One-pot organocatalytic enantioselective michael/povarov domino strategy for the construction of spirooctahydroacridine-3,3′-oxindole scaffolds

Article abstract of DOI:10.1002/chem.201402002

An asymmetric organocatalytic one-pot strategy for the construction of spirooctahydroacridine-3,3′-oxindole scaffolds has been successfully developed by means of a domino Michael/Povarov reaction sequence. The one-pot protocol affords the chiral spirocyclohexaneoxindoles bearing an octahydroacridine motif with five stereocenters in good to high yields (up to 89% yield) with excellent to perfect diastereoselectivities (up to >20:1 d.r.) and enantioselectivities (up to >99% ee). This highly efficient one-pot domino procedure will allow diversity-oriented syntheses of this intriguing class of compounds with potential biological activities. Domino construction: An efficient organocatalytic one-pot domino Michael/intramolecular Povarov reaction has been developed to provide enantiomerically enriched spirooctahydroacridine-3,3′-oxindole derivatives containing five stereogenic centers in good to high yields with excellent diastereo- and enantioselectivities (see scheme). This strategy not only adds to the limited repertory of examples of asymmetric synthesis of chiral spirocyclohexaneoxindoles and octahydroacridines, but also demonstrates a one-pot consecutive synthesis with an ecological and economical protocol.

Full text of DOI:10.1002/chem.201402002

DOI: 10.1002/chem.201402002
Communication
&
Organocatalysis
One-Pot Organocatalytic Enantioselective Michael/Povarov
Domino Strategy for the Construction of Spirooctahydroacridine-
3,3’-oxindole Scaffolds
Hao Wu and Yong-Mei Wang*[a]
Abstract: An asymmetric organocatalytic one-pot strategy
for the construction of spirooctahydroacridine-3,3’-oxin-
dole scaffolds has been successfully developed by means
of a domino Michael/Povarov reaction sequence. The one-
pot protocol affords the chiral spirocyclohexaneoxindoles
bearing an octahydroacridine motif with five stereocenters
in good to high yields (up to 89% yield) with excellent to
perfect diastereoselectivities (up to >20:1 d.r.) and enan-
tioselectivities (up to >99% ee). This highly efficient one-
pot domino procedure will allow diversity-oriented syn-
theses of this intriguing class of compounds with poten-
tial biological activities.
Domino, tandem, or cascade reactions that involve the forma-
tion of multiple carbon–carbon or carbon–heteroatom bonds
Figure 1. a) Some biologically active compounds with spirocyclohexaneoxin-
and stereocenters in one-pot reactions are a rapidly growing
research field within the construction of molecules with great
structural complexity by a minimum of manual operations,
thereby saving time, effort, and production cost.[1] The design
of organocatalytic domino reactions[2] is even more appealing,
not only because such processes are more efficient than step-
wise reactions, but also because organocatalysts, which allow
distinct modes of activation, are environmentally friendly,
robust, and nontoxic. Thus, the implementation of asymmetric,
organocatalytic, one-pot domino processes remains of great
interest to the synthetic community.[3]
dole core. b) Selected examples of biologically important chiral octahydro-
acridine derivatives. c) Construction of the chiral spirooctahydroacridine-3,3’-
oxindole skeleton by two known bioactive scaffolds.
biologically active natural alkaloids (Figure 1a).[6] Compared
with the spirooxindoles with cyclohexanone[7] and cyclohexene
moieties,[8] highly efficient methods for the enantioselective
construction of spirocyclohexaneoxindoles have been rarely
disclosed.[9] Furthermore, chiral octahydroacridine (OHA) is an-
other core structure with pharmacological interest, acting as
gastric acid secretion inhibitors (Figure 1b).[10] However, access
to optically active octahydroacridines has so far exclusively
been based on a chiral pool approach and the methodology
through asymmetric catalysis is quite limited.[3g] Because of the
significant medicinal value and structural complexities of the
two class of scaffolds, a sophisticated structure in which the
oxindole core is fused with an octahydroacridine moiety at the
C3-position might possess remarkable biological activities, thus
emerging as an attractive synthetic target (Figure 1c).[11] Never-
theless, enantiomerically enriched spirooctahydroacridine-3,3’-
oxindole scaffolds possessing the potential as an important
pharmacophore have not been constructed until now.
The spirocyclicoxindole scaffold defines the characteristic
structural core of a large family of alkaloid natural products
with strong bioactivity profiles and interesting structural prop-
erties.[4] The exceptional promise of a broad therapeutic poten-
tial has sparked intense interest in developing concise ap-
proaches for generating multifunctionalized chiral spirooxin-
doles and natural-product-like derivatives.[5] In particular, oxin-
doles incorporating a cyclohexane moiety are particularly strik-
ing structural motifs widely encountered in a number of
[a] H. Wu, Prof. Y.-M. Wang
State Key Laboratory of Elemento-Organic Chemistry
Department of Chemistry, Nankai University
Tianjin 300071 (China)
Fax: (+86)22-23504439
E-mail: ymw@nankai.edu.cn
Prompted by the above background and in the context of
our ongoing investigations in asymmetric synthesis of chiral
spirooxindoles,[5q] we envisioned that the chiral spirooctahy-
droacridine-3,3’-oxindole skeleton could be constructed in an
asymmetric organocatalytic domino Michael/intramolecular
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402002.
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Povarov reaction[12] sequence of rationally designed
3-substituted oxindoles (1), a,b-unsaturated alde-
hydes (2), and aniline derivatives (3) by means of
a one-pot strategy. The two stereocenters of the ini-
tial step employing aminocatalysis would direct the
subsequent aza-Diels–Alder reaction, hereby control-
ling the formation of the optically active spirooctahy-
droacridine-3,3’-oxindole derivatives containing five
stereocenters with excellent stereoselectivities
(Scheme 1).
Scheme 1. Proposed strategy for the one-pot organocatalytic asymmetric synthesis of
spirooctahydroacridine-3,3’-oxindole derivatives and its three challenges.
However, three challenges are associated with this
one-pot domino process:
1) The simultaneous creation of four new chemical bonds
(three carbon–carbon bonds and one carbon–nitrogen
bond) and five stereocenters including a spiro quaternary
center in one-pot.
Table 1. Optimization of organocatalytic one-pot domino Michael-Pova-
rov reaction conditions.[a]
2) Less reactive styrene-type substrates as the olefin compo-
nent in the Povarov reaction (only three examples of an
asymmetric catalytic protocol involving styrene derivatives
as the dienophiles in Povarov reaction have been repor-
ted[11c,12m,j]).
3) The control of diastereo- and enantioselectivity of the prod-
ucts.
Herein, we present the successful implementation of this or-
ganocatalytic one-pot domino strategy to access optically
active spirooctahydroacridine-3,3’-oxindole derivatives contain-
ing five stereocenters including a spiro quaternary center with
excellent enantio- and diastereopurities and significant oppor-
tunities for structural diversification (up to 89% yield, up to
>20:1 d.r., up to >99% ee).
In our initial investigation, we examined the reactivity of
3-substituted oxindole (1a) towards the proposed one-pot
domino reaction with trans-hex-2-enal (2a) and aniline (3a).
Gratifyingly, reaction of 1a and 2a with 20 mol% of Et2NH in
toluene at room temperature for 24 h, followed by the addi-
tion of aniline (3a, 1.5 equiv) and trifluoroacetic acid (TFA,
2.0 equiv) with stirring for another 5 h, furnished a 88% yield
of the expected product 4a although in an approximate 1:1
ratio of diastereomers (Table 1, entry 1, 1:1 d.r.). Then some
commercially available chiral secondary amines I–VII were
screened, because of their established abilities to activate a,b-
unsaturated aldehydes toward asymmetric transformations
(Table 1, entries 2–8). To our delight, reactions with the diphen-
yl prolinol silylether catalysts I–VI gave promising results with
good yields and stereoselectivities. Increasing the diarylprolinol
O-trimethylsilyl (O-TMS) ether to some bulkier ether groups, for
example, O-triethylsilyl (O-TES) and O-tert-butyl dimethyl (O-
TBS), led to higher diastereoselectivities and enantioselectivi-
ties (Table 1, entries 2 and 3 versus entries 4 and 5). Lower
yields and stereoselectivities were obtained when the electron-
ic nature of the aryl group in the catalyst III changed (Table 1,
entries 6–7). MacMillan’s imidazolidinone VII gave only traces
of the product (entry 8). So the diphenyl prolinol O-TES, III,
was chosen as the optimized catalyst, affording the desired
product 4a in 77% yield with 11:1 d.r. and 92% ee (Table 1,
Entry
Cat.
Additive
Solvent
t
[h]
Yield
[%][b]
d.r.[c]
ee
[%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[e]
15[f]
16[e]
17[e]
18[e]
19[e]
20[e]
Et2NH
I
II
III
IV
V
VI
VII
III
III
III
III
III
III
III
III
III
III
III
III
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
ether
THF
MTBE
DCM
CHCl3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
88
62
73
77
73
50
70
trace
80
trace
73
66
72
76
78
56
78
82
1:1
2:1
5:1
11:1
8:1
3:1
6:1
–
6:1
–
0
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
TFA
73
87
92
91
90
84
–
91
–
8:1
7:1
9:1
92
88
86
94
94
72
90
98
94
97
15:1
12:1
7:1
16:1
>20:1
15:1
>20:1
(R)-P1
(R)-P2
(R)-P3
(S)-P2
86
80
[a] Unless otherwise specified, all the reactions were performed in 0.1m
1a with 1:2 ratio of 1a/2a at room temperature by employing
20 mol% catalyst and additive. [b] Isolated yields of diastereomeric mix-
a
1
ture. [c] Determined by H NMR spectroscopy of a crude reaction mixture.
[d] Enantiomeric excess of major diastereoisomer as determined by HPLC
analysis. [e] 10 mol% catalyst and 10 mol% additive were used.
[f] 15 mol% catalyst and 15 mol% additive were used.
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entry 4). No significant improvement was achieved by conduct-
ing the one-pot domino reaction in various solvents although
comparable enantioselectivities and yields were obtained for
diethyl ether and methyl tert-butyl ether (MTBE) (entries 9–13).
When the catalyst and additive loading were both decreased
to 10 mol%, better stereoselectivities were obtained for the
product 4a (Table 1, entry 14, 15:1 d.r., 94% ee). Following
a screening of various additives revealed that the combination
of chiral Brønsted acids with the catalyst III afforded the prod-
uct in higher yield and excellent stereoselectivities (entries 17–
20). Eventually, the best outcome was obtained when 10 mol%
of (R)-P2 was employed as the additive, thus providing the de-
sired spirooctahydroacridine-3,3’-oxindole 4a in high yield with
excellent diastereoselectivity and enantioselectivity (Table 1,
entry 18, 82% yield, >20:1 d.r., 98% ee). Replacement of the
(R)-P2 to (S)-P2 furnished a comparable result in terms of yield
and stereocontrols (entry 20).
With the optimized conditions in hand, we subsequently
performed a study to probe the generality of our one-pot
domino strategy in synthesizing substituted spirooctahydro-
acridine-3,3’-oxindole derivatives by focusing upon variation of
3-substituted oxindoles (1), a,b-unsaturated aldehydes (2), and
aniline derivatives (3). The results are summarized in Scheme 2.
All of the reactions catalysed by the catalyst III proceeded
smoothly, affording the desired spirooctahydroacridine-3,3’-ox-
indole derivatives in good to high yields (30–89% yield) with
excellent diastereoselectivities (5:1–>20:1 d.r.) and excellent
enantioselectivities (84–>99% ee). Notably, minimal impact on
reactive efficiencies, enantioselectivities and diastereoselectivi-
ties was observed, regardless of the electronic nature or bulki-
Scheme 2. Synthesis of spirooctahydroacridine-3,3’-oxindole derivatives with five stereocenters. Unless otherwise specified, all the reactions were performed
in 0.1m 1a with a 1:2 ratio of 1a/2a at room temperature by employing 10 mol% catalyst and additive at room temperature. The reported yields are of the
1
sum of the diastereoisomers. The d.r. values were determined by H NMR spectroscopy of the crude mixture. The ee values were determined by chiral HPLC
on a Chiralcel column.
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ness of 4-substituted aniline derivatives (Scheme 2, 4a–j). In
addition, other different substitution patterns of the anilines
were also explored. There appears to be significant tolerance
towards electronic variations and positions of the substituents
of the anilines to access a variety of products (Scheme 2, 4k–
o). Three disubstituted anilines with electron-withdrawing
groups and electron-donating groups as well as 1-aminonaph-
thalene were utilized in the strategy, accessing the optically
active products 4p–s with tetrasubstituted aromatic moieties
in high yields with excellent stereocontrol (Scheme 2). Further
exploration of the substrate scope was focused upon various
3-substituted oxindoles (1) and a,b-unsaturated aldehydes (2).
Minimal impact of the chain length of aliphatic enals upon the
efficiencies and stereoselectivities was observed, though lower
yield and stereocontrol was obtained when cinnamaldehyde
was used (Scheme 2, 4u–x). Another 3-substituted bifunctional
oxindole 1b was also compatible under the optimized reaction
conditions, thus offering excellent stereoselectivities of the
products (Scheme 2, 4t and 4w). However, when conducting
the reaction with nucleophiles without the aromatic substitu-
ent on the double bond, no cyclization was observed (see the
Supporting Information, 4y). This may indicate the necessity of
the aryl substituent on the double bond to finish the intramo-
lecular Povarov reaction.[12a] The absolute configuration of the
stereogenic centers of the spirooctahydroacridine-3,3’-oxindole
derivative (4d) was unambiguously determined by X-ray crys-
tallographic analysis (Figure 2).[13]
Scheme 3. Transformation of the products into other spirooctahydroacri-
dine-3,3’-oxindole derivatives.
almost quantitative yield. It is worth noting that no great
changes took place in the enantioselectivity during the above
transformations.
To explain the stereochemical outcome of this one-pot
domino transformation, we have proposed a plausible mecha-
nism (Scheme 4). Initial nucleophilic attack of 3-substituted ox-
indole (1a) on the iminium-activated a,b-unsaturated aldehyde
(2a) via TS-A from the Re-face under the catalyst control by ef-
ficient shielding of the Si-face afforded the Michael addition
Figure 2. X-ray crystal structure of compound 4d.
To further expand the potential of this reaction, the versatile
transformations of the products into other structurally diverse
spirooctahydroacridine-3,3’-oxindole derivatives were per-
formed. As illustrated in Scheme 3, the 4-nitro moiety of the
spirooxindole 4b was smoothly reduced to 4-amino moiety
5b, which was incompatible to our one-pot domino strategy,
in 98% yield by a simple treatment with zinc powder and
NH4Cl in MeOH/H2O within 20 min. In addition, aryl bromide
moiety of 4d could be introduced a phenyl group in the posi-
tion of Br atom by means of a Suzuki coupling to give 6d in
Scheme 4. Proposed mechanism for the one-pot domino transformation.
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1H), 4.05 (s, 1H), 3.73 (d, J=10.8 Hz, 1H), 3.43 (t, J=8.9 Hz, 1H),
2.47–2.31 (m, 1H), 2.16 (m, 2H), 1.70 (m, 2H), 1.39 (d, J=13.4 Hz,
1H), 1.29 (m, 1H), 1.14 (m, 1H), 0.90 (m, 1H), 0.77–0.57 ppm (m,
4H); 13C NMR (101 MHz, CDCl3): d=182.84, 144.37, 143.36, 140.61,
132.12, 130.20, 129.31, 128.51, 127.63, 127.17, 126.52, 125.88,
125.25, 122.09, 117.91, 114.10, 110.21, 55.33, 53.83, 51.04, 40.28,
40.04, 37.40, 33.97, 32.94, 20.25, 14.08 ppm; HRMS (ESI): m/z calcd
for C29H30N2O+H [M+H]: 423.2431; found: 423.2436.
adduct B, which was then reacted with 4-bromoaniline (3d)
and TFA through condensation to provide iminium intermedi-
ate C. Subsequently, the intermediate C underwent the intra-
molecular Povarov reaction via an endo transition state (TS-D),
preferring the stabilized p–p stacking and chairlike conforma-
tion, to furnish the desired product 4d with the observed dia-
stereoselectivity. This p–p interaction could also be proved
when conducting the experiment with the substrate 1 bearing
no aromatic substituent on the double bond and thereby lack-
ing the ability to be involved in p–p interaction, no cyclization
was observed (see the Supporting Information, 4y). Notably,
the reaction demonstrated a proof-of-principle of the control
of stereoselectivity in Povarov reaction by the remote stereo-
genic center generated in situ by the one-pot domino organo-
catalytic reaction.
Acknowledgements
We thank for the grants from the National Basic Research Pro-
gram of China (973 Program: 2010CB833300) and the State
Key Laboratory of Elemento-Organic Chemistry.
In conclusion, we have developed an efficient organocatalyt-
ic one-pot domino Michael/intramolecular Povarov reaction to
provide the enantiomerically enriched spirooctahydroacridine-
3,3’-oxindole derivatives containing five stereogenic centers in
good to high yields with excellent diastereo and enantioselec-
tivities. Under optimal conditions, this protocol displays a great
tolerance towards a variety of different substrates. This strat-
egy not only adds to the limited repertory of examples of
asymmetric synthesis of chiral spirocyclohexaneoxindoles and
octahydroacridines, but also demonstrates a one-pot consecu-
tive synthesis with an ecological and economical protocol.
These one-pot tactics and the benign reaction media at ambi-
ent temperature further manifest the merit of this strategy. We
believe that these novel compounds based on spirooctahy-
droacridine-3,3’-oxindole skeletons prepared here might pos-
sess some biological activities. The application of this strategy
to synthesize more promising candidates for the biological
evaluation is currently underway.
Keywords: domino
organocatalysis · Povarov reaction · spirooctahydroacridine-
3,3’-oxindoles
reactions
·
Michael
reaction
·
[1] For reviews see: a) L. F. Tietze, G. Brasche, K. Gericke, Domino Reactions
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116, 1292–1297; Angew. Chem. Int. Ed. 2004, 43, 1272–1277; b) Y.
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Experimental Section
Typical experimental procedure for one-pot construction of
chiral spirooctahydroacridine-3,3’-oxindole derivatives
3-Substituted oxindole 1 (0.10 mmol, 1.0 equiv) was added to a so-
lution of cat. III (0.01 mmol, 0.1 equiv), (R)-P2 (0.01 mmol,
0.1 equiv), and 2 (0.20 mmol, 2.0 equiv) in toluene (1.0 mL) at room
temperature. The reaction was stirred for 24–48 h. Then the reac-
tion mixture was diluted with toluene (1.0 mL). Aniline derivative 3
(0.15 mmol, 1.5 equiv) was then added in the same pot followed
by TFA (0.2 mmol, 2 equiv) and the mixture was stirred for 5 h at
room temperature. When the reaction was completed, the mixture
was washed with 1m aq. HCl (2ꢁ3 mL) and sat. aq. Na2CO3 (2ꢁ
2 mL), dried, and concentrated. The crude product was purified by
silica-gel chromatography to give the corresponding products 4.
Data for compound 4a
[a]2D5 =+86.8 (c=0.3, CH2Cl2); HPLC: Chiralpak AD-H (hexane/
iPrOH=90/10, flow rate 1.0 mLminÀ1, l=254 nm), tR (major)=
7.119 min, tR (minor)=10.910 min; 98% ee; 1H NMR (400 MHz,
CDCl3): d=9.07 (s, 1H), 7.44 (d, J=7.4 Hz, 1H), 7.22–7.08 (m, 4H),
7.05 (d, J=7.1 Hz, 2H), 7.02–6.91 (m, 2H), 6.86 (d, J=7.7 Hz, 1H),
6.59 (d, J=7.9 Hz, 1H), 6.52 (t, J=7.3 Hz, 1H), 6.45 (d, J=7.5 Hz,
[5] For selected examples of the catalytic enantioselective construction of
spirooxindoles, see: a) C. Martin, E. M. Carreira, Eur. J. Org. Chem. 2003,
2209–2219; b) B. M. Trost, M. K. Brennan, Synthesis 2009, 3003–3025;
c) R. Rios, Chem. Soc. Rev. 2012, 41, 1060–1074; d) L. Hong, R. Wang,
Adv. Synth. Catal. 2013, 355, 1023–1052; e) B. M. Trost, N. Cramer, S. M.
Silverman, J. Am. Chem. Soc. 2007, 129, 12396–12397; f) X. H. Chen, Q.
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Communication
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Received: February 1, 2014
Published online on && &&, 0000
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
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Organocatalysis
H. Wu, Y.-M. Wang*
&& – &&
One-Pot Organocatalytic
Enantioselective Michael/Povarov
Domino Strategy for the Construction
of Spirooctahydroacridine-3,3’-
oxindole Scaffolds
Domino construction: An efficient or-
ganocatalytic one-pot domino Michael/
intramolecular Povarov reaction has
been developed to provide enantiomer-
ically enriched spirooctahydroacridine-
3,3’-oxindole derivatives containing five
stereogenic centers in good to high
yields with excellent diastereo- and
enantioselectivities (see scheme). This
strategy not only adds to the limited
repertory of examples of asymmetric
synthesis of chiral spirocyclohexane-
oxindoles and octahydroacridines, but
also demonstrates a one-pot consecu-
tive synthesis with an ecological and
economical protocol.
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ