Asymmetric synthesis of tetrahydro-β-carbolines via chiral phosphoric acid catalyzed transfer hydrogenation reaction

Article abstract of DOI:10.1021/ol400995c

Chiral phosphoric acid catalyzed enantioselective transfer hydrogenation of hydroxylactams has been realized to provide enantioenriched tetrahydro-β-carbolines in dioxane at room temperature (up to 94% yield, 90% ee).

Full text of DOI:10.1021/ol400995c

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Synthesis of Tetrahydro-β-
carbolines via Chiral Phosphoric Acid
Catalyzed Transfer Hydrogenation
Reaction
Qin Yin, Shou-Guo Wang, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
slyou@sioc.ac.cn
Received April 10, 2013
ABSTRACT
Chiral phosphoric acid catalyzed enantioselective transfer hydrogenation of hydroxylactams has been realized to provide enantioenriched
tetrahydro-β-carbolines in dioxane at room temperature (up to 94% yield, 90% ee).
Chiral tetrahydro-β-carbolines are of particular impor-
tance, astheyarekeystructuralunitsinnaturallyoccurring
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€
Figure 1. Selected tetrahydro-β-carboline natural products.
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alkaloids that exhibit interestingly biological activities
(Figure 1).1,2 Therefore, the development of an efficient
enantioselective synthesis of these polycycles is very essen-
tial. To date, the PictetÀSpengler reaction3 has proven to
be the most straightforward route for the construction of a
tetrahydro-β-carboline framework. However, the number
of successful catalytic enantioselective PictetÀSpengler re-
actions remains limited. Alternatively, asymmetric reduc-
tion of fused imine or iminium ions represents a practical
route to synthesize enantiopure indole alkaloids.4 In gen-
eral, precious metals such as ruthenium, rhodium, and
iridium are essential forthese transformations. Inaddition,
synthesis of the iminium ions usually requires a multistep
r
10.1021/ol400995c
XXXX American Chemical Society

procedure. On the other hand, organocatalytic transfer
hydrogenation with organic hydride donors5 has emerged
as a powerful method for the construction of diverse cyclic
and acyclic amines as well as heterocycles, serving as an
important supplement to the transition-metal catalyzed
asymmetric hydrogenation.
Catalytic asymmetric reactions involving N-acylimi-
nium ions represent a useful tactic for the construction of
chiral amines in organic synthesis. Compared to ketimines
and N-heterocycles, however, N-acyliminium ions have
been less explored in asymmetric hydrogenation reactions.
Recently, chiral phosphoric acid catalyzed enantioselective
intermolecular FriedelÀCrafts alkylations of indoles with
N-acyliminium ions formed in situ from hydroxylactams
have been reported by Rueping,6 Zhou,7 Lete,8 Masson,9
etc. In 2012, Zhou10 et al. reported an enantioselective
transfer hydrogenation reaction of 3-hydroxyisoindolin-1-
ones with a Hantzsch ester catalyzed by chiral phosphoric
acid. We envisaged that hydroxylactams 2, prepared easily
from tryptamine derivatives 1,11 could be suitable sub-
strates in the Brønsted acid catalyzed transfer hydrogena-
tion reaction. The corresponding N-acyliminium ions will
be formed when the hydroxylactams are treated with
Brønsted acid. Then the transfer hydrogenation of these
key intermediates in the presence of a chiral Brønsted
acid would afford optically active tetrahydro-β-carbo-
lines (Scheme 1). Herein, we report such an efficient
synthesis of enantioenriched tetrahydro-β-carbolines
via chiral phosphoric acid catalyzed asymmetric transfer
hydrogenation with the Hantzsch ester as the organic
hydride source.12
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Scheme 1. Proposed Hydrogenation of Hydroxylactams 2
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We began our exploration by testing substrate 2a
with Hantzsch ester 4a as the hydride source. Several
(S)-BINOL-derived phosphoric acids were tested in CH2Cl2,
and the results are summarized in Table 1. In all cases, full
conversions were obtained; the enantiocontrol, however,
varied dramatically (entries 1À6, Table 1). The SiPh3
substituted phosphoric acid (S)-5baffordedthe best results
(88% yield, 52% ee, entry 2, Table 1). Further screening of
the catalysts showed VAPOL-derived phosphoric acid 6
and SPINOL-derived phosphoric acid 713 were not effi-
cient catalysts in terms of enantiocontrol (entries 7À8,
Table 1). With (S)-5b as the catalyst, we further optimized
the reaction conditions by examining the solvents, and it
was found that solvents affected the reactivity and enan-
tioselectivity significantly (entries 9À15, Table 1). Dioxane
turned out to be the best choice with improved enantios-
electivity (75% ee, entry 12, Table 1).
Further screening of hydride donors revealed that the
utilization of Hantzsch ester 4b could further improve the
enantioselectivity (80% ee, entry 1, Table 2). Attempts
using molecular sieves or MgSO4 did not benefit the reac-
tion outcome (entries 2À5, Table 2). Finally, the reaction
with 5 mol % (S)-5b and Hantzsch ester 4b as the hydride
source in dioxane at room temperature led to the best
combination of isolated yield and enantioselectivity (91%
yield, 80% ee, entry 1, Table 2).
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T. B.; Wang, Q.; Gueritte, F. Chem.;Eur. J. 2011, 17, 9576. (r) Chen,
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Under the above optimized reaction conditions, various
substituted hydroxylactams 2 were examined to probe the
generality of the reaction. The results are shown in Table 3.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Evaluation of Catalysts and Solvents
Table 3. Substrate Scope
time
yield
(%)b
ee
entrya
1
CPA
R
solvent
CH2Cl2
(h)
(%)c
5a
2,4,6-(iPr)3-
C6H2
4
87
29
2
3
4
5b
5c
5d
SiPh3
CH2Cl2
CH2Cl2
CH2Cl2
3.5
6
88
78
78
52
27
8
1-naphthyl
3,5-(CF3)2-
C6H3
5
5
5e
5f
2-naphthyl
biphenyl
À
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
10
6
95
94
91
77
84
91
89
84
À
44
49
18
À30
41
63
22
75
À
6
7
6
5
8
7
À
12
2.5
6
9
5b
5b
5b
5b
5b
5b
5b
SiPh3
10
11
12
13
14
15
SiPh3
SiPh3
CHCl3
dioxane
Et2O
tBuOMe
EtOAc
8
SiPh3
24
48
48
24
SiPh3
SiPh3
60
85
6
SiPh3
55
a Reactions were performed with 2a (0.1 mmol), 4a (0.2 mmol), and
5 mol % CPA. b Isolated yield. c Determined by HPLC analysis.
Table 2. Screening of Hydride Donor and Additives
a Reactions were performed with 2 (0.1 mmol), 4b (0.2 mmol), and
5 mol % (S)-5b. b Isolated yield. c Determined by HPLC analysis.
time
(h)
yield
(%)b
ee
(%)c
entrya
additive
Substituted hydroxylactams 2bÀf containing an electron-
rich group (4-Me, 5-Me, 6-Me, 7-Me, 5-MeO) at dif-
ferent positions of the indole ring could be well tolerated,
affording their corresponding tetrahydro-β-carbolines in
68À93% yields with good enantioselectivity ranging from
77% to 85% ee (entries 2À6, Table 3). In addition, sub-
strates 2gÀj bearing an electron-poor group on the indole
moiety (5-Cl, 5-Br, 6-Br, 5-F) were also suitable substrates,
and the reduced products were obtained in excellent yields
1
2
3
4
5
À
24
72
72
72
24
91
35
40
85
90
80
75
79
73
77
˚
3 A MS
˚
4 A MS
˚
5 A MS
MgSO4
a Reactions were performed with 2a (0.1 mmol), 4b (0.2 mmol),
additive (50 mg), and 5 mol % (S)-5b. b Isolated yield. c Determined by
HPLC analysis.
Org. Lett., Vol. XX, No. XX, XXXX
C

and good enantioselectivity (90À94% yield, 82À90% ee,
entries 7À10, Table 3).
To gain insight into the origin of the enantioselectivity,
the reaction of the racemic substrate 2g with 0.6 equiv of
Hantzsch ester 4b was carried out in the presence of 5 mol %
of (S)-5b (eq 1). Interestingly, substrate 2g (20% ee) could
be recovered, indicating that a moderate kinetic resolution
of hydroxylactam exists during the asymmetric transfer
hydrogenation reaction.
Figure 2. X-ray structure of enantiopure (R)-3a.
configuration of product 3a obtained from the current study
was assigned as (R). This was also confirmed by an X-ray
crystallographic analysis of enantiopure 3a (Figure 2).
In summary, we have developed an efficient synthesis of
enantioenriched tetrahydro-β-carbolines via chiral phos-
phoric acid catalyzed enantioselective transfer hydrogena-
tion of hydroxylactams with up to 94% yield and 90% ee.
This methodology features the ready availability of the
starting materials, high yields, and mild reaction condi-
tions. Further improvement of the enantioselectivity and
application of the method into natural product synthesis
are currently ongoing in our group.
Scheme 2. Determination of the Absolute Configuration of 3a
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program 2010CB833300),
the National Natural Science Foundation of China
(20923005, 21025209, 21121062), and the Chinese Academy
of Sciences for generous financial support.
The absolute configuration of product 3a was estab-
lished by comparison of its optical rotation with that
derived from a known compound, as shown in Scheme 2.14
Compound 8b was synthesized via TfOH catalyzed cycliza-
tion of (S)-8a and subsequent reduction by the Hantzsch
ester. Then hydrolysis of the ester group in 8b followed by
radical decarboxylation yielded compound 3a with 99% ee.
By comparing the sign of the optical rotation, the absolute
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic data for all new com-
pounds and X-ray crystal data of 3a. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(14) Wakchaure, P. B.; Puranik, V. G.; Argade, N. P. Tetrahedron:
Asymmetry 2009, 20, 220.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX