Highly enantioselective 1,3-dipolar cycloaddition of imino esters with benzofuranone derivatives catalyzed by thiourea?quaternary ammonium salt

Article abstract of DOI:10.1016/j.tet.2018.11.025

Highly enantioselective 1, 3-dipolar cycloaddition of 2-arylidene-benzofuran- 3(2H)-ones with imino esters catalyzed by thiourea?quaternary ammonium salts has been developed. This reaction provides efficient construction of a range of chiral spiro[benzofuran-2,3′-pyrrolidine] in high yields (up to 99%) and with good enantioselectivities (up to 99% ee) under mild conditions.

Full text of DOI:10.1016/j.tet.2018.11.025

Accepted Manuscript
Highly enantioselective 1,3-dipolar cycloaddition of imino esters with benzofuranone
derivatives catalyzed by thiourea−quaternary ammonium salt
Ting Du, Zhaokun Li, Changwu Zheng, Guosheng Fang, Longhui Yu, Jun Liu, Gang
Zhao
PII:
S0040-4020(18)31365-6
https://doi.org/10.1016/j.tet.2018.11.025
TET 29936
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 May 2018
Revised Date: 10 November 2018
Accepted Date: 12 November 2018
Please cite this article as: Du T, Li Z, Zheng C, Fang G, Yu L, Liu J, Zhao G, Highly enantioselective 1,3-
dipolar cycloaddition of imino esters with benzofuranone derivatives catalyzed by thiourea−quaternary
ammonium salt, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.11.025.
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ACCEPTED MANUSCRIPT
Highly Enantioselective 1,3 Dipolar Cycloaddition of Imino Esters with
Benzofuranone Derivatives catalyzed by Thiourea−Quaternary
Ammonium Salt
Ting Dua, Zhaokun Lib, Changwu Zhengb, Guosheng Fanga, , Longhui Yub, Jun Liub,
Gang Zhaoa, b,
*
a
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026,
China
Fax: +86 21 64166128; e-mail: zhaog@mail.sioc.ac.cn (G. Zhao).
b
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
Br
OR1
CF3
O
N
3f (5 mol%)
NH
R1
N
CO2R2
S
NH
K2CO3 (3 equiv)
TBME, rt
CO2R2
O
R3
O
HN
CF3
R3
26 examples
up to 99% ee
>20:1 dr
R1 = Aryl, R2 = Me, Et, Bn, tBu,
R3 = Aryl
NO2
3f
* Corresponding author.
zhaog@mail.sioc.ac.cn (G. Zhao).

ACCEPTED MANUSCRIPT
Highly Enantioselective 1,3 Dipolar Cycloaddition of Imino Esters with
Benzofuranone Derivatives Catalyzed by Thiourea−Quaternary Ammonium Salt
Ting Dua, Zhaokun Lib, Changwu Zhengb, Guosheng Fanga, Longhui Yub, Jun Liub, Gang Zhaoa, b,
*
a
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
bKey Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China.
ARTICLE INFO
ABSTRACT
Article history:
Highly enantioselective 1, 3-dipolar cycloaddition of 2-arylidene-benzofuran- 3(2H)-ones with imino
esters catalyzed by thiourea−quaternary ammonium salts has been developed. This reaction provides
efficient construction of a range of chiral spiro[benzofuran-2,3'-pyrrolidine] in high yields (up to 99%)
and with good enantioselectivities (up to 99% ee) under mild conditions.
Keywords:
Asymmetric cyclization
Quaternary ammonium
Phase-transfer catalysis
1. Introduction
Highly substituted pyrrolidines are key structural motifs present in a number of biologically active natural products1. In particular,
the combination of highly substituted pyrrolidines with a furan-3(2H)-one ring systems are conferred valuable biological activities2.
For instance, Azaspirene is a novel angiogenesis inhibitor isolated from the fungus Neosartorya sp. Cephalimysin A showed significant
cytotoxicity against P388 cells and HL-60 cells (Figure 1). The synthetic and biological relevance of those compounds has encouraged
chemists to develop efficient synthetic strategies to construct these scaffolds3. Among the various methods developed, the catalytic
asymmetric 1,3-dipolar cycloaddition of azomethine ylides to alkenes is one of the most powerful and efficient strategy for the
construction of this highly substituted pyrrolidines4. In 2016, Ding and co-workers reported the first example of 1,3-dipolar
cycloaddition of 2-alkylidene-benzofuran-3-one with azomethine ylides using simple functional ionic liquids5. Soon after, Mukherjee
developed a cascade Michael addition/cyclization reaction for the highly enantioselective synthesis of 3, 2’-pyrrolidinyl
bispirooxindole derivatives6. In 2017, Albrecht reported asymmetric [3 + 2] cycloadditions of 2-arylidene-benzofuran- 3(2H)-ones with
imines derived from salicylaldehyde and diethyl aminomalonates in the presence of a chiral Brønsted base organocatalyst7.
O
OH
O
OH
OH
Ph
OMe
Ph
O
NH
O
NH
O
O
O
Azaspirene
Figure 1. Bioactive compounds
Cephalimysin A
Over the past years, the asymmetric phase-transfer catalysis has been developed as a powerful tool in asymmetric synthesis8. In
our group, we have developed a new family of bifunctional ammonium and phosphonium salts organocatalysts from simple acyclic
-amino acid, which have been applied to various enantioselective reactions9. To the best of our knowledge, the asymmetric reaction
* Corresponding author.
Zhaog@sioc.ac.cn (G. Zhao)
1

ACCEPTED MANUSCRIPT
between 2-arylidene-benzofuran- 3(2H)-ones and azomethine ylides has not been yet explored by the phase-transfer catalysis. Herein
we describe the application of chiral quaternary ammonium salts to catalyze the 1, 3-dipolar cycloaddition of
2-arylidene-benzofuran-3(2H)-ones with azomethine ylides.
2. Results and Discussion
Initially, we choose 2-benzylidenebenzofuran-3(2H)-one (1a) and imino ester (2a) as model reactants to optimize the reaction
conditions and the results are summarized in Table 1.
Table 1. Optimization of conditions and evaluation of chiral catalysts.
Entrya
1
Catalyst
3a
3b
3c
3d
3e
3f
base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOH
Cs2CO3
K3PO4
KF
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
t/h
2.5
2
Yield (%)b
92
drc
6:1
ee (%)d
73
74
65
38
96
98
88
90
97
94
98
95
99
99
86
39
93
96
97
2
95
11:1
6:1
3
2
91
4
2
90
14:1
13:1
11:1
2:1
5
1
98
6
1
96
7
3
92
3g
3h
3i
8
2
94
3:1
9
2.5
2
90
8:1
10
11
12
13
14
15
16
17
18
19
95
8:1
3j
3
91
11:1
10:1
13:1
15:1
10:1
11:1
10:1
14:1
8:1
3f
CHCl3
Et2O
8
95
3f
1
91
3f
TBME
THF
0.5
0.5
0.2
0.5
0.5
27
97
3f
96
3f
TBME
TBME
TBME
TBME
90
3f
94
3f
95
3f
86
3f
a
Unless otherwise noted, the reaction was performed with 0.10 mmol of 1a, 0.15 mmol of 2a and 3.0 equiv. of base in the presence of 5
mol% of catalyst 3 at rt.;
b Isolated yield.
c Determined by 1H NMR spectroscopy of crude mixtures.
d Determined by chiral HPLC analysis.
2

ACCEPTED MANUSCRIPT
The catalytic efficiency of different ammonium salt catalysts was first tested. Three types of quaternary ammonium salts that have
been developed in our lab were evaluated in this reaction, including the amide, urea and thiourea as the H-donor respectively. When
L-isoleucine-derived quaternary ammonium salt 3a was used as the catalyst, the product 4a was obtained in 92% yield and 73% ee
along with 6:1 dr (Table 1, entry 1), while the other type of quaternary ammonium salts 3b-3d with urea as the double H-donor did not
improve the enantioselectivity though, this bifunctional catalyst indeed enhanced the diastereoselectivity to 14 : 1 (Table 1, entries 2-4).
It is well-known that both H-Bond strength and acidity of thiourea are more than that of urea. So the thiourea catalysts 3e-3j were
prepared and evaluated in the reaction, to our delight, the use of catalyst 3f which is derived from L-isoleucine improved the
enantioselectivity to 98% ee along with 11 : 1 dr (Table 1, entry 6). Further optimization efforts were then performed on the solvent and
base, which showed the optimum conditions for this reaction were carried out with 5 mol% of catalyst 3f and 3 equivalents of K2CO3
in TBME at rt. (Table 1, entry 10).
R1
O
O
NH
3f (5 mol%)
R1
N
CO2R2
CO2R2
O
O
K2CO3 (3 equiv)
TBME, rt
1a
2
4
O
O
O
O
O
O
NH
CO2Me
NH
NH
NH
O
O
t
CO2Et
CO2Bn
CO2
4a
4b
4c
4d
97% yield, 99% ee
94:6 dr
96% yield, 95% ee
93:7 dr
99% yield, 93% ee
99% yeild, 99% ee
95:5 dr
96:4 dr
F
Cl
Br
F
O
O
O
O
NH
O
NH
O
NH
NH
O
O
CO2Me
CO2Me
CO2Me
CO2tB
4e
4f
4g
4h
92% yield, 98% ee
95:5 dr
93% yield, 98% ee
97:3 dr
94% yield, 96% ee
98:2 dr
97% yield, 99% ee
96:4 dr
Cl
Br
Me
C
O
O
O
O
NH
O
NH
O
NH
O
NH
O
CO2tB
CO2tBu
CO2tBu
CO2tBu
4i
4j
4k
4l
95% yield, 97% ee
97:3 dr
99% yield, 98% ee
96:4 dr
99% yield, 89% ee
92:5:3 dr
99% yield, 99% ee
96:4 dr
O
O
Cl
NH
O
NH
O
CO2tBu
CO2tBu
4m
4n
99% yield, 99% ee
94:6 dr
91% yield, 98% ee
96:4 dr
a The reaction was stirred for 0.5-1h
3

ACCEPTED MANUSCRIPT
Scheme 1. Exploration of Imino Ester Scope a
Under the optimized conditions, a range of imino esters with 2-benzylidenebenzofuran-3(2H)-one (1a) were examined in the
reaction (Scheme 1). When R1 in imino ester is fixed to phenyl group, the evaluation of different ester groups on azomethine ylides
indicated the bulky tert-butyl group was better than Me, Et and Bn, which gave rise to the product 4d in 99% yield, 99% ee and 95 : 5
dr. But when substituted imino esters were used, variation of the ester groups had little effect on the results respective to the high yields,
good diastereoselectivities and excellent ees obtained (4e-4h). Next, we fixed the R2 as tert-butyl group, the substituents on the aryl
moiety we tested at the ortho- or meta-position were well tolerated and the corresponding products (4h-4j, 4l-4n) were obtained with
excellent enantioselectivities (up to 99%) and good diastereoselectivities (up to 98 : 2). Reaction with 4-methyl substituted imino ester
was a little decrease of enantioselectivities to give the product in 89% ee (4k).
a The reaction was stirred for 0.5-1h
Scheme 2. Exploration of the scope of 2-arylidenebenzofuran-3(2H)-ones a
4

ACCEPTED MANUSCRIPT
To further extend the substrate scope, we next examined the reaction with various 2-arylidenebenzofuran-3(2H)-ones 1 under the
optimized conditions (Scheme 2). Generally, all the reactions proceeded well with 2-benzylidenebenzofuran-3(2H)-ones, affording the
products with good yields and high enantioselectivities. meta-Substituent on the aromatic ring of 2-arylidenebenzofuran-3(2H)-ones
resulted in a slight decrease of diastereoselectivity (4x). In addition, the reaction was also tolerated with 2-naphthyl and 2-furyl
substituents, delivering the desired products in excellent enantioselectivity and good diastereoselectivities (4y-4z). The absolute
configuration of the major isomer 4r was established by single-crystal X-ray analysis and the other products were assigned by analogy
(Figure 2).
Figure 2. X ray structure of 4r
3. Conclusions
In conclusion, we have developed a novel asymmetric [3 + 2] cycloaddition reaction of 2-arylidenebenzofuran-3(2H)-ones with
imino esters via chiral thiourea-quaternary ammonium salts catalysis. The reactions proceeded quite well to provide facile access to a
range of chiral pyrrolidine derivatives 4 bearing a benzofuran-3(2H)-one scaffold with excellent enantioselectivities and good
diastereoselectivies under mild conditions.
4. Experimental
4.1 General information
1
The H NMR spectra were recorded on a Bruker (400 MHz). All chemical shifts (δ) were given in ppm. Data were reported as follows:
chemical shift, intergration, multiplicity (s = single, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet) and coupling constants (Hz).
13C NMR spectra were recorded on a DPX-400 (400 MHz). Flash column chromatography was performed using H silica gel. For thin-layer
chromatography (TLC), silica gel plates (HSGF 254) were used and compounds were visualized by irradiation with UV light. Analytical high
performance liquid chromatography (HPLC) was carried out on SHIMADZU equipment using chiral columns. Melting points were
determined on a SGW X-4 melting point and were uncorrected. Optical rotations were measured on a JASCO P-1010 Polarimeter at λ =589
nm. IR spectra were recorded on a Perkin-Elmer 983G instrument. Mass spectra analysis was performed on API 200 LC/MS system (Applied
Biosystems Co. Ltd.). All phase-transfer catalysts 3a, 3d, 3e, 3f were synthesized according to procedures reported previously10.
2-arylidenebenzofuran-3(2H)-ones were synthesized according to known procedures11.
4.2 Synthesis path of ammonium salts 3b and 3c
4.2.1 (S)-N-(3,5-bis(trifluoromethyl)benzyl)-2-(3-(3,5 bis(trifluoromethyl)phenyl)ureido)-N,N,3,3-tetramethylbutan-1-aminium bromide
(3b)
1
white solid, mp: 122-123 °C; H NMR (CDCl3, 400 MHz) δ 9.40 (s, 1H), 8.25 (s, 2H), 8.02 (s, 1H), 7.96 (s, 2H), 7.41-7.44 (m, 1H), 7.38 (s,
1H), 5.34-5.37 (m, 1H), 5.15-5.19 (m, 1H), 4.26-4.30 (m, 1H), 4.00-4.14 (m, 2H), 3.33 (s, 3H), 3.27 (s, 3H), 1.09 (s, 9H); 13C NMR (CDCl3,
100 MHz) δ 155.5, 140.9, 133.2, 133.0 (q, J = 34.0 Hz), 131.7 (q, J = 33.0 Hz), 129.5, 125.0, 123.2 (q, J = 271.3 Hz), 122.4 (q, J = 271.7 Hz),
5

ACCEPTED MANUSCRIPT
117.8, 115.2, 68.2, 66.5, 52.9, 50.1, 49.6, 36.3, 26.1; 19F NMR (CDCl3, 376 MHz) δ -59.8 (s), -60.0 (s); IR (Neat): 3278, 3090, 2967, 1693,
1622, 1573, 1475, 1443, 1389, 1280, 1182, 1134, 1057; HRMS (ESI): calcd for [M-Br]+ (C26H28ON3F12)+ requires 626.2046; found 626.2027.
[α]D24.8 = -10.6 (c = 1.0, CHCl3).
4.2.2 (2S,3S)-N-(3,5-bis(trifluoromethyl)benzyl)-2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-N,N,3-trimethylpentan-1-aminium bromide
(3c)
white solid, mp: 120-121 °C; 1H NMR (CDCl3, 400 MHz) δ 9.38 (s, 1H), 8.22 (s, 2H), 8.02 (s, 1H), 7.98 (s, 2H), 7.39-7.43 (m, 2H), 5.31-5.34
(m, 1H), 5.13-5.17 (m, 1H), 4.46-4.53 (m, 1H), 4.24-4.30 (m, 1H), 4.24-4.30 (m, 1H), 3.73 (d, J = 13.2 Hz, 1H), 3.34 (s, 3H), 3.30 (s, 3H),
1.76-1.77 (m, 1H), 1.48-1.56 (m, 1H), 1.33-1.40 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H), 0.903 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
155.4, 140.9, 133.2, 133.0 (q, J = 34.1 Hz), 131.8 (q, J = 33.0 Hz), 129.5, 127.3, 126.5, 125.0, 123.1 (q, J = 271.3 Hz), 122.4 (q, J = 271.8 Hz),
117.8, 115.3, 68.7, 66.4, 50.5, 50.2, 49.0, 40.1, 24.9, 15.2, 11.5; 19F NMR (CDCl3, 376 MHz) δ -63.18 (s), -63.25 (s); IR (Neat): 3278, 3090,
2967, 1693, 1623, 1573, 1475, 1443, 1388, 1279, 1180, 1133; HRMS (ESI): calcd for [M-Br]+ (C26H28ON3F12)+ requires 626.2035; found
626.2024. [α]D24.7 = -6.2 (c = 1.0, CHCl3).
4.3 General Procedure for Directly Catalytic Asymmetric Synthesis of spiro[benzofuran-2,3'-pyrrolidine] 4a-4z.
A mixture of K2CO3 (0.30 mmol), catalyst 3f (0.005 mmol), 2-arylidenebenzofuran-3(2H)-ones (0.10 mmol), and in TBME (1.0 mL) was
stirred at rt. To the mixture was added the amino esters (0.15 mmol), the reaction mixture was stirred at same temperature until the reaction
was completed (the reaction time was monitored by TLC). The resultant solution was purified through flash column chromatography on silica
gel (eluent: petroleum ether: ethyl acetate = 8:1-6:1) to yield pure products 4a-4z. The diastereomeric ratio was determined by crude 1H NMR
or HPLC. The enantionmeric excesses of the products were determined by chiral stationary phase HPLC using a Chiralpak AD-H, Chiralpak
IC and Chiralpak PC-2 column.
4.3.1 Methyl (2S,2'R,4'S,5'R)-3-oxo-2',4'-diphenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4a)
white solid, mp: 103-104 °C; 1H NMR (CDCl3, 400 MHz) δ 7.42-7.46 (m, 1H), 7.27-7.31 (m, 5H), 7.15-7.25 (m, 6H), 6.93 (d, J = 8.4 Hz, 1H),
6.88 (t, J = 7.4 Hz, 1H), 4.89 (s, 1H), 4.57 (d, J = 10,4 Hz, 1H), 3.92 (d, J = 10.4 Hz, 1H), 3.71 (s, 3H), 2.32 (br, 1H); 13C NMR (CDCl3, 100
MHz) δ 199.3, 172.3, 170.7, 137.8, 136.5, 133.4, 129.3, 128.3, 128.1(2C), 127.6, 127.0, 123.9, 121.8, 121.3, 112.7, 97.6, 71.1, 64.6, 58.0, 52.4;
IR (Neat): 3343, 3067, 3041, 2929, 2859, 1739, 1714, 1610, 1476, 1461, 1324, 1300, 1205, 1178, 1143; HRMS (ESI): calcd for [M+H]+
(C25H22O4N)+ requires 400.1543; found 400.1541; enantiomeric excess: 99%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 80/20,
flow rate 1.0 mL/min; tmajor = 15.9 min, tminor = 31.5 min, λ = 254 nm); [α]D27.1 = -75.1 (c = 1.0, CHCl3).
4.3.2 Ethyl (2S,2'R,4'S,5'R)-3-oxo-2',4'-diphenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4b)
white solid, mp: 109-110 °C; 1H NMR (CDCl3, 400 MHz) δ 7.42-7.46 (m, 1H), 7.27-7.31 (m, 5H), 7.25-7.23 (m, 3H), 7.15-7.21 (m, 3H), 6.95
(d, J = 8.4 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 4.89 (s, 1H), 4.53 (d, J = 10.4 Hz, 1H), 4.10-4.22 (m, 2H), 3.88 (d, J = 10.4 Hz, 1H), 2.70 (br, 1H),
1.10 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 199.2, 171.8, 170.7, 137.8, 136.7, 133.4, 129.4, 128.3, 128.1, 128.0, 127.5, 127.1,
124.0, 121.8, 121.4, 112.7, 97.8, 71.4, 64.8, 61.3, 58.4, 14.0; IR (Neat): 3347, 3071, 3037, 2985, 2929, 1734, 1709, 1609, 1475, 1459, 1324,
1299, 1201, 1143, 1008; HRMS (ESI): calcd for [M+H]+ (C26H24O4N)+ requires 414.1700; found 414.1700; enantiomeric excess: 95%,
27.4
determined by HPLC (Chiralpak IC, hexane/i-PrOH 60/40, flow rate 1.0 mL/min; tmajor = 36.4 min, tminor = 7.1 min, λ = 254 nm); [α]D
-91.8 (c = 1.0, CHCl3).
=
4.3.3 Benzyl (2S,2'R,4'S,5'R)-3-oxo-2',4'-diphenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4c)
1
white solid, mp: 151-152 °C; H NMR (CDCl3, 400 MHz) δ 7.41-7.45 (m, 1H), 7.27-7.30 (m, 4H), 7.21-7.26 (m, 8H), 7.15-7.17 (m, 2H),
6.98-6.70 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 5.20 (d, J = 12.4 Hz, 1H), 5.06 (d, J = 12.4 Hz, 1H), 4.87 (s, 1H), 4.60 (d,
J = 10.4 Hz, 1H), 3.88 (d, J = 10.4 Hz, 1H), 2.55 (br, 1H); 13C NMR (CDCl3, 100 MHz) δ 198.9, 171.9, 170.6, 137.8, 136.8, 135.2, 133.1,
129.5, 128.4, 128.3, 128.1(3C), 127.7, 127.6, 127.1, 124.0, 123.9, 121.8(2C), 121.4, 112.9, 112.7, 97.9, 71.4, 66.9, 64.6, 58.4; IR (Neat): 3343,
3067, 3032, 2924, 1737, 1714, 1610, 1476, 1460, 1324, 1300, 1185, 1143; HRMS (ESI): calcd for [M+H]+ (C31H26O4N)+ requires 476.1856;
found 476.1855; enantiomeric excess: 93%, determined by HPLC (Chiralpak IC, hexane/i-PrOH 60/40, flow rate 1.0 mL/min; tmajor = 34.4 min,
tminor = 8.0 min, λ = 254 nm); [α]D27.6 = -72.1 (c = 1.0, CHCl3).
4.3.4 Tert-butyl (2S,2'R,4'S,5'R)-3-oxo-2',4'-diphenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4d)
white solid, mp: 132-133 °C; 1H NMR (CDCl3, 400 MHz) δ 7.45-7.41 (m, 1H), 7.23-7.29 (m, 8H), 7.11-7.19 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H),
6.81-6.89 (m, 1H), 4.85 (s, 1H), 4.40 (d, J = 10.8 Hz, 1H), 3.75 (d, J = 10.8 Hz, 1H), 2.75 (br, 1H), 1.27 (s, 9H); 13C NMR (CDCl3, 100 MHz)
δ 199.1, 171.1, 170.6, 137.7, 136.9, 133.5, 129.6, 128.3, 128.1, 127.9, 127.4, 127.1, 123.9, 121.7, 121.4, 112.7, 98.3, 81.9, 71.8, 65.5, 59.3,
27.8; IR (Neat): 3356, 2976, 2930, 1729, 1606, 1494, 1476, 1460, 1368, 1153; HRMS (ESI): calcd for [M+H]+ (C28H28O4N)+ requires
442.2013; found 442.2013; enantiomeric excess: 99%, determined by HPLC (Chiralpak IC, hexane/i-PrOH 90/10, flow rate 1.0 mL/min; tmajor
= 22.9 min, tminor = 10.3 min, λ = 254 nm); [α]D27.8 = -64.9 (c = 1.0, CHCl3).
6

ACCEPTED MANUSCRIPT
4.3.5 Methyl (2S,2'R,4'S,5'R)-2'-(4-fluorophenyl)-3-oxo-4'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4e)
white solid, mp: 124-125 °C; 1H NMR (CDCl3, 400 MHz) δ 7.34-7.38 (m, 1H), 7.18-7.25 (m, 3H), 7.05-7.17 (m, 5H), 6.78-6.91 (m, 4H), 4.76
(s, 1H), 4.47 (d, J = 10.4 Hz, 1H), 3.84 (d, J = 10.4 Hz, 1H), 3.62 (s, 3H), 2.95 (br, 1H); 13C NMR (CDCl3, 100 MHz) δ 199.1, 172.3, 170.6,
163.6, 161.1, 137.9, 133.2, 132.6, 132.6, 129.2, 128.8, 128.7, 128.1, 127.6, 123.9, 121.9, 121.2, 115.3, 115.0, 112. 7, 97.4, 70.3, 64.4, 57.5,
52.4, 29.65; IR (Neat): 3356, 3065, 3033, 2953, 2925, 1740, 1710, 1609, 1509, 1476, 1461, 1325, 1206, 1156, 1143, 880; HRMS (ESI): calcd
for [M+H]+ (C25H21O4NF)+ requires 418.1449; found 418.1446; enantiomeric excess: 98%, determined by HPLC (Chiralpak AD-H,
hexane/i-PrOH 70/30, flow rate 1.0 mL/min; tmajor = 9.8 min, tminor = 24.1 min, λ = 254 nm); [α]D26.1 = -105.8 (c = 1.0, CHCl3).
4.3.6 Methyl (2S,2'R,4'S,5'R)-2'-(4-chlorophenyl)-3-oxo-4'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4f)
white solid, mp: 91-92 °C; 1H NMR (CDCl3, 400 MHz) δ 7.35-7.39 (m, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.13-7.19 (m, 6H), 7.07-7.12 (m, 3H),
679-6.86 (m, 2H), 4.75 (s, 1H), 4.47 (d, J = 10.4 Hz, 1H), 3.83 (d, J = 10.4 Hz, 1H), 3.62 (s, 3H), 2.89 (br, 1H); 13C NMR (CDCl3, 100 MHz)
δ 198.9, 172.2, 170.6, 137.9, 135.4, 133.8, 133.1, 129.2, 128.5, 128.4, 128.1, 127.6, 124.0, 122.0, 121.2, 112.7, 97.3, 70.3, 64.4, 57.5, 52.4; IR
(Neat): 3365, 2953, 2925, 1740, 1715, 1611, 1477, 1462, 1205, 1144, 880; HRMS (ESI): calcd for [M+H]+ (C25H21O4NCl)+ requires 434.1154;
found 434.1156; enantiomeric excess: 98%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 70/30, flow rate 1.0 mL/min; tmajor = 9.7
min, tminor = 27.8 min, λ = 254 nm); [α]D27.1 = -149.6 (c = 1.0, CHCl3).
4.3.7 Methyl (2S,2'R,4'S,5'R)-2'-(4-bromophenyl)-3-oxo-4'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4g)
1
white solid, mp: 114-115 °C; H NMR (CDCl3, 400 MHz) δ 7.35-7.35 (m, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.07-7.18
(m, 7H), 6.79-6.86 (m, 2H), 4.73 (s, 1H), 4.47 (d, J = 10.4 Hz, 1H), 3.83 (d, J = 10.4 Hz, 1H), 3.61 (s, 3H), 2.98 (br, 1H); 13C NMR (CDCl3,
100 MHz) δ 198. 9, 172.2, 170.6, 137.9, 136.0, 133.0, 131.3, 129.2, 128.8, 128.1, 127.6, 124.0, 122.0(2C), 121.2, 112.7, 97.3, 70.3, 64.3, 57.5,
52.4; IR (Neat): 3356, 2952, 2924, 1740, 1714, 1611, 1477, 1462, 1214, 1205, 1010, 880; HRMS (ESI): calcd for [M+H]+ (C25H21O4NBr)+
requires 478.0648; found 478.0644; enantiomeric excess: 96%, determined by HPLC (Chiralpak PC-2, hexane/i-PrOH 90/10, flow rate 1.0
mL/min; tmajor = 19.9 min, tminor = 23.8 min, λ = 254 nm); [α]D26.4 = -156.6 (c = 1.0, CHCl3).
4.3.8 Tert-butyl(2S,2'R,4'S,5'R)-2'-(4-fluorophenyl)-3-oxo-4'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4h)
white solid, mp: 137-138°C; 1H NMR (CDCl3, 400 MHz) δ 7.42-7.46 (m, 1H), 7.22-7.31 (m, 5H), 7.11-7.19 (m, 3H), 6.94-6.98 (m, 3H), 6.87
(t, J = 7.4 Hz, 1H), 4.82 (s, 1H), 4.40 (d, J = 10.8 Hz, 1H), 3.74 (d, J = 10.8 Hz, 1H), 2.71 (br, 1H), 1.27 (s, 9H); 13C NMR (CDCl3, 100 MHz)
δ 199.0, 171.1, 170.6, 163.6, 161.2, 137.9, 133.3, 132.9(2C), 129.5, 128.9, 128.8, 127.9, 127.5, 124.0, 121.9, 121.3, 115.3, 115.1, 112.8, 98.1,
81.9, 71.0, 65.3, 58.9, 27.8; IR (Neat): 3352, 3065, 2977, 2930, 1707, 1610, 1509, 1475, 1460, 1223, 1156; HRMS (ESI): calcd for [M+H]+
(C28H27O4NF)+ requires 460.1919; found 460.1913; enantiomeric excess: 99%, determined by HPLC (Chiralpak ID3, hexane/i-PrOH 82/18,
flow rate 0.7 mL/min; tmajor = 8.3 min, tminor = 17.0 min, λ = 214 nm); [α]D26.8 = -78.9 (c = 1.0, CHCl3).
4.3.9 Tert-butyl (2S,2'R,4'S,5'R)-2'-(4-chlorophenyl)-3-oxo-4'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4i)
white solid, mp: 145-146 °C; 1H NMR (CDCl3, 400 MHz) δ 7.42-7.47 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.21-7,27 (m, 6H), 7.11-7.19 (m, 3H),
6.96 (d, J = 8.4 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 4.81 (s, 1H), 4.40 (d, J = 10.8 Hz, 1H), 3.73 (d, J = 10.8 Hz, 1H), 2.74 (br, 1H), 1.27 (s, 9H);
13C NMR (CDCl3, 100 MHz) δ198.9, 171.1, 170.6, 137.9, 135.8, 133.8, 133.2, 129.5, 128.5(2C), 127.9, 127.5, 124.0, 121.9, 121.3, 112.8,
110.0, 98.0, 81.9, 70.9, 65.3, 58.9, 27.8; IR (Neat): 3348, 2977, 2929, 1727, 1706, 1610, 1475, 1459, 1368, 1325, 1159; HRMS (ESI): calcd
for [M+H]+ (C28H27O4NCl)+ requires 476.1623; found 476.1617; enantiomeric excess: 97%, determined by HPLC (Chiralpak IC,
hexane/i-PrOH 90/10, flow rate 1.0 mL/min; tmajor = 21.4 min, tminor = 8.2 min, λ = 254 nm); [α]D26.9 = -129.8 (c = 1.0, CHCl3).
4.3.10 Tert-butyl (2S,2'R,4'S,5'R)-2'-(4-bromophenyl)-3-oxo-4'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4j)
white solid, mp: 148-149 °C; 1H NMR (CDCl3, 400 MHz) δ 7.42-7.47 (m, 1H), 7.39-7.41 (m, 2H), 7.31 (d, J = 7.0 Hz, 1H), 7.12-7.27 (m, 7H),
6.96 (d, J = 8.4 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 4.79 (s, 1H), 4.40 (d, J = 10.8 Hz, 1H), 3.73 (d, J = 10.8 Hz, 1H), 2.75 (br, 1H), 1.26 (s, 9H);
13C NMR (CDCl3, 100 MHz) δ 198.9, 171.1, 170.6, 137.9, 136.3, 133.2, 131.4, 129.5, 128.9, 127.9, 127.5, 124.0, 122.0, 121.9, 121.3, 112.8,
98.0, 81.9, 70.9, 65.3, 58.9, 27.8; IR (Neat): 3348, 2977, 2929, 1727, 1706, 1612, 1475, 1459, 1368, 1325, 1216, 1159; HRMS (ESI): calcd
for [M+H]+ (C28H27O4NBr)+ requires 520.1118; found 520.1111; enantiomeric excess: 98%, determined by HPLC (Chiralpak IC,
hexane/i-PrOH 90/10, flow rate 1.0 mL/min; tmajor = 22.6 min, tminor = 8.6 min, λ = 254 nm); [α]D27.2 = -130.9 (c = 1.0, CHCl3).
4.3.11 Tert-butyl (2S,2'R,4'S,5'R)-3-oxo-4'-phenyl-2'-(p-tolyl)-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4k)
white solid, mp: 141-142 °C; 1H NMR (CDCl3, 400 MHz) δ 7.40-7.45 (m, 1H), 7.29-7.31 (m, 1H), 7.23-7.26 (m, 2H), 7.05-7.19 (m, 7H), 6.96
(d, J = 8.4 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1H), 4.82 (s, 1H), 4.39 (d, J = 10.8 Hz, 1H), 3.73 (d, J = 10.8 Hz, 1H), 2.82 (br, 1H), 2.28 (s, 3H), 1.26
(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 199.2, 171.1, 170.6, 137.7(2C), 137.6, 134.0, 133.5, 129.6, 129.0, 127.8, 127.4, 127.0, 123.9, 121.7,
121.5, 112.7, 98.5, 81.8, 71.8, 65.4, 59.4, 29.7, 28.0, 27.8, 21.1; IR (Neat): 3339, 2925, 1732, 1710, 1612, 1474, 1458, 1368, 1325, 1300, 1215,
1163; HRMS (ESI): calcd for [M+H]+ (C29H30O4N)+ requires 456.2169; found 456.2165; enantiomeric excess: 89%, determined by HPLC
(Chiralpak IC, hexane/i-PrOH 90/10, flow rate 1.0 mL/min; tmajor = 27.4 min, tminor = 14.1 min, λ = 254 nm); [α]D27.4 = -85.3 (c = 1.0, CHCl3).
7

ACCEPTED MANUSCRIPT
4.3.12 Tert-butyl (2S,2'R,4'S,5'R)-2'-(3-chlorophenyl)-3-oxo-4'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4l)
white solid, mp: 136-137 °C; 1H NMR (CDCl3, 400 MHz) δ 7.43-7.47 (m, 1H), 7.31-7.33 (m, 2H), 7.12-7.26 (m, 8H), 6.97 (d, J = 8.4 Hz, 1H),
6.88 (t, J = 7.4 Hz, 1H), 4.80 (s, 1H), 4.40 (d, J = 10.8 Hz, 1H), 3.74 (d, J = 10.8 Hz, 1H), 2.75 (br, 1H), 1.28 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 198.7, 171.0, 170.6, 139.4, 137.9, 134.3, 133.2, 129.5(2C), 128.2, 127.9, 127.5(2C), 125.4, 124.0, 121.9, 121.4, 112.8, 97.9, 81.9, 70.9,
65.3, 58.8, 27.8; IR (Neat): 3365, 3075, 2977, 2929, 1722, 1612, 1476, 1461, 1369, 1324, 1157; HRMS (ESI): calcd for [M+H]+
(C28H27O4NCl)+ requires 476.1623; found 476.1618; enantiomeric excess: 99%, determined by HPLC (Chiralpak IC, hexane/i-PrOH 95/5,
flow rate 0.7 mL/min; tmajor = 35.0 min, tminor = 16.1 min, λ = 254 nm); [α]D27.7 = -103.2 (c = 1.0, CHCl3).
4.3.13 Tert-butyl (2S,2'R,4'S,5'R)-2'-(2-chlorophenyl)-3-oxo-4'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4m)
1
white solid, mp: 112-113 °C; H NMR (CDCl3, 400 MHz) δ 8.18 (d, J = 7.6 Hz, 1H), 7.41-7.47 (m, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.21-7.27
(m, 4H), 7.05-7.11 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1H), 5.29 (s, 1H), 4.59 (d, J = 11.4 Hz, 1H), 3.73 (d, J = 11.4 Hz, 1H),
2.79 (br, 1H), 1.25 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 196.9, 171.9, 170.3, 137.5, 136.0, 133.2, 132.1, 129.7, 129.6, 128.9, 128.8, 127.8,
127.5, 127.1, 123.8, 122.0, 121.6, 112.5, 98.2, 81.6, 66.6, 64.3, 57.0, 27.8; IR (Neat): 3382, 2977, 2929, 1720, 1613, 1477, 1463, 1368, 1302,
1155; HRMS (ESI): calcd for [M+H]+ (C28H27O4NCl)+ requires 476.1623; found 476.1616; enantiomeric excess: 99%, determined by HPLC
(Chiralpak IC, hexane/i-PrOH 90/10, flow rate 1.0 mL/min; tmajor = 12.4 min, tminor = 6.7 min, λ = 254 nm); [α]D28.1 = 264.4 (c = 1.0, CHCl3).
4.3.14 Tert-butyl (2S,2'R,4'S,5'R)-2'-(naphthalen-2-yl)-3-oxo-4'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4n)
1
white solid, mp: 172-173 °C; H NMR (CDCl3, 400 MHz) δ 7.70-7.84 (m, 4H), 7.40-7.45 (m, 3H), 7.31-7.33 (m, 1H), 7.23-7.27 (m, 3H),
7.11-7.20 (m, 3H), 6.98 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H), 5.02 (s, 1H), 4.45 (d, J = 10.8 Hz, 1H), 3.82 (d, J = 10.8 Hz, 1H), 2.87 (br,
1H), 1.29 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 199.1, 171.1, 170.7, 137.8, 134.4, 133.5, 133.1 (2C), 129.6, 128.2, 127.9(2C), 127.6, 127.4,
126.1(2C), 126.0, 125.1, 124.0, 121.8, 121.4, 112.7, 98.3, 81.9, 71.8, 65.5, 59.7, 27.8; IR (Neat): 3374, 2985, 2924, 1728, 1714, 1607, 1477,
1462, 1214, 1156; HRMS (ESI): calcd for [M+H]+ (C32H30O4N)+ requires 492.2169; found 492.2163; enantiomeric excess: 98%, determined
28.0
by HPLC (Chiralpak IC, hexane/i-PrOH 90/10, flow rate 1.0 mL/min; tmajor = 19.9 min, tminor = 12.9 min, λ = 254 nm); [α]D = -196.0 (c =
1.0, CHCl3).
4.3.15 Methyl (2S,2'R,4'S,5'R)-4'-(4-methoxyphenyl)-3-oxo-2'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4o)
1
white solid, mp: 138-139 °C; H NMR (CDCl3, 400 MHz) δ 7.46-7.42 (m, 1H), 7.30-7.22 (m, 6H), 7.16 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4
Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 2H), 4.85 (s, 1H), 4.48 (d, J = 10.4 Hz, 1H), 3.87 (d, J = 10.4 Hz, 1H), 3.69 (s, 6H), 3.06
(br, 1H); 13C NMR (CDCl3, 100 MHz) δ 199.1, 172.3, 170.6, 158.9, 137.7, 136.7, 130.3, 128.2, 128.1, 127.0, 125.2, 123.9, 121.8, 121.4, 113.5,
112.7, 97.7, 71.1, 64.8, 57.4, 55.0, 52.4; IR (Neat): 3365, 2953, 2924, 1740, 1715, 1612, 1515, 1477, 1462, 1301, 1253, 1180, 1144; HRMS
(ESI): calcd for [M+H]+ (C26H24O5N)+ requires 430.1649; found 430.1645; enantiomeric excess: 99%, determined by HPLC (Chiralpak AD-H,
hexane/i-PrOH 80/20, flow rate 1.0 mL/min; tmajor = 24.0 min, tminor = 27.6 min, λ = 254 nm); [α]D26.5 = -115.1 (c = 1.0, CHCl3).
4.3.16 Methyl (2S,2'R,4'S,5'R)-3-oxo-2'-phenyl-4'-(p-tolyl)-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4p)
white solid, mp: 138-139 °C; 1H NMR (CDCl3, 400 MHz) δ 7.41-7.45 (m, 1H), 7.30-7.21 (m, 6H), 7.09-7.13 (m, 2H), 6.98-7.00 (m, 2H), 6.94
(d, J = 8.4 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 4.85 (s, 1H), 4.51 (d, J = 10.4 Hz, 1H), 3.88 (d, J = 10.4 Hz, 1H), 3.70 (s, 3H), 2.99 (br, 1H), 2.22
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 199.3, 172.4, 170.7, 137.7, 137.1, 136.7, 130.4, 129.1, 128.8, 128.2, 128.0, 127.0, 123.9, 121.7, 121.4,
112.7, 97.7, 71.2, 64.8, 57.6, 52.3, 21.0; IR (Neat): 3361, 3030, 2982, 2952, 2924, 1743, 1611, 1477, 1461, 1213, 1143; HRMS (ESI): calcd
for [M+H]+ (C26H24O4N)+ requires 414.1700; found 414.1700; enantiomeric excess: 97%, determined by HPLC (Chiralpak IC, hexane/i-PrOH
70/30, flow rate 1.0 mL/min; tmajor = 40.4 min, tminor = 13.0 min, λ = 254 nm); [α]D22.2 = -97.2 (c = 1.0, CHCl3).
4.3.17 Methyl (2S,2'R,4'S,5'R)-4'-(4-chlorophenyl)-3-oxo-2'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4q)
white solid, mp: 126-127 °C; 1H NMR (CDCl3, 400 MHz) δ 7.37-7.41 (m, 1H), 7.15-7.24 (m, 6H), 7.07-7.12 (m, 4H), 6.88 (d, J = 8.4 Hz, 1H),
6.82 (t, J = 7.4 Hz, 1H), 4.78 (s, 1H), 4.42 (d, J = 10.4 Hz, 1H), 3.81 (d, J = 10.4 Hz, 1H), 3.63 (s, 3H), 3.13 (br, 1H); 13C NMR (CDCl3, 100
MHz) δ 198.8, 172.0, 170.5, 137.9, 136.5, 133.5, 131.9, 130.6, 128.3, 128.3, 128.2, 127.0, 124.0, 122.0, 121.2, 112.7, 97.4, 71.2, 64.6, 57.2,
52.4; IR (Neat): 3356, 3063, 3030, 2953, 2925, 2853, 1741, 1715, 1611, 1494, 1477, 1462, 1300, 1205, 1144; HRMS (ESI): calcd for [M+H]+
(C25H21O4NCl)+ requires 434.1154; found 434.1151; enantiomeric excess: 94%, determined by HPLC (Chiralpak IC, hexane/i-PrOH 90/10,
flow rate 0.9 mL/min; tmajor = 34.7 min, tminor = 25.4 min, λ = 254 nm); [α]D22.4 = -100.8 (c = 1.0, CHCl3).
4.3.18 Methyl (2S,2'R,4'S,5'R)-4'-(4-bromophenyl)-3-oxo-2'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4r)
white solid, mp: 127-128 °C; 1H NMR (CDCl3, 400 MHz) δ 7.37-7.42 (m, 1H), 7.15-7.26 (m, 8H), 7.04-7.06 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H),
6.82 (t, J = 7.6 Hz, 1H), 4.78 (s, 1H), 4.42 (d, J = 10.4 Hz, 1H), 3.79 (d, J = 10.4 Hz, 1H), 3.63 (s, 3H), 3.12 (br, 1H); 13C NMR (CDCl3, 100
MHz) δ 198. 8, 172.0, 170.5, 138.0, 136.4, 132.4, 131.3, 130.9, 128.3, 128.2, 127.0, 124.0, 122.0, 121.7, 121.2, 112.7, 97.3, 71.2, 64.5, 57.1,
52.5; IR (Neat): 3361, 3029, 2985, 2952, 2925, 2853, 1741, 1715, 1611, 1490, 1477, 1462, 1205, 1144; HRMS (ESI): clad for [M+H]+
(C25H21O4NBr)+ requires 478.0648; found 478.0645; enantiomeric excess: 94%, determined by HPLC (Chiral Pak IC, hexane/i-PrOH 90/10,
8

ACCEPTED MANUSCRIPT
flow rate 1.0 mL/min; tmajor = 30.3 min, tminor = 24.2 min, λ = 254 nm); [α]D25.9 = -108.3 (c = 1.0, CHCl3).
4.3.19 Tert-butyl (2S,2'R,4'S,5'R)-4'-(4-methoxyphenyl)-3-oxo-2'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4s)
1
white solid, mp: 133-134 °C; H NMR (CDCl3, 400 MHz) δ 7.42-7.46 (m, 1H), 7.22-7.31 (m, 6H), 7.16 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.4
Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 8.8 Hz, 2H), 4.83 (s, 1H), 4.34 (d, J = 10.8 Hz, 1H), 3.69-3.73 (m, 4H), 2.74 (br, 1H), 1.29 (s,
9H); 13C NMR (CDCl3, 100 MHz) δ 199.2, 171.2, 170.6, 158.8, 137.7, 137.1, 130.6, 128.3, 128.0, 127.1, 125.4, 123.9, 121.7, 121.5, 113.3,
112.8, 98.4, 81.8, 71.7, 65.6, 58.7, 55.1, 27.8; IR (Neat): 3361, 2975, 2930, 1721, 1612, 1515, 1476, 1461, 1369, 1299, 1252, 1157; HRMS
(ESI): calcd for [M+H]+ (C29H30O5N)+ requires 472.2118; found 472.2119; enantiomeric excess: 94%, determined by HPLC (Chiralpak PC-2,
hexane/i-PrOH 80/20, flow rate 1.0 mL/min; tmajor = 6.7 min, tminor = 9.1 min, λ = 254 nm); [α]D28.2 = 210.8 (c = 1.0, CHCl3).
4.3.20 Tert-butyl (2S,2'R,4'S,5'R)-3-oxo-2'-phenyl-4'-(p-tolyl)-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4t)
white solid, mp: 137-138 °C; 1H NMR (CDCl3, 400 MHz) δ 7.41-7.45 (m, 1H), 7.23-7.30 (m, 6H), 7.11-7.13 (m, 2H), 6.96-6.98 (m, 3H), 6.85
(t, J = 7.4 Hz, 1H), 4.83 (s, 1H), 4.36 (d, J = 10.8 Hz, 1H), 3.73 (d, J = 10.8 Hz, 1H), 2.74 (br, 1H), 2.21 (s, 3H), 1.29 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 199.2, 171.2, 170.7, 137.7, 137.0, 136.9, 130.5, 129.4, 128.6, 128.3, 128.0, 127.1, 123.9, 121.7, 121.5, 112.8, 98.3, 81.8,
71.8, 65.6, 58.8, 27.8, 21.0; IR (Neat): 3361, 2976, 2926, 1721, 1610, 1476, 1460, 1369, 1299, 1219, 1158; HRMS (ESI): calcd for [M+H]+
(C29H30O4N)+ requires 456.2169; found 456.2170; enantiomeric excess: 90%, determined by HPLC (Chiralpak PC-2, hexane/i-PrOH 80/20,
flow rate 1.0 mL/min; tmajor = 5.8 min, tminor = 7.9 min, λ = 254 nm); [α]D28.3 = 212.2 (c = 1.0, CHCl3).
4.3.21 Tert-butyl (2S,2'R,4'S,5'R)-4'-(4-fluorophenyl)-3-oxo-2'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4u)
white solid, mp: 132-133 °C; 1H NMR (CDCl3, 400 MHz) δ 7.44-7.48 (m, 1H), 7.20-7.30 (m, 8H), 6.97 (d, J = 8.4 Hz, 1H), 6.83-6.90 (m, 3H),
4.84 (s, 1H), 4.35 (d, J = 10.8 Hz, 1H), 3.74 (d, J = 10.8 Hz, 1H), 2.85 (br, 1H), 1.28 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 198.9, 171.0,
170.5, 163.4, 160.9, 137.9, 137.0, 131.1, 131.0, 129.2(2C), 128.3, 128.1, 127.1, 124.0, 121.9, 121.4, 114.9, 114.7, 112.7, 98.2, 82.0, 71.8, 65.5,
58.5, 27.8; IR (Neat): 3361, 2977, 2929, 1708, 1609, 1513, 1475, 1459, 1369, 1231, 1158; HRMS (ESI): calcd for [M+H]+ (C28H27O4NF)+
requires 460.1919; found 460.1919; enantiomeric excess: 99%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 90/10, flow rate 1.0
mL/min; tmajor = 9.4 min, tminor = 24.5 min, λ = 254 nm); [α]D28.4 = 224.5 (c = 1.0, CHCl3).
4.3.22 Tert-butyl (2S,2'R,4'S,5'R)-4'-(4-chlorophenyl)-3-oxo-2'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4v)
white solid, mp: 142-143 °C; 1H NMR (CDCl3, 400 MHz) δ 7.44-7.48 (m, 1H), 7.23-7.31 (m, 6H), 7.13-7.20 (m, 4H), 6.97 (d, J = 8.4 Hz, 1H),
6.88 (t, J = 7.6 Hz, 1H), 4.83 (s, 1H), 4.35 (d, J = 10.8 Hz, 1H), 3.73 (d, J = 10.8 Hz, 1H), 2.77 (br, 1H), 1.29 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 198.8, 170.8, 170.5, 137.9, 136.9, 133.3, 132.1, 130.8, 128.3, 128.2, 128.1, 127.1, 124.0, 122.0, 121.3, 112.8, 98.1, 82.1, 71.8, 65.4,
58.3, 27.8; IR (Neat): 3360, 3063, 3031, 2977, 2929, 1725, 1611, 1494, 1462, 1369, 1299, 1156; HRMS (ESI): calcd for [M+H]+
(C28H27O4NCl)+ requires 476.1550; found 476.1621; enantiomeric excess: 99%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 90/10,
flow rate 1.0 mL/min; tmajor = 10.0 min, tminor = 20.2 min, λ = 254 nm); [α]D28.4 = 213.7 (c = 1.0, CHCl3).
4.3.23 Tert-butyl (2S,2'R,4'S,5'R)-4'-(4-bromophenyl)-3-oxo-2'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4w)
white solid, mp: 140-141 °C; 1H NMR (CDCl3, 400 MHz) δ 7.46-7.49 (m, 1H), 7.23-7.32 (m, 8H), 7.12-7.14 (m, 2H), 6.97 (d, J = 8.4 Hz, 1H),
6.89 (t, J = 7.6 Hz, 1H), 4.83 (s, 1H), 4.35 (d, J = 10.8 Hz, 1H), 3.72 (d, J = 10.8 Hz, 1H), 2.75 (br, 1H), 1.30 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 198.8, 170.8, 170.5, 138.0, 136.8, 132.7, 131.2, 131.1, 128.3, 128.2, 127.0, 124.0, 122.0, 121.5, 121.3, 112.8, 98.1, 82.1, 71.8, 65.4,
58.3, 27.8; IR (Neat): 3348, 2981, 2933, 1723, 1611, 1489, 1477, 1462, 1369, 1325, 1299, 1156; HRMS (ESI): calcd for [M+H]+
(C28H27O4NBr)+ requires 520.1118; found 520.1115; enantiomeric excess: 99%, determined by HPLC (Chiralpak IC+AD-H, hexane/i-PrOH
90/10, flow rate 1.0 mL/min; tmajor = 19.1 min, tminor = 28.9 min, λ = 254 nm); [α]D27.5 = -81.7 (c = 1.0, CHCl3).
4.3.24 Tert-butyl (2S,2'R,4'S,5'R)-4'-(3-chlorophenyl)-3-oxo-2'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4x)
colorless oil; 1H NMR (CDCl3, 400 MHz) δ 7.44-7.49 (m, 1H), 7.23-7.31 (m, 7H), 7.08-7.13 (m, 3H), 7.00 (d, J = 8.0 Hz, 1H), 6.89 (t, J = 7.4
Hz, 1H), 4.84 (s, 1H), 4.35 (d, J = 10.8 Hz, 1H), 3.71 (d, J = 10.8 Hz, 1H), 2.80 (br, 1H), 1.30 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 198.8,
170.7, 170.5, 137.9, 136.7, 135.8, 133.7, 129.6, 129.2, 128.3, 128.2, 127.8, 127.6, 127.0, 124.0, 122.0, 121.3, 112.8, 98.0, 82.1, 71.8, 65.5,
58.5, 27.8; IR (Neat): 3352, 3071, 2989, 2929, 1716, 1613, 1477, 1461, 1369, 1299, 1156; HRMS (ESI): calcd for [M+H]+ (C28H27O4NCl)+
requires 476.1623; found 476.1622; enantiomeric excess: 98%, determined by HPLC (Chiralpak IC, hexane/i-PrOH 95/5, flow rate 0.7
mL/min; tmajor = 22.2 min, tminor = 17.4 min, λ = 254 nm); [α]D27.0 = -86.0 (c = 1.0, CHCl3).
4.3.25 Tert-butyl (2S,2'R,4'R,5'R)-4'-(furan-2-yl)-3-oxo-2'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4y)
1
white solid, mp: 134-135 °C; H NMR (CDCl3, 400 MHz) δ 7.47-7.51 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.26-7.30 (m, 2H),
7.18-7.22(m, 4H), 7.01 (d, J = 8.4 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.22 (br, 1H), 6.14 (d, J = 3.2 Hz, 1H), 4.83 (s, 1H), 4.40 (d, J = 10.0 Hz,
1H), 3.92 (d, J = 10.0 Hz, 1H), 2.85 (br, 1H), 1.43 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ199.7, 171.1, 170.6, 148.7, 142.3, 137.8, 136.1,
128.2, 128.0, 126.8, 124.0, 121.9, 121.1, 112.8, 110.1, 108.6, 96.9, 82.1, 70.7, 64.1, 51.9, 27.9; IR (Neat): 3356, 3309, 2976, 2928, 1710, 1609,
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ACCEPTED MANUSCRIPT
1503, 1475, 1458, 1369, 1325, 1297, 1249; HRMS (ESI): calcd for [M+H]+ (C26H26O5N)+ requires 432.1805; found 432.1809; enantiomeric
excess: 96%, determined by HPLC (Chiralpak IC, hexane/i-PrOH 70/30, flow rate 1.0 mL/min; tmajor = 21.0 min, tminor = 7.2 min, λ = 254 nm);
[α]D28.0 = -93.6 (c = 1.0, CHCl3).
4.3.26 Tert-butyl (2S,2'R,4'S,5'R)-4'-(naphthalen-2-yl)-3-oxo-2'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4z)
white solid, mp: 161-162 °C; 1H NMR (CDCl3, 400 MHz) δ 7.67-7.79 (m, 4H), 7.45 (d, J = 8.8 Hz, 1H), 7.37-7.42 (m, 3H), 7.24-7.33 (m, 6H),
6.92 (d, J = 8.4 Hz, 1H), 6.81 (t, J = 7.4 Hz, 1H), 4.91 (s, 1H), 4.53 (d, J = 10.8 Hz, 1H), 3.95 (d, J = 10.8 Hz, 1H), 2.67 (br, 1H), 1.21 (s, 9H);
13C NMR (CDCl3, 100 MHz) δ 199.3, 171.1, 170.7, 137.8, 136.9, 133.0, 132.6, 131.3, 128.8, 128.3, 128.1, 127.8, 127.4, 127.2, 127.1,
125.8(2C), 124.0, 121.8, 121.4, 112.7, 98.5, 81.9, 71.9, 65.6, 59.2, 27.8; IR (Neat): 3339, 3058, 2985, 2929, 1715, 1606, 1476, 1461, 1368,
1299, 1153; HRMS (ESI): calcd for [M+H]+ (C32H30O4N)+ requires 492.2169; found 492.2166; enantiomeric excess: 95%, determined by
HPLC (Chiralpak PC-2, hexane/i-PrOH 80/20, flow rate 1.0 mL/min; tmajor = 6.3 min, tminor = 8.6 min, λ = 254 nm); [α]D28.2 = -88.4 (c = 1.0,
CHCl3).
4.3.27 Methyl (2S,2'R,4'S,5'R)-5-methyl-3-oxo-2',4'-diphenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4oa)
white solid, mp: 112-113 ; 1H NMR (CDCl3, 400 MHz) δ 7.28 (t, J = 4.1 Hz, 4H), 7.25-7.12 (m, 7H), 7.08 (d, J = 1.9 Hz, 1H), 6.82 (d, J =
8.5 Hz, 1H), 4.84 (s, 1H), 4.53 (d, J = 10.2 Hz, 1H), 3.89 (d, J = 10.3 Hz, 1H), 3.70 (s, 3H), 2.19 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
199.3, 172.3, 169.1, 139.0, 136.7, 133.4, 131.3, 129.2, 128.2, 128.0, 127.5, 126.9, 123.3, 121.2, 112.2, 97.8, 71.2, 64.6, 58.0, 52.3, 20.4; IR
(Neat): 3030, 2951, 1740, 1717, 1618, 1601, 1490, 1452, 1436, 1383, 1312, 1283, 1243, 1207, 1177, 1110; HRMS (ESI): calcd for [M+H]+
(C26H24O4N)+ requires 414.1700; found 414.1700; enantiomeric excess: 98%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 80/20,
flow rate 1.0 mL/min; tmajor = 17.9 min, tminor = 32.1 min, λ = 254 nm); [α]D25 = -204.1 (c = 0.5, CHCl3).
4.3.28 Methyl (2S,2'R,4'S,5'R)-5-fluoro-3-oxo-2',4'-diphenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4ob)
white solid, mp: 41-42
;
1H NMR (CDCl3, 400 MHz) δ 7.34 (m, 1H), 7.23-7.12 (m, 11H), 6.89 (dd, J = 9.0, 3.6 Hz, 1H), 4.86 (s, 1H),
4.56-4.50 (d, J =12.0 Hz, 1H), 3.89 (d, J = 10.2 Hz, 1H), 3.71 (s, 3H), 3.15 (br, 1H); 13C NMR (CDCl3, 100 MHz) δ 198.9, 198.9 (isomer),
172.2, 166.8 (isomer), 157.5 (d, 1JCF = 241.0 Hz) 136.4, 133.1, 129.2, 128.3, 128.2, 128.1, 127.6, 126.9, 126.5, 125.5, 125.3, 113.7, 113.6
(isomer), 109.1, 108.9 (isomer), 99.1, 98.9 (isomer), 71.2, 69.9 (isomer), 64.5, 63.7 (isomer) , 58.2, 58.1 (isomer), 52.5, 52.4 (isomer); IR
(Neat): 2961, 2924, 2852, 1716, 1608, 1463, 1435, 1303, 1261, 1207, 1179, 1020; HRMS (ESI): calcd for [M+H]+ (C25H21O4NF)+ requires
418.1449; found 418.1449; enantiomeric excess: 89%, 90%, 91%, >99%, determined by HPLC (Chiralpak IC+AD-H, hexane/i-PrOH 90/10,
flow rate 1.0 mL/min; tmajor = 113.6 min, tminor = 95.8 min; tmajor = 59.4 min, tminor = 48.1 min; tmajor = 32.7 min, tminor = 31.1 min; tmajor = 38.0
min, λ = 254 nm); [α]D25 = -205.1 (c = 0.25, CHCl3).
4.3.29 Methyl (2S,2'R,4'S,5'R)-5-chloro-3-oxo-2',4'-diphenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate (4oc)
white solid, mp: 42-43 ; 1H NMR (CDCl3, 400 MHz) δ 7.36-7.23 (m, 3H), 7.23-7.10 (m, 9H), 6.88 (d, J = 8.8 Hz, 1H), 4.86 (s, 1H), 4.52 (d,
J = 10.2 Hz, 1H), 3.89 (d, J = 10.2 Hz, 1H), 3.70 (s, 3H), 3.15 (br, 1H); 13C NMR (CDCl3, 100 MHz) δ 198.1, 172.2, 168.9, 137.6, 136.4,
133.1, 129.2, 128.4, 128.3, 128.2, 127.0, 123.3, 122.4, 114.0, 98.8, 71.3, 64.5, 58.3, 52.4; IR (Neat): 2961, 2924, 2852, 1716, 1608, 1463,
1435, 1303, 1261, 1207, 1179, 1020; HRMS (ESI): calcd for [M+H]+ (C25H21O4NCl)+ requires 434.1154; found 434.1154; enantiomeric
excess: 86%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 85/15, flow rate 1.0 mL/min; tmajor = 17.4 min, tminor = 39.9 min, λ = 254
nm); [α]D25 = -29.1 (c = 0.5, CHCl3).
Acknowledgment
Financial support from Chinese Academy of Sciences (XDB 20020100) and the National Natural Science Foundation of China (Nos.
21272247, 21572247) is gratefully acknowledged.
Supplementary data
Supplementary data (details of condition optimization, NMR spectra, HPLC data and X-ray crystal data of compounds 4r) associated
with this article can be found in the online version, at http://
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