Highly Stereoselective [4+2] and [3+2] Spiroannulations of 2-(2-Oxoindolin-3-ylidene)acetic Esters Catalyzed by Bifunctional Thioureas

Article abstract of DOI:10.1002/chem.201500676

A new Michael-Michael cascade reaction between 2-(2-oxoindolin-3-ylidene)acetic esters 1 and nitroenoates 2, catalyzed by bifunctional thioureas, is investigated. The combination of the two Michael reactions results in a novel and facile [4+2] or [3+2] spiroannulation process, which is characterized by the following features: 1) two carbon-carbon bonds and four stereocenters, including a quaternary spiro carbon, are formed under mild conditions; 2) an unprecedented and stereochemically defined substitution pattern on the spirocarbocyclic unit is obtained; 3) the double-bond configuration of the donor-acceptor nitroenoate 2 determines the absolute configuration of the spiro center, whereas the remaining stereocenters are formed under control of the catalyst. The effect on the final stereochemical outcome of structural variations of each starting material, catalyst, and experimental conditions is analyzed in detail. In particular, the use of specifically designed chiral nitroenoates enables diverse polyfunctional spirocyclohexane derivatives containing six consecutive stereogenic centers to be constructed. To our knowledge, this is the first asymmetric organocatalytic strategy enabling both five- and six-membered β-nitro spirocarbocyclic oxindoles.

Full text of DOI:10.1002/chem.201500676

DOI: 10.1002/chem.201500676
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Spiro Compounds |Hot Paper|
Highly Stereoselective [4+2] and [3+2] Spiroannulations of
2-(2-Oxoindolin-3-ylidene)acetic Esters Catalyzed by Bifunctional
Thioureas
Magda Monari, Elisa Montroni, Andrea Nitti, Marco Lombardo, Claudio Trombini, and
Arianna Quintavalla*[a]
Abstract: A new Michael–Michael cascade reaction between
2-(2-oxoindolin-3-ylidene)acetic esters 1 and nitroenoates 2,
catalyzed by bifunctional thioureas, is investigated. The com-
bination of the two Michael reactions results in a novel and
facile [4+2] or [3+2] spiroannulation process, which is char-
acterized by the following features: 1) two carbon–carbon
bonds and four stereocenters, including a quaternary spiro
carbon, are formed under mild conditions; 2) an unprece-
dented and stereochemically defined substitution pattern on
the spirocarbocyclic unit is obtained; 3) the double-bond
configuration of the donor–acceptor nitroenoate 2 deter-
mines the absolute configuration of the spiro center, where-
as the remaining stereocenters are formed under control of
the catalyst. The effect on the final stereochemical outcome
of structural variations of each starting material, catalyst, and
experimental conditions is analyzed in detail. In particular,
the use of specifically designed chiral nitroenoates enables
diverse polyfunctional spirocyclohexane derivatives contain-
ing six consecutive stereogenic centers to be constructed. To
our knowledge, this is the first asymmetric organocatalytic
strategy enabling both five- and six-membered b-nitro spiro-
carbocyclic oxindoles.
Introduction
strategies, to expand structural and stereochemical diversity,
and extend the functional pattern of spirocyclic oxindoles.
In this scenario lie the b-amino spirocarbocyclic oxindoles,
which is a structural motif present in many bioactive indole al-
kaloids such as Gelsemine, Citrinadin A, and Marcfortine B
(Figure 1), and related families of prenylated indole alkaloids,[7]
including Paraherquamides,[8a,b] Sclerotiamide,[8c] Notoami-
des,[8d,e] Brevianamides,[8f,g] and Versicolamide B.[8e,h] Currently,
the most used organocatalytic strategies that address amino-
substituted spirooxindoles involve the introduction of a nitro
group[9] as the amino group precursor. However, only a few ex-
amples of the organocatalyzed enantioselective synthesis of
five- or six-membered b-nitro spirocarbocyclic oxindoles have
been reported (Scheme 1, Eq. 1 and 2).[10–12] Moreover, the syn-
thetic approach is almost invariably based on the use of nitro-
alkenes as Michael acceptors (Scheme 1, Eq. 1).[10] Only Kanger
and co-workers developed a Michael–aldol cascade reaction
employing nitroketones as donor/acceptor bifunctional syn-
thons to generate b-nitro d-hydroxy cyclopentane derivatives
(Scheme 1, Eq. 2).[11] The limited number of approaches avail-
able for the synthesis of b-nitro spirocarbocyclic oxindoles
mean that the development of innovative and efficient meth-
odologies remains highly desirable.
The oxindole scaffold is present in the core structure of an im-
pressive number of natural and synthetic bioactive com-
pounds.[1] In particular, five- and six-membered spirocyclic oxin-
doles are considered privileged molecular structures associated
with various compounds with potent pharmaceutical proper-
ties (Figure 1).[2] The considerable medicinal potential of the
spirocyclic oxindole structural motif has led the scientific com-
munity to design innovative and efficient synthetic ap-
proaches,[3,4] exploiting either metal catalysts or organocata-
lysts. The greatest efforts were devoted to the asymmetric syn-
thesis of the chiral backbone, often containing a sequence of
stereocenters that includes the demanding quaternary spiro
center at the 3-position of the oxindole ring. Domino reactions
are particularly suited to address this challenge through an or-
dered sequence of CÀC bond-forming reactions.[5] Indeed, or-
ganocascade processes have been recently employed in the
enantioselective synthesis of spirocyclic oxindoles.[6] However,
despite the considerable effort that has been made in this
field, much work is needed to develop more flexible synthetic
As part of our ongoing studies on the asymmetric thiourea-
catalyzed[13] conjugate addition of nitroalkanes to a,b-unsatu-
rated systems,[14] we designed a new asymmetric Michael–Mi-
chael domino process involving multiple donor–acceptor re-
agents such as oxindoles 1 and nitro compounds 2. A precisely
defined sequence of CÀC bond-forming reactions grants an ef-
[a] Prof. M. Monari, Dr. E. Montroni, A. Nitti, Prof. M. Lombardo,
Prof. C. Trombini, Dr. A. Quintavalla
Alma Mater Studiorum, University of Bologna
Via Selmi 2, 40126 Bologna (Italy)
E-mail: arianna.quintavalla@unibo.it
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500676.
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functional Takemoto’s catalyst I. The performance of the reac-
tion depended strongly on the nature of the N-protecting
group (Table 1, entries 1–3).
The N-Boc oxindole derivative 1c afforded the desired six-
membered b-nitro spirooxindole 3c with high conversion
(90%) as a single detectable diastereoisomer in 98% ee
(Table 1, entry 3). However, N-benzyl oxindole 1b showed both
a lower reactivity (60% conversion after 7 days) and poorer
enantioselectivity (75% ee, entry 2). Unprotected oxindole 1a
performed even less efficiently, yielding only acyclic intermedi-
ate 5a (Table 1, entry 1). From a mechanistic point of view, the
first step, namely the Michael addition of the nitronate derived
from 2 to 3-ylidene oxindole 1, afforded the anti acyclic
adduct 5, characterized by three new stereocenters. The abso-
lute configurations of Ca and Cb were controlled by the cata-
lyst, whereas C3 was stereolabile under the adopted reaction
conditions. As a consequence, 5 consisted of a 1:1 mixture of
two C3 epimers. The second step involved the formation of
a C3 enolate species of 5 and consequent intramolecular addi-
tion to the a,b-unsaturated ester, leading to a stereospecific
[4+2] spiroannulation with well-defined configurations of the
newly formed C3 and Ce stereocenters. The higher reactivity of
the N-Boc adduct 5c might be explained by considering that
the acidity of C3-H is significantly affected by the nature of the
N-protecting group (pKa C3-H of N-acetyloxindoleꢀ13).[15]
Thus, we carried out an optimization screening on 1c, first
testing the efficacy of catalysts I–XII. The best catalyst was the
(1R,2R)-cyclohexane-1,2-diamine-based catalyst I, whereas all
the Cinchona-derived bifunctional thioureas performed similar-
ly. In particular, the vinyl substituent on the quinuclidine
system (-R), the substituent on the quinoline ring (-R1), and the
group installed on the thiourea moiety (-R2) were systematical-
ly varied, without appreciable changes in reactivity or stereose-
lectivity. The spirooxindole 3c conversions ranged between 46
and 61% (7 days reaction time; Table 1, entries 4–11) and the
stereocontrol was invariably high (95–97% ee) with all the cata-
lysts except for VII and IX, which provided slightly worse re-
sults (86% ee; Table 1, entries 9 and 11). As expected, pseudo-
enantiomeric catalysts (II and V) afforded opposite enantio-
mers (Table 1, entries 4 and 7). The crucial role in determining
the enantioselectivity played by the thiourea moiety was con-
firmed by employing alkaloids X and XI (entries 12–13). Al-
though a bifunctional system was still present, these catalysts
exerted lower levels of stereocontrol (66–73% ee). Disappoint-
ingly, Jacobsen’s thiourea XII proved to be less competent
(Table 1, entry 14). Having established that the best per-
formance in terms of both reaction rate and stereocontrol was
obtained with catalyst I, we optimized the reaction conditions
using Takemoto’s catalyst. The effects of catalyst loading and
solvent were investigated (see the Supporting Information)
and the optimal conditions were elected as 10 mol% I and di-
chloromethane (CH2Cl2) as the reaction medium.
Figure 1. Natural and synthetic bioactive compounds containing a five- or
six-membered spirocyclic oxindole core.
ficient spiroannulation methodology leading to b-nitro spiroox-
indoles 3 and 4 (Scheme 1, Eq. 3).
Results and Discussion
Synthesis of 1’-(tert-butyl) 2-ethyl 6-(2-ethoxy-2-oxoethyl)-3-
nitro-2’-oxospiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxy-
late and analogues
To expand the scope of the reaction, our protocol was ap-
plied to a variety of 3-ylidene oxindoles (1c–p); we were de-
lighted to find that the process tolerated a range of substitu-
tion patterns (Table 2). The reactions proceeded smoothly
when the oxindole aromatic ring was decorated with either
Our preliminary investigations focused on the addition of ni-
troester (E)-2a to N-substituted (E)-ethyl 2-(2-oxoindolin-3-yli-
dene)acetates 1a–c promoted by commercially available bi-
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activate both the Michael donor
and the acceptor, and governs
the nitroalkane approach to the
3-ylidene oxindole during the
first step of the cascade reaction.
The thiourea moiety reasonably
coordinates
through
the
oxindole
multiple
hydrogen
bonds and the ester group par-
ticipates in the catalyst–sub-
strate interaction, enhancing the
electrophile reactivity and ensur-
ing a high enantioselectivity.
The relative configuration of
the stereocenters in this series of
products was unambiguously
identified through X-ray crystal-
lographic analysis of compound
3c.[18] Here, a trans orientation
between nitro and ester groups
and a cis orientation between
ester and Ce-chain were identi-
fied (Figure 2; see the Support-
ing Information for details).
We were also committed to
the challenging construction of
a second quaternary stereocen-
ter at the Ca position, contigu-
ous to the quaternary spiro
carbon (C3). To this end, the pro-
tocol was applied to substrates
1n–p, featuring a tetrasubstitut-
ed double bond. The reactivity
Scheme 1. Asymmetric organocatalytic syntheses of five- and six-membered b-nitro spirocarbocyclic oxindoles
(EWG=electron-withdrawing group; PG=protecting group).
electron-withdrawing groups (EWG; Table 2, entries 2–4) or
electron-donating groups (EDG; Table 2, entries 5–7), although
both the yield and ee were affected by the position of the sub-
stituent (Table 2, entries 2 and 3 vs. entry 4). As a general
trend, oxindoles substituted with an EWG reacted faster than
those with an EDG group (Table 2, entries 2–4 vs. entries 5–7).
The ethyl ester could be smoothly replaced by a benzyl
ester (74% yield and 96% ee in only 24 h, entry 8). We also in-
vestigated the replacement of the ester on the oxindole
double bond with other electron-withdrawing groups. The in-
sertion of an aromatic ketone (entry 9) provided a complex
mixture of compounds, from which the desired product 3k
was isolated in very good ee (90%), but in very low yield
Figure 2. Determination of the relative stereochemistry of b-nitro cyclohex-
ane spirooxindole 3c through X-ray crystallographic analysis.
(19%). The para-nitrophenyl derivative 1l afforded the product
in good yield but with poor stereocontrol (entry 10), whereas
the cyano-substituted substrate 1m showed both inadequate
yield and ee (entry 11). As demonstrated for the addition of ni-
troalkanes to 3-ylidene oxindoles,[14a] the ester group on the in-
dolinone exocyclic double bond is essential to force the
domino process on a well-defined and stereochemically unam-
biguous reaction pathway.[16] According to the dual activation
model,[17] the bifunctional organocatalyst can simultaneously
of these 3-ylidene oxindoles was much lower. The nitroalkane
conjugate addition did not proceed at all on derivative 1p
(R2 =NHBoc, R3 =CO2Me; entry 14), whereas two equivalents of
nitro compound and 20 mol% of catalyst I were required to
obtain the a-methylated product 3n in acceptable yield (en-
tries 12–13). However, the process retained an excellent stereo-
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regardless of the starting Z/E
Table 1. N-Protecting groups and catalyst screening in the asymmetric Michael–Michael organocascade reac-
tion between 3-ylidene oxindoles 1a–c and nitroester (E)-2a.[a]
double
bond configuration.
1H NMR spectra showed that
double-bond isomerization oc-
curred when pure 1n or 1o was
exposed to catalyst I,[21] likely via
an
intermediate
dienolate
(Scheme 2; see the Supporting
Information for experimental de-
tails). The observed stereocon-
vergence suggested that only
one of the two isomeric 3-yli-
dene-indolin-2-ones participated
as acceptor to the first intermo-
lecular Michael reaction with (E)-
2a. Moreover, 1D NOESY experi-
ments on product 3n indicated
the same relative stereochemis-
try previously observed for spi-
rooxindole 3c, leading us to hy-
pothesize that the (E)-configured
3-ylidene indolinone 1n was the
reactive species.
The good results obtained
with 3-ylidene oxindoles 1c–o
prompted us to explore different
nitro compounds (Tables 3 and
4), with the aim of further in-
creasing the structural and the
stereochemical diversity of the
b-nitro spirocyclohexane indoli-
nones 3.
We confirmed that replace-
ment of the ethyl ester with
a benzyl group was well tolerat-
ed (Table 3, entry 2). When we
moved to (E)-2c, the a,b-unsatu-
rated ketone triggered side reac-
tions, affording a complex mix-
ture of products (Table 3,
entry 3). The use of the cyano
derivative (E)-2d allowed the
corresponding spirooxindole 3s
to be obtained in high yield and
enantioselectivity, but with poor
Entry
Substrate
Cat.
t [d]
Product
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
I
I
I
II
III
IV
V
VI
VII
VIII
IX
X
4
7
3
7
7
7
7
7
7
7
7
7
7
7
3a
3b
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
trace
60
90
54
60
46
49
54
61
56
47
52
59
60
–
75
98
96[d]
96[d]
95[d]
96
97
86
95
86
66
73
63
9
10
11
12
13
14
XI
XII
[a] Reaction conditions: 1 (0.1 mmol), (E)-2a (0.12 mmol), catalyst (10 mol%), CH2Cl2 (0.15 mL), RT. [b] Deter-
mined by 1H NMR spectroscopic analysis of the crude mixture. Products 3b and 3c were detected as single
diastereoisomers. [c] Determined by chiral stationary phase HPLC (CSP-HPLC) analysis of isolated product 3.
[d] Opposite enantiomer was formed.
selectivity, allowing the isolation of spiroindolinone 3n, charac-
terized by two adjacent quaternary stereocenters, in 95% ee. A
possible explanation for the low yield of 3n might lie in the re-
activity of the allylic position, which was already demonstrated
for 3-ylidene oxindoles in the presence of bifunctional organo-
catalysts.[19] Under our reaction conditions, alkylidene indoli-
nones 1n and 1o could undergo deprotonation[20] to an inter-
mediate dienolate (Scheme 2), which was likely responsible for
a variety of side reactions that decreased the yield of the de-
sired spirocycle. Another interesting remark concerning sub-
strates 1n and 1o is that the a-methyl spirooxindole 3n was
formed with high ee and the same absolute stereochemistry,
diastereocontrol (Table 3, entry 4). Lastly, focusing our efforts
on the challenging construction of a fifth exocyclic stereocen-
ter, we applied our protocol to the trisubstituted nitroenoate
(E)-2e (Table 3, entry 5). The reactivity of this substrate was sig-
nificantly lower (20 mol% catalyst loading was required for ac-
ceptable conversion), but the desired product 3t, possessing
five contiguous stereocenters, was formed with an excellent
level of stereocontrol (96% ee).
Finally, we explored how the enoate geometry affected the
stereocontrol of the spiroannulation process by using (Z)-con-
figured a,b-unsaturated nitroesters 2a–e (Table 4).
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Table 2. Scope of the asymmetric organocatalytic synthesis of b-nitro spi-
rocyclohexane indolinones 3 from 3-ylidene oxindoles.[a]
Table 3. Scope of the asymmetric organocatalytic synthesis of b-nitro spi-
rocyclohexane indolinones 3 from (E)-a,b-unsaturated nitroesters.[a]
Entry Substrate R1/R2/R3
t [d] Product Yield [%][b] ee [%][c]
Entry
Substrate R4/R5
t [d] Product Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
H/CO2Et/H
3
2
1
2
5
2
3
1
1
2
1
2
2
7
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
73
82
63
42
77
76
78
74
19
83
47
40
38
–
98
96
97
82
97
95
94
96
90
55
23
95
95
–
1
2
3
4
5[f]
(E)-2a
(E)-2b
(E)-2c
(E)-2d
(E)-2e
CO2Et/H
3
1
1
2
4
3c
3q
3r
3s
3t[g]
73
65
–
90
40
98
>99
–
5-Cl/CO2Et/H
6-Cl/CO2Et/H
7-Cl/CO2Et/H
5-Me/CO2Et/H
5-OMe/CO2Et/H
5-OCF3/CO2Et/H
H/CO2Bn/H
H/COPh/H
H/pNO2Ph/H
H/CN/H
CO2Bn/H
COPh/H
CN/H
[d]
91[e]
96
CO2Et/Me
[a] Reaction conditions: 1c (0.1 mmol),
2 (0.12 mmol), catalyst I
(10 mol%), CH2Cl2 (0.15 mL), RT. [b] Yield of isolated product after flash-
chromatography. [c] Determined by CSP-HPLC analysis of isolated prod-
uct. [d] A complex mixture of products was obtained. [e] Product 3s was
obtained as a mixture of four diastereoisomers (dr=22:35:27:16). The re-
ported ee concerns the major isomer. [f] Catalyst I (20 mol%). [g] 1H NMR
spectroscopic analysis indicated that the relative stereochemistry of 3t
was as shown in Table 4.
9
10
11
1m
3m
3n
3n
3p
12[d] 1n
13[d] 1o
H/CO2Et/Me
H/Me/CO2Et
H/NHBoc/CO2Me
14
1p
[a] Reaction conditions:
1 (0.1 mmol), (E)-2a (0.12 mmol), catalyst I
(10 mol%), CH2Cl2 (0.15 mL), RT. [b] Yield of isolated product after flash
chromatography. [c] Determined by CSP-HPLC analysis of isolated product
3. [d] (E)-2a (0.2 mmol), catalyst I (20 mol%).
nary stereocenter is inverted. Considering the strong depend-
ence of bioactivity on stereochemistry, the development of ste-
reospecific processes that allow precisely defined stereoiso-
mers to be synthesized from different E/Z isomeric starting ma-
terials, is clearly highly desirable.
As a final test, nitroester (Z)-
2e, bearing
a
trisubstituted
double bond, was also em-
ployed in the Michael–Michael
[4+2] spiroannulation sequence
(Table 4, entry 4). Analogously to
the corresponding (E)-configured
compound, (Z)-2e exhibited
poor reactivity (35% yield), al-
though spirocycle 3t, containing
five contiguous stereocenters,
was obtained in 96% ee. Intrigu-
ingly, both (Z)-2e and (E)-2e
Scheme 2. Stereoconvergent organocatalyzed formation of a-methyl spirooxindole 3n starting from 1n or 1o.
We were pleased to observe that the Michael–Michael spi-
roannulation took place easily with (Z)-2a and (Z)-2b (Table 4,
entries 1 and 2), providing new diastereomeric b-nitro spiroox-
indoles 3u and 3v with excellent ee values. It is also worth
mentioning the different reaction profile of the stereoisomers
(E)- and (Z)-2d. Here, whereas the (Z)-a,b-unsaturated nitrile
2d provided the corresponding product 3w in high yield and
excellent enantio- and diastereoselectivity (entry 3), the latter
feature was not shared by (E)-a,b-unsaturated nitrile 2d
(Table 3, entry 4).[22] The relative stereochemistry of this series
of products was unambiguously established through X-ray
crystallographic analysis of 3u[18] (Figure 3; see the Supporting
Information for details).
It is very interesting to note that upon varying the nitroester
double bond geometry, the configuration of the spiro quater-
Figure 3. Determination of the relative stereochemistry of b-nitro cyclohex-
ane spirooxindole 3u through X-ray crystallographic analysis.
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Table 4. Spiroannulation domino reaction using (Z)-a,b-unsaturated ni-
troesters.[a]
Table 5. Optimization of the asymmetric Michael–Michael organocascade
protocol for the synthesis of b-nitro spirocyclopentane indolinones 4.[a]
Entry
Substrate R4/R5
t [d] Product Yield [%][b] ee [%][c]
1
2
3
4[d]
(Z)-2a
(Z)-2b
(Z)-2d
(Z)-2e
H/CO2Et
H/CO2Bn
H/CN
1
1
2
4
3u
3v
3w
3t
79
75
83
35
97
98
95
96
Me/CO2Et
Entry Catalyst
[mol%]
T
t
Conv.
d.r.[b,c] ee 4a
ee 6a
[a] Reaction conditions: 1c (0.1 mmol),
2 (0.12 mmol), catalyst I
[8C] [h] [%][b]
[%][d]
[%][d]
(10 mol%), CH2Cl2 (0.15 mL), RT. [b] Yield of isolated product after flash
chromatography. [c] Determined by CSP-HPLC analysis of the isolated
product. [d] Catalyst I (20 mol%).
1
2
3
4
5
6
7
8
9
10
I (10)
I (5)
I (10)
III (10)
V (10)
VI (10)
VII (10)
VIII (10)
IX (10)
IX (10)
RT 80
RT 72 82
5
60:40
60:40
99
99
92
96
>99
99[e]
92
À10 48 53
65:35 >99
0
0
0
0
0
48 42
48 58
48 59
48 90
48 75
48 90
70:30
70:30
80:20
80:20
80:20
85:15
85:15
99[e]
99
97
93
99
98
98
provided the same isomer 3t. To explain this result, we hy-
pothesized that the slow spirocyclization rate allowed catalyst I
to isomerize the double bond, through deprotonation of the
allylic position (see Scheme 2). Accordingly, it could be as-
sumed that, despite the concomitant presence in solution of
both (Z)-2e and (E)-2e, only one of them was directly involved
in the final ring-closing step.[23]
94
–
[f]
99
–
–
[f]
0
[f]
RT
5
90
[a] Reaction conditions: 1c (0.1 mmol), (E)-2 f (0.12 mmol), CH2Cl2
(0.15 mL). [b] Determined by 1H NMR spectroscopic analysis of the crude
mixture. [c] Assuming that 6a derived from a diastereoisomer of 4a, we
indicated also 4a/6a ratio as d.r. [d] Determined by CSP-HPLC analysis.
[e] Opposite enantiomer was formed. [f] The minor species was not 6a,
but a diastereoisomer of 4a.
Synthesis of 1’-(tert-butyl) 2-ethyl 5-(2-ethoxy-2-oxoethyl)-3-
nitro-2’-oxospiro[cyclopentane-1,3’-indoline]-1’,2-dicarboxy-
late and analogues
To test the versatility of the newly proposed spiroannulating
organocascade process, we decided to approach b-nitro spiro-
cyclopentane indolinones 4 (Table 5) by using nitro compound
2 f, characterized by a shorter functionality span between the
nitro and the enoate groups. When nitroester (E)-2 f was sub-
jected to the Michael–Michael organocascade sequence under
the previously optimized reaction conditions (entry 1), to our
delight, the spiroannulation to five-membered spirooxindole
proceeded even faster than that to the corresponding six-
membered analogue. However, two main products were isolat-
ed in a 60:40 ratio, a ratio that remained constant during the
reaction progress, also for prolonged times. In particular, the
most abundant b-nitro spirocyclopentane indolinone 4a was
accompanied by the spirocyclopentene oxindole 6a, both pro-
vided with excellent enantiocontrol. We hypothesized that 6a,
derived from a minor diastereoisomer, formed during the cas-
cade process through HNO2 elimination.[24]
we explored the scope of our route to b-nitro cyclopentane
spirooxindoles (Table 6). The protocol proved to be efficient
with both EWG- and EDG-substituted oxindoles 1 (Table 6, en-
tries 2 and 3). Again, ethyl and benzyl esters could be success-
fully exchanged (Table 6, entry 4). We were intrigued by the
construction of a quaternary stereocenter at the Ca position;
therefore, 3-ylidene oxindoles 1n and 1o were subjected to
the spiroannulation conditions (Table 6, entries 5 and 6). The
observed stereoconvergent behavior of these two substrates
was similar to that reported for six-membered spirooxindoles
(see Table 2, entries 12 and 13). Starting from either (E)- or (Z)-
configured 3-ylidene indolinone, the same spirocyclopentane
oxindole 4e was obtained (see Scheme 2). Interestingly, spiro-
cyclic compound 4e, featuring two consecutive all-carbon qua-
ternary stereocenters, was produced with high stereocontrol
(90:10 d.r. , 94% ee).
Finally, the following analogies between the spironnulations
with nitro compounds 2a–e, on one hand, and 2 f were re-
corded: 1) (Z)-2 f and (E)-2 f reacted in a stereodivergent
manner to provide b-nitro spirocyclopentane indolinones dif-
fering at the spiro carbon only (4 f: 90:10 d.r., 99% ee; Table 6,
entry 7). 2) Once again, the same reaction on 3-ylidene oxin-
doles 1n and 1o with (Z)-2 f provided spirocyclopentane 4g,
the C3-epimer of 4e, in low yield but with excellent stereocon-
trol (Table 6, entries 8 and 9). Thus, for five-membered spiroox-
indoles, it was also demonstrated that variation of the nitroest-
To optimize the b-nitro spirocyclopentane indolinone forma-
tion, we varied the catalyst loading (Table 5, entry 2) and the
reaction temperature (entry 3), but noted only a moderate
impact on the diastereoselectivity. Thus, we performed a brief
catalyst screening (Table 5, entries 4–9). The best trade-off be-
tween reaction rate and stereoselectivity was achieved with
catalyst IX, which gave 4a with 90% conversion, 85:15 d.r. and
98% ee in 48 h at 08C (Table 5, entry 9) and in only 5 h at
room temperature (entry 10). With these optimized conditions,
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synthesis of spirocyclic 2-oxindoles bearing a cyclopentene
motif has attracted much attention, because this architec-
ture is present in bioactive natural products[25a,b] and might
be efficiently employed in the construction of drug candida-
tes.[25c] Despite considerable synthetic effort,[26] relatively few
enantioselective organocatalytic approaches have been re-
ported[27] and the great majority exploit chiral tertiary phos-
phines as catalysts. Given that our Michael–Michael protocol
provided the spirocyclopentene derivative 6a (Table 5, en-
tries 1–5) in considerable amounts, we tried to optimize the
stereoselective formation of 6. Thus, we exposed the enan-
tioenriched spirocyclopentane 4a to quinuclidine, and spi-
rocyclopentene ent-6a was quantitatively obtained without
erosion of the enantiomeric excess (Scheme 3).[28]
Table 6. Scope of the asymmetric organocatalytic synthesis of b-nitro spirocy-
clopentane indolinones 4 from 3-ylidene oxindoles and nitroesters.[a]
Entry 1 R1/R2/R3
2 R4/R5 t [h] Product, yield [%][b] d.r.[c] ee [%][d]
(E)-2 f
1c
1
5
8
8
8
6
8
6
4
4
4a, 73
4b, 57
4c, 65
4d, 63
4e, 30
4e, 31
4 f, 52
4g, 36
4g, 30
85:15
98
H/CO2Et/H
CO2Et/H
(E)-2 f
1d
2
90:10 >99
5-Cl/CO2Et/H
1h
CO2Et/H
(E)-2 f
3
90:10
85:15
90:10
90:10
90:10
90:10
90:10
98
99
92
94
99
99
99
5-OMe/CO2Et/H CO2Et/H
The same approach was exploited to synthesize a small li-
brary of cyclopentene spiroindolinones (Scheme 3), includ-
ing 6 f, starting from the epimeric cyclopentane 4 f. The
base-promoted HNO2 elimination was also applied in the ef-
ficient synthesis of cyclohexene spiroindolinone[29] 8, which
was obtained in good yield (77%, with 2.5 equivalents of
quinuclidine).[30]
1j
(E)-2 f
4
H/CO2Bn/H
1n
CO2Et/H
(E)-2 f
5[e]
6[e]
7[e]
8[e]
9[e]
H/CO2Et/Me
1o
CO2Et/H
(E)-2 f
H/Me/CO2Et
1c
CO2Et/H
(Z)-2 f
H/CO2Et/H
1n
H/CO2Et
(Z)-2 f
H/CO2Et/Me
1o
H/CO2Et
(Z)-2 f
H/Me/CO2Et
H/CO2Et
Mechanistic hypotheses for the [4+2] and [3+2] spiroan-
nulations
[a] Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), catalyst IX (10 mol%),
CH2Cl2 (0.15 mL), RT. [b] Yield of isolated product. [c] Determined by 1H NMR
spectroscopic analysis of the crude mixture. [d] Determined by CSP-HPLC
analysis of the isolated product. [e] With methylated 3-ylidene oxindoles 1n–
o or (Z)-2 f as nitro compound, catalyst I provided the best results.
The observation that quinuclidine-promoted HNO2 elimina-
tion from 4a–d afforded ent-6a–d as enantiomers of the
unsaturated spirocyclic compounds 6a–d obtained in the
organocatalyzed spiroannulation process (Table 5 and
Table 6), required a deeper understanding of the reaction
mechanism. For six-membered spirooxindoles (Scheme 4A),
the 1H NMR spectrum of the crude mixture recorded after
three hours, showed very low amounts of both 3-ylidene oxin-
dole 1c and spirocyclohexane indolinone 3c. The main com-
ponent was the acyclic intermediate (bS)-5c, characterized by
Figure 4. Determination of the relative (7c) and absolute (4d) stereochemis-
try of b-nitro cyclopentane spirooxindoles through X-ray crystallographic
analysis.
er double bond geometry leads to inversion of configuration
of the spiro quaternary stereocenter.
The relative and absolute stereochemistry of b-nitro cyclo-
pentane spiroindolinones was unambiguously assessed by X-
ray crystallographic analysis of 4d and 7c (Figure 4),[18] the
latter derived from 4 f through Boc-removal (see Scheme 6 and
the Supporting Information for experimental details).
Having optimized the asymmetric organocatalytic synthesis
of b-nitro spirocyclopentane oxindoles 4, we focused our at-
tention on spirocyclopentene indolinones 6. Quite recently, the
Scheme 3. Base-promoted stereoselective synthesis of spirocyclopentene in-
dolinones 6 and spirocyclohexene indolinone 8.
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tion of ent-6a through base-pro-
moted HNO2 elimination from
4a (Scheme 3). These findings
lead us to conclude that the
simple inversion of configuration
at Cb determines the inversion
of both C3 and Cd configura-
tions during the ring-closure
step.
Concerning the spiroannula-
tion sequences carried out with
(Z)-configured nitroenoates, the
reaction pathways to six- and
five-membered spiroindolinones
are more similar, with the cycli-
zation of (bR)-acyclic intermedi-
ates being greatly favored in
both cases (Scheme 5).
Synthetic versatility and ma-
nipulations of 3-nitro-2’-oxo-
spiro[cyclohexane-1,3’-indo-
line]-2-carboxylates, 3-nitro-2’-
oxospiro[cyclopentane-1,3’-in-
doline]-2-carboxylates and 2’-
oxospiro[cyclopentane-1,3’-in-
dolin]-2-ene-2-carboxylates
We have hereto demonstrated
how the newly proposed spi-
roannulation procedure opens
an efficient and highly stereose-
lective route to a library of varia-
Scheme 4. Proposed mechanisms for the asymmetric organocatalytic [4+2] spiroannulation (A) and [3+2] spiroan-
nulation (B) employing (E)-configured nitroenoates.
an a,b-anti relationship (see the Supporting Information).
Given that X-ray crystallographic analysis assigned the a,b-
trans relative configuration to spirocyclic product 3c, we
assume that the bifunctional organocatalyst first promotes Cb
epimerization, followed by selective spirocyclization of (bR)-5c,
only (see the Supporting Information for further studies on the
spiroannulations mechanism).
In the case of five-membered spirooxindoles (Scheme 4B),
both the acyclic intermediates (bS)-9a and (bR)-9a are able to
cyclize. In the presence of bifunctional organocatalyst I, (bS)-
9a is formed more rapidly, then it equilibrates to (bR)-9a. The
intramolecular Michael reaction on (bR)-9a is kinetically fa-
vored, forming spirocyclopentane 4a as the major product.
However, in contrast to six-membered rings, (bS)-9a also un-
dergoes cyclization followed by loss of HNO2 to generate spiro-
cyclopentene 6a. Both the epimerization and the spirocycliza-
tion rates depend on the structure of the catalyst, as suggest-
ed by the results reported in Table 5. From a stereochemical
point of view, the two isomers 4a and 4a’ differ for all the ab-
solute configurations other than Ca. The opposite C3–Cd trans
relationship was demonstrated by X-ray crystallographic analy-
sis of 6d (see the Supporting Information) and by the forma-
Scheme 5. Common mechanism proposed for the asymmetric organocata-
lytic [4+2] and [3+2] spiroannulations employing (Z)-configured nitro-
enoates.
bly substituted and stereochemically diverse six- and five-
membered b-nitro spirooxindoles. Now we show how versatile
the functional groups present on these scaffolds are by sub-
jecting them to further transformations (Scheme 6). First, spiro-
cyclohexanes 3, spirocyclopentanes 4, and spirocyclopentenes
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Conclusion
Efficient and elegant syntheses
of complex organic molecules
with multiple stereogenic cen-
ters continue to be a primary
challenge in both academia and
the pharmaceutical industry. Cat-
alytic asymmetric cascade reac-
tions are remarkably attractive
for the development of synthetic
chemistry because of the high
stereocontrol that is often ach-
ieved and because these ap-
proaches can avoid time-con-
suming and costly intermediate
processes. With the aim of devel-
oping
a novel synthetic ap-
proach to spirocarbocyclic oxin-
doles, we envisioned an innova-
tive asymmetric [4+2] and [3+2]
spiroannulation protocol, involv-
Scheme 6. Synthetic elaborations on the optically active spirocyclohexane (3), spirocyclopentane (4) and spirocy-
clopentene (6) oxindoles (see the Supporting Information for experimental details). TFA=trifluoroacetic acid,
TEA=triethylamine, DCC=N,N’-dicyclohexylcarbodiimide.
ing
2-(2-oxoindolin-3-ylidene)-
acetic esters 1 and nitroenoates
2 as donor/acceptor synthons,
catalyzed by thiourea-based
bifunctional
organocatalysts,
6 could be easily deprotected to free-N spirooxindoles 7a–d,
as shown in Scheme 6. The b-nitro functionality can be quanti-
tatively reduced to yield b-amino spiroindolinones 10, which
might be further elaborated, as shown in the synthesis of sul-
fonamide derivative 11 a and (S)-alanine-conjugated spirooxin-
dole 11 b. Lastly, the stereoselective hydrogenation of cyclo-
pentene 6c provided spirocyclopentane oxindole 12 as
a single stereoisomer.
through a double Michael sequence. Two carbon–carbon
bonds and four stereocenters, including the spiro quaternary
center, are formed by using almost equimolar amounts of reac-
tants. A series of polyfunctional spirocyclohexane oxindoles 3
and spirocyclopentane oxindoles 4 were obtained in good
yields, very good diastereocontrol, and excellent enantiocon-
trol under mild conditions. The new cascade process allowed
us to address an unprecedented and stereochemically defined
substitution pattern on the spirocarbocyclic unit. Careful sub-
Synthesis of 1’-(tert-butyl) 2-ethyl 6-(2-ethoxy-2-oxoethyl)-3-
nitro-2’-oxo-4-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-di-
carboxylates possessing six contiguous stereocenters
The last part of this study is dedicated to exploring the oppor-
tunity offered by optically active 2,3-disubstituted nitroenoates
as Michael donor/acceptor synthons in our organocascade pro-
cess, eventually leading to the construction of spirocyclohex-
ane systems with six contiguous stereocenters. We report here
the matched pair made up by chiral anti nitro compounds 2g
and 2h (easily synthesized via nitro aldehydes 13) and Takemo-
to’s catalyst I (Scheme 7). When compounds 2g–h were sub-
jected to optimal cascade reaction conditions, two new b-nitro
spirocyclohexane oxindoles (14 and 15) were achieved in high
yields and with excellent stereoselectivity. We wish to stress
that very few examples[31] of an asymmetric organocatalytic ap-
proach to fully substituted spirocyclohexane indolinones have
been recorded, and that the peculiar stereochemical pattern
characteristic of 14 and 15 has, to our knowledge, not been re-
ported to date.
Scheme 7. Stereoselective synthesis of nitroenoates 2g and h and Michael–
Michael organocascade protocol applied to optically active nitro compounds
(see the Supporting Information for the complete study on the use of chiral
nitroesters).
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whereas the remaining stereocenters are formed under control
of the catalyst. Defined diastereoselective conditions that can
be used to generate different stereoisomeric spirocyclopen-
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analogues, the structural motif of which is present in many
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Experimental Section
General procedure for the synthesis of spirocyclohexane ox-
indoles
Nitro compound 2 (0.12 mmol) was added to a solution of catalyst
(10 mol%) and 3-ylidene oxindole 1 (0.1 mmol) in CH2Cl2 (0.15 mL).
The reaction was stirred at RT for the reported time. The conver-
1
sion was monitored by TLC and H NMR analysis. The crude mix-
ture was purified directly by flash chromatography on silica gel (cy-
clohexane/ethyl acetate, 9:1).
General procedure for the synthesis of spirocyclopentane
oxindoles
Nitro compound 2 (0.12 mmol) was added to a solution of catalyst
(10 mol%) and 3-ylidene oxindole 1 (0.1 mmol) in CH2Cl2 (0.15 mL).
The reaction was stirred at the reported temperature for the re-
ported time. The conversion was monitored by TLC and 1H NMR
analysis. The reactions carried out below RT were quenched at 08C
with HCl (1m), extracted with CH2Cl2, and concentrated under re-
duced pressure before the 1H NMR spectroscopic analysis and/or
the chromatographic purification. The reactions carried out at RT
were purified directly by flash chromatography on silica gel (cyclo-
hexane/ethyl acetate, 9:1 to 8:2).
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Acknowledgements
Acknowledgement for financial support is made to MIUR
(Rome) and the University of Bologna.
Keywords: asymmetric catalysis · domino reactions · Michael
addition · organocatalysis · spiro compounds
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Chem. Eur. J. 2015, 21, 11038 – 11049
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Full Paper
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I
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Received: February 16, 2015
Published online on June 1, 2015
Chem. Eur. J. 2015, 21, 11038 – 11049
www.chemeurj.org
11049
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim