Direct asymmetric vinylogous aldol reaction of allyl ketones with isatins: Divergent synthesis of 3-hydroxy-2-oxindole derivatives

Article abstract of DOI:10.1002/anie.201302274

6 in 1: The highly enantioselective title reaction is mediated by a bifunctional catalyst and leads to E-configured vinylogous aldol products (see scheme). These products are used as common intermediates in the synthesis of six biologically active 3-hydroxy-2-oxindole derivatives (e.g., CPC-1). Computational studies indicated that the observed stereoselectivity is a result of favorable secondary π-π* and H-bonding interactions in the transition state. Copyright

Full text of DOI:10.1002/anie.201302274

Angewandte
Chemie
DOI: 10.1002/anie.201302274
Asymmetric Synthesis
Direct Asymmetric Vinylogous Aldol Reaction of Allyl Ketones with
Isatins: Divergent Synthesis of 3-Hydroxy-2-Oxindole Derivatives**
Bo Zhu, Wen Zhang, Richmond Lee, Zhiqiang Han, Wenguo Yang, Davin Tan, Kuo-
Wei Huang,* and Zhiyong Jiang*
3-Hydroxy-2-oxindole derivatives, which contain a quaternary
stereogenic center at the 3-position, are a family of structur-
ally diverse natural or nonnatural products with interesting
biological activities.[1] The asymmetric synthesis of 3-hydroxy-
2-oxindole derivatives, such as donaxaridine (1),[1b–c] (R)-
chimonamidine (2),[1d] CPC-1 (3),[1e] and (ꢀ)-flustraminol B
(4)[1f] (Scheme 1, series I), has recently been intensely pur-
sued, as these compounds exhibit a broad spectrum of
biological activities and are promising potential drugs.
Previously established methods[2] for the preparation of
these derivatives mainly focused on the asymmetric hydrox-
ylation of 3-substituted 2-oxindoles[3] and the nucleophilic
addition to isatins,[4] employing compound A as a viable
synthon (Scheme 1). The synthesis of related 3-hydroxy-2-
oxindole derivatives (5–7) of series II has attracted consid-
erable interest for a long time because of their fascinating
architectures and potential biological activities. For example,
spirolactone 5 has shown potential cytotoxic activity.[1g–i]
Spiroether 6 was reported to be a CB2 agonist and is thus
a potential drug candidate for reducing neuropathic and bone
pains, and for treating a host of diseases, including osteo-
arthritis, atherosclerosis, osteoporosis, and cancers.[1g]
Hexahydrozaepino[2,3-b]indole 7, which bears a unique 5,7-
Scheme 1. Representative examples of biologically active 3-hydroxy-2-
oxindole derivatives and the design of a vinylogous aldol reaction from
retrosynthetic analysis.
bicyclic framework, can be used as a tranquilizer for mammals
and birds.[1h–i] However, to the best of our knowledge, no
asymmetric protocol that affords this class of compounds has
been presented to date.
of our ongoing research efforts toward the development and
utilization of synthetic tools for the formation of quaternary
stereogenic centers,[3b,6] we were interested in designing
a novel organocatalytic asymmetric reaction to achieve the
divergent synthesis of 3-hydroxy-2-oxindole derivatives,
including those in series I and II.
Compared with the traditional “single target” approach,
the design of a common intermediate is the key in the total
synthesis of different products through a divergent synthesis
strategy, which has enabled the formation of a variety of
target molecules without compromising efficiency.[5] As part
Retrosynthetic analyses suggested that the synthetic route
to intermediates A and B was reasonable. We deduced that
compound C could be assembled as the common intermediate
for the divergent synthesis of 3-hydroxy-2-oxindole deriva-
tives of series I and II. We therefore focused on the
asymmetric vinylogous aldol reaction of the carbonyl-acti-
vated allyl nucleophile D with isatin (Scheme 1).
The Mukaiyama-type aldol reaction of silyl dienol ethers
is the favored protocol to furnish vinylogous aldol adducts,
but can suffer from low atom economy and efficiency.[7] In this
context, a direct asymmetric approach for these reactions
would be highly valuable. In recent years, cyclic 2-furanone
derivatives have been used as versatile nucleophiles in direct
vinylogous aldol reactions, as shown by the research groups of
Zhang,[8a] Terada,[8b] Feng,[8c] and Lu.[8d] However, because of
the low electron density at the g position of the generated
dienolate,[9] the direct vinylogous aldol reaction of a simple
[*] B. Zhu,[+] W. Zhang,[+] Z. Han, W. Yang, Prof. Dr. Z. Jiang
Key Laboratory of Natural Medicine and Immuno-Engineering of
Henan Province, Henan University
Jinming Campus, Kaifeng, Henan, 475004 (P. R. China)
E-mail: chmjzy@henu.edu.cn
R. Lee,[+] D. Tan, Prof. Dr. K.-W. Huang
King Abdullah University of Science and Technology (KAUST),
Division of Physical Sciences and Engineering and KAUST Catalysis
Center
Thuwal, 23955-6900 (Saudi Arabia)
E-mail: hkw@kaust.edu.sa
[+] These authors contributed equally to this work.
[**] This work was supported by the NSFC (21072044) and the Program
for New Century Excellent Talents in University of the Ministry of
Education (NCET-11-0938) to Z.J. and by KAUST to K.-W.H.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302274.
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acyclic nucleophile is not favored, and the use of a bulky
modifier at the a position is necessary to discriminate the
reactive enolate site.[10] In 2010, Shibasaki and co-workers
disclosed the first direct asymmetric vinylogous aldol reaction
of acyclic allyl cyanide to ketones, catalyzed by a soft Lewis
acid/hard Brønsted base, with excellent enantioselectivities
for the quaternary center and (Z) selectivity for the alkene
moiety.[11] We envisioned that allyl ketones, which are similar
to allyl cyanide, but are more readily prepared and modified,
could be used as the precursors of D to achieve the desired
direct vinylogous aldol reaction. It is worth noting that, over
the past few years, allyl ketones have been widely employed
as valuable intermediates in organic synthesis,[12] but that
there is no reported example on their applications in catalytic
asymmetric reactions. Herein, we report a highly enantio- and
E-selective direct vinylogous aldol reaction of allyl ketones
with isatins, and the divergent synthesis of various related 3-
hydroxy-2-oxindole derivatives with important biological
activities.
At the onset of our studies to probe the feasibility of the
proposed strategy, allyl phenyl ketone 8a was reacted with N-
methyl isatin 9a in the presence of Et3N in toluene at 258C.
The reaction worked smoothly, and the proposed vinylogous
aldol product 10a, which bears an E-configured olefin, was
obtained as the sole adduct (Table 1, entry 1). Encouraged by
our preliminary results, we examined the enantioselective
variant in the presence of various bifunctional tertiary amine/
thiourea catalysts (CAT-1–CAT-5), which can be conveniently
prepared from l-amino acids and are effective in a variety of
asymmetric reactions, as reported by us and other
groups.[6c,8d,13] Our screening of reaction conditions revealed
that all reactions proceeded well within 3–5 h in toluene at
258C in the presence of 10 mol% of catalyst, and afforded the
chiral vinylogous aldol E-adduct 10a in high yields with
moderate to good enantioselectivities (Table 1, entries 2–6).
The best selectivity was achieved with catalyst CAT-3, which
was derived from l-valine (Table 1, entry 4, 88% ee). To
further optimize the reaction conditions, the reaction was
performed in different solvents with CAT-3 as the catalyst
(Table 1, entries 7–9),[14] and the use of Et2O resulted in the
highest enantioselectivity with enhanced reaction rates
(Table 1, entry 8). A variation of the reaction temperature
showed that the enantioselectivity improved only slightly at
a lower temperature (Table 1, entries 10–12), and that the
best results were achieved at ꢀ208C (entry 11). Moreover, the
catalyst loading could be reduced to 1.0 mol%, and after 12 h,
10a was isolated with an excellent yield and without
compromising the enantiomeric excess (Table 1, entry 14).
With the optimal conditions established, we investigated
the scope of the reaction (Table 2). First, we attempted the
direct vinylogous aldol reaction of a variety of allyl ketones
with N-methyl isatins in the presence of 10 mol% of CAT-3 in
Et2O at ꢀ208C (Table 2, entries 1–14). The corresponding
products 10a–n were obtained in 57–98% yields with 88–
96% ee and E/Z ratios of 19:1 to more than 99:1. Notably, the
vinylogous aldol product 10g, derived from allyl tert-butyl
ketone, was obtained with 89% ee (entry 8). Subsequently, we
examined the vinylogous aldol reaction of allyl ketones with
N-benzyl isatins, and the desired products 10o–q were
obtained with excellent yields, enantio- and diastereoselec-
tivities (entries 15–17). We also found that simple filtration
was enough to isolate these E-configured adducts with an
ee value of 98% to more than 99%.[15] Furthermore, various
other allyl ketones 8 and commercially available isatins 9
were reacted under the established conditions to give the
vinylogous aldol adducts (10r–z) with yields of 81–92%,
enantioselectivities of 90–96%, and E/Z ratios of 13:1 to more
than 99:1 (entries 18–26). These results demonstrated that the
best reaction outcome was achieved with unprotected isa-
tins.[2,16] Most importantly, we carried out the reactions
toward 10d and 10x on a gram scale, and found that the
reactivity and enantioselectivity remained excellent, and the
corresponding adducts were obtained after a simple filtration.
Since all adducts precipitate from their reaction mixture, this
methodology is suitable for large-scale production.
Table 1: Screening studies.[a]
Entry
Catalyst
Solvent
T [8C]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Et3N
toluene
toluene
toluene
toluene
toluene
toluene
hexane
Et2O
THF
Et2O
Et2O
Et2O
25
25
25
25
25
25
25
25
25
12
3
3
3
3
88[d]
89
91
86
82
83
99
99
99
99
99
84
93
96
n.a.
57
85
88
79
85
85
88
87
90
93
93
92
92
CAT-1
CAT-2
CAT-3
CAT-4
CAT-5
CAT-5
CAT-5
CAT-5
CAT-5
CAT-5
CAT-5
CAT-5
CAT-5
Density-functional theory (DFT) was employed to eluci-
date the observed enantioselectivity and preference for g over
a alkylation.[17] We suspected that the pendent pyrrole moiety
of bifunctional catalyst CAT-3 first deprotonates allyl ketone
8a at the g position, and that the protonated catalyst then
brings the resulting enolate and the isatin electrophile
together to form the hydrogen-bonded complex for the
5
1
0.1
0.2
0.5
2
12
4
9
10
11
12
13[e]
14[f]
0
ꢀ20
ꢀ40
ꢀ20
ꢀ20
ꢀ
crucial C C bond formation. We found that binding of
ꢀ
a) the electrophile to the two N H bonds of the thiourea
Et2O
Et2O
moiety and b) the enolate to the pyrrolium arm gives the
transition state (TS) with the lowest Gibbs free energy (Si-R-
TS), which leads to the g-alkylated R product, consistent with
our experimental observation (see the Supporting Informa-
tion for all structures). Upon a close analysis of the Mayer
bond order,[18] this preference of the thiourea to be H-bonded
12
[a] Reactions were performed with 8a (0.075 mmol), 9a (0.05 mmol),
and catalyst (0.005 mmol) in 0.5 mL solvent. [b] Yield of isolated product
1
(E/Z>99:1, determined by H NMR analysis of the crude reaction
mixture). [c] Determined by HPLC. [d] E/Z=49:1. [e] 5 mol% catalyst
was used. [f] 1 mol% catalyst was used. n.a.=not applicable.
2
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Table 2: Direct asymmetric vinylogous aldol reaction of allyl ketones 8 to
various isatins 9.[a]
Entry R1/R2/R3 (10)
t
Yield ee
E/Z[d]
[h] [%][b] [%][c]
1
2
Ph/H/Me (10a)
4
5
86
93
92
96
91
34:1
>99:1
4-ClPh/H/Me (10b)
4-BrPh/H/Me (10c)
4-MeOPh/H/Me (10d)
3-MeOPh/H/Me (10e)
2-naphthyl/H/Me (10 f)
2-thienyl/H/Me (10g)
tBu/H/Me (10h)
3
48 87
24 85
24 82
38:1
4[l]
5
96[e,f] >99:1[e,f]
94
95
93
89
96
91
90
92
88
95
>99:1
28:1
>99:1
>99:1
19:1
29:1
24:1
32:1
49:1
6
7
8
9
6
98
48 80
96 57
48 89
5
2
5
5
2
3
Figure 1. Transition-state structure featuring the possible binding ori-
Ph/4-Br/Me (10i)
entation of isatin to catalyst CAT-3 and g alkylation by the allylic
nucleophile to lead to observed R-g-product. Non-H-bonded hydrogen
atoms were omitted for clarity. Mayer bond orders of H-bonds (>0.03)
are given in parentheses.
10
11
12
13
14
15
16
17
18[j]
19
20[j]
21
22
23
24[m]
25
26
Ph/5-Me/Me (10j)
Ph/5-Br/Me (10k)
Ph/6-Br/Me (10l)
Ph/7-Cl/Me (10m)
2-naphthyl/5-Me/Me (10n)
Ph/H/Bn (10o)
4-MeOPh/H/Bn (10p)
Ph/5-Me/Bn (10q)
Ph/H/H (10r)
Ph/4-Br/H (10s)
Ph/5-Me/H (10t)
Ph/5-Cl/H (10u)
Ph/6-Br/H (10v)
89
92
90
86
93
93
42:1
98[e,g] >99:1[e,g]
99[e,h] >99:1[e,h]
24 95
92
8
>99[e,i]
>99:1[e,i]
42:1
13:1
>99:1
>99:1
48:1
24 82
24 85
30 90
30 92
24 91
24 85
24 87
30 81
30 83
96
95
93
92
92
90
4-MeOPh/H/H (10w)
4-MeOPh/5-Me/H (10x)
3-MeOPh/6-Br/H (10y)
3-MeOPh/7-Cl/H (10z)
13:1
96[e,k] >99:1[e,k]
94
92
>99:1
>99:1
[a] Reactions were performed with 8 (0.15 mmol), 9 (0.1 mmol), and
CAT-3 (0.01 mmol) in 1.0 mL Et2O. [b] Yields of isolated products based
on 9. [c] The ee values were determined by HPLC on a chiral stationary
phase. [d] The E/Z ratios were determined by 1H NMR analysis. [e] The
ee value and E/Z ratio were obtained after single recrystallization.
[f] Initial data: ee=90%, E/Z=33:1. [g] Initial data: ee=93%, E/
Z=28:1. [h] Initial data: ee=90%, E/Z=19:1. [i] Initial data: ee=95%,
E/Z>99:1. [j] Ethyl acetate was used as solvent. [k] Initial data:
ee=92%, E/Z>99:1. [l] 6 mmol scale, 1.75 g of 10d was obtained with
87% yield in 90% ee by simple filtration using Et2O as eluent.
[m] 6 mmol scale, 1.647 g of 10x was obtained in 81% yield with 92% ee
by simple filtration using Et2O as eluent.
Figure 2. Orbital correlation diagram between allyl ketone and isatin.
between the allyl phenyl ketone and isatin. Matching orbital
phases were identified between C1 with carbonyl C, and C3
with carbonyl O (3.173 ꢀ). In hindsight, the extra p–p*
interaction in Si-R-TS from the suitable alignment of the
orbitals offers greater thermodynamic stability to the tran-
sition state. We rationalize that the preference for g over
a alkylation is as a result of steric influences. From the
ꢀ
ꢀ
with the electrophile is likely a result of N H···O and two
perspective of the TS for the formation of the C C bond
ꢀ
additional nonclassical C H···O hydrogen-bonding interac-
through a alkylation, steric interaction between the allyl
phenyl ketone nucleophile and isatin electrophile is clearly
involved. Overall, the TS structures that lead to a-alkylated
products are 5.5–8.5 kcalmolꢀ1 more endergonic than the Si-
R-TS (see the Supporting Information).
ꢀ
ꢀ
tions between the acidic N H and C H bonds and the
carbonyl groups of isatin (Figure 1). The bond order of the C
ꢀ
C bond that is formed is 0.434.
To establish a rationale for the preferred formation of the
ꢀ
g-C C bond in the Si-R orientation, we compared the local
With the protocol for the asymmetric vinylogous aldol
reaction established, we proceeded to prepare the proposed
3-hydroxy-2-oxindole derivatives. The syntheses of com-
pounds 1–3 from series I were first demonstrated
(Scheme 2). The activated alkene of 10d was ozonolyzed
with O3, reduced with NaBH4, and then treated with tosyl
chloride to afford the corresponding product 11. Tosylate 11
was then converted to the desired (R)-chimonamidine 2 with
electronic properties of the optimized TS structure. Interest-
ingly, a significant secondary interaction was observed
between C3 of the nucleophile and the carbonyl O of isatin
in Si-R-TS (with a Mayer bond order of 0.047, Figure 2). The
high stereochemical discrimination can be further elaborated
by constructing a simple orbital-correlation diagram to
illustrate the symmetries of molecular-orbital interactions
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Scheme 2. Synthesis of (R)-chimonamidine and the key intermediates
of donaxaridine and CPC-1. Reagents and conditions: a) O3, CH2Cl2,
ꢀ788C, 30 min; b) NaBH4 (4.0 equiv), CH3OH, 258C, 3 h, 76% yield
(over two steps); c) TsCl (1.5 equiv), pyridine, 258C, 12 h, 68% yield;
d) MeNH2 (33% in C2H5OH), 758C, 10 h, 76% yield, 96% ee; e) NaN3
(3.0 equiv), DMF, 608C, 12 h, 86% yield, 96% ee. DMF=N,N-dime-
thylformamide, TsCl=p-toluenesulfonyl chloride.
96% ee through the treatment with methylamine. Upon
treatment with NaN3, compound 11 afforded azide 12,
which is an important intermediate in the preparation of
donaxaridine 1[1b–c] and CPC-1 3[1e]
.
We next prepared 3-hydroxy-2-oxindole derivatives of
series II from our vinylogous aldol adducts (Scheme 3). Ester
13 was obtained from the reduction of 10w with H2 on Pd/C
for 30 min, followed by a Baeyer–Villiger rearrangement
(BVR) with mCPBA. Spirolactone 5 was conveniently
obtained with 90% ee from 13 through its treatment with
1,1,3,3-tetramethylguanidine (TMG). Reduction of adduct
10d with H2 on Pd/C for 2 h afforded 14, which bears an
interesting 4-aryl-substituted butyl group at C3 and belongs to
a novel class of 3-hydroxy-2-oxindole derivatives with some
potential bioactivities. Alternatively, compound 10d could be
converted to amide 16 through a sequence of reduction, BVR,
and reaction with a solution of ammonia in methanol. To our
delight, treatment of 16 with LiAlH4 and then acetic
anhydride afforded the expected hyxahydrozaepino[2,3-
b]indole 7 without compromising the ee value. In an effort
to obtain spiroether 6, the important intermediate 17 was
prepared through reduction and protection of 10x. After
a BVR and another reduction, alcohol 18 was obtained, which
gave spiroether 19 after reaction with MsCl and NaH.
Following a highly efficient oxidation with ceric ammonium
nitrate (CAN), an aldol reaction, and an oxidation with
piperidine and H2O2, spiroether 6, the CB2 agonist, was
successfully obtained with 96% ee and 42% overall yield
from 10x.
Scheme 3. Synthesis of bioactive 3-hydroxy-2-oxindole derivatives of
series II. Reagents and conditions: a) Pd/C, H2, CH3OH, RT, 30 min,
97% yield; b) mCPBA (2.5 equiv), Na2HPO4, CH2Cl2, RT, 6 h, 83%
yield; c) TMG (1.1 equiv), THF, RT, 7 h, 93% yield, 90% ee; d) Pd/C,
H2, CH3OH, RT, 2 h, 95% yield, 96% ee; e) Pd/C, H2, CH3OH, RT,
30 min, 95% yield; f) mCPBA (2.5 equiv), Na2HPO4, CH2Cl2, RT, 6 h,
80% yield; g) NH3 (aq), CH3OH, RT, 1 h, 90% yield; h) LiAlH4, THF,
08C!RT; i) Ac2O, 50% yield of two steps, 96% ee; j) Pd/C, H2,
CH3OH, 258C, 30 min, 92% yield; k) Cs2CO3, (bromomethyl)cyclopro-
pane, DMF, 08C!RT, 98% yield; l) mCPBA (2.5 equiv), Na2HPO4,
CH2Cl2, RT, 6 h, 87% yield; m) NaBH4 (20 equiv), CH3OH, RT, 5 h,
89% yield; n) MsCl, Et3N, CH2Cl2, ꢀ108C, 1 h, 91% yield; o) NaH
(1.5 equiv), DMF, 08C!RT, 1 h, 92% yield; p) CAN (4.0 equiv),
CH3OH/CH3CN (v/v=2:1), RT, 5 min, 95% yield; q) H2O2, piperidine,
76% yield, 96% ee. mCPBA=meta-chloroperbenzoic acid.
tational studies strongly supported that the observed stereo-
chemistry is a result of favorable secondary p–p* and H-
bonding interactions. Further investigations, which involve
the use of allyl ketones in other asymmetric reactions and the
application of this catalytic approach to the divergent syn-
thesis of other natural products, are ongoing and will be
reported in due course.
In conclusion, we have developed the first highly enan-
tioselective direct vinylogous aldol reaction between allyl
ketones and isatins catalyzed by a readily prepared l-valine-
derived bifunctional tertiary amine/thiourea catalyst. A series
of E-configured vinylogous aldol adducts were obtained with
88% to more than 99% ee. This is the first application of allyl
ketones in a catalytic asymmetric reaction. Most importantly,
the reported synthetic method provides easy access to various
biologically important 3-hydroxy-2-oxindole derivatives
through divergent synthesis of with excellent results. Compu-
Received: March 18, 2013
Published online: && &&, &&&&
Keywords: 3-hydroxy-2-oxindoles · aldol reaction · allyl ketones ·
.
asymmetric synthesis · divergent synthesis
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Synthesis
B. Zhu, W. Zhang, R. Lee, Z. Han,
W. Yang, D. Tan, K.-W. Huang,*
Z. Jiang*
&&&& — &&&&
6 in 1: The highly enantioselective title
reaction is mediated by a bifunctional
catalyst and leads to E-configured vinyl-
ogous aldol products (see scheme).
These products are used as common
intermediates in the synthesis of six
biologically active 3-hydroxy-2-oxindole
derivatives (e.g., CPC-1). Computational
studies indicated that the observed ste-
reoselectivity is a result of favorable
secondary p–p* and H-bonding interac-
tions in the transition state.
Direct Asymmetric Vinylogous Aldol
Reaction of Allyl Ketones with Isatins:
Divergent Synthesis of 3-Hydroxy-2-
Oxindole Derivatives
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!