Application of isatin-derived saturated esters in the synthesis of 3,3′-spirooxindole γ-butyrolactams

Article abstract of DOI:10.1039/c9ob01347d

Stable while reactive isatin-derived saturated esters have been utilized as 3-carbon synthons in a base-promoted formal [3 + 2] annulation with N-Boc imines. The developed protocol offers a direct pathway for the rapid and divergent construction of two classes of 3,3′-spirooxindole γ-butyrolactam skeletons that are recognized as the privileged structures of various bioactive compounds. This protocol also has the advantages of mild reaction conditions, scalability and wide reaction scope.

Full text of DOI:10.1039/c9ob01347d

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Application of Isatin-derived Saturated Esters in the Synthesis oDOfI:310,.310’3-9/C9OB01347D
Spirooxindole -Butyrolactams
Jindong Zhu, Shuaishuai Fang, Shiyi Jin, Rui Ma, Tao Lu, Ding Du*
State Key Laboratory of Natural Medicines, School of Science, China Pharmaceutical
University, Nanjing, 210009, P. R. China.
E-mail: ddmn9999@cpu.edu.cn
Abstract: Stable while reactive isatin-derived saturated esters have been utilized as
3-carbon synthons in a base-promoted formal [3+2] annulation with N-Boc imines. The
developed protocol offers a direct pathway for the rapid and divergent construction of
two classes of 3,3’-spirooxindole -butyrolactam skeletons that are recognized as the
privileged structures of various bioactive compounds. This protocol also has the
advantages of mild reaction conditions, scalability and wide reaction scope.
Introduction
Spirooxindoles are well-recognized scaffolds that have attracted great attention from
the scientific community owing to their challenging structural architecture and unique
biological activities.1 Among them, the structurally similar 3,3'-spirooxindole
pyrrolidine1h, 2 and 3,3'-spirooxindole -butyrolactam3 frameworks are frequently
found as the privileged structures in numerous natural products and synthetic
compounds possessing significant pharmaceutical activities.
Over the past decades, a large number of synthetic methods for 3,3’-spirooxindole
pyrrolidines have been developed.1a, 1e, 1h, 4 Among these methods, the 1,3-dipolar
cycloaddition of azomethine ylides with methyleneoxindoles is the most powerful and
efficient strategy to access diverse 3,3’-spirooxindole pyrrolidines.1d, 5 By contrast,
there are limited documented synthetic approaches to 3,3'-spirooxindole -
6
butyrolactams. Therefore, in view of the importance of spirooxindole scaffolds, it is
still in demand to develop direct and versatile new synthetic methods to access more
structurally diverse 3,3'-spirooxindole -butyrolactams. As part of our interest in the
development of new methodologies and substrates for the divergent synthesis of

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DOI: 10.1039/C9OB01347D
7
spirooxindoles, we envisioned that the reactive while stable isatin-derived saturated
esters 1 could undergo diverse annulations under basic conditions for the synthesis of
spirooxindoles with structural diversity. Herein, we present a novel base-promoted
catalyst-free [3+2] annulation of isatin-derived saturated esters 1 with two types of N-
Boc imines for the divergent synthesis of spirooxindole -butyrolactams 3/4 and
bispirooxindole -butyrolactams 6/7.
H
Cl
O
N
CO2H
N
F
O
H
NH
O
N
N
O
N
H
O
O
3,3'-spirooxindole
pyrrolidine
N
N
Cl
Cl
H
H
spirotryprostatin B
MDM2 inhibitor
O
F
O
NH
O
H
N
Cl
OMe
N
Cl
O
H
N
H
O
N
H
O
COOH
3,3'-spirooxindole
-butyrolactam
N
COOH
H

CRTH2 receptor antagonist
5-oxoisorhynchophyllic acid
Figure 1. Representative bioactive 3,3’-spirooxindoles.
1) Most commonly used method for the synthesis of 3,3'-spirooxindole
pyrrolidines (previous work)
EWG
R3
R3
NH
R4
EWG
R1
R1
[2+3]
N
O
+
O
certain
conditions
N
N
R4
R2
R2
2) Application of isatin-derived saturated esters for the divergent
synthesis of 3,3'-spirooxindole -butyrolactams (this work)

O
O
O
Nu
R1
R1
LG
R1
E
LG
base
E=Nu
-LG
O
O
O
N
N
N
R2
1
R2
R2
LG = -OCH(CF3)2
structurally diverse
spirooxindoles
Isatin-derived
saturated esters
NBoc
R4
Boc
O
O
O
R5
NBoc
H
N
N
NBoc
O
R1
R1
N
R3
R3
O
R5
O
R4
[3+2] annulation
divergent synthesis
N
N
R2
R2
6/7
3/4
Scheme 1. Synthetic approaches to 3,3’-spirooxindole pyrrolidines and -butyrolactams.
Results and discussion
Our investigation started with the reaction between 4-nitrophenyl 2-(1-benzyl-2-

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oxoindolin-3-yl) acetate 1a and N-Boc aldimine precursor 2a (Table 1). Initially, a
variety of bases were tested using THF as a solvent (entries 1-8). It was found that
inorganic bases were superior to organic bases, and Cs2CO3 was established as the
optimal one (entry 4). After examination of several commonly used solvents (entries 9-
13), desired product 3a was obtained in 73% yield with excellent diastereoselectivity
when the reaction was carried out in ethyl acetate (entry 13). Further variation of the
leaving group of ester substrates convinced us that hexafluoroisopropyl ester 1b was
more suitable for this transformation resulting in a higher yield (83%) and equally
excellent diastereoselectivity (entry 14). It is noteworthy that the situ activation of 2-
(1-benzyl-2-oxoindolin-3-yl) acetic acid with pyBOP, HATU or DCC/DMAP in the
presence of hexafluoroisopropanol and Cs2CO3 did not give the desired product.
Table 1. Optimization of the reaction conditionsa
O
O
O
NBoc
NBoc
base
(2.5 equiv)
OR'
NHBoc
SO2Ph
Ph
O
Ph
O
+
O
+
Ph
solvent
N
N
N
Bn
Bn
Bn
O
4a
1
2a
3a
1a
R' = 4-NO2C6H4,
1b
R' =
N
1c
R' = -CH(CF3)2,
O
Entry
1
a
a
a
a
a
a
a
a
Base
DBU
Sol.
THF
Temp.(oC)
Yield (%)b
Dr (3a/4a)c
1
2
25
25
25
25
50
50
25
25
25
25
25
25
25
25
25
0
-
DIPEA
DMAP
Cs2CO3
K2CO3
K3PO4
THF
0
-
3
THF
0
57
-
>95:5
>95:5
>95:5
-
4
THF
5
THF
56
6
THF
47
7
t-BuOK
NaOH
THF
0
8
THF
44
>95:5
-
9
a
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Toluene
DCM
CH3CN
dioxane
EtOAc
EtOAc
EtOAc
0
10
11
12
13
14
15
a
a
a
a
b
c
trace
0
-
-
56
>95:5
>95:5
>95:5
-
73
83
complex
a
Unless otherwise noted, all reactions were carried out with 1a (0.2 mmol), 2a (1.2 equiv) and a base
(2.5 equiv) in an anhydrous solvent (2 mL) at room temperature typically for 30 mins. b Isolated yields
based on 1a. c dr values were determined by 1H NMR analysis of the crude products.

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With optimized conditions in hand, we then moved our attention to explore the
reaction scope initially through variation of the aldimine precursors 2 (Table 2). It was
found that the positions of the substituents on the benzene ring had great impact on the
diastereoselectivities (entries 2-15). A wide range of substrates 2b-k with diverse
substituents at p- or m-position of the benzene ring were well tolerant to this reaction,
affording the desired products 3b-k in good to high yields and diastereoselectivities
(entries 2-11). However, the reactions of 2-OMe- and 2-Me-substituted substrates 2l
and 2m gave rise to the diastereomers 4l and 4m, respectively, in excellent
diastereoselectivities (entries 12 and 13). The reactions of 2-Cl- and 2-Br-substituted
substrates 2n and 2o afforded the desired products in poor diastereoselectivities (entries
14 and 15). To our delight, the reactions of naphthyl and heteroaromatic imine
precursors 2p-s worked equally well to produce the desired products in moderate yields
(entries 16-19). In terms of more hindered 1-naphthyl, 2-furyl and 2-thienyl substrates,
diastereomers 4p, 4r and 4s were obtained as the major products in good to high
diastereoselectivities (entries 16, 18 and 19). It might be concluded that the ortho-steric
effect of phenyl ring or aromatic heterocycles have great impact on the stereoselectivity
of this reaction, and diastereomers 4 were obtained in much higher ratios for these cases
(entires 12-16, entries 18 and 19). The reaction of less hindered 2-naphthyl substrate
2q afforded 3q in an excellent diastereoselectivity (entry 17). We then evaluated the
reactions between aldimine precursor 2a and diverse esters 1d-g with different
substituents on the phenyl ring or nitrogen (entries 20-23). The reaction of 5-Cl
substituted ester 1d produced 3t and 4t in a good yield but with a lower
diastereoselectivity (entry 20), while the reaction of 5-Me substituted ester 1e afforded
3u in a lower yield but with an excellent diastereoselectivity (entry 21). The reactions
of N-Me- and N-Boc-protected esters 1f and 1g worked smoothly to give the
corresponding products 3v and 3w, respectively, in excellent diastereoselectivities
(entries 22 and 23). However, N-H free ester 1h was not suitable to this protocol (entry
24). Remarkably, all these reactions completed typically in 30 mins, and several
reactions were carried out under lower temperatures in order to gain better
diastereoselectivities (entries 7-13 and 19). The structure of 3 and 4 was verified by

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8
DOI: 10.1039/C9OB01347D
analysis of their NMR data and was further confirmed by X-ray crystallography of 3a.
Table 2. Scope of the reaction between esters 1 and imine precursors 2 a
O
O
O
NBoc
NBoc
R1
Cs2CO3
(2.5 equiv)
NHBoc
SO2Ph
OR'
R1
R2
O
R2
O
R2
O
+
+
AcOEt, rt
30 mins
N
N
N
R
R
R
R' = -CH(CF3)2
1
2
3
4
Entry
1
R, R1, 1
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, H, b
Bn, 5-Cl, d
Bn, 5-Me, e
Me, H, f
Boc, H, g
H, H, h
R2, 2
Yield (%),b 3/4
83, a
90, b
93, c
89, d
82, e
91, f
Dr (3/4) c
>95:5
83:17
82:18
82:18
80:20
83:17
80:20
92:8
C6H5, a
4-OMeC6H4, b
4-MeC6H4, c
4-FC6H4, d
4-ClC6H4, e
4-BrC6H4, f
4-CF3C6H4, g
3-FC6H4, h
3-ClC6H4, i
3-MeC6H4, j
3-OMeC6H4, k
2-OMeC6H4, l
2-MeC6H4, m
2-ClC6H4, n
2-BrC6H4, o
1-naphthyl, p
2-naphthyl, q
2-furyl, r
2
3
4
5
6
7 d
8 d
9 d
10 d
11e
12 e
13 d
14
15
16
17
18
19 e
20
21
22
23
24
65, g
86, h
85, i
>95:5
>95:5
85:15
<5:95
<5:95
51:49
54:46
<5:95
>95:5
18:82
<5:95
67:33
>95:5
>95:5
>95:5
-
86, j
87, k
85, l
88, m
87, n
87, o
59, p
60, q
50, r
49, s
2-thienyl, s
C6H5, a
77, t
C6H5, a
47, u
90, v
76, w
0
C6H5, a
C6H5, a
C6H5, a
a Unless otherwise noted, all reactions were carried out with 1 (0.2 mmol), 2 (1.2 equiv) and Cs2CO3 (2.5
equiv) in anhydrous ethyl acetate (2 mL) at room temperature typically for 30 mins.b Combined isolated
yields of 3 and 4 based on 1. c dr values were determined by 1H NMR analysis of the crude products.
d The reaction temperature was -20oC. e The reaction temperature was 0oC.
Since bispirooxindole motifs are also frequently found in bioactive compounds,9 we
then focus on the extension of this protocol to isatin-derived ketimines 5 (Table 3).

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Fortunately, the desired bispirooxindole -butyrolactams 6/7 were obtained in moderate
to good yields through the reactions of ester 1b and ketimines 5a-f (entries 1-6). The
reactions of the N-Bn- and N-Me-protected ketimines 5a and 5b had similar results in
terms of the reaction yield and diastereoselectivity (entries 1 and 2). However, the
diastereoselectivities of the reactions of ketimines 5c-f varied with the different
substituents on the benzene ring (entries 3-6). The reactions of 5-Me and 5-OMe-
substituted imines 5c and 5d gave products 6c and 6d, respectively, in good
diastereoselectivities (entries 3 and 4). The reaction of 5-F-substituted imine 5e resulted
in a poor diastereoselectivity (entry 5), while the reaction of 4-Cl-substituted imine 5f
afforded diastereomer 7f with an excellent diastereoselectivity (entry 6). Finally, the
reactions of two 5-substituted esters 1d and 1e were carried out to give the
corresponding products in high yields with moderate diastereoselectivities (entries 7
and 8). The structure of 6 and 7 was established by analysis of their NMR data and was
further confirmed by X-ray crystallography of 6b.10
Table 3. Scope of the reaction between ester 1a and isatin-derived ketimines 5
O
Boc
O
Boc
O
O
R3
O
R3
N
N
N
NBoc
O
N
R3
N
R1
R4
R1
OR'
R1
standard
conditions
O
+
+
O
O
R4
N
R4
N
Bn
N
Bn
Bn
7
R' = -CH(CF3)2
1
5
6
Entry
R1, 1
H, b
R3, R4, 5
Bn, H, a
Yield (%),a 6/7
80, a
Dr (6/7)b
85:15
84:16
87:13
80:20
42:58
<5:95
87:13
79:21
1
2
3
4
5
6
7
8
Me, H, b
86, b
H, b
H, b
H, b
H, b
Bn, 5-Me, c
Bn, 5-OMe, d
Bn, 5-F, e
Bn, 4-Cl, f
74, c
47, d
58, e
69, f
H, b
5-Cl, d
94, g
Bn, H, a
Bn, H, a
5-Me, e
91, h
a Combined isolated yields of 6 and 7 based on 1b. b dr values were determined by 1H NMR analysis
of the crude products.
A preliminary enantioselective study of this methodology was also undertaken by
employing several commonly used chiral organocatalysts (see ESI). After screening the

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reaction conditions, we found that product 3a could be obtained in 93% yield with an
excellent diastereoselectivity and 90.5:9.5 er by the reaction of 1b with imine 2a’ under
the catalysis of chiral phase transfer reagent PTC-A4 (Scheme 2). Unfortunately, this
reaction condition is not effective for the asymmetric synthesis of product 6a that was
obtained in 74% yield with an excellent diastereoselectivity but 50:50 er.
NBoc
2a'
Ph
H
CF3
3a
6a
93%, >95:5 dr
90.5:9.5 er
PTC-A4
HO
N
(10 mol%)
H
1b
LiOH (2.0 equiv)
PhMe/H2O (3:1)
CF3
PTC-A4
Br
74%, >95:5 dr
50:50 er
N
4a
Scheme 2. A preliminary enantioselective study of this methodology.
To further explore the utility of this protocol, a scale-up synthesis of products 3a/4a
and deprotection of the N-Boc group were then carried out (Scheme 3). The reaction
between 1b and 2a with 2 mmol scale under the standard conditions afforded desired
products 3a/4a in a slightly decreased yield (75 %) with 86:14 dr (Scheme 3a). The
deprotection of the N-Boc group of 3a and 6a with trifluoroacetic acid (TFA) produced
compound 8 and 9, respectively, in quantitative yields (Scheme 3b).
a) A scale-up synthesis of product 3a/4a
standard
conditions
1b + 2a
3a/4a
75 %, 86:14 dr
2 mmol
b) Deprotection of the products 3a and 6a
O
H
O
O
Bn
N
NH
N
TFA
TFA
DCM
99%
Ph
6a
3a
O
DCM
O
N
N
Bn
99%
8
Bn
9
Scheme 3. Synthetic applications.
Conclusions
In summary, we have designed a type of stable but reactive isatin-derived saturated
esters that have been applied successfully in a base-promoted formal [3+2] annulation

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for the divergent synthesis of two classes of structurally interesting 3,3'-spirooxindole
-butyrolactams. The diversity-oriented protocol developed herein offers a direct and
rapid access to a broad range of the desired spirooxindoles, especially the structurally
complex bispirooxindoles which may be attractive for potential drug discovery.
Moreover, this protocol has the advantages of mild reaction conditions and scalability
for the synthesis of the target compounds that can easily undergo deprotection of N-
Boc groups to afford N-H free lactams. A preliminary asymmetric synthesis study of
this protocol through chiral phase transfer catalysis was also demonstrated. Research
on the diversity-oriented synthesis of other spirooxindoles via diverse [3+m]
annulations of esters 1 is currently underway in our laboratory.
Acknowledgements
This work is funded by the National Natural Science Foundation of China (No.
21572270) and the “Double First-Class” University Project (CPU2018GY02 and
CPU2018GY35).
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10. CCDC 1913962 (6b) contains the supplementary crystallographic data for this paper.