Enantioselective organocatalyzed cascade reactions to highly functionalized quinolizidines

Article abstract of DOI:10.1016/j.tet.2011.03.007

An organocatalyzed one-pot Michael addition-Pictet-Spengler sequence of β-ketoamides and α,β-unsaturated aldehydes was developed, which provided access to highly substituted indolo[2,3-α]quinolizidines and benzo[α]quinolizidines in moderate to good yields

Full text of DOI:10.1016/j.tet.2011.03.007

Tetrahedron 67 (2011) 3034e3040
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective organocatalyzed cascade reactions to highly functionalized
quinolizidines
,
a
a
a
c
a,
*
Xiaoyang Dai a, Xiaoyu Wu a , Huihui Fang , Linlin Nie , Jie Chen , Hongmei Deng , Weiguo Cao
,
*
,
Gang Zhao b
*
a Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, People’s Republic of China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032,
People’s Republic of China
c Instrumental Analysis and Research Center, Shanghai University, 99 Shangda Road, Shanghai 200444, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
An organocatalyzed one-pot Michael addition-PicteteSpengler sequence of
b
-ketoamides and
a
,b
-un-
Received 4 January 2011
Received in revised form 22 February 2011
Accepted 3 March 2011
saturated aldehydes was developed, which provided access to highly substituted indolo[2,3-
a]quinoli-
zidines and benzo[ ]quinolizidines in moderate to good yields and good to excellent enantioselectivities.
a
For aromatic
obtained.
a,
b-unsaturated aldehydes 1aej products 10aer containing a stable enol configuration were
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Cascade
Quinolizidine
Cyclization
1. Introduction
N
N
N
OMe
H
N
H
H
H
N
H
N
H
Increased focus has recently been placed on the development of
organic cascade reactions that allow the formation of several bonds,
whether CeC, CeO or CeN, from simple and readily available
starting materials in one process.1 In order to provide enantiose-
lective synthesis of highly functionalized scaffolds effectively,
a number of examples of asymmetric cascade catalysis has been
developed.2,3 Among them, cascade reactions catalyzed by primary
or secondary chiral amines have attracted much interest, from
which a diversity of highly substituted carbocycles and heterocy-
cles have been generated.3,4
H
H
H
OH
H
OH
MeO2C
MeO2C
Geissoschizine
Dihydrocorynantheol
Corynantheol
N
N
N
H
H
N
H
H
H
OH
OH
MeO2C
Geissoschizol
Bhimberine
Fig. 1. Examples of indoloquinolizidine based natural alkaloids.
Indoloquinolizidine and benzoquinolizidine skeletons are found
in a number of natural alkaloids (Fig. 1). Their structural diversity
and stereochemical complexity have rendered them interesting
synthetic targets.5 Traditionally, optically pure quinolizidines are
prepared from the chiral pool.6 However, this strategyoften requires
multi-step functional group transformations and laborious pro-
tecting group manipulations. Therefore catalytic enantioselective
methods to access these compounds would be highly desired.
Although numerous asymmetric catalytic synthesis of quinolizi-
dines have been developed recently,7,8 relatively few utilized a cas-
cade strategy.8
ꢀ
Recently, we and Franzen and co-workers independently
reported efficient synthesis of highly functionalized quinolizidines
by organocatalyzed enantioselective cascade reactions between
a,b-unsaturated aldehydes and active methylene compounds, with
good yield and high enantioselectivity achieved (Scheme 1).8 To
attain practical applicability to the total synthesis of natural alka-
loids containing quinolizidine motifs, the development of more
efficient asymmetric cascade synthesis of these structures is still
highly desired.
* Corresponding authors. Fax: þ86 21 66134856; e-mail addresses: wuxy@
shu.edu.cn (X. Wu), wgcao@staff.shu.edu.cn (W. Cao), zhaog@mail.sioc.ac.cn
(G. Zhao).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.007

X. Dai et al. / Tetrahedron 67 (2011) 3034e3040
3035
Table 1
Screening studies of cascade reaction between
b-ketoamide 8a and cinnamic
aldehyde 1aa
Ar
O
Ar
OTMS
N
H
HN
O
6, Ar = Ph
9, Ar = 3,5-(CF3)2C6H3
O
N
H
8a
N
OH
(1) 10 mol% 6 or 9
+
and acid additive
CHO
Ph
(2) TFA
H
N
H
1a
10a Ph
Entry
Cat
Additive
Solvent
t (h)
Yield (%)b
ee (%)c
1
6
6
6
6
6
9
9
9
9
9
d
DCM
30
30
30
30
30
30
16
16
16
16
45
18
30
d
69
80
64
d
2
d
Toluene
CHCl3
CH3OH
THF
DCM
DCM
DCM
DCM
DCM
3c
4
d
d
5
6
7
8
9
10
d
d
d
d
44
48
66
55
61
92
92
92
93
89
A1d
A2d
A3d
A4d
Scheme 1. Organocatalyzed asymmetric syntheses of highly substituted
indoloquinolizidines.
Herein, we described a prolinol TMS ether9 catalyzed cascade
a
General conditions: (step 1) 8a (0.1 mmol), 1a (0.15 mmol), 6 or 9 (10 mol %) and
additive (10 mol %) in solvent (0.2 mL) at 20 ꢀC; (step 2) TFA (1 equiv), solvent
(0.3 mL) at 20 ꢀC.
reaction of
a,b-unsaturated aldehydes I and active methylene
tethered tryptamine or homoveratrylamine II for the direct syn-
thesis of indolo- or benzoquinolizidine (Scheme 2). Proceeding by
conjugate addition of ketoamides II to a,b-unsaturated aldehydes I
b
Yield referred to isolated pure product.
Enantiomeric excess was determined by chiral HPLC analysis.
A1: BzOH; A2: 4-NO2eC6H4CO2H; A3: 3,5-(NO2)2C6H3CO2H; A4: Acetic acid.
c
d
catalyzed by the prolinol ether catalyst, followed by acid-catalyzed
intramolecular PicteteSpengler cyclization via N-acylimminium
ion III,10,11 this cascade would effectively provide multi-ring het-
erocycles IV or V enantioselectively. Since most of the quinolizi-
dine-based alkaloids contain an ethyl or an ethylidene group at C3,
it would be convenient for further transformation with an acetyl
group pre-installed using II as nucleophile.
achieved, whereas the yield was much lower (entry 2); chloroform
led to both lower yield and enantioselectivity than DCM (entry 3);
in solvents, such as THF and methanol almost no product was
formed (entries 4, 5); DCM proved to be the best solvent in terms of
yield (entry 1). Catalyst 9 with bulkier aryl substituents delivered
better enantioselectivity without loss of reactivity (entry 6).
In attempts to improve the yield, a set of acid additives was next
screened (entries 7e10). It was shown that the reaction gave the
highest yield of the product without loss of enantioselectivity by
using 4-nitrobenzoic acid as the additive (entry 8). In the presence
of acid additive, the reaction time for full consumption of start
material ketoamide was shortened from 30 h to 16 h (entries 7e10).
After the optimized reaction conditions were determined
(entry 8, Table 1), the scope of this cascade reaction was next
examined (Table 2). We first investigated the one-pot cascade se-
O
O
O
O
R
O
N
H
NuH
II
*
*
N
Ar
NuH
R
Ar
OTMS
I
III
N
H
TFA
3
quence employing a,b-unsaturated aldehydes 1bej as electrophiles
O
1
OH
R
O
1
O
R
3
*
Table 2
N
*
N
Asymmetric cascade reaction of 8a and a,b
-unsaturated aldehydes 1beja
and / or
Nu
Nu
*
O
*
*
2
2
HN
O
IV
V
1) 9 (10% mol),
4-NO2-C6H4CO2H
(10 mol%)
O
N
OH
N
H
Scheme 2. Concept of Michael addition-PicteteSpengler cascade.
8a
+
N
H
H
2) TFA
CHO
Ar
Ar
2. Results and discussion
A model reaction between
10b-j
1b-j
b-ketoamide 8a and cinnamic alde-
Entry
Ar, 1
10
t (h)
Yield (%)b
ee (%)c
hyde 1a was examined under a set of reaction conditions (Table 1).
The conjugate addition was conducted at 20 ꢀC in DCM using 6 as
catalyst (entry 1). After full conversion of amide 8a, the reaction
mixture was diluted with DCM, followed by addition of stoichio-
metric amount of TFA, and stirred at 20 ꢀC for 30 min. Indoloqui-
nolizidine 10a was isolated as a single diastereomer in 45% yield
and 69% ee (entry 1). It was interesting that 10a, with phenyl group
at C2 adopted a stable enol configuration and the formation of
ketone tautomer was negligible.
1
2
3
4
5
6
7
8
9
2-BreC6H4, 1b
3-BreC6H4, 1c
4-BreC6H4, 1d
4-CleC6H4, 1e
2,4-Cl2eC6H3, 1f
4-FeC6H4, 1g
4-NO2eC6H4, 1h
2-MeOeC6H4, 1i
4-MeOeC6H4, 1j
10b
10c
10d
10e
10f
10g
10h
10i
16
24
16
16
24
16
24
60
60
73
56
70
76
78
90
66
95
70
93
94
97
94
98
92
95
85
77
10j
a
See footnote a of Table 1, DCM used as a solvent.
Yield referred to isolated pure product.
Enantiomeric excess was determined by chiral HPLC analysis.
b
c
After obtaining the initial result, a brief screen of solvents was
conducted; with toluene as a solvent, higher enantioselectivity was

3036
X. Dai et al. / Tetrahedron 67 (2011) 3034e3040
and
b-ketoamide 8a as nucleophile. As shown in Table 2, the domino
reaction proceeded well for aromatic
a,b-unsaturated aldehydes
bearing electron-donating or electron-withdrawing substituents on
aryl ring, providing the products in moderate to good yields as single
diastereoisomers. For aldehydes 1beh having electron-withdrawing
substituents on aryl ring, the enantioselectivities of 10beh were in
the range of 92e98% ee (entries 1e7). However,
a,b-unsaturated
aldehydes 1i and j with electron-donating substituents gave the
cyclized products with lower enantioselectivities (entries 8 and 9).
To further illustrate the power of this catalytic enantioselective
cascade reaction, other nucleophiles 8bed (Table 3) were examined
under the same reaction conditions for 8a. The methoxyl
substituted 8b and bromo substituted 8c served as good nucleo-
philes, providing the desired products in moderate to good yields
and good enantioselectivities (entries 1 and 2). The reaction yields
are in agreement with the fact that bromo-indolyl ring is less
electron-rich than the methoxyl analogue.
Table 3
Further expanding of substrate scopea
O
R1
O
O
HN
O
Fig. 2. X-ray structure of 10n.
R1
N
OH
N
H
8b, R1 = MeO
8c, R1 = Br
O
CH3
CHO
N
H
CH3
H
H
Ar
Ar
or
or
1
O
O
HN
O
N
OH
Cascade condition
N
H
Ac
N
MeO
MeO
MeO
Ac
CH3
CH3
MeO
8d
H
Ar
Ar
MeO
H
Ar
10
MeO
MeO
H
MeO
TS2
unfavored
Entry
8
1
10
t (h)
Yield (%)b
ee (%)c
TS1
favored
1
2
3
4
5
6
7
8
8b
8c
1a
1a
1a
1b
1d
1f
10k
10l
24
24
24
30
24
18
18
18
76
56
76
86
90
85
85
81
94
87
95
92
90
86
79
89
8d
8d
8d
8d
8d
8d
10m
10n
10o
10p
10q
10r
Fig. 3. Putative transition states in cyclization.
ether 9.9 The substrate controlled formation of 11b-position chirality
could be exemplified by the transition states depicted in Fig. 3.
Diastereoisomer 10n formed exclusively due to less steric interaction
1i
1j
a
See footnote a of Table 2.
Yield referred to isolated pure product.
Enantiomeric excess was determined by chiral HPLC analysis.
b
c
between the equatorial
b-proton and the 3,4-dimethoxyphenyl
moiety in TS1, as compared to that between the axial
the 3,4-dimethoxyphenyl moiety in TS2.
a-proton and
Indoloquinolizidines and benzoquinolizidines with alkyl sub-
stituents at C2 position are common intermediates in the total
synthesis of some natural alkaloids.6 As pointed out in previous
We were pleased to find that 8d also worked well in the reaction
conditions, affording the benzoquinolizidine products in good
yields and enantioselectivities (entries 3e8). To our delight, in all
cases, only one diastereoisomer was observed.
ꢀ
report by Franzen and Zhang, cascade reactions between aliphatic
a,b-unsaturated aldehyde and indole tethered active methylene
The absolute configuration of the cyclization products were
determined to be 2R,12bS for indoloquinolizidines and 2R,11bS for
benzoquinolizidines by single crystal X-ray diffraction analysis of
10n (Fig. 2).12 The stereochemistry at C2 position of 10n originated
from conjugate addition of active methylene nucleophile 8d
compound 2 resulted in decomposition of aldehyde.8b In our case,
the cascade reactions between 8a and 1k proceeded smoothly to
afford the cyclized products (Scheme 3). Surprisingly, a mixture of
inseparable ketone and enol (10s and 10s’) was formed. And such
tautomeric pairs were inseparable by chromatography. Methylene
to
a
,
b-unsaturated aldehyde 1b catalyzed by chiral prolinol TMS
This study
O
O
O
Cascade condition
81% yield
N
O
N
OH
CH
HN
O
CHO
+
+
n-Pr
N
H
N
H
CH
N
H
H
CH
H
n-Pr
8a
1k
n-Pr
10s'
10s
10s : 10s' = 1:1
Previous report by Franzen et. al
O
Cascade condition
HN
O
CHO
Decomposition of 1l
+
Et
N
H
OMe
2
1l
Scheme 3. Cascade reactions employing aliphatic a,b-unsaturated aldehyde.

X. Dai et al. / Tetrahedron 67 (2011) 3034e3040
3037
compound 8 in our study was more reactive as compared with 2 in
4.3. General procedure for catalytic cascade reaction:
ꢀ
Franzen and co-workers’ report.
preparation of compounds 10aer
3. Conclusions
To a mixture of catalyst 9 (0.01 mmol, 0.1 equiv) and benzoic
acid (0.01 mmol, 0.1 equiv) in DCM (0.2 mL) was added -ketoa-
mide 8 (0.1 mmol, 1 equiv) under an atmosphere of N2. Followed by
the addition of -unsaturated aldehyde 1 (0.15 mmol, 1.5 equiv).
The reaction was stirred at 20 ꢀC and followed by TLC. After full
consumption of -ketoamide 8, the reaction mixture was diluted
with DCM (0.3 mL). Then TFA (0.1 mmol, 1 equiv) was added. The
reaction mixture was stirred at 20 ꢀC for 0.5 h. The reaction mixture
was diluted with DCM (5 mL) and washed with saturated NaHCO3
(3 mL). The aqueous phase was extracted with DCM (2ꢁ5 ml). The
combined organic phases were dried over Na2SO4 and concentrated
in vacuo. The residue was purified by flash chromatography on
silica gel eluting with a petroleum ether and ethyl acetate mixture
to give pure compounds 10.
b
In summary, we have developed an operationally simple
asymmetric organocatalyzed cascade process for the preparation of
indoloquinolizidines and benzoquinolizidines. The highly func-
tionalized products were obtained from readily available reagents
in moderate to good yields and good to excellent enantioselectiv-
a,b
b
ities. Moreover, the aliphatic
were inactive substrates in the previous protocol reported by
a,b-unsaturated aldehydes, which
8a,b
ꢀ
Franzen and co-workers,
worked well and afforded indoloqui-
nolizidines as a mixture of ketone and enol tautomers. Application
of this method in total synthesis of natural alkaloids is currently
underway in our laboratory and will be reported in due course.
4. Experimental
4.3.1. (2S,12bS,Z)-3-(1-Hydroxyethylidene)-2-phenyl-1,2,3,6,7,12b-
4.1. General information
hexahydroindolo[2,3
a
]quinolizin-4(12H)-one (10a). Pale yellow
solid; 1H NMR (CDCl3, 500 M):
d
15.63 (s, 1H), 7.64 (s, 1H), 7.50
Thin-layer chromatography (TLC) carried out on 0.25 mm silica
gel plates visualized with UV light and/or by staining with ethanolic
phosphomolybdic acid (PMA) or iodine. Flash column chromatog-
(d, J¼7.5 Hz, 1H), 7.35e7.40 (m, 2H), 7.27e7.29 (m, 4H), 7.15
(t, J¼7.5 Hz, 1H), 7.11 (t, J¼7.5 Hz, 1H), 5.17e5.20 (m, 1H), 4.49
(d, J¼10.5 Hz, 1H), 4.06e4.08 (m, 1H), 2.82e2.89 (m, 3H), 2.42
(dt, J¼13 and 3 Hz, 1H), 2.16 (td, J¼13 and 5 Hz, 1H), 1.83 (s, 3H);
raphy was performed on silica gel H (10e40
m). NMR spectra were
recorded on Bruker AM500 (500 MHz). Chemical shifts (
d) are given
13C NMR (CDCl3, 125 M):
d 173.1, 170.2, 143.7, 136.3, 132.8, 132.4,
in parts per million relative to TMS, coupling constants (J) in hertz.
Optical rotations were taken on JASCO P1030. High-resolution mass
spectra were recorded on Bruker ApeXIII 7.0 TESLA FTMS. Enan-
tiomeric excesses were determined by chiral HPLC using a Waters
or Shimadzu instrument.
129.2, 127.5, 127.2, 126.9, 122.4, 120.1, 111.2, 109.9, 97.2, 51.7, 39.3,
25
38.2, 37.4, 21.3, 19.0; [
a
]
ꢂ73.0 (c 0.50, CHCl3); HRMS (ESI) calcd
D
for (C23H23N2O2)þ 359.1754, found 359.1756; HPLC (Phenomenex
amylose-2, Hexane/Isopropanol¼1:1, Flow rate¼1.00 mL/min,
l
¼220 nm): tR¼4.50 min (minor enantiomer), tR¼5.52 min (major
enantiomer).
4.2. Procedure for the synthesis of 8aed
4.3.2. (2R,12bS,Z)-2-(2-Bromophenyl)-3-(1-hydroxyethylidene)-
To
a
solution of tryptamine (4.5 g, 28 mmol) in dry
1,2,3,6,7,12b-hexahydroindolo[2,3
a
]quinolizin-4(12H)-one
15.64 (s, 1H),
dichloroethane (30 mL) was added dropwise fresh diketene (2.2 g,
26 mmol) for 0.5 h at 0 ꢀC. The mixture was stirred for 12 h at 0 ꢀC.
After evaporation of the solvent under reduced pressure, the crude
product was purified by flash chromatography on silica gel (AcOEt/
Hexane 1/1) to afford 8a (6.0 g, 94% yield) as a white solid.
(10b). Pale yellow solid; 1H NMR (CDCl3, 500 M):
d
7.72 (s, 1H), 7.64 (d, J¼7.5 Hz, 1H), 7.49 (d, J¼7.5 Hz, 1H), 7.28e7.32
(m, 2H), 7.20 (d, J¼7.5 Hz, 1H), 7.10e7.18 (m, 3H), 5.20e5.22 (m, 1H),
4.49 (d, J¼11.5 Hz, 1H), 4.41e4.42 (m, 1H), 2.81e2.94 (m, 3H), 2.50
(d, J¼13 Hz, 1H), 2.02e2.12 (m, 1H), 1.78 (s, 3H); 13C NMR (CDCl3,
125 M):
d 173.7, 170.2, 142.4, 133.5, 132.5, 129.7, 128.8, 127.9, 126.8,
4.2.1. N-(2-(1H-Indol-3-yl)ethyl)-3-oxobutanamide (8a)13. White
122.3, 119.9, 118.4, 111.0, 110.0, 97.4, 49.1, 39.3, 38.1, 34.2, 21.2, 19.0;
25
solid; 1H NMR (CDCl3, 500 M):
d
8.25e8.40 (br, 1H), 7.59
[a
]
ꢂ36.5 (c 0.52, CHCl3); HRMS (ESI) calcd for (C23H22N2O2Br)þ
D
(d, J¼7.5 Hz, 1H), 7.34 (d, J¼8 Hz, 1H), 7.15e7.25 (m, 1H), 7.10e7.12
(m, 1H), 7.02 (s, 1H), 6.94 (s, 1H), 3.60 (t, J¼6.5 Hz, 2H), 3.30 (s, 2H),
2.98 (t, J¼6.5 Hz, 2H), 2.18 (s, 3H).
437.0859, found 437.0858; HPLC (Daicel Chiralpak ADH, Hexane/
Isopropanol¼4:1, Flow rate¼0.7 mL/min, ¼220 nm): tR¼9.98 min
l
(minor enantiomer), tR¼21.62 min (major enantiomer).
4.2.2. N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)-3-oxobutanamide
4.3.3. (2S,12bS,Z)-2-(3-Bromophenyl)-3-(1-hydroxyethylidene)-
(8b)14. White solid; 1H NMR (CDCl3, 500 M):
d
8.85 (s, 1H), 7.25
1,2,3,6,7,12b-hexahydroindolo[2,3
a
]quinolizin-4(12H)-one
15.68 (s, 1H), 7.68
(s, 1H), 7.18 (d, J¼8.5 Hz, 1H), 7.08e7.12 (m, 1H), 7.01 (s, 1H), 6.92
(s, 1H), 6.79e6.82 (m, 1H), 3.78 (s, 3H), 3.48e3.58 (m, 2H), 3.21
(s, 2H), 2.85e2.93 (m, 2H), 2.08 (s, 3H).
(10c). Yellow solid; 1H NMR (CDCl3, 500 M):
d
(s, 1H), 7.40e7.52 (m, 3H), 7.10e7.32 (m, 5H), 5.17 (d, J¼11.5 Hz, 1H),
4.46 (d, J¼12 Hz, 1H), 4.04e4.06 (m, 1H), 2.81e2.92 (m, 3H), 2.40
(d, J¼13 Hz, 1H), 2.10e2.20 (m, 1H), 1.83 (s, 3H); 13C NMR (CDCl3,
4.2.3. N-(2-(5-Bromo-1H-indol-3-yl)ethyl)-3-oxobutanamide
125 M): d 173.6, 170.0, 146.2, 136.4, 132.4, 130.7, 130.6, 130.3, 126.9,
(8c). White solid; 1H NMR (CDCl3, 500 M):
d
9.01 (s, 1H), 7.64
126.3, 123.3, 122.4, 120.0, 118.5, 111.0, 110.2, 96.5, 48.9, 39.3, 38.1,
25
(s, 1H), 7.10e7.20 (m, 3H), 6.94 (s, 1H), 3.47e3.53 (m, 2H), 3.27
37.4, 21.2, 19.1; [
a
]
ꢂ70.9 (c 0.54, CHCl3); HRMS (ESI) calcd for
D
(s, 2H), 2.83e2.87 (m, 2H), 2.12 (s, 3H); 13C NMR (CDCl3, 125 M):
(C23H22N2O2Br)þ 437.0859, found 437.0856; HPLC (Daicel Chiralpak
d
204.5, 166.1, 135.0, 129.1, 124.6, 123.7, 121.1, 112.9, 112.3, 112.1, 49.8,
ADH, Hexane/Isopropanol¼4:1, Flow rate¼0.7 mL/min, ¼220 nm):
l
39.9, 30.7, 24.9.
tR¼10.03min(minorenantiomer), tR¼27.49min(majorenantiomer).
4.2.4. N-(3,4-Dimethoxyphenethyl)-3-oxobutanamide (8d). White
4.3.4. (2S,12bS,Z)-2-(4-Bromophenyl)-3-(1-hydroxyethylidene)-
solid; 1H NMR (CDCl3, 500 M):
d
6.93e6.99 (br, 1H), 6.81 (d, J¼8 Hz,
1,2,3,6,7,12b-hexahydroindolo[2,3
a
]quinolizin-4(12H)-one
15.66 (s, 1H), 7.68 (s,
1H), 6.70e6.75 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.51 (t, J¼7 Hz,
(10d). Yellow solid; 1H NMR (CDCl3, 500 M):
d
2H), 3.38 (s, 2H), 2.77 (t, J¼7 Hz, 2H), 2.24 (s, 3H); 13C NMR (CDCl3,
1H), 7.48e7.52 (m, 3H), 7.27 (d, J¼8 Hz, 1H), 7.10e7.18 (m, 4H),
5.14e5.19 (m, 1H), 4.45 (d, J¼12 Hz, 1H), 4.02e4.04 (m, 1H),
2.82e2.90 (m, 3H), 2.38 (dt, J¼12 and 2.5 Hz, 1H), 2.16 (td, J¼12 and
125 M):
d 204.6, 165.5, 149.1, 147.8, 131.4, 120.7, 112.0, 111.5, 56.0,
55.9, 49.7, 41.0, 35.3, 31.1.

3038
X. Dai et al. / Tetrahedron 67 (2011) 3034e3040
5 Hz, 1H), 1.82 (s, 3H); 13C NMR (CDCl3, 125 M):
d
173.4, 170.0, 151.6,
(10i). Yellow solid; 1H NMR (CDCl3, 500 M):
d 15.60 (s, 1H), 7.64 (s,
142.7, 136.4, 132.5, 132.1, 129.4, 126.9, 122.4, 120.0, 118.5, 111.0, 110.1,
1H), 7.49 (d, J¼7.5 Hz, 1H), 7.24e7.31 (m, 2H), 7.05e7.19 (m, 3H),
6.92e6.97 (m, 2H), 5.16e5.21 (m,1H), 4.47 (d, J¼12 Hz,1H), 4.39e4.40
(m,1H), 3.96 (s, 3H), 2.79e2.93 (m, 3H), 2.48 (d, J¼12 Hz,1H), 2.01 (td,
25
96.7, 48.9, 39.3, 37.8, 37.3, 21.2, 19.0; [
a]
ꢂ28.4 (c 0.55, CHCl3);
D
HRMS (ESI) calcd for (C23H22N2O2Br)þ 437.0859, found 437.0858;
HPLC (Daicel Chiralpak ADH, Hexane/Isopropanol¼4:1, Flow
J¼12 and 4.5 Hz, 1H), 1.78 (s, 3H); 13C NMR (CDCl3, 125 M):
d 172.7,
rate¼0.7 mL/min,
l
¼220 nm): tR¼14.78 min (minor enantiomer),
170.5, 156.7, 136.3, 133.1, 131.5, 128.9, 128.1, 127.0, 122.1, 120.7, 119.8,
tR¼60.72 min (major enantiomer).
118.4, 110.9, 110.5, 109.8, 97.6, 55.6, 49.6, 39.2, 34.5, 32.2, 21.3, 18.8;
25
[a]
þ124.8 (c 0.52, CHCl3); HRMS (ESI) calcd for (C24H25N2O3)þ
D
4.3.5. (2S,12bS,Z)-2-(4-Chlorophenyl)-3-(1-hydroxyethylidene)-
389.1860, found 389.1861; HPLC (Daicel Chiralpak ADH, Hexane/Iso-
1,2,3,6,7,12b-hexahydroindolo[2,3
a
]quinolizin-4(12H)-one
15.65 (s, 1H), 7.66
propanol¼4: 1, Flow rate¼0.65 mL/min, ¼220 nm): tR¼8.07 min
l
(10e). Yellow solid; 1H NMR (CDCl3, 500 M):
d
(minor enantiomer), tR¼14.25 min (major enantiomer).
(s, 1H), 7.50 (d, J¼7.5 Hz, 1H), 7.10e7.40 (m, 7H), 5.16e5.19 (m, 1H),
4.45 (d, J¼12 Hz, 1H), 4.03e4.05 (m, 1H), 2.80e2.91 (m, 3H), 2.38
(d, J¼12 Hz, 1H), 2.15 (td, J¼12 and 4.5 Hz, 1H), 1.82 (s, 3H); 13C NMR
4.3.10. (2S,12bS,Z)-3-(1-Hydroxyethylidene)-2-(4-methoxyphenyl)-
1,2,3,6,7,12b-hexahydroindolo[2,3
a
]quinolizin-4(12H)-one
15.61 (s, 1H), 7.72 (s,
(CDCl3, 125 M):
d
173.4, 170.0,142.2, 136.4, 132.8, 132.5, 129.4, 126.9,
(10j). Yellow solid; 1H NMR (CDCl3, 500 M):
d
122.4, 120.0, 118.5, 111.0, 110.2, 96.8, 48.9, 39.3, 37.7, 37.4, 21.2, 19.0;
1H), 7.49 (d, J¼7.5 Hz, 1H), 7.27e730 (m, 1H), 7.09e7.20 (m, 4H), 6.90
(d, J¼8.5 Hz, 2H), 5.15e5.20 (m,1H), 4.48 (d, J¼10 Hz, 1H), 4.00e4.02
(m, 1H), 3.81 (s, 3H), 2.79e2.92 (m, 3H), 2.39 (dt, J¼10 and 3 Hz, 1H),
2.12 (td, J¼10 and 4.5 Hz, 1H), 1.83 (s, 3H); 13C NMR (CDCl3, 125 M):
25
[
a]
ꢂ37.5 (c 0.80, CHCl3); HRMS (ESI) calcd for (C23H22N2O2Cl)þ
D
393.1364, found 393.1366; HPLC (Daicel Chiralpak ADH, Hexane/
Isopropanol¼4:1, Flow rate¼0.7 mL/min, ¼220 nm): tR¼16.86 min
l
(minor enantiomer), tR¼42.70 min (major enantiomer).
d 173.0,170.2,158.6,136.4,135.6,132.9,128.6,126.9,122.2,120.0,118.4,
114.3,111.0,110.0,97.5, 55.4, 49.0,39.3, 37.6, 37.4, 21.3,18.9;[
a
]
25 þ10.2
D
4.3.6. (2R,12bS,Z)-2-(2,4-Dichlorophenyl)-3-(1-hydroxyethylidene)-
(c 0.55, CHCl3); HRMS (ESI) calcd for (C24H25N2O3)þ 389.1860, found
389.1861; HPLC (Daicel Chiralpak ADH, Hexane/Isopropanol¼4:1,
1,2,3,6,7,12b-hexahydroindolo[2,3
NMR (CDCl3, 500 M): 15.66 (s, 1H), 7.74 (s, 1H), 7.45e7.52 (m, 3H),
a
]quinolizin-4(12H)-one (10f). 1H
d
Flow rate¼0.65 mL/min, ¼220 nm): tR¼12.20 min (minor enantio-
l
7.22e7.30 (m, 2H), 7.10e7.18 (m, 3H), 5.17e5.22 (m, 1H), 4.45 (d,
J¼13 Hz, 1H), 4.39e4.41 (m, 1H), 2.82e2.94 (m, 3H), 2.48 (dt, J¼13
and 2.5 Hz, 1H), 2.08 (td, J¼13 and 4 Hz, 1H), 1.78 (s, 3H); 13C NMR
mer), tR¼23.78 min (major enantiomer).
4.3.11. (2S,12bS,Z)-3-(1-Hydroxyethylidene)-9-methoxy-2-phenyl-
(CDCl3, 125 M):
d
173.8, 170.1, 139.5, 136.4, 133.8, 133.6, 132.2, 130.4,
1,2,3,6,7,12b-hexahydroindolo[2,3
a
]quinolizin-4(12H)-one
15.62 (s, 1H), 7.55 (s,
130.0, 127.6, 126.8, 122.4, 120.0, 118.4, 111.0, 110.1, 96.8, 49.1, 39.3,
(10k). Yellow solid; 1H NMR (CDCl3, 500 M):
d
25
35.3, 34.0, 21.2, 19.0; [
a
]
ꢂ43.1 (c 0.56, CHCl3); HRMS (ESI) calcd
1H), 7.37 (t, J¼7.5 Hz, 2H), 7.27 (t, J¼6.5 Hz, 2H), 7.14 (d, J¼9 Hz, 1H),
6.94 (d, J¼2.5 Hz, 1H), 6.80 (dd, J¼9 and 2.5 Hz, 1H), 5.16e5.19 (m,
1H), 4.45e4.48 (m, 1H), 4.05e4.07 (m, 1H), 3.84 (s, 3H), 2.75e2.83
(m, 3H), 2.40 (dt, J¼12 and 3 Hz, 1H), 2.15 (td, J¼12 and 4 Hz, 1H),
D
for (C23H21N2O2Cl2)þ 427.0975, found 427.0972; HPLC (Daicel
Chiralpak ADH, Hexane/Isopropanol¼4:1, Flow rate¼0.7 mL/min,
l
¼220 nm): tR¼9.41 min (minor enantiomer), tR¼24.64 min (major
enantiomer).
1.82 (s, 3H); 13C NMR (CDCl3, 125 M):
d 173.2, 170.5, 154.4, 143.7,
133.7, 131.4, 129.0, 127.7, 127.4, 127.0, 112.2, 111.7, 109.9, 100.5, 97.2,
25
4.3.7. (2S,12bS,Z)-2-(4-Fluorophenyl)-3-(1-hydroxyethylidene)-
56.0, 49.0, 39.3, 38.2, 37.5, 21.3, 19.0; [
a]
ꢂ17.7 (c 0.57, CHCl3);
D
1,2,3,6,7,12b-hexahydroindolo[2,3
a
]quinolizin-4(12H)-one
15.65 (s, 1H), 7.72 (s,
HRMS (ESI) calcd for (C24H25N2O3)þ 389.1860, found 389.1861;
(10g). Yellow solid; 1H NMR (CDCl3, 500 M):
d
HPLC (Daicel Chiralpak ADH, Hexane/Isopropanol¼4:1, Flow
1H), 7.50 (d, J¼7.5 Hz, 1H), 7.23e7.32 (m, 3H), 7.16 (t, J¼7.5 Hz, 1H),
7.02e7.13 (m, 3H), 5.13e5.19 (m, 1H), 4.46 (d, J¼12 Hz, 1H),
4.05e4.06 (m, 1H), 2.77e2.95 (m, 3H), 2.40 (d, J¼12 Hz, 1H), 2.15
(td, J¼12 and 4.5 Hz, 1H), 1.82 (s, 3H); 13C NMR (CDCl3, 125 M):
rate¼0.7 mL/min, ¼220 nm): tR¼14.75 min (minor enantiomer),
l
tR¼29.15 min (major enantiomer).
4.3.12. (2S,12bS,Z)-9-Bromo-3-(1-hydroxyethylidene)-2-phenyl-
d
173.3, 170.0, 160.9, 139.3, 136.4, 132.6, 129.2, 129.1, 126.9, 122.3,
1,2,3,6,7,12b-hexahydroindolo[2,3
a
]quinolizin-4(12H)-one
15.58 (s, 1H), 7.82 (s,
25
120.0, 118.5, 115.7, 111.0, 97.2, 48.9, 39.3, 37.5, 37.5, 21.2, 19.0; [
a
]
(10l). Yellow solid; 1H NMR (CDCl3, 500 M):
d
D
ꢂ37.2 (c 0.55, CHCl3); HRMS (ESI) calcd for (C23H22N2O2F)þ
1H), 7.60 (d, J¼1.5 Hz, 1H), 7.36 (d, J¼7.5 Hz, 2H), 7.28 (d, J¼6.5 Hz,
2H), 7.20e7.23 (m, 3H), 7.12 (d, J¼8.5 Hz,1H), 5.13e5.18 (m, 1H), 4.47
(d, J¼12 Hz,1H), 4.06e4.08 (m,1H), 2.70e2.88 (m, 3H), 2.42 (dt, J¼12
and 3 Hz, 1H), 2.65 (td, J¼12 and 4 Hz, 1H), 1.82 (s, 3H); 13C NMR
377.1660, found 377.1656; HPLC (Daicel Chiralpak ADH, Hexane/
Isopropanol¼4:1, Flow rate¼0.7 mL/min, ¼220 nm): tR¼16.61 min
l
(minor enantiomer), tR¼34.74 min (major enantiomer).
(CDCl3, 125 M): d 173.3, 170.2, 143.6, 135.0, 134.2, 129.2, 128.7, 127.6,
4.3.8. (2S,12bS,Z)-3-(1-Hydroxyethylidene)-2-(4-nitrophenyl)-
127.1, 125.0, 121.1, 113.1, 112.4, 109.7, 97.1, 48.9, 39.2, 38.2, 37.3,
25
1,2,3,6,7,12b-hexahydroindolo[2,3
a
]quinolizin-4(12H)-one
15.71 (s, 1H), 8.23 (d,
21.1, 19.0; [
a
]
ꢂ44.2 (c 0.04, CHCl3); HRMS (ESI) calcd for
D
(10h). Yellow solid; 1H NMR (CDCl3, 500 M):
d
(C23H22N2O2Br)þ 437.0859, found 437.0858; HPLC (Daicel Chiralpak
J¼13 Hz, 2H), 7.70 (s, 1H), 7.47e7.52 (m, 3H), 7.28 (d, J¼8 Hz, 1H),
7.17 (t, J¼7 Hz, 1H), 7.12 (t, J¼7 Hz, 1H), 5.16e5.21 (m, 1H), 4.44 (d,
J¼12 Hz, 1H), 4.18e4.20 (m, 1H), 2.84e2.90 (m, 3H), 2.46 (dt, J¼12
and 3.5 Hz, 1H), 2.25 (td, J¼12 and 4.5 Hz, 1H), 1.81 (s, 3H); 13C NMR
ADH, Hexane/Isopropanol¼4:1, Flow rate¼0.65 mL/min, ¼220 nm):
l
tR¼9.39 min (minor enantiomer), tR¼20.41 min (major enantiomer).
4.3.13. (2S,11bS,Z)-3-(1-Hydroxyethylidene)-9,10-dimethoxy-2-phe-
(CDCl3, 125 M):
d
173.9, 169.8, 151.6, 147.1, 136.4, 132.0, 128.6, 126.8,
nyl-2,3,6,7-tetrahydro-1H-pyrido[2,1
a
]isoquinolin-4(11bH)-one
15.57 (s, 1H),
124.3, 122.5, 120.1, 118.6, 111.0, 110.4, 96.2, 48.9, 39.4, 38.5, 37.1,
(10m). Yellow solid; 1H NMR (CDCl3, 500 M):
d
25
21.2, 19.1; [
a
]
D
þ11.8 (c 0.45, CHCl3); HRMS (ESI) calcd for
7.32e7.42 (m, 2H), 7.25e7.30 (m, 3H), 6.60 (s, 1H), 6.36 (s, 1H),
4.87e4.90 (m, 1H), 4.31 (d, J¼12 Hz, 1H), 4.00e4.02 (m, 1H), 3.85 (s,
3H), 3.79 (s, 3H), 2.81e2.91 (m, 2H), 2.65 (d, J¼12 Hz, 1H), 2.44 (d,
J¼13 Hz, 1H), 2.04 (td, J¼12 and 4 Hz, 1H), 1.81 (s, 3H); 13C NMR
(C23H21N3O4Na)þ 426.1424, found 426.1424; HPLC (Daicel Chir-
alpak ADH, Hexane/Isopropanol¼4:1, Flow rate¼0.7 mL/min,
l
¼220 nm): tR¼24.80 min (minor enantiomer), tR¼58.67 min
(major enantiomer).
(CDCl3, 125 M): d 172.6, 169.9, 148.6, 147.8, 144.0, 131.5, 128.8, 127.7,
127.6, 126.8, 111.5, 108.7, 97.4, 56.3, 56.0, 51.5, 39.4, 38.9, 38.5,
25
4.3.9. (2S,12bS,Z)-3-(1-Hydroxyethylidene)-2-(2-methoxyphenyl)-
1,2,3,6,7,12b-hexahydroindolo[2,3a]quinolizin-4(12H)-one
29.0, 18.9; [
a
]
ꢂ103.9 (c 0.51, CHCl3); HRMS (ESI) calcd for
D
(C23H26NO4)þ 380.1856, found 380.1852; HPLC (Daicel Chiralpak

X. Dai et al. / Tetrahedron 67 (2011) 3034e3040
3039
ADH, Hexane/Isopropanol¼4:1, Flow rate¼0.7 mL/min,
l
¼220 nm):
(s,1H), 7.18 (d, J¼8.5 Hz, 2H), 6.90 (d, J¼8.5 Hz, 2H), 6.60 (s,1H), 6.37
(s, 1H), 4.86e4.89 (m, 1H), 4.31 (dd, J¼13 and 3 Hz, 1H), 3.95e3.96
(m, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.80e2.91 (m, 2H),
2.63e2.68 (m, 1H), 2.40 (dt, J¼13 and 3 Hz, 1H), 2.00 (td, J¼13 and
tR¼14.62 min (minorenantiomer), tR¼17.33 min (majorenantiomer).
4.3.14. (2R,11bS,Z)-2-(2-Bromophenyl)-3-(1-hydroxyethylidene)-
9,10-dimethoxy-2,3,6,7-tetrahydro-1H-pyrido[2,1
a
]isoquinolin-4
15.58 (s,
4.5 Hz, 1H), 1.81 (s, 3H); 13C NMR (CDCl3, 125 M):
d 172.5, 169.9,
(11bH)-one (10n). Yellow solid; 1H NMR (CDCl3, 500 M):
d
158.4, 147.8, 135.9, 128.7, 128.4, 128.2, 127.6, 114.2, 111.5, 108.7, 97.6,
1H), 7.63 (d, J¼8 Hz, 1H), 7.28 (t, J¼7.5 Hz, 1H), 7.13e7.19 (m, 2H),
6.61 (s, 1H), 6.37 (s, 1H),4.88e4.91 (m, 1H), 4.31e4.35 (m, 2H), 3.84
(s, 3H), 3.79 (s, 3H), 2.88e2.90 (m, 2H), 2.66e2.68 (m, 1H), 2.52 (dt,
J¼13.5 and 3 Hz, 1H), 1.94 (td, J¼13.5 and 5 Hz, 1H), 1.76 (s, 3H); 13C
56.3, 56.0, 55.4, 51.5, 39.6, 38.9, 37.6, 29.0, 18.8; [
a
]
25 þ87.3 (c 0.71,
D
CHCl3); HRMS (ESI) calcd for (C24H28NO5)þ 410.1962, found
410.1967; HPLC (Daicel Chiralpak ADH, Hexane/Isopropanol¼4:1,
Flow rate¼0.65 mL/min, ¼220 nm): tR¼14.00 min (major enan-
l
NMR (CDCl3, 125 M):
d
173.1, 170.0, 147.9, 147.8, 142.7, 133.5, 129.8,
tiomer), tR¼14.72 min (minor enantiomer).
128.6, 128.1, 127.8, 127.6, 123.8, 111.5, 108.8, 97.6, 56.4, 56.0, 51.6,
25
38.9, 38.3, 36.2, 28.9, 18.9; [
a
]
D
ꢂ88.5 (c 0.75, CHCl3); HRMS (ESI)
4.3.19. Mixture of ketone and enol tautomers (10s and 10s’). Yellow
calcd for (C23H25NO4Br)þ 458.0962, found 458.0971; HPLC (Daicel
solid; 1H NMR (CDCl3, 500 M):
d 15.1 (s, 0.5H), 7.90e8.00 (m, 1H),
Chiralpak ADH, Hexane/Isopropanol¼4:1, Flow rate¼0.65 mL/min,
7.48e7.53 (m, 1H), 7.32e7.38 (m, 1H), 7.10e7.20 (m, 2H), 5.10e5.20
(m, 1H), 4.80e4.90 (m, 1H), 3,37 (m, 0.5H), 2.70e2.93 (m, 3.5H),
2.33e2.43 (m, 1H), 2.26 (s, 1.5H), 2.07e2.21 (m, 1H), 1.99 (s, 1.5H),
1.80e1.83 (m, 0.5H), 1.37e1.55 (m, 4H), 0.3e1.03 (m, 3H).
l
¼220 nm): tR¼8.63 min (minor enantiomer), tR¼13.97 min (major
enantiomer).
4.3.15. (2S,11bS,Z)-2-(4-Bromophenyl)-3-(1-hydroxyethylidene)-
9,10-dimethoxy-2,3,6,7-tetrahydro-1H-pyrido[2,1
a
]isoquinolin-4
15.59 (s,
Acknowledgements
(11bH)-one (10o). Yellow solid; 1H NMR (CDCl3, 500 M):
d
1H), 7.49 (d, J¼8.5 Hz, 2H), 7.16 (d, J¼8.5 Hz, 2H), 6.60 (s,1H), 6.34 (s,
1H), 4.86e4.90 (m, 1H), 4.27 (dd, J¼12 and 3 Hz, 1H), 3.96e3.97 (m,
1H), 3.84 (s, 3H), 3.79 (s, 3H), 2.82e2.87 (m, 2H), 2.64 (d, J¼13 Hz,
1H), 2.37 (dt, J¼12 and 3 Hz, 1H), 2.03 (td, J¼12 and 4.5 Hz, 1H), 1.80
The generous financial support from the National Natural Sci-
ence Foundation of China (No. 20802043 and No. 21072125) and
the Foundations of Education Commission of Shanghai Municipal-
ity (Nos. J50102) are gratefully acknowledged. Manuscript revision
by Dr. He-gui Gong at Shanghai University is also gratefully
acknowledged.
(s, 3H); 13C NMR (CDCl3, 125 M):
d 172.9, 169.8, 147.9, 147.9, 143.1,
132.0, 129.5, 128.0, 127.6, 120.7, 111.6, 108.6, 96.9, 56.3, 56.0, 51.4,
25
39.3, 38.9, 38.1, 28.9, 18.9; [
a]
ꢂ28.4 (c 0.77, CHCl3); HRMS (ESI)
D
calcd for (C23H25NO4Br)þ 458.0962, found 458.0971; HPLC (Daicel
Supplementary data
Chiralpak ADH, Hexane/Isopropanol¼4:1, Flow rate¼0.65 mL/min,
The original spectra of 1H NMR, 13C NMR and HPLC of all prod-
ucts are supplied. The supplementary data files are to be used as an
aid for the refereeing of the paper only. Supplementary data related
to this article can be found online at doi:10.1016/j.tet.2011.03.007.
These data include MOL files and InChIKeys of the most important
compounds described in this article.
l
¼220 nm): tR¼11.74 min (minor enantiomer), tR¼14.22 min (ma-
jor enantiomer).
4.3.16. (2R,11bS,Z)-2-(2,4-Dichlorophenyl)-3-(1-hydroxyethylidene)-
9,10-dimethoxy-2,3,6,7-tetrahydro-1H-pyrido[2,1
a
]isoquinolin-4
15.60 (s,
(11bH)-one (10p). Yellow solid; 1H NMR (CDCl3, 500 M):
d
1H), 7.47 (d, J¼2 Hz,1H), 7.22e7.24 (m, 1H), 7.12 (d, J¼8 Hz,1H), 6.61
(s, 1H), 6.35 (s, 1H), 4.87e4.93 (m, 1H), 4.34e4.35 (m, 1H), 4.28 (dd,
J¼12 and 3 Hz,1H), 3.85 (s, 3H), 3.80 (s, 3H), 2.83e2.89 (m, 2H), 2.67
(d, J¼14.5 Hz, 1H), 2.46 (dt, J¼12 and 3 Hz, 1H), 1.95 (td, J¼12 and
References and notes
1. Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis;
WILEY-VCH GmbH KGaA: Weinheim, Germany, 2006.
2. For recent reviews, see: (a) Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed.
2004, 43, 3754; (b) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev.
3.5 Hz, 1H), 1.76 (s, 3H); 13C NMR (CDCl3, 125 M):
d 173.2, 169.9,
147.9, 147.9, 139.8, 133.8, 133.3, 130.5, 130.0, 127.8, 127.6, 127.4, 111.6,
108.6, 97.0, 56.4, 56.0, 51.6, 38.9, 36.0, 35.5, 28.9, 18.9; [
a
]
25 ꢂ65.5 (c
€
D
2005, 105, 1001; (c) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
0.75, CHCl3); HRMS (ESI) calcd for (C23H24NO4Cl2)þ 448.1077, found
2007, 46, 1570; (d) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 1477; (e) Yu,
X. H.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037; (f) Bertelsen, S.; Jørgensen, K.
A. Chem. Soc. Rev. 2009, 38, 2178.
448.1083; HPLC (Daicel Chiralpak ADH, Hexane/Isopropanol¼4:1,
Flow rate¼0.7 mL/min, ¼220 nm): tR¼12.58 min (minor enan-
l
€
3. For select recent examples, see: (a) Enders, D.; Huttl, M. R. M.; Grondal, C.;
Raabe, G. Nature 2006, 441, 861; (b) Marigo, M.; Bertelsen, S.; Landa, A.;
Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 5475; (c) Enders, D.; Narine, A. A.;
Benninghaus, T.; Raabe, G. Synlett 2007, 1667; (d) Wang, J.; Li, H.; Xie, H.-X.; Zu,
L.-S.; Shen, X.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 9050; (e) Zu, L.-S.; Li,
H.; Xie, H.-X.; Wang, J.; Jiang, W.; Tang, Y.; Wang, W. Angew. Chem., Int. Ed. 2007,
46, 3732; (f) Hayashi, Y.; Toyoshima, M.; Gotoh, H.; Ishikawa, H. Org. Lett. 2009,
11, 45; (g) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48,
1304; (h) Zu, L. S.; Zhang, S. L.; Xie, H. X.; Wang, W. Org. Lett. 2009, 11, 1627; (i)
Jiang, H.; Elsner, P.; Jensen, K. L.; Falcicchio, A.; Marcos, V.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2009, 48, 6844.
4. For examples of chiral primary amine catalyzed cascade reactions, see: (a) Wu,
L. Y.; Bencivenni, G.; Mancinelli, M.; Mazzanti, A.; Bartoli, G.; Melchiorre, P.
Angew. Chem., Int. Ed. 2009, 48, 7196; (b) Galzerano, P.; Pesciaioli, F.; Mazzanti,
A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7892; (c) Benci-
venni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.; Bar-
toli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200; (d) Yang, Y. Q.; Chai,
Z.; Wang, H. F.; Chen, X. Q.; Cui, H. F.; Zheng, C. W.; Xiao, H.; Li, P.; Zhao, G.
Chem.dEur. J. 2010, 16, 2852 For examples of chiral secondary amine catalyzed
cascade reactions, see: (e) McGarraugh, P. G.; Brenner, S. E. Org. Lett. 2009, 11,
5654; (f) Liu, Y. K.; Ma, C.; Jiang, K.; Liu, T. Y.; Chen, Y. C. Org. Lett. 2009, 11, 2848;
(g) Nielsen, M.; Jacobsen, C. B.; Paixao, M. W.; Holub, N.; Jørgensen, K. A. J. Am.
Chem. Soc. 2009, 131, 10581; (h) Jiang, H.; Falcicchio, A.; Jensen, K. L.; Paixao, M.
W.; Bertelsen, S.; Jørgensen, K. A. J. Am. Chem. Soc. 2009, 131, 7153; (i) Lathrop,
S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628; (j) Jiang, K.; Jia, Z. J.; Yin, X.;
Wu, L.; Chen, Y. C. Org. Lett. 2010, 12, 2766; (k) Rendler, S.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2010, 132, 5027.
tiomer), tR¼17.78 min (major enantiomer).
4.3.17. (2S,11bS,Z)-3-(1-Hydroxyethylidene)-9,10-dimethoxy-2-(2-
methoxyphenyl)-2,3,6,7-tetrahydro-1H-pyrido[2,1
a
]isoquinolin-4
15.52 (s,
(11bH)-one (10q). Yellow solid; 1H NMR (CDCl3, 500 M):
d
1H), 7.24e7.27 (m, 1H), 7.07 (dd, J¼7.5 and 1.5 Hz, 1H), 6.90e6.96
(m, 2H), 6.60 (s, 1H), 6.38 (s, 1H), 4.84e4.87 (m, 1H), 4.30e4.35 (m,
2H), 3.93 (s, 3H), 3.84 (s, 3H), 3.78 (s, 3H), 2.85e2.89 (m, 2H),
2.64e2.67 (m, 1H), 2.50 (dt, J¼13 and 3 Hz, 1H), 1.89 (td, J¼13 and
4 Hz, 1H), 1.76 (s, 3H); 13C NMR (CDCl3, 125 M):
d 172.2, 170.3, 156.8,
147.8, 147.7, 131.9, 129.1, 128.7, 127.9, 127.7, 120.6, 111.5, 110.6, 109.0,
97.8, 56.4, 56.0, 55.5, 52.1, 39.0, 36.4, 32.4, 29.0, 18.7; [
a
]
25 þ129.0 (c
D
0.69, CHCl3); HRMS (ESI) calcd for (C24H28NO5)þ 410.1962, found
410.1967; HPLC (Daicel Chiralpak ADH, Hexane/Isopropanol¼4:1,
Flow rate¼0.65 mL/min, ¼220 nm): tR¼10.08 min (minor enan-
l
tiomer), tR¼16.61 min (major enantiomer).
4.3.18. (2S,11bS,Z)-3-(1-Hydroxyethylidene)-9,10-dimethoxy-2-(4-
methoxyphenyl)-2,3,6,7-tetrahydro-1H-pyrido[2,1
a
]isoquinolin-4
15.54
(11bH)-one (10r). Yellow solid; 1H NMR (CDCl3, 500 M):
d

3040
X. Dai et al. / Tetrahedron 67 (2011) 3034e3040
5. (a) The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Academic: New
York, NY, 1998; Vol 50; (b) Szantay, C.; Honty, K. In The Chemistry of Hetero-
cyclic Compounds; Saxton, J. E., Ed.; Wiley: New York, NY, 1994; Vol. 25,
pp 161e216; (c) Baxter, E. W.; Marino, P. S. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Springer: NewYork, NY, 1992; Vol. 8,
pp 197e319.
A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796; (j)
Jiang, J.; Qing, J.; Gong, L. Z. Chem.dEur. J. 2009, 15, 7031.
ꢀ
ꢀ
8. (a) Franzen, J.; Fisher, A. Angew. Chem., Int. Ed. 2009, 48, 787; (b) Zhang, W.;
ꢀ
Franzen, J. Adv. Synth. Catal. 2010, 352, 499; (c) Wu, X. Y.; Dai, X. Y.; Nie, L. L.;
Fang, H. H.; Chen, J.; Ren, Z. J.; Cao, W. G.; Zhao, G. Chem. Commun. 2010, 2733;
(d) Fang, H. H.; Wu, X. Y.; Nie, L. L.; Dai, X. Y.; Chen, J.; Cao, W. G.; Zhao, G. Org.
6. For selected examples of quinolizidine synthesis based on starting materials
from the chiral pool, see: (a) Martin, S. F.; Chen, K. X.; Eary, C. T. Org. Lett. 1999, 1,
79; (b) Yu, S.; Berner, O. M.; Cook, J. M. J. Am. Chem. Soc. 2000, 122, 7827; (c)
Deiters, A.; Chen, K.; Eary, C. T.; Martin, S. F. J. Am. Chem. Soc. 2003, 125, 4541;
(d) Amat, M.; Perez, M.; Minaglia, A. T.; Casamitjana, N.; Bosch, J. Org. Lett. 2005,
7, 3653; (e) Stork, G.;Tang,P. C.; Casey, M.; Goodman,B.; Toyota, M. J. Am. Chem. Soc.
Lett. 2010, 12, 5366.
9. For examples of prolinol TMS ether promoted conjugate addition of active
ꢀ
methylene to
a
,
b-unsaturated aldehyde, see: (a) Brandau, S.; Landa, A.; Franzen,
J.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 4305; (b) Carlone,
A.; Cabrera, S.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 1101;
(c) Carlone, A.; Marigo, M.; North, C.; Landa, A.; Jørgensen, K. A. Chem. Commun.
2006, 4928.
ꢀ
2005, 127, 16255; (f) Amat, M.; Santos, M. M. M.; Bassas, O.; Llor, N.; Escolano, C.;
ꢀ
ꢀ
Gomez-Esque, A.; Molins, E.; Allin, S. M.; McKee, V.; Bosch, J. J. Org. Chem. 2007, 72,
5193; (g) Ma, J.; Yin, W. Y.; Zhou, H.; Cook, J. M. Org. Lett. 2007, 9, 3491.
10. For reviews of N-acylimminium cyclization, see: (a) Maryanoff, B. E.; Zhang, H.
C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431; (b)
Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311.
11. For examples of asymmetric N-acylimminium cyclization, see: (a) Taylor, M. S.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558; (b) Raheem, I. T.; Thiara, P. S.;
Jacobsen, E. N. Org. Lett. 2008, 10, 1577; (c) Also see Ref 7e and Ref 7i.
12. Crystallographic data for the structure 3n has been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication no. CCDC
785666. These data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
7. Examples of quinolizidine syntheses by asymmetric catalysis: (a) Santos, L. S.;
Pilli, R. A.; Rawal, V. H. J. Org. Chem. 2004, 69, 1283; (b) Frisch, K.; Landa, A.;
Saaby, S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 6058; (c) Wu, T. R.;
Chong, J. M. J. Am. Chem. Soc. 2006, 128, 9646; (d) Szawkalo, J.; Czarnocki, S. J.;
Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.; Czarnocki, Z.;
Drabowicz, J. Tetrahedron: Asymmetry 2007, 18, 406; (e) Raheem, I. T.; Thiara, P.
S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404; (f) Mergott,
D. J.; Zuend, S. J.; Jacobsen, E. N. Org. Lett. 2008, 10, 745; (g) Jana, C. K.; Studer, A.
Chem.dEur. J. 2008, 14, 6326; (h) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.;
Ohsawa, A. Org. Lett. 2006, 8, 1533; (i) Muratore, M. E.; Holloway, C. A.; Pilling,
13. Sabri, S. S.; Ei-Abadelah, M. M.; Owals, W. M. J. Chem. Eng. Data 1984, 29, 229.
14. Jackson, A. H.; Shannon, P. V. R.; Wilkins, D. J. J. Chem. Soc., Chem. Commun.1987, 653.