Thieme chemistry journal awardees - Where are they now? Asymmetric br?nsted acid catalyzed transfer hydrogenations

Article abstract of DOI:10.1055/s-0029-1219528

Asymmetric hydrogenations are of great importance in the synthesis of optically active amines. This account highlights the development of the first metal-free transfer hydrogenation that is both highly enantioselective and inspired by natures dehydrogen?ase. Further focus is given to the extension of this bioinspired process to provide a variety of valuable, biologically active products and natural products under mild reaction conditions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219528

852
ACCOUNT
Thieme Chemistry Journal Awardees – Where Are They Now?
Asymmetric Brønsted Acid Catalyzed Transfer Hydrogenations
Asymmetric Brønsted
a
gzedTransfe
n
H
ydrogena
u
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092665; E-mail: Magnus.Rueping@rwth-aachen.de
Received 12 November 2009
lective metal-free transfer hydrogenation using nature’s
dehydrogenase as a role model and we like to highlight
our attempts for the development and generalization of
this hydrogenation protocol.
Abstract: Asymmetric hydrogenations are of great importance in
the synthesis of optically active amines. This account highlights the
development of the first metal-free transfer hydrogenation that is
both highly enantioselective and inspired by nature’s dehydrogen-
ase. Further focus is given to the extension of this bioinspired pro-
cess to provide a variety of valuable, biologically active products
and natural products under mild reaction conditions.
2
Nature’s Reductions: Dehydrogenases as a
Role Model
1
2
3
Introduction
Nature’s Reductions: Dehydrogenases as a Role Model
Brønsted Acid catalyzed Transfer Hydrogenation of
Ketimines
Nicotinamide adenine dinucleotide (NADH) is an impor-
tant co-factor in nature, which serves as a hydride source
for a broad variety of reductions, including reductive am-
inations. One very important example represents the
glutamate dehydrogenase catalyzed reductive amination
of 2-ketoglutarate to provide the amino acid glutamate
(Equation 1). The reaction is reversible although the equi-
librium favors glutamate formation.
4
5
5.1
Asymmetric Organocatalytic Reduction of Quinolines
Asymmetric Organocatalytic Reduction of N-Heterocycles
Asymmetric Brønsted Acid Catalyzed Hydrogenation of
Indoles
5.2
Asymmetric Brønsted Acid Catalyzed Hydrogenation of
Benzoxazines, Benzthiazines, Benzoxazinones, Quinoxa-
lines, Quinoxalinones and Benzodiazepinones
Asymmetric Organocatalytic Reduction of Pyridines
Asymmetric Organocatalytic Reductions in Cascade
Sequences
6
7
By means of detailed kinetic studies and crystallographic
structure analysis a mechanism for the action of glutamate
8
Conclusion
glutamate NAD(P)+
+
2-ketoglutarate
Key words: binol phosphate, Brønsted acid, Hantzsch ester, trans-
+ NAD(P)H
NH3
+
fer hydrogenation, organocatalysis, asymmetric reduction
Equation 1 Reductive amination of 2-ketoglutarate to glutamate
catalyzed by glutamate dehydrogenase
K89
1
Introduction
H
N
H
D165
H
Compounds with hydrogen as part of the stereocenter are
frequently found in various biologically active com-
pounds and natural products. Asymmetric hydrogenation
of unsaturated compounds, including olefins, carbonyls
and imines represents the most important and convenient
route to the corresponding optically active products. So
far, most of these enantioselective reductions rely on dif-
ferent transition-metal-catalyzed high-pressure hydroge-
nations, hydrosilylations and transfer hydrogenations.
While almost all of these metal-catalyzed processes show
high reactivities and selectivities most of these protocols
suffer from significant drawbacks including a limited sub-
strate scope and difficulties encountered with catalyst sep-
aration and recycling. Given the above limitations an
alternative approach to chiral amines would be of great
value. In this account we would like to disclose our stud-
ies towards the development of the first highly enantiose-
O
O
O
H
S380
O
H2C
CH2
O
H
O
H
N
O
H
O
O
H
N
H
H
H
H2N
Q110
H
N
K113
N
H
O
OH
OH
NH2
O
O
N
O
P
NADH
N
O
N
P O
O
N
O
OH
OH
Figure 1 Proposed activation mechanism: a-imino glutarate is acti-
vated through a catalytic protonation by aspartate D165 which ena-
bles a hydride transfer from the NADH to provide the amino acid
glutamate
SYNLETT 2010, No. 6, pp 0852–0865
Advanced online publication: 18.02.2010
DOI: 10.1055/s-0029-1219528; Art ID: S12909ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
0

ACCOUNT
Asymmetric Brønsted Acid Catalyzed Transfer Hydrogenations
853
dehydrogenase was proposed by Stillman and co-workers
(Figure 1).1
3
Brønsted Acid Catalyzed Transfer Hydroge-
nation of Ketimines
The enzyme consists of different amino acids in the cata-
lytic active pocket yet it was proposed that the aspartate
D165 is crucial for the reductive amination as it proto-
nates the a-imino glutarate which is formed from ammo-
nia and 2-ketoglutarate to give a highly reactive iminium
ion. The subsequent hydride transfer from NADH leads to
the formation of the amino acid glutamate. This proposed
mechanism was later supported by site-directed mutagen-
esis studies in which the putative catalytic aspartyl residue
was replaced by other amino acids. Although the modified
enzymes still appeared to be correctly folded the high cat-
alytic activity was lost.2 This clearly indicated the crucial
Based on the above activation mechanism and analogous
to nature’s dehydrogenases we wondered whether it
would be possible to accomplish the transfer hydrogena-
tion of imines with a combination of NADH as a hydride
source and catalytic amounts of a Brønsted acid. The acti-
vation of the imine would be achieved by catalytic proto-
nation which would result in the formation of an iminium
ion. This would enable the subsequent hydride transfer to
yield the corresponding amine in a bioinspired fashion,
mimicking the mechanism of glutamate dehydrogenase
(Scheme 1).
role that aspartate plays in the transfer hydrogenation and 1,4-Dihydropyridines, also known as Hantzsch esters
underlines the protonation step as key step for the reduc- (HEH),3 are commonly known as synthetic analogues of
tive amination.
NADH. In 1955 Mauzerall and Westheimer4 showed for
Biographical Sketches
Magnus Rueping studied at University to work with Chemistry
at
RWTH
the Technical University of Professor David A. Evans Aachen University. His
Berlin, Trinity College on enantioselective transi- group’s research activities
Dublin and ETH Zürich, tion-metal catalysis. In Au- are directed toward the de-
where he completed his di- gust 2004 he was directly velopment and simplifica-
ploma thesis under the di- appointed to a C3-profes- tion of synthetic catalytic
rection of Professor Dieter sorship, the Degussa En- methodology and technolo-
Seebach. He stayed in the dowed Professorship of gy, and their application in
Seebach group and obtained Synthetic Organic Chemis- the rapid synthesis of di-
his Ph.D. from the ETH in try, at the Goethe-Universi- verse functional natural and
2002 working on the synthe- ty Frankfurt. After four unnatural molecules, not
sis and structural and years in Frankfurt he re- only to address chemical,
biological aspects of oli- ceived several offers of aca- biological and physical
go(hydroxybutanoates) and demic positions and decided problems but also to gener-
of b- and g-peptides. Mag- to accept a Chair and Full ate new molecules with po-
nus then moved to Harvard Professorship of Organic tentially interesting properties
Erli Sugiono graduated toral fellow in the group of and was appointed to the po-
from the Johannes Guten- Prof. Dr. Hans Wolfgang sition of senior scientist in
berg University of Mainz Spiess working with PD Dr. 2009. Her work centers on
and obtained her Ph.D. un- Ingo Schnell investigating the development of new
der the direction of PD Dr. the orientation of phospho- methodologies for asym-
Heiner Detert within the re- lipid bilayers within poly- metric catalytic transforma-
search group of Prof. Dr. mer matrices in magnetic tions,
catalytic
flow
Herbert Meier. She then fields. After a two and half reactions and the synthesis
moved to the Max Planck years stay at the Max Planck of biologically active com-
Institute of Polymer Re- Institute she joined Prof. pounds.
search (Mainz) as a postdoc- Rueping’s group in 2005
Fenja R. Schoepke was Fonds der Chemischen In- Aachen University in 2009.
born in Dortmund, Germa- dustrie for her postgraduate She is currently working on
ny in 1982. She graduated studies. She started her organocatalytic
transfer
with distinction from the Ph.D. in the group of Prof. hydrogenations and the im-
Goethe University in Frank- Rueping at the Goethe Uni- mobilization of organocata-
furt 2007 and was awarded a versity and transferred with lysts.
stipend from the German his group to the RWTH
Synlett 2010, No. 6, 852–865 © Thieme Stuttgart · New York

854
M. Rueping et al.
ACCOUNT
R3
PMP
Bu
PMP
Me
R3
R2
PMP
Me
HN
HN
F
N
HN
"hydride"
HN
R1
R2
R1
Brønsted acid
1
3
MeO
potential Brønsted acids:
AcOH, HCl, TFA, HBF4, CSA,
DPP
3a: 92%
3b: 67%
3c: 76%
potential hydride sources:
O
Ph
Ph
Et
PMP
O
O
HN
HN
H
H
HN
H
H
RO
OR
Me
CO2Me
H2N
N
H
2
N
R
Hantzsch ester
3d: 70%
3e: 75%
3f 77%
2a R: Et
2b R: t-Bu
2c R: allyl
Figure 2 A new Brønsted acid catalyzed transfer hydrogenation
H
H
H
H
As the reduction of ketimines leads to the formation of a
stereocenter it seemed reasonable to apply a chiral proton
source as the catalyst.11 In the aforementioned transfer hy-
drogenation of ketimines diphenyl phosphate (DPP) per-
formed best in terms of yields. Therefore, we decided to
employ chiral phosphoric acids based on the BINOL core
structure.12,13 These had previously been used for the res-
olution of amines, as ligand in metal catalysis and more
recently by Akiyama and Terada in metal-free activation
of imines.14,15
H
NaBH4
R3SiH
H
H
H
Scheme 1 Development of a biomimetic transfer hydrogenation of
ketimines with NADH analogues
the first time that these dihydropyridines are able to re-
duce carbonyl compounds by a direct hydrogen transfer to
the substrate. Since then a broad range of transfer hydro-
genations conducted with HEH in combination with dif-
ferent Lewis acids and additives has been reported.5,6
Additionally, List and MacMillan and their respective co-
workers have reported the highly enantioselective organo-
catalytic transfer hydrogenations of enones and enals ap-
plying chiral imidazolidinone catalysts.7,8
The synthesis of the chiral BINOL phosphates can be ac-
complished according to the strategy outlined in
Scheme 3.13–16 The protected (R)-3,3¢-dibromo-1,1¢-bi-
naphthyl-2,2¢-diol (4a) or the octahydro derivative were
prepared in two steps from BINOL or H8-BINOL by pro-
tection of the hydroxyl groups with methoxymethyl
groups, followed by bromination. The Suzuki coupling of
4a with various aryl boronic acids gave the corresponding
3,3-aryl-substituted BINOL derivatives. Subsequent
deprotection and phosphorylation yielded the desired cat-
alysts 5a–e while catalyst 5f can be prepared by a protocol
We decided to examine a Brønsted acid catalyzed transfer
hydrogenation of ketimines 1 with Hantzsch dihydropyri-
dine 2a as the hydride source to afford the corresponding
amines 3 (Scheme 2).9 Initial investigations started with
the identification of a suitable Brønsted acid.10 From the
different acids tested, diphenyl phosphate (DPP) gave the
highest efficiency in the reduction of ketimine 1.
Br
Ar
1. Pd(PPh3)4
ArB(OH)2
2. HCl (concd)
O
O
H
H
OMOM
OMOM
O
O
O
P
OH
3. POCl3, pyr.
HCl, H2O
EtO
OEt
R2
R1
R2
R1
N
HN
Br
Ar
N
Ar
H
2a
4a
5
5a Ar = 3,5-(CF3)2C6H3
5b Ar = 9-phenanthryl
5c Ar = anthracenyl
R
5 mol% DPP
R
3
1
5d Ar = [H8]-anthracenyl
Scheme 2 Brønsted acid catalyzed transfer hydrogenation of ket-
5e Ar = [H8]-9-phenantrhyl
imines
SiR3
Further examination of the reaction conditions showed
that the transformation proceeded efficiently in nonpolar
aromatic or halogenated solvents. With the optimal reac-
tion conditions in hand we extended our studies to evalu-
ate the substrate scope. As shown in Figure 2 the reaction
conditions are applicable to differently substituted alkyl
and aryl ketimines, including a-imino esters, and the
products could be isolated in good to excellent yields.
O
O
O
O
O
O
P
P
OH
OH
SiR3
Ar
6
5f Ar = 2,4,6-(i-Pr)3C6H2
6a R = SiPh3
6b R = [H8]-SiPh3
Scheme 3 Synthesis of differently substituted BINOL-phosphoric
acids 5 and 6
Synlett 2010, No. 6, 852–865 © Thieme Stuttgart · New York

ACCOUNT
Asymmetric Brønsted Acid Catalyzed Transfer Hydrogenations
855
established by List and co-workers.17a The synthesis of the
silylated Brønsted acids 6 was accomplished following a
general procedure reported by Yamamoto18 and MacMill-
an.17b This involved a Brook-type rearrangement of the
BINOL-derivative 4b using t-BuLi and subsequent phos-
phorylation.
PMP
Me
PMP
Me
PMP
Me
HN
HN
HN
OMe
3h: 72%, 76% ee
F
3g: 82%, 84% ee
3i: 91%, 78% ee
After having prepared several chiral BINOL–phosphoric
acid derivatives 5a–e, we started to investigate the utility
of these catalysts on the enantioselective transfer hydro-
genation of ketimines 1 (Scheme 4).
PMP
PMP
Ph
HN
HN
HN
Me
Me
Me
Ph
3k: 71%, 74% ee (98)a
O
O
3l: 82%, 70% ee (94)a
H
H
3j: 71%, 72% ee
EtO
OEt
a After one recrystallization from methanol
R3
R2
R3
R2
N
HN
R1
N
Figure 3 Scope of the asymmetric biomimetic transfer hydrogena-
tion of ketimines
2a
H
R1
5 mol% 5a
3
1
ArO
ArO
O
Scheme 4 Organocatalytic asymmetric transfer hydrogenation of
ketimines
R3
R2
P
H
R3
H
R2
OH
N
N
5
R1
R1
1
3
After reaction optimization, including a survey of differ-
ent solvents, temperatures, Hantzsch esters and Brønsted
acid catalysts, we found that indeed enantioselectivities
were observed and our best results were obtained with
Brønsted acid catalyst 5a and dihydropyridine 2a. Thus a
broad range of differently substituted ketimines could be
reduced to the corresponding amines in good yields and
with good enantioselectivities (Figure 3).11
O
O
H
H
ArO
ArO
O
O–
P
RO
OR
R3
R2
+
N
H
N
A
H
R1
2
Scheme 5 Proposed mechanism of the Brønsted acid catalyzed
List et al. and MacMillan et al. described catalytic enanti-
oselective reductive aminations employing the same com-
bination of BINOL–phosphoric acid and Hantzsch ester.17
By using phosphoric acids with sterically more demand-
ing residues in the 3,3-position of the BINOL skeleton
(i.e. catalyst 5f and 6a) they obtained better enantioselec-
tivities even in a one-pot procedure. Antilla and You
subsequently reported an enantioselective transfer hydro-
genation of a-imino esters yielding enantioenriched a-
amino acids.19 More recently, the Antilla group succeeded
in the use of acetyl-protected imines. This procedure
clearly demonstrates a significant improvement over our
initial reaction in that the deprotection step is much easier
to accomplish.20
transfer hydrogenation of ketimines
acid in such a way that the nucleophile then has to ap-
proach from the less hindered si-face as the re-face is ef-
fectively shielded (Figure 4, left). More detailed
theoretical investigations by Goodman and Himo re-
vealed a plausible bifunctional activation in which the
ketimine is protonated, and the dihydropyridine is activat-
ed by a hydrogen bond formed from the Lewis basic oxy-
gen of the phosphoryl group (Figure 4, right).21 The
phosphoric acid catalyst thereby acts as a Brønsted acid/
Lewis base bifunctional catalyst.
With regard to the mechanism we assume that the Brøn-
sted acid catalyzed transfer hydrogenation proceeds simi-
larly to the reaction of the glutamate dehydrogenase
(Scheme 5).11
In the first step of the transfer hydrogenation the imine is
activated by the chiral Brønsted acid catalyst which re-
sults in the generation of an iminium ion, a chiral ion pair
A. Subsequent hydride transfer from the Hantzsch ester 2
results in the desired chiral amine 3 and the catalyst is re-
generated. The absolute configuration of the amine can be
explained by a stereochemical model based on the X-ray
crystal structure of the chiral Brønsted acid catalyst. In the
transition state the ketimine is activated by the Brønsted
Figure 4 Stereochemical model of the BINOL–phosphoric acid ca-
talyzed activation of ketimines
Synlett 2010, No. 6, 852–865 © Thieme Stuttgart · New York

856
4
M. Rueping et al.
ACCOUNT
R2
*
Asymmetric Organocatalytic Reduction of
Quinolines
R2
*
R2
a)
H–
1,4-hydride
addition
H–
protonation
R1
Building on this first organocatalytic, enantioselective
transfer hydrogenation of ketimines, the reduction of oth-
er imines, such as quinolines, seemed feasible. The result-
ing tetrahydroquinolines are widely distributed in nature.
Due to their importance as synthetic intermediates in the
preparation of pharmaceuticals, agrochemicals, and in
material science, considerable effort has been made to
prepare these molecules and numerous synthetic method-
ologies have been reported. Established methods include
homogeneous and heterogeneous metal-catalyzed hydro-
genations, hydroborations and transfer hydrogenations.22
However, all these methods still suffer from a limited sub-
strate scope and examples of efficient asymmetric hydro-
genations of aromatic and heteroaromatic compounds are
scarce. Thus, the development of a Brønsted acid cata-
lyzed, enantioselective hydrogenation of quinolines
would be highly desirable as it provides an efficient and
straightforward metal-free access to optically pure tet-
rahydroquinolines.
R1
N
H
R1
N
H
N
H
H
O
O
O
O
O
B
A
O
C
P
P
P
OR
OR
OR
RO
RO
RO
1,2-hydride
addition
key step: enantioselective
hydride transfer
R2
*
*
N
H
R1
8/10
b)
H–
R1
R1
Brønsted
acid
catalyzed
protonation
R1
*
1,4-hydride
addition
N
H
H
O
N
H
N
O
O
P
O
H
D
E
O
O
P
OR
F
P
RO
OR
OR
RO
RO
1,2-hydride
addition
key step: enantioselective
proton transfer
In accordance with our previous studies we presumed that
the reduction of quinolines could proceed via a Brønsted
acid catalyzed protonation of the quinoline to form an in-
termediary chiral ion pair A or D (Scheme 6). The subse-
quent first hydride transfer would then occur in the 4-
position of the quinoline and the enamine B or E would be
formed. The following isomerization should yield the cor-
responding iminium ion C or F, and a second hydride
transfer would result in the desired tetrahydroquinoline.
Depending on the nature of the quinoline and the substitu-
tion pattern the stereodetermining step in this hydrogena-
tion cascade has to vary. In the case of 2- and 4-substituted
quinolines enantioselectivity will be induced by the hy-
dride transfer (Scheme 6a). However, in the case of 3-sub-
stituted quinolines neither the 1,2- nor the 1,4-hydride
addition provides a stereocenter and, therefore, the enan-
tiodetermining step has to be an asymmetric Brønsted acid
catalyzed protonation (Scheme 6b).
R1
*
N
12
H
Scheme 6 Proposed mechanism of a) enantioselective hydride
transfer and b) enantioselective protonation as a function of the sub-
stitution pattern of the quinoline
O
O
H
H
EtO
OEt
N
H
diphenylphosphate
N
H
Ph
N
Ph
8a: 92%
7a
Scheme 7 First metal-free reduction of quinolines
Hence our initial investigations focused on the explora-
tion of appropriate Brønsted acids for the reduction of 2-
phenyl-substituted quinoline 7a with Hantzsch dihydro-
pyridine 2a as the hydride source. The experiments re-
vealed that several Brønsted acids promote this
transformation. The highest activity, however, was
achieved with diphenyl phosphate, providing the corre-
sponding 2-substituted 1,2,3,4-tetrahydroquinoline 8a in
excellent yields (Scheme 7).23
O
O
H
H
EtO
OEt
N
H
1–2 mol% cat. 5b
N
Ph
N
Ph
H
7a
8a: 97% ee
Scheme 8 BINOL–phosphoric acid catalyzed transfer hydrogena-
tion of 2-substituted quinolines
Encouraged by these studies, we turned our attention to
extend the procedure to the asymmetric variant by em-
ploying chiral BINOL-phosphates.24 Initial studies on the
structural influence of the catalyst revealed that catalyst
5b, bearing phenanthryl groups in the 3,3¢-position of the
BINOL scaffold, promoted the enantioselective hydroge-
nation with an excellent level of asymmetric induction,
and the desired tetrahydroquinoline 8a could be isolated
with an enantiomeric excess of 97% ee (Scheme 8).
Further examinations concentrated on the substrate scope
of this first Brønsted acid catalyzed cascade transfer hy-
drogenation of 2-substituted quinolines. The results are
summarized in Figure 5. In general, 2-substituted quino-
lines with aromatic and heteroaromatic residues as well as
Synlett 2010, No. 6, 852–865 © Thieme Stuttgart · New York

ACCOUNT
Asymmetric Brønsted Acid Catalyzed Transfer Hydrogenations
857
1) CH2O, AcOH
2) NaBH4
aliphatic substituents were tolerated in this enantioselec-
tive transfer hydrogenation and the corresponding tet-
rahydroquinolines could be isolated in good yields and
with excellent enantioselectivities. Interestingly, haloge-
nated aromatic and aliphatic residues were also tolerated
in this metal-free hydrogenation.
2a,
1 mol% 5b
88–95%
90–95%
R
N
N
R
N
R
H
Me
O
O
OMe
OMe
N
N
F
Me
Me
N
H
N
H
(+)-cuspareine
88%, 90% ee
(+)-galipinine
89%, 91% ee
8a: 92%, 97% ee
8b: 93%, 98% ee
Me
N
Me
N
H
N
H
(–)-angustureine
79%, 90% ee
Me
8c: 65%, 97% ee
8d: 93%, 99% ee
Scheme 9 Synthesis of natural product alkaloids applying the enan-
tioselective Brønsted acid catalyzed transfer hydrogenation of 2-sub-
stituted quinolines
O
N
H
N
H
CF3
ed derivatives 9. To date, no direct enantioselective ap-
proach to 4-substituted tetrahydroquinolines 10 has been
described. So far, multistep reactions have been employed
to obtain these valuable chiral 4-substituted tetrahydro-
quinolines,28 which have been shown to have biological
activity in vivo.29 Therefore, the development of the first
catalytic asymmetric route to these products would be a
substantial improvement (Scheme 10).
8e: 91%, 99% ee
8f: 93%, 91% ee
Cl
N
H
N
H
OMe
8g: 90%, 98% ee
8h: 91%, 88% ee
R2
R2
N
H
8i: 88%, 90% ee
2a/2b
1–2 mol% cat. 6b
R1
N
R1
N
H
Figure 5 Substrate scope of the transfer hydrogenation of 2-substi-
tuted quinolines 7
10
9
Scheme 10 Asymmetric Brønsted catalyzed transfer hydrogenation
of 4-substituted quinolines
The synthetic potential of this highly enantioselective cas-
cade transfer hydrogenation was demonstrated in the syn-
thesis of biologically active tetrahydroquinoline natural
products, such as galipinine, cuspareine and angus-
tureine.25 Thus, the organocatalytic hydrogenation of
readily available 2-substituted quinolines, which were
prepared by simple alkylation of 2-methylquinoline, gen-
erated the tetrahydroquinoline derivatives with excellent
enantioselectivities. The enantioenriched products were
subsequently N-methylated to give the desired natural
products in good overall yields (Scheme 9).
Given that the stereocenter is further away from both the
protonated nitrogen and the catalytic center of the phos-
phoric acid catalyst, a larger residue in the 3,3-position of
the BINOL skeleton would be necessary. Following opti-
mization of the reaction parameter, the best results so far,
with regard to both reactivity and selectivity, have been
obtained with a combination of catalyst 6b and tert-butyl
Hantzsch ester 2b. A preliminary substrate scope is shown
in Figure 6, demonstrating that several 4-substituted tet-
rahydroquinolines can be prepared in good yields and
with good to excellent enantioselectivities.30
Mirroring our Brønsted acid catalyzed transfer hydroge-
nation, Du and co-workers reported the use of double ax-
ially chiral phosphoric acids in the reduction of 2-
substituted quinolines giving rise to the corresponding tet-
rahydroquinolines with comparable enantioselectivities.26
Additionally, Metallinos et al. reported a Brønsted acid
catalyzed enantioselective reduction of the structurally re-
lated disubstituted 1,10-phenanthrolines.27
To conclude our investigations of the transfer hydrogena-
tion of quinolines, we examined the reduction of 3-substi-
tuted quinolines 11. This reaction proceeds via an
enantioselective Brønsted acid catalyzed protonation
(Scheme 6b) and represents the first direct access to
optically active 3-substituted tetrahydroquinolines 12
(Scheme 11). Similar to the 4-substituted quinolines, ap-
plication of Brønsted acid catalyst 6b gave the best chiral
In addition to the transfer hydrogenation of 2-substituted
quinolines we also examined the reduction of 4-substitut-
Synlett 2010, No. 6, 852–865 © Thieme Stuttgart · New York

858
M. Rueping et al.
ACCOUNT
4-substituted quinolines which proceed through an enan-
tioselective hydride transfer as a key step, this latest reac-
tion cascade involves a new enantioselective Brønsted
acid catalyzed proton transfer as the enantiodifferentiat-
ing step. This is not only the first example of an organo-
catalytic protonation in a cascade reaction but it can also
be applied in the preparation of new molecular scaffolds
with up to three new stereocenters in a mild and efficient
one-pot reaction sequence.
Cl
N
H
N
H
10a: 96%, 92% ee
OMe
10b: 81%, 90% ee
Ph
O
5
Asymmetric Organocatalytic Reduction of
N-Heterocycles
Cl
N
Cl
N
H
H
10c: 67%, 75% ee
10d: 96%, 84% ee
5.1
Asymmetric Brønsted Acid Catalyzed
Hydrogenation of Indoles
Figure 6 Scope of the Brønsted acid catalyzed transfer hydrogena-
tion of 4-substituted quinolines
Indolines 15 represent a substantial core structure of many
natural alkaloids which possess widespread biological
and pharmaceutical activity. To date only the metal-cata-
lyzed reduction of trimethyl-3H-indole has been reported
in order to obtain 2,3,3-trimethylindoline with high enan-
tioselectivities.32 Given the comparable structural features
of indoles and quinolines, the application of our Brønsted
acid catalyzed transfer hydrogenation to the reduction of
indoles 14 seemed reasonable (Scheme 12).
R
R
2c
5 mol% 6b
N
N
H
12
11
Scheme 11 Reduction of 3-substituted quinolines to the optically
active 3-substituted tetrahydroquinolines
induction. Evaluation of various Hantzsch esters revealed
the allyl ester 2c to be a superior hydride source resulting
in slightly better enantioselectivities than the ethyl deriv-
ative 2a.
R2
R2
R2
R2
R3
R3
2a
R1
R1
1 mol% 5c
This optimized reaction protocol can be applied to the re-
duction of various 3- and 2,3-substituted quinolines to
provide the corresponding tetrahydroquinolines or oc-
tahydroacridines in good yields and with high enantio-
selectivities (Figure 7).31 In contrast to our previously
developed asymmetric transfer hydrogenations of 2- and
N
N
H
14
15
Scheme 12 Brønsted acid catalyzed transfer hydrogenation of indoles
Indeed, with Brønsted acid 5e and Hantzsch ester 2a we
were able to isolate a broad range of differently substitut-
ed 2,3,3-indolines 15 in high yields and with excellent
enantioselectivities up to 99% ee (Figure 8).33
OMe
N
H
N
H
5.2
Asymmetric Brønsted Acid Catalyzed Hydro-
genation of Benzoxazines, Benzthiazines,
Benzoxazinones, Quinoxalines, Quinoxalin-
ones and Benzodiazepinones
12a: 76%, 84% ee
12b: 67%, 85% ee
S
Dihydro-2H-benzoxazines 20, dihydro-2H-benzthiazines
21, dihydro-2H-quinoxalines 22 as well as dihydro-2H-
benzoxazinones 23, diyhdro-2H-quinoxalinones 24 and
dihydro-2H-benzdiazepinones 25 are common structural
motifs in a large number of natural products and are re-
ported to have various interesting biological activities
(Figure 9). They have also been employed as important
chiral building blocks in the synthesis of many pharma-
ceuticals, such as promising antidepressants, calcium an-
tagonists as well as anti-inflammatory, antinociceptive,
antibacterial, antimicrobial agents and non-nucleoside
HIV-1 reverse transcriptase inhibitors.34
F
N
H
N
H
12d: 50%, 86% ee
12c: 77%, 85% ee
Ph
N
H
13
N
H
87%, cis/trans = 1:8
12e: 58%, 82% ee
13a: cis = 99% ee
13b: trans = 94% ee
Furthermore, the reduction of benzoxazinones leads to cy-
clic aryl-substituted amino acid derivatives, which can be
Figure 7 Substrate scope of the Brønsted acid catalyzed enantio-
selective protonation of 3-substituted quinolines.
Synlett 2010, No. 6, 852–865 © Thieme Stuttgart · New York

ACCOUNT
Asymmetric Brønsted Acid Catalyzed Transfer Hydrogenations
859
whole set of imine-containing heterocycles (Figure 9).
Similar to our previously reported procedure, it was antic-
ipated that the chiral Brønsted acid would activate the
substrates through catalytic protonation thereby enabling
the hydride transfer from the dihydropyridine to occur
(Scheme 13). However, in the case of the quinoxalines a
double 1,2-hydride addition has to take place in order to
isolate the desired dihydro-2H-quinoxalines 22.
OMe
N
H
N
H
15a: 99%, 97% ee
15b: 84%, >99% ee
MeO
Ar
N
H
N
H
O
O
X
P
15c: 92%, 97% ee
15d: 86%, 99% ee
O
OH
*
X
N
R1
R2
N
H
R2
Ar
R1
20 X: O
5
21 X: S
CF3
Me
22 X: NH
16 X: O
17 X: S
18 X: N
N
H
R2
N
H
HEH 2
Ar
15e: 93%, >99% ee
15f: 86%, 75% ee
O–
O
O
N
X
H
P
O
F
R1
N
H
Ar
chiral ion pair A
N
H
Scheme 13 Mechanism of the transfer hydrogenation of various
imine-containing heterocycles
15g: 93%, 98% ee
15h: 92%, 96% ee
O
The subsequent reaction optimization showed that highest
enantioselectivities were obtained if catalyst 5b was ap-
plied in the reduction of benzoxazines, benzthiazines and
benzoxazinones,36 while the Brønsted acid 5c gave supe-
rior results in the reduction of quinoxalines and quinoxalin-
ones.37
N
OEt
H
15i: 87%, 90% ee
Figure 8 Substrate scope of the first metal-free transfer hydrogena-
tion of 2,3,3-substituted indoles
H
More detailed investigation of the catalyst’s activity en-
abled us to decrease the catalyst loading from 10 mol% to
0.01 mol% (substrate/catalyst ratio = 10000:1). We were
pleased to observe that the reduction of benzoxazines with
only 0.01 mol% of catalyst, proceeded without consider-
able loss in reactivity and selectivity and that the corre-
sponding 2H-dihydrobenzoxazine 20a could be isolated
in remarkable 90% yield and 93% ee. This corresponds to
a TON of 9000 and a TOF of 500 h–1 (Table 1). To date
this is the lowest catalyst loading reported for an organo-
catalytic enantioselective transformation. The remark-
able, low catalyst loadings and the excellent
enantioselectivities of our metal-free transformation ren-
der this approach a competitive process compared to
enantioselective metal-catalyzed reductions.36
O
S
N
R1
R3
R5
R2
N
H
R4
N
H
R6
N
H
20
22
21
O
H
H
N
N
O
O
O
R11
R7
R9
N
H
R8
N
H
25
N
H
R10
R12
24
23
Figure 9 Further desired amine-containing heterocycles
further transformed to the open-chain amino acids. The
catalytic enantioselective reduction of imine-containing
heterocycles is a direct and most efficient approach to
these important compounds. Surprisingly, so far only few
catalysts have been reported that catalyze the reduction of
these cyclic imines and typically they are restricted to
alkyl-substituted derivates, particularly methyl and ethyl
derivatives.35
Unfortunately, the reduction of the benzodiazepinones 19
proceeded with very low conversion. To circumvent the
lack of catalyst reactivity we tested BINOL-based N-tri-
flylphosphoramides which, due to the strongly electron-
withdrawing triflyl groups, have a considerably lower pKa
and, hence, a higher reactivity (Scheme 14).38a So far
these catalyst have mainly been employed in asymmetric
Brønsted acid catalyzed carbonyl activations, including
Encouraged by the successful organocatalytic enantiose-
lective transfer hydrogenation of imines,11 quinolines24
and indoles33 we became interested in extending our bio-
inspired strategy to the transfer hydrogenation of the
Synlett 2010, No. 6, 852–865 © Thieme Stuttgart · New York

860
M. Rueping et al.
ACCOUNT
H
N
Table 1 Catalyst Loading of the Brønsted Acid Catalyzed Transfer
Hydrogenation of Benzoxazines
S
O
R5
R3
R1
O
O
H
R6
N
H
R4
H
N
H
R2
N
H
EtO
OEt
20
21
22
O
N
O
N
HEH:
Cat:
2a
5b
2a
2a
2a
H
5b
5c/5f
Brønsted acid 5b
Ph
N
H
Ph
O
H
N
16a
20a
H
N
O
O
O
R11
R7
R9
Entry
Loading of 5b (%) Yield (%)
ee (%)
R8
N
H
R10
N
H
N
H
R12
1
2
3
4
5
6
10
5
91
95
93
94
95
90
96
96
96
96
96
93
23
24
25
HEH:
Cat:
2a
5b
2a
5c/5d
2c
26
2
Figure 10 Reaction parameter for the transfer hydrogenation of va-
rious imines
1
0.1
0.01
reduction of substituted pyridines is still a great challenge
and only a few metal-catalyzed reductions are known.40
a)
O
O
H
N
H
N
O
O
1. 2a, 5 mol% 26
2. DMF, AcCl, Py
R
R
2a
N
N
5 mol% 5c
Ar
Ar
N
R1
N
R1
19
O
27
28
H
b)
25
NC
NC
Me
Scheme 14 N-Triflylphosphoramide-catalyzed transfer hydrogena-
tion of benzodiazepinones
2a
5 mol% 5c
Me
N
R2
N
R2
H
30
29
Diels–Alder reactions, dipolar cycloadditions, ene reac-
tions, protonations or Nazarov cyclizations.38
Scheme 15 Transfer hydrogenation of pyridines to the correspon-
ding piperidines
Indeed, with the application of 5 mol% of the N-triflyl-
phosphoramide 26 we were able to isolate the dihydroben-
zodiazepinones 25 in good yields and with excellent
enantioselectivities.39 Thus, we were able to develop a
general protocol for the transfer hydrogenation of a whole
set of different N-heterocycles. Typically both, the best
reactivities and the best selectivities were achieved with
the Hantzsch ethyl ester in combination with phenantryl-,
anthracenyl- or triisopropylphenyl-substituted BINOL–
phosphoric acid catalysts (Figure 10). In general, the re-
ductions proceeded smoothly under mild reaction condi-
tions and provided differently substituted alkyl- and aryl-
substituted products in good yields and with excellent
enantioselectivities throughout (Figure 11).
Due to the extensive biological activity, as well as the lack
of catalytic asymmetric methods for the preparation of
these products, we considered it important to examine an
organocatalytic Brønsted acid catalyzed pyridine reduc-
tion. Based on our previously developed protocols, we de-
vised a metal-free BINOL–phosphoric acid catalyzed
reduction of pyridine derivatives 27 and 29 to obtain the
corresponding piperidine derivatives (Scheme 15).41 With
5 mol% of Brønsted acid 5c and dihydropyridine 2a as the
hydrogen source we were able to isolate a broad range of
different azadecalinones 28 as well as tetrahydropyridines
30 in good yields and with excellent enantioselectivities
(Figure 11). Furthermore, we were able to demonstrate
that the transfer hydrogenation of pyridine 27c leads to the
corresponding hexahydroquinolinone 28c which can eas-
ily be converted to the alkaloid diepi-pumiliotoxin C
(Scheme 16).
6
Asymmetric Organocatalytic Reduction of
Pyridines
Piperidine alkaloids and derivates belong to another very
important class of N-heterocycles. Numerous natural
products with wide biological and pharmaceutical proper-
ties contain this significant structural core. From a syn-
thetic point of view the most convenient and efficient
access to these compounds is the catalytic asymmetric hy-
drogenation of pyridines. However, the enantioselective
It is worth noting that this first enantioselective Brønsted
acid catalyzed cascade reduction of pyridines not only
gives the corresponding products in good yields and with
excellent enantioselectivities but also provides a simple
and straightforward route to decahydroquinoline or pipe-
ridine alkaloid natural products.43,44 As previously only
metal-catalyzed hydrogenations of pyridines have been
Synlett 2010, No. 6, 852–865 © Thieme Stuttgart · New York

ACCOUNT
Asymmetric Brønsted Acid Catalyzed Transfer Hydrogenations
861
O
O
O
O
O
O
Br
N
H
Cl
N
H
N
H
N
H
N
H
N
H
Me
Br
OMe
Ph
20a: 95%, 98% ee
20e: 92%, 98% ee
20b: 93%, >99% ee
20d: 93%, 98% ee
20c: 94%, 98% ee
20f: 95%, >99% ee
S
S
S
S
S
S
Br
N
H
N
H
N
H
N
H
N
H
N
H
Me
Ph
Br
F
21a: 87%, >99% ee
21b: 50%, 96% ee
21d: 51%, 94% ee
21c: 78%, 94% ee
21e: 70%, >99% ee
21f: 54%, 93% ee
H
N
H
N
H
N
H
N
H
N
H
N
Cl
Cl
Br
O
N
H
N
H
N
H
N
H
N
H
N
H
Cl
OMe
22c: 98%, 96% ee
Br
22a: 88%, 96% ee
22b: 73%, 94% ee
22d: 95%, 92% ee
22e: 93%, 97% ee
22f: 93%, 82% ee
Cl
O
O
O
O
O
O
O
O
O
O
O
O
Cl
N
H
N
H
N
H
N
H
N
H
N
H
S
Br
Br
OMe
23a: 92%, >99% ee
23c: 90%, >99% ee
23b: 91%, >99% ee
23d: 55%, 96% ee
23e: 90%, 98% ee
23f: 81%, 90% ee
H
N
H
N
H
N
H
N
O
O
O
H
N
O
O
N
H
N
H
N
H
N
H
N
H
S
24a: 58%, 91% ee
24b: 75%, 97% ee
24c: 56%, 91% ee
24d: 60%, 97% ee
24e: 23%, 90% ee
H
N
H
O
O
H
N
H
O
O
H
N
O
N
H
N
O
N
Cl
Cl
Cl
Cl
Br
Cl
Cl
N
H
N
H
N
H
N
H
Cl
N
H
N
H
F
NO2
NO2
OMe
MeO
NO2
25f: 86%, 98% ee
25b: 83%, 95% ee
25a: 93%, 95% ee
25c: 87%, 99% ee
25d: 94%, 99% ee
25e: 52%, 97% ee
O
O
O
O
O
N
N
H
N
N
H
N
H
H
H
28e: 83%, 87% ee
28d: 66%, 92% ee
28c: 69%, 89% ee
28a: 84%, 91% ee
28b: 72%, 91% ee
NC
NC
NC
NC
N
H
N
N
H
N
H
H
30d: 68%, 89% ee
30a: 73%, 90% ee
30c: 47%, 86% ee
30b: 55%, 84% ee
Figure 11 Substrate scope of the transfer hydrogenation of an array of various imine-containing heterocycles
described which did not result in these valuable products
and gave typically lower enantioselectivities, our newly
developed metal-free Brønsted acid catalyzed procedure
7
Asymmetric Organocatalytic Reductions in
Cascade Sequences
represents an important contribution to the enantioselec- We were able to mimic nature’s reduction by replacing
tive reduction of pyridines.
the dehydrogenase and NADH system with the simple
combination of a readily available Brønsted acid and a di-
Synlett 2010, No. 6, 852–865 © Thieme Stuttgart · New York

862
M. Rueping et al.
ACCOUNT
O
O
tral to the utility of this new multiple reaction cascade in
asymmetric synthesis is the requirement that the last
Brønsted acid catalyzed activation step in this sequence
proceeds with high enantiocontrol.
a)
+
O
Me
N
NH2
5c
HEH 2a
.
Me
H
O
R3
R3
R2
O
5c
+
b)
R1
HEH 2a
R2
NH2
N
H
N
H
R1
32
31
H
N
H
Michael
addition
28c
diepi-pumiliotoxin C
H+
28 or 30
R1
R1
Scheme 16 Synthesis of diepi-pumiliotoxin C. Reagents and condi-
tions: (a) EtOH, 50 °C, 12 h, then 140 °C, 2 h;42 (b) Ref. 43e.
O
O
H+
R3
R3
R2
hydropyridine. However, enzyme-catalyzed reactions not
only proceed with excellent yields and enantioselectivi-
ties they also typically build up very complex structures
starting from simple compounds in a minimum number of
steps. These enzymatic multistep sequences are often re-
alized in domino and multicomponent reactions and, thus,
are blueprints for organic synthesis. Over the past few
years the development of organocatalytic domino reac-
tions has become a highly dynamic and topical research
area in catalysis.45,46
A
B
H+
H2N
isomerization
R2
NH2
transfer
hydrogenation
HEH 2a
H+
cyclization
R3
R2
R3
R2
H+
R3
H+
OH
R1
N
R2
N
H
R1
N
R1
H
H2O
H
D
C
–B*
E
isomerization/
protonation
elimination
As part of our studies we have developed a new asymmet-
ric organocatalytic cascade reaction in which multiple
steps are catalyzed by a chiral Brønsted acid catalyst and
which provides valuable tetrahydropyridines and aza-
decalinones with high enantioselectivities. Based on our
original biomimetic strategy and our experience in chiral
ion-pair catalysis, we envisioned a new organocatalytic
multiple reaction cascade comprising a one-pot Michael
addition–isomerization–cyclization–elimination–isomer-
ization–transfer hydrogenation sequence in which each
single step is catalyzed by the same chiral Brønsted acid
(Scheme 17).
Scheme 18 Mechanism of the Brønsted acid catalyzed domino
reaction sequence
Indeed we were able to develop such a transformation by
applying the ideal combination of Brønsted acid 5c and
dihydropyridine 2a.47 In this new three-component reac-
tion each step of the six-step sequence is catalyzed by the
same chiral Brønsted acid allowing rapid, direct and effi-
cient access to valuable tetrahydropyridines and azadeca-
linones from simple readily available starting materials
with the highest levels of enantiocontrol (Figure 12).
Thus, we were additionally able to demonstrate that our
organocatalytic hydrogenation protocol is amenable to
complex molecular cascading.
.
R3
O
R3
R2
5c
+
R1
HEH 2a
R2
NH2
An additional cascade reaction involving a Brønsted acid
catalyzed transfer hydrogenation was developed by List
and co-workers.48 In contrast to their previously devel-
oped chiral salt catalyzed transfer hydrogenation of
enones8d (Scheme 19) this reaction sequence started from
linear diketones and afforded substituted cyclohexyl-
amines with high diastereo- and enantioselectivities
(Scheme 20).
N
H
R1
31
32
28/30
Scheme 17 Brønsted acid catalyzed reaction sequence
In our reaction design (Scheme 18) we assumed that ex-
posure of a mixture of enamine 31 and vinyl ketone 32 to
catalytic amounts of Brønsted acid should lead to the for-
mation of the corresponding 1,4-addition products A and
B. Subsequent Brønsted acid catalyzed cyclization of A,
which is in an acid-catalyzed equilibrium with B, would
give the hemiaminal C which upon rapid water elimina-
tion results in the formation the dihydropyridine D, an in-
termediate also observed in the asymmetric pyridine
reduction. The following Brønsted acid catalyzed proton-
ation should effect the generation of an iminium ion, a
chiral ion pair E which is activated for an enantioselective
hydride transfer to give the desired product 28 or 30. Cen-
The reaction proceeds via an intramolecular aldol conden-
sation followed by a double transfer hydrogenation se-
quence. The proposed catalytic cycle was recently
verified by mass spectrometry in which all crucial inter-
mediates were detected.49 Additionally, this study showed
that mass spectroscopy is a well-suited technique for the
determination of reaction pathways in Brønsted acid ca-
talysis and is certain to be applied in the future for mech-
anistic investigations.
Synlett 2010, No. 6, 852–865 © Thieme Stuttgart · New York

ACCOUNT
Asymmetric Brønsted Acid Catalyzed Transfer Hydrogenations
863
NC
NC
.
C6H4OR2.
O
NH2
OR2
HN
N
H
N
H
5f
+
O
OMe
Br
HEH 2a
X
X
R1
R1
22a: 89%, 96% ee
22b: 77%, 97% ee
36
2a
35
O
O
–B*
H
–B*
C6H4OR2
MeO
F
+
C6H4OR2
+
C6H4OR2
HN
H
N
N
N
H
N
H
CF3
O
F
2a
X
22c: 55%, 99% ee
R1
R1
R1
22d: 52%, 97% ee
O
O
C6H4OR2
C6H4OR2
Napth
PEP
PMP
HN
HN
HN
HN
N
H
N
H
O
n-Bu
i-Bu
Me
OMe
Br
23a: 74%, 97% ee
36a: 75%
90% ee, 10:1 dr
36b: 76%
94% ee, 3:1 dr
23b: 73%, 99% ee
36c: 73%
82% ee, 2:1 dr
36d: 72%
92% ee, 99:1 dr
O
O
Scheme 20 Brønsted acid catalyzed cascade sequence to substituted
cyclohexylamines
S
N
H
N
H
Me
has grown at an extraordinary pace. As seen in this ac-
count the initially developed bioinspired transfer hydro-
genation of imines represented a key starting point for the
development of many powerful reductions. The generality
of this BINOL–phosphate–dihydropyridine combination
is particularly noteworthy when compared to nature’s de-
hydrogenase–NADH system. Thus, a broad range of di-
verse cyclic and acyclic amines as well as heterocycles
can be readily obtained with impressive enantioselectivi-
ties by applying this convenient method which is striking
due to its almost optimal reaction conditions and the oper-
ational simplicity and practicability. Similar to nature’s
multicomponent domino reactions it was possible to im-
plement the catalytic asymmetric Brønsted acid catalyzed
transfer hydrogenation in efficient multistep reaction se-
quences showing that this protocol is amenable to be ap-
plied in complex molecular cascades. Although we have
been able to achieve a broader substrate scope and simi-
larly high reactivities and selectivities compared to our
natural role model, dehydrogenase, we are far from being
as efficient. Therefore, the future goal is to improve the re-
action in such a way that, similar to nature’s NADH, our
hydride source dihydropyridine can be recycled or em-
ployed in catalytic amounts. We are confident that this or-
ganocatalytic hydrogenation procedure which provides a
series of valuable biologically active products with re-
markable levels of selectivity will find widespread appli-
cation in organic synthesis.
CF3
O
23c: 78%, 99% ee
23d: 47%, 92% ee
N
H
23e: 66%, 89% ee
Figure 12 Substrate scope of the Brønsted acid catalyzed cascade
RO
RO
O
O–
+H3N
CO2t-Bu
i-Pr
P
O
O
R1
5f
R1
HEH 2a
R2
R3
R2
R3
34
33
O
O
O
O
Me
CO2Et
i-Pr
Et
34b: 98%,
98% ee
34a: 71%,
96% ee
34c: 99%,
96% ee
34d: 99%,
84% ee
Scheme 19 Brønsted acid catalyzed transfer hydrogenation of en-
ones
8
Conclusion
Acknowledgment
In the five years since we reported the highly enantiose-
lective Brønsted acid catalyzed transfer hydrogenation
which was inspired by nature’s dehydrogenase, this field
Financial support by the Evonik Degussa, the DFG (Priority Pro-
gramme Organocatalysis) and the FCI (Fonds der Chemischen In-
dustrie) is gratefully acknowledged.
Synlett 2010, No. 6, 852–865 © Thieme Stuttgart · New York

864
M. Rueping et al.
ACCOUNT
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Bolte, M. Org. Lett. 2005, 7, 3781. (b) Rueping, M.;
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Eds.; J. Wiley & Sons: New York, 2007, 162–170.
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Ed. 2006, 45, 2617. (b) Rueping, M.; Azap, C. Angew.
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