Organocatalytic sequential Michael reactions: Stereoselective synthesis of multifunctionalized tetrahydroindan derivatives

Article abstract of DOI:10.1021/ol1029832

Multifunctionalized tetrahydroindan derivatives with four stereocenters were constructed via two sequential Michael reactions between cyclic γ,δ-unsaturated-β-ketoester and nitroalkenes initiated with 0.5-2 mol % of cinchona alkaloid based bifunctional organocatalysts and then with 1 equiv of tetramethylguanidine for cyclization. The desired products could be obtained in high yields (up to 99% yield) with excellent enantioselectivities (95-99% ee) as well as diastereoselectivities (up to >99:1 dr) even on a gram scale.(Figure Presented)

Full text of DOI:10.1021/ol1029832

Organocatalytic Sequential Michael Reactions: Stereoselective
Synthesis of Multifunctionalized Tetrahydroindan Derivatives
Peng He, Xiaohua Liu,* Jian Shi, Lili Lin, Xiaoming Feng*
†Key Laboratory of Green Chemistry & Technology, Ministry of Education, College
of Chemistry, Sichuan University, Chengdu 610064, China.
E-mail: xmfeng@scu.edu.cn
1. General information …………………………………………………………………S2
2. Typical procedure for catalysts preparation ……………………………………...S2
3. Typical procedure for racemic samples preparation ……………….......................S3
4. Typical procedure for catalytic sequential Michael reactions ……….....…………S3
5. Typical procedure for gram-scale synthesis and transformations of the product ...S3
6. Crystal data and structure refinement for product 3i ……………………………..S4
7. Proposed transition state…………………………………………………………..S5
8. Analytical and spectral characterization data for the products ………………..S5-25
9. Copies of NMR spectra for the products ……………………………………..S26-48
10. References ……………………………………………………………………...S48
S1

1. General information
1H NMR spectra were recorded on commercial instruments (400 or 600 MHz). Chemical shifts
were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard
(CDCl3, δ = 7.26). Spectra were reported as follows: chemical shift (δ ppm), multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), integration
and assignment. 13C NMR spectra were collected on commercial instruments (100 or 150 MHz)
with complete proton decoupling. Chemical shifts are reported in ppm from the tetramethylsilane
with the solvent resonance as internal standard (CDCl3, δ = 77.0). Enantiomeric excesses (ee)
were determined by HPLC analysis using the corresponding commercial chiralpak column as
o
20
stated in the experimental procedures at 23 C. Optical rotations were reported as follows: [a]D
(c: g/100 mL, in solvent). HRMS was recorded on a commercial apparatus (ESI Source). All
catalytic reactions were run in dried glassware, THF, toluene and diethyl ether (Et2O) were
distilled from sodium benzophenone ketyl. CH2Cl2 was distilled over CaH2. The
cyclic-,-unstaturated--ketoesters 11 and nitroolefins2 were prepared according to the literature
procedures.
2. Typical procedure for catalysts preparation (4c, 4d, 4e)
Preparation of 4d3 (4e was prepared from quinidine in the same procedure):
To a solution of quinine (4.0 g, 12.4 mmol) in DMF (40 mL) under nitrogen atmosphere, NaH
(1.36 g, 57% suspension in mineral oil, 32.3 mmol) was added in small portions and the resulting
mixture was stirred at room temperature for 2 h. Then BnCl (1.56 mL, 13.6 mmol) was added
dropwise via a syringe in 10 min. The mixture was stirred at room temperature overnight. After
the starting material was completely consumed, brine (40 mL) was added carefully and the
resulting mixture was extracted with ethyl acetate (300 mL). The organic phase was washed with
H2O (3×100 mL), brine (100 mL) and dried over Na2SO4. The solvent was removed in vacuo to
afford a light yellow oil (5.1 g, 99%). This crude product (Q-Bn) was used without further
purification. Under N2 atmosphere, a suspension of Q-Bn (5.1 g, 12.3 mmol) and NaSEt (4.2 g,
o
50.0 mmol) in dry DMF (60 mL) was stirred at 110 C for 8-12 hours. The reaction mixture was
cooled to room temperature, and the reaction was quenched with H2O (60 mL). The solution was
acidified to pH =2 by conc. HCl. This aqueous solution was washed by ethyl acetate (2×100 mL)
and its pH value was adjusted to 8 by conc. ammonium hydroxide. The resulting mixture was
extracted with ethyl acetate (2×150 mL). The combined organic phase was dried over Na2SO4, and
concentrated in vacuo to afford a yellowish solid. This solid was washed by CH2Cl2 (2×30 mL)
and then dissolved in aqueous HCl (2 N, 150 mL). The resulting solution was washed by ethyl
acetate (50 mL) and adjusted to pH = 7 by conc. ammonium hydroxide. The aqueous phase was
extracted by ethyl acetate (3×80 mL). The organic phase was dried with Na2SO4. After
concentration, 4d was obtained as a white powder (3.97g, 80%).
S2

3. Typical procedure for racemic samples preparation
To a test tube, the nitroolefin 2 (0.1 mmol), cyclic-,-unstaturated--ketoester 1 (0.15 mmol, 1.5
equiv) and TMG (1.0 equiv, 12 L) in CH2Cl2 (1.0 mL) was stirred at room temperature for 20 h.
Racemic product 3 was isolated via column chromatography (1/2, CH2Cl2/petroleum ether).
4. Typical procedure for catalytic sequential Michael reactions
OH
1) 1 mol % 4d
O
H
CH2Cl2, 0 oC, t1
CO2Et
R
NO2
+
R
2) TMG, 0 oC, 20 h
CO2Et
H
NO2
2a-s
1
3a-s
To a test tube, the nitroolefin 2 (0.1 mmol) and catalyst 4d (1 mol %, 0.4 mg) in CH2Cl2 (0.5 mL)
was stirred at 30 oC for 30 min, then cyclic-,-unstaturated--ketoester 1 (0.15 mmol, 1.5 equiv)
o
was added and the mixture were stirred for the stated reaction time (20-84 h) at 0 C. If the
catalyst loading was 0.5 mol % (Table 2, entries 1, 3, 6, 7, 8 and 15), the solution of catalyst in
CH2Cl2 was used. After the nitroolefin was completely consumed (monitored by TLC), TMG (1.0
equiv, 12 L) was added under 0 oC, and the reaction mixture was stirred for further 20 h. Product
3 was isolated via column chromatography (1/2, CH2Cl2/petroleum ether). Unreacted nitroolefin
should be separated by column chromatography (EtOAc/petroleum ether) to avoid the byproduct
in the second Michael reaction (Table 2, entries 2, 12, 13, 18 and 19). Then CH2Cl2 (1.5 mL),
TMG (1.0 equiv, 12 L) was added under 0 oC and the reaction was stirred for further 20 h.
Product 3 was isolated via column chromatography (1/2, CH2Cl2/petroleum ether).
5. Typical procedure for gram-scale synthesis and transformations of the
product
To a round bottom flasks, the nitroolefin 2a (8 mmol, 1.19g) and catalyst 4e (1 mol %, 32 mg) in
CH2Cl2 (5 mL) was stirred at 30 oC for 30 min, then cyclic-,-unstaturated--ketoester 1 (12
mmol, 1.5 equiv) was added. The mixture was stirred for 66 h at 0 oC. Then TMG (300 L) was
added in small portions under 0 oC, and the reaction mixture was stirred for further 20 h. Product
3a was isolated in 85% yield (2.25 g) with 97% ee. After a simple recrystallization
(CH2Cl2/petroleum ether = 1:10) the product could be isolated in 65% yield with 99% ee.
S3

To a solution of the product 3a (0.5 mmol, 165.5 mg) in EtOH (3 mL) was added zinc powder (15
equiv, 0.49g), the reaction was heated to 60 oC and HCl (12M, 54 equiv) was added. 15 Minutes
later, the reaction mixture was cooled to room temperature and the solution was made weakly
basic (pH = 8) with NaOH (2M) and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The
combined organic layer was washed once with brine, dried (Mg2SO4) and evaporated to give
yellow oil. Flash silica gel column chromatography (EtOAc/petroleum ether = 1:3) to afford the
product 3aa (138.5 mg, 92% yield) as colorless oil.
6. Crystal data and structure refinement for product 3i
Identification code
Empirical formula
Formula weight
Temperature / K
Crystal system
3i
C18H20BrNO5
410.26
293.0
Orthorhombic
Space group
P212121
Unit cell dimensions
a = 6.4249(4) A alpha = 90.00
b = 13.8112(5) A beta = 90.00
c = 20.5311(8) A gamma = 90.00
Volume / A3
1821.85(15)
Z
4
Caluculated density / mg mm-3
 / mm-1
1.496
2.284
F(000)
840
Crystal size / mm3
Theta range for data collection
Index ranges
0.35 × 0.32 × 0.30
2.95 to 26.37o
-5<=h<=8, -17<=k<=16, -25<=l<=15
7595
Reflections collected
Independent reflections
3708 [R(int) = 0.0247]
S4

Data / restraints / parameters
Goodness-of-fit on F2
Final R indexes [I>2 sigma (I)]
Final R indexes [all data]
Largest diff. peak/hole / e A-3
CCDC
3708 / 0 / 235
1.018
R1 = 0.0473, wR2 = 0.0806
R1 = 0.0825, wR2 = 0.0938
0.302/-0.389
803725
7. Proposed transition state
N
N
O
Bn
O
Bn
N
Bn
O
O
H
H
N
H
Ar
N
H
H
H
N
H
H
H
O
H
H
H
O
H
O
O
O
O
O
O
H
-O
-O
-O
O
N+
O
N+
O
N+
O
H
Ar
O
O
Ar
B
A
C
Si face attack
favorable
Si face attack
disfavorable
Re face attack
disfavorable
O
O
O
O
O
O
5
5
5
OEt
OEt
OEt
H
H
H
6
6
6
Ar
Ar
Ar
NO2
NO2
NO2
(6S)
(6R)
(6S)
We think that the transition A should be more reasonable which gave the (6S)-product as the major.
In transition state B, although the Si face attackment would result in (6S)-product, there was steric
repulsion between the cyclopentene and substituent on nitroolefin. Similarly, transition state C
should also be disfavorable which generated minor (6R)-product for the steric hindrance between
the Ar group of nitroolefin and quinuclidine moiety of the catalysts.
8. Analytical and spectral characterization data for the products
Ethyl 4-hydroxy-7-nitro-6-phenyl-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3a:
white solid; 32.8 mg, 97% yield; [a]D20 = -286.3 (c = 0.40 in CH2Cl2); >99:1 dr,
OH
CO2Et
determined by NMR analysis; 97% ee, determined by HPLC analysis [Daicel
chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t (minor) =
5.13 min, t (major) = 5.56 min]; 1H NMR (400 MHz, CDCl3) δ = 12.55 (s, 1H),
NO2
3a
7.30–7.25 (m, 3H), 7.05–7.01 (m, 2H), 4.62 (dd, J = 12.3, 5.3 Hz, 1H), 4.54 (d, J = 5.3 Hz, 1H),
4.11 (m, 1H), 4.02 (m, 1H), 3.07 (dd, J = 18.3, 9.1 Hz, 1H), 2.88 (m, 1H), 2.41–2.31 (m, 1H),
2.11–2.01 (m, 1H), 1.87–1.77 (m, 1H), 1.64 (m, 2H), 1.42–1.32 (m, 1H), 1.08 (t, J = 7.1 Hz, 3H)
ppm; 13C NMR (101MHz, CDCl3) δ = 173.87, 171.07, 136.89, 128.37, 128.28, 127.87, 97.85,
89.54, 60.91, 44.25, 43.57, 34.49, 31.59, 30.92, 24.76, 13.87 ppm; ESI-HRMS: calcd for
(C18H21NO5+Na+): 354.1312, found: 354.1327.
S5

0.40
0.20
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
Minutes
Retention Time
5.128
Area
% Area
49.11
1
2
3588460
3718230
5.570
50.89
2.00
1.00
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
Minutes
4.00
4.50
5.00
5.50
6. 00
6.50
7.00
Retention Time
5.125
Area
391236
29104452
% Area
1.33
1
2
5.552
98.67
Ethyl 4-hydroxy-7-nitro-6-(o-tolyl)-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3b:
white solid; 22.1 mg, 64% yield; [a]D20 = -305.6 (c = 0.25 in CH2Cl2); >99:1 dr,
determined by NMR analysis; 98% ee, determined by HPLC analysis [Daicel
chiralcel ADH, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t (minor) =
6.88 min, t (major) = 5.93 min]; 1H NMR (400 MHz, CDCl3) δ = 12.47 (s, 1H),
7.16–7.09 (m, 3H), 7.00 (m, 1H), 4.98 (d, J = 5.3, 1H), 4.69 (dd, J = 11.8, 5.3,
1H), 4.18–3.96 (m, 2H), 3.15–3.04 (m, 2H), 2.40–2.32 (m, 1H), 2.29 (s, 3H), 2.06–1.97 (m, 1H),
1.84 (m, 1H), 1.66 (m, 2H), 1.35 (m, 1H), 1.12 (t, J = 7.1, 3H) ppm; 13C NMR (101 MHz, CDCl3)
δ = 173.49, 171.06, 137.46, 135.47, 130.69, 128.22, 127.38, 125.51, 99.13, 88.87, 60.98, 43.57,
38.64, 35.13, 31.66, 30.45, 24.68, 19.13, 13.85 ppm; ESI-HRMS: calcd for (C19H23NO5+Na+):
368.1468, found: 368.1473.
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0.00
1.00
2.00
3.00
4.00
5.00
分钟
6.00
7.00
8.00
9.00
10.00
Retention Time
5.838
Area
% Area
50.07
1
2
435884
434692
6.752
49.93
S6

2.00
0.00
0.00
1.00
2.00
3.00
4.00
5.00
10
6.00
7.00
8.00
9.00
Retention Time
5.931
Area
% Area
99.14
0.86
1
2
39880012
347195
6.877
Ethyl 4-hydroxy-7-nitro-6-(p-tolyl)-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3c:
white solid; 33.8 mg, 98% yield; [a]D20 = -328.1 (c = 0.33 in CH2Cl2); >99:1
dr, determined by NMR analysis; 95% ee, determined by HPLC analysis
[Daicel chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t
(minor) = 4.74 min, t (major) = 5.85 min]; 1H NMR (600 MHz, CDCl3) δ =
12.54 (s, 1H), 7.07 (d, J = 7.9, 2H), 6.91 (d, J = 8.0, 2H), 4.59 (dd, J = 12.4, 5.2, 1H), 4.51 (d, J =
5.2, 1H), 4.13 (m, 1H), 4.00 (m, 1H), 3.05 (dd, J = 18.5, 9.1, 1H), 2.89–2.83 (m, 1H), 2.34 (m,
1H), 2.30 (s, 3H), 2.08–2.02 (m, 1H), 1.81 (m, 1H), 1.67–1.59 (m, 2H), 1.36 (m, 1H), 1.10 (t, J =
7.1, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ = 173.74, 171.12, 137.51, 133.78, 129.09, 128.12,
97.96, 89.64, 60.91, 43.89, 43.55, 34.48, 31.58, 30.92, 24.77, 21.08, 13.90 ppm; ESI-HRMS:
calcd for (C19H23NO5+Na+): 368.1468, found: 368.1486.
2.00
1.50
1.00
0.50
0.00
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4. 50
5.00
5.50
6.00
6.50
7.00
7.50
8.00
8.50
9.00
9.50
10.00
Minutes
Retention Time
4.712
Area
% Area
49.57
1
2
18295905
18613477
5.801
50.43
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4. 50
5.00
5.50
6.00
6.50
7.00
7.50
8.00
8.50
9.00
9.50
10 .00
Minutes
Retention Time
4.740
Area
% Area
2.31
1
2
1103771
5.845
46612431 97.69
S7

Ethyl 4-hydroxy-6-(2-methoxyphenyl)-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3d:
white solid; 28.9 mg, 80% yield; [a]D20 = -321.7 (c = 0.16 in CH2Cl2); >99:1 dr,
OH
CO2Et
determined by NMR analysis ; 96% ee, determined by HPLC analysis [Daicel
chiralcel IA, n-hexane/i-PrOH = 95/5, 1.0 mL/min, λ = 254 nm, t (minor) = 6.86
min, t (major) = 7.42 min]; 1H NMR (600 MHz, CDCl3) δ = 12.52 (s, 1H), 7.23
NO2
MeO
3d
(t, J = 7.7, 1H), 6.97 (d, J = 7.3, 1H), 6.89 (t, J = 7.4, 1H), 6.82 (d, J = 8.2, 1H),
5.16 (d, J = 4.8, 1H), 4.65 (m, 1H), 4.09 (m, 1H), 4.01 (dq, J = 10.8, 7.1, 1H), 3.71 (s, 3H), 3.02
(dd, J = 18.1, 9.0, 1H), 2.84–2.78 (m, 1H), 2.35–2.29 (m, 1H), 1.91 (m, 1H), 1.85–1.77 (m, 1H),
1.66–1.60 (m, 2H), 1.33 (m, 1H), 1.06 (t, J = 7.1, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ =
174.07, 171.12, 158.27, 128.95, 128.72, 125.68, 119.95, 110.50, 98.12, 88.94, 60.76, 55.38, 43.55,
35.83, 31.24, 29.85, 24.57, 13.81 ppm; ESI-HRMS: calcd for (C19H23NO6+Na+): 384.1418, found:
384.1429.
1.00
0.50
0.00
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4. 50
5.00
5.50
6.00
6.50
7.00
7.50
8.00
8.50
9.00
9.50
10.00
Minutes
Retention Time
6.829
Area
% Area
1
2
13980076 49.06
14514890 50.94
7.384
0.30
0.20
0.10
0.00
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4. 50
5.00
5.50
6.00
6.50
7.00
7.50
8.00
8.50
9.00
9.50
10.00
Minutes
Retention Time
6.861
Area
% Area
1.75
1
2
70856
7.418
3974772 98.25
Ethyl 4-hydroxy-6-(3-methoxyphenyl)-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3e:
white solid; 28.9 mg, 80% yield; [a]D20 = -346.2 (c = 0.24 in CH2Cl2); 98:2 dr,
determined by HPLC analysis; 96% ee, determined by HPLC analysis [Daicel
chiralcel IA, n-hexane/i-PrOH = 95/5, 1.0 mL/min, λ = 254 nm, t (minor) =
6.76 min, t (major) = 7.37 min]; 1H NMR (600 MHz, CDCl3) δ = 12.54 (s, 1H),
7.19 (t, J = 7.9, 1H), 6.79 (dd, J = 8.2, 2.2, 1H), 6.62 (d, J = 7.7, 1H), 6.57 (s,
OH
CO2Et
NO2
3e
OMe
1H), 4.59 (dd, J = 12.4, 5.3, 1H), 4.52 (d, J = 5.3, 1H), 4.13 (m, 1H), 4.05–3.99 (m, 1H), 3.77 (s,
3H), 3.06 (dd, J = 18.4, 9.1, 1H), 2.92–2.86 (m, 1H), 2.34 (m, 1H), 2.09–2.03 (m, 1H), 1.84–1.78
(m, 1H), 1.67–1.59 (m, 2H), 1.36 (m, 1H), 1.10 (t, J = 7.1, 3H) ppm; 13C NMR (151 MHz, CDCl3)
δ = 173.87, 171.04, 159.43, 138.54, 129.32, 120.81, 114.58, 112.54, 97.82, 89.49, 60.92, 55.16,
S8

44.21, 43.54, 34.52, 31.57, 30.98, 24.78, 13.91 ppm; ESI-HRMS: calcd for (C19H23NO6+Na+):
384.1418, found: 384.1419.
1.00
0.80
0.60
0.40
0.20
0.00
1.00
2.00
3.00
4.00
5.0 0
6.00
7.0 0
8 .00
Minutes
9.00
10 .0
0
11.0 0
12.00
13.00
14.00
15 .00
Retention Time
6.757
Area
% Area
49.11
49.72
0.61
1
2
3
4
11839213
11987930
147341
7.385
12.903
13.447
135120
0.56
3.00
2.00
1.00
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
10.00
11.00
12.00
13.00
14 .00
15 .00
Minutes
Retention Time
6.763
Area
1313412
% Area
1.95
1
2
3
4
7.373
64557144
750070
95.63
1.11
12.886
13.464
883998
1.31
Ethyl 6-([1,1,-biphenyl]-4-yl)-4-hydroxy-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3f:
white solid; 36.5 mg, 95% yield; [a]D20 = -231.2 (c = 0.52 in CH2Cl2); >99:1
dr; 96% ee, determined by HPLC analysis [Daicel chiralcel IA,
n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t (minor) = 6.26 min, t
(major) = 7.66 min]; 1H NMR (600 MHz, CDCl3) δ = 12.57 (s, 1H), 7.56 (d,
OH
CO2Et
NO2
3f
Ph
J = 7.4, 2H), 7.50 (d, J = 8.1, 2H), 7.42 (t, J = 7.6, 2H), 7.33 (t, J = 7.4, 1H), 7.09 (d, J = 8.1, 2H),
4.64 (dd, J = 12.3, 5.2, 1H), 4.59 (d, J = 5.2, 1H), 4.14 (m, 1H), 4.03 (m, 1H), 3.09 (dd, J = 18.2,
9.1, 1H), 2.95–2.89 (m, 1H), 2.40–2.33 (m, 1H), 2.11–2.04 (m, 1H), 1.82 (m, 1H), 1.68–1.60 (m,
2H), 1.43–1.35 (m, 1H), 1.10 (t, J = 7.1, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ = 173.92,
171.08, 140.60, 140.48, 135.95, 128.76, 128.73, 127.36, 127.04, 127.02, 97.87, 89.56, 60.99,
43.96, 43.61, 34.56, 31.61, 30.99, 24.79, 13.92 ppm; ESI-HRMS: calcd for (C24H25NO5+Na+):
430.1625, found: 430.1642.
S9

3 .0 0
2 .5 0
2 .0 0
1 .5 0
1 .0 0
0 .5 0
0 .0 0
1 .0 0
2 .0 0
3 .0 0
4 .0 0
5 .0 0
6 .0 0
7 .0 0
8 .0 0
9 .0 0
1 0 .0 0
M in u te s
Retention Time
6.193
Area
% Area
1
2
38022026 48.13
40971135 51.87
7.568
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
分钟
Retention Time
6.265
Area
1420278
% Area
1.89
1
2
7.655
73528686 98.11
Ethyl 6-(4-fluorophenyl)-4-hydroxy-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3g:
white solid; 33.3 mg, 95% yield; [a]D20 = -214.4 (c = 0.36 in CH2Cl2); >99:1
dr, determined by NMR analysis; 97% ee, determined by HPLC analysis
[Daicel chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t
OH
CO2Et
NO2
1
3g
F
(minor) = 5.29 min, t (major) = 6.36 min]; H NMR (600 MHz, CDCl3) δ =
12.53 (s, 1H), 6.98 (m, 4H), 4.60 (dd, J = 12.4, 5.3, 1H), 4.53 (d, J = 5.3, 1H), 4.15–4.01 (m, 2H),
3.05 (dd, J = 18.4, 9.1, 1H), 2.87–2.81 (m, 1H), 2.34 (m, 1H), 2.06 (m, 1H), 1.86–1.79 (m, 1H),
1.69–1.59 (m, 2H), 1.41–1.34 (m, 1H), 1.08 (t, J = 7.1, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ
= 173.87, 170.93, 132.73, 132.70, 129.85, 129.77, 115.44, 115.22, 97.76, 89.36, 60.97, 43.52,
43.50, 34.39, 31.56, 30.86, 24.67, 13.87 ppm; ESI-HRMS: calcd for (C18H20FNO5+Na+):
372.1218, found: 372.1229.
1.00
0.50
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
Minutes
Retention Time
5.272
Area
% Area
1
2
11303651
10846650
51.03
48.97
6.356
S10

2.00
1.00
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
Minutes
Retention Time
5.294
Area
495562
31914258
% Area
1
2
1.53
6.356
98.47
Ethyl 6-(4-chorophenyl)-4-hydroxy-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3h:
20
OH
yellow oil; 35.0 mg, 96% yield; [a]D = -209.5 (c = 0.43 in CH2Cl2); >99:1
dr, determined by NMR analysis; 96% ee, determined by HPLC analysis
[Daicel chiralcel IA, n-hexane/i-PrOH = 95/5, 1.0 mL/min, λ = 254 nm, t
CO2Et
NO2
1
3h
Cl (minor) = 5.40 min, t (major) = 6.91 min]; H NMR (600 MHz, CDCl3) δ =
12.54 (s, 1H), 7.25 (d, J = 8.4, 2H), 6.97 (d, J = 8.4, 2H), 4.61 (dd, J = 12.5, 5.3, 1H), 4.51 (d, J =
5.3, 1H), 4.15–4.00 (m, 2H), 3.05 (dd, J = 18.5, 9.0, 1H), 2.86–2.79 (m, 1H), 2.34 (m, 1H), 2.06
(m, 1H), 1.85–1.79 (m, 1H), 1.64 (m, 2H), 1.41–1.34 (m, 1H), 1.09 (t, J = 7.1, 3H) ppm; 13C NMR
(101 MHz, CDCl3) δ = 174.02, 170.87, 135.55, 133.82, 129.58, 128.61, 97.57, 89.26, 61.03, 43.64,
43.51, 34.42, 31.55, 30.87, 24.68, 13.89 ppm; ESI-HRMS: calcd for (C18H20ClNO5+Na+):
388.0922, found: 388.0934.
0.80
0.60
0.40
0.20
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
Minutes
Retention Time
5.398
Area
% Area
1
2
7763640 50.37
7649710 49.63
6.958
3.00
2.00
1.00
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
Minutes
Retention Time
5.402
Area
1036321
% Area
2.08
1
2
6.910
48807252 97.92
S11

(3aS,6R,7S,7aR)-ethyl
6-(4-bromophenyl)-4-hydroxy-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3i:
20
OH
yellow oil; 34.8 mg, 85% yield; [a]D = -197.1 (c = 0.63 in CH2Cl2); >99:1
H
CO2Et
dr, determined by NMR analysis; 96% ee, determined by HPLC analysis
[Daicel chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t
(minor) = 5.25 min, t (major) = 6.86 min]; 1H NMR (400 MHz, CDCl3) δ =
H
NO2
3i
Br
12.54 (s, 1H), 7.40 (d, J = 8.3, 2H), 6.91 (d, J = 8.3, 2H), 4.61 (dd, J = 12.4, 5.3, 1H), 4.50 (d, J =
5.3, 1H), 4.17–3.98 (m, 2H), 3.05 (dd, J = 18.4, 9.0, 1H), 2.87–2.77 (m, 1H), 2.34 (m, 1H),
2.11–2.05 (m, 1H), 1.82 (m, 1H), 1.67–1.51 (m, 2H), 1.37 (m, 1H), 1.09 (t, J = 7.1, 3H) ppm; 13C
NMR (101 MHz, CDCl3) δ = 174.05, 170.85, 136.08, 131.57, 129.93, 122.02, 97.46, 89.20, 61.05,
43.71, 43.52, 34.43, 31.56, 30.88, 24.69, 13.90 ppm; ESI-HRMS: calcd for (C18H20BrNO5+Na+):
432.0417, found: 432.0433.
1.80
1.60
1.40
1.20
1.00
0.80
0.60
0.40
0.20
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6. 00
6.50
7.00
7.50
8.00
8.50
9.00
Minutes
Retention Time
5.283
Area
% Area
1
2
20247158 50.70
19687684 49.30
6.942
3 .0 0
2 .5 0
2 .0 0
1 .5 0
1 .0 0
0 .5 0
0 .0 0
0 .5 0
1 .0 0
1 .5 0
2 .0 0
2 .5 0
3 .0 0
3 .5 0
4 .0 0
4 .5 0
5 .0 0
5 .5 0
6. 0 0
6 .5 0
7 .0 0
7 .5 0
8 .0 0
8 .5 0
9 .0 0
Min u te s
Retention Time
5.250
Area
% Area
1.79
1
2
1016285
6.858
55632413 98.21
Ethyl 6-(4-cyanophenyl)-4-hydroxy-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3j:
white solid; 24.9 mg, 70% yield; [a]D20 = -236.5 (c = 0.40 in CH2Cl2); 89:11
dr, determined by NMR analysis; 97% ee, determined by HPLC analysis
[Daicel chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t
(minor) = 8.94 min, t (major) = 15.10 min]; 1H NMR (400 MHz, CDCl3) δ
OH
CO2Et
NO2
3j
CN
= 12.56 (s, 1H), 7.58 (d, J = 8.2, 2H), 7.16 (d, J = 8.2, 2H), 4.66 (dd, J = 12.4, 5.4, 1H), 4.58 (d, J
= 5.4, 1H), 4.15–3.99 (m, 2H), 3.07 (dd, J = 18.5, 8.9, 1H), 2.85–2.76 (m, 1H), 2.36 (m, 1H),
2.12–2.02 (m, 1H), 1.88–1.80 (m, 1H), 1.72–1.60 (m, 2H), 1.42–1.34 (m, 1H), 1.07 (t, J = 7.1, 3H)
ppm; 13C NMR (101 MHz, CDCl3) δ = 174.49, 170.59, 142.70, 132.59, 132.23, 129.11, 118.49,
111.97, 96.87, 88.99, 61.16, 44.19, 43.54, 34.53, 31.54, 30.82, 24.61, 13.88 ppm; ESI-HRMS:
S12

calcd for (C19H20N2O5+Na+): 379.1264, found: 379.1263.
0.80
0.60
0.40
0.20
0.00
1.00
2.00
3. 00
4.00
5.00
6.00
7.00
8. 00
9.00
10.00
11.00
12.00
13 .00
14.0 0
15.00
16 .00
17.00
18 .00
Minutes
Retention Time
8.939
Area
% Area
1
2
17122181 49.83
17241994 50.17
15.403
2.00
1.50
1.00
0.50
0.00
1.00
2.00
3. 00
4.00
5.00
6.00
7.00
8. 00
9.00
10.00
11.00
12.00
13.00
14.00
15.00
16.00
17.00
18 .00
Minutes
Retention Time
8.939
Area
% Area
1.43
1
2
977971
15.109
67473341 98.57
Ethyl6-(4-fluoro-3-phenoxyphenyl)-4-hydroxy-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3k:
20
OH
yellow oil; 37.9 mg, 86% yield; [a]D = -185.0 (c = 0.4 in CH2Cl2); >99:1
CO2Et
dr, determined by NMR analysis; 97% ee, determined by HPLC analysis
OPh
[Daicel chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t
(minor) = 5.41 min, t (major) = 6.94 min]; 1H NMR (600 MHz, CDCl3) δ =
NO2
3k
F
12.50 (s, 1H), 7.33 (t, J = 8.0, 2H), 7.09 (m, 2H), 6.92 (d, J = 8.0, 2H), 6.83–6.78 (m, 1H), 6.76 (m,
1H), 4.57 (dd, J = 12.4, 5.3, 1H), 4.46 (d, J = 5.3, 1H), 4.15–4.05 (m, 2H), 2.95 (dd, J = 18.4, 9.1,
1H), 2.87–2.79 (m, 1H), 2.32 (m, 1H), 2.06 (m, 1H), 1.85–1.78 (m, 1H), 1.66–1.56 (m, 2H),
1.42–1.34 (m, 1H), 1.11 (t, J = 7.1, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ = 173.97, 170.82,
157.35, 155.17, 152.69, 143.21, 143.09, 133.98, 129.70, 124.55, 123.11, 122.15, 117.06, 116.83,
97.41, 89.17, 61.01, 43.56, 43.37, 34.44, 31.51, 30.84, 24.61, 13.93 ppm; ESI-HRMS: calcd for
(C24H24FNO6+Na+): 464.1480, found: 464.1488.
0.30
0.20
0.10
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
8.00
Minutes
Retention Time
5.424
Area
% Area
50.38
1
2
3169603
3122215
6.957
49.62
S13

2.00
1.00
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
8.00
Minutes
Retention Time
5.415
Area
% Area
1.78
1
2
489316
26970571
6.943
98.22
(E)-ethyl 4-hydroxy-7-nitro-6-styryl-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3l:
yellow oil; 21.4 mg, 60% yield; [a]D20 = -365.8 (c = 0.26 in CH2Cl2); >99:1 dr,
determined by NMR analysis; 97% ee, determined by HPLC analysis [Daicel
chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t (minor) =
5.37 min, t (major) = 6.06 min]; 1H NMR (600 MHz, CDCl3) δ = 12.55 (s, 1H),
OH
CO2Et
Ph
NO2
3l
7.32–7.27 (m, 4H), 7.24–7.20 (m, 1H), 6.37 (d, J = 15.6, 1H), 5.94 (dd, J = 15.6, 8.1, 1H), 4.49
(dd, J = 12.3, 4.9, 1H), 4.25–4.19 (m, 2H), 4.09 (dd, J = 8.0, 4.9, 1H), 3.10–3.04 (m, 1H), 2.96
(dd, J = 18.2, 9.5, 1H), 2.32–2.26 (m, 1H), 2.13 (m, 1H), 1.84–1.78 (m, 1H), 1.68–1.54 (m, 2H),
1.44 (m, 1H), 1.27 (t, J = 7.1, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ = 173.80, 171.22,
136.52, 133.88, 128.54, 127.82, 126.54, 124.50, 96.80, 89.17, 60.99, 43.19, 41.64, 35.33, 31.38,
31.07, 24.66, 14.18 ppm; ESI-HRMS: calcd for (C20H23NO5+Na+): 380.1468, found: 380.1462.
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
8. 00
8. 50
9. 00
9. 50
10 .00
Minutes
Retention Time
5.401
Area
% Area
48.48
1
2
35561245
37788729
6.092
51.52
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
0.50
1.00
1.50
2 .00
2.50
3.00
3.5 0
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7 .50
8. 00
8. 50
9. 0 0
9. 50
10 .00
Minutes
Retention Time
5.371
Area
733165
% Area
1.61
1
2
6.063
44823018 98.39
S14

Ethyl 6-(benzo[d][1,3]dioxol-5-yl)-4-hydroxy-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3m:
20
OH
white solid; 24.8 mg, 66% yield; [a]D = -310.5 (c = 0.36 in CH2Cl2);
CO2Et
>99:1 dr, determined by NMR analysis; 98% ee, determined by HPLC
O
analysis [Daicel chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ =
NO2
1
3m
O
254 nm, t (minor) = 6.91 min, t (major) = 8.28 min]; H NMR (600 MHz,
CDCl3) δ = 12.52 (s, 1H), 6.70 (d, J = 7.9, 1H), 6.50 (m, 2H), 5.95–5.93 (m, 2H), 4.56 (dd, J =
12.4, 5.2, 1H), 4.46 (d, J = 5.2, 1H), 4.17–4.12 (m, 1H), 4.04 (m, 1H), 3.04 (dd, J = 18.8, 8.9, 1H),
2.92–2.86 (m, 1H), 2.37–2.31 (m, 1H), 2.07 (m, 1H), 1.85–1.78 (m, 1H), 1.66–1.56 (m, 2H),
1.41–1.34 (m, 1H), 1.12 (t, J = 7.1, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ = 173.69, 171.02,
147.65, 147.23, 130.68, 121.81, 108.45, 108.13, 101.13, 98.00, 89.57, 60.92, 43.98, 43.48, 34.46,
31.57, 30.95, 24.71, 13.93 ppm; ESI-HRMS: calcd for (C19H21NO7+Na+): 398.1210, found:
398.1217.
0.80
0.60
0.40
0.20
0.00
0.00
1.00
2.00
3.00
4.00
5.00
分钟
6.00
7.00
8.00
9.00
10.00
Retention Time
6.962
Area
% Area
49.99
1
2
11099934
11105143
8.307
50.01
3.00
2.50
2.00
1.50
1.00
0.50
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
8. 00
8. 50
9. 00
9. 50
10 .00
Minutes
Retention Time
6.910
Area
506239
46094698
% Area
1.09
1
2
8.283
98.91
Ethyl 4-hydroxy-6-(naphthalen-1-yl)- 7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3n:
20
OH
white solid; 27.8 mg, 73% yield; [a]D = -332.0 (c = 0.24 in CH2Cl2); >99:1 dr,
determined by NMR analysis; 95% ee, determined by HPLC analysis [Daicel
chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t (minor) = 7.89
CO2Et
NO2
3n
1
min, t (major) = 7.07 min]; H NMR (400 MHz, CDCl3) δ = 12.47 (s, 1H), 8.10
(d, J = 8.3, 1H), 7.82 (d, J = 7.6, 1H), 7.76 (d, J = 8.2, 1H), 7.45 (m, 3H), 7.23 (d,
J = 7.2, 1H), 5.64 (d, J = 5.3, 1H), 4.82 (dd, J = 12.2, 5.3, 1H), 4.00 (m, 1H), 3.81 (m, 1H), 3.18
(dd, J = 18.0, 8.4, 1H), 3.12–3.04 (m, 1H), 2.45–2.34 (m, 1H), 2.07–1.96 (m, 1H), 1.91–1.80 (m,
1H), 1.68 (m, 2H), 1.35 (m, 1H), 0.79 (t, J = 7.1, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ =
173.59, 171.00, 133.70, 133.55, 132.55, 128.70, 128.42, 126.31, 126.14, 125.73, 124.53, 122.12,
99.31, 88.73, 60.83, 43.59, 37.33, 35.28, 31.58, 30.40, 24.71, 13.56 ppm; ESI-HRMS: calcd for
S15

(C22H23NO5+Na+): 404.1468, found: 404.1474.
0.20
0.10
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
8.00
8.50
9.00
9.50
10.00
Minutes
Retention Time
6.393
Area
% Area
6.34
1
2
3
4
392398
2610672
392299
7.078
42.18
6.34
7.557
7.893
2793925
45.14
0.80
0.60
0.40
0.20
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
8.00
8.50
9.00
9.50
10.00
Minutes
Retention Time
7.070
Area
% Area
98.97
1.03
1
2
9048374
93962
7.890
Ethyl 4-hydroxy-6-(naphthalen-2-yl)- 7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3o:
20
OH
white solid; 37.7 mg, 99% yield; [a]D = -284.9 (c = 0.47 in CH2Cl2);
>99:1 dr, determined by NMR analysis; 95% ee, determined by HPLC
analysis [Daicel chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ =
CO2Et
NO2
1
3o
254 nm, t (minor) = 5.62 min, t (major) = 7.55 min]; H NMR (600 MHz,
CDCl3) δ = 12.62 (s, 1H), 7.79 (m, 2H), 7.75 (d, J = 8.5, 1H), 7.50 – 7.43 (m, 3H), 7.15 (d, J = 8.4,
1H), 4.73 (d, J = 5.2, 1H), 4.68 (dd, J = 12.3, 5.3, 1H), 4.12 (m, 1H), 3.98–3.91 (m, 1H), 3.15 (dd,
J = 18.1, 9.2, 1H), 2.97–2.90 (m, 1H), 2.38 (m, 1H), 2.05 (m, 1H), 1.87–1.79 (m, 1H), 1.69–1.60
(m, 2H), 1.37 (m, 1H), 1.04 (t, J = 7.1, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ = 174.02, 171.12,
134.53, 133.14, 132.98, 128.13, 128.01, 127.64, 127.40, 126.25, 126.18, 126.06, 97.95, 89.58,
60.98, 44.34, 43.68, 34.63, 31.63, 30.96, 24.79, 13.88 ppm; ESI-HRMS: calcd for
(C22H23NO5+Na+): 404.1468, found: 404.1478.
3 .5 0
3 .0 0
2 .5 0
2 .0 0
1 .5 0
1 .0 0
0 .5 0
0 .0 0
1 .0 0
2 .0 0
3 .0 0
4 .0 0
5 .0 0
6 .0 0
7 .0 0
8 .0 0
9 .0 0
1 0 .0 0
M in u te s
S16

Retention Time
5.585
Area
% Area
48.81
1
2
34101810
35759883
7.511
51.19
3.00
2.50
2.00
1.50
1.00
0.50
0.00
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
分钟
Retention Time
5.625
Area
% Area
2.52
1
2
1170484
45250162
7.551
97.48
Ethyl 6-(furan-2-yl)-4-hydroxy-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3p:
20
OH
yellow oil; 25.7 mg, 80% yield; [a]D = -204.8 (c = 0.40 in CH2Cl2); >99:1 dr,
determined by NMR analysis; 96% ee, determined by HPLC analysis [Daicel
chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t (minor) =
5.49 min, t (major) = 6.05 min]; 1H NMR (600 MHz, CDCl3) δ = 12.53 (s, 1H),
CO2Et
O
NO2
3p
7.31 (s, 1H), 6.27 (s, 1H), 6.05 (d, J = 3.1, 1H), 4.68 (d, J = 4.8, 1H), 4.50 (dd, J = 11.9, 4.8, 1H),
4.21–4.11 (m, 2H), 3.06 (dd, J = 18.0, 9.6, 1H), 3.02–2.98 (m, 1H), 2.30 (m, 1H), 2.10 (m, 1H),
1.84–1.76 (m, 1H), 1.68–1.55 (m, 2H), 1.39 (m, 1H), 1.20 (t, J = 7.1, 3H) ppm; 13C NMR (151
MHz, CDCl3) δ = 174.56, 170.86, 150.75, 142.77, 110.32, 108.76, 95.77, 88.47, 61.02, 43.24,
38.33, 35.65, 31.30, 31.16, 24.88, 14.03 ppm; ESI-HRMS: calcd for (C16H19NO6+Na+): 344.1105,
found: 344.1113.
0.40
0.20
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
Minutes
Retention Time
5.483
Area
% Area
1
2
4998749 49.00
5202464 51.00
6.059
1.50
1.00
0.50
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
Minutes
Retention Time
5.486
Area
200571
% Area
1.11
1
2
6.051
17830577 98.89
S17

Ethyl 4-hydroxy-7-nitro-6-(thiophen-2-yl)-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3q:
colorless oil; 24.3 mg, 72% yield; [a]D20 = -277.6 (c = 0.33 in CH2Cl2); >99:1 dr,
OH
CO2Et
determined by NMR analysis; 97% ee, determined by HPLC analysis [Daicel
S
chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t (minor) =
5.31 min, t (major) = 6.09 min]; 1H NMR (400 MHz, CDCl3) δ = 12.53 (s, 1H),
NO2
3q
7.18 (d, J = 5.1, 1H), 6.95–6.91 (m, 1H), 6.73 (d, J = 3.4, 1H), 4.87 (d, J = 4.9, 1H), 4.56 (dd, J =
11.8, 5.0, 1H), 4.21–4.06 (m, 2H), 3.11–2.95 (m, 2H), 2.37–2.27 (m, 1H), 2.13 (m, 1H), 1.85 (m,
1H), 1.70–1.51 (m, 2H), 1.43–1.33 (m, 1H), 1.15 (t, J = 7.1, 3H) ppm; 13C NMR (101 MHz,
CDCl3) δ = 173.78, 170.88, 140.99, 127.32, 126.20, 125.10, 99.02, 89.45, 61.07, 43.21, 39.67,
34.75, 31.49, 31.31, 24.94, 13.96 ppm; ESI-HRMS: calcd for (C16H19NO5S+Na+): 360.0876,
found: 360.0885.
1.60
1.40
1.20
1.00
0.80
0.60
0.40
0.20
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6. 00
6.50
7.00
7.50
8.00
8.50
9.00
Minutes
Retention Time
5.289
Area
% Area
1
2
14904222 49.33
15310359 50.67
6.058
3.00
2.50
2.00
1.50
1.00
0.50
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6. 00
6.50
7.00
7.50
8.00
8.50
9.00
Minutes
Retention Time
5.309
Area
% Area
1.47
1
2
577550
6.088
38746424 98.53
Ethyl 6-cyclohexyl-4-hydroxy-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3r:
20
OH
white soild; 20.9 mg, 62% yield; [a]D = 51.7 (c = 0.41 in CH2Cl2); 99:1 dr,
determined by HPLC analysis; 99% ee, determined by HPLC analysis [Daicel
chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t (minor) =
5.78 min, t (major) = 7.29 min]; 1H NMR (600 MHz, CDCl3) δ = 12.77 (s, 1H),
CO2Et
NO2
3r
5.04 (dd, J = 7.2, 4.2, 1H), 4.30–4.21 (m, 1H), 4.16–4.08 (m, 1H), 3.16 (dd, J = 13.2, 4.2, 1H),
2.82–2.67 (m, 2H), 2.15 (dt, J = 13.1, 6.6, 1H), 2.00–1.84 (m, 4H), 1.77–1.73 (m, 4H), 1.67 (m,
2H), 1.51–1.45 (m, 2H), 1.28 (t, J = 7.1, 3H), 1.20–1.00 (m, 4H) ppm; 13C NMR (101 MHz,
CDCl3) δ = 175.48, 172.35, 95.45, 84.90, 60.53, 44.71, 42.19, 40.92, 36.52, 31.08, 30.70, 29.91,
27.91, 26.53, 26.28, 26.22, 25.87, 14.18 ppm; ESI-HRMS: calcd for (C18H27NO5+Na+): 360.1781,
found: 360.1789.
S18

0.80
0.60
0.40
0.20
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
10.00
Minutes
Retention Time
4.404
Area
% Area
1
2
3
4
245167
260974
1.14
1.21
4.787
5.820
9929175 46.01
11147286 51.65
7.497
3.00
2.00
1.00
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
8.00
8.50
9.00
9.50
10.00
Minutes
3.00
2.00
1.00
0.00
5.60
5.80
6.00
6.20
6.40
6.60
6.80
7.00
7.20
7.40
7.60
7.80
8.00
8.20
8.40
8.60
8.80
9.00
Minutes
Retention Time
4.379
Area
% Area
0.94
1
2
3
4
451719
4683
4.778
0.01
5.778
240981
0.50
7.285
47275366 98.55
Ethyl 4-hydroxy-6-isopropyl-7-nitro-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate 3s:
20
OH
white solid; 14.8 mg, 50% yield; [a]D = 71.5 (c = 0.13 in CH2Cl2); 97:3 dr,
determined by HPLC analysis; 99% ee, determined by HPLC analysis [Daicel
chiralcel ADH, n-hexane/i-PrOH = 95/5, 1.0 mL/min, λ = 254 nm, t (minor) =
5.97 min, t (major) = 5.18 min]; 1H NMR (600 MHz, CDCl3) δ = 12.78 (s, 1H),
CO2Et
NO2
3s
5.02 (dd, J = 5.3, 3.0, 1H), 4.29–4.24 (m, 1H), 4.12 (m, 1H), 3.12 (dd, J = 8.9, 2.9, 1H), 2.78 (m,
1H), 2.74–2.68 (m, 1H), 2.14 (m, 1H), 2.01–1.94 (m, 2H), 1.89–1.84 (m,1H), 1.66 (m, 1H),
1.55–1.44 (m, 2H), 1.28 (t, J = 7.1, 3H), 1.00 (d, J = 6.7, 3H), 0.94 (d, J = 6.8, 3H) ppm; 13C NMR
(150 MHz, CDCl3): δ = 175.40, 172.30, 95.82, 85.09, 60.54, 45.54, 40.99, 36.70, 32.45, 29.89,
27.87, 25.71, 20.88, 20.17, 14.15 ppm; ESI-HRMS: calcd for (C15H23NO5+Na+): 320.1468, found:
320.1474.
S19

1.00
0.50
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6. 00
6.50
7.00
Minutes
Retention Time
4.609
Area
% Area
0.54
1
2
3
4
126638
114974
4.726
0.49
5.186
11560663 49.39
11606759 49.58
5.974
3.00
2.00
1.00
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6. 00
6.50
7.00
Minutes
3.00
2.00
1.00
0.00
5.00
5.10
5.20
5.30
5.40
5.50
5.60
5.70
5.80
5.90
6.00
6.10
6.20
Minutes
Retention Time
4.742
Area
% Area
2.77
1
2
3
898891
5.182
31453900 96.83
132096 0.41
5.975
Ethyl 7-amino-4-oxo-6-phenyloctahydro-1H-indene-5-carboxylate 3aa:
colorless oil; 25.7 mg, 92% yield; [a]D20 = -141.7 (c = 1.5 in CH2Cl2); >99:1 dr,
determined by NMR analysis; 99% ee, determined by HPLC analysis [Daicel
chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, t (minor) =
6.08 min, t (major) = 6.82 min]; 1H NMR (600 MHz, CDCl3) δ = 12.49 (s, 1H),
7.29 (t, J = 7.2, 2H), 7.22 (t, J = 7.2, 1H), 7.16 (d, J = 7.2, 2H), 4.10–4.05 (m,
OH
CO2Et
NH2
3aa
1H), 4.01–3.95 (m, 1H), 3.87 (d, J = 4.8, 1H), 2.89 (dd, J = 8.0, 2.4, 1H), 2.77 (dd, J = 8.0, 5.4,
1H), 2.29–2.26 (m, 1H), 1.95–1.90 (m, 1H), 1.87–1.83 (m, 1H), 1.84–1.77 (m, 1H), 1.63–1.51 (m,
3H), 1.17–1.35 (br, 2H), 1.08 (t, J = 7.2, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ = 174.75,
172.01, 139.81, 129.64, 128.73, 127.83, 127.64, 126.61, 100.29, 60.29, 53.27, 46.96, 44.28, 40.39,
31.29, 30.08, 24.96, 13.92. ESI-HRMS: calcd for (C18H23NO3+H+): 302.1751, found: 302.1754.
S20

1900
1557
1214
871
528
185
-158
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
10.00
Minutes
Retention Time
6.01
Area
% Area
1
2
14034.23
15431.39
47.6292
52.3708
6.83
2149
1761
1373
985
597
209
-179
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
10.00
[Minutes]
Retention Time
6.08
Area
% Area
0.3107
1
2
132.26
6.82
42433.84
99.6893
Ethyl 2-(cyclopent-1-enecarbonyl)-4-nitro-3-phenylbutanoate 5a:
white solid; 32.8 mg, 99% yield; 81:19 dr, determined by NMR analysis;
98% ee ( minor 92% ee), determined by HPLC analysis [Daicel chiralcel IA,
n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, major diastereomer: t
(minor) = 16.28 min, t (major) = 14.47 min; minor diastereomer: t (minor) =
21.41 min, t (major) = 8.67 min]; 1H NMR (600 MHz, CDCl3) δ = 7.32–7.16
O
O
OEt
Ph
NO2
5a
(m, 5H), 6.85–6.78 (m, 1H), 4.89 (m, 2H), 4.51 (d, J = 9.5, 1H), 4.32–4.26 (td, J = 9.4, 4.7, 1H),
4.19 (q, J = 7.1, 2H), 2.64–2.56 (m, 1H), 2.56–2.46 (m, 1H), 2.45–2.37 (m, 1H), 2.33–2.26 (m,
1H), 1.88–1.76 (m, 2H), 1.24 (t, J = 7.1, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ = (190.40,
190.33, 1C), (167.93, 167.32, 1C), (147.90, 1C), (146.70, 1C), (145.15, 145.11, 2C), (136.82,
136.45, 2C), (128.88, 128.82, 2C), (128.21, 128.04, 1C), (77.91, 77.86, 1C), (62.02, 61.75, 1C),
(57.66, 57.26, 1C), (43.14, 42.85, 1C), (34.39, 34.16, 1C), (30.74, 30.57, 1C), 22.54, (13.98, 13.65,
1C) ppm; ESI-HRMS: calcd for (C18H21NO5+Na+): 354.1312, found: 354.1310.
0.20
0.10
0.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
26.00
Minutes
Retention Time
8.774
Area
% Area
27.64
1
4171425
S21

2
3
4
14.854
15.937
22.049
3178286
3596360
4144206
21.06
23.83
27.46
1.00
0.50
0.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
26.00
Minutes
Retention Time
8.668
Area
3758571
31454265
20492
% Area
10.60
88.73
0.06
1
2
3
4
14.469
16.283
21.406
217669
0.61
HPLC spectra of 5a catalyzed by 4e (Daicel chiralcel IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min,
λ = 254 nm):
0.60
0.40
0.20
0.00
6.00
7.00
8.00
9.00
10.00
11.00
12.00
13.00
14.00
15.00
16.00
17.00
18.00
19.00
20.00
21.00
22.00
23.00
24.00
25.00
26.00
Minutes
Retention Time
8.891
Area
% Area
2.11
1
2
3
4
464867
509709
15.106
2.32
16.199
18467603
2547953
83.98
11.59
22.446
HPLC spectra of racemic 3a catalyzed by TMG (Daicel chiralcel IA, n-hexane/i-PrOH = 95/5, 1.0
mL/min,λ=254nm):
2.00
1.50
1.00
0.50
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
分钟
Retention Time
5.958
Area
% Area
1
2
24006699
24695633
49.29
50.71
6.604
HPLC spectra of 3a catalyzed by 4e (Daicel chiralcel IA, n-hexane/i-PrOH = 95/5, 1.0 mL/min,
S22

λ=254nm):
2.00
1.00
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
8.00
分钟
Retention Time
5.947
Area
% Area
97.26
2.74
1
2
23365394
657571
6.612
HPLC spectra of 3a catalyzed by 4d (Daicel chiralcel IA, n-hexane/i-PrOH = 95/5, 1.0 mL/min,
λ=254nm):
2.00
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
分钟
Retention Time
5.964
Area
649942
34558793
% Area
1
2
1.85
6.598
98.15
Ethyl 2-hydroxy-5-nitro-4,6-diphenylcyclohex-1-enecarboxylate 3ta:4
yellow oil; 29.7 mg, 75% yield; 68:32 dr, determined by HPLC analysis; 92%
ee ( minor 92% ee), determined by HPLC analysis [Daicel chiralcel ODH,
n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 254 nm, major diastereomer: t
(minor) = 13.14 min, t (major) = 15.70 min; minor diastereomer: t (minor) =
OH
CO2Et
Ph
Ph
3ta
NO2
1
9.13 min, t (major) = 6.15 min]; major diastereomer: H NMR (400 MHz,
CDCl3) δ = 12.48 (s, 1H), 7.36–7.10 (m, 10H), 5.30 (dd, J = 12.4, 5.6, 1H), 4.64 (d, J = 5.6, 1H),
4.12–3.99 (m, 2H), 3.68–3.58 (m, 1H), 2.98 (dd, J = 19.6, 7.2, 1H), 2.64 (dd, J = 19.2, 11.2, 1H),
1
1.04 (t, J = 7.2, 3H) ppm; minor diastereomer: H NMR (400 MHz, CDCl3) δ = 12.71 (s, 1H),
7.35–7.23 (m, 8H), 7.05 (d, J = 6.8, 2H), 4.95–4.92 (m, 1H), 4.55 (s, 1H), 4.10–3.97 (m, 2H), 3.43
(m, 1H), 3.32 (dd, J = 18.4, 12.0, 1H), 2.78 (dd, J = 18.4, 6.4, 1H), 0.97 (t, J = 7.2, 3H) ppm.
0 .8 0
0 .6 0
0 .4 0
0 .2 0
0 .0 0
2
.0 0
4 .0 0
6 . 0 0
8 .0 0
1 0 .0 0
1 2 .00
1 4 .00
1 6 .00
1 8 .00
2 0 .0 0
?
?
Retention Time
Area
% Area
S23

1
2
3
4
6.191
8.791
10665536
10563902
20742785
20712773
17.01
16.85
33.09
33.04
12.695
15.736
2
1
1
1
1
1
0
0
0
0
0
. 0
. 8
. 6
. 4
. 2
. 0
. 8
. 6
. 4
. 2
. 0
0
0
0
0
0
0
0
0
0
0
0
2
. 0
0
4
. 0
0
6
. 0
0
8
. 0
0
1
0
. 0
?
0
1
2
. 0 0
1
4
. 0 0
1
6
. 0 0
1
8
. 0 0
2 0 . 0 0
?
Retention Time
6.151
Area
% Area
30.89
1.32
1
2
3
4
24710737
1053897
2532009
51697343
9.130
13.140
3.17
15.704
64.63
Ethyl 3-hydroxy-5-methyl-6-nitro-1,4,5,6-tetrahydro-[1, 1’-biphenyl]-2-carboxylate 3tb:4
OH
yellow oil; 18.4 mg, 60% yield; 64:36 dr, determined by HPLC analysis; 99% ee
( minor 98% ee), determined by HPLC analysis [Daicel chiralcel ODH,
n-hexane/i-PrOH = 95/5, 1.0 mL/min, λ = 254 nm, major diastereomer: t (minor)
= 6.71 min, t (major) = 7.04 min; minor diastereomer: t (minor) = 5.82 min, t
CO2Et
Ph
NO2
3tb
(major) = 6.31 min]; 1H NMR (400 MHz, CDCl3) δ = 12.58 (s, 1H), 7.33 (t, J = 7.3 Hz, 2H), 7.28
(s, 1H), 7.22 (d, J = 7.2 Hz, 2H), 4.65 (t, J = 2.9 Hz, 1H), 4.46 (d, J = 2.2 Hz, 1H), 4.06 – 3.94 (m,
2H), 2.57 (dd, J = 18.6, 6.9 Hz, 1H), 2.47 (dd, J = 18.6, 10.1 Hz, 1H), 2.32 (m, 1H), 1.07 (d, J =
6.8 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H).
0.60
0.40
0.20
0.00
1.00
2.00
3.00
4.00
5.00
? ?
6.00
7.00
8.00
9.00
Retention Time
Area
% Area
21.76
21.54
26.89
29.80
1
2
3
4
5.798
6.303
6.719
7.051
5609625
5554190
6933645
7683646
S24

1.00
0.80
0.60
0.40
0.20
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50
7.00
7.50
8.00
8.50
? ?
Retention Time
5.824
Area
% Area
0.35
1
2
3
4
70569
6961043
16265
6.305
34.40
0.08
6.709
7.040
13190221
65.18
S25

9. Copies of NMR spectra for the products
OH
CO2Et
NO2
3a
S26

OH
CO2Et
NO2
3b
S27

OH
CO2Et
NO2
3c
S28

OH
CO2Et
NO2
MeO
3d
S29

S30