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Organocatalytic strategies for enantioselective

metal-free reductions
Cite this: Catal. Sci. Technol., 2014,
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4, 2708
Sergio Rossi, Maurizio Benaglia,* Elisabetta Massolo and Laura Raimondi

One of the most important chemical transformations is the reduction of multiple bonds, carbon–carbon as
well as carbon–heteroatom double bonds, since it leads very often to the generation of new stereocenters
in the molecule. The replacement of metal-based catalysts with equally efficient metal-free counterparts is
very appealing in view of possible future applications of non toxic, low cost, and environmentally friendly
promoters on an industrial scale. This perspective will focus specially, but not exclusively, on the enantio-
selective reduction of the carbon nitrogen double bond; despite the historical need for and continued interest
in chiral amines, their synthesis remains challenging. Three metal-free catalytic methodologies available for
the reduction of carbon–nitrogen double bond will be discussed: i) binaphthol-derived phosphoric acids catalyzed
Received 10th January 2014, reductions, with dihydropyridine-based compound as the reducing agent; ii) trichlorosilane mediated reductions,
Accepted 2nd April 2014
in the presence of catalytic amounts of chiral Lewis bases; iii) metal-free hydrogenation of imines through FLP
(Frustrated Lewis Pair) methodology, that involves the use of a combination of a strong Lewis acid with a variety
DOI: 10.1039/c4cy00033a
of sterically encumbered Lewis bases, for examples phosphines or tertiary amines, to activate hydrogen at
www.rsc.org/catalysis ambient conditions. Special attention will be devoted to the most recent applications of the last five years.

1. Introduction commercialization is not without problems. A key reason

responsible for this is the lack of general solutions to address
Though a large number of chiral molecules that find their issues related to chirality. In addition, development is mostly
application in pharmaceutical, flavors, and agrochemicals focused upon cost effectiveness, rather than on application
industries are in pipeline, their development and and research of advanced, state-of-the-art technologies.
Despite several difficulties and many open questions,
Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, 20133 Milano, enantioselective catalysis is rapidly becoming more and more
Italy. E-mail: [email protected]; Fax: +39 02 50314159 popular also at the industrial level: examples come from

Sergio Rossi was born in Bergamo Maurizio Benaglia was born

in 1983. In 2007 he obtained in Bergamo in 1966; after com-
his Laurea in Chemistry, at the pleting his doctoral studies at
University of Milan, Italy and in the University of Milan with
2010 he completed his doctoral Prof. Cinquini, he spent two
studies on the activation of years as postdoc working with
trichlorosilyl derivatives with Prof. Jay Siegel, at UCSD, San
chiral Lewis bases under the Diego. Back to Italy, he became
supervision of Prof. Benaglia, in 2006 associate professor at
at the University of Milan. the Department of Chemistry
In 2011, he joined the group of the University of Milan. In
of Prof. Denmark with a post- 2001 he was awarded with the
Sergio Rossi doctoral fellowship, at the Maurizio Benaglia “G. Ciamician” Medal of the
University of Urbana-Champaign, Italian Chemical Society. He is
USA, where he worked on Lewis base-catalyzed asymmetric author of more than 150 publications on scientific international
sulfenylation reactions. In 2012 he moved back to Milan, as journals, including three patents, five review articles and six book
postdoctoral fellow, where he is developing enantiomerically chapters. His research interests focus on catalytic reactors in
pure tetrachlorosilane-based Lewis acids for catalysis He is flow chemistry, novel synthetic methods, design of new chiral
author of 13 papers on international journals. organocatalysts and chiral supramolecular assemblies.

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technologies such as asymmetric hydrogenation.1 As stereo- multiple bonds, carbon–carbon as well as carbon–nitrogen
selective methodologies develop over time, declining costs double bonds, since it leads very often to the generation of
enable companies to access public-domain technologies. new stereocenters in the molecule. The outcome of a reduc-
Enantioselective catalysis has witnessed increased activity tion process is therefore the production of different stereo-
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in terms of extensive academic and industrial investment. isomers and the control of the reaction, in the attempt to
Industries are keen on further growth in the market for obtain preferentially one stereoisomer over the others, which
“chiral technologies”, as new processes and reactions are dis- requires the use of a “chiral technology”. The replacement of
covered and applied in pharmaceutical synthesis. Further- metal-based catalysts with equally efficient metal-free counter-
more, the rising complexity of new chemical entities calls parts is very appealing in view of possible applications in the
for the evolution of advanced catalytic chemo- and stereo- future of non toxic, low cost, and environmentally friendly
selective technologies.2 promoters on industrial scale.
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Indeed, the importance of catalysis to the pharmaceutical The perspective will focus specially, but not exclusively, on
industry has steadily increased over the past two decades.3 the enantioselective reduction of the carbon–nitrogen double
Catalysis in pharmaceutical R&D has been attracting con- bond. Despite the historical need for and continued interest
tinuously increasing attention due to increasing regulatory in chiral amines, their synthesis remains challenging.7 This
requirements that force companies to develop and study is especially true in the context of introducing nitrogen into
single-enantiomer drugs, environmental protection laws and a pharmaceutical compound, with all its complexity and
the pressure to reduce drug development cost and time; the multifunctionality, or into an advanced intermediate via an
picture is completed by the continued discovery of new prac- operationally simple, preferably one-step, procedure allowing
tical catalysts from both academia and industry, that make high chemo-, regio-, diastereo-, and enantiocontrol. It is obvi-
available possible new solutions for production.4 Catalysis is ous that catalytic asymmetric hydrogenation of prochiral
one of the solutions that companies are exploring to address unsaturated compounds, such as olefins, ketones, and imines,
the problem of the increasing complexity of chemical targets. has been intensively studied and is considered a versatile
The average number of manipulations required to synthesize method for access to chiral compounds. However, stereo-
an active pharmaceutical ingredient (API) continues to grow selective hydrogenation of carbon–nitrogen double bonds,
and currently amounts to an average of 12 synthetic steps. including those inserted in heteroaromatic compounds, is
Finally catalysis plays a fundamental role in companies’ much less explored, presumably because of different prob-
strategies aimed to set up a second generation process to lems, the main being the deactivation and/or poisoning of
develop environmentally favorable API manufacturing pro- catalysts by compounds containing nitrogen and sulfur atoms.
cesses, without compromising the safety, efficacy and quality Despite the difficulties cited above, the search for catalysts
of the final product.5 enabling efficient asymmetric hydrogenation of aromatic/
In this context, the advent of organocatalysis6 brought heteroaromatic compounds continues and it is driven by the
new attractive possibilities, to realize stereoselective cata- prospect of straightforward and efficient routes to optically
lytic synthesis of complex chiral molecules, bearing several active saturated or partially saturated chiral heterocyclic com-
functional groups, with metal-free processes. One of the most pounds.8 On the other hand enantioselective, metal-catalyzed
important chemical transformations is the reduction of hydrogenations suffer from other drawbacks: catalysts are

Elisabetta Massolo was born Laura Raimondi received her

in Milan in 1988. She received PhD in Chemical Sciences at
her Laurea in Chemistry in the Università di Milano, Italy
2012 working on the design and in 1989 with Prof. Cinquini.
the synthesis of new chiral She worked at the University of
atropisomeric ligands. She is California (Los Angeles, USA)
currently completing her PhD with Prof. Houk (1989–1990);
program under the supervision of she then become Researcher at
Prof. Benaglia at the University the Università di Milano, and
of Milan, Italy. At present, she Associate Professor in Organic
is working on the development Chemistry in 1998. Her scientific
of novel synthetic strategies to interests are mainly in the appli-
Elisabetta Massolo promote stereoselective reactions. Laura Raimondi cation of Molecular Modelling
In particular, she is studying techniques to the study of organic
the use of chlorosilane-derivatives in enantioselective reductions, reactions. Her research activity is well documented by 90 publi-
the reactivity of nitroacrilates and the use of amines and bifunc- cations on scientific journals of international relevance. In 1996
tional catalysts in new synthetic methodologies. Prof. Raimondi was awarded the Ciamician Medal by the Società
Chimica Italiana for her scientific activity.

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generally quite expensive species, typically constituted by an

enantiomerically pure ligand (whose synthesis may be costly,
long and difficult) and a metal species, in many cases a pre-
cious element. Since chiral amines are finding applications
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in an increasing number of fields,7 such as pharmaceuti-

cals, agrochemicals and fragrances, the possibility to develop
an organocatalytic approach has attracted much attention
because it might represent a solution to the problems due to
the presence of toxic metal, whose leaching could contami-
nate the product.
Today three metal-free catalytic methodologies are avail-
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able for the reduction of the carbon–nitrogen double bond,9 espe-

cially of ketoimines: i) binaphthol-derived phosphoric acids
catalyzed reductions with a dihydropyridine-based compound as
the reducing agent; ii) trichlorosilane mediated reductions, in the Scheme 1 Hydrogen activation promoted by frustrated Lewis pair.
presence of catalytic amounts of chiral Lewis bases; iii) metal-free
hydrogenation of imines through FLP (Frustrated Lewis Pair)
methodology, which involves the use of a combination of a of the quasi-linear P⋯H–H⋯B activation mechanism cast
strong Lewis acid, like tris(perfluorophenyl)borane B(C6F5)3 some doubts on the corresponding transition state. According
with a variety of sterically encumbered Lewis bases, for exam- to these new results, a transition state in a linear arrangement
ples phosphines or tertiary amines, to activate hydrogen at only appears for rather large P⋯B distances over 4.5 Å. Such
ambient conditions. The most representative examples of all values seem to be artificially induced by the quantum chemi-
three methodologies will be presented in the discussion section, cal method (B3LYP) which is well known to overestimate
with special attention on the most recent applications of the steric congestion. With a properly dispersion-corrected den-
last four–five years. sity functional no linear transition state exists and only one
minimum with a rather large H–H distance of about 1.67 Å
2. Frustrated Lewis Pairs could be found. This points to an alternative bimolecular
(FLP)-catalyzed reductions mechanism in which H2 access into the frustrated P⋯B bond
is the rate-determining step. Further theoretical studies to
Hydrogenation catalysis is the most common transformation address this important question are needed in order to eluci-
used in the chemical industry and it is employed in the prep- date fully the mechanism.
aration of scores of commercial targets, including natural Following the initial studies on metal-free catalytic hydro-
products, commodities and fine chemicals.10 Recently, stud- genation of imines,13a it was proposed that the substrate
ies have been directed to the exploitation of non-transition could serve as the base-partner of an FLP and thus only a cata-
metal systems for the activation of H2 and subsequent use in lytic amount of a Lewis acid, as tris-pentafluorophenyl borane,
hydrogenation. A novel and promising approach to the utili- should be required. Indeed, a series of differently substituted
zation of hydrogen in catalysis has emerged from studies imines were reduced by hydrogen using a catalytic amount
related to the use of a proper combination of a Lewis of B(C6F5)3 (Scheme 2).13b For poorly basic imines, addition
acid and a Lewis base, in which steric demands preclude of catalytic amount of sterically encumbered phosphine
classical adduct formation. Such systems have been termed accelerated the reduction. This presumably results from the
“frustrated Lewis pairs” or “FLPs”.11 In these unique Lewis greater ease with which phosphine/borane cleaves hydrogen
acid–base (LA–LB) adducts, the steric hindrance precludes heterolytically.
the formation of stable donor–acceptor complexes, on account The application to asymmetric synthesis is a logical and
of which these pairs are able kinetically to promote various highly desirable extension of these findings. Indeed, stereo-
unprecedented reactions with organic and inorganic mole- selective methodologies can be designed based on the con-
cules. Their most remarkable reactivity is the heterolytic cleav- sideration that FLP reductions can be viewed as a catalytic
age of hydrogen at room temperature, the capacity of which version of borohydride reductions. In 2011 Stephan studied
was long thought to be the exclusive characteristic of transi- the catalytic hydrogenation of chiral ketimines using tris-
tion metals (Scheme 1). pentafluorophenyl borane as a catalyst.14 Using imines derived
Computational studies12 suggest the generation of a from camphor and menthone, the reductions proceed with
phosphine–borane “encounter complex”, stabilized by H⋯F quantitative yields and high diastereoselectivities (up to 99% d.e.).
interactions. In this “species” the boron and phosphorus Generally, the reduction of chiral imines with B(C6F5)3
centers are close but fail to form a P to B dative bond as a resulted in excellent diastereoselectivities when the stereo-
result of steric congestion. Interaction of H2 in the reactive genic center was close to the unsaturated carbon center, prob-
pocket between the donor and acceptor sites results in ably due to the proximity of the stereocenter to the approach
heterolytic cleavage of H2. However more recent studies12b of the sterically bulky reductive [HB(C6F5)3]− species.

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Scheme 3 Enantioselective hydrogenation of ketoimines with chiral

boranes.

the use of the diastereomerically pure salts as catalysts for

the hydrogenation process gave more encouraging results. By
using 3′, full conversion into the product was achieved in
48% e.e. for the S enantiomer, while 2′ led to the R enantiomer
with higher enantioselectivity (79% e.e.) and up to 83% e.e.
for N-PMP substituted imines. More recently, Klankermayer
and co-workers developed a modified version of the previously
described camphor borane featuring a strongly enhanced
stability.16 After the first hydrogenation experiment, which
yielded the desired amine with full conversion and 76%
Scheme 2 Catalytic cycles for imine reductions.
enantiomeric excess, the recycled solid catalyst 4 was subse-
quently retransferred to the autoclave, mixed with toluene and
substrate and pressurized with 25 bar hydrogen. Four consecu-
Recently, an important breakthrough was obtained by tive runs demonstrated constant levels of conversion and
Klankermayer, who developed the first stereoselective cata- enantioselectivity, confirming the effectiveness and stability of
lytic FLP hydrogenation, employing sterically crowded chiral this novel chiral FLP catalyst.
boranes as Lewis acids (Scheme 3). After early experiments It should be also mentioned that in 2012 the same group
with pinene-derived chiral boranes,15a able to promote the reported the enantioselective hydrosilylation of various imines
reduction of acetophenone derived ketimines with only 13% e.e., using a slightly modified version of the previous camphor
in 2010 a chiral borane derived from camphor allowed a high derived catalyst.17 Hydrosilylation of sterically hindered imine
enantiomeric excess (up to 83%) in the enantioselective reduction afforded only negligible conversion and the introduction of an
of imines.15b The hydroboration of a 2-phenyl bicycloheptene electron-withdrawing group in the acetophenone moiety led to
derivative 1 using bis(perfluorophenyl)borane in toluene or relatively low conversion, albeit with high enantioselectivity.
pentane gave the diastereomeric boranes 2 and 3 in a 20 : 80 However, the presence of a methoxy donor group strongly
ratio as confirmed by multinuclear NMR spectroscopy. Treat- enhanced the conversion (up to 90%), while retaining high
ment of an n-pentane solution of the boranes mixture with levels of enantioselectivity (up to 85% e.e.).
hydrogen at 25 °C in the presence of tri-tert-butylphosphine The field of chiral FLP catalysts is clearly in its infancy,
resulted in the precipitation of a colorless solid in 53% yield, but it is undoubtedly attracting the interest of several groups.
which multinuclear NMR spectroscopy confirmed to be a mix- Du envisioned that direct hydroboration of chiral dienes
ture of the activated FLP salts 2′ and 3′. bearing two terminal olefins with HB(C6F5)2 could provide
In the presence of a 5 mol% amount of a 1 : 1 mixture of simple access to a new class of chiral borane catalysts for the
the two diastereoisomers at 65 °C and 25 bar hydrogen, asymmetric hydrogenation of imines.18 In this strategy,
imine N-(1-phenylethylidene)aniline was transformed into the binaphthyl based chiral diene 5 acts like a “ligand” to gener-
corresponding secondary amine with a 20% e.e. Obviously, ate the borane catalyst in situ without further isolation, thus

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However, their synthetic utility as chiral catalysts for

stereoselective reactions has been quite limited until recently.
The key to successfully realizing enantioselective transforma-
tions using a chiral Brønsted acid is to activate chemically
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the substrate via protonation and to control stereochemically

the reaction outcome through the chiral environment created
by the chiral conjugated base, which exists in the proximity
of the substrate.21 Among the various organic Brønsted acids,
chiral phosphoric acids have gained great attention in the last
few years and have proved to be very successful catalysts.22
The great popularity of these compounds originates from
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their several positive characteristics. One important feature is

that the phosphoryl oxygen would function as a Brønsted
basic site; therefore an acid/base dual function can be antici-
pated, even for monofunctional phosphoric acid catalysts
(Fig. 1). Furthermore, two substituents can be directly intro-
duced at the phosphorous atom, thus creating a chiral envi-
ronment close to the catalytically active site. Due to their
symmetry, the commercial availability of both the enantio-
Scheme 4 Novel chiral boranes for FLP catalyzed enantio-selective
mers and the numerous protocols for introducing substitu-
hydrogenations.
ents at the 3,3′-position of the binaphthyl backbone, BINOL
derivatives were generally selected as chiral scaffold to con-
struct enantiomerically pure phosphoric acids.
ensuring easy operation and rapid evaluation (Scheme 4). In 2005 Rueping reported the first enantioselective
Moreover, terminal olefins offer the advantage of generating Brønsted acid-catalysed hydrogenation of ketoimines.23 A
enantiomerically pure boranes by hydroboration, instead of screening of various phosphoric acids selected compound 7
the diastereoisomer mixture which would be obtained in the as the best performing catalyst, showing that not only steric
case of internal olefins. After proper tuning of the reaction but also electronic effects of the 3,3′ substituents on the
conditions and of the substituents at the 3,3′-positions of binaphthol scaffold played a role in this transformation, while
binaphthyl framework, a variety of imines was smoothly screening of solvents established that nonpolar solvents were
hydrogenated in good yields and high enantioselectivities essential (68–84% e.e. in benzene, Scheme 5). The phosphoric
(up to 89% e.e.). acid acts as a bifunctional catalyst, not only activating the
One of the main issues related to FLP catalytic systems is
the reduced stability in the presence of air and moisture, thus
complicating their effective recycling. Recently, Rieger and Repo
described a chiral intramolecular FLP catalyst (cat. 6, Scheme 4)
with high air and moisture stability, foreshadowing the extended
applicability of these systems.19 This catalyst was used in the
hydrogenation of imines with a moderate catalytic loading,
leading to an enantiomeric excess up to 37% e.e.
These results represent only the beginning of a very prom-
ising area, that calls for the design and the development of
new, more efficient, highly stereoselective FLP catalytic sys-
tems for the activation of hydrogen and other small organic
molecules.20

3. Chiral phosphoric acids-catalyzed

reductions
Another opportunity for realizing enantioselective metal-free
reductions comes from the use of chiral phosphoric acids.
The electrophilic activation of a substrate by means of a
Brønsted acid is, undoubtedly, the most straightforward and
common approach employed to promote a reaction and hence
they have been widely utilized as efficient catalysts for numer- Fig. 1 Structural elements characterizing binaphthol-derived chiral
ous organic transformations. phosphoric acids.

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the aromatic ring did not affect significantly the enantio-

selectivity (Scheme 6).
It is remarkable to observe that previously only N-Ar
imines derived from acetophenone were used as substrates
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in this catalytic reduction methodology. Based on NMR stud-

ies, the authors proposed transition state A (Scheme 6)
wherein the phosphoric acid formed H-bonds with both
the hydroxyl and the imine functions of the substrate.
The hydride transfer would then occur from the Re face
of the imines to deliver the amines with the observed (S)
configuration.
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One important breakthrough in the field was achieved by

Scheme 5 Enantioselective phosphoric acid catalyzed reduction of Antilla and Li, when they reported the enantioselective hydro-
ketoimines. genation of enamides by exploiting chiral phosphoric acid
catalysis.27 Although highly efficient examples of reductive
amination of ketones and hydrogenation of ketoimines
ketoimines but also coordinating the Hantzsch ester through catalysed by chiral Brønsted acids were already reported,
hydrogen bonding with the Lewis basic site PO. these reactions were limited primarily to reactants derived
At the same time, independently List and MacMillan from aniline and its analogues. As a result, the deprotection
described novel, modified chiral phosphoric acids for of the aromatic group to release the amino group could be
performing the same reaction efficiently. List group relatively difficult, rendering these methods less synthetically
observed that a differently substituted catalyst (8, (R) appealing. On the contrary, when considering N-acyl enamide
3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydro- substrates, the acyl group of the reduction product can be
gen phosphate (TRIP)) under optimized conditions showed removed easily under standard procedures in good yield.
significantly improved performance in many aspects, e.g. shorter Indeed phosphoric acid 10 was able to promote efficiently
reaction times, lower temperature, higher yields and e.e. values the reaction. In the hypothesized catalytic cycle, in the pres-
(80–98% yields, 80–93% e.e.) and, most notably, much lower ence of the catalyst and the cocatalyst acetic acid, the
catalyst loading.24 Moreover, this catalyst was also able to enamide is tautomerized to the corresponding imine, which
reduce highly enantioselectively aliphatic ketoimines and could is activated by the acid via an iminium intermediate. In the
be employed also in the first enantioselective organocatalytic following step, only the chiral phosphoric acid is active
reductive amination reaction. enough to catalyse the reduction of the imine, while acetic
Soon after, MacMillan's group explored properly this acid probably contributes merely to keep a sufficient concen-
organocatalytic reductive amination,25 observing that the tration of iminium intermediate.
ortho-triphenylsilyl phosphoric acid 9 in the presence of
MS 5 Å facilitates the desired coupling of acetophenone and
4-OMe-aniline in high conversion and with excellent levels
of enantiocontrol at 40 °C (87% yield, 94% e.e.). The scope
of this reaction is quite wide, as a variety of substituted
acetophenone derivatives can be successfully coupled, includ-
ing electron-rich, electron-deficient, as well as ortho, meta,
and para substituted aryl ketone systems. Notably, methyl
alkyl substituted ketones are also suitable substrates, thus
highlighting a key benefit of reductive amination versus imine
reduction: imines derived from alkyl–alkyl ketones are unsta-
ble to isolation, a fundamental limitation that is bypassed
using this route.
In 2010 Wang and co-workers reported the first examples
of enantioselective transfer hydrogenation of ortho-hydroxyaryl
alkyl unprotected N–H ketimines using a chiral phosphoric
acid as a catalyst and Hantzsch ester as the hydrogen source.26
The hindered (S)-3,3′-bis(triphenylsilyl)-substituted phosphoric
acid 9 turned out to be the most effective in terms of transfer
of the stereochemical information. Under optimal conditions,
the unsubstituted amine was isolated in 94% yield with 92% e.
e., while the presence of either an electron-withdrawing or an
electron-donating group at the C-3, C-4, and C-5 positions of Scheme 6 Stereoselective reduction of enamides.

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The phosphoric acid-catalysed reduction protocol was

extended to α-imino esters and their derivatives, and employed
even in a gram scale synthesis of a chiral intermediate.28 The
enantioselectivity was highly dependent on the steric size of
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the ester R′′ group; high e.e. were obtained for substrates
bearing bulky ester groups such as i-Pr and t-Bu, whereas only
33% e.e. was observed for the methyl ester substrate. As for
the scope of R′, several substituted phenyl isopropyl esters
containing either electron-donating or electron-withdrawing
groups all led to good yields and excellent e.e. (Scheme 7).
However, a low reactivity was observed in the case of the alkyl-
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substituted imino ester.

Independently, Antilla and co-workers developed an
organocatalytic reduction process for the enantioselective synthe-
sis of protected α-amino acids, by employing a VAPOL-derived
phosphoric acid.29 Derivative 11 was found to be superior in this
reaction to BINOL-derived phosphoric acid, as well as to a
small library of alternative chiral phosphoric acid catalysts.
Scheme 8 Dynamic kinetic resolution reactions.
However, the analogous reductive amination process involv-
ing in situ imino ester formation was not efficient and was
selective only when starting materials bearing aliphatic sub-
stituents were used. Enders has recently described the reduc- oxygen-free conditions are required as substantial acetophen-
tion of ketoimines and α-imino esters with catecholborane one and p-formylanisidine formation was observed in the pres-
via Brønsted acid catalysis.30 Under optimized conditions, ence of oxygen, presumably via an oxidative cleavage of the
various electron-rich as well as electron-deficient aromatic enamine intermediate.
α-imino esters with different substitution patterns were reduced A few years later, List reported the use of DKR in the cata-
in very good enantioselectivity and high chemical yield. lytic asymmetric reductive amination of racemic α-branched
List's group discovered an interesting variation on this ketones.32 An important feature of this process is its toler-
theme, realizing the direct reductive amination of α-branched ance of a variety of different substituents whilst maintaining
aldehydes via an efficient dynamic kinetic resolution (DKR).31 excellent enantioselectivity. Simple alkyl-substituted substrates
Under the reductive amination conditions an α-branched are particularly reactive, requiring only a very low amount of
aldehyde undergoes a fast racemization in the presence of the catalyst, while sterically more-demanding substrates, as well
amine and acid catalyst via an imine/enamine tautomerization. as aromatic substrates, require slightly higher catalyst load-
The reductive amination of one of the two imine enantiomers ings; α,β-unsaturated, α-branched ketones could be converted
would then have to be faster than that of the other, resulting into the desired product in reasonable yields and excellent
in an enantiomerically enriched product via a dynamic kinetic selectivity.
resolution (Scheme 8). TRIP catalyst 8 once again turned out In 2013, Akiyama's group developed the Brønsted acid-
to be the most effective and enantioselective catalyst for this catalyzed asymmetric hydrogen transfer reaction of indolines,
transformation and provided the chiral amine product in by employing imines as hydrogen acceptors; the work repre-
50% yield and an enantiomeric excess of 68%, which could be sents the first example of an efficient oxidative kinetic resolu-
raised to 87% yield and 96% e.e. under optimized conditions. tion of secondary amines.33 This approach allowed the
The efficient removal of water formed during the reaction isolation of 2-substituted and 2,3-disubstituted indolines in
seems to be important as the enantiomeric ratio improved high yields and excellent enantioselectivities, allowing at the
considerably upon using 5 Å molecular sieves; furthermore, same time the synthesis of chiral amines in a nearly enantio-
pure form (Scheme 9).
From a mechanistic point of view, one enantiomer of the
indoline would preferentially participate in this hydrogen
transfer reaction and be converted into a cyclic imine, which
would immediately isomerize to a stable indole. On the basis
of the bifunctional nature of the phosphoric acid, the authors
hypothesized a dicoordinated cyclic transition state, where
the Brønsted acidic proton activates the ketoimine and the
Lewis basic phosphoryl oxygen coordinates to the indoline
N–H. The most favorable TS resulting from DFT calculations
shows the N-aryl group of the ketoimine and the 2-phenyl
Scheme 7 Stereoselective reduction of imino esters. group of the indoline to have no unfavorable steric interactions.

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Brønsted acid and is reduced to the desired tetrahydroquin-

oline. Subsequent proton transfer will then restore the phos-
phoric acid. The absolute configuration of the products can
be explained by a stereochemical model, where the approach
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of the hydride nucleophile is favoured from the less hindered

Si face since the Re face is shielded by the large phenanthryl
group of the catalyst.
The methodology was then applied to the enantioselective
reduction of pyridine derivatives.35 Catalyst 10 worked effi-
ciently in the hydrogenation of this class of compounds to
furnish the corresponding hexahydroquinolinones with high
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Scheme 9 Catalytic oxidative kinetic resolution of indolines. enantioselectivities and with analogous mechanism. How-
ever, the mechanistic picture is quite different in the case of
3-substituted quinolones. The key step of the transfer hydro-
In contrast, the steric hindrance between the 3,3′-substituents genation of 3-substituted quinolines is the enantioselective
of the chiral phosphoric acid and the two aryl groups of the protonation of the intermediary enamine, which, after 1,2-hydride
substrates destabilizes the other possible transition states. addition, leads to 3-substituted tetrahydroquinolines with good
The phosphoric-acid-catalysed methodology was success- enantioselectivities (Scheme 10).36a Moreover, the strategy was
fully used also in the reduction of CN bonds of heterocyclic successful also in the reduction of 2,3-substituted quinolines,
systems. Examples of efficient catalysts for the asymmetric which allowed isolation of the octahydroacridine in good yield
hydrogenation of aromatic and heteroaromatic compounds and with excellent diastereo- and enantioselectivities.36b
are quite rare, even amongst the chiral Rh, Ru, and Ir com- At the end of this section it is worth mentioning that chi-
plexes. It was therefore an important breakthrough the ral phosphoric acids have been employed also for CO and
development by Rueping's group in 2006 of an enantioselective CC bonds stereoselective reductions. About the carbonyl
organocatalytic partial reduction of quinoline derivatives34 reduction, in 2011, Antilla reported the first example of
which are of great synthetic importance in the preparation of enantioselective reduction of ketones catalyzed by a chiral
pharmaceuticals and agrochemicals, as well a structural key phosphoric acid derivative.37 The reduction of variously
element of many alkaloids. This represented the first exam- substituted acetophenones with catecholborane promoted by
ple of a metal-free reduction of heteroaromatic compounds. a series of BINOL-derived phosphoric acids gave the desired
After screening of a variety of sterically congested phosphoric product with only modest enantioselectivity, catalyst 8 being
acids, (R)-(−)-9-phenanthryl-1,1′-binaphthyl-2,2′-diyl hydrogen- the best performing one.
phosphate was selected as catalyst of choice to generate However, it was found that an increase in the enantio-
2-phenyltetrahydroquinoline in 97% e.e. (Scheme 10). meric excess could be obtained by lowering the reaction tem-
The first step in the enantioselective cascade hydrogena- perature to −20 °C and by using 4-(dimethylamino)pyridine
tion is the protonation of quinoline through a Brønsted acid (DMAP) as an additive; this pyridine derivative is likely to
catalyst to generate the iminium ion, followed by the transfer form the corresponding pyridium phosphate salt, a very weak
of the first hydride from dihydropyridine to generate the cor- acid (species 13, Scheme 11). The substrates bearing either
responding enamine, which reacts in a second cycle with the electron-donating or electron-withdrawing groups on the phe-
nyl ring furnished the resulting chiral alcohols with good
selectivity; labile functional groups, such as nitrile, nitro,
ester, iodide and bromide, were generally well tolerated.
The boron center is believed to act as a Lewis acid to acti-
vate the carbonyl, while the PO moiety can act as a Lewis
base to increase the nucleophilicity of catecholborane. Simulta-
neously, the hydride from unreacted catecholborane is added
to the activated carbonyl under the influence of a chiral envi-
ronment to form the hydroboration product and regenerate
the catalyst.
Regarding CC reductions, the reduction of unsaturated
carbonyl derivatives was already described in 2006. The organic
salt of (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl
hydrogen phosphate 8 (TRIP) and morpholine was able to
promote transfer hydrogenation via Hantzsch dihydropyridine
of α,β-unsaturated aldehydes with high levels of enantio-
selectivity, ranging between 96% and >98% e.e. (Scheme 12).38
Scheme 10 Enantioselective reduction of heterocycles. The reaction proceeds via an iminium ion intermediate since

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Perspective Catalysis Science & Technology

substoichiometric amount of the HCl salt of a chiral imidazolinone

(81% yield and 81% e.e.).39
The phosphoric-acid catalysed protocol was successfully
employed also in the reduction of unsaturated ketones
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(Scheme 12).40
The combination of (R)-(TRIP) (acid 8) and valine was
selected as best performing catalyst; the effect of the amino
acid seems to be important as corresponding glycine derived
catalyst gave significantly reduced enantioselectivity, as well
as the reaction promoted by the phosphoric acid alone.
When the opposite enantiomeric counteranion ((S)-TRIP) was
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used, the same major enantiomer was formed but with much
lower enantioselectivity, thus demonstrating the existence of
a matched/mismatched catalyst–ion pair combination effect.

Scheme 11 Enantioselective chiral phosphoric acid catalyzed 4. Trichlorosilane-promoted reductions

reduction of ketones.
The third organocatalytic approach to perform a stereoselective
reduction involves the use of trichlorosilane. This reagent
salts of tertiary amines are ineffective, and stereoselection pre- is a very cheap, colorless, volatile liquid, easily supplied
sumably occurs in the cationic transition state of the reaction from the silicon industry. Purified trichlorosilane is the
by means of a stereochemical communication with the chiral principal precursor to ultrapure silicon in the semiconductor
phosphate counteranion, possibly through CH⋯O hydrogen- industry; it is the basic ingredient used in the production
bonding interaction. Notably the procedure was used success- of purified polysilicons. Because of its reactivity and wide
fully to convert citral into (R)-citronellal with an e.e. value of availability, it is frequently used in the synthesis of silicon-
90%, the highest enantioselectivity reported for this reaction containing organic compounds, for example in the prepara-
until then. tion of perfluoroalkyltrichlorosilane, employed in surface
The result represented an advancement compared to science and nanotechnology to form self-assembled mono-
the previous studies by List and MacMillan, where chiral layers. In order to act as reagent able to reduce CN bonds,
imidazolidinone-based catalysts did not give satisfactory trichlorosilane needs to be activated by coordination with bases,
results in the reduction of sterically non-hindered aliphatic such as N,N-dimethylformamide, acetonitrile and trialkylamines,
substrates. Indeed it should be mentioned that in 2004 to generate hexacoordinated hydridosilicate, the real active
the first example of an enantioselective metal-free transfer reducing agent that operates under mild conditions.41 The
hydrogenation of an olefin was described, the reduction of use of chiral Lewis bases offers the possibility to control the
β-methyl, α,β-unsaturated aldehyde, in the presence of a absolute stereochemistry of the process and it has been
widely explored in the last few years, leading to the develop-
ment of some very efficient catalysts. Since two reviews have
recently covered the topic,42 only the most representative
classes of chiral catalysts will be presented here, with the
intent to show the wide applicability of trichlorosilane to a
great variety of substrates and also to introduce properly
the argument to non-experts in the field.
Most of the chiral Lewis bases developed for trichlorosilane
activation derive from natural α-aminoacids. After seminal
works by Matsumura with proline,43 the first successful
catalyst for trichlorosilane-mediated enantioselective reduc-
tions of ketoimines was reported by Malkov and Kočovský
(e.e. up to 93%).44 They identified as organocatalyst of choice
the N-methyl-(S)-valine-derived type 14 compounds, commer-
cially available since 2009. The screening of a variety of
N-methyl-(S)-amino acids highlighted valine as chiral element
of choice to perform stereocontrol and allowed to individuate
key features of the catalytic system: the N-methyl formamide
moiety of the catalyst is fundamental to achieve high levels of
enantioselectivity, while the anilide moiety must have a
Scheme 12 Phosphoric acid catalyzed reductions of CC bonds. NH group; arene–arene interactions may play an important

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role in determining the stereoselectivity of the catalyst, and imines and ketones in the presence of trichlorosilane.52
bulkier groups in the 3,5-positions of the aromatic ring Secondary alcohols could be synthesized with high enantio-
(diisopropyl and di-tert-butyl) have a positive effect on the selectivity (up to 97%) employing a catalytic amount of
enantioselectivity of the process. In the proposed transition N-formyl-α′-(2,4,6-triethylphenyl)-(S)-proline (catalyst 17). The
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state coordination of the silicon atom by the two carboxyamide selection of the best performing compound was the result of
groups guarantees chemical activation of the reducing agent, the screening of a series of α′-arylproline derivatives. Both the
whereas the formation of a hydrogen-bond between the sec- carbonyl group at the α-position and a 2,4,6-triethylphenyl
ondary amide group of the catalyst and the substrate repre- group at the 5 position in the proline ring are crucial in
sents an element of stereocontrol. The N-aryl group is believed determining the high enantioselectivity. In a closely related
to play an important role in the stereocontrol because it should work,53 our group reported a similar use of chiral amino acids,
be involved in π–π stacking interaction between the catalyst whose ability to form hydrogen bonds with the substrate pro-
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and the substrate (Scheme 13). The general applicability of vides an easy route to induce enantioselectivity. This approach
catalyst 14, known as Sigamide, was then successfully investi- was applied for the first time to the HSiCl3 mediated reduction
gated in the reduction of multifunctionalized ketimines bear- of carbon–nitrogen double bonds employing proline-derived
ing heterocyclic and aliphatic moieties.45 Lewis bases as catalysts (catalyst 18, Scheme 13), leading to
The popularity of this catalytic species is demonstrated high chemical yields and enantiomeric excess up to 75%. It is
also by the development of immobilized versions of 14 on important to point out that in 2009 Schreiner published a
different supports, in order to realize a recoverable system. detailed investigation of the influence that non aromatic
Heterogeneous materials were employed; Merrifield, Wang, groups in N-formylprolinamide may have on the enantio-
TentaGel and Marshall resins, were all employed to immobilize meric excesses of ketoimine reductions, also employing com-
the organocatalysts through an ethereal bond (catalyst type 15).46 putational methods in the attempt to get some mechanistic
By operating under the best experimental conditions, with the insights in the process.54 By working with a series of novel
Merrifield-anchored catalyst, the product was isolated in good chiral organocatalysts derived from proline, valine, and
yield and in an e.e. about 10% lower than the enantio- pipecolinic acid, the dominant role of the amino acid scaffold
selectivity obtained with the non-supported catalyst. Other in the enantiodifferentiating step was demonstrated. DFT
recovery strategies have been employed, including the use of mechanistic studies seem to confirm that the catalyst not only
gold nanoparticles,47 block polymethacrylate polymers48 and coordinates to trichlorosilane, but also reacts as a proton donor
a fluorous tag.49 in the crucial transition structure; indeed, the importance of
Later Sun and co-workers developed a N-formyl derivative the presence of acidic NH proton of a secondary amide group,
of (S)-pipecolinic acid (catalyst 16), able to promote the able to bind to the basic nitrogen of the reacting imine, has
reduction of N-aryl ketimines with trichlorosilane with high been demonstrated. Although the authors suggest that the
yields and good enantioselectivities.50 Switching from the stereoselective steps for proline, pipecolinic acid and valine-
five-membered ring of proline to a six-membered ring had a derived catalysts may be different, from computational studies
beneficial effect on enantioselectivity. The reduction of ali- they propose a general picture for the catalytic reduction of
phatic ketoimines51 was also accomplished in this work, where ketoimines with trichlorosilane, that could be described as a
the independence of the imine geometry on the selectivity of formal H+/H− transfer to the CN double bond. However other,
the reaction was demonstrated. more refined computational studies are needed to elucidate
It is interesting to note that in 2006 Matsumura reported further the mechanism of these reactions.
the activity of N-formyl proline derivatives in the reduction of A contribution by Matsumura in 2006 opened the way
towards the development of a novel class of catalysts for
trichlorosilane-mediated reductions, derived from chiral amino
alcohols, showing that N-picolinoylpyrrolidine derivatives were
able to activate trichlorosilane in the reduction of aromatic
imines.55 Catalyst 19 gave the best results, leading to enantio-
selectivities up to 80%. The authors proposed that both the
nitrogen atom of the picolinoyl group and the carbonyl oxygen
were involved in the coordination and activation of silicon
atoms. Based on these seminal works, our group has recently
focused on the design and synthesis of a wide class of catalysts
prepared by simple condensation of a chiral aminoalcohol
with picolinic acid derivatives. We56 and Zhang57 reported
independently in a preliminary communication the use of
ephedrine and pseudoephedrine-derived picolinamides in
the reduction of N-aryl and N-benzyl ketimines promoted by
trichlorosilane. The pyridine ring, the free hydroxyl group
Scheme 13 Enantioselective HSiCl3-mediated reductions of ketoimines. and N-alkyl substitution in the aminoalcohol portion were

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Perspective Catalysis Science & Technology

identified as key structural elements, necessary to secure good imidazole catalyst 21 derived from prolinol.59 This was
stereocontrol; the presence of two stereogenic centers on the employed in the reduction of a wide range of aromatics and
aminoalcohol moiety with the correct relative configuration, aliphatics ketimines with just 1 mol% of catalyst and a short
as in (1R,2S)-(−)-ephedrine, as well as of the methyl groups on reaction time, obtaining up to 96% yield and 87% e.e. The
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the amide nitrogen and on the stereocenter in position 2 of same catalyst was then reported for the high selective reduc-
the amino alcohol chain are also necessary to direct efficiently tive amination of a large variety of ketones and aryl or ali-
the stereochemistry of the imine attack by trichlorosilane. In phatic amines.60
the proposed stereoselection model (Scheme 14), leading However the search for novel enantiomerically pure Lewis
to the experimentally observed preferred formation of the bases able to act as catalysts in enantioselective reduction pro-
R isomer of the product, the steric interaction between the cesses is endless. For example in Fig. 2 new organocatalysts,
pyridine ring and N-aryl group is much less significant than based on a different chiral scaffold developed by Malkov and
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that observed in the model leading to the opposite enantio- Kočovský were reported. Chiral oxazolines containing isoquinoline
mer. 4-Bromo and 4-chloro picolinic derivatives showed 22 were employed in the reduction of both aromatic ketones
remarkable catalytic properties. Working at 0 °C with catalyst and imines with trichlorosilane.61 The best enantiomeric excess
20 the chiral amine was obtained in quantitative yield and reached in the reduction of ketones was 87%, while even better
88% enantiomeric excess; a further improvement was results were achieved in the ketimines’ reduction (92% e.e.).
observed by performing the reaction at −20 °C: enantio- The authors hypothesized coordination of trichlorosilane by
selectivity reached 95% e.e. and at the same time no erosion the catalyst would generate a hexacoordinated silicon species
of the chemical yield was observed, with the reduction that would act as the actual reducing species. When a ketone
product isolated in quantitative yield. Even by working with a is the reactive substrate, further activation would be provided
1% mol amount, catalyst 20 promoted the reduction in 90% by coordination of a molecule of trichlorosilane by the car-
yield after only 2 hours. Good results were also obtained in bonyl oxygen.
the enantioselective reduction of N-alkyl imines, a transforma- Almost at the same time, Sun published a novel catalyst
tion only recently accomplished organocatalytically. featuring a sulfinamide group as the stereocontrolling ele-
A very convenient enantioselective organocatalytic three- ment.62 This family of organocatalysts was found to be able
component methodology was also developed; the reductive to activate trichlorosilane for the stereoselective reduction of
amination process, starting simply from a mixture of a N-aryl ketimines with good yields and enantioselectivities,
ketone and an aryl amine, opens an easy access to chiral catalyst 23 being the most successful compound in terms of
amines with a straightforward experimental methodology. stereoselection. Based on the assumption that the mecha-
The hydrosilylation of a range of substrates derived from nism would involve two molecules of Lewis base for the acti-
(R)-1-phenylethylamine was also examined (eq. (b), Scheme 14). vation of HSiCl3, a novel chiral bis-sulfinamide was then
When chiral picolinamide 20 was employed as a catalyst, the developed.63 After a screening of different derivatives, the
control of the stereoselectivity was total, as demonstration of compound of choice was found to be a bis-sulfinamide bear-
the presence of a cooperative effect between the Lewis basic ing a five-methylene linkage. Catalyst 24 promoted the reduc-
catalyst and the (R)-methyl benzyl residue at the imine nitro- tion of the model substrate, N-phenylimine of acetophenone,
gen.58 The approach was extended to the synthesis of several with 96% e.e. (Fig. 2).
enantiomerically pure secondary amines with C1 or C2 sym- The success of the trichlorosilane-mediated reduction meth-
metry. Also the imine derived from methyl isopropyl ketone odology is demonstrated by its application to the reduction of
was readily reduced in >98% yield, to afford an enantio- different classes of compounds, leading to the formation of
merically pure direct precursor of (R)-isopropyl methyl amine. highly functionalized chiral molecules. Indeed trichlorosilane
At the same time Jones reported the use of the N-methyl was used to reduce both α-and β-imino esters (Scheme 15).
Zhang recently reported the first highly efficient protocol
for the organocatalytic synthesis of α-amino esters.64 Notably
the prolinol-derived catalyst of choice, compound 25, exhibited
only moderate enantioselectivities in the hydrosilylation of
N-aryl β-enamino esters, but promoted the reduction of α-imino
esters with high enantioselectivities (up to 93% e.e.). The
introduction of a bulky group at C4 of the pyrrolidine ring

Scheme 14 Chiral picolinamides in HSiCl3-mediated enantioselective Fig. 2 Chiral Lewis bases in trichlorosilane-mediated enantioselective
reductions. reductions.

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Scheme 15 HSiCl3-mediated stereoselective reductions of iminoesters.

was decisive in order to obtain high stereoselectivities. The were reduced in high yields and enantioselectivities typically
addition of small quantities of pentanoic acid was crucial for ranging from 90% to 95%.68 It is worth mentioning that
the efficiency of the process. N-acyl β-enamino esters were totally inactive in the present
More studies have been performed on the reduction of organocatalytic system. The reaction is supposed to proceed
β-imino esters. N-Sulfinyl L-proline amide 26 has been used for through the imine tautomer rather than its enamine counter-
the enantioselective reduction of a range of N-alkyl β-enamino part. In the proposed mechanism the nitrogen atom of the
esters.65 The use of water as an additive proved to be crucial pyridine ring and the carbonyl oxygen atom of the catalyst
to obtain high levels of reactivity and enantioselectivity, accel- are coordinated to HSiCl3, while the imine is activated by the
erating the enamine–imine tautomerization and increasing hydroxyl group of the Lewis base through hydrogen bonding.
the electrophilicity of the imine through protonation of the More recent studies from this group have focused on
nitrogen atom. At the same time our group employed success- α-substituted-β-enamino esters. It should be mentioned that
fully ephedrine-derived catalyst 20 to reduce a series of N-benzyl a few years ago catalyst 14 had been used to develop a new
and N-α-methylbenzyl-β-enaminoesters. Then, hydrogenolysis protocol for the enantioselective synthesis of β-aminoacids
of the enantiomerically enriched N-benzyl-β-aminoesters, followed derivatives from enamine precursors.69 Treatment of the
by LDA-promoted ring closure, afforded enantiomerically pure β-ketoester or β-ketonitrile with p-anisidine afforded enamines,
4-aryl or 4-alkyl substituted β-lactams.66 Furthermore, we reported which as such cannot be reduced by HSiCl3. Since the
a novel class of chiral prolinol derivatives to promote the enamine–imine equilibration is facilitated by Brønsted acids,
hydrosilylation of α-imino and β-imino esters.67 In nearly all a number of acid additives were examined, among which
cases, catalyst 27 was the most effective in the reduction of a AcOH (one mol equivalent) emerged as a good compromise
range of electron rich and electron deficient substrates. Good between reactivity and selectivity. Enamine was reduced to give
results were obtained also with catalyst 28 at −30 °C for 48 h. the amino ester in high yield and 89% e.e. More recently, a
In the presence of 10 mol% of Lewis base, β-enamino esters novel class of chiral Lewis base catalysts, prepared from a readily

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Perspective Catalysis Science & Technology

available chiral source, was developed by Zhang (catalyst 29).70 methodology is the addition of one equivalent of water to
A wide variety of N-aryl β-aryl and -heteroaryl substrates were react with HSiCl3 to generate a controlled amount of strong
reduced in very good yields (up to 98%) and selectivity (up to Brønsted acid, HCl. In this way the reaction proceeds through
99 : 1 syn/anti and 99% e.e.). This methodology was used in the the generation of electrophilic indolenium ions by C3 proton-
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synthesis under very mild reaction conditions of both the ation with the in situ formed HCl, and subsequent chiral
taxol C13 side chain and of a potent hypocholesterolemic agent; Lewis base 31 catalyzed enantioselective hydrosilylation with
the removal of water and oxygen from the reaction system was HSiCl3 (Scheme 16). The same group has recently studied the
not necessary, suggesting the generation of a Brønsted acid reduction of 3-aryl-1,4-benzooxazines,73 that compares favor-
that promoted enamine tautomerisation. Lewis base-catalyzed ably with the phosphoric acid-based approach. The catalyst of
asymmetric hydrosilylation of α-acetamido-β-enamino esters was choice was found to be the N-sulfinyl L-phenylalanine derived
also reported in the presence of catalyst 30, to afford amide 32, which allowed the production of a broad range of
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smoothly the corresponding products with high yields (up to 3-substituted 3,4-dihydro-2H-1,4-benzooxazines in very good
99%), excellent enantioselectivities (up to 98% e.e.) and chemical yield and high enantioselectivity, even with a low
moderate diastereoselectivities (up to 80 : 20 d.r.).71 The lower catalyst loading (2 mol%). A stereochemical match between
diastereocontrol observed in this study is ascribed by the the carbon and the sulfur stereogenic centers is crucial for the
authors to the role of the hydrogen of the α-acetamide group. enantiocontrol. The stereoselective synthesis of chiral hetero-
Indeed, the enamine isomerization forms preferentially the cyclic building blocks such as dihydrobenzodiazepinones was
E-imine; however in this case the Z-imine can be stabilized also accomplished, by using picolinamides 25.74 The corre-
by hydrogen bonding between the hydrogen of the sponding products were obtained in excellent yields (up to 99%)
α-acetamide group and the nitrogen of the imine. In this and enantioselectivities (up to 98%).
way, considerable amounts of Z-imine could be generated,
resulting in lowers levels of diastereoselectivity. 5. Outlook and perspectives
Finally it is worth mentioning that the methodology has
been already applied to the reductions of heterocyclic sys- The advent of organocatalysis brought new attractive possi-
tems. For example, Sun reported the first direct enantio- bilities, to realize stereoselective catalytic synthesis of com-
selective hydrosilylation of prochiral 1H-indoles by combined plex chiral molecules, even bearing several functional groups,
Brønsted acid/Lewis base activation.72 The key factor for this with metal-free processes. The enantioselective organocatalytic

Scheme 16 HSiCl3-mediated stereoselective reductions of heterocyclic compounds.

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Notes and references

1 For general reviews on asymmetric hydrogenation, see: (a)
A. M. Palmer and A. Zanotti-Gerosa, Curr. Opin. Drug Discovery
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

Dev., 2010, 13, 698–719; (b) G. Shang, W. Li and X. Zhang,

Transition Metal-Catalyzed Homogeneous Asymmetric
Hydrogenation, in Catalytic Asymmetric Synthesis, ed. I. Ojima,
Wiley, Hoboken, 3rd edn, 2010, pp. 343–436.
2 J. Aleman and S. Cabrera, Chem. Soc. Rev., 2013, 42, 774–793.
3 C. A. Busacca, D. R. Fandrick, J. J. Song and
C. H. Senanayake, Adv. Synth. Catal., 2011, 353, 1825–1864.
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Fig. 3 Stereoselective reduction of unsaturated ketones and reductive

aldol reaction. 4 V. Farina, J. T. Reeves, C. H. Senanayake and J. J. Song,
Chem. Rev., 2006, 106, 2734–2763.
5 P. J. Dunn, Green Chem., 2013, 15, 3099–3104.
methodologies described in the present chapter are a clear 6 Enantioselective Organocatalysis. Reactions and Experimental
demonstration of the enormous potentiality of metal-free cata- procedures, ed. P. I. Dalko, Wiley VCH, Weinheim, 2007.
lytic reductions. But it is also evident that this is only the 7 For a recent review on chiral amine synthesis see:
beginning of the story; even if both pharmaceutical companies T. C. Nugent and M. El-Shazly, Adv. Synth. Catal., 2010, 352,
and fine chemicals suppliers continue to invest heavily in 753–819.
chiral technologies, the chiral market is still steadily growing 8 For a review on hydrogenation of heteroaromatic compounds
and always calls for new stereoselective catalytic strategies for see: Y.-G. Zhou, Acc. Chem. Res., 2007, 40, 1357–1366. See also
the synthesis of chiral molecules. FLP-based catalytic chiral F. Glorius, Org. Biomol. Chem., 2005, 3, 4171–4175.
methods are almost a totally unexplored field. On the other 9 Recent reviews: (a) J. G. de Vries and N. Mršić, Catal. Sci.
hand in trichlorosilane-mediated reductions the search for Technol., 2011, 1, 727–735; (b) M. Rueping, J. Dufour and
new and more efficient chiral Lewis bases is still very active. F. R. Schoepke, Green Chem., 2011, 13, 1084–1105.
In this context recently the use of enantiomerically pure phos- 10 For a special issue on hydrogenation and transfer
phine oxides75 as catalysts in HSiCl3-mediated reactions has hydrogenation see: M. J. Krische and Y. Sun, Acc. Chem. Res.,
been introduced. The reduction of 1,3-diphenylbutenone pro- 2007, 40, 1237–1419.
moted by catalytic amounts of 2,2′-bis(diphenylphosphanyl)- 11 Reviews: (a) D. W. Stephan and G. Erker, Angew. Chem., Int. Ed.,
1,1′-binaphthyl dioxide 33 ((S)-BINAPO) at 0 °C led to the cor- 2010, 49, 46–76; (b) D. W. Stephan, Chem. Commun., 2010, 46,
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As a further development, it was shown that, after performing D. Chen and J. Klankermayer, Top. Curr. Chem., 2013, 334,
the 1,4-reduction, the generated trichlorosilyl enolate should 1–26; (e) Pioneering work: G. C. Welch, R. R. San Juan,
react with the electrophilic aldehyde to afford the aldol prod- J. D. Masuda and D. W. Stephan, Science, 2006, 314,
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