Stereoselective Organocatalytic Construction of Spiro Oxindole Pyrrolidines Using Unsaturated α-Ketoesters and α-Ketoamides

Article abstract of DOI:10.1002/ejoc.202100022

We have investigated the stereoselective formation of spiro oxindole pyrrolidines via formal [3+2] cycloaddition of oxindole imines with ketoesters and ketoamides. Bifunctional squaramide organocatalyst was able to induce enantioselectivity of up to 60 %

Full text of DOI:10.1002/ejoc.202100022

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doi.org/10.1002/ejoc.202100022
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Stereoselective Organocatalytic Construction of Spiro
Oxindole Pyrrolidines Using Unsaturated α-Ketoesters and
α-Ketoamides
Tibor Peňaška,[a] Vitalii Palchykov,[a, b] Erik Rakovský,[c] Gabriela Addová,[a] and
Radovan Šebesta*[a]
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We have investigated the stereoselective formation of spiro
oxindole pyrrolidines via formal [3+2] cycloaddition of oxin-
dole imines with ketoesters and ketoamides. Bifunctional
squaramide organocatalyst was able to induce enantioselectiv-
ity of up to 60% ee, increased to 72% ee after re-crystallization,
in the formation of spiro pyrrolidines with ketoesters. Interest-
ingly, ketoamides provided alternative spiro oxindole pyrrole
products in addition to the main product, which was formed via
a different reaction pathway. Structures of spiro oxindole
pyrrolidine as well as pyrrole products were confirmed by X-ray
crystallographic analysis. Two new squaramide based catalysts
were synthesized and tested. DFT calculation helped elucidate
the reaction course.
Introduction
rooxindols utilize a variety of activation modes. Initially,
covalent enamine/iminium activation led to spirooxindols with
fused six-membered rings.[7] Later, activation modes based on
non-covalent interactions also led to many strategies towards
various chiral spirooxindol derivatives. Spirooxindol pyrrolidines
were synthesized by [3+2]-type cycloadditions, which rely
mostly on non-covalent activation by chiral Brønsted acids or
hydrogen bond donors such as thioureas or squaramides. The
typical strategy involves [3+2] cycloaddition of isatin-derived
azomethine ylides with activated alkenes. Again, enones and
α,β-unsaturated aldehydes benefit from iminium activation.[8]
Xu and co-workers developed squaramide-catalyzed asymmet-
ric dipolar cycloaddition between azomethine ylide and
aromatic nitroalkenes.[9] Azomethine ylide was formed in situ
from an imine via a 1,3-proton shift. Based on this strategy,
fluorinated imines reacted with nitroalkenes too.[10] Isatine-
derived azomethine ylides underwent dipolar cycloaddition
with arylidene azlactones or maleimides when chiral thioureas
or squaramides were used as catalysts.[11] Other, somewhat less
reactive dipolarophiles, such as activated alkynes, allenes,
methyleneindolinones, or imines, required stronger Brønsted
acid for activation.[12] Oxindol-core was recently incorporated
into axially-chiral compounds via atroposelective kinetic reso-
lution mediated by Brønsted acids.[13]
As a part of our interest in the organocatalytic formation of
chiral heterocycles, we have recently investigated [3+2] cyclo-
addition of azomethine ylides with unsaturated esters.[14] In this
work, we have found out that unsaturated esters probably bind
inefficiently to various hydrogen-bonding organocatalysts,
which led to a racemic reaction. We reasoned that analogous
unsaturated ketoesters or ketoamides might be much more
efficient acceptors of hydrogen bonds from a chiral catalyst.
This fact could lead to an enantioselective dipolar cycloaddition
reaction. In this context, we decided to study the formal
cycloaddition of azomethine ylides generated from oxindole
imines and unsaturated keto esters and keto amides. Herein, we
Carbo- and heterocyclic structures are omnipresent in natural
products and human-made drugs, and other bioactive com-
pounds. Many synthetic methods are devoted to the construc-
tion and manipulation of heterocyclic compounds. However,
efficient synthesis and functionalization of chiral heterocycles
have been identified as persisting synthetic challenges from the
pharmaceutical industry‘s standpoint.[1]
The significance of chiral heterocycles has been recognized
as an important task, and various catalytic methods are being
developed both by transition metal catalysis,[2] and
organocatalysis.[3] Indol-based chiral heterocycles,[4] and more
specifically, those with oxindole core are prominent core
structures among bioactive heterocyclic compounds. Because
of their wide-spread occurrence and importance, many syn-
thetic strategies have been devised for their preparation.[5]
Spirooxindol core is an interesting structural motif found in
natural alkaloids, such as horsfiline, rychnophylline, or spirotry-
prostatins, and several pharmaceuticals with anticancer or
antiviral properties.[6] Organocatalytic strategies towards spi-
[a] Dr. T. Peňaška, Dr. V. Palchykov, Dr. G. Addová, Prof. Dr. R. Šebesta
Department of Organic Chemistry, Faculty of Natural Sciences,
Comenius University in Bratislava
Mlynská dolina, Ilkovičova 6, 84215 Bratislava, Slovakia
E-mail: radovan.sebesta@uniba.sk
www.radovansebesta.com
[b] Dr. V. Palchykov
Research Institute of Chemistry and Geology
Oles Honchar Dnipro National University
Gagarina Av. 72, Dnipro, 49010, Ukraine
[c] Dr. E. Rakovský
Department of Inorganic Chemistry
Faculty of Natural Sciences, Comenius University in Bratislava
Mlynská dolina, Ilkovičova 6, 84215 Bratislava, Slovakia
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100022
Part of the “Organocatalysis” Special Collection.
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present results of the investigation of organocatalyzed formal
dipolar cycloaddition of imine-derived azomethine ylides with
unsaturated ketoesters and amides.
Product 4a was obtained in yield 52–57% and selectivity 23–
42% ee. The catalyst C6 with a longer carbon chain provided
higher selectivity than catalyst C5. When catalyst C7 with two
quinine units was used,[17] the chemical yield of the product was
60%, and enantiomeric excess was 20% ee. In comparison with
squaramides, thioureas typically have lower acidity and differ-
ent distance of hydrogen bond donor sites. There was no
significant change in yield (60%) and enantioselectivity (20%
ee) with thiourea catalyst C8.[18] Commercially available natural
quinine (C9) gave product 4a in low yield (26%) as a racemate.
The results of the initial catalyst screening in terms of yields and
enantioselectivity are summarized in Figure 1.
We continued our investigation by screening several other
hydrogen-bond donor catalysts in the reaction of isatine 1a,
benzylamine (2), and ketoester 3a (Figure 2). The results show
that squaramides with tertiary (C10 and C11),[19] secondary
(C12)[20] and primary (C13)[19a] amino group gave the required
product 4a with moderate yield (28–53%) and very poor
enantiomeric purities (4–16% ee). Aminoindanol squaramide
C14[21] with a free hydroxyl group afforded comparable results.
Thiosquaramides, as sulfur derivatives of commonly used
squaramides, have been studied in recent years due to their
higher acidity compared to squaramides. When we carried out
the model reaction with thiosquaramides C15, and C16,[22] the
cycloaddition product 4a was obtained in good yields (46–
77%) but in virtually racemic form. Various other catalysts, such
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Results and Discussion
We started our study with testing of several quinine-based
organocatalysts C1-9 in a model multicomponent reaction
system. The reaction between N-benzylisatine (1a), benzyl-
amine (2), and β,γ-unsaturated α-ketoester 3a afforded spiro-
oxindole pyrrolidine 4a with four stereogenic centers adjacent
(Scheme 1).
In our previous study, bifunctional quinine-based squara-
mides afforded racemic but diastereomerically pure cyclo-
addition products with unsaturated esters.[14] With ketoester 3a,
we assumed a better activation via hydrogen bonds due to the
presence of two carbonyl groups. More efficient catalyst-
substrate binding could result in higher stereoselectivity too.
Reactions were performed in dichloromethane (DCM) for 1–
24 h with 10 mol-% of catalyst. It was crucial to mix first
benzylisatine (1a) with benzylamine (2) and stir for a few
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minutes at À 5 C and only then add the keto ester 3a. This
addition order was necessary for preventing undesired com-
petitive reaction between benzylamine (2) and ketoester 3a.
We also observed partial decomposition of imine intermediate
after one hour. Therefore, the reaction is started at a lower
[15]
°
temperature of À 5 C. Using squaramide catalyst C1,
we
obtained new spirocyclic oxindole 4a in a good yield (73%) but
with low enantiomeric purity of 18% ee. Lowering the temper-
°
ature to À 30 C and longer reaction time led only to a small
improvement of selectivity with catalyst C1 (34% ee). The
squaramide catalyst C2[16] gave a slightly lower yield (57%) but
considerably higher enantioselectivity (60% ee). The lower
temperature did not improve the selectivity with catalyst C2.
Diastereoisomeric, quinidine-based catalysts C3, and C4 were
also tested.[15–16] This little difference of spatial arrangement
caused decrease of selectivity and yield (46–64%, 12–26% ee).
We have synthesized new squaramide catalysts C5 and C6,
which have phenyl group on the double bond of the
quinuclidine moiety. The phenyl group has been installed by a
Pd-catalyzed Heck reaction with phenyl bromide (for more
details, see SI). We hypothesized that additional π-π stacking
between reactants and catalyst might improve selectivity.
However, no improvement of reaction outcomes was observed.
Scheme 1. Test multicomponent reaction for the screening of catalysts.
Figure 1. Quinine-based catalysts used in this study.
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of organocatalyst C2. As mentioned above, the reaction in
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2
dichloromethane proceeded with the yield of 57% and the
enantiomeric excess 60% ee (Table 1, entry 1). Other tested
chlorinated solvents, 1,2-dichloroethane (DCE), and CHCl3 gave
slightly lower yields and enantioselectivity (Table 2, entries 2–3).
In cyclic ethers such as THF, 2-methyltetrahydrofuran (Me-THF),
and 1,4-dioxane, the reaction had the highest enantioselectivity
of 60% ee, but yields were lower than in DCM (Table 1,
entries 4–6). Surprisingly, a mixture of DCM and 1,4-dioxane (v/
v 1:1) brought a lower enantioselectivity 44% ee of the
cycloaddition (Table 1, entry 7). Slightly lower yields and
enantioselectivities were observed in acyclic ethers compared
to cyclic ones (Table 1, entries 8–10). The cycloaddition also
proceeded in aromatic solvents toluene, xylene, and
trifluoromethylbenzene (Table 1, entries 11–13), but neither
yield nor enantioselectivity was improved. Solvents with a free
hydroxy group (2,2,2-trifluroethanol, methanol, and L-ethyl
lactate) were not suitable for this reaction. In these solvents, the
reactions did not proceed, and only starting materials were
recovered. Protic solvents probably hindered the formation of
the azomethine ylide, thus making the cycloaddition ineffective.
In the further inquiry, we focused on the effect of additives
(Table 2). Acidic additives, such as benzoic and p-nitrobenzoic
acid, caused a decrease in yield and stereoselectivity (Table 2,
entries 2–3). On the other hand, a base diisopropylethylamine
(DIPEA) and dimethylacetamide (DEA) as an additive solvent for
higher solubility, gave comparable result as the reaction with-
out any additives (Table 2, entries 1 and 4–6). Re-crystallization
of the spiro-oxindol product 4a from absolute ethanol
increased its enantiomeric purity up to 72% ee (Table 2,
entries 1 and 5, see in brackets).
We have evaluated the [3+2] cycloaddition reaction scope
using a set of ketoesters 3a–f with squaramide catalyst C2. In
general, as shown in Table 3, keto esters 3a–d with an electron-
donating substituent on the aromatic core provide better
results than those with electron-withdrawing substituents 3e–f
(Table 3, entries 1–4 vs. entries 5–6). On the other hand, the
substituent R1 on the ester functional group affects hydrogen-
bond activation, thus on yield and selectivity. The best
enantioselectivity (48–52% ee) was obtained using ethyl ester
3a and tert-butyl ester 3d (Table 1, entries 1 and 4) compared
with benzyl ester 3b and methyl ester 3c (Table 1, entries 2–3).
We have assumed that this is due to the steric effect and
possible competitive π-π bonding of benzene core between
the ester functional group and other aromatic systems in the
reaction mixture. We examined the activity of catalyst C1 with
substrates 3a–b. The corresponding products 4a–b were
isolated in higher yields but with markedly lower selectivity
than with catalyst C2 (Table 1, entries 1–2, see in brackets).
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Figure 2. Other catalysts used in this study.
as Dixon’s thiourea C17[23] with a strongly basic center,
sulfamide catalyst C18,[24] hybrid peptide-thiourea C19, thio/
ureas C20,[25] and C21[26] and also commercially available chiral
phosphoric acid C22[27] gave the product 4a in moderate yield
(10–57%) and with very low enantioselectivity (0–12% ee).
The reaction did not proceed when guanidines (C23 and
C24) and phase-transfer catalysts (C25 and C26) were used, for
catalyst structures, see SI. For more details of the testing
conditions and preparation of racemic samples for HPLC
analysis, see SI.
We selected the most efficient catalyst, quinine-based
squaramide C2, that gave the best enantioselectivity (60% ee)
for further optimization.
First, we have studied the effect of solvent on the cyclo-
addition of benzylisatin (1a), benzylamine (2) and keto ester 3a.
We have employed standard conditions (rt, 24 h) with 10 mol%
°
Lowering the temperature to À 30 C did not provide better
results (Table 1, entry 4).
We have briefly explored the use of N-methylisatine in this
type of cycloaddition. However, the related products were
probably unstable and challenging to analyze by chiral HPLC,
see SI for characterization data.
Next, we turn our attention on α,β-unsaturated keto amides
5a–d, which were easily prepared from the appropriate (E)-4-(4-
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Table 1. Solvent screening in the reaction between oxindole 1a, benzylamine (2) and ketoester 3a.
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Entry
Solvent
Yield 4a [%]
ee [%]
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10
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20
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22
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52
53
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57
1
2
3
4
5
6
7
8
DCM
DCE
CHCl3
THF
57 (73)[a]
47
56
60 (18)[a]
43
32
34
60
Me-THF
1,4-dioxane
1,4-dioxane/DCM (1:1)
TBME
CpOMe
DME
Toluene
Xylene
Ph-CF3
CF3CH2OH
MeOH
L-ethyl lactate
42 (40)[a]
60 (18)[a]
26 (40)[a]
60 (20)[a]
36
29
33
29
37
21
54
0
44
44
54
54
30
26
48
–
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10
11
12
13
14
15
16
0
0
–
–
[a] Data in brackets are for catalyst C1 (10 mol%).
Table 2. Additive effects on the cycloaddition of benzylisatine (1a), benzylamine (2) and ketoester 3a.
Entry
Additive (equiv)
Yield [%]
ee [%]
1
2
3
–
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10
36
49
47
33
60 (72)[b]
0
p-Nitrobenzoic acid (2 equiv)
Benzoic acid (0.5 equiv)
DIPEA (0.5 equiv)
26
58
4
5[a]
6
DIPEA (0.5 equiv)
Dimethylacetamide (1 equiv)
57 (67)[b]
55
°
[a] Reaction in Me-THF/DCM (2:1). [b] Data in brackets are enantiomeric excess of product 4a after re-crystallization in abs. EtOH at 5 C.
methoxyphenyl)-2-oxobut-3-enoyl chloride (see SI). We tested
these keto amides with quinine-based catalyst C2 that gave
good results with ketoesters 3. These reactions provided
corresponding spiro-oxindole pyrrolidines 6 with keto amide
substituents. Spiro-oxindole pyrrolidines 6 were formed as a
mixture of three diastereoisomers in a typical ratio of d.r. 4:3:2.
These diastereomers were separated by column chromatogra-
phy. Interestingly, a new unexpected spiro-oxindole 7 was
formed with ketoamides 5a–c (Scheme 2). The results are
summarized in Table 4. Products 6 were isolated in moderate
yields of 20–68% with low enantiomeric purities of 0–18% ee.
For more details (reaction with catalyst C1 see SI.
uously determined by single-crystal X-ray diffraction analyses
(Figure 3). For details, see SI.
From a mechanistic point of view, these results can be
explained by the formation of enolate A as a key intermediate.
On the one hand, enolate A predictably converts into spirocycle
B, which upon protonation affords main spirocyclic products 6
(Scheme 3, route I). The chemoselectivity of this step depends
explicitly on the nature of the amide group. The content of the
side product 7 is larger for dialkylamino groups NMe2 and
N(CH2)4. On the other hand, pyrrole products 7 were not
observed with monoalkylamino group NHMe and NHBn.
Unfortunately, the enantiomeric purity of all products was low
(up to 26% ee).
In addition to 1D and 2D NMR spectroscopy, structures, and
configurations of products 4a, 6a, 6b, and 7a were unambig-
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Table 3. Functional group effect-keto esters.
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2
3
4
5
6
7
8
9
Entry[a]
R1
R2[b]
Product
Yield [%]
ee [%]
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13
14
15
16
17
18
19
20
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22
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1
2
3
4
5
6
Et
MeO
MeO
MeO
MeO
Br
4a
4b
4c
4d
4e
4f
57 (73)[a]
43 (72)[a]
71
60 (18)[a]
30 (0)[a]
28
Bn
Me
tBu
Et
87 (78)[b]
35
52 (48)[b]
nd[c]
Bn
Br
27
nd[c]
°
[a] Data in brackets are for catalyst C1 (10 mol%). [b] Data in brackets are for the reaction at À 30 C. [c] Optimal conditions for HPLC were not found.
by NOESY spectroscopy and X-ray crystallographic analysis (see
SI). The reason ketoamides also undergo a secondary pathway
towards pyrrole products 7 might be explained by the higher
basicity of the ketoamide enolate A compared to corresponding
ketoester enolate. It is due to the stronger electron-withdrawing
effect of the ester group in comparison with an amide.
Therefore, protonation of the more basic ketoamide enolate
(route II) thus competes with the main reaction route I towards
spiro-oxindol pyrrolidines 4 and 6. The differences between
ketoester and ketoamide enolates likely also influence the
diastereoselectivity of the reaction. Protonation/deprotonation
of these enolates can change enolate configuration and thus
may lead to different facial preferences in the ring-closing step
of the reaction (see Supporting information for more details).
Scheme 2. [3+2] cycloaddition reaction with keto amides 5.
To understand the mechanisms of the formation of
spirocyclic oxindole pyrrolidine, we have conducted DFT
calculations. We have employed long-range corrected hybrid
On the other hand, enolate A can be protonated by a
conjugate base formed in previous steps (Scheme 3, route II). In
this way, formed intermediate C can undergo cyclization via the
addition of imine nitrogen atom on the keto amide carbonyl to
produce intermediate D, which can then form 1,3-oxazetidine E.
Alternatively, the formation of intermediate E can proceed
directly from intermediate C as a [2+2]-type cycloaddition.
After the elimination of benzaldehyde, final product 7 is
formed. GCMS and 1H NMR confirmed the presence of
benzaldehyde in the reaction mixture. Structures, absolute and
relative configurations of compounds 6 and 7 were confirmed
density ωB97X-D functional for geometrical optimizations,[28]
and 6-31G* basis set. Energies were refined with Minnesota
functional MN15,[29] using Karlsruhe triple-zeta def2-TZVP basis
set.[30] The solvent effects of DCM were accounted for by the
polarizable continuum model (PCM) using the integral equation
formalism variant (IEFPCM).[31] This functional accounts for long-
range London dispersion effects.
The calculations support the notion that spirocyclization is a
two-step process comprising a Michael addition of a carbanion
formed from oxindole imine to either keto ester or keto amide.
Table 4. Functional group effect – keto amides.
Entry
R (5a-d)
Yield of 6
[%]
ee of 6
[%]
Yield of 7
[%]
ee of 7
[%]
1
2
3
4
NMe2 (a)
NHMe (b)
N(CH2)4 (c)
NHBn (d)
36[a]
68
20
18
0
10
24
5
33
19
0
26
61
4
0
–
[a] The sum of three diastereoisomers that were isolated with the total dr 4:3:2 and 0–18% ee. Their revised structures are shown in SI.
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Figure 3. X-Ray crystallographic structures of compounds 4a, 6a, 6b, and
7a.
Scheme 3. Proposed reaction mechanism (PMP=p-MeOÀ C6H4).
The enolate, which is formed in this step, is then cyclized via
addition to imine functionality (Figure 4).
Calculations also support creating the pyrrole by-product 7
via the formation of 1,3-oxazetidine intermediate E either via [2
+2]-type cycloaddition or a stepwise process. Oxazetidine
intermediate E then decomposes via a retro [2+2] cyclo-
addition to release product 7a and benzaldehyde. The structure
of the product 7a was unambiguously confirmed by X-ray
crystallographic analysis. Figure 5 depicts DFT calculated tran-
sition states for the formation of 1,3-oxazetidine intermediate E
(TS-[2+2]) and for its decomposition to pyrrole derivative 7a
(TS-retro-[2+2]).
oxindole pyrrolidines. Chiral quinine-based squaramide organo-
catalyst can provide ketoester product with an enantiomeric
purity of 60% ee, which can be augmented by re-crystallization
up to 72% ee. Interestingly, keto amides also afford alternative
cyclization product with spirocyclic pyrrole moiety. The identity
of keto ester and keto amide spiro-oxindol pyrrolidines, as well
as alternative spiro-pyrrole product, were confirmed by X-ray
crystallographic analyses, and mechanistic details were eluci-
dated by DFT calculations.
We have also calculated concerted [3+2] cycloaddition
reactions from neutral ylide; see SI for more details.
Conclusion
We have shown that in situ formed oxindole imines react with
unsaturated keto esters and keto amides to provide spirocyclic
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49
50
51
52
53
54
55
56
57
Figure 4. Reaction profiles calculated at ωB97X-D/6-31G*//MN15/def2-TZVP (DCM) level.
Experimental Section
Representative procedure for the synthesis of spiro oxindole
pyrrolidines
To a mixture of isatine 1 (1.0 equiv; 0.126 mmol) and MgSO4
(10 equiv; 1.26 mmol) in DCM (1.5 mL) benzylamine (1.1 equiv;
°
0.139 mmol) was added in one portion under stirring at À 5 to 0 C.
After 10 min mixture of ketoester/ketoamide 3 or 5 (1.0 equiv;
0.126 mmol) and catalyst C (10 mol%) in DCM (1.5 mL) was added.
The reaction mixture was then gradually warm to room temper-
ature and stirred for 24 h. The solvent was evaporated in vacuo and
the crude reaction mixture was purified by column chromatography
on SiO2 (hexane/EtOAc 3:1!1:1).
Characterization data
Ethyl 2-((3R,3’R,4’S,5’R)-1-benzyl-3’-(4-methoxyphenyl)-2-oxo-5’-
phenylspiro[indoline-3,2’-pyrrolidin]-4’-yl)-2-oxoacetate (4a)
Figure 5. Transition states calculated at ωB97X-D/6-31G*//MN15/def2-TZVP
(DCM) level. Molecular models rendered with CYLview20.[32]
White solid; yield of 57% (35 mg), 60% ee (72% ee after re-
crystallization in abs. EtOH at 5 C); [α]D20 +83.2 (CHCl3, c 0.25); Rf
°
(hexane/EtOAc, 3:1) 0.27; m.p. 144–146 C; 1H NMR (600 MHz,
°
CDCl3): δ 7.71 (d, J=6.7 Hz, 1H), 7.55 (d, J=7.5 Hz, 2H), 7.35 (t, J=
7.5 Hz, 2H), 7.29–7.27 (m, 1H), 7.21–7.08 (m, 5H), 6.90 (d, J=8.5 Hz,
2H), 6.83 (d, J=7.3 Hz, 2H), 6.52 (d, J=8.5 Hz, 2H), 6.44 (d, J=
7.2 Hz, 1H), 5.53 (d, J=10.6 Hz, 1H), 5.11–5.06 (m, 2H), 4.55 (d, J=
6.9 Hz, 1H), 4.52 (d, J=3.4 Hz, 1H), 4.06–4.00 (m, 2H), 3.67 (s, 3H),
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2.84 (s, 1H), 1.13 (t, J=7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ
1247 (s), 1174 (m), 1029 (s), 830 (m), 751 (s), 698 (s), 543 (m) cmÀ 1
.
HPLC: Chiralpak IC, n-hexane/iPrOH 90:10, 1 mL/min, 215 nm, tR =
32.33 and 39.96 min.
1
2
3
4
5
6
7
8
9
190.9, 177.0, 160.7, 158.8, 142.1, 139.9, 134.9, 131.1, 129.5, 129.0,
128.9, 128.5, 128.4, 128.4, 127.3, 126.8, 126.3, 124.3, 122.6, 113.4,
109.6, 72.6, 63.5, 62.4, 56.8, 55.0, 54.9, 43.9, 13.7. HRMS-ESI+ (m/z):
calculated for [C35H33N2O5]+: 561.2389, found: 561.2384. IR (ATR):
3325 (w), 1701 (s), 1611 (m), 1514 (m), 1456 (m), 1370 (m), 1249 (s),
Ethyl 2-((3R,3’R,4’S,5’R)-1-benzyl-3’-(4-bromophenyl)-2-oxo-5’-
phenylspiro[indoline-3,2’-pyrrolidin]-4’-yl)-2-oxoacetate (4e)
1176 (s), 1029 (m), 753 (s), 701 (s), 598 (m), 546 (m), 478 (m) cmÀ 1
.
HPLC: Chiralpak IB, n-hexane/i-PrOH 90:10, 1 mL/min, 215 nm, tR =
25.02 and 30.82 min.
20
White solid; yield of 35% (27 mg); [α]D À 57.5 (CHCl3, c 0.50); Rf
(hexane/EtOAc, 3:1) 0.33; m.p. 159–160 C; 1H NMR (600 MHz,
°
CDCl3): δ 7.70 (dd, J=5.5, 3.1 Hz, 1H), 7.53 (d, J=7.5 Hz, 2H), 7.36 (t,
J=7.6 Hz, 2H), 7.28 (t, J=7.3 Hz, 1H), 7.24–7.18 (m, 3H), 7.13 (dd,
J=5.5, 3.1 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H),
6.81 (d, J=6.4 Hz, 2H), 6.50–6.46 (m, 1H), 5.54 (d, J=10.6 Hz, 1H),
5.14–5.01 (m, 2H), 4.58–4.46 (m, 2H), 4.09–3.97 (m, 2H), 2.84 (s, 1H),
1.13 (t, J=7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ 190.7, 176.6,
160.7, 142.0, 139.6, 134.8, 133.4, 131.1, 130.5, 130.1, 129.3, 128.9,
128.6, 128.6, 128.3, 127.5, 126.7, 124.3, 122.8, 121.5, 109.8, 72.4,
63.5, 62.5, 56.8, 55.0, 43.9, 13.7. HRMS-ESI+ (m/z): calculated for
[C34H29BrN2O4K]+: 647.0942 and 649.0922, found: 647.0942 and
649.0920 (both isotopes of Bromine) IR (ATR): 2962 (w), 2925 (w),
1717 (s), 1610 (m), 1488 (m), 1466 (m), 1364 (m), 1246 (m), 1174
(m), 1074 (m), 1029 (s), 1009 (s), 800 (m), 751 (s), 729 (s), 696 (s), 489
(w) cmÀ 1. HPLC: conditions not found.
Benzyl 2-((3R,3’R,4’S,5’R)-1-benzyl-3’-(4-methoxyphenyl)-2-oxo-
5’-phenylspiro[indoline-3,2’-pyrrolidin]-4’-yl)-2-oxoacetate (4b)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Pale yellow solid; yield of 43% (34 mg), 30% ee; [α]D20 +3.2 (CHCl3,
c 0.18); Rf (hexane/EtOAc, 3:1) 0.29; m.p. 73–74 C; 1H NMR
°
(600 MHz, CDCl3): δ 7.73–7.66 (m, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.37–
7.32 (m, 3H), 7.28–7.07 (m, 10H), 6.90 (d, J=8.7 Hz, 2H), 6.83 (d, J=
7.2 Hz, 2H), 6.52 (d, J=8.7 Hz, 2H), 6.47–6.42 (m, 1H), 5.52 (d, J=
10.5 Hz, 1H), 5.15–5.05 (m, 2H), 5.00 (q, J=12.1 Hz, 2H), 4.53 (d, J=
13.7 Hz, 2H), 3.66 (s, 3H), 2.86 (s, 1H). 13C NMR (151 MHz, CDCl3): δ
187.8, 174.5, 157.9, 156.2, 139.5, 137.2, 132.4, 131.6, 128.5, 126.9,
126.4, 126.3, 126.1, 126.1, 126.0, 125.9, 125.9, 125.7, 124.8, 124.3,
123.6, 121.7, 120.1, 110.8, 107.1, 70.0, 65.4, 60.9, 54.4, 52.5, 52.3,
41.3. HRMS-ESI+ (m/z): calculated for [C40H34N2O5K]+: 661.2100,
found: 661.2101. IR (ATR): 2930 (w), 1717 (s), 1610 (m), 1513 (m),
1455 (m), 1247 (m), 1176 (m), 1028 (m), 750 (s), 696 (s), 543 (w)
Benzyl 2-((3R,3’R,4’S,5’R)-1-benzyl-3’-(4-bromophenyl)-2-oxo-5’-
phenylspiro[indoline-3,2’-pyrrolidin]-4’-yl)-2-oxoacetate (4f)
cmÀ 1
. HPLC: Chiralpak IB, n-hexane/i-PrOH 90:10, 1 mL/min,
215 nm, tR =19.87 and 23.35 min.
20
White solid; yield of 27% (23 mg); [α]D À 88.4 (CHCl3, c 0.20); Rf
(hexane/EtOAc, 3:1) 0.41; m.p. 133–134 C; 1H NMR (600 MHz,
°
CDCl3): δ 7.69–7.67 (m, 1H), 7.47 (d, J=7.1 Hz, 2H), 7.37–7.32 (m,
3H), 7.28–7.18 (m, 9H), 7.14–7.12 (m, 2H), 7.10 (d, J=8.4 Hz, 2H),
6.83 (d, J=8.4 Hz, 2H), 6.81 (d, J=6.5 Hz, 2H), 6.48–6.47 (m, 1H),
5.52 (d, J=10.5 Hz, 1H), 5.12–5.04 (m, 2H), 5.00 (q, J=12.1 Hz, 2H),
4.54–4.48 (m, 2H). 13C NMR (151 MHz, CDCl3): δ 190.2, 176.6, 160.4,
142.0, 139.6, 134.8, 134.1, 133.3, 131.1, 130.6, 130.1, 129.3, 128.9,
128.7, 128.7, 128.6, 128.6, 128.2, 127.5, 126.7, 124.3, 122.8, 121.5,
109.8, 72.4, 68.0, 63.4, 56.8, 55.0, 43.9. HRMS-ESI+ (m/z): calculated
for [C39H32N2O4]+: 671.1540 and 673.1519, found: 671.1544 and
673.1520. (both isotopes of Bromine) IR (ATR): 3033 (w), 2957 (w).
2925 (w), 1717 (s), 1611 (m), 1489 (m), 1467 (m), 1363 (m), 1279 (m),
1279 (m), 1243 (m), 1175 (m), 1074 (m), 1010 (m), 750 (m), 731 (m),
695 (s) cmÀ 1. HPLC: conditions not found.
Methyl 2-((3R,3’R,4’S,5’R)-1-benzyl-3’-(4-methoxyphenyl)-2-oxo-
5’-phenylspiro[indoline-3,2’-pyrrolidin]-4’-yl)-2-oxoacetate (4c)
Pale yellow solid; yield of 71% (49 mg), 28% ee; [α]D20 +17.2 (CHCl3,
c 0.35); Rf (hexane/EtOAc, 3:1) 0.29; m.p. 130–132 C; 1H NMR
°
(600 MHz, CDCl3): δ 7.73–7.68 (m, 1H), 7.55 (d, J=7.4 Hz, 2H), 7.35
(t, J=7.6 Hz, 2H), 7.28 (d, J=7.4 Hz, 1H), 7.21–7.05 (m, 5H), 6.90 (d,
J=8.7 Hz, 2H), 6.83 (d, J=7.1 Hz, 2H), 6.52 (d, J=8.7 Hz, 2H), 6.46–
6.42 (m, 1H), 5.53 (d, J=10.6 Hz, 1H), 5.13–5.04 (m, 2H), 4.55 (d, J=
3.1 Hz, 1H), 4.52 (s, 1H), 3.66 (s, 3H), 3.57 (s, 3H), 2.91 (s, 1H). 13C
NMR (151 MHz, CDCl3): δ 190.5, 177.0, 161.1, 158.8, 142.1, 139.8,
135.0, 131.0, 129.5, 129.0, 128.9, 128.6, 128.5, 128.3, 127.4, 126.8,
126.2, 124.3, 122.7, 113.4, 109.7, 72.6, 63.5, 57.0, 55.0, 54.8, 52.9,
43.9. HRMS-ESI+ (m/z): calculated for [C34H31N2O5]+: 547.2227,
found: 547.2230. IR (ATR): 3326 (w), 2922 (w), 2852 (w), 1709 (s),
1610 (m), 1513 (m), 1465 (m), 1367 (m), 1249 (s), 1174 (s), 1029 (m),
752 (s), 701 (s), 597 (m), 546 (m), 477 (m) cmÀ 1. HPLC: Chiralpak IC,
n-hexane/i-PrOH 90:10, 1 mL/min, 215 nm, tR =72.36 and
81.03 min.
2-((3R,3’S,4’R,5’R)-1-Benzyl-3’-(4-methoxyphenyl)-2-oxo-5’-phe-
nylspiro[indoline-3,2’-pyrrolidin]-4’-yl)-N,N-dimethyl-2-oxo-
acetamide ((R,S,R,R)-6a)
White solid; yield of 8% (6 mg), 4% ee; Rf (hexane/EtOAc 1:1) 0.62;
1
°
m.p. 184–186 C; H NMR (CDCl3, 600 MHz): δ 7.46 (m, 2H), 7.41 (d,
J=7.3 Hz, 1H), 7.33 (m, 2H), 7.29 (m, 2H), 7.28–7.20 (m, 6H), 7.15 (t,
J=7.7 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.78 (d, J=8.7 Hz, 2H), 6.65 (d,
J=7.7 Hz, 1H), 4.99 (d, J=15.8 Hz, 1H), 4.98 (d, J=10.4 Hz, 1H), 4.93
(d, J=15.8 Hz, 1H), 4.81 (d, J=11.5 Hz, 1H), 3.81 (t, J=11.1 Hz, 1H),
3.75 (s, 3H), 2.59 (br.s, 1H), 2.49 (s, 3H), 2.46 (s, 3H). 13C NMR (CDCl3,
151 MHz): δ 196.4, 180.6, 163.4, 158.7, 143.6, 140.7, 135.8, 130.4,
130.3, 129.6, 129.5, 128.8, 128.4, 127.8, 127.2, 125.3, 122.9, 114.0,
109.4, 68.4, 67.2, 63.1, 55.3, 54.7, 44.7, 36.6, 35.6. HRMS-ESI+ (m/z):
calculated for [C35H34N3O4]+: 560.2544; found: 560.2545. IR (ATR):
3331 (w), 3030 (w), 2929 (w), 1710 (s), 1641 (s), 1610 (s), 1513 (s),
1487 (s), 1466 (s), 1352 (s), 1303 (m), 1248 (s), 1176 (s), 1114 (m),
Tert-butyl 2-((3R,3’R,4’S,5’R)-1-benzyl-3’-(4-methoxyphenyl)-
2-oxo-5’-phenylspiro[indoline-3,2’-pyrrolidin]-4’-yl)-
2-oxoacetate (4d)
Pale yellow solid; yield of 87% (65 mg), 52% ee; [α]D20 +11.2 (CHCl3,
c 0.50); Rf (hexane/EtOAc, 3:1) 0.39; m.p. 93–94 C; 1H NMR
°
(600 MHz, CDCl3): δ 7.73–7.68 (m, 1H), 7.55 (d, J=7.4 Hz, 2H), 7.34
(t, J=7.6 Hz, 2H), 7.28–7.25 (m, 1H), 7.20–7.05 (m, 5H), 6.90 (d, J=
8.7 Hz, 2H), 6.80 (d, J=7.3 Hz, 2H), 6.52 (d, J=8.7 Hz, 2H), 6.44–6.40
(m, 1H), 5.52 (d, J=10.5 Hz, 1H), 5.13–5.03 (m, 2H), 4.53–4.49 (m,
2H), 3.66 (s, 3H), 2.84 (s, 1H), 1.32 (s, 9H). 13C NMR (151 MHz, CDCl3):
δ 191.7, 177.1, 159.8, 158.8, 142.1, 140.2, 135.0, 131.2, 129.6, 129.0,
128.9, 128.5, 128.5, 128.3, 127.3, 126.8, 126.4, 124.4, 122.6, 113.4,
109.6, 83.7, 72.6, 63.6, 56.6, 55.3, 55.0, 43.9, 27.5. HRMS-ESI+ (m/z):
calculated for [C37H36N2O5K]+: 627.2256, found: 627.2260. IR (ATR):
3346 (w), 2973 (w), 2932 (w), 1711 (s), 1610 (m), 1513 (m), 1367 (m),
1080 (m), 1029 (s), 833 (m), 808 (m), 732 (s), 698 (s), 550 (m) cmÀ 1
.
HPLC: Chiralpak IB, n-hexane/i-PrOH 95:5, 1.2 mL/min, 215 nm, t=
24.97 and 42.49 min.
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2-((2’R,3’S,4’R,5’S)-1-Benzyl-3’-(4-methoxyphenyl)-2-oxo-5’-
phenylspiro[indoline-3,2’-pyrrolidine]-4’-yl)-N,N-dimethyl-2-oxo-
acetamide ((R,S,R,S)-6a)
2-((2’R,3’R,4’S,5’R)-1-Benzyl-3’-(4-methoxyphenyl)-2-oxo-5’-
phenylspiro[indoline-3,2’-pyrrolidine]-4’-yl)-N-methyl-2-oxo-
acetamide (6b)
1
2
3
4
5
6
7
8
9
White solid; yield of 12% (8 mg), 18% ee; Rf (hexane/EtOAc 1:1)
White solid; yield of 68% (47 mg), 0% ee; Rf (hexane/EtOAc 1:1)
0.55; m.p. 195–197 C; 1H NMR (CDCl3, 600 MHz): δ 7.75 (d, J=
0.51; m.p. 155–156 C; 1H NMR (CDCl3, 600 MHz): δ 7.75 (d, J=
°
°
7.0 Hz, 1H), 7.63 (d, J=7.2 Hz, 2H), 7.36 (t, J=7.6 Hz, 2H), 7.26 (m,
1H), 7.18–7.12 (m, 3H), 7.08 (t, J=7.5 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H),
6.64 (d, J=8.8 Hz, 2H), 6.45 (d, J=7.5 Hz, 2H), 6.37 (d, J=8.1 Hz,
1H), 5.85 (t, J=11.3 Hz, 1H), 5.77 (d, J=11.0 Hz, 1H), 5.10 (d, J=
16.1 Hz, 1H), 4.32 (d, J=11.7 Hz, 1H), 4.20 (d, J=16.1 Hz, 1H), 3.72
(s, 3H), 2.71 (s, 3H), 2.61 (br.s, 1H), 2.16 (s, 3H). 13C NMR (CDCl3,
151 MHz): δ 198.0, 179.1, 164.5, 159.2, 143.4, 142.1, 135.2, 129.7,
129.4, 129.3, 128.8, 128.5, 128.1, 127.3, 126.9, 126.6, 123.8, 123.0,
113.9, 109.4, 72.5, 60.4, 55.2, 53.6, 53.2, 43.5, 36.5, 35.8. HRMS-ESI+
(m/z): calculated for [C35H34N3O4]+: 560.2544; found: 560.2548. IR
(ATR): 3338 (w), 2925 (w), 1708 (s), 1634 (s), 1612 (s), 1513 (m), 1489
(m), 1467 (m), 1355 (s), 1312 (m), 1247 (s), 1178 (s), 1131 (m), 1057
(m), 1029 (s), 995 (s), 845 (m), 826 (m), 796 (m), 779 (m), 745 (s), 734
6.9 Hz, 1H), 7.62 (d, J=7.3 Hz, 2H), 7.32 (t, J=7.6 Hz, 2H), 7.23 (t, J=
7.3 Hz, 1H), 7.20–7.14 (m, 3H), 7.13-7.07 (m, 2H), 6.88 (d, J=8.7 Hz,
2H), 6.84 (d, J=7.2 Hz, 2H), 6.51 (d, J=8.7 Hz, 2H), 6.43 (d, J=
8.3 Hz, 1H), 6.26 (d, J=5.1 Hz, 1H), 5.61 (d, J=10.4 Hz, 1H), 5.31 (dd,
J=13.1, 10.4 Hz, 1H), 5.09 (d, J=16.0 Hz, 1H), 4.54 (d, J=16.0 Hz,
1H), 4.49 (d, J=13.2 Hz, 1H), 3.66 (s, 3H), 2.85 (s, 1H), 2.64 (d, J=
5.2 Hz, 3H). 13C NMR (CDCl3, 151 MHz): δ 195.9, 177.7, 160.9, 158.9,
142.1, 140.9, 135.2, 131.4, 129.6, 129.1, 128.7, 128.6, 128.5, 128.2,
127.5, 127.0, 126.5, 124.6, 122.8, 113.5, 109.7, 72.8, 63.5, 55.2, 54.7,
54.6, 44.1, 25.8. HRMS-ESI+ (m/z): calculated for [C34H32N3O4]+:
546.2387; found: 546.2392. IR (ATR): 3383 (w), 3065 (w), 3034 (w),
3001 (w), 2936 (w), 1736 (m), 1711 (s), 1683 (s), 1612 (m), 1583 (m),
1515 (s), 1496 (m), 1466 (m), 1437 (m), 1373 (m), 1248 (s), 1181 (s),
1112 (m), 1029 (m), 1011 (m), 989 (m), 935 (m), 901 (m), 830 (s), 775
(s), 754 (s), 727 (m), 701 (s), 600 (m), 546 (m) cmÀ 1. HPLC: Chiralpak
IC, n-hexane/iPrOH 90:10, 1.0 mL/min, 215 nm, tR =57.76 and
92.63 min.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
(s), 698 (s), 676 (s), 641 (m), 624 (s), 577 (s), 543 (s), 515 (m) cmÀ 1
HPLC: Chiralcel OD-H, n-hexane/iPrOH 90:10, 1.0 mL/min, 215 nm,
tR =40.92 and 48.07 min.
.
2-((2’R,3’R,4’S,5’R)-1-Benzyl-3’-(4-methoxyphenyl)-2-oxo-5’-
phenylspiro[indoline-3,2’-pyrrolidine]-4’-yl)-N,N-dimethyl-2-oxo-
acetamide ((R,R,S,R)-6a)
(2’R,3’R)-1-benzyl-3’-(4-methoxyphenyl)-N-methyl-2-oxo-3’,4’-di-
hydrospiro[indoline-3,2’-pyrrole]-5’-carboxamide (7b)
20
White solid; yield of 5% (3 mg), 0% ee; Rf (hexane/EtOAc 1:1) 0.38;
White solid; yield of 16% (11 mg), 16% ee; [α]D À 122.3 (CHCl3, c
1
1
°
°
m.p. 135–136 C; H NMR (CDCl3, 600 MHz): δ 7.31–7.26 (m, 3H), 7.20
0.15); Rf (hexane/EtOAc 1:1) 0.38; m.p. 173–175 C; H NMR (CDCl3,
(d, J=7.0 Hz, 2H), 7.14 (d, J=4.3 Hz, 1H), 7.06 (t, J=7.7 Hz, 1H), 6.89
(d, J=8.5 Hz, 2H), 6.81 (t, J=7.5 Hz, 1H), 6.70 (d, J=7.4 Hz, 1H), 6.61
(d, J=8.6 Hz, 2H), 6.59 (d, J=7.9 Hz, 1H), 5.09 (d, J=15.7 Hz, 1H),
4.77 (d, J=15.7 Hz, 1H), 4.23 (t, J=9.0 Hz, 1H), 3.70 (s, 3H), 3.65 (dd,
J=18.3, 8.6 Hz, 1H), 3.56 (dd, J=18.2, 9.4 Hz, 1H), 2.93 (d, J=5.1 Hz,
3H). 13C NMR (CDCl3, 151 MHz): δ 176.4, 175.6, 162.3, 158.8, 142.5,
135.4, 129.7, 129.0, 128.9, 128.7, 127.8, 127.4, 126.6, 125.5, 122.7,
113.7, 109.6, 85.4, 55.3, 51.3, 44.2, 40.3, 26.1. HRMS-ESI+ (m/z):
calculated for [C27H25N3O3Na]+: 462.1788; found: 462.1788. IR (ATR):
3386 (w), 2967 (w), 2932 (w), 1714 (s), 1678 (s), 1608 (s), 1542 (m),
1515 (m), 1489 (s), 1467 (s), 1431 (m), 1354 (s), 1309 (m), 1256 (s),
1176 (s), 1145 (m), 1118 (m), 1022 (s), 959 (s), 904 (w), 834 (s), 796
(m), 762 (s), 727 (s), 706 (s), 598 (s) cmÀ 1. HPLC: Chiralpak IB, n-
hexane/i-PrOH 95:5, 1.2 mL/min, 215 nm, t=57.24 and 71.02 min.
600 MHz): δ 7.68 (m, 3H), 7.37 (t, J=7.7 Hz, 2H), 7.28 (t, J=7.4 Hz,
1H), 7.19-7.15 (m, 3H), 7.08 (m, 2H), 6.93 (d, J=8.7 Hz, 2H), 6.87 (d,
J=6.7 Hz, 2H), 6.52 (d, J=8.8 Hz, 2H), 6.42 (m, 1H), 5.46–5.39 (m,
2H), 5.08 (d, J=16.0 Hz, 1H), 4.57 (d, J=16.0 Hz, 1H), 4.48 (d, J=
12.7 Hz, 1H), 3.66 (s, 3H), 2.76 (s, 3H), 2.19 (s, 3H). 13C NMR (CDCl3,
151 MHz): δ 196.1, 177.7, 164.3, 158.8, 142.1, 141.5, 135.2, 131.5,
129.4, 129.0, 128.8, 128.7, 128.6, 128.4, 127.5, 127.0, 126.9, 124.5,
122.8, 113.5, 109.6, 72.6, 62.5, 55.8, 55.2, 54.7, 44.1, 36.6, 36.0.
HRMS-ESI+ (m/z): calculated for [C35H34N3O4]+: 560.2544; found:
560.2548. IR (ATR): 3355 (w), 3189 (w), 2919 (s), 2850 (m), 1711 (s),
1637 (s), 1609 (s), 1512 (s), 1487 (m), 1466 (s), 1408 (m), 1362 (m),
1247 (s), 1174 (s), 1101 (m), 1077 (m), 1029 (s), 829 (m), 807 (m), 752
(s), 697 (s), 543 (s) cmÀ 1. HPLC: Chiralpak IB, n-hexane/iPrOH 90:10,
1.0 mL/min, 215 nm, tR =24.30 and 31.92 min.
1-((2’R,3’R,4’S,5’R)-1-Benzyl-3’-(4-methoxyphenyl)-2-oxo-5’-
phenylspiro[indoline-3,2’-pyrrolidine]-4’-yl)-2-(pyrrolidin-1-yl)
ethane-1,2-dione (6c)
(2’R,3’R)-1-benzyl-3’-(4-methoxyphenyl)-N,N-dimethyl-2-oxo-3’,
4’-dihydrospiro[indoline-3,2’-pyrrole]-5’-carboxamide (7a)
20
White solid; yield of 24% (14 mg), 19% ee; [α]D À 82.9 (CHCl3, c
20
°
0.28); Rf (hexane/EtOAc 1:1) 0.18; Rf (EtOAc) 0.59; m.p. 195–196 C;
White solid; yield of 20% (15 mg), 10% ee; [α]D À 77.1 (CHCl3, c
1H NMR (CDCl3, 600 MHz): δ 7.32–7.27 (m, 3H), 7.23 (d, J=7.0 Hz,
2H), 7.04 (t, J=7.8 Hz, 1H), 6.96 (d, J=8.6 Hz, 2H), 6.74 (t, J=7.6 Hz,
1H), 6.67 (d, J=8.7 Hz, 2H), 6.60 (d, J=7.8 Hz, 1H), 6.51 (d, J=
7.5 Hz, 1H), 5.08 (d, J=15.8 Hz, 1H), 4.77 (d, J=15.8 Hz, 1H), 4.07
(dd, J=8.2, 6.9 Hz, 1H), 3.72 (s, 3H), 3.69 (dd, J=17.8, 6.7 Hz, 1H),
3.61 (dd, J=17.7, 8.4 Hz, 1H), 3.26 (s, 3H), 3.09 (s, 3H). 13C NMR
(CDCl3, 151 MHz): δ 176.5, 175.9, 165.3, 158.8, 142.7, 135.5, 130.1,
129.3, 129.3, 128.9, 127.8, 127.3, 126.9, 126.0, 122.7, 113.8, 109.3,
86.2, 55.3, 50.5, 44.1, 43.9, 38.4, 35.1. HRMS-ESI+ (m/z): calculated
for [C28H27N3O3Na]+: 476.1945; found: 476.1942. IR (ATR): 3039 (w),
2931 (w), 2831 (w), 1710 (s), 1634 (s), 1609 (s), 1513 (s), 1487 (s),
1468 (s), 1442 (m), 1410 (m), 1362 (s), 1344 (s), 1305 (m), 1240 (s),
1205 (m), 1174 (s), 1148 (m), 1114 (m), 1075 (s), 1035 (m), 949 (m),
915 (m), 876 (m), 829 (s), 803 (m), 757 (s), 720 (m), 698 (s), 628 (s),
591 (s), 546 (s) cmÀ 1. HPLC: Chiralpak IC, n-hexane/i-PrOH 90:10,
1.0 mL/min, 211 nm, tR =78.33 and 89.16 min.
0.28); Rf (hexane/EtOAc 1:1) 0.34; m.p. 120–121 C; H NMR (CDCl3,
1
°
600 MHz): δ 7.72 (d, J=6.8 Hz, 1H), 7.64 (d, J=7.2 Hz, 2H), 7.34 (t,
J=7.6 Hz, 2H), 7.26 (m, 1H), 7.18 (m, 3H), 7.11–7.06 (m, 2H), 6.93 (d,
J=8.7 Hz, 2H), 6.86 (d, J=6.9 Hz, 2H), 6.53 (d, J=8.8 Hz, 2H), 6.42
(d, J=8.5 Hz, 1H), 5.50 (d, J=10.7 Hz, 1H), 5.44 (dd, J=12.7, 10.7 Hz,
1H), 5.08 (d, J=16.0 Hz, 1H), 4.56 (d, J=16.0 Hz, 1H), 4.47 (d, J=
12.8 Hz, 1H), 3.66 (s, 3H), 3.32 (m, 1H), 3.25–3.19 (m, 2H), 2.23 (m,
1H), 1.69-1.56 (m, 4H), 1.41 (m, 1H). 13C NMR (CDCl3, 151 MHz): δ
196.7, 177.6, 161.3, 158.8, 142.1, 141.6, 135.2, 131.5, 129.5, 129.0,
128.7, 128.7, 128.1, 127.5, 127.0, 127.0, 124.6, 122.8, 113.5, 109.6,
72.7, 62.7, 55.8, 55.2, 54.5, 46.9, 46.8, 44.1, 26.4, 23.4. HRMS-ESI+ (m/
z): calculated for [C37H36N3O4]+: 586.2700; found: 586.2703. IR (ATR):
3332 (w), 2962 (w), 1716 (s), 1631 (s), 1610 (s), 1513 (s), 1487 (m),
1454 (s), 1362 (s), 1249 (s), 1176 (s), 1100 (s), 1078 (s), 1028 (s), 910
(m), 862 (m), 798 (s), 752 (s), 729 (s), 698 (s), 592 (m) cmÀ 1. HPLC:
Eur. J. Org. Chem. 2021, 1693–1703
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doi.org/10.1002/ejoc.202100022
Chiralpak IB, n-hexane/i-PrOH 90:10, 1.0 mL/min, 215 nm, tR =26.85
and 36.26 min.
Acknowledgements
1
2
This work was supported by the Slovak Research and Develop-
ment Agency (grant APVV-18-0242). Vitalii Palchykov thanks SAIA
and the National Scholarship Programme of the Slovak Republic
for an individual scholarship. We thank Dr. Ján Moncoľ from the
Slovak University of Technology, Faculty of Chemical and Food
Technology for the access to the Cu microsource-equipped
diffractometer. This work was supported in part through the
Comenius University in Bratislava CLARA@UNIBA.SK high perform-
ance computing facilities, services and staff expertise of Centre for
Information Technology; https://uniba.sk/en/HPC-Clara.
3
4
5
6
7
8
9
(2’R,3’R)-1-Benzyl-3’-(4-methoxyphenyl)-5’-(pyrrolidine-
1-carbonyl)-3’,4’-dihydrospiro[indoline-3,2’-pyrrol]-2-one (7c)
20
White solid; yield of 33% (21 mg), 26% ee; [α]D À 92.7 (CHCl3, c
1
°
0.22). Rf (hexane/EtOAc 1:1) 0.20; m.p. 163–165 C; H NMR (CDCl3,
600 MHz): δ 7.30–7.25 (m, 3H), 7.20 (d, J=6.8 Hz, 2H), 7.04 (td, J=
7.8, 1.1 Hz, 1H), 6.93 (d, J=8.6 Hz, 2H), 6.78 (t, J=7.6 Hz, 1H), 6.65
(d, J=7.7 Hz, 1H), 6.63 (d, J=8.7 Hz, 2H), 6.58 (d, J=7.8 Hz, 1H),
5.11 (d, J=15.8 Hz, 1H), 4.75 (d, J=15.8 Hz, 1H), 4.14–4.10 (m, 1H),
3.80 (m, 2H), 3.71 (s, 3H), 3.70 (dd, J=17.9, 8.5 Hz, 1H), 3.62 (m, 2H),
3.59 (dd, J=17.9, 8.5 Hz, 1H), 1.96-1.85 (m, 4H). 13C NMR (CDCl3,
151 MHz): δ 176.7, 176.3, 162.6, 158.7, 142.6, 135.5, 129.4, 129.4,
129.2, 128.9, 127.74, 127.3, 127.0, 125.7, 122.6, 113.7, 109.3, 86.1,
55.3, 50.4, 48.8, 46.6, 44.1, 43.0, 26.4, 24.1. HRMS-ESI+ (m/z):
calculated for [C30H29N3O3Na]+: 502.2101; found: 502.2102. IR (ATR):
2973 (w), 2948 (w), 2872 (w), 1717 (s), 1599 (s), 1513 (s), 1487 (s),
1450 (s), 1363 (s), 1345 (s), 1305 (m), 1268 (m), 1245 (s), 1175 (s),
1139 (m), 1110 (m), 1079 (m), 1027 (s), 998 (m), 962 (m), 930 (m),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Conflict of Interest
The authors declare no conflict of interest.
839 (m), 819 (m), 753 (s), 734 (m), 698 (s), 598 (m), 544 (m) cmÀ 1
.
Keywords: Asymmetric organocatalysis · [3+2] Cycloaddition ·
Heterocycles · Pyrrolidine · Spiro oxindole
HPLC: Chiralpak IB, n-hexane/i-PrOH 95:5, 1.2 mL/min, 215 nm, tR =
55.23 and 63.17 min.
N-Benzyl-2-((2’R,3’R,4’S,5’R)-1-benzyl-3’-(4-methoxyphenyl)-
2-oxo-5’-phenylspiro[indoline-3,2’-pyrrolidine]-4’-yl)-2-oxo-
acetamide (6d)
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White solid; yield of 61% (48 mg), 4% ee; Rf (hexane/EtOAc 3:1)
0.18; m.p. 134–135 C; 1H NMR (CDCl3, 600 MHz): δ 7.76 (d, J=
°
6.8 Hz, 1H), 7.61 (d, J=7.4 Hz, 2H), 7.29–7.22 (m, 6H), 7.20–7.14 (m,
3H), 7.13–7.08 (m, 2H), 7.03 (d, J=6.7 Hz, 2H), 6.89 (d, J=8.6 Hz,
2H), 6.84 (d, J=7.3 Hz, 2H), 6.62 (t, J=5.7 Hz, 1H), 6.51 (d, J=8.6 Hz,
2H), 6.43 (d, J=7.3 Hz, 1H), 5.63 (d, J=10.4 Hz, 1H), 5.34 (dd, J=
13.0, 10.6 Hz, 1H), 5.09 (d, J=16.0 Hz, 1H), 4.54 (d, J=16.0 Hz, 1H),
4.50 (d, J=13.1 Hz, 1H), 4.33 (dd, J=14.8, 6.7 Hz, 1H), 4.17 (dd, J=
14.8, 5.6 Hz, 1H), 3.66 (s, 3H), 2.84 (br s, 1H). 13C NMR (CDCl3,
151 MHz): δ 195.9, 177.6, 160.0, 158.9, 142.1, 140.8, 136.7, 135.2,
131.4, 129.6, 129.1, 128.8, 128.7, 128.7, 128.5, 128.2, 127.9, 127.8,
127.5, 127.0, 126.5, 124.6, 122.8, 113.5, 109.7, 72.8, 63.7, 55.2, 54.8,
54.8, 44.1, 43.3. HRMS-ESI+ (m/z): calculated for [C40H36N3O4]+:
622.2700; found: 622.2705. IR (ATR): 3330 (w), 3028 (w), 2928 (w),
1717 (s), 1676 (s), 1609 (s), 1512 (s), 1487 (m), 1453 (m), 1358 (m),
1247 (s), 1175 (s), 1127 (m), 1106 (m), 1078 (m), 1028 (m), 981 (m),
830 (m), 750 (s), 696 (s), 593 (m), 543 (m) cmÀ 1. HPLC: Chiralpak IC,
n-hexane/i-PrOH 90:10, 1.0 mL/min, 211 nm, tR =54.85 and
78.80 min.
X-ray crystallographic analysis
Crystals for X-ray single-crystal analysis were obtained by slow
evaporation from concentrated EtOH, EtOH/1,4-dioxane, or EtOH/
EtOAc solutions. The crystallographic experimental data and refine-
ment details are reported in supporting information, Table S2.
Deposition Numbers 2052333 (for 4a), 2054164 (for 6a), 2054322
(for 6b), and 2054327 (for 7a) contain the supplementary
crystallographic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre and
Fachinformationszentrum Karlsruhe Access Structures service
www.ccdc.cam.ac.uk/structures.
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Manuscript received: January 31, 2021
Revised manuscript received: February 3, 2021
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