Enantioselective direct Mannich reactions of 3-substituted oxindoles catalyzed by chiral phosphine via dual-reagent catalysis

Article abstract of DOI:10.1016/j.tet.2018.06.030

A combination of an amino acid-derived chiral phosphine catalyst and methyl acrylate to catalyze the direct Mannich reaction of 3-substituted oxindoles and imines has been reported to afford 3-tetrasubstituted oxindole derivatives which are key structures

Full text of DOI:10.1016/j.tet.2018.06.030

Accepted Manuscript
Enantioselective direct Mannich reactions of 3-substituted oxindoles catalyzed by
chiral phosphine via dual-reagent catalysis
Qiaowen Jin, Changwu Zheng, Gang Zhao, Gang Zou
PII:
S0040-4020(18)30719-1
10.1016/j.tet.2018.06.030
TET 29626
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 March 2018
Revised Date: 11 June 2018
Accepted Date: 13 June 2018
Please cite this article as: Jin Q, Zheng C, Zhao G, Zou G, Enantioselective direct Mannich reactions of
3-substituted oxindoles catalyzed by chiral phosphine via dual-reagent catalysis, Tetrahedron (2018),
doi: 10.1016/j.tet.2018.06.030.
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ACCEPTED MANUSCRIPT
Enantioselective Direct Mannich Reactions of 3-substituted Oxindoles
Catalyzed by Chiral Phosphine via Dual-Reagent Catalysis
Qiaowen Jina, Changwu Zhengb, Gang Zhaob, *, and Gang Zoua, *
a School of Chemistry
＆Molecular Engineering, East China University of Science＆Technology, 130
Meilong Road, Shanghai 200237, China
Fax: (+86)-21-6425-3881; e-mail: zougang@ecust.edu.cn
b
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
Fax: (+86)-21-6416-6128; e-mail: zhaog@sioc.ac.cn
Pg2
HN
R1
PPh2
R1
R2
*P (10 mol %)
HN
S
Pg2
methyl acrylate (10 mol %)
ether, -40 o
+
O
N
R2
O
HN
CF3
C
N
N
Pg1
Pg1
Pg1 = Bn, Boc, Me, Pg2 = Boc, Ts, Cbz,
R1 = aryl, alkyl, F, R2 = aryl, alkyl
29 examples
up to 99% ee
99:1 dr
*P:
CF3
* Corresponding author.
zhaog@sioc.ac.cn (G. Zhao)
* Corresponding author.
zougang@ecust.edu.cn (G. Zou)

ACCEPTED MANUSCRIPT
Enantioselective Direct Mannich Reactions of 3-Substituted Oxindoles Catalyzed
by Chiral Phosphine via Dual-Reagent Catalysis
Qiaowen Jina, Changwu Zhengb, Gang Zhaob, *, and Gang Zoua, *
aSchool of Chemistry
＆Molecular Engineering, East China University of Science＆Technology, 130 Meilong Road, Shanghai 200237, 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:
A combination of an amino acid-derived chiral phosphine catalyst and methyl acrylate to catalyze
the direct Mannich reaction of 3-substituted oxindoles and imines has been reported to afford
3-tetrasubstituted oxindole derivatives which are key structures for biological activities. The
products are formed with a quaternary carbon and featured with two adjacent chiral centers.
Various N-EDG(electron-donating group) and N-EWG(electron-withdrawing group) protected
oxindoles, including 3-aryl and 3-alkyl substituted ones, have been evaluated with aromatic and
aliphatic imines under this catalytic system, smoothly giving desired products in good yields as
well as excellent diastereo- and enantioselectivities.
Keywords:
Mannich-type reactions
Nucleophilic phosphines
Dual-reagent catalysis
1. Introduction
3,3’-Pyrrolidinyl spirooxindole scaffolds are important structural motifs found in a wide array of natural and synthesized
biologically active molecules.1 For instance, MI-147,2 which is a rationally designed molecule based on natural occurring
spirotryprostatin A, functions as a specific and potent inhibitor of MDM2-p53 interaction to selectively inhibit the growth of
tumor cells (Figure 1). The direct Mannich-type reaction of 3-substituted oxindoles with imines is a straightforward method for
making enantioenriched spirooxindole consisting of adjacent chiral centers. However, enantioselective synthesis of the
stereogenic centers is problematic due to the steric congestion when two chiral centers at the 3-position of oxindole formed
simultaneously. Since Chen and co-workers3 reported the first reaction between N-Boc-3-alkyl oxindoles and N-Boc-imines in
the presence of bifunctional thiourea-tertiary amine in 2008, several progresses have been made in this field4-11 . However, to the
best of our knowledge, the general flexibility of the reported catalyst system in the reactions between N-protected oxindoles
bearing kinds of 3-position substituents and different N-protected imines was still challenging. Herein, we attempt to address this
problem by development of a novel catalytic system which is effective for the Mannich reactions of 3-aryl, alkyl or halogen
substituted N-Bn and N-Boc protected oxindoles with aromatic or aliphatic imines.
Figure 1. Natural product and unnaturally bioactive analogue.
Recently our group has developed chiral phosphine catalyzed Mannich-type reactions of several nucleophiles to
N-Boc-imines, via asymmetric dual-reagent catalysis by zwitterions formed from the phosphine catalyst and methyl acrylate in
situ12-15. This novel catalytic strategy exhibited high efficiency and an excellent degree of enantiocontrol in creating chiral
compounds. As a continued study, we are testing this strategy in the reaction of 3-substituted oxindoles with imines. Various
kinds of oxindoles, not only aromatic imines but also aliphatic imines, have worked well. High yields and high diastereo- and
enantioselectivities have been obtained (Scheme 1).
* Corresponding author.
zhaog@sioc.ac.cn (G. Zhao)
* Corresponding author.
zougang@ecust.edu.cn (G. Zou)
1

ACCEPTED MANUSCRIPT
Scheme 1. The asymmetric Mannich reaction of 3-substituted oxindoles with imines
2. Results and Discussion
We chose N-benzyl oxindole 1a and N-Boc-imine 2a as models, and several conditions were examined. When the reaction
was performed in toluene at room temperature in the presence of bifunctional chiral phosphine catalysts 3a, 3b, and 3c derived
from L-phenylalanine, the better results came with 3c bearing a thiourea moiety which afforded the desired product 4aa with 94:6
dr and 76 % ee (Table 1, entries 1-3). Herein, with the thiourea part in place, five additional chiral phosphine catalysts derived
from isoleucine and -tert-butyl-leucine were evaluated. The results shown that catalyst 3e with a strongly electron-withdrawing
L
trifluoromethyl group at the 3,5-positions of the phenyl thiourea from -tert-butyl-leucine, turned out to be the best one, giving
L
the desired product in 87% yield, 92:8 dr and 78% ee (Table 1, entries 4-8). Solvent and temperature effect were then
investigated. The use of ether as solvent improved the enantioselectivity to 85% ee (Table 1, entries 9-12). Under lower
o
temperature, we got the optimal conditions as demonstrated in entry 15 by running the reaction in 1.0 mL of ether at -40 C to
provide the product with 95:5 dr and 94% ee (Table 1, entries 13-15). The reaction could not proceed without methyl acrylate
until the temperature rose up to room temperature and only 68:32 dr and 61% ee were obtained, suggesting the indispensable role
of methyl acrylate in imparting stereocontrol (Table 1, entry 16).
Table 1. Optimization of conditions and evaluation of chiral catalysts.
Entry a
1
Cat.
3a
3b
3c
3d
3e
3f
3g
3h
3e
3e
3e
3e
3e
3e
3e
3e
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
CHCl3
THF
Et2O
Et2O
Et2O
Temperature (oC)
Time
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
40 min
10 min
10 min
30 min
3 h
Yield (%)b
88
dr c
ee (%)c
16
41
76
69
78
57
31
34
78
73
24
85
89
91
94
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
71:29
90:10
94:6
94:6
92:8
88:12
86:14
87:13
87:13
84:16
86:14
92:8
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16f
86
87
88
87
89
90
91
89
89
87
90
87
89
88
92:8
94:6
95:5
-20
-40
r.t.
Et2O
6 h
Et2O
1h
75
68:32
61
2

ACCEPTED MANUSCRIPT
a Unless otherwise noted, the reaction was conducted with 0.1 mmol of 1a, 0.2 mmol of 2a, and 0.01 mmol of acrylate in the presence of
10 mol % of catalyst 3 in 1 mL of solvent.
b Isolated yield.
c Determined by chiral HPLC analysis.
f Without methyl acrylate
.
Under the optimized conditions, a series of substituted N-benzyl oxindoles were examined and the results were summarized
in Scheme 2. All the reactions proceeded well for N-benzyl oxindoles based on 1a bearing electron-donating and
electron-withdrawing groups on the benzene ring (4ba-4ha), and different substitution positions had no significant effect on the
results except the 4-substitued product 4ca, which had a slightly decreased enantioselectivity. When 3-benzyl, 3-methyl, 3-allyl
and 3-benzoxylethyl substituted oxindoles were examined, good to high diastereoselectivities were obtained albeit with lower
enantioselectivities (4ia-4la, 83-89% ee). Besides these substrates, the reaction with the 3-phenyl substituted oxindole 1m, which
with a modified conditions (catalyst 3c in DCM at -40 oC), gave the corresponding product 4ma in 90% yield with a little inferior
enantioselectivity (81% ee).
a Performed in DCM at -40oC with 3c.
Scheme 2. Exploring the scope of the N-benzyl protected oxindoles
Next, we continued to try other N-protected oxindoles with a variety of imines to test the catalytic system. When the
N-methyl, N-Boc protected 3-alkyl oxindoles 1n and 1o were examined, both excellent diastereo- and enantioselectivities were
obtained (Scheme 3, 4na and 4oa) while the N-Boc oxindole substrate gave a higher ee value. A little inferior result with N-Boc
3-phenyl-oxindole 1p was observed in terms of the enantioselectivity, even if the reaction could proceed with high efficiency to
give the product in high yield and diastereoselectivity (90% yield, 96:4 dr). It should be noted that substrates with different
N-protecting group in previous reactions had never been achieved with one catalytic system. The absolute configuration of the
resulted 4ra was determined by comparison of the NMR spectra and specific optical rotation with the literature data8 and other
adducts were assigned by analogy according to 4ra. We also applied N-Boc-3-fluorooxindole 1s with 2a in the presence of
catalysts 3d in DCM at room temperature, giving the desired product 4sa in 94 % yield with 95:5 dr and 94 % ee. With excellent
results achieved with different N-protected oxindoles, we then chose to investigate the reactions of N-Boc oxindoles with a
3

ACCEPTED MANUSCRIPT
variety of imines. Reactions with imines 2b-2e bearing electron-withdrawing or electron-donating substituents at the benzene
rings proceeded smoothly to afford the desired products in high yields as well as excellent diastereo- and enantioselectivities
(4ob-4oe). Similar results were obtained when heteroaromatic imine 2f was examined (4of). Aliphatic imines 2g and 2h were
also well tolerated in this reaction, giving the desired products with excellent diastereo- and enantioselectivities albeit with low
yields (4og and 4oh). Noteworthy, this type of reactions with both aliphatic and aromatic imines to give excellent diastereo- and
enantioselectivities products was also extremely rare in previous reports. Reactions with N-Cbz imine 2j and N-Ts imine 2i were
also tested and the inferior results obtained suggested the Boc group at the imine nitrogen played a key role in this reaction (4ai
and 4aj). The adduct 4rk and 4tk, obtained by the reaction of 1r, 1t and the aliphatic imine 2k in 99% ee,97:3 dr, and 99%
ee, >19:1dr respectively were readily converted to spirooxindole derivative 6which contains a key skeleton of the nature product
(+)-elacomine(Scheme 4).8 Thus, we have succeeded in providing oxindole derivatives that have adjacent quaternary and tertiary
chiral centers in satisfactory yields and stereoselectivities with wide substrate scope.
a Performed in DCM at -40oC with 3c. b 3d was used in DCM at room temperature. c The reaction was stirred for 24h.
Scheme 3. Exploration of a variety of oxindoles and imines a
Scheme 4. Transformation to spirooxindole
To get some insight into this reaction, 31P NMR analysis of 3e and methyl acrylate in deuterated ether was performed (Figure
2). We proposed a zwitterion intermediate A was formed during the reaction as a new P NMR chemical shift was generated at
δ=26 ppm when catalyst 3e and methyl acrylate was first mixed. This was further confirmed by ESI-MS (see the Supporting
4

Information) with a single peak (m/z AforC(MC+EHP)+T:6E43D.25M00)AoNbseUrvSedC. RA InPewTsingle resonance appeared at δ=27 ppm when
nucleophile 1a was mixed with the above solution, suggesting the zwitterion A was converted into a new species which we
proposed to be the ion-pair B. On the basis of these experimental results and previous related studies, a plausible transition state
was proposed to explain the stereochemistry of the product (Scheme 5). Firstly, the chiral phosphine adds to the methyl acrylate
to form the phosphonium enolate A which trapped by nucleophile 3-substituted oxindole 1 to generate the ion-pair B. At the
same time, the N-Boc-imine is activated by the thiourea moiety through hydrogen bonding, giving strict conformational control
that results in an excellent recognition of the Re-face of the imine by the chiral ion pair. These interactions control the
stereochemical outcome of the reaction.
Figure 2. The 31P NMR spectra research in ether
5

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Scheme 5. Possible reaction mechanism and transition state
6

ACCEPTED MANUSCRIPT
3. Conclusions
In summary, we have developed a new catalytic method for the synthesis of optically active 3-tetrasubstituted oxindoles using
chiral bifunctional thiourea-phosphine via a dual-reagent catalysis. Adjacent quaternary and tertiary chiral centers have been created
efficiently by the phosphine-catalyzed reactions of 3-substituted oxindoles with imines. Various N-EDG and N-EWG protected
oxindoles, including 3-aryl and 3-alkyl substituted ones, reacted with aromatic and aliphatic N-protected-imines smoothly in this
catalyst system, giving the desired products in good yields as well as excellent diastereo- and enantioselectivities. Further studies on
this topic are underway in our laboratories.
4. Experimental
4.1 General information
Nuclear magnetic resonance spectra were recorded at 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 = quarter, br = broad, m= multiplet, cm = complex multiplet) and
coupling constants (Hz). 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 using chiral columns. Melting points were uncorrected. Optical rotations were measured at λ = 589
nm. High-resolution mass spectra were recorded using TOF mass analyzer. The synthesis of 3-substituted oxindoles,16-17 23-10,18 and the
catalysts 3a-3h12-15 were performed according to reported methods.
4.2 General procedure for the preparation of substrates 1
A mixture of corresponding oxindole (0.1 mmol, 1.0 equiv) and indium chloride (0.01 mmol, 0.1 equiv) in acetonitrile (5 mL) was stirred
at 0oC for 5 min NaBH4 (0.2 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for another 10 min. The
resulting solution was poured into satd. aq.NH4Cl, and the organic layer was separated and dried over Na2SO4. The solvent was removed under
reduced pressure and the residue was purified by silica gel chromatography (petrolume ether/ethyl acetate = 9/1-5/1) to afford the product
1d-1f and 1q.
A mixture of NaH (0.2 mmol, 2.0eq) and ylide salt19 (0.2mmol, 2.0eq) was stirred at 0oC for 1h under N2 protection. Then
6-methoxyindoline-2,3-dione (0.1 mmol, 1.0eq) was added and the mixture was stirred under 80oC for 2h. The resulting solution was poured
into satd.aq.NH4Cl, and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure and the
product was dissolved in CH3CN, follwed by DMAP (0.2 mmol, 2.0eq), (Boc)2O (0.2 mmol, 2.0eq) were added ,the mixture was stirred under
room temperature for 20min. The crude product product was also obtained after the solvent was removed under reduced pressure and then
dissloved in EA and stirred with Pd/C under H2 condition for 4h under room temperature. The mixture was filtered and purified by silica gel
chromatography (petrolume ether/ethyl acetate = 8/1-5/1) to afford the product 1t
4.2.1 Ethyl 2-(1-benzyl-5-chloro-2-oxoindolin-3-yl) acetate (1d)
1
29.8 mg, 87% yield, yellow solid, m.p. 65-66oC. H NMR (400 MHz, CDCl3): δ(ppm) = 7.25-7.30 (m, 6H), 7.11 (dd, J = 1.2 Hz, J = 8.4
Hz,1H), 6.61 (d, J = 8.4 Hz, 1H), 4.90 (s, 2H), 4.11-4.16 (m, 2H), 3.82-3.85 (m, 1H), 3.12 (dd, J = 4.0 Hz, J = 16.8 Hz,1H), 2.88 (dd, J = 7.6
Hz, J = 17.2 Hz,1H), 1.19 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 176.3, 170.7, 142.1, 135.4, 129.9, 128.9, 128.1, 127.9,
127.8, 127.3, 124.5, 110.0, 61.1, 44.0, 41.9, 34.7, 14.1. IR (KBr): 3064, 3031, 2980, 2928, 1720, 1611, 1485, 1431, 1343, 1261, 1207, 1165,
1029. HRMS (ESI) m/z: [M+H]+ Calcd for C19H19ClNO3 344.1048, found 344.1045.
4.2.2 Ethyl 2-(1-benzyl-6-chloro-2-oxoindolin-3-yl) acetate (1e)
30.5 mg, 89% yield, yellow solid, m.p. 93-94oC. 1H NMR (400 MHz, CDCl3): δ(ppm) = 7.27-7.33 (m, 5H), 7.16 (dd, J = 0.8 Hz, J = 8.0 Hz,
1H), 6.96 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 4.89 (s, 2H), 4.10-4.14 (m, 2H), 3.81 (dd, J = 4.0 Hz, J = 7.2 Hz, 1H),
3.12 (dd, J = 4.4 Hz, J = 17.2 Hz, 1H), 2.87 (dd, J = 8.0 Hz, J = 17.2 Hz, 1H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) =
176.8, 170.7, 144.8, 135.3, 134.0, 128.9, 127.8, 127.3, 126.6, 124.8, 122.4, 109.7, 61.1, 44.1, 41.5, 34.8, 14.1. IR (KBr): 3062, 3030, 2980,
2929, 1723, 1610, 1588, 1498, 1441, 1373, 1339, 1257, 1206, 1112, 1072, 1029, 923, 841, 699, 524. HRMS (ESI) m/z: [M+H]+ Calcd for
C19H19NO3Cl 344.1048, found 344.1044.
4.2.3 Ethyl 2-(1-benzyl-7-chloro-2-oxoindolin-3-yl) acetate (1f)
29.8 mg, 87% yield, yellow oil. 1H NMR (400 MHz, CDCl3): δ(ppm) = 7.23-7.30 (m, 5H), 7.15-7.18 (m, 2H), 6.94 (dd, J = 7.2 Hz, J = 8.0 Hz,
1H), 5.37 (dd, J = 16.4 Hz, J = 21.2 Hz, 2H), 4.12-4.16 (m, 2H), 3.88 (dd, J = 4.4 Hz, J = 7.6 Hz, 1H), 3.12 (dd, J = 4.4 Hz, J = 16.8 Hz, 1H),
2.90 (dd, J = 7.6 Hz, J = 16.8 Hz, 1H), 1.20 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 177.3, 170.7, 139.6, 137.7, 131.1,
130.9, 128.5, 127.1, 126.6, 123.4, 122.3, 115.4, 61.1, 45.1, 41.7, 35.1, 14.1. IR (KBr): 3064, 3030, 2980, 2929, 1723, 1610, 1588, 1489, 1454,
1440, 1373, 1339, 1206, 1072, 1029, 841, 699, 524. HRMS (ESI) m/z: [M+H]+ Calcd for C19H19NO3Cl 344.1048, found 344.1045.
7

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4.2.4 Tert-butyl 5-bromo-3-(2-ethoxy-2-oxoethyl)-2-oxoindoline-1-carboxylate (1q)
1
31.4 mg, 79% yield, yellow oil. H NMR (400 MHz, CDCl3): δ(ppm) = 7.75 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 1.2 Hz, J = 8.8 Hz, 1H), 7.37
(br, 1H), 4.09-4.15 (m, 2H), 3.84-3.87 (m, 1H), 3.08 (dd, J = 4.4 Hz, J = 17.2 Hz, 1H), 2.96 (dd, J = 6.8 Hz, J = 17.2 Hz, 1H), 1.64 (s, 9H),
1.20 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 174.2, 170.2, 149.0, 139.4, 131.4, 129.1, 126.6, 117.3, 116.7, 84.7, 61.3, 42.3,
35.0, 28.1, 14.0. IR (KBr): 3447, 2981, 2934, 1731, 1603, 1474, 1394, 1370, 1337, 1297, 1155, 1109, 1066, 1028, 1003, 943, 821, 737, 528.
HRMS (ESI) m/z: [M+H]+ Calcd for C17H21NO5Br 398.0598, found 398.0599.
4.2.5 tert-butyl 3-((1,3-dioxolan-2-yl)methyl)-6-methoxy-2-oxoindoline-1-carboxylate (1t)
134 mg, 7% yield for three steps, yellow oil. 1H NMR (400 MHz, CDCl3): δ(ppm) = 7.40 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 0.8 Hz, J = 8.4 Hz,
1H), 6.61 (dd, J = 2.4 Hz, J = 8.4 Hz, 1H), 5.07 (dd, J = 3.6 Hz, J = 6.0 Hz, 1H), 3.84-3.89 (m, 1H), 3.74-3.81 (m, 6H), 3.58-3.61 (m, 1H),
2.30-2.36 (m, 1H), 2.07-2.13 (m, 1H), 1.57 (s, 9H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 176.5, 159.7, 149.3, 141.0, 124.8, 119.2, 109.8,
102.0, 101.6, 84.1, 65.0, 64.7, 55.5, 41.8, 35.1, 28.1. IR (KBr): 2955, 2926, 1793, 1762, 1727, 1616, 1499, 1349, 1304, 1255, 1148, 1025, 853,
771. HRMS (ESI) m/z: [M+Na]+ Calcd for C18H23NO6Na 372.1418, found 372.1420.
4.3 General Procedure for the product 4.
To a solution of the catalyst 3 (0.01 mmol, 0.1 equiv) in solvent (1.0 mL) was added methyl acrylate (0.01 mmol, 0.1 equiv), and the
mixture was stirred at room temperature for 10 min, and then the compound 1 was added. The resulting mixture was vigorously stirred for 10
o
min at room temperature and the cooled to -40 C before the imine 2 (0.2 mmol, 2.0 equiv) was introduced. When the reaction was finished
(determined by TLC analysis), the crude mixture was warmed to the room temperature and purified by flash column chromatography to afford
the product 4.
4.3.1 Ethyl 2-((R)-1-benzyl-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-2-oxoindolin-3-yl)acetate (4aa)
45.2 mg, 88% yield, white solid, m.p. 47-48oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.37-7.39 (m, 1H), 7.19-7.20 (m, 3H), 7.08 (t, J = 7.2
Hz, 1H), 7.01-7.04 (m, 2H), 6.97 (t, J = 7.6 HZ, 2H), 6.80-6.90 (m, 4H), 6.60 (d, J = 6.0 HZ, 1H), 6.29-6.31 (m, 1H), 5.13 (d, J = 10.0 Hz, 1H),
4.66 (s, 2H), 3.86-3.90 (m, 2H), 3.52 (d, J = 16.0 Hz, 1H), 3.14 (d, J = 16.0 Hz, 1H), 1.44 (s, 9H), 0.89 (t, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ(ppm) = 178.0, 169.7, 155.4, 143.6, 137.1, 135.2, 128.8, 128.6, 128.5, 127.5, 127.4, 127.3, 127.2, 127.1, 123.5, 109.3, 79.8,
60.5, 59.5, 53.3, 44.0, 39.9, 28.4, 13.8. IR (KBr): 3397, 3061, 3032, 2978, 2930, 1704, 1612, 1492, 1467, 1455, 1367, 1174, 1025, 882, 752,
699, 552. HRMS (ESI) calcd for C31H35N2O5 (M+H)+ 515.2540, found 515.2535. [α]29.0D = -48.2 (c 0.5, CHCl3) HPLC (Daicel Chiralpak
AD-H, i-PrOH/Hexane=20:80, 254 nm, 1.0 mL/min): major 36.9 min, minor 11.3 min. Enantiomeric excess: 96%.
4.3.2 Ethyl 2-((R)-1-benzyl-5-bromo-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-2-oxoindolin-3-yl)acetate (4ba)
1
52.1 mg, 88% yield, white solid, m.p. 74-75oC. H NMR (400 MHz, CDCl3) δ(ppm) = 7.49 (s, 1H), 7.19-7.21 (m, 3H), 7.09-4.14 (m, 2H),
7.00 (t, J = 7.6 Hz, 2H), 6.87 (m, 4H), 6.48 (d, J = 10.0 Hz, 1H), 6.14 (d, J = 8.4 Hz, 1H), 5.09 (d, J = 10.0 Hz, 1H), 4.62 (dd, J = 16.0 Hz,
21.2 Hz, 2H), 3.86-3.93 (m, 2H), 3.50 (d, J = 16.0 Hz, 1H), 3.12 (d, J = 16.0 Hz, 1H), 1.43 (s, 9H), 0.98 (t, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ(ppm) = 177.5, 169.5, 155.2, 144.6, 136.7, 134.6, 131.4, 131.1, 128.6, 127.7, 127.6, 127.5, 127.4, 127.0, 126.5, 115.0, 110.7,
80.0, 60.8, 59.2, 53.5, 44.0, 39.5, 28.3, 13.8. IR (KBr): 3400, 3063, 3032, 2978, 2932, 1707, 1608, 1468, 1454, 1427, 1366, 1347, 1313, 1238,
1172, 1021. HRMS (ESI) m/z: [M+H]+ Calcd for C31H34BrN2O5 593.1646, found 593.1643. [α]24.2D = -88.7 (c 1.35, CHCl3) HPLC (Daicel
Chiralpak AD-H, i-PrOH/Hexane=20:80, 220 nm, 0.7 mL/min): major 40.0 min, minor 11.3 min. Enantiomeric excess: 97%.
4.3.3 Ethyl 2-((R)-1-benzyl-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-4-chloro-2-oxoindolin-3-yl)acetate (4ca)
1
49.3 mg, 90% yield, white solid, m.p. 52-53oC. H NMR (400 MHz, CDCl3) δ(ppm) = 7.21-7.23 (m, 3H), 7.06-7.10 (m, 1H), 6.96-7.01 (m,
4H), 6.92-6.95 (m, 4H), 6.69 (d, J = 10.0 Hz, 1H), 6.18 (q, J = 2.8 Hz, 1H), 5.65 (d, J = 10.0 Hz, 1H), 4.62 (dd, J = 16.0 Hz, 32.2 Hz, 2H),
3.82-3.94 (m, 2H), 3.72 (d, J = 16.0 Hz, 1H), 3.53 (d, J = 16.0 Hz, 1H), 1.44 (s, 9H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ(ppm) = 177.5, 169.5, 155.2, 144.6, 136.7, 134.6, 131.4, 131.1, 128.6, 127.7, 127.6, 127.5, 127.4, 127.0, 126.5, 115.0, 110.7, 80.0, 60.8, 59.2,
53.5, 44.0, 39.5, 28.3, 13.8. IR (KBr): 3376, 2977, 2924, 2852, 1737, 1711, 1608, 1586, 1497, 1495, 1410, 1391, 1349, 1313, 12287, 1169,
1024. HRMS (ESI) m/z: [M+H]+ Calcd for C31H34ClN2O5 549.2151, found 549.2148. [α]22.0D = -43.4 (c 0.15, CHCl3) HPLC (Daicel Chiralpak
IC, i-PrOH/Hexane=20:80, 220 nm, 0.7 mL/min): major 8.8 min, minor 10.5 min. Enantiomeric excess: 89%.
4.3.4 Ethyl 2-((R)-1-benzyl-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-5-chloro-2-oxoindolin-3-yl)acetate (4da)
50.9 mg, 93% yield, white solid, m.p. 68-69oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.36 (d, J = 1.6 Hz, 1H), 7.20-7.22 (m, 3H), 7.09-7.13
(m, 1H), 6.98-7.04 (m, 3H), 6.87-6.89 (m, 4H), 6.50 (d, J = 10.0 Hz, 1H), 6.19 (q, J = 8.0 Hz, 1H), 5.11 (d, J = 10.0 Hz, 1H), 4.63 (dd, J =
16.0 Hz, 22.0 Hz, 2H), 3.84-3.95 (m, 2H), 3.50 (d, J = 16.0 Hz, 1H), 3.12 (d, J = 16.0 Hz, 1H), 1.44 (s, 9H), 0.98 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ(ppm) = 177.6, 169.5, 155.2, 142.1, 136.7, 134.7, 130.8, 128.6, 128.5, 127.8, 127.7, 127.5, 127.4, 127.3, 127.0,
8

ACCEPTED MANUSCRIPT
123.7, 110.2, 80.0, 60.8, 59.2, 53.5, 44.1, 39.5, 28.4, 13.9. IR (KBr): 3376, 3063, 3032, 2978, 2932, 1371, 1610, 1488, 1454, 1432, 1347, 1171,
1021. HRMS (ESI) m/z: [M+H]+ Calcd for C31H34N2O5Cl 549.2151, found 549.2148. [α]22.4D = -72.2 (c 0.75, CHCl3) HPLC (Daicel Chiralpak
AD-H, i-PrOH/Hexane=10:90, 220 nm, 0.7 mL/min): major 75.0 min, minor 21.6 min. Enantiomeric excess: 96%.
4.3.5 Ethyl 2-((R)-1-benzyl-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-6-chloro-2-oxoindolin-3-yl)acetate (4ea)
49.8 mg, 91% yield, white solid, m.p. 60-61oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.28 (d, J = 8.0 Hz, 1H), 7.22-7.23 (m, 3H), 7.11 (m, J
= 8.0 Hz, 1H), 7.00-7.04 (m, 3H), 6.91-6.92 (m, 2H), 6.86 (d, J = 7.2 Hz, 1H), 6.49 (d, J = 10.0 Hz, 1H), 6.30 (q, J = 0.8 Hz, 1H), 5.11 (d, J =
10.0 Hz, 1H), 4.62 (s, 2H), 3.83-3.93 (m, 2H), 3.49 (d, J = 16.0 Hz, 1H), 3.12 (d, J = 16.0 Hz, 1H), 1.43 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H). 13
C
NMR (100 MHz, CDCl3) δ(ppm) = 178.0, 169.6, 155.3, 144.8, 136.8, 134.6, 134.3, 128.7, 127.7, 127.6, 127.4, 127.1, 124.3, 122.4, 109.9,
80.0, 60.7, 59.3, 53.2, 44.1, 39.7, 28.4, 13.9. IR (KBr): 3403, 3063, 3032, 2978, 2932, 1709, 1609, 1492, 1454, 1368, 1343, 1243, 1173, 1026.
HRMS (ESI) m/z: [M+H]+ Calcd for C31H34N2O5Cl 549.2151, found 549.2144. [α]22.0D = -58.0 (c 0.5, CHCl3) HPLC (Daicel Chiralpak AD-H,
i-PrOH/Hexane=20:80, 220 nm, 1.0 mL/min): major 21.1 min, minor 24.4 min. Enantiomeric excess: 95%.
4.3.6 Ethyl 2-((R)-1-benzyl-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-7-chloro-2-oxoindolin-3-yl)acetate (4fa)
51.5 mg, 94% yield, white solid, m.p. 132-133oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.31 (d, J = 6.8 Hz, 1H), 7.20-7.21 (m, 3H), 7.13 (t,
J = 7.2 Hz, 1H), 6.98-7.06 (m, 4H), 6.92-6.94 (m, 2H), 6.80 (d, J = 7.2 Hz, 2H), 6.51 (d, J = 10.0 Hz, 1H),5.11 (d, J = 33.6 Hz, 1H), 5.10 (s,
1H), 4.93 (d, J = 16.0 Hz, 2H), 3.82-3.96 (m, 2H), 3.52 (d, J = 16.0 Hz, 1H), 3.13 (d, J = 16.0 Hz, 1H), 1.43 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ(ppm) = 178.6, 169.5, 155.3, 139.9, 137.2, 136.6, 132.0, 131.2, 128.3, 127.7, 127.6, 127.3, 126.8, 126.5, 123.3,
121.9, 115.3, 80.0, 60.7, 59.7, 53.1, 45.2, 40.1, 28.4, 13.9. IR (KBr): 3400, 3063, 3032, 2978, 2932, 1709, 1608, 1584, 1497, 1466, 1425, 1391,
1351, 1244, 1166, 1137, 1078, 1015. HRMS (ESI) m/z: [M+H]+ Calcd for C31H34ClN2O5 549.2151, found 549.2151. [α]22.6D = +65.3 (c 2.5,
CHCl3) HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=20:80, 220 nm, 1.0 mL/min): major 30.3 min, minor 7.4 min. Enantiomeric excess:
94%.
4.3.7 Ethyl 2-((R)-1-benzyl-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-5-methoxy-2-oxoindolin-3-yl)acetate (4ga)
1
48.9 mg, 90% yield, white solid, m.p. 60-61oC. H NMR (400 MHz, CDCl3) δ(ppm) = 7.21-7.23 (m, 3H), 7.11-7.14 (m, 1H), 7.02-7.05 (m,
3H), 6.91-6.93 (m, 4H), 6.56-6.63 (m, 2H), 6.21 (d, J = 8.8 Hz, 1H), 5.15 (d, J = 9.6 Hz, 1H), 4.65 (s, 2H), 3.82-3.96 (m, 2H), 3.79 (s, 3H),
3.52 (d, J = 16.0 Hz, 1H), 3.14 (d, J = 16.0 Hz, 1H), 1.46 (s, 9H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 177.7,
169.7, 155.8, 155.4, 137.1, 137.0, 135.2, 130.1, 128.5, 127.6, 127.5, 127.4, 127.3, 127.1, 113.1, 110.6, 109.7, 79.9, 60.6, 59.4, 55.8, 53.7, 44.1,
39.8, 28.4, 13.9. IR (KBr): 3393, 3062, 3032, 2978, 2933, 1702, 1603, 1495, 1454, 1435, 1412, 1367, 1348, 1297, 1241, 1177, 1079, 1029,
1016. HRMS (ESI) m/z: [M+H]+ Calcd for C32H37N2O6 545.2646, found 545.2640. [α]22.7D = -114.1 (c 0.65, CHCl3) HPLC (Daicel Chiralpak
AD-H, i-PrOH/Hexane=20:80, 220 nm, 1.0 mL/min): major 38.1 min, minor 12.9 min. Enantiomeric excess: 93%.
4.3.8 Ethyl 2-((R)-1-benzyl-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-5-methyl-2-oxoindolin-3-yl)acetate (4ha)
1
48.5 mg, 92% yield, white solid, m.p. 35-36oC. H NMR (400 MHz, CDCl3) δ(ppm) = 7.19 (br, 4H), 7.07-7.10 (m, 1H), 6.97-7.01 (m, 2H),
6.81-6.88 (m, 5H), 6.57 (d, J = 10.0 Hz, 1H), 6.17 (d, J = 8.0 Hz, 1H), 5.11 (d, J = 10.0 Hz, 1H), 4.62 (d, J = 16.0 Hz, 19.2 Hz, 2H), 3.80-3.91
(m, 2H), 3.49 (d, J = 16.0 Hz, 1H), 3.11 (d, J = 16.0 Hz, 1H), 2.31 (s, 3H), 1.44 (s, 9H), 0.91 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ(ppm) = 177.9, 169.8, 155.4, 141.2, 137.2, 135.3, 132.0, 128.9, 128.8, 128.5, 127.6, 127.5, 127.3, 127.2, 127.1, 124.2, 109.0, 79.8, 60.5, 59.5,
53.4, 44.0, 39.9, 28.4, 21.2, 13.8. IR (KBr): 3431, 3062, 2979, 1774, 1737, 1610, 1499, 1469, 1393, 1369, 1350, 1288, 1249, 1151, 1113, 1003.
HRMS (ESI) m/z: [M+H]+ Calcd for C32H37N2O5 529.2697, found 526.2693. [α]22.5D = -36.3 (c 0.7, CHCl3) HPLC (Daicel Chiralpak AD-H,
i-PrOH/Hexane=10:90, 220 nm, 0.7 mL/min): major 96.9 min, minor 22.4 min. Enantiomeric excess: 92%.
4.3.9 Tert-butyl ((S)-((R)-1,3-dibenzyl-2-oxoindolin-3-yl)(phenyl)methyl)carbamate (4ia)
49.2 mg, 95% yield, white solid, m.p. 48-49oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.39 (d, J = 7.2 Hz, 1H), 6.98-7.13 (m, 12H), 6.88-6.93
(m, 4H), 6.46 (d, J = 8.0 Hz, 2H), 6.02 (d, J = 8.0 Hz, 1H), 5.27 (d, J = 8.0 Hz, 1H), 4.56 (d, J = 16.0 Hz, 1H), 4.30 (d, J = 16.0 Hz, 1H), 3.69
(d, J = 13.2 Hz, 1H), 3.32 (d, J = 13.2 Hz, 1H), 1.47 (s, 9H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 178.1, 169.6, 155.3, 144.8, 136.8, 134.6,
134.3, 128.7, 127.7, 127.6, 127.4, 127.1, 124.3, 122.4, 109.9, 80.0, 60.7, 59.3, 53.1, 44.1, 39.7, 28.4, 13.9. IR (KBr): 3399, 3060, 3031, 2977,
2927, 1697, 1612, 1493, 1467, 1454, 1384, 1367, 1311, 1171, 1042, 1022. HRMS (ESI) m/z: [M+H]+ Calcd for C34H35N2O3 519.2642, found
519.2639. [α]24.0D = +12.4 (c 0.65, CHCl3) HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=20:80, 254 nm, 1.0 mL/min): major 9.4 min,
minor 5.0 min. Enantiomeric excess: 89%.
4.3.10 Tert-butyl ((S)-((R)-1-benzyl-3-methyl-2-oxoindolin-3-yl)(phenyl)methyl)carbamate (4ja)
1
41.5 mg, 94% yield, white solid, m.p. 67-68oC. H NMR (400 MHz, CDCl3) δ(ppm) = 7.38-7.40 (m, 1H), 7.18-7.23 (m, 3H), 7.00-7.12 (m,
5H), 6.95-6.97 (m, 2H), 6.81-6.83 (m, 2H), 6.66 (d, J = 9.6 Hz, 1H), 6.39-6.41 (m, 1H), 5.18 (d, J = 9.6 Hz, 1H), 4.84 (d, J = 16.0 Hz, 1H),
4.59 (d, J = 16.0 Hz, 1H), 1.67 (s, 3H), 1.47 (s, 9H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 179.4, 155.7, 142.1, 138.3, 135.1, 131.9, 128.6,
128.1, 127.6, 127.4, 127.3, 127.1, 126.9, 123.4, 122.7, 109.3, 79.6, 59.7, 52.0, 43.5, 28.4, 22.1. IR (KBr): 3402, 2928, 1713, 1611, 1494, 1170.
9

ACCEPTED MANUSCRIPT
HRMS (ESI) m/z: [M+H]+ Calcd for C28H31N2O3 443.2329, found 443.2326. [α]23.3D = -32.4 (c 0.5, CHCl3) HPLC (Daicel Chiralpak AD-H,
i-PrOH/Hexane=20:80, 220 nm, 0.7 mL/min): major 11.7 min, minor 9.8 min. Enantiomeric excess: 86%.
4.3.11 Tert-butyl ((S)-((R)-3-allyl-1-benzyl-2-oxoindolin-3-yl)(phenyl)methyl)carbamate (4ka)
42.1 mg, 90% yield, white solid, m.p. 160-161oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.36-7.38 (m, 1H), 7.15-7.19 (m, 3H), 6.92-7.07 (m,
7H), 6.83-6.84 (m, 2H), 6.74-6.76 (m, 1H), 6.32-6.34 (m, 1H), 5.39-5.48 (m, 1H), 5.17 (d, J = 9.6 Hz, 1H), 5.06 (d, J = 16.8 Hz, 1H), 4.96 (dd,
J = 1.6. Hz, J = 16.0 Hz, 1H), 4.66 (s, 2H), 2.86-2.91 (m, 2H), 1.44 (s, 9H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 178.3, 155.5, 142.6, 138.2,
135.0, 131.8, 129.4, 128.7, 128.5, 128.1, 127.6, 127.5, 127.3, 127.2, 127.1, 126.9, 124.1, 122.4, 119.6, 109.2, 79.6, 58.6, 56.1, 43.4, 39.5, 28.4.
IR (KBr): 3403, 3061, 3004, 2930, 1712, 1640, 1612, 1500, 1490, 1467, 1454, 1382, 1366, 1245, 1171, 1021. HRMS (ESI) m/z: [M+H]+
Calcd for C30H33N2O3 469.2486, found 469.2484. [α]22.9D = -21.6 (c 0.5, CHCl3) HPLC (Daicel Chiralpak IC, i-PrOH/Hexane=20:80, 220 nm,
0.7 mL/min): major 13.9 min, minor 7.9 min. Enantiomeric excess: 84%.
4.3.12 Tert-butyl ((S)-((R)-1-benzyl-3-(2-(benzyloxy)ethyl)-2-oxoindolin-3-yl)(phenyl)methyl)carbamate (4la)
51.1 mg, 91% yield, white solid, m.p. 54-55oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.259-7.33 (m, 1H), 7.20-7.28 (m, 3H), 7.10-7.16 (m,
3H), 7.01-7.06 (m, 5H), 6.97 (m, 2H), 6.858-6.90 (m, 2H), 6.71-6.73 (m, 3H), 6.26-6.28 (m, 1H), 5.13 (d, J = 9.6 Hz, 1H), 4.53 (d, J = 16.0 Hz,
1H), 4.22 (d, J = 12.0 Hz, 1H), 4.17 (s, 1H), 4.04 (d, J = 12.0 Hz, 1H), 3.30-3.35 (m, 1H), 3.10-3.16 (m, 1H), 2.87-2.95 (m, 1H), 2.26-2.32 (m,
1H), 1.44 (s, 9H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 178.8, 155.6, 143.4, 138.0, 137.9, 135.3, 128.9, 128.4, 128.2, 128.1, 127.6, 127.5,
127.4, 127.3, 127.2, 127.1, 127.0, 124.0, 122.2, 109.3, 79.6, 72.9, 66.6, 60.1, 54.5, 43.5, 34.9, 28.4. IR (KBr): 3400, 3061, 3031, 2976, 2928,
2863, 1712, 1611, 1585, 1494, 1467, 1454, 1366, 1240, 1174, 1106, 1078, 1044. HRMS (ESI) m/z: [M+H]+ Calcd for C36H39N2O4 563.2904,
found 563.2897. [α]23.1D = -3.1 (c 0.75, CHCl3) HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=20:80, 220 nm, 0.7 mL/min): major 59.7 min,
minor 12.8 min. Enantiomeric excess: 83%.
4.3.13 Tert-butyl ((S)-((R)-1-benzyl-2-oxo-3-phenylindolin-3-yl)(phenyl)methyl)carbamate (4ma)
44.8 mg, 89% yield, white solid, m.p. 77-78oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.53 (d, J = 8.0 Hz, 2H), 7.34-7.40 (m, 3H), 7.28 (d, J
= 7.2 Hz, 1H), 7.20-7.22 (m, 3H), 7.09-7.12 (m, 1H), 7.03 (d, J = 4.0 Hz, 4H), 6.98-7.00 (m, 2H), 6.85-6.87 (m, 2H), 6.64 (d, J = 9.2 Hz, 1H),
6.34-6.37 (m, 1H), 5.87 (d, J = 9.2 Hz, 1H), 4.69-4.79 (m, 2H), 1.30 (s, 9H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 177.7, 155.3, 141.7,
138.8, 137.6, 134.9, 131.3, 128.9, 128.7, 128.2, 127.9, 127.5, 127.4, 127.3, 126.9, 126.8, 124.6, 122.9, 109.5, 79.4, 61.3, 58.2, 43.7, 28.3. IR
(KBr): 3408, 3060, 3032, 2977, 2929, 1704, 1610, 1500, 1467, 1454, 1366, 1292, 1227, 1169, 1021. HRMS (ESI) m/z: [M+H]+ Calcd for
C33H33N2O3 505.2486, found 505.2482. [α]22.8D = -158.1 (c 0.85, CHCl3) HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=20:80, 220 nm, 0.7
mL/min): major 25.6 min, minor 12.1 min. Enantiomeric excess: 81%.
4.3.14 Ethyl 2-((R)-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-1-methyl-2-oxoindolin-3-yl)acetate (4na)
1
40.7 mg, 93% yield, white solid, m.p. 177-178oC. H NMR (400 MHz, CDCl3) δ(ppm) = 7.32 (d, J = 7.2 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H),
6.95-7.05 (m, 4H), 6.81 (d, J = 7.2 Hz, 2H), 6.59 (d, J = 10.0 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H),5.03 (d, J = 10.0 Hz, 1H), 3.79-3.88 (m, 2H),
3.48 (d, J = 16.0 Hz, 1H), 3.10 (d, J = 16.0 Hz, 1H), 2.92 (s, 3H), 1.43 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm)
= 177.7, 169.9, 155.4, 144.0, 137.0, 128.9, 128.6, 127.3, 127.2, 127.1, 123.2, 122.4, 107.9, 79.8, 60.5, 59.7, 53.3, 39.0, 28.4, 25.8, 13.8. IR
(KBr): 3393, 3059, 3032, 2978, 2933, 1703, 1613, 1495, 1471, 1423, 1380, 1368, 1350, 1314, 1240, 1168, 1130, 1078, 1043, 993. HRMS
(ESI) m/z: [M+H]+ Calcd for C25H31N2O5 439.2227, found 439.2225. [α]23.3 = -49.1 (c 0.8, CHCl3) HPLC (Daicel Chiralpak IC,
D
i-PrOH/Hexane=50:50, 220 nm, 1.0 mL/min): major 13.8 min, minor 7.2 min. Enantiomeric excess: 96%.
4.3.15 Tert-butyl (R)-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-3-(2-ethoxy-2-oxoethyl)-2-oxoindoline-1-carboxylate (4oa)
1
49.7 mg, 95% yield, white solid, m.p. 56-57oC. H NMR (400 MHz, CDCl3) δ(ppm) = 7.42-7.44 (m, 1H), 7.31 (br, 1H), 7.15-7.16 (m, 2H),
7.04-7.08 (m, 1H), 6.97-7.01 (m, 2H), 6.80 (d, J = 7.2 Hz, 2H), 6.26 (d, J = 10.0 Hz, 1H), 5.00 (d, J = 10.0 Hz, 1H), 3.79-3.89 (m, 2H), 3.53 (d,
J = 16.0 Hz, 1H), 3.09 (d, J = 16.0 Hz, 1H), 1.57 (s, 9H), 1.43 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 177.1,
169.6, 155.2, 148.3, 140.3, 136.3, 128.8, 127.9, 127.6, 127.4, 127.1, 124.3, 122.6, 114.9, 84.0, 80.1, 60.8, 60.2, 54.0, 39.5, 28.3, 28.0, 13.6. IR
(KBr): 3417, 2979, 2931, 1788, 1735, 1607, 1494, 1467, 1392, 1369, 1352, 1293, 1248, 1152, 1091, 1078, 1023, 1006. HRMS (ESI) m/z:
[M+H]+ Calcd for C29H37N2O7 525.2595, found 525.2595. [α]23.0
= -4.3 (c 1.0, CHCl3) HPLC (Daicel Chiralpak AD-H,
D
i-PrOH/Hexane=20:80, 220 nm, 1.0 mL/min): major 7.4 min, minor 5.8 min. Enantiomeric excess: 98%.
4.3.16 Tert-butyl (R)-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-2-oxo-3-phenylindoline-1-carboxylate (4pa)
49.9 mg, 90% yield, white solid, m.p. 70-71oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.43-7.47 (m, 3H), 7.34 (t, J = 7.6 Hz, 2H), 7.22-7.28
(m, 2H), 6.99-7.13 (m, 5H), 6.92 (d, J = 7.6 Hz, 2H), 6.37 (d, J = 9.2 Hz, 1H), 5.77 (d, J = 9.2 Hz, 1H), 1.57 (s, 9H), 1.31 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ(ppm) = 177.1, 155.2, 148.3, 138.8, 138.4, 136.9, 130.3, 128.9, 128.5, 127.6, 127.5, 127.4, 127.3, 124.6, 114.9, 84.5, 79.7,
61.8, 58.9, 28.3, 28.1. IR (KBr): 3422, 3061, 2979, 2932, 1787, 1737, 1604, 1497, 1465, 1286, 1150, 1050. HRMS (ESI) m/z: [M+Na]+ Calcd
for C31H34NaN2O5 537.2360, found 537.2356. [α]26.6D = -153.0 (c 0.75, CHCl3) HPLC (Daicel Chiralpak PC-II, i-PrOH/Hexane=5:95, 220 nm,
10

ACCEPTED MANUSCRIPT
0.5 mL/min): major 11.6 min, minor 9.0 min. Enantiomeric excess: 86%.
4.3.17 Tert-butyl (R)-5-bromo-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-3-(2-ethoxy-2-oxoethyl)-2-oxoindoline-1-carboxylate
(4qa)
57.7 mg, 96% yield, white solid, m.p. 63-64oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.44 (d, J = 0.8 Hz, 1H), 7.27-7.35 (m, 2H), 7.02-7.11
(m, 3H), 6.82 (d, J = 7.2 Hz, 2H), 6.15 (d, J = 11.2 Hz, 1H), 4.98 (d, J = 10.0 Hz, 1H), 3.87-3.93 (m, 2H), 3.52 (d, J = 16.8 Hz, 1H), 3.08 (d, J
= 16.8 Hz, 1H), 1.56 (s, 9H), 1.44 (s, 9H), 1.03 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 176.3, 169.5, 155.1, 148.1, 139.4,
135.9, 131.8, 130.4, 127.9, 127.7, 127.1, 125.7, 117.1, 116.6, 84.4, 80.3, 61.1, 60.2, 54.1, 39.2, 28.4, 28.1, 13.8. IR (KBr): 3417, 2979, 2933,
1789, 1735, 1602, 1586, 1494, 1474, 1423, 1393, 1369, 1337, 1298, 1249, 1154, 1099, 1067, 1028. HRMS (ESI) m/z: [M+H]+ Calcd for
C29H36BrN2O7 603.1700, found 603.1725. [α]23.6D = -59.6 (c 1.15, CHCl3) HPLC (Daicel Chiralpak IC, i-PrOH/Hexane=50:50, 220 nm, 1.0
mL/min): major 3.9 min, minor 15.1 min. Enantiomeric excess: 99%.
4.3.18 Tert-butyl (R)-3-((S)-((tert-butoxycarbonyl)amino)(m-tolyl)methyl)-3-(2-ethoxy-2-oxoethyl)-2-oxoindoline-1-carboxylate (4ob)
1
50.5 mg, 94% yield, white solid, m.p. 55-56oC. H NMR (400 MHz, CDCl3) δ(ppm) = 7.44-7.46 (m, 1H), 7.29-7.31 (m, 1H), 7.14-7.16 (m,
2H), 6.86-6.88 (m, 2H), 6.60 (br, 2H), 6.22 (d, J = 10.0 Hz, 1H), 4.97 (d, J = 10.0 Hz, 1H), 3.81-3.89 (m, 2H), 3.52 (d, J = 16.8 Hz, 1H), 3.08
(d, J = 16.4 Hz, 1H), 2.10 (s, 3H), 1.57 (s, 9H), 1.43 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 177.1, 169.6,
155.2, 148.4, 140.4, 137.1, 136.2, 128.8, 128.4, 128.0, 127.9, 127.3, 124.3, 124.2, 122.7, 114.8, 84.0, 80.0, 60.8, 60.3, 54.0, 39.6, 28.4, 28.1,
21.2, 13.6. IR (KBr): 3420, 2980, 2933, 1788, 1735, 1608, 1499, 1353, 1249, 1153, 1025. HRMS (ESI) m/z: [M+H]+ Calcd for C30H39N2O7
539.2752, found 539.2753. [α]22.9D = -6.1 (c 0.65, CHCl3) HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=10:90, 220 nm, 0.7 mL/min):
major 12.5 min, minor 9.4 min. Enantiomeric excess: 97%.
4.3.19 Tert-butyl (R)-3-((S)-((tert-butoxycarbonyl)amino)(4-chlorophenyl)methyl)-3-(2-ethoxy-2-oxoethyl)-2-oxoindoline-1-carboxylate
(4oc)
51.9 mg, 93% yield, white solid, m.p. 65-66oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.46 (d, J = 7.6 Hz, 1H), 7.32-7.34 (m, 1H), 7.18-7.24
(m, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 6.31 (d, J = 10.0 Hz, 1H), 5.99 (d, J = 10.0 Hz, 1H), 3.84-3.91 (m, 2H), 3.54 (d, J =
16.8 Hz, 1H), 3.09 (d, J = 16.4 Hz, 1H), 1.59 (s, 9H), 1.45 (s, 9H), 0.98 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 177.1,
169.4, 155.1, 148.1, 140.3, 135.1, 133.6, 129.1, 128.5, 127.6, 124.5, 122.6, 115.1, 84.4, 80.3, 60.9, 59.6, 53.7, 39.5, 28.3, 28.0, 13.7. IR
(KBr):2980, 2933, 1788, 1736, 1607, 1492, 1466, 1352, 1248, 1151, 1090, 1014. HRMS (ESI) m/z: [M+H]+ Calcd for C29H36ClN2O7
559.2206, found 559.2205. [α]24.1D = -14.9(c 2.5, CHCl3) HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=10:90, 220 nm, 0.7 mL/min): major
47.5 min, minor 14.3 min. Enantiomeric excess: 97%.
4.3.20 Tert-butyl (R)-3-((S)-((tert-butoxycarbonyl)amino)(4-methoxyphenyl)methyl)-3-(2-ethoxy-2-oxoethyl)-2-oxoindoline-1-carboxylate
(4od)
52.6 mg, 95% yield, white solid, m.p. 60-61oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.46 (d, J = 7.2 Hz, 1H), 7.28-7.30 (m, 1H), 7.14-7.19
(m, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 8.4 Hz, 2H), 6.20 (d, J = 9.6 Hz, 1H), 4.96 (d, J = 10.4 Hz, 1H), 3.79-3.89 (m, 2H), 3.66 (s, 3 H),
3.51 (d, J = 16.4 Hz, 1H), 3.06 (d, J = 16.4 Hz, 1H), 1.57 (s, 9H), 1.43 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm)
= 177.3, 169.6, 158.9, 155.2, 148.4, 140.4, 128.8, 128.5, 128.2, 128.1, 124.3, 122.6, 115.0, 112.9, 84.0, 80.0, 60.8, 59.7, 55.1, 54.1, 39.6, 28.4,
28.1, 13.7. IR (KBr): 2979, 2934, 1793, 1767, 1731, 1611, 1481, 1465, 1368, 1309, 1291, 1251, 1153, 1032. HRMS (ESI) m/z: [M+H]+ Calcd
for C30H39N2O8 555.2701, found 555.2700. [α]23.5D = -10.1 (c 0.85, CHCl3) HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=10:90, 220 nm,
0.7 mL/min): major 35.7 min, minor 23.7 min. Enantiomeric excess: 98%.
4.3.21 Tert-butyl (R)-3-((S)-((tert-butoxycarbonyl)amino)(4-fluorophenyl)methyl)-3-(2-ethoxy-2-oxoethyl)-2-oxoindoline-1-carboxylate
(4oe)
1
48.7 mg, 90% yield, white solid, m.p. 49-50oC. H NMR (400 MHz, CDCl3) δ(ppm) = 7.42-7.44 (m, 1H), 7.29-7.31 (m, 1H), 7.14-7.21 (m,
2H), 6.75-6.78 (m, 2H), 6.67 (t, J = 8.4 Hz, 2H), 6.28 (d, J = 10.0 Hz, 1H), 4.97 (d, J = 10.0 Hz, 1H), 3.79-3.89 (m, 2H), 3.51 (d, J = 16.8 Hz,
1H), 3.06 (d, J = 16.8 Hz, 1H), 1.56 (s, 9H), 1.42 (s, 9H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 177.1, 169.4, 162.0
(d, J = 245.5 Hz), 155.1, 148.1, 140.2, 132.3 (d, J = 3.0 Hz), 129.0, 128.7 (d, J = 8.2 Hz), 127.7, 124.4, 122.5, 115.0, 114.3 (d, J = 21.4 Hz),
84.3, 80.2, 60.9, 59.5, 53.8, 39.5, 28.3, 28.0, 13.6. 19F NMR (376 MHz, CDCl3) δ -114.5 (m). IR (KBr): 3412, 2980, 2932, 1788, 1736, 1606,
1509, 1466, 1393, 1369, 1352, 1248, 1151, 1088, 1042. HRMS (ESI) m/z: [M+H]+ Calcd for C29H36FN2O7 543.2501, found 543.2501.
[α]23.1D = -18.7 (c 0.6, CHCl3) HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=10:90, 220 nm, 0.7 mL/min): major 23.8 min, minor 12.2 min.
Enantiomeric excess: 98%.
4.3.22 Tert-butyl (R)-3-((R)-((tert-butoxycarbonyl)amino)(thiophen-2-yl)methyl)-3-(2-ethoxy-2-oxoethyl)-2-oxoindoline-1-carboxylate (4of)
1
47.7 mg, 90% yield, white solid, m.p. 43-44oC. H NMR (400 MHz, CDCl3) δ(ppm) = 7.62 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H),
7.26-7.30 (m, 1H), 7.21 (t, J = 7.6 Hz, 2H), 6.99 (d, J = 4.2 Hz, 1H), 6.69 (dd, J = 4.0 Hz, J = 4.8 Hz, 1H), 6.44 (d, J = 3.2 Hz, 1H), 6.21 (d, J
11

ACCEPTED MANUSCRIPT
= 10.0 Hz, 1H), 5.33 (d, J = 10.4 Hz, 1H), 3.82-3.90 (m, 2H), 3.50 (d, J = 16.4 Hz, 1H), 3.08 (d, J = 16.4 Hz, 1H), 1.59 (s, 9H), 1.47 (s, 9H),
0.98 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 176.9, 169.4, 155.1, 148.5, 141.0, 139.7, 129.2, 128.0, 126.1, 125.3, 124.6,
124.5, 122.6, 115.1, 84.1, 80.3, 60.9, 56.3, 54.0, 39.9, 28.4, 28.1, 13.7. IR (KBr):3411, 2979, 2933, 1788, 1734, 1607, 1494, 1467, 1393, 1369,
1351, 1315, 1293, 1249, 1152, 1089, 753, 610. HRMS (ESI) m/z: [M+H]+ Calcd for C27H35N2O7S 531.2159, found 531.2158. [α]24.9D = -9.8 (c
0.7, CHCl3) HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=10:90, 220 nm, 1.0 mL/min): major 14.5 min, minor 24.7 min. Enantiomeric
excess: 96%.
4.3.23 Tert-butyl (R)-3-((S)-((tert-butoxycarbonyl)amino)(cyclohexyl)methyl)-3-(2-ethoxy-2-oxoethyl)-2-oxoindoline-1-carboxylate (4og)
25.4 mg, 48% yield, white solid, m.p. 39-40oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.85 (d, J = 8.0 Hz, 1H), 7.31-7.35 (m, 1H), 7.17-7.20
(m, 2H), 5.56 (d, J = ), 2.92 (d, J = 16.0 Hz, 1H), 1.63 (s, 9H), 1.43-1.52 (m, 13H), 1.23 (br, 1H), 0.92-1.08 (m, 10H). 13C NMR (100 MHz,
CDCl3) δ(ppm) = 177.7, 169.7, 156.3, 149.0, 140.6, 128.7, 128.8, 124.8, 122.1, 115.1, 84.2, 79.6, 61.5, 60.6, 52.4, 41.3, 38.6, 32.8, 28.4, 28.1,
27.4, 26.2, 25.9, 25.7, 13.6. IR (KBr):2979, 2928, 2853, 1793, 1768, 1731, 1696, 1480, 1465, 1368, 1290, 1119, 753. HRMS (ESI) m/z:
[M+Na]+ Calcd for C29H42NaN2O7 553.2884, found 553.2866. [α]27.0
= -6.6(c 0.8, CHCl3) HPLC (Daicel Chiralpak IC,
D
i-PrOH/Hexane=15:85, 220 nm, 0.7 mL/min): major 6.1 min, minor 19.6 min. Enantiomeric excess: 99%.
4.3.24 Tert-butyl (R)-3-((S)-1-((tert-butoxycarbonyl)amino)-3-phenylpropyl)-3-(2-ethoxy-2-oxoethyl)-2-oxoindoline-1-carboxylate (4oh)
24.8 mg, 45% yield, white solid, m.p. 45-46oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.81 (d, J = 8.4 Hz, 1H), 7.28-7.31 (m, 1H), 7.17-7.20
(m, 2H), 7.09-7.14 (m, 2H), 7.05-7.07 (m, 1H), 6.95 (d, J = 6.8 Hz, 2H), 5.44 (d, J = 10.4 Hz, 1H), 4.00 (dt, J = 2.4 Hz, J = 10.8 Hz, 1H),
3.77-3.82 (m, 2H), 3.32 (d, J = 16.0 Hz, 1H), 2.94 (d, J = 16.0 Hz, 1H), 2.59-2.63 (m, 1H), 2.38-2.43 (m, 1H), 1.64 (s, 9H), 1.49 (s, 9H),
1.33-1.41 (m, 1H), 1.21-1.27 (m, 1H), 0.93 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 177.4, 169.6, 156.1, 149.0, 140.9,
140.7, 128.9, 128.5, 128.3, 126.0, 124.9, 122.1, 115.2, 84.5, 79.8, 60.7, 56.0, 53.3, 40.6, 32.4, 32.2, 28.4, 28.1, 13.6. IR (KBr):2978, 2929,
2855, 1768, 1731, 1698, 1496, 1479, 1464, 1368, 1250, 1151, 1027, 751, 699. HRMS (ESI) m/z: [M+Na]+ Calcd for C31H40NaN2O7 575.2728,
found 575.2705. [α]27.1D = -3.2(c 1.7, CHCl3) HPLC (Daicel Chiralpak IC, i-PrOH/Hexane=15:85, 220 nm, 0.7 mL/min): major 7.1 min, minor
11.7 min. Enantiomeric excess: 98%.
4.3.25 Tert-butyl (R)-3-((1,3-dioxolan-2-yl)methyl)-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-2-oxoindoline-1-carboxylate (4ra)
47.1 mg, 90% yield, colorless oil. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.39-7.42 (m, 1H), 7.33-7.35 (m, 1H), 7.12-7.15 (m, 2H), 6.93-7.02
(m, 3H), 6.79 (d, J = 7.2 Hz, 2H), 6.31 (d, J = 9.6 Hz, 1H), 4.99 (d, J = 9.6 Hz, 1H), 4.61 (dd, J = 2.4 Hz, J = 7.2 Hz, 1H), 3.71-3.76 (m, 1H),
3.60-3.64 (m, 1H), 3.51-3.55 (m, 2H), 2.70 (dd, J = 7.6 Hz, J = 14.4 Hz, 1H), 2.46 (dd, J = 2.8 Hz, J = 14.4 Hz, 1H), 1.54 (s, 9H), 1.40 (s, 9H).
13C NMR (100 MHz, CDCl3) δ(ppm) = 177.4, 155.3, 148.5, 139.9, 136.8, 128.5, 127.6, 127.4, 127.3, 127.2, 123.9, 123.8, 114.8, 101.5, 83.8,
79.8, 64.9, 64.4, 61.1, 53.7, 38.4, 28.3, 28.0. IR (KBr): 2978, 1718, 1152, 752. HRMS (ESI) m/z: [M+Na]+ Calcd for C29H36N2NaO7 547.2415,
found 547.2424. [α]26.4D = 12.0 (c 0.71, CHCl3) HPLC (Daicel Chiralpak IC, i-PrOH/Hexane=20:80, 220 nm, 1.0 mL/min): major 6.2 min,
minor 56.2 min. Enantiomeric excess: 97%.
4.3.26 Tert-butyl (S)-3-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-3-fluoro-2-oxoindoline-1-carboxylate (4sa)
43.3 mg, 95% yield, yellow oil. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.59 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.34 (t, J = 8.0 Hz,
1H), 7.22 (t, J = 7.6 Hz, 1H), 7.09-7.15 (m, 3H), 6.98 (d, J = 7.2 Hz, 2H), 6.22 (d, J = 8.8 Hz, 1H), 5.51 (dd, J = 6.4 Hz, J = 8.4 Hz, 1H), 1.57
(s, 9H), 1.45 (s, 9H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 170.6 (d, J = 22.7 Hz), 155.3, 148.0, 140.4, 134.5, 131.8, 128.3, 128.1, 127.7,
125.0 (d, J = 8.6 Hz), 122.8 (d, J = 18.7 Hz), 115.3, 91.5 (d, J = 245.5 Hz), 90.5, 85.0, 80.2, 58.9, 28.4, 28.0. 19F NMR (376 MHz, CDCl3) δ
-156.9 (s). IR (KBr): 3430, 2977, 2932, 1772, 1723, 1498, 1151. HRMS (ESI) m/z: [M+H]+ Calcd for C25H30N2O5F 457.2133, found 457.2125.
[α]23.2D = +34.8 (c 0.6, CHCl3) HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=10:90, 254 nm, 1.0 mL/min): major 7.1 min, minor 9.7 min.
Enantiomeric excess: 94%.
4.3.27 Ethyl 2-((R)-1-benzyl-3-((S)-((4-methylphenyl)sulfonamido)(phenyl)methyl)-2-oxoindolin-3-yl)acetate (4ai)
1
49.4 mg, 87% yield, white solid, m.p. 82-83oC. H NMR (400 MHz, CDCl3) δ(ppm) = 7.33-7.38 (m, 3H), 7.17-7.19 (m, 3H), 6.96-7.00 (m,
2H), 6.88-6.93 (m, 5H), 6.72 (t, J = 8.0 Hz, 2H), 6.58 (d, J = 8.0 Hz, 3H), 6.28 (q, J = 3.2 Hz, 1H), 4.94 (d, J = 10.4 Hz, 1H), 4.63 (d, J = 16.0
Hz, J = 30.0 Hz, 2H), 3.79-3.95 (m, 2H), 3.62 (d, J = 16.4 Hz, 1H), 3.16 (d, J = 16.4 Hz, 1H), 2.22 (s, 3H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ(ppm) = 177.8, 169.6, 143.3, 142.6, 137.7, 134.9, 134.5, 128.9, 128.8, 128.5, 128.1, 127.5, 127.3, 127.2, 127.1, 127.0,
126.7, 123.5, 122.5, 109.3, 62.3, 60.6, 53.2, 44.0, 40.2, 21.3, 13.8. IR (KBr):3263, 3060, 2980, 2924, 1715, 1612, 1489, 1467, 1455, 1429,
1370, 1333, 1163, 1086, 1056, 923, 813, 737, 700, 670, 558. HRMS (ESI) m/z: [M+Na]+ Calcd for C33H32SNaN2O5 591.1924, found
591.1905. [α]28.9D = -72.1(c 0.8, CHCl3) HPLC (Daicel Chiralpak IC, i-PrOH/Hexane=40:60, 220 nm, 1.0 mL/min): major 37.9 min, minor
67.1 min. Enantiomeric excess: 74%.
4.3.28 Ethyl 2-((R)-1-benzyl-3-((S)-(((benzyloxy)carbonyl)amino)(phenyl)methyl)-2-oxoindolin-3-yl)acetate (4aj)
49.3 mg, 90% yield, white solid, m.p. 47-48oC. 1H NMR (400 MHz, CDCl3) δ(ppm) = 7.30-7.38 (m, 6H), 7.19-7.20 (m, 3H), 7.08 (t, J = 7.2
12

ACCEPTED MANUSCRIPT
Hz, 1H), 6.83-7.03 (m, 9H), 6.31-6.33 (m, 1H), 5.21 (d, J = 9.6 Hz, 1H), 5.14 (d, J = 12.4 Hz, 1H), 5.07 (d, J = 12.4 Hz, 1H), 4.26-4.70 (m,
2H), 3.77-3.91 (m, 2H), 3.47 (d, J = 16.0 Hz, 1H), 3.12 (d, J = 16.0 Hz, 1H), 0.90 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) =
177.4, 169.6, 156.1, 149.0, 140.9, 140.7, 128.9, 128.5, 128.3, 126.0, 124.9, 122.1, 115.2, 84.5, 79.8, 60.7, 56.0, 53.3, 40.6, 32.4, 32.2, 28.4,
28.1, 13.6. IR (KBr):3339, 3061, 3032, 2979, 2924, 1719, 1612, 1495, 1466, 1454, 1369, 1345, 1189, 1026, 755, 698, 456. HRMS (ESI) m/z:
[M+Na]+ Calcd for C34H32NaN2O5 571.2203, found 571.2196. [α]28.7 = -32.2 (c 1.0, CHCl3) HPLC (Daicel Chiralpak IC,
D
i-PrOH/Hexane=50:50, 220 nm, 1.0 mL/min): major 12.6 min, minor 8.0 min. Enantiomeric excess: 88%.
4.3.29(R)-tert-butyl3-((1,3-dioxolan-2-yl)methyl)-3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-oxoindoline-1-carboxylate (4rk)
1
34.3 mg, 70% yield, yellow oil. H NMR (400 MHz, CDCl3) δ(ppm) = 7.85 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.18-7.26 (m, 2H),
5.68 (d, J = 10.4 Hz, 1H), 4.48 (dd, J = 2.4 Hz, J = 7.6 Hz, 1H), 4.04 (dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 3.75 (q, J = 6.8 Hz, 1H), 3.53-3.62 (m,
4H), 2.52-2.57 (m, 1H), 2.34 (dd, J = 2.4 Hz, J = 14.4 Hz, 1H), 1.63 (s, 9H), 1.48 (s, 9H), 0.71 (d, J = 6.8 Hz, 3H), 0.64 (d, J = 6.4 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ(ppm) = 178.1, 156.6, 149.3, 140.1, 129.1, 128.4, 124.6, 123.1, 115.2, 101.6, 84.0, 79.3, 64.8, 64.4, 61.7, 52.1,
40.8, 28.7, 28.4, 28.1, 22.6, 16.5. IR (KBr):2976, 2932, 1792, 1766, 1727, 1696, 1480, 1367, 1290, 1152, 1002, 774, 757. HRMS (ESI) m/z:
[M+H]+ Calcd for C26H39N2O7 491.2752, found 491.2749. [α]29.4D = 1.3 (c 2.0, CHCl3) HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=5:95,
220 nm, 1.0 mL/min): major 22.9 min, minor 5.4 min. Enantiomeric excess: 99%.
4.3.30(R)-tert-butyl3-((1,3-dioxolan-2-yl)methyl)-3-((S)-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-6-methoxy-2-oxoindoline-1-carbo
xylate (4tk)
1
35.3 mg, 68% yield, off-white oil. H NMR (400 MHz, CDCl3) δ(ppm) = 7.49 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.74 (dd, J = 2.0
Hz, J = 8.0 Hz, 1H), 5.66 (d, J = 10.4 Hz, 1H), 4.49 (dd, J = 2.4 Hz, J = 7.6 Hz, 1H), 4.00 (dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 3.85 (s, 3H),
3.75-3.80 (m, 1H), 3.56-3.65 (m, 3H), 2.48-2.53 (m, 1H), 2.29 (dd, J = 2.4 Hz, J = 14.0 Hz, 1H), 1.63 (s, 9H), 1.48 (s, 9H), 0.72 (d, J = 6.8 Hz,
3H), 0.64 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 178.6, 159.9, 156.6, 149.3, 141.0, 123.6, 120.7, 110.2, 102.0, 101.7, 84.0,
79.3, 64.8, 64.4, 61.7, 55.5, 51.7, 40.8, 28.6, 28.4, 28.2, 28.1, 22.6, 16.5, 15.4. IR (KBr):2974, 2932, 1793, 1767, 1725, 1696, 1493, 1392,
1255, 1150, 1031, 775. HRMS (ESI) m/z: [M+H]+ Calcd for C27H41N2O8 521.2863, found 521.2892. [α]25.6D = 5.9 (c 1.7, CHCl3) HPLC
(Daicel Chiralpak PC-II, i-PrOH/Hexane=5:95, 220 nm, 0.8 mL/min): major 7.4 min, minor 29.4 min. Enantiomeric excess: 84%.
4.4 Transformation of spirooxindole 5 and 6
A dried 10 mL flask was charged with 4rk (49.0 mg, 0.1 mmol, 99% ee) and cooled to 0 oC. A hydrogen chloride solution (4M) in ethyl
acetate (0.6 mL) was slowly added. After stirred for 10 min. the mixture was allowed to warm to room temperature and stirred for 1 h. All
volatile compounds were removed by rotary evaporator and the crude was dried in vacuo. To the crude HCl salt, DCM (0.6 mL) was added the
suspension was cooled to 0 oC. Et3N (40.4 mg, 0.4 mmol) was added and the reaction mixture was allowed to warm to room temperature. After
stirred for 1 h, water was added and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure
and the residue was purified by silica gel chromatography (petrolume ether/ethyl acetate = 1/3) to afford the product 5.
The corresponding spirooxindole product (0.1mmol, 1.0eq) was dissolved in MeOH and cooled to 0oC. Sodium cyanoborohydride (0.4
mmol4.0eq) was added slowly and the mixture was allowed to stir under room temperature for 30min. The resulting solution was poured into
satd.aq.NH4Cl, extracted with EA, the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure
and the residue was purified by silica gel chromatography (dichloromethane / methanol = 9/1) to afford the product 6
4.4.1 (2'S,3R)-2'-isopropyl-2',4'-dihydrospiro[indoline-3,3'-pyrrol]-2-one (5)
14.3 mg, 63% yield, yellow oil. 1H NMR (400 MHz, CDCl3) δ(ppm) = 8.62 (s, 1H), 7.70-7.71 (m, 1H), 7.15-7.27 (m, 2H), 7.04-7.07 (m, 1H),
6.90 (d, J = 8.0 Hz, 1H), 4.00 (dd, J = 2.4 Hz, J = 9.6 Hz, 1H), 3.25 (d, J = 18.0 Hz, 1H), 2.91 (d, J = 18.0 Hz, 1H), 2.19-2.27 (m, 1H), 1.19 (d,
J = 6.4 Hz, 3H), 3.25 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm) = 180.9, 162.8, 140.2, 135.1, 128.0, 123.0, 122.4, 109.8, 89.8,
54.5, 50.8, 30.4, 21.8, 20.3. IR (KBr):3427, 2958, 2870, 1709, 1619, 1484, 750. HRMS (ESI) m/z: [M+H]+ Calcd for C14H17N2O 229.1335,
found 229.1334. [α]24.2D = -58.6 (c 0.3, CHCl3) HPLC (Daicel Chiralpak IC, i-PrOH/Hexane=10:90, 220 nm, 1.0 mL/min): major 15.8 min,
minor 11.6 min. Enantiomeric excess: 99%.
4.4.2 (2'S,3R)-2'-isopropyl-6-methoxyspiro[indoline-3,3'-pyrrolidin]-2-one (6)
1
11.4 mg, 44% yield, colorless oil. H NMR (400 MHz, CDCl3) δ(ppm) = 7.06 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.51 (d, J = 8.4 Hz, 1H),
3.64-3.71 (m, 4H), 3.46 (br, 1H), 3.35 (d, J = 8.4 Hz, 1H), 2.28 (m, 2H), 1.98 (br, 1H), 1.04 (d, J = 6.4 Hz, 3H), 0.35 (d, J = 6.4 Hz, 3H). 13
C
NMR (100 MHz, CDCl3) δ(ppm) = 181.4, 160.4, 142.0, 123.2, 122.3, 108.2, 98.1, 73.2, 56.1, 55.6, 43.7, 38.2, 29.5, 22.3, 19.8. IR (KBr):2924,
1709, 1632, 1506, 1462, 1155. HRMS (ESI) m/z: [M+H]+ Calcd for C15H21N2O2 261.1603, found 261.1614. [α]29.1D = 3.2 (c 0.15, CHCl3)
HPLC (Daicel Chiralpak AS-H, i-PrOH/Hexane=10:90, 220 nm, 1.0 mL/min): major 10.7 min, minor 17.0 min. Enantiomeric excess: 73%.
13

ACCEPTED MANUSCRIPT
Acknowledgment
Financial support from Chinese Academy of Sciences (XDB 20020100) and the National Natural Science Foundation of China (Nos.
21272247, 21572247, 21290184) is gratefully acknowledged.
Supplementary data
Supplementary data (NMR spectra, HPLC data) associated with this article can be found in the online version, at http://
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