaches,
showing ground-breaking examples of organocatalysts, such as proline derivatives, hydrogen
aims to provide a flavor of the creativity and innovation in the area, showing ground-breaking
bond-mediated, Cinchona alkaloids or phosphoric acids catalysts, which work cooperatively with
examples of organocatalysts, such as proline derivatives, hydrogen bond-mediated, Cinchona alkaloids
different catalytic partners.
or phosphoric acids catalysts, which work cooperatively with different catalytic partners.
Keywords: organocatalysis; metallocatalysis; photocatalysis; synergistic; cooperative; asymmetric;
Keywords: organocatalysis; metallocatalysis; photocatalysis; synergistic; cooperative; asymmetric; catalysis
catalysis
1. Introduction
1. Introduction
The origins of asymmetric organocatalysis date back to the intuitive experiment of two remarkable
The origins of asymmetric organocatalysis date back to the intuitive experiment of two
scientists, Bredig and Fiske, during the first decade of the 1900s. They reported the first enantioselective
remarkable scientists, Bredig and Fiske, during the first decade of the 1900s. They reported the first
addition reaction of HCN to benzaldehyde 1 mediated by Cinchona alkaloids as organocatalyst [1]
enantioselective addition reaction of HCN to benzaldehyde 1 mediated by Cinchona alkaloids as
(Scheme 1).
organocatalyst [1] (Scheme 1).
Catalyst:
O OH N
HCN HO H
H * CN
Ia
1 2
N
Ia
Scheme 1.
Scheme Addition of
1. Addition of HCN
HCN to
to benzaldehyde
benzaldehyde 1, performed by
1, performed by Bredig
Bredig and
and Fiske.
Fiske.
In hindsight, the results obtained were a breakthrough as it was the first use of a small organic
molecule as a catalyst. For several reasons, however, asymmetric organocatalysis was not born;
Catalysts 2019, 9, x; doi: FOR PEER REVIEW www.mdpi.com/journal/catalysts
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Catalysts 2019, 9, x FOR PEER REVIEW 2 of 36
Catalysts 2019, 9, 928 2 of 35
In hindsight, the results obtained were a breakthrough as it was the first use of a small organic
molecule as a catalyst. For several reasons, however, asymmetric organocatalysis was not born; it was
it was probably only at the beginning of the new millennium that the field was mature enough to
probably only at the beginning of the new millennium that the field was mature enough to bloom.
bloom. This is testified by the fact that two ground breaking pioneers in the field of organic chemistry,
This is testified by the fact that two ground breaking pioneers in the field of organic chemistry,
Benjamin List [2] (Scheme 2a) and David MacMillan [3] (Scheme 2b), simultaneously reported two
Benjamin List [2] (Scheme 2a) and David MacMillan [3] (Scheme 2b), simultaneously reported two
different, albeit complementary, activations with aminocatalysts, giving birth to a “Gold Rush” in
different, albeit complementary, activations with aminocatalysts, giving birth to a “Gold Rush” in
organocatalysis [4]. In particular, their studies highlighted the possibility of carrying out asymmetric
organocatalysis [4]. In particular, their studies highlighted the possibility of carrying out asymmetric
reactions with organocatalysts based on enamine or iminium ion or activation.
reactions with organocatalysts based on enamine or iminium ion or activation.
Scheme 2. (a) Ketone activation via aminocatalysis, performed by List; and (b) aldehyde activation via
Scheme 2 (a) Ketone activation via aminocatalysis, performed by List; and (b) aldehyde activation via
aminocatalysis, performed by MacMillan.
aminocatalysis, performed by MacMillan.
The main advantage of using organocatalysts derives from their user-friendliness: No anhydrous
The main
conditions advantage
are required; they ofare using
highly organocatalysts
stable in a broad derives from their user-friendliness:
range of temperatures and in most common No
anhydrous conditions are required; they are highly stable in a broad range of
chromatographic and reaction conditions; and moreover, their waste disposal operation has a lower temperatures and in
most common impact
environmental chromatographic
respect to otherandcatalysts.
reaction conditions; and moreover, their waste disposal
operation
Inspired by this new technology platform,respect
has a lower environmental impact severaltoscientists
other catalysts.
discovered a large variety of catalysts,
Inspired by this new technology platform,
which directly came from the chiral pool or undergo synthetic several scientists discovered
modifications a large analogous
to generate variety of
catalysts,
compounds which directlyimpacting
positively came from thethe chiral pool
economy of theor entire
undergo synthetic
process, thanksmodifications to generate
to the availability and
analogous compounds positively
affordability of the starting materials [5].impacting the economy of the entire process, thanks to the
availability and affordability
An incredible of the startingcapable
range of organocatalysts materials [5].
of promoting enantioselective reactions were found,
An incredible
enabling range of
transformations organocatalysts
thanks capable of promoting
to different activations, via iminium enantioselective
ion or enaminereactions
activationwere
[6],
found, enabling transformations thanks to different activations, via iminium
via protonation or deprotonation (chiral basic [1] or acidic catalysts [7]), coordination via hydrogen ion or enamine
activation
bond [8,9],[6],
andvia
viaprotonation or deprotonation
steric hindrance (chiral
[6,10,11] (Figure basic
1). The [1] or acidicofcatalysts
combination [7]), activations
the different coordinationin
via hydrogen bond [8,9], and via steric hindrance [6,10,11] (Figure 1). The combination of
one catalyst to interact with different reaction partners is noteworthy; a bifunctional, or multifunctional, the different
activations
catalyst is ainmolecule
one catalystwhichto interact
exhibitswith
moredifferent
than one reaction partners
functional groupis noteworthy; a bifunctional,
capable of interacting and
or multifunctional, catalyst is a molecule which exhibits more
orientating with two different substrates during a catalytic process [12]. than one functional group capable of
interacting and orientating with two different substrates during a catalytic process [12].
Catalysts 2019, 9, 928 3 of 35
Figure 1. Different methods of substrate activation.

Figure 1. Different methods of substrate activation.
With the purpose of imitating the perfect performance of enzymes, chemists began to synthesize a
With the purpose of imitating the perfect performance of enzymes, chemists began to synthesize
few bifunctional catalysts able to bring together the different reaction partners.
a few bifunctional catalysts able to bring together the different reaction partners.
These compounds have different multiple catalytic sites spaced out by a linker or spacer, which
These compounds have different multiple catalytic sites spaced out by a linker or spacer, which
confer to its structure a proper dimension, rigidity and geometry in order to perform the reaction in a
confer to its structure a proper dimension, rigidity and geometry in order to perform the reaction in
stereoselective way. The benefit of this modus operandi is directly linked to entropic energy: keeping
a stereoselective way. The benefit of this modus operandi is directly linked to entropic energy:
the activated reacting partners in proximity and orientating them in a specific way to obtain the desired
keeping the activated reacting partners in proximity and orientating them in a specific way to obtain
product with stereocontrol.
the desired product with stereocontrol.
A remarkable deficiency of this process is correlated to the many synthetic steps needed to obtain
A remarkable deficiency of this process is correlated to the many synthetic steps needed to obtain
these catalysts. As an alternative and complementary approach, some research groups focused on
these catalysts. As an alternative and complementary approach, some research groups focused on
synergistic catalysis, a relatively new technology platform which allows the simultaneous activation of
synergistic catalysis, a relatively new technology platform which allows the simultaneous activation
both reaction partners by two distinct catalytic cycles. The reduction of the ∆E(HOMO-LUMO) causes
of both reaction partners by two distinct catalytic cycles. The reduction of the ΔE(HOMO-LUMO)
a substantial decrease in the activation energy of the desired reaction, which increases the constant rate
causes a substantial decrease in the activation energy of the desired reaction, which increases the
driving the desired pathway compared to possible side reactions (Figure 2).
constant rate driving the desired pathway compared to possible side reactions (Figure 2).
Figure 2. Synergistic catalysis.

Figure 2. Synergistic catalysis.
The activated species can rapidly react, making reactions possible that would otherwise be
inefficientactivated
The species canwith
or even impossible rapidly react, making
traditional reactions
mono-catalysis possible The
methods. thatreaction
would otherwise
between two be
inefficient or even impossible with traditional mono-catalysis methods. The reaction
intermediates present in low sub-stoichiometric concentrations should be, in principle, difficult; between two
intermediates
however, present kinetic
considering in low aspects,
sub-stoichiometric
the reactionconcentrations should be,
between two activated in principle,should
intermediates difficult;
be
however, considering kinetic aspects, the reaction between two activated intermediates
promising due to the narrowing of the HOMO-LUMO, which causes a large decrease in the activation should be
promising due to the narrowing of the HOMO-LUMO, which causes a large decrease
energy and, as a consequence, increases the rate constant to drive the desired synthetic pathway. in the activation
energy and,nature
While as a consequence,
takes advantageincreases the rate separation
from physical constant tobetween
drive thecatalytic
desiredmoieties
syntheticinpathway.
the enzymes
While nature takes advantage from physical separation between catalytic
active sites, a synergistic catalytic system could undergo self-quenching, rendering both catalysts moieties in the
enzymes active sites, a synergistic catalytic system could undergo self-quenching, rendering
inactive. For this reason, research groups interested in catalysis involving two or more catalytic cycles both
catalysts
which actinactive. For thisneed
in cooperation, reason, research
to select groups interested
the catalysts combination in catalysis involving
judiciously. two catalysis
Synergistic or more
catalytic cycles which act in cooperation, need to select the catalysts combination judiciously.
opens the possibility to screen several combinations of a wide range of catalysts for a particular reaction.
Synergistic
In catalysis
this scenario, opens the
synergistic possibility
catalysis to screen
attracted several
increasing combinations
interest of a wide
in the academic range of catalysts
community.
for aInparticular
this reviewreaction.
we willInfocus
this on
scenario,
selected synergistic
strategies catalysis
and reportsattracted increasing
that exploit interest
synergistic in the
catalysis
academic community.
with disrupting innovation; the cooperation of organocatalysts with other catalytic species of different
In this
nature, suchreview we will
as organo-, focus
metal- or on selected strategies
photo-catalysts, and
will be reports that exploit synergistic catalysis
discussed.
with disrupting innovation; the cooperation of organocatalysts with other catalytic species of
different nature, such as organo-, metal- or photo-catalysts, will be discussed.
Catalysts 2019, 9, 928 4 of 35
2. Proline-Derivatives Catalysis
2. Proline-Derivatives Catalysis
Proline is the only natural α-amin oacid with a secondary amine; its nitrogen, part of the
Proline is the only natural α-amin oacid with a secondary amine; its nitrogen, part of the pyrrolidine
pyrrolidine heterocycle, has an increased pKa with respect to other amin oacids. Thanks to the
heterocycle, has an increased pKa with respect to other amin oacids. Thanks to the carboxylic acid
carboxylic acid moiety, proline can also behave as a bifunctional catalyst: The nitrogen can act as a
moiety, proline can also behave as a bifunctional catalyst: The nitrogen can act as a Lewis base while
Lewis base while the carboxylate portion as a general Brønsted acid. Following condensation of the
the carboxylate portion as a general Brønsted acid. Following condensation of the nitrogen with
nitrogen with carbonyl compounds, proline activates reagents via the corresponding enamine or
carbonyl compounds, proline activates reagents via the corresponding enamine or iminium ion [2].
iminium ion [2]. Proline can be used to functionalise α,β-unsaturated aldehyde 9 with nucleophiles,
Proline can be used to functionalise α,β-unsaturated aldehyde 9 with nucleophiles, via iminium ion,
via iminium ion, or saturated aldehydes 10 with electrophiles via enamine (Scheme 3). When proline
or saturated aldehydes 10 with electrophiles via enamine (Scheme 3). When proline itself is used as a
itself is used as a catalyst, the carboxylic moiety will aid in imparting stereoselectivity by orienting
catalyst, the carboxylic moiety will aid in imparting stereoselectivity by orienting the approaching
the approaching reaction partner via an intermolecular hydrogen bond.
reaction partner via an intermolecular hydrogen bond.
Scheme 3. Proline activation modes: (a) via iminium ion, (b) via enamine.
Scheme 3. Proline activation modes: (a) via iminium ion, (b) via enamine.
To improve enantioselectivity and to expand the applicability of proline beyond H-bond acceptors,
To derivatives
proline improve enantioselectivity and to expand
bearing steric hindered groups, the applicability
or longer of proline
alkyl chains werebeyond
preparedH-bond
[6,9].
acceptors, proline derivatives bearing steric hindered groups, or longer alkyl chains
Catalytic equivalents of proline, such as imidazolidinone-based MacMillan catalysts or prolinamides were prepared
[6,9]. Catalytic
derivatives, also equivalents
proved extremelyof proline, such[3,4].
successful as imidazolidinone-based MacMillan catalysts or
prolinamides
Proline and its derivatives effectively catalyze asuccessful
derivatives, also proved extremely multitude[3,4].
of reactions; an interesting example is the
asymmetric intramolecular aldol reaction, a breakthroughareport
Proline and its derivatives effectively catalyze multitude of reactions; an interesting example
by Hajos-Parrish-Eder-Sauer-Wiechert [13,14].
is the asymmetric intramolecular aldol reaction, a breakthrough report by Hajos-Parrish-Eder-Sauer-
This reaction was used by two distinct industrial research groups who discovered a synthetic strategy to
Wiechert
obtain [13,14].
a very Thisintermediate
versatile reaction was in used bysynthesis,
organic two distinct industrial researchketone
the Wieland–Miescher groups who discovered
[15].
a synthetic strategy to obtain a very versatile intermediate in organic synthesis,
Proline was also used in asymmetric synthesis to obtain compounds of natural or pharmacological the Wieland–
Mieschersuch
interest, ketone [15]. [16], or eritromicine antibiotics [17]. It was also exploited in different and more
as steroids
Proline was also used
versatile reaction pathways, suchinas asymmetric
the cyclisationsynthesis
of racemictodiketones
obtain [18],
compounds ofKnoevenagel
or to effect natural or
pharmacological
condensation interest,
[19,20], such reactions,
Mannich as steroidsand[16], or eritromicine
many more [21]. antibiotics [17]. It was also exploited
in different and more versatile reaction pathways, such as the cyclisation of racemic diketones [18],
or toSynergistic
2.1. effect Knoevenagel condensation
Catalysis with [19,20],
Proline-Based Mannich reactions, and many more [21].
Catalysts
2.1.1. Combination with Transition Metal-Based Catalysts

The combination of transition metal catalysis and organocatalysis gained increasing recognition,
improving several reactions [22]. One of the first groundbreaking examples of metal- and
organo-catalysis working in concert was reported by the Cordova research group in 2006 [23].
2.1. Synergistic Catalysis with Proline-Based Catalysts
2.1. Synergistic Catalysis with Proline-Based Catalysts
The combination of transition metal catalysis and organocatalysis gained increasing recognition,
The
Catalysts combination
2019, 9, 928 of transition metal catalysis and organocatalysis gained increasing recognition, 5 of 35
improving several reactions [22]. One of the first groundbreaking examples of metal- and organo-
improving several reactions [22]. One of the first groundbreaking examples of metal- and organo-
catalysis working in concert was reported by the Cordova research group in 2006 [23]. They proposed
catalysis working in concert was reported by the Cordova research group in 2006 [23]. They proposed
a direct
They catalytic
proposed allylic
a direct alkylation
catalytic ofalkylation
allylic aldehydesofand cyclic and
aldehydes ketones.
cyclicThe intermolecular
ketones. α-allylic
The intermolecular
a direct catalytic allylic alkylation of aldehydes and cyclic ketones. The intermolecular α-allylic
alkylation
α-allylic reaction,reaction,
alkylation which which
has the hasadvantage of being
the advantage highly
of being chemo-
highly chemo-and andregio-selective,
regio-selective, was
alkylation reaction, which has the advantage of being highly chemo- and regio-selective, was
performed through an unprecedented combination of palladium and enamine mediated catalysis. catalysis.
performed through an unprecedented combination of palladium and enamine mediated catalysis.
They described the reaction of 3-phenylpropionaldehyde (11, 3 equiv.)
They equiv.) with allyl acetate (12, 11 equiv.)
equiv.)
They described the reaction of 3-phenylpropionaldehyde (11, 3 equiv.) with allyl acetate (12, 1 equiv.)
in the presence
presenceof ofaacatalytic
catalyticamount
amountofof palladium catalyst
palladium [Pd(PPh
catalyst [Pd(PPh3)4] (5
) mol%)
] (5 and
mol%) pyrrolidine
and VIII
pyrrolidine
in the presence of a catalytic amount of palladium catalyst [Pd(PPh3)4] 3(54 mol%) and pyrrolidine VIII
(10 mol%)
VIII in dimethyl
(10 mol%) sulfoxide
in dimethyl at room
sulfoxide temperature.
at room The corresponding
temperature. The corresponding α-benzylic alcohol
α-benzylic 14 was
alcohol 14
(10 mol%) in dimethyl sulfoxide at room temperature. The corresponding α-benzylic alcohol 14 was
isolated
was in 72%
isolated in 72%yield after
yield 16 16
after h byh byreduction
reductionwith
withNaBH
NaBH 4 ofofthe
the α-allylic
α-allylic alkylated
alkylated aldehyde 13
isolated in 72% yield after 16 h by reduction with NaBH4 4of the α-allylic alkylated aldehyde 13
(Scheme
(Scheme 4). 4).
(Scheme 4).
Scheme 4. Synergistic catalysis mediated by palladium and pyrrolidine.

pyrrolidine.
Scheme 4. Synergistic catalysis mediated by palladium and pyrrolidine.
Merging two
two powerful
powerfulcatalytic
catalyticcycles
cyclesenables
enables both
both electrophilic
electrophilic and and nucleophilic
nucleophilic activation.
activation. As
As Merging
depicted two powerful
in Scheme 5, the catalytic
C–C bond cycles enables both
formationisisallowedelectrophilic
allowedby bythe and
thecatalyticnucleophilic
catalyticenamine activation.
enamine intermediate As
intermediate 11a
depicted in Scheme 5, the C–C bond formation
depicted ininScheme
generated 5, theattacks
situ, which C–C bond formation isgenerated
the catalytically allowed by the catalytic
electrophilic enamineπ-allyl
palladium intermediate 11a
π-allyl complexes
generated in situ, which attacks the catalytically generated electrophilic intermediate
palladium π-allyl complexes
12a. Reductive elimination and subsequent hydrolysis of the iminium
12a. iminium intermediate regenerates the
12a. Reductive elimination
Pd(0) and the amine catalyst and subsequent hydrolysis of the iminium intermediate regenerates the
VIII, and
catalyst VIII, and yields
yields the α-allylic alkylated
the α-allylic alkylated aldehyde
aldehyde 13.
13.
Pd(0) and the amine catalyst VIII, and yields the α-allylic alkylated aldehyde 13.
Scheme 5. Mechanistic insight in synergistic palladium and pyrrolidine-based

pyrrolidine-based catalysis.
catalysis.
Scheme 5. Mechanistic insight in synergistic palladium and pyrrolidine-based catalysis.
The reaction proved to work smoothly with a range of aldehydes 15 (Scheme 6a) and ketones 18
(Scheme 6b) with high chemoselectivity. Unfortunately, the catalytic asymmetric variant provided
the α-allylic alkylated alcohol 17 or ketone 19 with high enantioselectivity, but in moderate yields
(yields 25% and 20%, ee 74% and 88%, respectively).
the α-allylic alkylated alcohol 17 or ketone 19 with high enantioselectivity, but in moderate yields
Catalysts 2019, 9,alkylated
the α-allylic 928 6 of 35
alcohol 17 or ketone 19 with high enantioselectivity, but in moderate yields
Scheme 6. General
Scheme 6. General α-allylation
α-allylation of
of aldehydes
aldehydes (a)
(a) or
or ketones
ketones (b) via synergistic
(b) via synergistic catalysis
catalysis mediated
mediated by
by
Scheme 6. General α-allylation of aldehydes (a) or ketones (b) via synergistic catalysis mediated by
palladium and pyrrolidine.
Since then, several synergistic catalytic approaches based on transition metal catalysis and
Since then, several synergistic catalytic approaches based on transition metal catalysis and
aminocatalysis were developed. Prompted by the great results obtained through synergistic catalysis
aminocatalysis were developed. Prompted by the great results obtained through synergistic catalysis
and their growing interest in natural product-like
product-like compound
compound synthesis
synthesis [24–26].
[24–26]. Wu
Wu et al. described a
and their growing interest in natural product-like compound synthesis [24–26]. Wu et al. described a
novel and promising one-pot combination of silver triflate and proline catalysis provided an efficient
novel and promising one-pot combination of silver triflate and proline catalysis provided an efficient
route for the
the synthesis
synthesisof
of1,2-dihydroisoquinoline
1,2-dihydroisoquinolinederivatives
derivatives2222via multicomponent
via multicomponent reactions of of
reactions 2-
route for the synthesis of 1,2-dihydroisoquinoline derivatives 22 via multicomponent reactions of 2-
alkynylbenzaldehydes
2-alkynylbenzaldehydes 20,20,
amines 21,21,
amines and ketones
and ketones1818
[27] (Scheme
[27] (Scheme7).7).
alkynylbenzaldehydes 20, amines 21, and ketones 18 [27] (Scheme 7).
Scheme 7.
Scheme Synergistic catalysis
7. Synergistic catalysis mediated
mediated by
by silver-based
silver-based and
and proline
proline catalysis.
catalysis.
Scheme 7. Synergistic catalysis mediated by silver-based and proline catalysis.
Merging two
Merging two powerful
powerful catalytic
catalytic cycles
cycles enables
enables both
both electrophilic
electrophilic and and nucleophilic
nucleophilic activation.
activation.
The Merging
mild metal twoLewis
powerful acids catalytic
tested, cycles
such enables
as silver,both electrophilic
coordinate the and nucleophilic
triple bond of activation.
the starting
The mild metal Lewis acids tested, such as silver, coordinate the triple bond of the starting 2-
The mild metal
2-alkynylbenzaldehyde Lewis acids
20, tested,
making itsuch
more as silver, coordinate
electrophilic, while the triple
proline bond of
simultaneously the starting
generates 2-
alkynylbenzaldehyde 20, making it more electrophilic, while proline simultaneously generates the
alkynylbenzaldehyde
the nucleophilic enamine 20, intermediate.
making it more electrophilic, while proline simultaneously generates the
nucleophilic enamine intermediate.
nucleophilic enamine
Together with intermediate.
Together with silver,
silver, gold
gold was
was used
used asas the
the metal
metal partner.
partner. The
The first
first example
example of of Au(I)-enamine
Au(I)-enamine
Together
synergistic with silver,
catalysis was gold wasinused
reported 2008 as
by the metal
Kirsh et partner.
al. [28]. Theauthors
The first example
performedof Au(I)-enamine
a cyclisation
synergistic catalysis was reported in 2008 by Kirsh et al. [28]. The authors performed a cyclisation of
synergistic
of the alkynecatalysis
aldehydeswas23 reported
to 24 orin252008 by Kirsh
providing et al. [28].
racemic The authors
products with performed
excellent yieldsa cyclisation
(Scheme 8a). of
8a).
the alkyne aldehydes 23 to 24 or 25 providing racemic products with excellent yields (Scheme
the
The alkyne aldehydes
proposed mechanism 23 to
mechanismfeatures 24 or 25 providing
featuresa asimultaneous racemic
simultaneous products
enamine with
formation excellent
at the yields
terminal (Scheme 8a).
aldehyde
The proposed enamine formation at the terminal aldehyde and
The proposed
and a π-acid mechanism
activation features
at the a simultaneous
triple bond. Thisenamine
protocol,formation
however, at the terminal
comes with aldehyde
an and
inherent
a π-acid activation at the triple bond. This protocol, however, comes with an inherent challenge: If R
a π-acid activation
challenge: If R is at the
H, the triple bond. This protocol,
Au(I)-catalysed cyclisation however,
results comes
in an with an inherent
exocyclic terminal challenge:
alkene If R
after
is H, the Au(I)-catalysed cyclisation results in an exocyclic terminal alkene after protodeauration,
is H, the Au(I)-catalysed
protodeauration, cyclisation
which isomerizes
spontaneously results in
isomerizes an exocyclic terminal
to the thermodynamically alkene after protodeauration,
which spontaneously to the thermodynamically more stablemore stable compound
compound 25. This
which
25. This spontaneously
isomerization isomerizes
removes the to
new the thermodynamically
stereogenic center more
created stable
during the compound
carbon-carbon 25. bond
This
isomerization removes the new stereogenic center created during the carbon-carbon bond formation
isomerization
formation removes the new stereogenic center created during the carbon-carbon bond formation
step. If R isstep. If R isgroup,
a methyl a methyl group, a quaternary
a quaternary stereocenterstereocenter
bearing productbearing 24 product
is created 24in is up
created
to 72%in
step.
up to If72%
R isyield.
a methyl group, a quaternary
An enantioselective versionstereocenter bearing
of this reaction wasproduct 24 is created
later reported in up to et
by Jørgensen 72%al.
(Scheme 8b) [29]. They exploited the sterically bulky Jørgensen-Hayashi catalyst X to induce the attack
of 26 to an α,β-unsaturated aldehyde 9 via iminium-ion activation. The first Michael addition creates
yield. An enantioselective version of this reaction was later reported by Jørgensen et al. (Scheme 8b)
[29]. They exploited the sterically bulky Jørgensen-Hayashi catalyst X to induce the attack of 26 to an
α,β-unsaturated aldehyde
Catalysts 2019, 9, x FOR 9 via iminium-ion activation. The first Michael addition7 creates
PEER REVIEW of 36 an
intermediate, which undergoes synergistic enamine/Au(I) catalysis to obtain the carbocyclisation
Catalysts 2019, 9, 928 7 of 35
yield. An enantioselective version of this reaction was later reported by Jørgensen et al. (Scheme 8b)
reaction with high enantio-enrichment of 28 in good to excellent yields.
[29]. They exploited the sterically bulky Jørgensen-Hayashi catalyst X to induce the attack of 26 to an
α,β-unsaturated
an intermediate, aldehyde
which 9 via iminium-ion
undergoes activation. The catalysis
synergistic enamine/Au(I) first Michael addition
to obtain creates an
the carbocyclisation
intermediate,
reaction with highwhich undergoes synergistic
enantio-enrichment of 28 enamine/Au(I) catalysis
in good to excellent to obtain the carbocyclisation
yields.
reaction with high enantio-enrichment of 28 in good to excellent yields.
Scheme 8. General α-allylation of aldehydes (a) or ketones (b) via synergistic catalysis mediated by
Scheme
palladium8. General
Scheme and
α-allylation
pyrrolidine.
8. General
of aldehydes (a) or ketones (b) via synergistic catalysis mediated by
α-allylation of aldehydes (a) or ketones (b) via synergistic catalysis mediated by
palladium and
palladium pyrrolidine.
and pyrrolidine.
Inspired by
Inspired by metal-associated
metal-associated enzymes,
enzymes, Kudo’s
Kudo’s research group designed
research group designed aa biomimetic
biomimetic catalysis,
catalysis,
exploitingInspired
the by metal-associated
cooperation of a enzymes, Kudo’s
resin-supported research
peptide group
catalyst designed
and a
Fe-basedbiomimetic
metal catalysis,
catalyst.
exploiting thethe
exploiting cooperation
cooperationofofaaresin-supported peptide
resin-supported peptide catalyst
catalyst andand Fe-based
Fe-based metal
metal catalyst.
catalyst.
The combination
The of theofpeptide
combination the containing
peptide polyleucine
containing and FeCl
polyleucine and2 in two catalytic cycles was highly
FeCl in two catalytic cycles was
The combination of the peptide containing polyleucine and FeCl2 in two catalytic2 cycles was highly
efficient
highly to allow
efficient to the asymmetric
allow the oxyamination
asymmetric of aldehydes
oxyamination of in aqueous
aldehydes in mediamedia
aqueous [30] (Scheme
[30] 9). 9).
(Scheme
efficient to allow the asymmetric oxyamination of aldehydes in aqueous media [30] (Scheme 9).
Scheme 9. Synergistic iron- and peptide-mediated catalysis.

The oxyamination of 3-phenylpropanal 11 is performed with TEMPO 29 using iron(III) chloride
The oxyamination of 3-phenylpropanal 11 is performed with TEMPO 29 using iron(III) chloride
inThe
the oxyamination
presence of theofpeptide catalyst. The 11
3-phenylpropanal reaction is carriedwith
is performed out TEMPO
in THF/H29 2O using
1/2 (v/v) at room
iron(III) chloride
in the presence of the peptide catalyst. The reaction is carried out in THF/H2 O 1/2 (v/v) at room
temperature;
in the presence increasing the amount
of the peptide of water
catalyst. The in the system
reaction THF/H2out
is carried O from 1/1 to 1/2
in THF/H 2O increases
1/2 (v/v)the
at room
temperature;
hydrophobic increasing
effect and the amount
causes an of waterofin
acceleration the the system
desired THF/H
product 2 O from
formation. 1/1
The to results
best 1/2 increases
were the
temperature; increasing the amount of water in the system THF/H2O from 1/1 to 1/2 increases the
hydrophobic effect and causes an acceleration of the desired product formation. The best
obtained by introducing a polyleucine chain between the terminal prolyl residue of peptide catalyst results were
hydrophobic effect and causes an acceleration of the desired product formation. The best results were
obtained
and itsby introducing
support. a polyleucine
This structural changechain between
enhances the terminal
the reaction prolyl
rate and residue
increases of peptide catalyst and
the enantioselectivity
obtained by introducing a polyleucine chain between the terminal prolyl residue of peptide catalyst
its support.
[31]. This structural change enhances the reaction rate and increases the enantioselectivity [31].
and its support. This structural change enhances the reaction rate and increases the enantioselectivity
Following studies showed that the amount of iron(III) chloride could be decreased to catalytic
[31].
amount using dioxygen as the oxidant [32]. The best improvement is achieved by performing the
reaction with iron(II) chloride under an air atmosphere; the oxyaminated product is obtained within 1 h,
without using an oxidazing agent. This reaction system proved to be efficient enough that the loading
Following studies showed that the amount of iron(III) chloride could be decreased to catalytic
Catalysts
amount2019, 9, 928
using dioxygen as the oxidant [32]. The best improvement is achieved by performing 8 of 35
the
reaction with iron(II) chloride under an air atmosphere; the oxyaminated product is obtained within
1 h, without using an oxidazing agent. This reaction system proved to be efficient enough that the
of the peptide catalyst could be reduced to 3 mol% without any loss in yield and enantioselectivity,
loading of the peptide catalyst could be reduced to 3 mol% without any loss in yield and
by increasing the reaction time.
enantioselectivity, by increasing the reaction time.
Based on this concept, in 2018 Rios et al. reported the first synergistic organocascade reaction for
Based on this concept, in 2018 Rios et al. reported the first synergistic organocascade reaction for
the synthesis of cyclopropanes 32 with an unusual cis configuration between the benzoxazole and the
the synthesis of cyclopropanes 32 with an unusual cis configuration between the benzoxazole and
substituted phenyl ring with good yields and steroselectivities [33] (Scheme 10).
the substituted phenyl ring with good yields and steroselectivities [33] (Scheme 10).
Scheme 10. Synergistic catalysis mediated by palladium and Jørgensen-Hayashi catalyst.

Scheme 10. Synergistic catalysis mediated by palladium and Jørgensen-Hayashi catalyst.
The reaction proceeds via a simultaneous organocatalytic activation of enals with a secondary
amine The reaction
catalyst andproceeds
the metalviaLewis
a simultaneous
acid-basedorganocatalytic activation ofthe
activation of benzoxazoles; enals with a secondary
stereocontrol in this
amine catalyst and the metal Lewis acid-based activation of benzoxazoles; the stereocontrol
protocol is imparted by the chiral organocatalyst, thus avoiding the need of expensive chiral ligands in this
protocol is imparted
for the metal. by the chiral
The palladium organocatalyst,
catalyst coordinates thus
to theavoiding
nitrogenthe need
atom of of
theexpensive chiral
heterocycle, ligands
increasing
for the metal. The palladium catalyst coordinates to the nitrogen atom of the heterocycle,
the acidity of the adjacent alkyl chain, while the Jørgensen-Hayashi catalyst X activates the enals,increasing
the acidity of
generating an the adjacent alkyl
electrophilic chain, while
iminium-ion the Jørgensen-Hayashi
intermediate; catalyst
these two species can Xthen
activates the enals,
react rapidly to
generating
generate a newan electrophilic
C–C bond iniminium-ion intermediate;
the cyclopropane precursorthese two11).
(Scheme species can then react rapidly to
generate a new C–C bond in the cyclopropane precursor (Scheme 11).
Scheme 11. Mechanistic insight in the synthesis of the cyclopropane precursor to compounds 32a and 32b.
Scheme 11. Mechanistic insight in the synthesis of the cyclopropane precursor to compounds 32a and
32b.
The same research group reported another interesting example by merging organocatalysis via
iminium-ion with ytterbium-based metal catalysis to prepare dihydroacridines [34]. The reaction
The same research group reported another interesting example by merging organocatalysis via
proceeds via the activation of quinolines derivatives 33 with Yb(OTf)3 and the concurrent enals
iminium-ion with ytterbium-based metal catalysis to prepare dihydroacridines [34]. The reaction
activation via iminium-ion by the TMS-protected diaryl prolinol X (Scheme 12).
proceeds via the activation of quinolines derivatives 33 with Yb(OTf)3 and the concurrent enals
The metal Lewis acid coordinates the aromatic nitrogen and increases the nucleophilicity of
activation via iminium-ion by the TMS-protected diaryl prolinol X (Scheme 12).
the α-methylene that can react with the iminium-ion generated from the enal. The formed enolate
The metal Lewis acid coordinates the aromatic nitrogen and increases the nucleophilicity of the
intermediate undergoes an intramolecular aldol reaction with the carbaldehyde. The subsequent
α-methylene that can react with the iminium-ion generated from the enal. The formed enolate
6-exo-trig cyclisation, followed by a dehydration, yields the desired dihydroacridine 34.
Catalysts
Catalysts 2019,
2019, 9,
9, xx FOR
FOR PEER
PEER REVIEW
REVIEW 99 of
of 36
36
intermediate
intermediate undergoes
undergoes anan intramolecular
intramolecular aldol
aldol reaction
reaction with
with the
the carbaldehyde.
carbaldehyde. The
The subsequent
subsequent 6-
6-
Catalysts 2019, 9, 928 9 of 35
exo-trig
exo-trig cyclisation,
cyclisation, followed
followed by
by aa dehydration,
dehydration, yields
yields the
the desired
desired dihydroacridine
dihydroacridine 34.
34.
Scheme 12. Merging organocatalysis via iminium-ion with ytterbium-based metal catalysis.
2.1.2. Combination with Other Organocatalysts

In 2007, Hong et al. reported an interesting method to access a precursor employed in the total
synthesis of (+)-palitantine (Scheme 13) [35].
The reaction is a formal self-dimerization [4 + 2] addition of (E)-4-acetoxycrotonaldehyde
activated by L-proline in presence of a trialkyl amine as a co-catalyst. Given the type of reaction, the
pathway can only evolve if the reagent is activated in two different ways by the same catalyst. This
is, fortunately, the case, given the complementary types of activation that proline can effect. While
Scheme
Scheme
Scheme 12. Merging
12. Merging organocatalysis via
via iminium-ion with ytterbium-based metal catalysis.
one aldehyde is 12. Mergingvia
activated organocatalysis
an electrophilic iminium-ion
iminium-ion withintermediate,
ytterbium-based metal
the catalysis.
other one proceeds
through
2.1.2. a nucleophilic
Combination with dienamine intermediate. At this point, the electronic rearrangement will
Other Organocatalysts
2.1.2.
2.1.2. Combination
Combination with
with Other
Other Organocatalysts
Organocatalysts
produce the intermediate compound 37 with the formation of two new C–C bonds. Triethylamine
In 2007, Hong et al. reported an interesting method to access a precursor employed in the total
In
was added 2007, Hong
asHong
In 2007, et al.
a co-catalyst reported
to improve
et al. reported an interesting
the reaction
an interesting method
time and
method to
to access aa precursor
the yield;
access this way,employed
precursor the reaction
employed in the
the total
in could be
total
synthesis of (+)-palitantine (Scheme 13) [35].
synthesis
carried
synthesis of
outofat(+)-palitantine
a lower temperature,
(+)-palitantine (Scheme 13)
13) [35].
(Schemeproviding [35]. a higher enantiomeric excess.
The
The reaction
reaction is is aa formal
formal self-dimerization
self-dimerization [4 [4 ++ 2]2] addition
addition of of (E)-4-acetoxycrotonaldehyde
(E)-4-acetoxycrotonaldehyde
activated
activated by L-proline in presence of a trialkyl amine as a co-catalyst. Given
by L-proline in presence of a trialkyl amine as a co-catalyst. Given the the type
type ofof reaction,
reaction, the
the
pathway
pathway can can only
only evolve
evolve ifif thethe reagent
reagent is is activated
activated in in two
two different
different ways
ways by by the
the same
same catalyst.
catalyst. This
This
is,
is, fortunately,
fortunately, the the case,
case, given
given thethe complementary
complementary types types of of activation
activation thatthat proline
proline cancan effect.
effect. While
While
one
one aldehyde is activated via an electrophilic iminium-ion intermediate, the other one proceeds
aldehyde is activated via an electrophilic iminium-ion intermediate, the other one proceeds
through
through aa nucleophilic
nucleophilic dienaminedienamine intermediate.
intermediate. At At this
this point,
point, the
the electronic
electronic rearrangement
rearrangement will will
produce
produce the intermediate compound 37 with the formation of two new C–C bonds. Triethylamine
the intermediate compound 37 with the formation of two new C–C bonds. Triethylamine
was
was added
added as aa co-catalyst
asSchemeco-catalyst to
to improve
improve
13. Formation of newthe
theC–Creaction
bondstime
reaction time and
and the
mediated the yield;
yield; this
by proline this way,
and way, thethe reaction
reaction could
triethylamine. could bebe
carried out at Scheme
a lower 13. Formation ofproviding
temperature, new C–C bonds a highermediated by prolineexcess.
enantiomeric and triethylamine.
carried out at a lower temperature, providing a higher enantiomeric excess.
The reaction is a formal self-dimerization [4 + 2] addition of (E)-4-acetoxycrotonaldehyde activated
While Hong
by L-proline presented
in presence a synergistic
of a trialkyl amine asactivation
a co-catalyst. using thethe
Given sametypecatalyst to activate
of reaction, the two
the pathway can
reaction partners, Xu et al. reported an enantioselective domino oxa-Michael-Mannich
only evolve if the reagent is activated in two different ways by the same catalyst. This is, fortunately, reaction
between
the salicylaldehyde
case, given the complementary 38 and types cyclohexenones
of activation39, thatactivating
proline can the reaction
effect. Whilepartners with isa
one aldehyde
combination
activated via anof aelectrophilic
primary and a secondaryintermediate,
iminium-ion chiral aminethe (Scheme 14) proceeds
other one [36]. through a nucleophilic
dienamine intermediate. At this point, the electronic rearrangement will produce the intermediate
compound 37 with the formation of two new C–C bonds. Triethylamine was added as a co-catalyst
to improve the reaction time and the yield; this way, the reaction could be carried out at a lower
temperature, SchemeScheme 13.
providing 13.aFormation
Formation of
of new
new C–C
higher enantiomeric C–C bonds
bonds mediated
excess.mediated by by proline
proline and
and triethylamine.
triethylamine.
While Hong presented a synergistic activation using the same catalyst to activate the two reaction
While
While Hong presented a synergistic activation using the
the same
same catalyst
catalyst to activate the
the two
partners, XuHong et al. presented
reported aansynergistic activation
enantioselective domino usingoxa-Michael-Mannich toreaction
activate between two
reaction partners,
reaction partners, Xu
Xu et et al. reported
al. reported an an enantioselective domino oxa-Michael-Mannich reaction
salicylaldehyde 38 and cyclohexenones 39, enantioselective
activating the reaction domino oxa-Michael-Mannich
partners with a combination reaction
of a
between
between salicylaldehyde
salicylaldehyde 38
38 and
and cyclohexenones
cyclohexenones 39,
39, activating
activating the
the reaction
reaction partners
partners with
with aa
primary and a secondary chiral amine (Scheme 14) [36].
combination
combination of of aa primary
primary and and aa secondary
secondary chiralchiral amine
amine (Scheme
(Scheme 14) 14) [36].
[36].
Scheme 14. Synergistic catalysis based on a primary and a secondary amines activation.
Catalysts 2019, 9, 928 10 of 35
Scheme 14. Synergistic catalysis based on a primary and a secondary amines activation.
The amino acid, a primary amine, condenses with salicylaldehyde 38 to form imine 38a. A proline
The amino acid, a primary amine, condenses with salicylaldehyde 38 to form imine 38a. A
derivative XI generates an iminium-ion intermediate reacting with cyclohexenones 39 (Scheme 15).
proline derivative XI generates an iminium-ion intermediate reacting with cyclohexenones 39
The intermediates formed with the two different catalysts can then react via an oxa-Michael-Mannich
(Scheme 15). The intermediates formed with the two different catalysts can then react via an oxa-
reaction. The depicted transition state was confirmed by Fourier-transform ion cyclotron resonance
Michael-Mannich reaction. The depicted transition state was confirmed by Fourier-transform ion
mass spectroscopy.
cyclotron resonance mass spectroscopy.
Scheme 15. Mechanistic insight in the enantioselective domino oxa-Michael-Mannich reaction.

Scheme 15. Mechanistic insight in the enantioselective domino oxa-Michael-Mannich reaction.
2.1.3. Combination with Photocatalysts
Photochemical reactions, together with enzymatically catalysed reactions, are generally considered
as thePhotochemical
beginning of thereactions,
green chemistrytogether withfor
concept enzymatically
synthetic chemistrycatalysed reactions,
[37]. Solar light isare generally
undoubtedly
considered
the cleanestas the beginning
source of energy of andthethe green chemistry
photon concepta for
is considered synthetic
traceless chemistry
regent [37]. Solar light
[38]. Photocatalysis withis
undoubtedly the cleanest source of energy and the photon is considered
visible light [39] is undoubtedly one of the emerging strategies to meet the increasing demand for morea traceless regent [38].
Photocatalysis
sustainable with visible
chemical light [39] is undoubtedly one of the emerging strategies to meet the
processes.
increasing demand for more
A number of powerful methods sustainable chemical
has been processes.
recently developed applying organometallic complexes
such as [Ru(bpy)3 ] and [Ir(ppy)2 (dtb-bpy)] where recently
A number of 2+ powerful methods has+ been bpy = 2,2developed
0 -bipyridine,applying organometallic
ppy = 2-phenylpyridine
complexes
and dtb-bpysuch= 4,4 as
0 [Ru(bpy)3] and
-di-tertbutyl-2,2 2+ 0 [Ir(ppy)[40,41].
-bipyridine 2(dtb-bpy)] + where
The redox bpy = of
potential 2,2′-bipyridine, ppy =can
the metal complexes 2-
phenylpyridine and dtb-bpy =
be readily fine-tuned by ligand modification. 4,4′-di-tertbutyl-2,2′-bipyridine [40,41]. The redox potential of the
metalHowever,
complexes duecan to be
thereadily
high cost fine-tuned by ligand
and potential modification.
toxicity of the ruthenium and iridium salts, as well as
their However, due to theorganic
limited availability, high cost dyesand potential
could also betoxicity of the ruthenium
successfully and iridium
used in photoredox salts, instead
catalysis as well
as their limited availability,
of a metal catalyst [42]. organic dyes could also be successfully used in photoredox catalysis
instead of a metal note
Of particular catalyst [42].
is the cooperative combination of photocatalysis with an organocatalytic cycle,
Of particular note is the cooperative
offering catalytic methods for the enantioselective combinationα-alkylation
of photocatalysis with an organocatalytic[43]
[41], α-perfluoroalkylation cycle,
or
offering catalytic methods for the
α-benzylation [44] of aldehydes (Scheme 16). enantioselective α-alkylation [41], α-perfluoroalkylation [43] or α-
benzylation [44] of
In the first aldehydes
case, (Schemethe
in particular, 16).authors proposed two interwoven catalytic cycles that
simultaneously generate an electron-rich enamine from the condensation of an aldehyde with the
chiral amine catalyst and an electron-deficient alkyl radical via reduction of an alkyl bromide with a
Ru(II) photoredox catalyst. It is well known that [Ru(bpy)3 ]2+ will readily accept a photon from a light
source to populate the *[Ru(bpy)3 ]2+ metal to ligand charge transfer (MLCT) excited states. These high
energy intermediates remove a single electron from a sacrificial quantity of enamine to form Ru(I)
that react via single-electron transfer with the α-bromocarbonyl substrate to furnish the reactive alkyl
radical (and Ru(II)) able to react with the enamine formed in the complementary organocatalytic cycle.
Catalysts 2019, 9, 928 11 of 35
Scheme 16. Synergistic catalysis of proline derivative working in combination with photocatalysis
Scheme 16. Synergistic catalysis of proline derivative working in combination with photocatalysis
performed by theby
performed MacMillan research
the MacMillan researchgroup.
group.
The sameIn the reaction of α-alkylation

first case, in particular, of thealdehydes was proposed
authors proposed by Zeitler
two interwoven et al.cycles
catalytic in 2011,
that using a
metal-free cooperative
simultaneously asymmetric
generate organophotoredox
an electron-rich enamine fromcatalysis approach
the condensation mediated
of an aldehyde by withluminescent
the
organicchiral
dyesamine[42]. catalyst and an electron-deficient alkyl radical via reduction of an alkyl bromide with a
Ru(II) photoredox
[Ru(bpy) catalyst.
2+ has been It is well known that [Ru(bpy) 3]2+ will readily accept a photon from a light
3] replaced with eosin EY that acts as a photoredox catalyst. After its
source to populate the *[Ru(bpy)3] metal to ligand charge transfer (MLCT) excited states. These high
2+
excitation with visible light and the population of its more stable triplet state (3 EY*), the eosin excited
energy intermediates remove a single electron from a sacrificial quantity of enamine to form Ru(I)
state follows
that reacta reductive quenching.
via single-electron transferThewithoxidation of a catalytic
the α-bromocarbonyl amount
substrate of enamine
to furnish occurs
the reactive alkyl to form
–
EY· , which
radicalsubsequently
(and Ru(II)) able reacts viawith
to react single-electron transfer
the enamine formed in (SET) with alkyl halide
the complementary to provide the
organocatalytic
electron-deficient
cycle. alkyl radical (RAD).
The sameofreaction
The addition of α-alkylation
this radical of aldehydes was
to the electron-rich proposed
olefin of theby enamine
Zeitler et al. in 2011,
that using a
is simultaneously
metal-free cooperative asymmetric organophotoredox catalysis approach mediated by luminescent
generated within the organocatalytic cycle merges both activation pathways. In the catalytic cycle,
organic dyes [42].
the subsequent oxidation of the amino radical to the iminium species provides the electron for the
[Ru(bpy)3]2+ has been replaced with eosin EY that acts as a photoredox catalyst. After its
reductive quenching
Catalysts
excitation2019, of PEER
9, x FOR
with thelight
visible dye
REVIEWexcited
and state 3 EY*
the population (Scheme
of its 17).triplet state (3EY*), the eosin excited
more stable 12 of 36
state follows a reductive quenching. The oxidation of a catalytic amount of enamine occurs to form
EY⋅–, which subsequently reacts via single-electron transfer (SET) with alkyl halide to provide the
electron-deficient alkyl radical (RAD).
The addition of this radical to the electron-rich olefin of the enamine that is simultaneously
generated within the organocatalytic cycle merges both activation pathways. In the catalytic cycle,
the subsequent oxidation of the amino radical to the iminium species provides the electron for the
reductive quenching of the dye excited state 3EY* (Scheme 17).
Scheme 17. Mechanistic

Scheme insight
17. Mechanistic insightininthe
the reported proline
reported proline and
and photo-synergistic
photo-synergistic catalysis.
catalysis.
3. Hydrogen Bonding Catalysis

Hydrogen bonding is an electrostatic interaction, so the typical value of bond energy between
the catalyst and a substrate is around 10–30 kJ/mol. Asymmetric catalysts that can form hydrogen
bonds are able to orient reagents, since the hydrogen bond is extremely directional. Moreover, by
Catalysts 2019, 9, 928 12 of 35
3. Hydrogen Bonding Catalysis

Hydrogen bonding is an electrostatic interaction, so the typical value of bond energy between the
catalyst and a substrate is around 10–30 kJ/mol. Asymmetric catalysts that can form hydrogen bonds
are able to orient reagents, since the hydrogen bond is extremely directional. Moreover, by exalting
acidity of the reaction partner, these kinds of catalyst affect the reactivity of the chemical species which
they coordinate. In 1990, Kelly reported a reactivity study based on the Diels-Alder reaction between an
α,β-unsaturated aldehyde as a dienophile, and different dienes. Bis-phenol derivatives act as catalysts
and establish a double hydrogen bond with the oxygen on the dienophile; this implies that the gap in
energy between the HOMO-LUMO orbitals decreases and, therefore, the speed of the desired reaction
increases [45].
Usually a catalyst that exploits only hydrogen bonds to activate the reagents is not enough to
establish the required stereocontrol; in fact, in general, an additional chiral catalyst or a bifunctional
catalyst is needed. For example, Tsogoeva et al. reported the use of chiral diamino-compounds
(XV–XVIII) as stoichiometric additives, besides a dipeptide catalyst (XIX–XX), to increase the efficiency
Catalysts 2019, 9, xaddition
of a conjugate FOR PEERof
REVIEW
2-nitropropane 46 to 2-cyclohexen-1-one 39 (Scheme 18). 13 of 36
Scheme 18.
Scheme Chiral diamino-compounds
18. Chiral diamino-compounds as
as stoichiometric
stoichiometric additive
additive to
to aa dipeptide
dipeptide catalyst.
catalyst.
Bifunctional catalysts tend to be widely used since the spatial proximity of the catalytic units,
generating two types of interaction with the reagents, may promote a controlled transition state
giving rise to high enantioselectivity. Jacobsen et al. reported ground-breaking examples in the area,
with chiral thiourea bifunctional catalysts [9]; it was established that the presence of two m-CF3 groups
with chiral thiourea bifunctional catalysts [9]; it was established that the presence of two m-CF3
on the aromatic ring improves the efficiency of the reaction [8,12,46].
groups on the aromatic ring improves the efficiency of the reaction [8,12,46].
A related group of bifunctional catalysts is the squaramide-derived one, introduced by Rawal.
Thanks to the higher efficiency shown, this type of catalyst is proving increasingly successful
Thanks to the higher efficiency shown, this type of catalyst is proving increasingly successful (Scheme
19) [47]. Moreover, thiosquaramides show superior performance compared to thioureas, as described
by Wheeler and et al. [48].
with chiral thiourea bifunctional catalysts [9]; it was established that the presence of two m-CF3
groups on the aromatic ring improves the efficiency of the reaction [8,12,46].
Catalysts 2019, 9, 928 13 of 35
Thanks to the higher efficiency shown, this type of catalyst is proving increasingly successful (Scheme
19) [47]. Moreover,
(Scheme thiosquaramides
19) [47]. Moreover, show superior
thiosquaramides showperformance compared tocompared
superior performance thioureas, to
as thioureas,
described
by Wheeler and
as described et al. [48].
by Wheeler and et al. [48].
19. The
Scheme 19.
Scheme Theaddition
additiontoto
nitrostyrene catalyzed
nitrostyrene of squaramide-derived
catalyzed catalyst,
of squaramide-derived introduced
catalyst, by Rawal.
introduced by
Rawal.
Hydrogen bonding is very relevant in biological systems for several reasons; indeed,
the architecture
Catalysts of PEER
2019, 9, x FOR
Hydrogen hydrogen
bonding REVIEWbonding
is very bifunctional
relevant catalysts
in biological is inspired
systems by thereasons;
for several interactions within
14 of 36
indeed, the
the cavity of enzymes. For example, Malkov reported an interesting study about
architecture of hydrogen bonding bifunctional catalysts is inspired by the interactions within the the activation of
reagents
two by dipeptide-derivatives
reagents by dipeptide-derivatives XXII in in
XXII ananenantioselective
enantioselective reaction
reaction ofof ketimines
ketimines 51 using
using
cavity of enzymes. For example, Malkov reported an interesting study about the activation of two
trichlorosilane. The complementarity
trichlorosilane. complementarity between
between the the reagents and the “catalytic site”, along with the the
weak interaction
weak interactionestablished,
established, recalls
recalls an enzyme.
an enzyme. In theIntransition
the transition state
state 51a, 51a,non-covalent
three three non-covalent
contacts
contacts
are are established
established between thebetween the
catalyst catalyst
and the twoand the twotwo
reagents, reagents,
hydrogentwobonds
hydrogen
and onebonds
π-π and one π-
interaction
π interaction (Scheme 20), thus emphasizing the importance of non-covalent bonds
(Scheme 20), thus emphasizing the importance of non-covalent bonds [49]. Therefore, synergistic [49]. Therefore,
synergistic that
activations activations
exploit that exploit thebond
the hydrogen hydrogen
can helpbond can weak
when help when weak interactions
interactions are not enough are not
for
enough for successful
successful activation. activation.
Scheme 20. Enantioselective

Scheme 20. Enantioselective reduction
reduction of
of ketimines
ketimines to
to the
the corresponding
corresponding secondary
secondary amines
amines with
with aa
dipeptide-derived catalyst.
dipeptide-derived catalyst.
3.1. Synergistic Catalysis with Hydrogen Bonding Catalysts

3.1. Synergistic Catalysis with Hydrogen Bonding Catalysts
A catalytic system, combining Cinchona alkaloid-derived squaramide-based catalyst with AgSbF6
A catalytic
was reported system,
by Zhao, Shi combining Cinchona
et al. to perform alkaloid-derived
a highly diastereo- andsquaramide-based catalyst[3 with
enantio-selective formal + 2]
AgSbF 6 was reported by Zhao, Shi et al. to perform a highly diastereo- and enantio-selective formal
cycloaddition of α-aryl isocyanoacetates 52 with N-aryl-substituted maleimides 54 (Scheme 21) [50].
[3 + 2] cycloaddition of α-aryl isocyanoacetates 52 with N-aryl-substituted maleimides 54 (Scheme
21) [50].
A catalytic system, combining Cinchona alkaloid-derived squaramide-based catalyst with
AgSbF6 was reported by Zhao, Shi et al. to perform a highly diastereo- and enantio-selective formal
[3 + 2] cycloaddition of α-aryl isocyanoacetates 52 with N-aryl-substituted maleimides 54 (Scheme
Catalysts 2019, 9, 928 14 of 35
21) [50].
Scheme 21. Synergistic catalysis combining a Cinchona alkaloid-derived squaramide-based catalyst

Scheme 21. Synergistic catalysis combining a Cinchona alkaloid-derived squaramide-based catalyst
with AgSbF .
with AgSbF66.
The high stereocontrol is provided by the synergistic catalytic system, in which one carbonyl
The high stereocontrol is provided by the synergistic catalytic system, in which one carbonyl
group of the maleimide is hydrogen-bonded to the squaramide motif; at the same time, Ag(I)
group of the maleimide is hydrogen-bonded to the squaramide motif; at the same time, Ag(I) chelates
chelates to the terminal carbon of the isocyano group, enhancing the acidity of the isocyanoacetate
to the terminal carbon of the isocyano group, enhancing the acidity of the isocyanoacetate proton that
proton that can, therefore, be deprotonated by the quinuclidine nitrogen of the Cinchona catalyst.
can, therefore, be deprotonated by the quinuclidine nitrogen of the Cinchona catalyst. This
This multifunctional, well-designed, transitional state orients the isocyanoacetate enolate to attack
multifunctional, well-designed, transitional state orients the isocyanoacetate enolate to attack the
the maleimide; subsequently, a 5-endo-dig cyclisation takes place, forming the product 55 with a
maleimide;
Catalysts 2019, subsequently, a 5-endo-dig cyclisation takes place, forming the product 55 with a15third
9, x FOR PEER REVIEW of 36
third stereocentre.
stereocentre.
Oh and Kim developed a domino aldol-cyclisation reaction between aldehydes 10 and methyl
Oh and Kim developed
α-isocyanoacetate a domino
56 [51]. This aldol-cyclisation
synergistic reaction
catalysis exploits between
a chiral cobalt aldehydes 10 andworks
complex, which methyl
in
α-isocyanoacetate
concert 56 [51].
with an achiral This synergistic
thiourea catalysis exploits a chiral cobalt complex, which works in
(Scheme 22).
concert with an achiral thiourea (Scheme 22).
Scheme 22. Domino aldol-cyclisation reaction between aldehydes 9 and methyl α-isocyanoacetate 56
Scheme 22. Domino aldol-cyclisation reaction between aldehydes 9 and methyl α-isocyanoacetate 56
catalysed by cobalt and thiourea catalysts.
3.1.2. Combination with other Organocatalysts

In 2011, Jacobsen reported a novel and elegant synergistic strategy to obtain tricyclic structures
by [5 + 2] dipolar cycloaddition using a dual catalytic system [52].
The system consists of two different types of thiourea-based catalysts; while XXIV exploits the
primary amino group for enamine activation, XXIII activates the other reaction partner via a H-bond.
The synergistic catalysis was demonstrated with a series of reactions run with different bifunctional
chiral catalysts in the presence and absence of XXIII; this way, a clear and dramatic cooperative effect
was observed (Scheme 23).
Catalysts 2019, 9,22.
Scheme 928Domino aldol-cyclisation reaction between aldehydes 9 and methyl α-isocyanoacetate 56
15 of 35

In 2011, Jacobsen reported a novel and elegant synergistic strategy to obtain tricyclic structures by
In 2011, Jacobsen reported a novel and elegant synergistic strategy to obtain tricyclic structures
[5 + 2] dipolar cycloaddition using a dual catalytic system [52].
by [5 + 2] dipolar cycloaddition using a dual catalytic system [52].
Scheme 23. Synergistic catalysis mediated by two different thiourea-based catalysts.

Scheme 23. Synergistic catalysis mediated by two different thiourea-based catalysts.
The authors propose that XXIII induce ionization to the pyrylium ion and acts as a
The authors propose
carboxylate-binding agentthat XXIII induce
to generate, ionization with
cooperatively to theXXIV
pyrylium ionamine
whose and acts as a carboxylate-
condenses with the
binding agent to generate, cooperatively with XXIV whose amine condenses with the ketone to yield
ketone to yield dienamine after tautomerisation, the reactive ion pair that undergoes intramolecular
cycloaddition. The initial substrate condensation with the primary amine function present on catalyst
XXIV generates an electron delocalization, which involves a C–C bond breaking, also leaving a positive
charge on the oxygen atom. The second catalyst XXIII, by forming a hydrogen bond, assists the leaving
group on the substrate. In this regard, the dipolarophile cycloaddition may occur.
Pihko developed a three-component reaction yielding a β,γ-functionalized aldehyde exploiting
the synergy of a chiral secondary amine catalyst and a multiple-hydrogen-bond catalyst. This synthesis
is a versatile strategy to avoid self-condensation of aldehydes and the whole study exemplifies the
importance of evaluating the reactivity of each reaction partner during the synthesis design [53].
During the first reaction step, an aliphatic aldehyde 10, activated as iminium-ion by the amine catalyst,
undergoes condensation with nitromethane 60, activated by the multiple H-bond donor catalyst XXV,
providing a nitro-olefin 61. The nitro-olefin can then be activated by the H-bond catalyst and reacts
with the nucleophilic aldehyde activated via enamine by the secondary amine catalyst, to yield the
β,γ-functionalised aldehyde 62 (Scheme 24).
exemplifies the importance of evaluating the reactivity of each reaction partner during the synthesis
design [53]. During the first reaction step, an aliphatic aldehyde 10, activated as iminium-ion by the
amine catalyst, undergoes condensation with nitromethane 60, activated by the multiple H-bond
donor catalyst XXV, providing a nitro-olefin 61. The nitro-olefin can then be activated by the H-bond
catalyst and reacts with the nucleophilic aldehyde activated via enamine by the secondary amine
Catalysts 2019, 9, 928 16 of 35
catalyst, to yield the β,γ-functionalised aldehyde 62 (Scheme 24).
24. Synergistic
Scheme 24.
Scheme Synergisticcatalysis mediated
catalysis by aby
mediated chiral secondary
a chiral amine amine
secondary catalystcatalyst
and a multiple
and a hydrogen
multiple
bond thiourea-based catalyst.
hydrogen bond thiourea-based catalyst.
3.1.3. Combination with Photocatalyst
3.1.3. Combination with Photocatalyst
Photoredox catalysis has emerged recently as a powerful tool for the generation of synthetically
Photoredox catalysis has emerged recently as a powerful tool for the generation of synthetically
useful high-energy organic intermediates such as free radicals [54] and radical anions and cations [55,56].
useful high-energy organic intermediates such as free radicals [54] and radical anions and cations
Successful efforts to induce enantioselective catalytic control in such photocatalysed processes have
[55,56]. Successful efforts to induce enantioselective catalytic control in such photocatalysed
relied, thus far, on covalent organocatalysis, and only recently on chiral anion-binding catalysts [57].
processes have relied, thus far, on covalent organocatalysis, and only recently on chiral anion-binding
Stephenson et al. describe the successful development of a dual catalyst strategy with a chiral
catalysts [57].
H-bond donor catalyst XXVI in combination with [Ru(bpy)3 ]2+ , for the enantioselective oxidative
Stephenson et al. describe the successful development of a dual catalyst strategy with a chiral
alkylation of tetrahydroisoquinolines 63 with silyl ketene acetals 64 via enantioselective oxidative
H-bond donor catalyst XXVI in combination with [Ru(bpy)3]2+, for the enantioselective oxidative
Mannich reactions, to yield tetrahydroisoquinoline-derived β-amino esters 65 [58].
alkylation of tetrahydroisoquinolines 63 with silyl ketene acetals 64 via enantioselective oxidative
An accurate screening of the reaction conditions, suitable for both transformations, allowed the
Mannich reactions, to yield tetrahydroisoquinoline-derived β-amino esters 65 [58].
combination of two very different methodologies for obtaining products with high enantiomeric excess
An accurate screening of the reaction conditions, suitable for both transformations, allowed the
in good yields (Scheme 25).
combination of two very different methodologies for obtaining products with high enantiomeric
The asymmetric reduction of 1,2-diketones provides enantiomerically enriched α-hydroxy ketones,
excess in good yields (Scheme 25).
which are very useful as organic frameworks building blocks and as important intermediates in the
pharmaceutical industry [59]. Based on the first work of Knowles et al. [60], where the presence of a
hydrogen-bonding interaction between a Brønsted acid catalyst XXVII and the ketyl intermediate was
verified, Jiang et al. reported the first example of asymmetric photoredox reduction of 1,2-diketones
through a dual catalysis platform using a H-bonding organocatalyst [61]. In an attempt to work
without using metals as catalysts, they tested a dicyanopyrazine-derived chromophore (DPZ) as the
photoredox catalyst instead of ruthenium derivatives. The reaction worked with 0.5 mol% of DPZ,
1.0 equiv of THIQ-2 (2-naphthyl N-substituted tetrahydroisoquinolines), 10 mol% guanidinium salt
XXVII and 10 mol% of NaBArF in PhCl solvent at 0 ◦ C and under irradiation with a 3 W blue LED,
giving chiral secondary alcohols 67. All tested 1,2-diketones react completely, providing optically
active α-hydroxy ketones in 60%–99% yields with 80%–98% ee (Scheme 26).
Catalysts 2019, 9, 928 17 of 35
Scheme 25. Synergistic catalysis mediated by hydrogen bond thiourea-based catalyst and Ru-based
photocatalyst.
The asymmetric reduction of 1,2-diketones provides enantiomerically enriched α-hydroxy

ketones, which are very useful as organic frameworks building blocks and as important
intermediates in the pharmaceutical industry [59]. Based on the first work of Knowles et al. [60],
where the presence of a hydrogen-bonding interaction between a Brønsted acid catalyst XXVII and
the ketyl intermediate was verified, Jiang et al. reported the first example of asymmetric photoredox
reduction of 1,2-diketones through a dual catalysis platform using a H-bonding organocatalyst [61].
In an attempt to work without using metals as catalysts, they tested a dicyanopyrazine-derived
chromophore (DPZ) as the photoredox catalyst instead of ruthenium derivatives. The reaction
worked with 0.5 mol% of DPZ, 1.0 equiv of THIQ-2 (2-naphthyl N-substituted
tetrahydroisoquinolines), 10 mol% guanidinium salt XXVII and 10 mol% of NaBArF in PhCl solvent
at 0 °C and under irradiation with a 3 W blue LED, giving chiral secondary alcohols 67. All tested 1,2-
diketones react completely, providing optically active α-hydroxy ketones in 60%–99% yields with
Scheme
80%–98% 25. Synergistic
25.
ee (Scheme
Scheme 26).catalysis
Synergistic mediated
catalysis by hydrogen
mediated bond thiourea-based
by hydrogen catalyst andcatalyst
bond thiourea-based Ru-based photocatalyst.
and Ru-based
photocatalyst.
The asymmetric reduction of 1,2-diketones provides enantiomerically enriched α-hydroxy

ketones, which are very useful as organic frameworks building blocks and as important
intermediates in the pharmaceutical industry [59]. Based on the first work of Knowles et al. [60],
where the presence of a hydrogen-bonding interaction between a Brønsted acid catalyst XXVII and
the ketyl intermediate was verified, Jiang et al. reported the first example of asymmetric photoredox
reduction of 1,2-diketones through a dual catalysis platform using a H-bonding organocatalyst [61].
In an attempt to work without using metals as catalysts, they tested a dicyanopyrazine-derived
chromophore (DPZ) as the photoredox catalyst instead of ruthenium derivatives. The reaction
Scheme 26. Hydrogen-bond based catalyst working in concert with photocatalysis [60].
worked with Scheme0.5 mol% of DPZ,
26. Hydrogen-bond 1.0 equiv
based catalyst workingof THIQ-2
in concert (2-naphthyl [60].
with photocatalysis N-substituted
tetrahydroisoquinolines), 10 amol%
The possibility to select chiralguanidinium
Brønsted acidsalt
forXXVII
protonand 10 mol%
shuttle of NaBArF
permits in PhCl
two distinct solvent
reductions,
at 0 °C and
The under irradiation
possibility to select awith a
chiral 3 W blue
Brønsted LED,
acid giving
for chiral
proton secondary
shuttle permitsalcohols
two 67. All
distinct
through highly enantioselective protonation, and allows the synthesis of diverse and valuable chiral tested 1,2-
reductions,
diketoneshighly
through
α-hydroxy react completely,
with highproviding
enantioselective
ketones optically
protonation,
ee values. andactive
allowsα-hydroxy ketones
the synthesis in 60%–99%
of diverse yieldschiral
and valuable with
80%–98% eeketones
α-hydroxy (Scheme 26).high ee values.
with
4. Cinchona Alkaloids Organocatalysis
Cinchona alkaloids are a complex mixture of organic compounds derived from the bark of Cinchona
and used for the treatment of malaria fever. This class of compounds presents five chiral centers and
two different heterocycles, quinuclidine and a quinolinic one. (Figure 3)
Cinchona alkaloids are bifunctional catalysts (Figure 4); the nitrogen atom in the quinuclidinic ring
works as a base activator site which can deprotonate and activate through a base-catalyzed mechanism
a nucleophile having a pKa = up to 10–11. After deprotonation, a tight ion pair is formed between the
protonated catalyst and the deprotonated nucleophile, enabling a better enantiocontrol thanks to the
steric hindrance. The 9-OH acts as a H-bond donor activating the electrophilic species [62] (Figure 4).
Cinchona alkaloids can be functionalized on the 9-OH with a range of functional groups, to obtain
Scheme 26. Hydrogen-bond based catalyst working in concert with photocatalysis [60].
modular catalysts according to operative needs. In addition, their versatility derives from the fact that
they can be easily functionalized as required in other positions, for example on the C5’ position, [63]
The possibility to select a chiral Brønsted acid for proton shuttle permits two distinct reductions,
or the nitrogen atom of the quinuclidinic portion can be quaternized to provide, for example, PTC
through highly enantioselective protonation, and allows the synthesis of diverse and valuable chiral
catalysts that enable the activation of nucleophilic substrates with a pKa values between 11 and 21
α-hydroxy ketones with high ee values.
(Scheme 27).
4. Cinchona Alkaloids Organocatalysis

Cinchona alkaloids are a complex mixture of organic compounds derived from the bark of
Cinchona
Catalysts and
2019, used
for the treatment of malaria fever. This class of compounds presents five 18
9, 928 chiral
of 35
centers and two different heterocycles, quinuclidine and a quinolinic one. (Figure 3)
Figure 3. Cinchona alkaloids.
Cinchona alkaloids are bifunctional catalysts (Figure 4); the nitrogen atom in the quinuclidinic
ring works as a base activator site which can deprotonate and activate through a base-catalyzed
mechanism a nucleophile having a pKa = up to 10–11. After deprotonation, a tight ion pair is formed
between the protonated catalyst and the deprotonated nucleophile, enabling a better enantiocontrol
thanks to the steric hindrance. The 9-OH acts as a H-bond donor activating the electrophilic species
[62] (Figure 4). Figure 3. Cinchona alkaloids.
Figure 3. Cinchona alkaloids.
Cinchona alkaloids are bifunctional catalysts (Figure 4); the nitrogen atom in the quinuclidinic
ring works as a base activator site which can deprotonate and activate through a base-catalyzed
mechanism a nucleophile having a pKa = up to 10–11. After deprotonation, a tight ion pair is formed
between the protonated catalyst and the deprotonated nucleophile, enabling a better enantiocontrol
thanks to the steric hindrance. The 9-OH acts as a H-bond donor activating the electrophilic species
[62] (Figure 4).
PTC catalysts that enable the activation of nucleophilic substrates with a pKa values between 11 and
21 (Scheme 27).
Figure 4. Cinchona alkaloids as bifunctional catalysts.
modular catalysts according to operative needs. In addition, their versatility derives from the fact
that they can be easily functionalized as required in other positions, for example on the C5’ position,
[63] or the nitrogen atom of the quinuclidinic portion can be quaternized to provide, for example,
modular catalysts according to operative needs. In addition, their versatility derives from the fact
that they can be easily functionalized as required in other positions, for example on the C5’ position,
[63] or the nitrogen atom of the quinuclidinic portion can be quaternized to provide, for example,
Scheme
Scheme 27. Quinuclidinic proton
27. Quinuclidinic proton quaternarization.
quaternarization.
Cinchona alkaloids were first employed in organic chemistry in 1859 as a chiral auxiliary by
Pasteur for the resolution of the racemate of tartaric acid [64]. The first asymmetric reaction
employing Cinchona alkaloids was reported in 1912 by Bredig and Fiske [1]. Cinchonine Ia
deprotonates HCN, forming a tight chiral ion pair that directs the attack of cyanide onto the
benzaldehyde enantioselectively (Scheme 28).
Catalysts 2019, 9, 928 19 of 35
Scheme 27. Quinuclidinic proton quaternarization.

Pasteur for the resolution of the racemate of tartaric acid [64]. The first asymmetric reaction employing
Pasteur for the resolution of the racemate of tartaric acid [64]. The first asymmetric reaction
Cinchona alkaloids was reported in 1912 by Bredig and Fiske [1]. Cinchonine Ia deprotonates HCN,
employing Cinchona alkaloids was reported in 1912 by Bredig and Fiske [1]. Cinchonine Ia
forming a tight chiral ion pair that directs the attack of cyanide onto the benzaldehyde enantioselectively
deprotonates HCN, forming a tight chiral ion pair that directs the attack of cyanide onto the
(Scheme 28).
benzaldehyde enantioselectively (Scheme 28).
HCN
N
O OH HO H
HCN CN
H * CN O
N
Ia N
HO Ph H
2 Chiral ion pair
1 B*-R 1
Ia
Catalyst: N
H
OH N
N HO O
* H CN
CN
HO H 2 Ph H
N
Chiral ion pair
B*- (Sub-R)
N
Ia
Scheme 28. First asymmetric reaction employing cinchonine Ia as catalysts.

Scheme 28. First asymmetric reaction employing cinchonine Ia as catalysts.
Furthermore, Wynberg and Hiemstra developed, in 1981, an enantioselective 1,4-addition of thiols

Furthermore,
Catalysts 2019, 9, x FOR Wynberg and Hiemstra developed, in 1981, an enantioselective 1,4-addition
PEER REVIEW 20 of of
36
to unsaturated ketones [65,66] (Scheme 29).
thiols to unsaturated ketones [65,66] (Scheme 29).
Scheme 29. Enantioselective 1,4-addition of thiols to unsaturated ketones.

Since then, Cinchona alkaloids have been used extensively in organocatalysis. The most common
Since then,
derivatives Cinchona alkaloids
are functionalized have
at the C9been used extensively
position, with eitherinbulky
organocatalysis. The most moieties,
groups, H-bonding common
derivatives are functionalized at the C9 position, with either bulky
or primary amines able to condense with carbonyls (Figure 5) [67,68]. groups, H-bonding moieties, or
primary amines able to condense with carbonyls (Figure 5) [67,68].
Since then, Cinchona alkaloids have been used extensively in organocatalysis. The most common
derivatives are functionalized at the C9 position, with either bulky groups, H-bonding moieties, or
Catalysts 2019, 9, 928 20 of 35
primary amines able to condense with carbonyls (Figure 5) [67,68].
Figure 5. Cinchona alkaloids derivatives functionalized at the C9 position.

Figure 5. Cinchona alkaloids derivatives functionalized at the C9 position.
4.1. Synergistic Catalysis with Cinchona Alkaloids
4.1. Synergistic Catalysis with Cinchona Alkaloids
A remarkable example of Cinchona-derived bifunctional catalysts in combination with
A remarkable
metal-catalysts example
exploits of Cinchona-derived
copper(I) triflate to performbifunctional catalysts
an asymmetric in combination
Conia-ene with metal-
reaction of β-ketoesters
Catalysts
catalysts 2019, 9, x FOR
exploits30). PEER REVIEW
copper(I) triflate to perform an asymmetric Conia-ene reaction of β-ketoesters 21 of 70
36
70 [69] (Scheme
[69] (Scheme 30).
Scheme 30. Synergistic catalysis mediated by Cinchona-derived bifunctional catalysts in combination

with copper(I) triflate.
The organocatalyst acts as a Brønsted base and as a ligand for the copper enolate, imparting high
The organocatalyst acts as a Brønsted base and as a ligand for the copper enolate, imparting high
levels of enantiocontrol. In a preliminary study, the thiourea-based organocatalysts derived from
9-amino-9-deoxyepicinchonidine were tested in synergy with transition-metal ions [70–72].
Lectka et al. reported a high-yielding diastero- and enantio-selective synthesis of β-lactam
products exploiting a synergistic catalytic system, in which a chiral nucleophile organic molecule
works in concert with an achiral Lewis acidic metal salt [73–78] (Scheme 31).
The
Catalysts organocatalyst
2019, 9, 928 acts as a Brønsted base and as a ligand for the copper enolate, imparting
21high
of 35
Scheme 31. β-lactams synthesis thanks to benzoylquinine and indium cooperative catalysis.
Scheme 31. β-lactams synthesis thanks to benzoylquinine and indium cooperative catalysis.
According to their mechanistic studies, the pure organocatalytic pathway with Cinchona catalyst
According to their mechanistic studies, the pure organocatalytic pathway with Cinchona catalyst
activates acyl chlorides, providing ketene-derived zwitterionic enolates that subsequently add to
activates acyl chlorides, providing ketene-derived zwitterionic enolates that subsequently add to
electrophilic imines 73, giving rise to β-lactam four-members rings 74 with excellent enantiomeric
electrophilic imines 73, giving rise to β-lactam four-members rings 74 with excellent enantiomeric
excess (over 95%), albeit in modest yields from 40% to 65%.
excess (over 95%), albeit in modest yields from 40% to 65%.
Aiming to improve the yields and suppressing the formation of undesired by-products,
Aiming to improve the yields and suppressing the formation of undesired by-products, they
they proposed the addition of a Lewis acid catalyst to activate the imine. The combination of
proposed the addition of a Lewis acid catalyst to activate the imine. The combination of In(OTf)3, as
In(OTf)3 , as a Lewis acid, and benzoylquinine XXX, as a Brønsted base, proved to be the optimal one
a Lewis acid, and benzoylquinine XXX, as a Brønsted base, proved to be the optimal one for the
for the synthesis of β-lactams, using a powerful synergistic strategy maintaining high levels of diastero-
synthesis
Catalysts of 9,β-lactams,
2019, x FOR PEERusing a powerful synergistic strategy maintaining high levels of diastero-
REVIEW and
22 of 36
and enantio-selectivity, while improving the yields (Scheme 32).
enantio-selectivity, while improving the yields (Scheme 32).
Scheme 32. Mechanistic insight in the β-lactams synthesis exploiting synergistic catalysis.

An asymmetric Michael reaction between 1-azido-2-(2-nitrovinyl)benzene 76 and acetone 3,
catalyzed by a combination of an amino acid with a Cinchona-derived bifunctional catalyst XXIX, was
reported by Ramachary [79].
As depicted in Scheme 33, the proposed transition state features a network of hydrogen bonds
between the thiourea catalyst XXIX with the azido- and nitro-group on the electrophile 76. Acetone
3, on the other hand, is activated via enamine by the amino acid XIIIe, which is also part of the H-
Catalysts 2019, 9, 928 22 of 35

catalyzed 4.1.2.
by aCombination
combination withof amino acid with a Cinchona-derived bifunctional catalyst XXIX,
an Organocatalysts
Other
was reported by Ramachary [79].
As depicted
catalyzedin by Scheme 33, the
a combination of anproposed transition
amino acid with state features
a Cinchona-derived a network
bifunctional catalystof hydrogen
XXIX, was bonds
between the thiourea
reported catalyst [79].
by Ramachary XXIX with the azido- and nitro-group on the electrophile 76. Acetone 3,
As depicted in Scheme 33, the proposed transition state features a network of hydrogen bonds
on the other hand, is activated via enamine by the amino acid XIIIe, which is also part of the H-bond
between the thiourea catalyst XXIX with the azido- and nitro-group on the electrophile 76. Acetone
network with the quinuclidinic nitrogen. The proximal effect influenced the facial approach between
3, on the other hand, is activated via enamine by the amino acid XIIIe, which is also part of the H-
both activated reagents.
bond network with the quinuclidinic nitrogen. The proximal effect influenced the facial approach
between both activated reagents.
Scheme 33. Asymmetric

Scheme Michael
33. Asymmetric reaction
Michael reactioncatalyzed bya a
catalyzed by combination
combination of amino
of amino acid
acid XIIIe the with the
XIIIe
with
Cinchona-derived
Cinchona-derived bifunctional
bifunctional catalyst
catalyst XXIX.
XXIX.
Enantioselective additions of aldehydes to nitro-olefins, catalyzed by a combination of proline

Enantioselective additions of aldehydes to nitro-olefins, catalyzed by a combination of proline
and a quinidine-thiourea catalyst and developed by Zhao (Scheme 34) [80,81], were recently further
and a quinidine-thiourea catalyst and developed by Zhao (Scheme 34) [80,81], were recently further
investigated by Sunoj [82]. The two original research papers are a Michael addition of butanone 78
investigated by Sunoj [82]. The two original research papers are a Michael addition of butanone 78 to
to nitrostyrene 49 and a tandem Michael-Michael cascade reaction. The proline condenses with the
nitrostyrene 49 and a tandem Michael-Michael cascade reaction. The proline condenses with the
aldehyde 80 to form a nucleophilic enamine, while the Cinchona alkaloid activates the nitro-olefin via a
aldehyde 80 to form a nucleophilic enamine, while the Cinchona alkaloid activates the nitro-olefin via
H-bond network. In the tandem cascade reaction, the condensation of proline occurs more rapidly
a H-bond network. In the tandem cascade reaction, the condensation of proline occurs more rapidly
with the aldehyde than with the ketone, given the difference in reactivity (Scheme 34).
with the aldehyde than with the ketone, given the difference in reactivity (Scheme 34).
Scheme 34. Michael addition reaction between nitrostyrene and ketone 78 (a) or α,β-unsaturated
Scheme 34. Michael
dicarbonylic addition
compound 80 (b). reaction between nitrostyrene and ketone 78 (a) or α,β-unsaturated
dicarbonylic compound 80 (b).
The Cinchona catalyst XXIX establishes a tight H-bond network, with a well-defined geometry;
the thiourea coordinates with the proline carboxylate group while the protonated quinuclidinic ring
with the nitrostyrene. Following the first Michael addition, and several rearrangements of hydrogen
bonds, the intermediate is oriented in such a way that the electronic deficiency on the carbon adjacent
Catalysts 2019, 9, 928 23 of 35
The Cinchona catalyst XXIX establishes a tight H-bond network, with a well-defined geometry;
the thiourea coordinates with the proline carboxylate group while the protonated quinuclidinic ring
with the nitrostyrene. Following the first Michael addition, and several rearrangements of hydrogen
bonds, the intermediate is oriented in such a way that the electronic deficiency on the carbon adjacent
to the nitro-group is near the electrophilic position, so that a new Michael addition can occur to yield
the cyclic
Catalysts product
2019, 9, x FOR81 after
PEER hydrolysis (Scheme 35).
REVIEW 24 of 36
Mechanistic insights
Scheme 35. Mechanistic
Scheme insights in
in the
the enantioselective
enantioselective addition
addition of aldehydes to nitro-olefins.

Asymmetric alkylation of cyclic ketones with alkyl bromides, to obtain of α-alkylated products,
Asymmetric alkylation of cyclic ketones with alkyl bromides, to obtain of α-alkylated products,
has been studied by Melchiorre et al., with high levels of regio-, diastereo-, and enantioselectivity [83].
has been studied by Melchiorre et al., with high levels of regio-, diastereo-, and enantioselectivity
Cyclohexanone derivatives 82 were reacted with substituted benzyl bromide 83 using quinine-derived
[83]. Cyclohexanone derivatives 82 were reacted with substituted benzyl bromide 83 using quinine-
primary amines Ig or Ii as catalyst.
derived primary amines Ig or Ii as catalyst.
The process is confirmed as photochemical since it requires light in order to proceed.
The process is confirmed as photochemical since it requires light in order to proceed. The
The experiments were conducted using a household full-spectrum 23 W compact fluorescent lightbulb
experiments were conducted using a household full-spectrum 23 W compact fluorescent lightbulb
(CFL). The electron-rich enamine 82a, formed from the condensation of ketones 82 (or aldehydes) with
(CFL). The electron-rich enamine 82a, formed from the condensation of ketones 82 (or aldehydes)
a chiral secondary amine Ig/I (Cinchona-based catalyst), and the electron-accepting alkyl bromide 83
with a chiral secondary amine Ig/I (Cinchona-based catalyst), and the electron-accepting alkyl
form the coloured EDA complexes by means of molecular aggregations, which occur in the ground
bromide 83 form the coloured EDA complexes by means of molecular aggregations, which occur in
state of both compounds [84]. Light irradiation induced an electron transfer from the enamine to the
the ground state of both compounds [84]. Light irradiation induced an electron transfer from the
bromide and a facile radical fragmentation of the latter. The ion pair radical puts the two reagents into
enamine to the bromide and a facile radical fragmentation of the latter. The ion pair radical puts the
two reagents into a geometrically restricted chiral space and into very close proximity. This condition
facilitated a stereo controlled radical combination within the solvent cage to form a new carbon–
carbon bond and the α-carbonyl stereogenic centre of the final product 84 (Scheme 36).
Catalysts 2019, 9, 928 24 of 35
a geometrically restricted chiral space and into very close proximity. This condition facilitated a stereo
controlled radical combination within the solvent cage to form a new carbon–carbon bond and the
Catalysts
α-carbonyl2019, stereogenic
9, x FOR PEERcentre
REVIEWof the final product 84 (Scheme 36). 25 of 36
Scheme 36. Mechanistic insights in the intermolecular asymmetric alkylation of cyclic ketones with
Scheme 36. Mechanistic insights in the intermolecular asymmetric alkylation of cyclic ketones with
alkyl bromides, mediated by Cinchona alkaloids-based catalysis merged with photocatalysis.
alkyl bromides, mediated by Cinchona alkaloids-based catalysis merged with photocatalysis.
In this, the photocatalyst is not present but the photochemically reactive species is the adduct
formedIn this, the photocatalyst
by molecular is not
aggregation present
of the but the photochemically
two reagents reactive species is the adduct
with the chiral catalyst.
formed by molecular aggregation of the two reagents with the chiral catalyst.
Another example of synergistic photoredox activation for the direct β-arylation of ketones in
Another
combination with example of synergistic
Cinchona alkaloids photoredox
is presentedactivation for the
by MacMillan direct
[85]. Theβ-arylation of ketones
authors showed in
the use
combination with Cinchona alkaloids is presented by MacMillan [85]. The authors showed
of [Ir(ppy)3 ] as a photocatalyst to promote a single-electron transfer with 1,4-dicyanobenzene 85 to the use of
[Ir(ppy)
afford the3] as a photocatalyst to promote a single-electron transfer with 1,4-dicyanobenzene 85 to
corresponding arene radical anion. Iridium complexes have a strong absorption in the
afford the
visible range, corresponding
allowing themarene radical
to accept anion.from
a photon Iridium complexes
a variety of lighthave
sourcesa strong absorption
to populate in the
the *Ir(ppy) 3
visible range, allowing them to accept a photon from a variety of
metal-to-ligand charge transfer excited state, which has strong reductant properties. light sources to populate the
*Ir(ppy) 3 metal-to-ligand charge transfer excited state, which has strong reductant properties.
In combination with this photoredox step, cyclohexanone 82 should condense with the amine
In combination
group of a Cinchona-derivedwith this photoredox step,
organocatalyst Ik tocyclohexanone 82 should
form the electron-rich condense with the amine
enamine.
group of a Cinchona-derived organocatalyst Ik to form the electron-rich enamine.
At this juncture the photoredox and organocatalytic cycles would merge, as the electron-deficient
Ir (ppy)this
IV At juncture the photoredox and organocatalytic cycles would merge, as the electron-
3 intermediate should readily accept an electron, via SET, from the electron-rich enamine
deficient Ir IV(ppy)3 intermediate should readily accept an electron, via SET, from the electron-rich
to generate the corresponding radical cation and subsequent β-enamine radical formation,
enamine to generate the corresponding radical cation and subsequent β-enamine radical formation,
eventually giving the β-arylation product 86 with promising levels of enantioselectivity (82% yield,
50% ee) (Scheme 37).
Catalysts 2019, 9, 928 25 of 35
eventually giving the β-arylation product 86 with promising levels of enantioselectivity (82% yield,
50% ee)2019,
Catalysts
Catalysts (Scheme
2019, 9, 37).
9, xx FOR
FOR PEER
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REVIEW 26
26 of
of 36
36
Scheme
Scheme 37.
37. Enantioselective
Enantioselective β-arylation
β-arylation of
β-arylation of cyclohexanone
cyclohexanone exploiting
exploiting synergistic
synergistic catalysis
catalysis of
of Cinchona
Cinchona
alkaloids and photocatalyst.
alkaloids and photocatalyst.
5. Phosphoric
5. Phosphoric Acids
Acids Catalysis
Catalysis
AA powerful
powerfulclass
classofofchiral catalyst
chiral used
catalyst in asymmetric
used synthesis
in asymmetric is represented
synthesis by BINOL-derived
is represented by BINOL-
phosphoric acids used as Brønsted acids in electrophilic catalysis, imitating what
derived phosphoric acids used as Brønsted acids in electrophilic catalysis, imitating what nature nature does does
with
enzymes. The phosphoric acid group can decrease the energy of the LUMO
with enzymes. The phosphoric acid group can decrease the energy of the LUMO orbital of an orbital of an electrophilic
substrate through
electrophilic the formation
substrate through theof an intermolecular
formation hydrogen bond.
of an intermolecular Thanks to
hydrogen the high
bond. steric
Thanks tohindered
the high
substituents, substrates are confined to an extremely limited space, enabling stereocontrol.
steric hindered substituents, substrates are confined to an extremely limited space, enabling Thanks to
the Brønsted acid and Lewis base sites, and to the potential steric hindrance, BINOL derivatives
stereocontrol. Thanks to the Brønsted acid and Lewis base sites, and to the potential steric hindrance, can
have multiple
BINOL modes
derivatives canofhave
activation (Figure
multiple modes 6). of activation (Figure 6).
6. Activation modes
Figure 6.
Figure modes of substrates
substrates by phosphoric
phosphoric acids.
Figure 6. Activation
Activation modes of
of substrates by
by phosphoric acids.
acids.
In 1975, Cornforth used a similar catalyst derived from phosphinic acid for the hydration reaction
In 1975, Cornforth used a similar catalyst derived from phosphinic acid for the hydration
of alkenes, paving the way for the study of chiral phosphoric catalyst [86,87]. Despite the early
reaction of alkenes, paving the way for the study of chiral phosphoric catalyst [86,87]. Despite the
reports by Cornforth, it was only several decades later that chiral phosphoric acids were used as
early reports by Cornforth, it was only several decades later that chiral phosphoric acids were used
catalysts; in 2004, Akiyama [88] and Terada [89] simultaneously developed a Mannich reaction using
as catalysts; in 2004, Akiyama [88] and Terada [89] simultaneously developed a Mannich reaction
two different BINOL-derived catalysts, a phosphoric acid and a phosphoramide, respectively [90]
using two different BINOL-derived catalysts, a phosphoric acid and a phosphoramide, respectively
(Scheme 38).
[90] (Scheme 38).
Catalysts
Catalysts 2019, 9, 928 26 of 35
Catalysts 2019,
2019, 9,
9, xx FOR
FOR PEER
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REVIEW 27
27 of
of 36
36
Scheme
Scheme 38.
38. Mannich
Mannich reaction performed using
reaction performed using BINOL-derived
BINOL-derived catalysts.
catalysts.
5.1.
5.1. Synergistic Catalysis with
with Phosphoric Acids
5.1. Synergistic
Synergistic Catalysis
Catalysis with Phosphoric
Phosphoric Acids
Acids
5.1.1.
5.1.1. Combination
Combination with with Transition
Transition Metal-Based
Metal-Based Catalysts
Catalysts
Beller et al. developed an asymmetric hydrogenation of imines, using an inexpensive metal catalyst
Beller
Beller et
et al.
al. developed
developedwith an
an asymmetric
asymmetric hydrogenation
hydrogenation of
of imines,
imines, using
using an inexpensive
an such
inexpensive metal
metal
and ligand in combination TRIP [91], mimicking well-known biocatalysts, as iron-based
catalyst and ligand
catalyst and ligand in combination with TRIP [91], mimicking well-known biocatalysts, such
such as iron-
as
hydrogenases [92]. in combination
The iron complexwith TRIP [91],
catalyst XXXIImimicking well-known
and chiral acid XXXI biocatalysts,
work synergistically iron-
in a
based
based hydrogenases
hydrogenases [92].
[92]. The
The iron
iron complex
complex catalyst
catalyst XXXII
XXXII and
and chiral
chiral acid
acid XXXI
XXXI work
work synergistically
synergistically
cooperative manner, enabling enantioselective hydrogenation (Scheme 39).
in
in aa cooperative
cooperative manner,
manner, enabling
enabling enantioselective
enantioselective hydrogenation
hydrogenation (Scheme
(Scheme 39).
39).
Scheme 39. Asymmetric hydrogenation of imines using iron-based catalyst XXXII synergistically with
Scheme
Scheme 39.
39. Asymmetric
Asymmetric hydrogenation
hydrogenation of
of imines
imines using
using iron-based
iron-based catalyst
catalyst XXXII
XXXII synergistically
synergistically
TRIP XXXI.
with
with TRIP
TRIP XXXI.
XXXI.
The Brønsted acid (S)-TRIP protonates the starting imine to form the corresponding chiral
The
The Brønsted
ion-pair. Brønsted acid
acid (S)-TRIP
(S)-TRIP
This intermediate protonates
protonates
accepts the
the starting
the hydride starting imine to
to form
form the
imine complex,
from Knölker the corresponding
corresponding
producing chiral
chiral ion-
ion-
enantioenriched
pair. This intermediate
pair. This amines.
secondary accepts the hydride from Knölker complex, producing enantioenriched
intermediate accepts the hydride from Knölker complex, producing enantioenriched
secondary
secondary amines.
amines.
Luo
Luo et al.
et al. developed
developed thethe first
first regio-
regio- and
and enantio-selective
enantio-selective hetero-Diels-Alder
hetero-Diels-Alder reaction
reaction ofof
cyclopentadienes employing a chiral phosphoric acid/InBr 3 catalytic system (Scheme 40) [93].
cyclopentadienes employing a chiral phosphoric acid/InBr3 catalytic system (Scheme 40) [93].
The chiral phosphoric acid XXXIII proved to be unable to catalyse the reaction; by combining it
with a 2019,
Catalysts transition
9, 928 metal Lewis acid, the synergistic catalytic system is competent in activating the
27 of 35
reaction partners towards the hetero-Diels-Alder pathway with good results in terms of both
reactivity (99% yield) and enantioselectivity (ee 99%). It was shown that the free InBr3 favours the DA
Luo et al. developed the first regio- and enantio-selective hetero-Diels-Alder reaction of
pathway rather than HDA, demonstrating that the synergistic combinations of phosphoric acid and
cyclopentadienes employing a chiral phosphoric acid/InBr3 catalytic system (Scheme 40) [93].
metal Lewis acid was needed for effective catalysis.
Scheme 40. Enantioselective hetero-Diels–Alder reaction of cyclopentadienes exploiting a chiral

Scheme 40. Enantioselective hetero-Diels–Alder reaction of cyclopentadienes exploiting a chiral
phosphoric acid/InBr3 catalytic system.
phosphoric acid/InBr3 catalytic system.
The chiral phosphoric acid XXXIII proved to be unable to catalyse the reaction; by combining
5.1.2.
it withCombination
a transition with
metalother
Lewis Organocatalysts
acid, the synergistic catalytic system is competent in activating the
reaction
An partners towards the fluorination
elegant asymmetric hetero-Diels-Alder pathway
of carbonyl with goodcarried
compounds, results out
in terms of both reactivity
in a biphasic system,
(99%reported
was yield) and
byenantioselectivity
Toste [94]. (ee 99%). It was shown that the free InBr3 favours the DA pathway
rather than
The HDA, salt
sodium demonstrating
of the chiralthat the synergistic
phosphoric combinations
acid XXXIV acts asof phosphoric
a PTC, acid and
transporting metal Lewis
Selectfluor 96
acid
as was needed
a double chiralfor effective
ionic catalysis.
pair, at the interphase; the carbonyl compound present in the organic phase
is activated via enamine by the primary amine function of aminoacid derived XXXV. The two
activated substrates can then react at the interphase, where an additional weak interaction is
established between
An elegant the amino
asymmetric group andof
fluorination one of the oxygens
carbonyl of XXXIV
compounds, (Scheme
carried out in41).
a biphasic system,
was reported by Toste [94].
The sodium salt of the chiral phosphoric acid XXXIV acts as a PTC, transporting Selectfluor 96 as
a double chiral ionic pair, at the interphase; the carbonyl compound present in the organic phase is
activated via enamine by the primary amine function of aminoacid derived XXXV. The two activated
substrates can then react at the interphase, where an additional weak interaction is established between
the amino group and one of the oxygens of XXXIV (Scheme 41).
To avoid disrupting the well-balanced H-bond network, it was necessary to protect the carboxylic
moiety of the amino acid.
A direct asymmetric γ-alkylation of α-substituted linear α,β-unsaturated aldehydes 98 with
secondary alcohols 99 was reported by Melchiorre (Scheme 42) [95].
The reaction is formally a SN 1 reaction that proceeds through nucleophile attack of the activated
98 compound to the carbocation generated from 99. The activate-nucleophile species is the
dienamine, generated from the condensation between 60 -hydroxy-9-amino-9-deoxy-epiquinidine
and the α,β-unsaturated aldehyde. The phosphoric acid protonates the pro-electrophile generating
a stabilized carbocation that can be intercepted by the dienamine. A complex mechanistic model is
proposed where the Cinchona catalyst coordinates with two phosphoric acids, on one hand via the
60 -OH and on the other hand with the protonated quinuclidinic nitrogen. The mechanistic model is
supported by the fact that a 60 -OH group is needed for high enantiomeric excess.
Catalysts 2019, 9, 928 28 of 35
Scheme 41. Asymmetric fluorination of α-branched cyclohexanones exploiting the combination of

Scheme
Catalysts 2019, 9,41. Asymmetric
x FOR fluorination of α-branched cyclohexanones exploiting the combination 30
PEER REVIEW of of 36
chiralchiral
anion phase-transfer and enamine catalysis.
anion phase-transfer and enamine catalysis.
H
To avoid disrupting the well-balanced H-bond network, it was necessary to protect the
O
carboxylicOmoiety of the amino acid.OH Bn
Im 20mol%
A direct
H asymmetric γ-alkylation of α-substituted linear
XXXVI or XXXVI α,β-unsaturated aldehydes 98 with
30mol%
+
secondary alcohols 99 was reported by Melchiorre (Scheme 42) [95].
Me2N NMe2 CHCl3 0.1M
Bn 50 °C, 16 h Me2N NMe2
98 99 100
Catalysts:
H
R1
N O O
H2N P
H O OH
HO
R1
N
R= H XXXVI
Im R= 4-NO2C6H4 XXXVII
Scheme Asymmetric
42. 42.
Scheme γ-alkylation of
Asymmetricγ-alkylation of α-substituted linearα,β-unsaturated
α-substituted linear α,β-unsaturated aldehydes
aldehydes with with
secondary alcohols.
secondary alcohols.
The reaction is formally a SN1 reaction that proceeds through nucleophile attack of the activated
98 compound to the carbocation generated from 99. The activate-nucleophile species is the
dienamine, generated from the condensation between 6′-hydroxy-9-amino-9-deoxy-epiquinidine and
the α,β-unsaturated aldehyde. The phosphoric acid protonates the pro-electrophile generating a
stabilized carbocation that can be intercepted by the dienamine. A complex mechanistic model is
proposed where the Cinchona catalyst coordinates with two phosphoric acids, on one hand via the
6′-OH and on the other hand with the protonated quinuclidinic nitrogen. The mechanistic model is
Catalysts 2019, 9, 928 29 of 35

Stereocontrol in light-driven photochemical reactions still remains one of the most ambitious
goals [96]. To achieve this goal, many dual catalytic systems based on the contemporary use of
transition-metal photosensitizers and stereocontrollers have been successfully introduced, leading to
the establishment of highly stereoselective protocols for the assembly of chiral molecules [60,97].
Phipps et al. disclose the direct Minisci-type addition of α-amino alkyl radicals 102 to the 2-position
of basic heteroarenes 101, with excellent control of both enantioselectivity and regioselectivity, by virtue
of a combination of asymmetric Brønsted acid catalysis and photoredox catalysis [98].
Protonation significantly reduces the energy of the LUMO of the heteroarene, and the conjugate
anion of the chiral acid remain associated with the pyridinium cation through electrostatic and
hydrogen-bonding interactions. Therefore, the substrate is activated by a chiral environment.
They use RAEs (Redox Active Ester), as precursors to N-acyl α-amino alkyl radicals,
which are prochiral and nucleophilic radicals that possess hydrogen bond donor functionality.
Breaking into several fragments of the RAE is induced via electron transfer from an Ir(II)
species generated after irradiation of photocatalyst [Ir(dF(CF3 )ppy)2 (dtbpy)]PF6 , with dF(CF3 )ppy
= 2-(2,4-difluorophenyl)-5-(trifluoromethyl)-pyridinyl and dtbpy = 4,40 -bis(tert-butyl)-bipyridine,
Catalysts
with blue 2019, 9, x FOR
LEDs. PEER
The REVIEW
chiral Brønsted acid were (R)-TRIP XXXI or (R)-TCYP XXXVIII (Scheme31 of 36
43).
Scheme 43.
Scheme Minisci-type addition
43. Minisci-type addition of
of α-amino alkyl radicals
α-amino alkyl radicals to
to the
the 2-position
2-position of
of basic
basic heteroarenes
heteroarenes
performed thanks to a combination of Brønsted acid catalysis and photoredox catalysis.
performed thanks to a combination of Brønsted acid catalysis and photoredox catalysis.
Ooi et al., instead, developed a highly enantioselective α-coupling of N-arylaminomethanes

Ooi et al., instead, developed a highly enantioselective α-coupling of N-arylaminomethanes 105
105 with N-sulfonyl aldimines 104 using a chiral tetraaminophosphonium ion XXXIX and Ir-centred
with N-sulfonyl aldimines 104 using a chiral tetraaminophosphonium ion XXXIX and Ir-centred
photosensitizer with visible light irradiation [99]. They adopted N-sulfonyl imines as the precursors of
photosensitizer with visible light irradiation [99]. They adopted N-sulfonyl imines as the precursors
anion radicals due to their affinity to the hydrogen-bond donor catalyst (Scheme 44).
of anion radicals due to their affinity to the hydrogen-bond donor catalyst (Scheme 44).
Scheme 44. Enantioselective α-coupling of N-arylaminomethanes catalyzed by chiral tetraaminophosphonium

Scheme 44. Enantioselective α-coupling of N-arylaminomethanes catalyzed by chiral
ion and Ir-centred photosensitizer.
tetraaminophosphonium ion and Ir-centred photosensitizer.
The iridium complex [Ir(ppy)2(bpy)]BArF (where Hppy = 2-phenylpyridine, bpy = 2,2′-

bipyridine, HBArF = tetrakis [3,5-bis(trifluoromethyl)phenyl]-borate) was reversibly promoted to its
excited state, under visible light irradiation. Subsequent reductive quenching of the *Ir(III) species
with 105 lead to the formation of electronically neutral Ir(II) complex and the cation-radical of 105 in
presence of the counterion BArF−. The Ir(II) complex gives an electron to the imine 104 to form the
corresponding anion-radical that should be spontaneously paired with the positively charged of the
Ir(III) complex.
Catalysts 2019, 9, 928 30 of 35
The iridium complex [Ir(ppy)2 (bpy)]BArF (where Hppy = 2-phenylpyridine, bpy = 2,20 -bipyridine,
HBArF = tetrakis [3,5-bis(trifluoromethyl)phenyl]-borate) was reversibly promoted to its excited state,
under visible light irradiation. Subsequent reductive quenching of the *Ir(III) species with 105 lead to
the formation of electronically neutral Ir(II) complex and the cation-radical of 105 in presence of the
counterion BArF− . The Ir(II) complex gives an electron to the imine 104 to form the corresponding
anion-radical that should be spontaneously paired with the positively charged of the Ir(III) complex.
This complex would undergo prompt ion exchange with the catalysis, to afford the parent
photosensitizer and the adduct between the imine anion-radical and the Brønsted acid XXXIX.
At the same time, an aminomethyl radical is formed via deprotonation of the Ph2 NMe cation-radical
by a basic species. Then, a coupling reaction between the imine anion-radical and the aminomethyl
radical take place by means of the chiral catalyst to enantioselectively produce the 1,2-diamine
derivatives 106.
6. Conclusions
Synergistic catalysis evolved from organocatalysis combined with other types of catalysis to
access new activation modes. As discussed, there is a range of different combinations that have been
discovered and many more that still need to be designed. We believe that this relatively new field of
catalysis holds high potential and will greatly contribute to synthetic chemistry, both in academia and
in industry.
Author Contributions: A.S. and V.N. contributed equally to this work. A.S., V.N., A.B., F.F., A.A. and A.C. all
collectively conceived the project, drafted and revised the manuscript.
Funding: This research received no external funding.
Acknowledgments: Aurora Cacciapuoti (http://www.auroracacciapuoti.com) is gratefully acknowledged for the
graphical abstract illustration. Cristian De Luca and Francesca Della Penna are gratefully acknowledged for
their support.
Conflicts of Interest: The authors declare no conflict of interest.
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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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Figure 1. Different methods of substrate activation.

Figure 2. Synergistic catalysis.

2.1.1. Combination with Transition Metal-Based Catalysts

Scheme 4. Synergistic catalysis mediated by palladium and pyrrolidine.

Scheme 5. Mechanistic insight in synergistic palladium and pyrrolidine-based

Scheme 9. Synergistic iron- and peptide-mediated catalysis.

Scheme 10. Synergistic catalysis mediated by palladium and Jørgensen-Hayashi catalyst.

2.1.2. Combination with Other Organocatalysts

Scheme 15. Mechanistic insight in the enantioselective domino oxa-Michael-Mannich reaction.

The sameIn the reaction of α-alkylation

Scheme 17. Mechanistic

3. Hydrogen Bonding Catalysis

3. Hydrogen Bonding Catalysis

Scheme 20. Enantioselective

3.1. Synergistic Catalysis with Hydrogen Bonding Catalysts

Scheme 21. Synergistic catalysis combining a Cinchona alkaloid-derived squaramide-based catalyst

3.1.2. Combination with other Organocatalysts

3.1.2. Combination with Other Organocatalysts

Scheme 23. Synergistic catalysis mediated by two different thiourea-based catalysts.

The asymmetric reduction of 1,2-diketones provides enantiomerically enriched α-hydroxy

The asymmetric reduction of 1,2-diketones provides enantiomerically enriched α-hydroxy

4. Cinchona Alkaloids Organocatalysis

Figure 3. Cinchona alkaloids.

Figure 4. Cinchona alkaloids as bifunctional catalysts.

Scheme 27. Quinuclidinic proton quaternarization.

Scheme 28. First asymmetric reaction employing cinchonine Ia as catalysts.

Furthermore, Wynberg and Hiemstra developed, in 1981, an enantioselective 1,4-addition of thiols

Scheme 29. Enantioselective 1,4-addition of thiols to unsaturated ketones.

Figure 5. Cinchona alkaloids derivatives functionalized at the C9 position.

Scheme 30. Synergistic catalysis mediated by Cinchona-derived bifunctional catalysts in combination

4.1.2. Combination with Other Organocatalysts

4.1.2. Combination with Other Organocatalysts

Scheme 33. Asymmetric

Enantioselective additions of aldehydes to nitro-olefins, catalyzed by a combination of proline

4.1.3. Combination with Photocatalysts

Scheme 40. Enantioselective hetero-Diels–Alder reaction of cyclopentadienes exploiting a chiral

Scheme 41. Asymmetric fluorination of α-branched cyclohexanones exploiting the combination of

5.1.3. Combination with Photocatalysts

Ooi et al., instead, developed a highly enantioselective α-coupling of N-arylaminomethanes

Scheme 44. Enantioselective α-coupling of N-arylaminomethanes catalyzed by chiral tetraaminophosphonium

The iridium complex [Ir(ppy)2(bpy)]BArF (where Hppy = 2-phenylpyridine, bpy = 2,2′-

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