Asymmetric phase-transfer-catalyzed conjugate addition of glycine imine to exocyclic α,β-unsaturated ketones: Construction of polycyclic imines containing three stereocenters

Article abstract of DOI:10.1021/jo300500r

We developed a facile, one-pot, multistep transformation between glycine imine and exocyclic α,β-unsaturated ketones in reactions catalyzed by chiral phase-transfer catalysts (PTC). A series of polycyclic imines containing three adjacent stereocenters were obtained in good to high yields with high diastereo- and enantioselectivities. Further transformation of the imines could afford N-fused polycyclic compounds with four adjacent stereocenters.

Full text of DOI:10.1021/jo300500r

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pubs.acs.org/joc
Asymmetric Phase-Transfer-Catalyzed Conjugate Addition of Glycine
Imine to Exocyclic α,β-Unsaturated Ketones: Construction of
Polycyclic Imines Containing Three Stereocenters
Jing Nie, Ming-Qing Hua, Heng-Ying Xiong, Yan Zheng, and Jun-An Ma*
Department of Chemistry, Tianjin University, Tianjin 300072, P. R. China
S
* Supporting Information
ABSTRACT: We developed a facile, one-pot, multistep transformation between glycine imine and exocyclic α,β-unsaturated
ketones in reactions catalyzed by chiral phase-transfer catalysts (PTC). A series of polycyclic imines containing three adjacent
stereocenters were obtained in good to high yields with high diastereo- and enantioselectivities. Further transformation of the
imines could afford N-fused polycyclic compounds with four adjacent stereocenters.
benzofuranones.6c Encouraged by these results and as a part
of our continued interest in catalytic asymmetric synthesis,
we envisioned that N-fused polycyclic compounds with four
INTRODUCTION
Asymmetric catalytic conjugate addition (ACCA) of glycine
imines to electrophilic acceptor substrates has been recognized
■
stereocenters could be constructed by simple multistep trans-
as a convenient and powerful methodology for the synthesis
of enantiomerically enriched α-amino acids.1,2 In the past few
formation between glycine imine 2 and exocyclic olefin
acceptors 1 in the presence of chiral phase-transfer catalysts
years, a great effort has been devoted to the development of
(Figure 1). Herein, we present the first asymmetric catalytic
highly selective and efficient catalytic systems and the
utilization of various α,β-unsaturated acceptors including α,β-
unsaturated esters, β-aryl nitroalkenes, α,β-unsaturated ketones,
arylidene malonates, and alkylidene bisphosphonates in these
synthetically useful addition reactions.3,6b Furthermore, sub-
sequent transformations of these chiral adducts provide rapid
and efficient access to highly functionalized pyrrolidine deriva-
tives, which serve as important synthetic intermediates for the
preparation of a vast array of natural products and biologically
active compounds.4 Despite promising progress made in this
area, the use of exocyclic olefin acceptors as electrophilic
substrates for the construction of three or more stereo-
centers has not been reported and thus remains an interesting
challenge.
Asymmetric phase-transfer catalysis is emerging as an area of
intense interest in enantioselective synthesis owing to its
operational simplicity, mild reaction conditions, and environ-
mentally benign and safe characters.5 Efforts from our
Figure 1. Asymmetric conjugate addition for the construction of
polycyclic compounds.
laboratory have focused on the design and synthesis of new
chiral phase-transfer catalysts from readily available chiral 1,1′-
binaphthyl-2,2′-diol.6 These interesting quaternary ammonium
and phosphonium salts have been shown to give excellent
enantioselectivity for the conjugate additions of sterically
hindered nitroalkanes6a and glycine imine6b to bulky β-aryl-
substituted enones as well as asymmetric amination reactions of
conjugate addition of glycine imines to exocyclic α,β-unsaturated
ketones. The reaction proceeded with good stereocontrol to
Received: March 7, 2012
Published: April 13, 2012
© 2012 American Chemical Society
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Figure 2. Binol-derived quaternary ammonium salts as chiral phase-transfer catalysts.
give polycyclic imine derivatives with high enantio- and dia-
stereopurity. Such studies would be of immense benefit to ex-
panding the scope of the conjugate reactions of glycine imines
in organic synthesis.
With the optimal condition in hand, we subsequently investi-
gated the scope of this asymmetric one-pot multistep synthesis
of 3 by employing a series of exocyclic α,β-unsaturated ketones 1.
As shown in Table 2, various polycyclic imines 3a−r were
obtained with uniformly high diastereo- and enantioselectiv-
ities. It was found that when aryl aldehyde-derived tetralones
with electron-neutral or -withdrawing groups on aromatic rings
were used, the multistep reactions proceeded smoothly to give
3a−c in 82−89% yields (entries 1−3). However, the presence
of electron-donating substituents on aromatic rings decreased
the reaction rate, and relatively lower yields were obtained
(entries 4 and 5). α,β-Unsaturated ketone bearing the naphthyl
ring also furnished the corresponding product 3f in 75% yield
with 92/8 dr and 86% ee (entry 6). Notably, 4-chromanone-
and 4-thiochromanone-derived exocyclic α,β-unsaturated
ketones7 are also viable substrates, affording the desired pro-
ducts 3g−r in 81−97% yields (entries 7−18). In addition, we
investigated the reactions with exocyclic α,β-unsaturated
ketones derived from alkyl aldehydes. These substrates were
found to be unsuitable for this asymmetric transformation
and poor yields (<10%) were observed.
To test the feasibility of potential large-scale application of
this one-pot multistep transformation, the reaction of (E)-2-
benzylidene-1-tetralones 1a was repeated on a 1.48 g (6.3 mmol)
scale, and product 3a was isolated in 90% yield with 95/5 dr and
90% ee (Scheme 1a). Further transformation of the polycyclic
imine 3a furnished the crystalline derivative 4 whose absolute
stereochemistry was determined to be (2R,3S,3aR,9bR) from
single-crystal X-ray structural analysis.8 Thus, we established
that the absolute configuration of the major stereoisomer 3a is
(2R,3S,3aR). In addition, the chiral phase-transfer catalyst IIIb
can be readily recovered in 97% yield and recycled with one
simple regenerating process. Anion exchange of recovered
catalyst IIIb using Amberlyst-26A (OH− form) gave (S)-IIIb
(OH−). The methanol solution of (S)-IIIb (OH−) was treated
with 40% HBr aqueous solution (excess) at room temperature
to give the reactivated catalyst (S)-IIIb (Br−) in 92% yield
(Scheme 1b). The regenerated catalyst (S)-IIIb (Br−) could be
RESULTS AND DISCUSSION
■
To validate our hypothesis, the model reaction of (E)-2-
benzylidene-1-tetralone 1a with N-(diphenylmethylene)glycine
tert-butyl ester 2 was performed in the presence of tetra-
butylammonium bromide (1.0 equiv) and Cs2CO3 (1.0 equiv)
in toluene. When the conjugate addition is complete (48 h,
detected by TLC), the crude mixture was directly treated with
2 N hydrochloric acid. Gratifyingly, the desired cyclization
product 3a was obtained in 88% isolated yield with moderate
diastereoselectivity (75:25 dr). Subsequent attempts to extend
this one-pot multistep protocol to the catalytic asymmetric
version were carried out by using chiral phase-transfer catalysts
I−IV (Figure 2). The results are listed in Table 1. Our pre-
viously reported dinuclear N-spiro-ammonium salts I and
II gave uniformly high diastereoselectivities, but low yields
and enantioselectivities were observed (entries 1−6). Based
on these preliminary results, we felt that dinuclear N-spiro-
ammonium salts could be unsuitable for this conjugate addition
of exocyclic α,β-unsaturated ketone substrates. Next, several
monoquaternary ammonium salts III and IV were tested in the
same reaction (entries 7−9). We were pleased to find that the
morpholine-derived catalyst IIIb, bearing bulky aryl groups on
3,3′-positions of the binaphthyl scaffold, afforded the cyclization
product 3a in 59% yield with high diastereo- and enantio-
selecitivity (95/5 dr, 90% ee). Screening of solvents revealed
that toluene was the optimal solvent under the reaction
conditions used (entries 10−14 vs 8). Further optimization by
changing the concentration of reactants, the catalyst loading,
the temperature, and the reaction time (entries 15−19) led to
the discovery that the best results were obtained when 1 mol %
of IIIb was used at 15 °C for 96 h (89% yield, 95/5 dr, 90% ee,
entry 19).
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Table 1. Effect of Chiral PTC, Solvent, Temperature, And Other Reaction Conditions for One-Pot Synthesis of Polycyclic
a
Imines
b
c
d
entry
catalyst (mol %)
solvent
temp (°C)
yield (%)
dr
ee (%)
1
Ia (1)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
15
20
25
20
22
26
35
17
59
38
16
52
14
48
33
70
75
62
90
89
91:9
90:10
90:10
95:5
94:6
95:5
94:6
95:5
95:5
97:3
95:5
94:6
97:3
94:6
91:9
91:9
95:5
94:6
95:5
6
6
2
Ib (1)
3
Ic (1)
12
11
8
4
IIa (1)
IIb (1)
IIc (1)
IIIa (1)
IIIb (1)
IV (1)
5
6
62
23
90
<5
10
86
5
7
8
9
10
11
12
13
14
IIIb (1)
IIIb (1)
IIIb (1)
IIIb (1)
IIIb (1)
IIIb (1)
IIIb (1)
IIIb (3)
IIIb (1)
IIIb (1)
Et2O
CH2Cl2
xylene
80
82
85
86
90
86
90
benzene
toluene
toluene
toluene
toluene
toluene
e
15
f
16
17
g
18
g
19
a
Unless otherwise noted, all reactions were carried out with N-(diphenylmethylene)glycine tert-butyl ester 2 (59.0 mg, 0.2 mmol), (E)-2-
benzylidene-1-tetralones 1a (49.2 mg, 0.21 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), and 1 mol % of PTC in solvent (1 mL) for the stated time. Then
b
c
2 N hydrochloric acid (1.0 mL) and THF (1.0 mL) were added at 0 °C, and stirring was maintained for 6 h. Isolated yield. Determined by HPLC
d
e
f
g
or 1H NMR analysis. Determined by HPLC analysis using a chiral stationary phase. 0.5 mol/L of 2 was used. 1.0 mol/L of 2 was used. Reaction
time was 96 h.
0.2 mmol) in toluene (0.2 mL) under argon atmosphere, the resulting
solution was stirred at 15 °C for 96 h, 2 N hydrochloric acid (1.0 mL)
and THF (1.0 mL) were added at 0 °C, and stirring was maintained
for 6 h at 0 °C. The resulting mixture was neutralized by addition of
solid NaHCO3 and extracted with CH2Cl2. The organic extracts were
dried over MgSO4 and concentrated. The residue was purified by
column chromatography on silica gel (AcOEt/petroleum ether = 1/10
as eluant) to furnish the conjugate adducts.
reused without an appreciable loss of reactivity and stereo-
selectivity.
CONCLUSION
■
In summary, we have successfully developed a convenient and
efficient one-pot multistep transformation of glycine imine and
exocyclic α,β-unsaturated ketones by using chiral phase-transfer
catalysts. A series of polycyclic imines with three adjacent
stereocenters were obtained under mild reaction conditions
in good to excellent yields with high diastereo- and enantio-
selectivities. Subsequent synthetic transformation of polycyclic
imines could secure the formation of N-fused polycyclic com-
pounds featuring four adjacent stereocenters. Moreover, the
chiral phase-transfer catalyst could be easily recovered and
reused after one simple regenerating process. Further exten-
sion of this protocol to the synthesis of natural products and
compounds of pharmaceutical significance is underway in our
laboratory.
(2R,3S,3aR)-tert-Butyl 3-phenyl-3,3a,4,5-tetrahydro-2H-benzo[g]-
indole-2-carboxylate (3a): 61.8 mg, 89% yield; yellow oil; [α]20
−55.7 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 1.42 (s, 9H),
D
1
1.75−1.86 (m, 1H), 2.18−2.24 (m, 1H), 2.94−2.98 (m, 2H), 3.11−
3.19 (m, 1H), 3.35 (t, J = 6.0 Hz, 1H), 4.67 (dd, J = 7.6 and 2.4 Hz,
1H), 7.22 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 6.4 Hz, 2H), 7.33−7.40 (m,
5H), 8.28 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 174.4,
171.9, 141.0, 140.1, 131.3, 129.6. 128.7, 128.6, 127.8, 127.0, 126.5,
126.4, 81.2, 80.2, 55.9, 55.6, 29.8, 28.2, 28.0; MS (ESI) m/z 348.2
[M + H]+; HRMS (ESI) found m/z 348.1958 [M + H]+, calcd for
C23H25NO2 + H 348.1960; IR (KBr) ν 3059, 2975, 2930, 2868, 1734,
1618, 1578, 1458, 1366, 1255, 1152, 1071, 1031, 959, 845, 700 cm−1;
dr = 95/5, er = 95/5, determined by HPLC analysis (Chiralpak AD-H,
n-hexane/2-propanol = 95/5, 1.0 mL/min, 254 nm UV detector), tR =
10.3 min (minor) and tR = 14.0 min (major).
EXPERIMENTAL SECTION
■
Materials. Tetrahydrofuran (THF), diethyl ether, benzene, and
toluene were distilled from sodium/benzophenone prior to use;
CH2Cl2 was distilled from CaH2. All purchased reagents were used
without further purification. 3,3-Disubstituted (S)-Binol-derived phase-
transfer catalysts Ia−c,6a IIa−c,6b IIIa,b,3b,c,6b and and IV,9 as well as
exocyclic α,β-unsaturated ketones,10 were synthesized according to the
literature.
(2R,3S,3aR)-tert-Butyl 3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-
benzo[g]indole- 2-carboxylate (3b): 59.8 mg, 82% yield; white solid;
mp 120−121 °C; [α]20D −67.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 1.42 (s, 9H), 1.72−1.83 (m, 1H), 2.16−2.20 (m, 1H),
2.93−2.96 (m, 2H), 3.05−3.12 (m, 1H), 3.32 (t, J = 10.0 Hz, 1H),
4.60 (dd, J = 7.6 and 2.4 Hz, 1H), 7.06 (t, J = 8.4 Hz, 2H), 7.21 (d, J =
7.6 Hz, 1H), 7.27−7.32 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 8.26 (d, J =
8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 174.3, 171.7, 163.1,
160.6, 141.0, 135.7, 131.3, 129.5. 129.3 (d, JC−F = 7.8 Hz), 128.7,
126.5, 126.4, 115.6, 115.4, 81.3, 80.1, 55.6, 55.2, 29.8, 28.1, 28.0;
General Procedure for One-Pot Multistep Synthesis of
Polycyclic Imines 3. N-(Diphenylmethylene)glycine tert-butyl ester
(59.0 mg, 0.2 mmol) was added to a mixture of substituted enones
(0.21 mmol), (S)-IIIb (2.9 mg, 0.002 mmol), and Cs2CO3 (65.2 mg,
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a
Table 2. Scope of Chiral PTC-Catalyzed One-Pot Multistep Synthesis of Polycyclic Imines 3
a
Unless otherwise noted, all reactions were carried out with N-(diphenylmethylene)glycine tert-butyl ester 2 (59.0 mg, 0.2 mmol), exocyclic α,β-
unsaturated ketones 1 (0.21 mmol), Cs2CO3 (65.2 mg, 0.2 mmol), and 1 mol % of PTC IIIb (2.9 mg, 0.002 mmol) in 0.2 mL of toluene at 15 °C for
b
c
96 h. Then 2 N hydrochloric acid (1.0 mL) and THF (1.0 mL) were added at 0 °C, and stirring was maintained for 6 h. Isolated yield. Determined
d
1
by H NMR or HPLC analysis. Determined by HPLC analysis using a chiral stationary phase.
MS (ESI) m/z 366.2 [M + H]+; HRMS (ESI) found: m/z 366.1864
[M + H]+, calcd for C23H24FNO2 + H 366.1864; IR (KBr) ν 3069,
2977, 2934, 2886, 1727, 1620, 1602, 1510, 1459, 1367, 1214, 1158,
1076, 1033, 848, 768 cm−1; dr = 96/4, er = 95/5, determined by HPLC
analysis (Chiralpak AD-H, n-hexane/2-propanol = 95/5, 1.0 mL/min,
254 nm UV detector), tR = 13.8 min (minor) and tR = 17.1 min
(major).
ν 3064, 2976, 2947, 2888, 1726, 1620, 1604, 1493, 1458, 1367, 1212,
1150, 1076, 1012, 844, 759 cm−1; dr = 92/8, er = 95.5/4.5, determined
by HPLC analysis (Chiralpak AD-H, n-hexane/2-propanol = 95/5,
1.0 mL/min, 254 nm UV detector), tR = 13.1 min (minor) and tR =
15.9 min (major).
(2R,3S,3aR)-tert-Butyl 3-(4-methoxyphenyl)-3,3a,4,5-tetrahydro-
2H-benzo[g]indole-2 -carboxylate (3d): 56.8 mg, 75% yield; white
1
solid; mp 108−110 °C; [α]20 −59.7 (c 1.0, CH2Cl2); H NMR
(2R,3S,3aR)-tert-Butyl 3-(4-chlorophenyl)-3,3a,4,5-tetrahydro-
2H-benzo[g]indole-2-carboxylate (3c). 67.4 mg, 88% yield; white
D
(400 MHz, CDCl3) δ 1.43 (s, 9H), 1.72−1.83 (m, 1H), 2.17−2.22
(m, 1H), 2.93−2.97 (m, 2H), 3.05−3.12 (m, 1H), 3.30 (t, J = 10.4 Hz,
1H), 3.83 (s, 3H), 4.60 (dd, J = 7.6 and 2.4 Hz, 1H), 6.92 (d, J = 8.8 Hz,
2H), 7.20−7.30 (m, 4H), 7.38 (t, J = 6.8 Hz, 1H), 8.26 (d, J = 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 174.4, 172.0, 158.6, 141.0,
131.9, 131.2, 129.6. 128.7, 126.5, 126.4, 114.1, 81.1, 80.2, 55.5, 55.3,
55.2, 29.8, 28.2, 28.0; MS (ESI) m/z 378.2 [M + H]+; HRMS (ESI)
found: m/z 378.2064 [M + H]+, calcd for C24H27NO3+H 378.2054;
IR (KBr) ν 2996, 2975, 2936, 2841, 1733, 1614, 1601, 1518, 1455,
1362, 1253, 1150, 1076, 1032, 836 cm−1; dr = 94/6, er = 95.5/4.5,
solid; mp 127−128 °C; [α]20 −52.4 (c 1.0, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) δ 1.43 (s, 9H), 1.73−1.84 (m, 1H), 2.15−2.21 (m,
1H), 2.94−2.96 (m, 2H), 3.06−3.13 (m, 1H), 3.32 (t, J = 10.0 Hz,
1H), 4.61 (dd, J = 7.6 and 2.4 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.29
(t, J = 8.4 Hz, 3H), 7.34−7.41 (m, 3H), 8.25 (d, J = 7.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 174.2, 171.6, 140.9, 138.6, 132.7, 131.4,
129.5. 129.1, 128.8, 128.7, 126.6, 126.5, 81.4, 80.1, 55.6, 55.2, 29.8,
28.1, 28.0; MS (ESI) m/z 382.2 [M + H]+; HRMS (ESI) found: m/z
382.1568 [M + H]+, calcd for C23H24ClNO2 + H 382.1572; IR (KBr)
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Scheme 1. Large-Scale Synthesis, Recovery of Catalyst IIIb, and Further Transformation of Polycyclic Imine 3a
determined by HPLC analysis (Chiralpak AD-H, n-hexane/2-propanol
= 95/5, 1.0 mL/min, 254 nm UV detector), tR = 17.9 min (minor) and
tR = 27.2 min (major).
1071, 1032, 845, 764 cm−1; dr = 92/8, er = 93/7, determined
by HPLC analysis (Chiralpak AD-H, n-hexane/2-propanol = 95/5,
1.0 mL/min, 254 nm UV detector), tR = 15.0 min (minor) and tR =
33.9 min (major).
(2R,3S,3aR)-tert-Butyl 3-(3-phenoxyphenyl)-3,3a,4,5-tetrahydro-
2H-benzo[g]indole-2-carboxylate (3e): 67.7 mg, 77% yield; yellow
oil; [α]20D −40.4 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.45
(s, 9H), 1.74−1.85 (m, 1H), 2.20−2.26 (m, 1H), 2.95−2.99 (m, 2H),
3.09−3.16 (m, 1H), 3.34 (t, J = 10.0 Hz, 1H), 4.65 (dd, J = 7.6 and
2.4 Hz, 1H), 6.92−6.95 (m, 1H), 7.04−7.15 (m, 5H), 7.22 (d, J =
7.6 Hz, 1H), 7.27−7.41 (m, 5H), 8.27 (d, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 174.3, 171.7, 157.5, 157.1, 142.3, 141.0, 131.3,
129.9. 129.8, 129.5, 128.7, 126.5, 126.4, 123.4, 122.7, 118.9, 118.3,
117.3, 81.3, 80.1, 55.7, 55.5, 29.8, 28.3, 28.1; MS (ESI) m/z 440.2
[M + H]+; HRMS (ESI) found m/z 440.2220 [M + H]+, calcd for
C29H29NO3 +H 440.2235; IR (KBr) ν 3033, 2976, 2929, 2866, 1732,
1601, 1580, 1487, 1456, 1367, 1250, 1215, 1151, 1071, 1012, 959, 849,
753 cm−1; dr = 96/4, er = 93.5/6.5, determined by HPLC analysis
(Chiralpak AD-H, n-hexane/2-propanol = 95/5, 1.0 mL/min, 254 nm
UV detector), tR = 12.6 min (minor) and tR = 21.8 min (major).
(2R,3S,3aR)-tert-Butyl 3-(naphthalen-1-yl)-3,3a,4,5-tetrahydro-
2H-benzo[g]indole-2-carboxylate (3f): 59.6 mg, 75% yield; yellow
oil; [α]20D −78.6 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.28
(s, 9H), 1.89−1.99 (m, 1H), 2.15−2.21 (m, 1H), 2.92−2.95 (m, 2H),
3.40−3.47 (m, 1H), 4.21 (t, J = 9.6 Hz, 1H), 5.00 (dd, J = 7.6 and
1.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.38−7.43
(m, 1H), 7.49−7.53 (m, 3H), 7.61 (d, J = 7.2 Hz, 1H), 7.82 (d, J =
8.0 Hz, 1H), 7.91−7.93 (m, 1H), 8.10−8.12 (m, 1H), 8.34 (d, J =
7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 174.6, 172.0, 141.1,
137.0, 134.2, 132.3, 131.3, 129.8. 129.1, 128.8, 127.5, 126.6, 126.5,
126.1, 125.6, 125.5, 124.9, 123.3, 81.2, 81.0, 57.0, 50.8, 29.9, 29.1, 27.8;
MS (ESI) m/z 398.2 [M + H]+; HRMS (ESI) found m/z 398.2115
[M + H]+, calcd for C27H27NO2 + H 398.2124; IR (KBr) ν 3021,
2960, 2926, 2868, 1733, 1618, 1601, 1515, 1459, 1366, 1253, 1151,
(2R,3S,3aR)-tert-Butyl 3-phenyl-2,3,3a,4-tetrahydrochromeno-
[4,3-b]pyrrole-2-carboxylate (3g): 65.3 mg, 93% yield; white solid;
1
mp 90−92 °C; [α]20 −90.7 (c 1.0, CH2Cl2); H NMR (400 MHz,
D
CDCl3) δ 1.44 (s, 9H), 3.40 (t, J = 10.0 Hz, 1H), 3.49−3.56 (m, 1H),
4.02−4.09 (m, 1H), 4.57−4.61 (m, 1H), 4.65 (dd, J = 7.2 and 2.4 Hz,
1H), 6.96 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 7.28−7.32
(m, 3H), 7.36−7.41 (m, 3H), 8.09 (dd, J = 6.4 and 1.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 171.3, 169.1, 158.0, 138.9, 133.5, 128.9,
127.6. 127.4, 126.4, 121.4, 117.6, 117.4, 81.6, 80.7, 70.5, 52.1, 52.0,
28.0; MS (ESI) m/z 350.2 [M + H]+; HRMS (ESI) found m/z
350.1751 [M + H]+ calcd for C22H23NO3 + H 350.1762; IR (KBr) ν
3030, 2975, 2925, 2871, 1733, 1623, 1620, 1574, 1472, 1456, 1367,
1315, 1219, 1151, 1031, 1004, 957, 835, 760 cm−1; dr = 90/10, er =
95.5/4.5, determined by HPLC analysis (Chiralpak AD-H, n-hexane/
2-propanol = 95/5, 1.0 mL/min, 254 nm UV detector), tR = 13.5 min
(minor) and tR = 15.5 min (major).
(2R,3S,3aR)-tert-Butyl 3-p-tolyl-2,3,3a,4-tetrahydrochromeno-
[4,3-b]pyrrole-2-carboxylate (3h): 70.2 mg, 96% yield; white solid;
mp 127−128 °C; [α]20D −58.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 1.45 (s, 9H), 2.37 (s, 3H), 3.38 (t, J = 10.0 Hz, 1H), 3.47−
3.53 (m, 1H), 4.05 (t, J = 11.6 Hz, 1H), 4.56−4.63 (m, 2H), 6.96 (d,
J = 8.4 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 7.17−7.22 (m, 4H), 7.39
(t, J = 7.6 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 171.4, 169.1, 158.0, 137.0, 135.7, 133.4, 129.5. 127.5, 126.4,
121.4, 117.6, 117.4, 81.6, 80.7, 70.6, 52.1, 51.7, 28.0, 21.1; MS (ESI)
m/z 364.2 [M + H]+; HRMS (ESI) found m/z 364.1907 [M + H]+,
calcd for C23H25NO3 + H 364.1916; IR (KBr) ν 3056, 2972, 2913,
2882, 1743, 1625, 1609, 1571, 1517, 1460, 1366, 1313, 1213, 1152,
1037, 1000, 956, 811, 764 cm−1; dr = 93/7, er = 95/5, determined by
4213
dx.doi.org/10.1021/jo300500r | J. Org. Chem. 2012, 77, 4209−4216

The Journal of Organic Chemistry
Featured Article
HPLC analysis (Chiralpak AD-H, n-hexane/2-propanol = 95/5,
1.0 mL/min, 254 nm UV detector), tR = 13.7 min (minor) and tR =
16.5 min (major).
(2R,3S,3aR)-tert-Butyl 3-phenyl-2,3,3a,4-tetrahydrothio-
chromeno[4,3-b]pyrrole-2-carboxylate (3m): 69.3 mg, 95% yield;
yellow oil; [α]20 −160.6 (c 1.0, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3) δ 1.43 (s, 9H), 2.98 (dd, J = 8.0 and 4.4 Hz, 1H), 3.20 (t, J =
12.4 Hz, 1H), 3.38 (t, J = 9.6 Hz, 1H), 3.46−3.54 (m, 1H), 4.63 (dd,
J = 6.8 and 2.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz,
1H), 7.29−7.33 (m, 4H), 7.31−7.41 (m, 2H), 8.37 (d, J = 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 171.3, 170.7, 139.2, 137.8,
131.3, 128.9, 128.3. 127.8, 127.7, 127.4, 126.9, 124.9, 81.5, 79.7, 56.0,
55.1, 30.9, 28.0; MS (ESI) m/z 366.2 [M + H]+; HRMS (ESI) found
m/z 366.1522 [M + H]+, calcd for C22H23NO2S + H 366.1521; IR
(KBr) ν 3062, 2976, 2928, 1733, 1647, 1558, 1541, 1457, 1363, 1213,
1152, 1079, 1029, 955, 844, 759 cm−1; dr = 90/10, er = 96.5/3.5, deter-
mined by HPLC analysis (Chiralpak IA, n-hexane/2-propanol =97/3,
1.0 mL/min, 254 nm UV detector), tR = 12.8 min (major) and tR = 14.9
min (minor).
(2R,3S,3aR)-tert-Butyl 3-(4-methoxyphenyl)-2,3,3a,4-tetrahydro-
chromeno[4,3-b]pyrrole-2-carboxylate (3i): 68.4 mg, 90% yield;
white solid; mp 112−113 °C; [α]20D −61.6 (c 1.0, CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 1.44 (s, 9H), 3.35 (t, J = 10.0 Hz, 1H), 3.43−
3.50 (m, 1H), 3.83 (s, 3H), 4.04 (t, J = 11.6 Hz, 1H), 4.55−4.60 (m,
2H), 6.90−6.96 (m, 3H), 7.03 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 8.4 Hz,
2H), 7.39 (t, J = 7.6 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 171.4, 169.1, 158.9, 158.0, 133.4, 130.7, 128.6. 126.3,
121.4, 117.6, 117.4, 114.2, 81.6, 80.7, 70.6, 55.3, 52.0, 51.4, 28.0; MS
(ESI) m/z 380.2 [M + H]+; HRMS (ESI) found m/z 380.1856 [M +
H]+, calcd for C23H25NO4 + H 380.1872; IR (KBr) ν 3033, 2974,
2905, 2833, 1726, 1634, 1611, 1515, 1469, 1417, 1370, 1312, 1250,
1160, 1031, 1007, 825, 755 cm−1; dr = 96/4, er = 96.5/3.5, determined
by HPLC analysis (Chiralpak AD-H, n-hexane/2-propanol =90/10,
1.0 mL/min, 254 nm UV detector), tR = 13.2 min (minor) and tR =
17.6 min (major).
(2R,3S,3aR)-tert-Butyl 3-p-tolyl-2,3,3a,4-tetrahydrothio-
chromeno[4,3-b]pyrrole-2-carboxylate (3n). 71.4 mg, 94% yield;
yellow oil; [α]20 −140.6 (c 1.0, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3) δ 1.45 (s, 9H), 2.38 (s, 3H), 2.98 (dd, J = 7.6 and 4.8 Hz, 1H),
3.19 (t, J = 12.4 Hz, 1H), 3.62 (t, J = 9.6 Hz, 1H), 3.43−3.51 (m, 1H),
4.60 (dd, J = 6.8 and 2.4 Hz, 1H), 7.15−7.25 (m, 6H), 7.31 (t, J =
7.2 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
171.3, 170.7, 137.9, 137.0, 136.2, 121.3, 129.5. 128.7, 127.8, 127.6,
126.9, 124.9, 81.5, 79.7, 55.5, 55.1, 30.9, 28.0, 21.1; MS (ESI) m/z
380.2 [M + H]+; HRMS (ESI) found m/z 380.1679 [M + H]+, calcd
for C23H25NO2S + H 380.1678; IR (KBr) ν 3053, 2978, 2920, 1732,
1607, 1591, 1516, 1442, 1367, 1216, 1153, 1088, 1030, 956, 845,
760 cm−1; dr = 92/8, er = 96.5/3.5, determined by HPLC analysis
(Chiralpak IA, n-hexane/2-propanol =97/3, 1.0 mL/min, 254 nm UV
detector), tR = 12.7 min (major) and tR = 14.3 min (minor).
(2R,3S,3aR)-tert-Butyl 3-(4-fluorophenyl)-2,3,3a,4-tetrahydro-
chromeno[4,3-b]pyrrole-2 -carboxylate (3j): 71.3 mg, 97% yield;
white solid; mp 107−109 °C; [α]20D −82.8 (c 1.0, CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 1.43 (s, 9H), 3.37 (t, J = 10.0 Hz, 1H), 3.42−
3.50 (m, 1H), 4.03 (t, J = 11.6 Hz, 1H), 4.54−4.60 (m, 2H), 6.95 (d,
J = 8.4 Hz, 1H), 7.00−7.08 (m, 3H), 7.26−7.30 (m, 2H), 7.38 (t, J =
7.2 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
171.1, 168.9, 163.2, 160.8, 158.0, 134.5, 133.5, 129.1 (d, JC−F = 7.9
Hz), 126.4. 121.5, 117.5, 117.4, 115.9, 115.6, 81.7, 80.7, 70.4, 52.1,
51.3, 28.0; MS (ESI) m/z 368.2 [M + H]+; HRMS (ESI) found m/z
368.1657 [M + H]+, calcd for C22H22FNO3+H 368.1667; IR (KBr) ν
2976, 2926, 2871, 1732, 1651, 1609, 1557, 1512, 1471, 1456, 1367,
1315, 1227, 1150, 1002, 956, 833, 759 cm−1; dr = 95/5, er = 94/6,
determined by HPLC analysis (Chiralpak AD-H, n-hexane/2-propanol =
95/5, 1.0 mL/min, 254 nm UV detector), tR = 19.3 min (minor) and tR =
21.0 min (major).
(2R,3S,3aR)-tert-Butyl 3-(4-methoxyphenyl)-2,3,3a,4-tetrahydro-
thiochromeno[4,3-b]pyrrole-2-carboxylate (3o): 74.8 mg, 94% yield;
yellow oil; [α]20 −106.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3) δ 1.44 (s, 9H), 2.98 (dd, J = 8.0 and 4.4 Hz, 1H), 3.18 (t, J =
12.4 Hz, 1H), 3.33 (t, J = 9.6 Hz, 1H), 3.40−3.47 (m, 1H), 3.83 (s,
3H), 4.55 (dd, J = 7.2 and 2.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 7.17
(t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 3H), 7.31 (t, J = 7.6 Hz, 1H),
8.35 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 171.4, 170.8,
158.9, 137.8, 131.3, 131.0, 128.7. 128.2, 127.8, 126.9, 124.9, 114.3,
81.5, 79.7, 55.3, 55.2, 55.0, 30.8, 28.0; MS (ESI) m/z 396.2 [M + H]+;
HRMS (ESI) found m/z 396.1628 [M + H]+, calcd for C23H25NO3S +
H 396.1626; IR (KBr) ν 3062, 2976, 2929, 2835, 1731, 1613, 1589,
1514, 1441, 1366, 1248, 1150, 1068, 1030, 954, 828, 759 cm−1; dr =
97/3, er = 96.5/3.5, determined by HPLC analysis (Chiralpak AD-H,
n-hexane/2-propanol = 95/5, 1.0 mL/min, 254 nm UV detector), tR =
16.9 min (minor) and tR = 20.8 min (major).
(2R,3S,3aR)-tert-Butyl 3-(2-chlorophenyl)-2,3,3a,4-tetrahydro-
chromeno[4,3-b]pyrrole-2-carboxylate (3k): 74.0 mg, 96% yield;
1
white solid; mp 115−116 °C; [α]20 −152.6 (c 1.0, CH2Cl2); H
D
NMR (400 MHz, CDCl3) δ 1.38 (s, 9H), 3.47−3.54 (m, 1H), 3.93
(t, J = 10.0 Hz, 1H), 4.07−4.13 (m, 1H), 4.55−4.59 (m, 1H), 4.87
(dd, J = 7.6 and 2.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 7.6
Hz, 1H), 7.22−7.26 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.36−7.43 (m,
3H), 8.09 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.8,
168.7, 158.0, 137.0, 134.2, 133.5, 130.0, 128.7, 128.4. 127.4, 126.5,
121.4, 117.6, 117.4, 81.5, 79.5, 70.5, 53.2, 48.2, 27.9; MS (ESI) m/z
384.1 [M + H]+; HRMS (ESI) found m/z 384.1361 [M + H]+, calcd
for C22H22ClNO3 + H 384.1374; IR (KBr) ν 3064, 2976, 2930, 2885,
1721, 1631, 1611, 1574, 1472, 1456, 1364, 1314, 1224, 1156, 1061,
1034, 1003, 841, 762 cm−1; dr > 99/1, er = 93.5/6.5, determined
by HPLC analysis (Chiralpak AD-H, n-hexane/2-propanol = 95/5,
1.0 mL/min, 254 nm UV detector), tR = 19.9 min (minor) and tR =
25.5 min (major).
(2R,3S,3aR)-tert-Butyl 3-(4-fluorophenyl)-2,3,3a,4-tetra-
hydrothiochromeno[4,3-b]pyrrole-2-carboxylate (3p): 74.1 mg,
96% yield; white solid; mp 88−90 °C; [α]20 −130.0 (c 1.0, CH2Cl2);
D
1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 2.95 (dd, J = 8.0 and 4.4
Hz, 1H), 3.18 (t, J = 12.4 Hz, 1H), 3.36 (t, J = 9.6 Hz, 1H), 3.39−3.47
(m, 1H), 4.56 (dd, J = 6.8 and 2.8 Hz, 1H), 7.07 (t, J = 8.4 Hz, 2H), 7.16
(t, J = 7.6 Hz, 1H), 7.22−7.32 (m, 4H), 8.35 (d, J = 8.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 171.1, 170.6, 163.3, 160.8, 137.7, 134.8,
131.4, 129.3 (d, JC−F = 7.8 Hz), 128.3. 127.6, 126.9, 125.0, 115.8, 115.6,
81.7, 79.6, 55.2, 55.1, 30.8, 28.0; MS (ESI) m/z 384.1 [M + H]+; HRMS
(ESI) found m/z 384.1428 [M + H]+, calcd for C22H22FNO2S + H
384.1435; IR (KBr) ν 3063, 2978, 2918, 1732, 1606, 1590, 1511, 1441,
1367, 1224, 1151, 1088, 1030, 956, 833, 760 cm−1; dr = 93/7, er = 92/8,
determined by HPLC analysis (Chiralpak OD-H, n-hexane/2-propanol =
95/5, 1.0 mL/min, 254 nm UV detector), tR = 15.0 min (minor) and tR =
17.3 min (major).
(2R,3S,3aR)-tert-Butyl 3-(2-bromophenyl)-2,3,3a,4-tetrahydro-
chromeno[4,3-b]pyrrole-2-carboxylate (3l): 83.5 mg, 97% yield;
1
white solid; mp 110−111 °C; [α]20 −158.1 (c 1.0, CH2Cl2); H
D
NMR (400 MHz, CDCl3) δ 1.38 (s, 9H), 3.40−3.47 (m, 1H), 3.97 (t,
J = 10.0 Hz, 1H), 4.08−4.14 (m, 1H), 4.56−4.60 (m, 1H), 4.85 (dd,
J = 7.6 and 1.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 7.02 (t, J = 7.6 Hz,
1H), 7.15 (t, J = 7.6 Hz, 1H), 7.33−7.43 (m, 3H), 7.61 (d, J = 8.0 Hz,
1H), 8.09 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.7,
168.7, 158.0, 138.9, 133.5, 133.3, 128.7, 128.6, 128.0, 126.5, 124.9,
121.4, 117.5, 117.3, 81.6, 79.8, 70.4, 53.9, 50.5, 27.9; MS (ESI) m/z
428.1 [M + H]+; HRMS (ESI) found m/z 428.0856 [M + H]+, calcd
for C22H22BrNO3 + H 428.0856; IR (KBr) ν 3063, 2977, 2930,
2872, 1737, 1626, 1609, 1573, 1471, 1456, 1367, 1314, 1220, 1151,
1022, 1002, 957, 835, 759 cm−1; dr = 97/3, er = 95/5, determined
by HPLC analysis (Chiralpak AD-H, n-hexane/2-propanol = 95/5,
1.0 mL/min, 254 nm UV detector), tR = 21.7 min (minor) and tR =
28.2 min (major).
(2R,3S,3aR)-tert-Butyl 3-(2-chlorophenyl)-2,3,3a,4-tetrahydro-
thiochromeno[4,3-b]pyrrole-2-carboxylate (3q): 68.6 mg, 86%
yield; white solid, mp 90−92 °C; [α]20 −160.1 (c 1.0, CH2Cl2);
D
1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 3.01 (dd, J = 8.0 and 4.4
Hz, 1H), 3.27 (t, J = 12.8 Hz, 1H), 3.49−3.56 (m, 1H), 3.98 (t, J = 9.6
Hz, 1H), 4.80 (dd, J = 6.8 and 2.4 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H),
7.21−7.25 (m, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.38−7.44 (m, 2H), 8.36
4214
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The Journal of Organic Chemistry
Featured Article
(d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.8, 170.5,
137.8, 137.5, 134.3, 131.4, 130.0, 128.9, 128.4, 127.7, 127.4, 126.8,
124.9, 81.5, 78.8, 55.8, 51.7, 31.1, 27.9; MS (ESI) m/z 400.1 [M + H]+;
HRMS (ESI) found m/z 400.1133 [M + H]+, calcd for C22H22ClNO2S
+ H 400.1142; IR (KBr) ν 3061, 2977, 2930, 2872, 1738, 1613, 1591,
1477, 1441, 1367, 1218, 1152, 1087, 1033, 956, 843, 758 cm−1; dr > 99/
1, er = 95.5/4.5, determined by HPLC analysis (Chiralpak IA, n-hexane/
2-propanol =97/3, 1.0 mL/min, 254 nm UV detector), tR = 17.9 min
(major) and tR = 21.6 min (minor).
(2R,3S,3aR)-tert-Butyl 3-(2-bromophenyl)-2,3,3a,4-
tetrahydrothiochromeno[4,3-b]pyrrole-2-carboxylate (3r): 72.3 mg,
81% yield; white solid; mp 65−67 °C; [α]20D −161.1 (c 1.0, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 3.04 (dd, J = 8.4 and 4.4
Hz, 1H), 3.29 (t, J = 12.8 Hz, 1H), 3.43−3.50 (m, 1H), 4.03 (t, J = 9.6
Hz, 1H), 4.77 (dd, J = 6.8 and 2.4 Hz, 1H), 7.13−7.18 (m, 2H), 7.22
(d, J = 8.0 Hz, 1H), 7.28−7.39 (m, 3H), 7.62 (d, J = 8.0 Hz, 1H), 8.36
(d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.7, 170.4,
139.4, 137.8, 133.2, 131.4, 128.7, 128.6. 128.4, 128.1, 127.6, 126.8,
125.0, 124.9, 81.5, 79.3, 56.5, 53.9, 31.0, 27.9; MS (ESI) m/z 444.1
[M + H]+; HRMS (ESI) found m/z 444.0627 [M + H]+, calcd for
C22H22BrNO2S + H 444.0624; IR (KBr) ν 3058, 2977, 2929, 1736,
1610, 1591, 1578, 1474, 1440, 1367, 1253, 1152, 1087, 1022, 956, 843,
759 cm−1; dr > 99/1, er = 92.5/7.5, determined by HPLC analysis
(Chiralpak IA, n-hexane/2-propanol =97/3, 1.0 mL/min, 254 nm UV
detector), tR = 20.3 min (major) and tR = 22.9 min (minor).
Large-Scale Synthesis of 3a. N-(Diphenylmethylene)glycine tert-
butyl ester 2 (1.77 g, 6.0 mmol) was added to a mixture of enone
1a (1.48 g, 6.3 mmol), (S)-IIIb (87.0 mg, 0.3 mmol), and Cs2CO3
(1.96 g, 6.0 mmol) in toluene (6.0 mL) under argon atmosphere, the
resulting solution was stirred at 15 °C for 96 h, 2 N hydrochloric acid
(30 mL) and THF (30 mL) were added at 0 °C, and stirring was
maintained for 6 h at 0 °C. The resulting mixture was neutralized by
addition of solid NaHCO3 and extracted with CH2Cl2. The organic
extracts were dried over MgSO4 and concentrated. The residue was
purified by column chromatography on silica gel (AcOEt/petroleum
ether =1/10 as eluant) to furnish the conjugate adducts 3a (1.88 g,
90% yield, 95/5 dr, 90% ee, determined by 1H NMR and HPLC
analysis).
washed with brine, and dried with MgSO4. Concentration and
flash chromatography (AcOEt/petroleum ether = 1/10−1/4
as eluant) afforded (2R,3S,3aR,9bR)-tert-butyl 3-phenyl-
2,3,3a,4,5,9b-hexahydro-1H-benzo[g]indole-2-carboxylate
(76.9 mg, 0.22 mmol, 55% yield) as a white solid: mp 69−
70 °C; [α]20 −22.9 (c 1.0, CH2Cl2); H NMR (400 MHz,
D
CDCl3) δ 1.41 (s, 9H), 1.63−1.73 (m, 1H), 1.92 (s, 1H),
2.15−2.24 (m, 1H), 2.85−3.03 (m, 4H), 4.06 (dd, J = 28.0 and
8.8 Hz, 2H), 7.12−7.27 (m, 4H), 7.31 − 7.38 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 174.6, 140.9, 139.9, 135.6, 128.5,
128.4, 127.9, 126.8, 126.4, 125.8, 124.3, 81.3, 68.8, 63.4, 56.4,
50.9, 28.9, 28.0, 24.1; MS (ESI) m/z 350.2 [M + H]+; HRMS
(ESI) found m/z 350.2115 [M + H]+, calcd for C23H27NO2 +
H 350.2110; IR (KBr) ν 3334, 3063, 3029, 2977, 2926, 2865,
1723, 1603, 1492, 1455, 1367, 1316, 1229, 1158, 1106, 1031,
951, 910, 847, 742 cm−1; er = 95/5, determined by HPLC
analysis (Chiralpak AD-H, n-hexane/2-propanol = 90/10, 0.8
mL/min, 254 nm UV detector), tR = 10.8 min (minor) and
tR = 11.7 min (major).
Step 2: (2R,3S,3aR,9bR)-tert-Butyl 1-(4-bromobenzoyl)-3-phenyl-
2,3,3a,4,5,9b-hexahydro-1H-benzo[g]indole-2-carboxylate (4).
(2R,3S,3aR,9bR)-tert-Butyl 3-phenyl-2,3,3a,4,5,9b-hexahydro-1H-
benzo[g]indole-2-carboxylate (52.4 mg, 0.15 mmol) in 0.5 mL of
CH2Cl2 was added to a mixture of 4-bromobenzoyl chloride (66.0 mg,
0.3 mmol) and Et3N (63 μL, 0.45 mmol) in dry CH2Cl2 (2 mL) at
0 °C under argon atmosphere, and then stirring was maintained for
24 h at room temperature. The resulting mixture was quenched with
aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts
were dried over MgSO4 and concentrated. The residue was purified by
column chromatographyon silica gel (AcOEt/petroleum ether = 1/5
as eluant) to afford the product (75.1 mg, 0.14 mmol, 94% yield) as a
white solid. Recrystallization of this product from CH2Cl2/hexane
furnished suitable crystals for X-ray structure analysis: mp 207−
208 °C; [α]20D −161.1 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ 0.94 (s, 9H), 1.73−1.86 (m, 2H), 2.29−2.33 (m, 1H), 2.86−2.92 (m,
1H), 3.05−3.18 (m, 2H), 4.61 (d, J = 8.0 Hz, 1H), 4.97 (d, J = 12.0
Hz, 1H), 7.13−7.23 (m, 6H), 7.29−7.36 (m, 3H), 7.56 (d, J = 8.0 Hz,
2H), 7.67 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ170.2,
139.9, 136.9, 136.0, 135.5, 131.6, 130.2, 128.8, 128.7, 128.0, 127.8,
126.4, 125.6, 125.5, 123.1, 82.1, 73.3, 64.3, 57.1, 49.0, 30.6, 27.3, 22.2;
MS (ESI) m/z 554.1 [M + H]+; HRMS (ESI) found m/z 554.1301
[M + Na]+, calcd for C30H30BrNO3 + Na 554.1301; IR (KBr) ν 3059,
3034, 2977, 2934, 2869, 1729, 1642, 1587, 1483, 1456, 1401, 1368,
1347, 1253, 1200, 1152, 1066, 1009, 995, 848, 745 cm−1; er = 95/5
(>99.99/0.01 after recrystallization), determined by HPLC analysis
(Chiralpak AD-H, n-hexane/2-propanol =80/20, 1.0 mL/min, 254 nm
UV detector), tR = 20.9 min (major) and tR = 24.8 min (minor).
Recovery and Reuse of Catalyst of IIIb. The catalyst IIIb was
recovered (MeOH/CH2Cl2 = 1/8 as eluent) in 97% yield. Anion
exchange of recovered catalyst IIIb using Amberlyst-26A (OH− form)
gave (S)-IIIb (OH−). The methanol solution of (S)-IIIb (OH−) was
treated with 40% HBr aqueous solution (excess) at room temperature.
The resulting mixture was poured into water and extracted with
CH2Cl2. The organic extracts were washed with 5% K2CO3 aqueous
solution and dried over MgSO4. Evaporation of solvents gave reac-
tivated catalyst (S)-IIIb of 77.6 mg in 92% yield.
N-(Diphenylmethylene)glycine tert-butyl ester (59.0 mg, 0.2 mmol)
was added to a mixture of substituted enones (49.2 mg, 0.21 mmol),
recovered (S)-IIIb (2.9 mg, 0.002 mmol), and Cs2CO3 (65.2 mg,
0.2 mmol) in toluene (0.2 mL) under argon atmosphere, the resulting
solution was stirred at 15 °C for 96 h, 2 N hydrochloric acid (1.0 mL)
and THF (1.0 mL) were added at 0 °C, and stirring was maintained
for 6 h at 0 °C. The resulting mixture was neutralized by addition of
solid NaHCO3 and extracted with CH2Cl2. The organic extracts were
dried over MgSO4 and concentrated. The residue was purified by
column chromatographyon silica gel (AcOEt/petroleum ether =1/10
as eluant) to furnish the conjugate adducts 3a (61.8 mg, 90% yield,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra and HPLC analytic results for products
3a−r and 4, as well as crystallographic data for compound 4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: majun_an68@tju.edu.cn.
■
1
94/6 dr, 90% ee, determined by H NMR and HPLC analysis).
Synthetic Transformations of 3a. Step 1: (2R,3S,3aR,9bR)-
tert-Butyl 3-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[g]indole- 2-
carboxylate. To a solution of (2R,3S,3aR)-tert-butyl 3-phenyl-
3,3a,4,5-tetrahydro-2H-benzo[g]indole-2-carboxylate (139.0 mg,
0.4 mmol) in 4 mL of AcOH was added zinc powder (30 equiv
in portions at room temperature. The resultant mixture was
stirred for 1.5 h at 45 °C (monitored by TLC). After zinc
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science Foun-
dation of China (NSFC) (No. 20972110 and 21002068) for
financial support.
ο
powder was filtered off, the filtrate was cooled to 0 C. The
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■
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