Organocatalytic enantioselective conjugate addition-cyclization domino reactions of o-N-protected aminophenyl α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetlet.2013.07.031

A highly enantioselective synthesis of biologically useful tetrahydroquinolines has been developed through the asymmetric organocatalytic conjugate addition-cyclization reaction of malonates with o-N-protected aminophenyl α,β-unsaturated aldehydes using a diphenylprolinol TMS ether as an organocatalyst followed by reductive deoxygenation. This novel protocol allows for the formation of 4-substituted chiral tetrahydroquinolines, which are not easily accessible using other methodologies, in good yields with high enantioselectivities (up to >99% ee).

Full text of DOI:10.1016/j.tetlet.2013.07.031

Tetrahedron Letters 54 (2013) 4978–4981
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic enantioselective conjugate addition–cyclization
domino reactions of o-N-protected aminophenyl a,b-unsaturated
aldehydes
⇑
Seungpyeong Heo , Shinae Kim , Sung-Gon Kim
Department of Chemistry, Kyonggi University, San 94-6, Iui-dong, Yeongtong-gu, Suwon 443-760, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective synthesis of biologically useful tetrahydroquinolines has been developed
through the asymmetric organocatalytic conjugate addition–cyclization reaction of malonates with
Received 29 May 2013
Revised 27 June 2013
Accepted 5 July 2013
Available online 15 July 2013
o-N-protected aminophenyl
a,b-unsaturated aldehydes using a diphenylprolinol TMS ether as an
organocatalyst followed by reductive deoxygenation. This novel protocol allows for the formation of
4-substituted chiral tetrahydroquinolines, which are not easily accessible using other methodologies,
in good yields with high enantioselectivities (up to >99% ee).
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Organocatalysis
Asymmetric catalysis
Conjugate addition
Domino reaction
Tetrahydroquinoline
Tetrahydroquinolines are valuable building blocks found in
numerous biologically active natural products and pharmacologi-
cally relevant therapeutic agents.1 Molecules containing the tetra-
hydroquinoline scaffold exhibit a broad range of bioactivities,
such as anti-HIV, antibacterial, antifungal, antimalarial, antitumor,
and cardiovascular activities.2 This scaffold is also present in anti-
oxidants, dyes, and photosensitizers.3 In addition, chiral tetrahy-
scaffold still remains an active field of research and has attracted
our attention.
Asymmetric organocatalysis, which results in better reproduc-
ibility and greater operational simplicity than traditional metal
catalysis, has attracted considerable attention during the past
decade.10 Organocatalysts have several important advantages
which are usually inexpensive, readily available, robust, and non-
toxic. Furthermore, asymmetric organocatalysis is a very promis-
droquinoline scaffold is found in
a number of important
biologically active natural products and pharmaceutical com-
pounds, some notable examples being (+)-Galipinine, isolated from
the trunk bark of the South American tree Galipea officinalis,4 Penip-
requinolone, isolated from Penicillium simplicissimum and fungus
Penicillium janczewskii,5 Torcetrapib (CP-529,414), a potent cho-
lesteryl ester transfer protein inhibitor,6 and Virantmycin, which
has antiviral activity7 (Fig. 1). Because of the importance of these
‘privileged’ structures, numerous synthetic methods for tetrahy-
droquinolines have been reported. Recently, enantioselective syn-
thetic approaches to the generation of chiral tetrahydroquinolines
that rely mainly on the asymmetric hydrogenation of heteroaro-
matic compounds have been developed.8 The nucleophilic addition
of imines, the Povarov reaction, and organocatalysis have also been
used for the construction of chiral tetrahydroquinoline scaffold.9
Consequently, the development of an efficient enantioselective
synthetic method for the generation of the tetrahydroquinoline
OMe
OH
OH
OMe
O
N
Me
N
H
O
O
(+)-Galipinine
Peniprequinolone
MeO2C
N
CF3
HO2C
Cl
F3C
CF3
N
H
N
EtO2C
OMe
⇑
Virantmycin
Corresponding author. Tel.: +82 31 249 9631; fax: +82 31 249 9639.
E-mail address: sgkim123@kyonggi.ac.kr (S.-G. Kim).
Torcetrapib
These authors contributed equally to this work.
Figure 1. Representative biologically active chiral tetrahydroquinolines.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.031

S. Heo et al. / Tetrahedron Letters 54 (2013) 4978–4981
4979
Table 1
ing strategy that provides efficient and environmentally friendly
Screening of the reaction conditionsa
access to enantiomerically pure compounds in the synthesis of nat-
ural products and biologically active compounds. In particular,
organocatalytic domino reaction, in which two or more bond-
forming transformations occur under the same reaction conditions
and subsequent reactions result as a consequence of the function-
ality formed in the previous step, is useful for assembling complex
chiral molecular frameworks with high yields and remarkable
enantioselectivities from simple starting materials.11
O
O
Ph
Ph
OTMS
MeO
OMe
N
H
I
O
O
O
(20 mol%)
+
N
Cbz
3a
OH
NHCbz
1a
MeO
OMe
additive
(20 mol%)
solvent, rt
2a
As part of a research program related to the development of syn-
thetic methods for the enantioselective construction of stereogenic
carbon centers,12 we recently developed a novel catalytic asymmet-
Entry
Additive
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
—
CH2Cl2
CH2Cl2
MeOH
EtOH
i-PrOH
MeOH
MeOH
MeOH
MeOH
MeOH
72
72
36
48
48
24
60
72
72
48
10
20
56
62
65
77
28
22
18
28
ndd
ndd
87
60
61
89
90
97
97
96
NaOAC
NaOAC
NaOAC
NaOAC
LiOAc
—
AcOH
PhCO2H
4-NO2C6H4CO2H
ric Michael reaction of o-hydroxyphenyl a,b-unsaturated aldehydes
using an organocatalyst, which afforded enantioenriched chroman
derivatives through the cascade cyclization domino reaction.12f,12g
With the objective of developing a new methodology for producing
enantioenriched tetrahydroquinolines, we considered the use of
o-N-protected aminophenyl a,b-unsaturated aldehydes as electro-
philes in organocatalytic asymmetric Michael reactions.
10
Although o-N-protected aminobenzaldehydes have been exten-
sively used as starting substrates in organocatalytic asymmetric
reactions,13 to our knowledge, organocatalytic reactions using o-
a
Unless otherwise specified, the reaction was carried out in solvent (0.3 M) with
1.5 equiv of dimethyl malonate 2a relative to the o-N-Cbz-aminophenyl
a
,b-unsaturated aldehyde 1a in the presence of 20 mol % catalyst I and additive.
b
N-protected aminophenyl
a,b-unsaturated aldehydes, which are
Isolated yield after chromatographic purification.
Determined by chiral-phase HPLC analysis after reduction.
Not determined.
c
readily obtained using the Wittig reaction of o-N-protected amino-
benzaldehydes and (triphenyl-phosphoranylidene)acetaldehyde,
have not been previously reported. Herein, we report the first
example of the enantioselective synthetic method of 4-substituted
chiral tetrahydroquinolines through the asymmetric organocata-
lytic conjugate addition–cyclization domino reaction of malonates
d
Table 2
Asymmetric synthesis of tetrahydroquinolines 4 through organocatalytic domino
reactions of 1 with 2a,b
with o-N-protected aminophenyl
this novel transformation, the reaction of malonates as nucleo-
philes with o-N-protected aminophenyl ,b-unsaturated aldehyde
substrates in the presence of an appropriate organocatalyst was as-
sumed to form highly enantioselective Michael adducts, which
were hemiacetalized to 4-substituted tetrahydroquinolin-2-ols.
Subsequent reductive deoxygenation allowed the production of
4-substituted tetrahydroquinolines with high enantiopurity
(Scheme 1).
a,b-unsaturated aldehydes. In
O
O
O
O
O
a
NHPG
I (20 mol%)
LiOAc
RO
OR
OH
RO
OR
1
Et3SiH
+
(20 mol%)
BF3 OEt2
O
O
MeOH, rt
CH2Cl2
N
N
RO
OR
0 o
C
PG
PG
2
3
4
Entry
PG
R
Time (h)
Yieldc 3 (%)
Yieldc 4 (%)
eed (%)
With this speculation in mind, our initial investigation began
1
2
3
4
5
6
7
8
9
Bn
Me
Me
Me
Me
Me
Et
48
48
24
24
36
24
24
36
28
36
36
22
14
75
77
82
45
55
44
37
59
64
5
—
nde
nde
84
89
94
66
98
49
88
92
96
with the reaction of o-N-Cbz-aminophenyl
hyde 1a and dimethyl malonate (2a). Based on the results of our
previous work,12 the
-diphenyl- -prolinol TMS ether catalyst I
was initially selected as an organocatalyst in this Michael reac-
tion,14,15 and the results are shown in Table 1. The reaction med-
ium had a substantial impact on the conversion efficiency in this
reaction. It is notable that aprotic solvents gave sluggish reaction
activity. In CH2Cl2, regardless of the use of additives, the desired
product, tetrahydroquinolin-2-ol 3a, was obtained in very poor
a,b-unsaturated alde-
CO2Et
Boc
Cbz
Ts
Cbz
Ts
Cbz
Ts
Cbz
Ts
12
84
83
74
80
91
73
81
77
a
,a
L
Et
i-Pr
i-Pr
Bn
10
11
Bn
a
Unless otherwise specified, the reactions were carried out in MeOH (0.3 M) with
1.5 equiv of malonate 2 relative to the o-N-protected aminophenyl ,b-unsaturated
a
aldehydes 1 in the presence of catalyst I (20 mol %) and LiOAc (20 mol %).
O
O
O
b
X
Reactions were carried out in CH2Cl2 (0.1 M) at 0 °C with 1.0 equiv of crude
NHPG
tetrahydroquinolinols
3 using 2.0 equiv triethylsilane and 3.0 equiv boron
RO
RO
OR
Organocatalyst
trifluoride etherate.
+
c
Isolated yield after chromatographic purification.
Determined by chiral HPLC analysis.
Not determined.
O
O
O
O
d
e
X
X
NHPG
O
RO
RO
OR
yield even after 72 h (entries 1 and 2). When MeOH was used as
the solvent with NaOAc as the additive , a 56% yield and 87% ee
were achieved (entry 3). Other protic solvents such as EtOH and
i-PrOH induced similar favorable reactivities but slightly dimin-
ished enantioselectivities (entries 4 and 5). The best result was ob-
tained in MeOH with LiOAc additive (77% yield and 89% ee, entry
6). However, the use of acid additives decreased the efficiencies
of the reactions somewhat but significantly increased enantiose-
lectivities (up to 97% ee, entries 8–10).
O
O
Reductive
OR
OH
OR
deoxygenation
X
N
PG
N
PG
Scheme 1. Asymmetric synthesis of 4-substituted tetrahydroquinolines through
organocatalytic conjugate addition–cyclization domino reaction.

4980
S. Heo et al. / Tetrahedron Letters 54 (2013) 4978–4981
Under these optimized conditions (20 mol % of I as the catalyst,
Subsequently, the reaction of several substituted N-Cbz- or Ts-
protected aminophenyl ,b-unsaturated aldehydes with dimethyl
malonate (2a) was also investigated under the optimized condi-
tions (Table 3).16 Generally, the substituent’s electronic features
and position on the aromatic ring did not significantly influence
the enantiocontrol in the asymmetric reactions of substituted
20 mol % LiOAc as the additive, in MeOH at rt), in order to obtain
the further satisfactory methodology for the formation of 4-substi-
tuted chiral tetrahydroquinolines, the effects of the protecting
a
group on o-aminophenyl a,b-unsaturated aldehyde 1 and the ester
group on malonates 2 were investigated not only in this organocat-
alytic domino reaction but also in following reductive deoxygen-
ation (Table 2). We reasoned that the protecting group on the o-
o-N-Cbz-aminophenyl
a,b-unsaturated aldehydes, while the best
results (up to 93% ee) were obtained in the reaction of
aminophenyl
role in governing the reactivity and stereoselectivity in this pro-
cess, thus various o-N-protected aminophenyl ,b-unsaturated
a
,b-unsaturated aldehydes 1 played an important
6-methyl-N-Cbz-aminophenyl
5-bromo-N-Cbz-aminophenyl
3 and 10). However, in the cases of substituted N-Ts-aminophenyl
a
,b-unsaturated aldehyde and
a
,b-unsaturated aldehyde (entries
a
aldehydes were prepared and their influences on the reaction were
investigated. It appeared that the more electron-withdrawing
amine substituents (Bn < Cbz < Ts) clearly provide increased effi-
ciency of reaction and enantiocontrol. Although o-N-Boc-amino-
a,b-unsaturated aldehydes, 6-substituted groups had opposing
influences on the reaction efficiency and the asymmetric induc-
tion; the corresponding 6-substituted N-Ts-protected tetrahydro-
quinolin-2-ols were obtained in excellent yields (95%) with
moderate enantioselectivities (79% ee, entry 4). The absolute con-
figurations of these products were assigned based on previous
studies. The reaction of dimethyl malonate (2a) with phenyl
phenyl
to o-N-Cbz-aminophenyl
a
,b-unsaturated aldehyde gave a similar reaction pattern
,b-unsaturated aldehyde, the corre-
a
sponding o-N-Boc-tetrahydroquinolin-2-ol afforded the desired
tetrahydroquinoline in low yield in the following reductive deoxy-
genation step (entry 3). Under same reaction conditions, the cata-
a,b-unsaturated aldehydes or o-hydroxycinnamaldehydes cata-
lyzed by the same organocatalyst I has been reported to give addi-
tion products of (R)-configuration.12f,15 It is expected that the
absolute configuration for the products of the present reaction
can be assigned by analogy as being the same.
lytic reaction of o-N-Ts-aminophenyl
a,b-unsaturated aldehyde
and dimethyl malonate (2a) at rt followed by reduction with Et3-
SiH in the presence of BF3ꢀOEt2 furnished the desired N-Ts-tetrahy-
droquinoline with 94% ee (entry 5). Although the Cbz-protecting
group gave a slightly reduced enantioselectivity compared with
the Ts group, we evaluated both further because they show differ-
ent advantages during the deprotection process. The scope of the
Once the conjugate addition–cyclization reaction of malonates
with o-N-protected aminophenyl
a,b-unsaturated aldehydes had
been demonstrated to synthesize 4-substituted enantioenriched
tetrahydroquinolines, the reaction was extended via its application
with other nucleophiles.17 As represented in Scheme 2, nitrometh-
ane (5) was evaluated in this novel reaction to expand the scope for
the preparation of enantioenriched tetrahydroquinoline deriva-
tives.18 Nitromethane (5) underwent the conjugate addition–
cyclization domino reaction with o-N-protected aminophenyl
reaction of various malonates 2 with o-N-Cbz-aminophenyl
a,b-
unsaturated aldehyde or o-N-Ts-aminophenyl
aldehyde was explored. o-N-Ts-aminophenyl
a
,b-unsaturated
a,b-unsaturated
aldehyde provided a better enantiocontrol than o-N-Cbz-amino-
phenyl ,b-unsaturated aldehyde in all cases of the reactions with
a
various malonates, except for those with dibenzyl malonates, in
a,b-unsaturated aldehydes 1 to produce the desired 4-nitromethyl
which both gave similar results (entries 10 and 11).
N-protected tetrahydroquinolines 6 in good yield, which can be
reduced to 4-nitromethyl tetrahydroquinolines
enantioselectivities (87–88% ee).
7 with good
In conclusion, a novel organocatalytic conjugate addition–cycli-
zation domino reaction was developed for the efficient preparation
of chiral 4-substituted tetrahydroquinoline derivatives. The cata-
Table 3
Asymmetric synthesis of tetrahydroquinolines 4 through organocatalytic domino
reactions of various substituted aldehydes 1 with 2aa,b
lytic reaction of o-N-protected aminophenyl a,b-unsaturated alde-
2
4
hydes and malonates followed by reductive deoxygenation
provided the corresponding tetrahydroquinolines in good yields
with high enantioselectivities (up to >99% ee). Moreover, nitro-
methane was also subjected to this novel reaction resulting in
enantioenriched tetrahydroquinolines with good enantioselectivi-
ties. The resulting tetrahydroquinolinols and tetrahydroquinolines
can readily transform a variety of derivatives in a few short steps
owing to the synthetic versatility of the amine, hydroxy, carboxylic
ester, and nitro group. Studies on the biological activity of these
compounds against especially NF-kB in A549 cell are currently
underway and the results will be presented in due course.
O
O
O
O
O
I
(20 mol%)
LiOAc
MeO
OMe
OH
MeO
X
OMe
1 NHPG
X
Et3SiH
1a-k
(20 mol%)
BF3 OEt2
+
O
O
MeOH, rt
CH2Cl2
N
N
X
0 o
C
PG
PG
4a-k
MeO
OMe
3
2a
Entry
PG
X
Time (h)
Yieldc 3 (%)
Yieldc 4 (%)
eed (%)
1
2
3
4
Cbz
Ts
Cbz
Ts
Cbz
Cbz
Ts
Cbz
Ts
H
H
24
36
36
36
36
48
60
48
60
60
60
77
82
74
95
65
66
62
58
63
74
67
84
83
79
81
76
83
76
76
77
81
64
89
94
93
79
89
92
92
90
80
93
>99
6-Me
6-Me
4-Cl
5-Cl
5-Cl
4-Br
4-Br
5-Br
5-Br
5
6e
7e
8
I
NO2
NO2
O
9e
(20 mol%)
LiOAc
10
11
Cbz
Ts
NHPG
1
Et3SiH
(20 mol%)
BF3 OEt2
+
a
N
PG
: PG = Cbz,
76% yield
: PG = Ts,
72% yield
OH
N
PG
Unless otherwise specified, the reactions were carried out in MeOH (0.3 M) with
1.5 equiv of malonate 2a relative to the o-N-protected aminophenyl ,b-unsatu-
MeOH, rt
CH2Cl2
0 o
C
CH3NO2
5
a
rated aldehydes 1 in the presence of catalyst I (20 mol %) and LiOAc (20 mol %).
6a
6b
7a
: PG = Cbz,
b
Reactions were carried out in CH2Cl2 (0.1 M) at 0 °C with 1.0 equiv of crude
83% yield, 87% ee
tetrahydroquinolinols 3 using 2.0 equiv triethylsilane and 3.0 equiv boron tri-
7b
: PG = Ts,
fluoride etherate.
88% yield, 86% ee
c
Isolated yield after chromatographic purification.
Determined by chiral HPLC analysis.
Reaction was performed at 0 °C.
d
Scheme 2. Organocatalytic conjugate addition–cyclization domino reaction of
nitromethane (5) with o-N-protected aminophenyl ,b-unsaturated aldehydes 1.
e
a

S. Heo et al. / Tetrahedron Letters 54 (2013) 4978–4981
4981
Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416; (c) Dalko, P. I.
Enantioselective Organocatalysis; Wiley-VCH: Weinheim, 2007; (d) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (e) Pellisier, H.
Tetrahedron 2007, 63, 9267; (f) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed.
2008, 47, 4638; (g) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178;
(h) Pellissier, H. Recent Developments in Asymmetric Organocatalysis; RSC:
Cambridge, 2010.
Acknowledgments
This research was supported by Nano-Material Development
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Technology
(2012-049648), and by Kyonggi University Research Assistant Fel-
lowship 2012.
11. For selected reviews on organocatalytic domino reaction, see: (a) Enders, D.;
Grondal, C.; Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570; (b) Grondal,
C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167; (c) Albrecht, Ł.; Jiang, H.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2011, 50, 8492; (d) Pellissier, H. Adv.
Synth. Catal. 2012, 354, 237.
Supplementary data
12. (a) Choi, K.-S.; Kim, S.-G. Tetrahedron Lett. 2010, 51, 5203; (b) Choi, K.-S.; Kim,
S.-G. Synthesis 2010, 3999; (c) Lee, Y.; Kim, S.-G. Bull. Korean Chem. Soc. 2011,
32, 311; (d) Gwon, S. H.; Kim, S.; Kim, S.-G. Bull. Korean Chem. Soc. 2011, 32,
4163; (e) Do, J.; Kim, S.-G. Tetrahedron Lett. 2011, 52, 2353; (f) Lee, Y.; Seo, S.
W.; Kim, S.-G. Adv. Synth. Catal. 2011, 353, 2671; (g) Choi, K.-S.; Kim, S.-G. Eur. J.
Org. Chem. 2012, 1119; (h) Gwon, S. H.; Kim, S.-G. Bull. Korean Chem. Soc. 2012,
33, 2781; (i) Gwon, S. H.; Kim, S.-G. Tetrahedron: Asymmetry 2012, 23, 1251; (j)
Seo, S. W.; Kim, S.-G. Tetrahedron Lett. 2012, 53, 2809.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.07.
031.
References and notes
13. (a) Sundén, H.; Rios, R.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Córdova, A. Adv.
Synth. Catal. 2007, 349, 827; (b) Li, H.; Wang, J.; Xie, H.; Zu, L.; Jiang, W.;
Duesler, E. N.; Wang, W. Org. Lett. 2007, 9, 965; (c) Liu, X.; Lu, Y. Org. Biomol.
Chem. 2010, 8, 4063; (d) Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.;
Wang, W. Nat. Commun. 2012, 2, 211.
1. For reviews on tetrahydroquinolines, see: (a) Katritzky, A. R.; Rachwal, S.;
Rachwal, B. Tetrahedron 1996, 52, 15031; (b) Kouznetsov, V.; Palma, A.; Ewert,
C.; Varlamov, A. J. Heterocycl. Chem. 1998, 35, 761; (c) Mitchinson, A.; Nadin, A.
J. Chem. Soc., Perkin Trans. 1 2000, 17, 2862; (d) Zhou, Y.-G. Acc. Chem. Res. 2007,
40, 1357; (e) Sridharan, V.; Suryavanshi, P. A.; Menéndez, J. C. Chem. Rev. 2011,
111, 7157.
2. (a) Ding, C. Z.; Hunt, J. T.; Ricca, C.; Manne, V. Bioorg. Med. Chem. Lett. 2000, 10,
273; (b) Urbina, J. M.; Cortés, J. C. G.; Palma, A.; López, S. N.; Zacchino, S. A.;
Enriz, R. D.; Ribas, J. C.; Kouznetzov, V. V. Bioorg. Med. Chem. 2000, 8, 691; (c)
Liou, J.-P.; Wu, Z.-Y.; Kuo, C.-C.; Chang, C.-Y.; Lu, P.-Y.; Chen, C.-M.; Hsieh, H.-P.;
Chang, J.-Y. J. Med. Chem. 2008, 51, 4351; (d) Ramesh, E.; Manian, R. D. R. S.;
Raghunathan, R.; Sainath, S.; Raghunathan, M. Bioorg. Med. Chem. 2009, 17, 660;
(e) Skerlj, R. T.; Bridger, G. J.; Kaller, A.; McEachern, E. J.; Crawford, J. B.; Zhou,
Y.; Atsma, B.; Langille, J.; Nan, S.; Veale, D.; Wilson, T.; Hartwig, C.; Hatse, S.;
Princen, K.; De Clercq, E.; Schols, D. J. Med. Chem. 2010, 53, 3376.
3. (a) Dorey, G.; Lockhart, B.; Lestage, P.; Casara, P. Bioorg. Med. Chem. Lett. 2000,
10, 935; (b) Agbo, S. I.; Hallas, G.; Towns, A. D. Dyes Pigm. 2000, 47, 33; (c) Chen,
R.; Yang, X.; Tian, H.; Sun, L. J. Photochem. Photobiol. A 2007, 189, 295.
4. (a) Rakotoson, J. H.; Fabre, N.; Jacquemond-Collet, I.; Hannedouche, S.;
Fourasté, I.; Moulis, C. Planta Med. 1998, 64, 762; (b) Jacquemond-Collet, I.;
Hannedouche, S.; Fabre, N.; Fourasté, I.; Moulis, C. Phytochemistry 1999, 51,
1167.
5. (a) Kusano, M.; Koshino, H.; Uzawa, J.; Fujioka, S.; Kawano, T.; Kimura, Y. Biosci.,
Biotechnol., Biochem. 2000, 64, 2559; (b) Schmeda-Hirschmann, G.;
Hormazabal, E.; Astudillo, L.; Rodriguez, J.; Theoduloz, C. World J. Microbiol.
Biotechnol. 2005, 21, 27; (c) He, J.; Lion, U.; Sattler, I.; Gollmick, F. A.; Grabley, S.;
Cai, J.; Meiners, M.; Schünke, H.; Schaumann, K.; Dechert, U.; Krohn, M. J. Nat.
Prod. 2005, 68, 1397.
6. (a) Sikorski, J. A. J. Med. Chem. 2006, 49, 1; (b) Brousseau, M. E.; Schaefer, E. J.;
Wolfe, M. L.; Bloedon, L. T.; Digenio, A. G.; Clark, R. W.; Mancuso, J. P.; Rader, D.
J. N. Eng. J. Med. 2004, 350, 1505; (c) Pal, M. Tetrahedron 2009, 65, 433; (d)
DePasquale, M.; Cadelina, G.; Knight, D.; Loging, W.; Winter, S.; Blasi, E.; Perry,
D.; Keiser, J. Drug Dev. Res. 2009, 70, 35.
7. (a) Omura, S.; Nakagawa, A.; Hashimoto, H.; Oiwa, R.; Iwai, Y.; Hirano, A.;
Shibukawa, N.; Kojima, Y. J. Antibiot. 1980, 33, 1395; (b) Nakagawa, A.; Iwai, Y.;
Hashimoto, H.; Miyazaki, N.; Oiwa, R.; Takahashi, Y.; Hirano, A.; Shibukawa, N.;
Kojima, Y.; Omura, S. J. Antibiot. 1981, 34, 1408; (c) Morimoto, Y. J. Heterocycl.
Chem. 1998, 35, 279.
8. (a) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2006,
45, 2260; (b) Tang, W.-J.; Zhu, S.-F.; Xu, L.-J.; Zhou, Q.-L.; Fan, Q.-H.; Zhou, H.-F.;
Lam, K.; Chan, A. S. C. Chem. Commun. 2007, 613; (c) Wang, X.-B.; Zhou, Y.-G. J.
Org. Chem. 2008, 73, 5640; (d) Guo, Q.-S.; Du, D.-M.; Xu, J. Angew. Chem., Int. Ed.
2008, 47, 759; (e) Han, Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am. Chem. Soc.
2009, 131, 9182; (f) Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.; He, Y.; Fan,
Q.-H.; Xiang, J.; Yu, Z.-X.; Chan, A. S. C. J. Am. Chem. Soc. 2011, 133, 9878.
9. (a) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006,
45, 3683; (b) Fustero, S.; Moscardó, J.; Jiménez, D.; Pérez-Carrión, M. D.;
Sánche-Roselló, M.; del Pozo, C. Chem. Eur. J. 2008, 14, 9868; (c) Liu, H.;
Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc. 2009, 131,
4598; (d) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science 2010,
327, 986; (e) Xie, M.; Chen, X.; Zhu, Y.; Gao, B.; Lin, L.; Liu, X.; Feng, X. Angew.
Chem., Int. Ed. 2010, 49, 3799; (f) Kang, Y. K.; Kim, S. M.; Kim, D. Y. J. Am. Chem.
Soc. 2010, 132, 11847; (g) Jia, Z.-X.; Luo, Y.-C.; Xu, P.-F. Org. Lett. 2011, 13, 832;
(h) Mori, K.; Ehara, K.; Kurihara, K.; Akiyama, T. J. Am. Chem. Soc. 2011, 133,
6166; (i) Dagousset, G.; Zhu, J.-P.; Masson, G. J. Am. Chem. Soc. 2011, 133,
14804; (j) Tan, H. R.; Ng, H. F.; Chang, J.; Wang, J. Chem. Eur. J. 2012, 18, 3865.
10. For selected reviews on organocatalysis, see: (a) Berkessel, A.; Gröger, H.
Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005; (b) Erkkilä, A.;
14. For reviews on organocatalysis based on
a,a-diarylprolinol O-silyl ether, see:
(a) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876; (b) Mielgo, A.;
Palomo, C. Chem. Asian J. 2008, 3, 922; (c) Melchiorre, P.; Marigo, M.; Carlone,
A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138; (d) Xu, L.-W.; Li, L.; Shi, Z.-
H. Adv. Synth. Catal. 2010, 352, 243; (e) Jensen, K. L.; Dickmeiss, G.; Jiang, H.;
Albrecht, Ł.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248.
15. For organocatalytic conjugate addition of malonates to
a,b-unsaturated
aldehydes, see: (a) Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2006, 45, 4305; (b) Palomo, C.; Landa, A.; Mielgo, A.;
Oiarbide, M.; Puente, Á.; Vera, S. Angew. Chem., Int. Ed. 2007, 46, 8431; (c)
Wang, Y.; Li, P.; Liang, X.; Ye, J. Adv. Synth. Catal. 2008, 350, 1383; (d) Maltsev,
O. V.; Kucherenko, A. S.; Zlotin, S. G. Eur. J. Org. Chem. 2009, 5134; (e) Fleischer,
I.; Pfaltz, A. Chem. Eur. J. 2010, 16, 95.
16. Typical procedure for the synthesis of 4a. An amber 2-dram vial equipped with a
magnetic stir bar, containing catalyst
I
(16 mg, 0.05 mmol), LiOAc (3 mg,
0.05 mmol), and o-N-Cbz aminophenyl
a,b-unsaturated aldehyde 1a (70 mg,
0.25 mmol) was charged with MeOH (0.8 mL) at room temperature. The
solution was stirred for 5 min before the addition of dimethyl malonate 2a
(42 lL, 0.38 mmol). The resulting mixture was stirred at constant temperature
until complete consumption of 1a was observed as determined by TLC. The
resulting mixture was directly purified by silica gel chromatography (20%
EtOAc/hexane) to afford the compounds 3a (80 mg, 77% yield), which were
subjected to the following reductive deoxygenation reaction. To a solution of
tetrahydroquinolinols 3a in CH2Cl2 (1.5 mL) at 0 °C were added Et3SiH (61
lL,
0.38 mmol) and BF3ꢀOEt2 (70
l
L, 0.57 mmol) in sequence. After 30 min, the
reaction was treated with saturated aqueous NaHCO3, extracted with EtOAc.
The combined organic layer were washed with brine, dried over anhydrous
MgSO4, and concentrated in vacuo. The crude residue was purified by flash
column chromatography (10% EtOAc/hexane) to afford the desired products 4a
(64 mg, 84% yield) as
a
colorless gum.½a D24
ꢁ
0.87 (c 1.1, CHCl3); 1H NMR
(400 MHz, CDCl3) 7.72 (d, J = 6.0 Hz, 1H), 7.32–7.45 (m, 5H), 7.22 (td, J = 8.4,
1.2 Hz, 1H), 7.17 (dd, J = 7.6, 0.8 Hz, 1H), 7.02 (dd, J = 7.6, 0.8 Hz, 1H), 5.29 (s,
2H), 3.92–4.01 (m, 1H), 3.75 (s, 3H), 3.63–3.78 (m, 3H), 3.60 (s, 3H), 2.11–2.20
(m, 1H), 1.93–2.04 (m, 1H); 13C NMR (100 MHz, CDCl3) 168.4, 168.3, 154.6,
137.6, 136.4, 130.4, 128.6, 128.2, 128.1, 127.9, 127.5, 124.2, 123.8, 67.6, 53.9,
52.6, 52.4, 42.3, 37.1, 29.7, 26.5; MS (ESI) m/z (%) 398 (M+H+, 100); Anal. Calcd
for C22H23NO6ꢀH2O: C, 63.60; H, 6.07; N, 3.37. Found: C, 63.21; H, 6.08; N, 3.11;
Chiralpak AD-H column and AD-H guard column (5% EtOH:hexanes, 1.0 mL/
min flow, k = 220 nm); major-isomer tr = 30.3 min and minor-isomer
tr = 34.4 min; 89% ee.
17. In order to expand reaction scope, malonitrile and bis(phenylsulfonyl)methane
have been used in this reaction as nuleophile, but the reaction was complicated
in the using malonitrile and was not proceeded in the case of
bis(phenylsulfonyl)methane.
18. For organocatalytic conjugate addition of nitroalkanes to enones, see: (a)
Wang, Y.; Li, P.; Liang, X.; Zhang, T. Y.; Ye, J. Chem. Commun. 2008, 1232; (b) Zu,
L.; Xie, H.; Li, H.; Wang, J.; Wang, W. Adv. Synth. Catal. 2007, 349, 2660; (c)
Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, Á.; Vera, S. Angew.
Chem., Int. Ed. 2007, 46, 8431; (d) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett.
2007, 9, 5307; (e) Hojabri, L.; Hartikka, A.; Moghaddam, F. M. Adv. Synth. Catal.
2007, 349, 740; (f) Mei, K.; Jin, M.; Zhang, S.; Li, P.; Liu, W.; Chen, X.; Xue, F.;
Duan, W.; Wang, W. Org. Lett. 2009, 11, 2864; (g) Li, P.; Wang, Y.; Liang, X.; Ye, J.
Chem. Commun. 2008, 3302; (h) Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem.
Commun. 2005, 5346.