Catalytic enantioselective henry reactions of isatins: Application in the concise synthesis of (S)-(-)-spirobrassinin

Article abstract of DOI:10.1002/chem.201101025

When isatin a cat! A highly efficient, cupreine-catalyzed, enantioselective Henry reaction of readily available isatins and nitroalkanes has been developed (see scheme). The products are produced in excellent yields and good enantioselectivities under mild reaction conditions and without chromatography. The utility of the strategy has been demonstrated in the facile synthesis of (S)-(-)-spirobrassinin without the need for protecting groups. Copyright

Full text of DOI:10.1002/chem.201101025

COMMUNICATION
DOI: 10.1002/chem.201101025
Catalytic Enantioselective Henry Reactions of Isatins: Application in the
Concise Synthesis of (S)-(À)-Spirobrassinin
Lu Liu,[a] Shilei Zhang,[a] Fei Xue,[a] Guangshun Lou,[a] Haoyi Zhang,[a] Shichao Ma,[a]
Wenhu Duan,[a, b] and Wei Wang*[a, b, c]
3-Substituted 3-hydroxyoxindoles are the core structural
unit in a large array of fascinating natural products with a
broad spectrum of intriguing biological activities .[1] CPC-
of the solid products. These features render this synthetic
tool particularly attractive for practical application in drug
discovery, development, and production. Moreover, the syn-
thetic value has been demonstrated in the efficient synthesis
of natural product (S)-(À)-spirobrassinin in four steps for
the first time without requiring protecting groups.
Asymmetric aldol reactions with isatins[3] give direct entry
to the chiral 3-substituted 3-hydroxyoxindole framework
(Scheme 1). Significant effort has been focused on the cata-
1,[2a] convolutamydines,[2b] maremycins,[2c] diazonamide A,[2d]
leptosin D,[2e] o-hydroxyglucoisatisin,[2f] witindolinone C,[2g]
TMC-95A-D,[2h] celogentin K,[2i] arundaphine,[2j] paratunam-
ACHTUNGTRENNUNG
ides A–D,[2k] and neuroprotectins A and B[2l] are representa-
Scheme 1. The catalytic asymmetric Henry reaction of isatins with nitro-
alkanes.
tive examples. Notably, the scaffold has emerged as a “privi-
leged” structure in drug discovery.[2a] Accordingly, the devel-
opment of efficient methods for the construction of func-
tionalized frameworks with this structure is of considerable
synthetic and biological importance.
Herein, we wish to disclose a simple, cupreine-catalyzed,
enantioselective Henry reaction of readily accessible nitroal-
kanes with isatins under mild reaction conditions to make
the valuable chiral 3-substituted 3-hydroxyoxindoles. Good
to high enantioselectivities and high yields have been ob-
tained. Furthermore, the enantioselectivities can be readily
improved to excellent levels (94–99%) by simple treatment
lytic enantioselective aldol reactions of aldehydes and ke-
tones.[4] Nevertheless, the asymmetric Henry (nitroaldol) re-
action of isatins with readily available nitroalkanes remains
elusive.[5] These aldol adducts are highly valuable building
blocks for the total synthesis of 3-substituted 3-hydroxyoxin-
dole-derived natural products and their analogues because
the versatile nitro functionality can easily be transformed
into a variety of functional groups, such as amine, nitrile
oxide, ketone, carboxylic acid, hydrogen, and so forth.[6] De-
spite this, to the best of our knowledge, no such process has
been reported so far.
The creation of a chiral quaternary center is a challenging
subject in asymmetric synthesis.[7] To date, the development
of enantioselective nitroaldol reactions with ketones has
met with limited success. In reported studies, acyclic a-keto
esters and very active trifluoromethyl ketones are exclusive-
ly employed.[8] However, the use of useful cyclic ketones,
such as isatins, has not been disclosed. Due to the sensitive
nature of substrate structures, the enantioselectivity and re-
action yield of each aldol reaction varies significantly.
In noncovalent bifunctional Brønsted acid–base mediated
asymmetric catalysis, the conventional wisdom is that non-
polar aprotic solvents are preferred since they can minimize
the interruption of interactions between the substrates and
the catalyst.[9] However, in our initial investigation of the
catalytic asymmetric Henry reaction of isatin (1a) with ni-
[a] L. Liu, Dr. S. Zhang, Dr. F. Xue, Dr. G. Lou, Dr. H. Zhang, S. Ma,
Prof. Dr. W. Duan, Prof. Dr. W. Wang
School of Pharmacy
East China University of Science and Technology
130 Mei-long Road, Shanghai 200237 (P.R. China)
[b] Prof. Dr. W. Duan, Prof. Dr. W. Wang
Shanghai Institute of Materia Medica
Chinese Academy of Sciences
555 Zuchongzhi Road, Shanghai 201203 (P.R. China)
[c] Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico
MSC03 2060, Albuquerque, NM 87131-0001 (USA)
Fax : (+1)505-277-2609
E-mail: wwang@unm.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101025.
Chem. Eur. J. 2011, 17, 7791 – 7795
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7791

Table 1. Exploration of the catalytic asymmetric Henry reaction of isatin
with nitromethane.[a]
Table 2. Scope of I-catalyzed nitroaldol reactions with isatins.[a]
X
R
R’
3
T
[h]
Yield ee
[%][b] [%]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3 f
3g
3h
3
3
3
2
2
3
4
99
99
99
99
99
99
99
91[c] (99)[d]
5-Me
5-MeO
4-Cl
5-Cl
6-Cl
7-Cl
5-F
92[c] (99)[d]
89[c] (98)[d]
74[c] (95)[d]
81[c] (97)[d]
80[c] (99)[d]
80[c] (99)[d]
89[c] (98)[d]
88,[c]10:1 d.r.[e]
1.5 99
12
Catalyst
Solvent
Additive
t [h]
Yield [%][b]
ee [%][c]
H
Me 3i
99
99
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
DMF
DMF
DMF
DMA
DMSO
THF
MeCN
DMA
DMA
DMA
none
none
none
none
none
none
none
none
none
none
none
none
none
H2O
PhCO2H
Na2HPO4
10
14
14
10
24
3
97
92
90
95
95
95
96
94
97
96
98
99
96
99
99
95
4
0
0
0
0
86
4
58
34
88
23
87
64
88
N
)
)
II
IV
V
VI
I
II
III
IV
I
I
I
I
I
10 6-Br
H
Me 3j
13
AHCTUNGTERNNUNG )
(94,[d] 4:1 d.r.[e]
11
12
13
14
H
H
H
H
Me
Bn
CH2CO2Me
H
H
H
H
Et
3k
3l
3m
2
3
2
99
99
99
99
86[c]
85[c]
83[c]
93,[c] 7:1 d.r.[e]
5
3n 16
AHCTUNGTRENNUNG
(95,[d] 10:1 d.r.[e]
10
12
3
[a] Unless specified, see the Experimental Section. [b] The yield was ob-
tained after workup. [c] This ee refers to the product without treatment
with CH2Cl2. [d] This ee refers to the product after treatment with
4
12
18
2
3
2
1
CH2Cl2. [e] Determined by H NMR spectroscopy.
I
I
91 (99)[d]
85
mine the scope of this asymmetric transformation. As re-
vealed in Table 2, the process proves to be a general strategy
for the synthesis of useful chiral 3-substituted 3-hydroxyox-
indoles (3) with significant structural variations. Impressive-
ly, in all cases, the reactions proceeded quickly (1.5–13 h), in
excellent yields (99%), without purification by chromatog-
raphy, and with good to high overall enantioselectivities
(74–93% ee). The crude product was sufficiently pure
(>95% purity) for yield calculation, characterization, and
chiral HPLC analysis. In the case of products obtained as a
solid (all except 3k–m, which are oils), the enantioselectivi-
ty could be further improved to excellent levels (94–99%,
Table 2, entries 1–10 and 14) by washing with CH2Cl2 (see
the Experimental Section for details). It should be noted
that, in some cases (e.g., products 3a–c, e, f, i, j, and n, ee
values shown in parenthesis), the obtained solid had a
higher enantiopurity based on chiral HPLC analysis. How-
ever, in the case 3d g, and h, the filtrate exhibited a higher
enantiopurity than the solid. It appears that isatins (1) with
electron-neutral and -donating substituents exhibit slightly
better enantioselectivity than those bearing electron-with-
drawing groups (Table 2, entries 1–3 and 11–13 vs. 4–8 and
10). If nitroethane (2b) or nitropropane (2c) was used as
the nucleophile, two stereogenic centers were created with
high ee (88, 84, and 93%) and good d.r. (10:1, 3:1, and 7:1;
Table 2, entries 9, 10, and 14). Again, the ee and d.r. values
could be further improved by washing the solid with
CH2Cl2. Finally, it seems that variation of the protecting
group on the N atom in isatins (1) had limited impact on
the enantioselectivity (Table 2, entries 11–13). The absolute
[a] Unless specified, see the Experimental Section. [b] Yield after
workup. [c] Determined by chiral HPLC analysis (Chiralpak AD-H).
[d] This ee refers to after the solid product was washed with CH2Cl2.
tromethane (2a) in the presence of various bifunctional or-
ganocatalysts (I–VI; Table 1),[10–12] we found that in nonpolar
aprotic CH2Cl2 very little enantioselectivity (0–4% ee) was
observed in spite of the high yields (Table 1, entries 1–5). In-
terestingly, high enantioselectivity (86%, Table 1, entry 6)
was obtained if the reaction was carried out in polar DMF
with cupreine (I),[9g,10] although catalysts II–IV[11] displayed
poor enantioselectivity (Table 1, entries 7–9). These studies
indicate that both the 6’- and 9-OH groups were critical for
the stereocontrol of the reaction (Table 1, entries 6–9). No-
tably, in DMF, the reaction time was significantly reduced
and the desired product 3a was produced in an almost quan-
titative yield (Table 1, entry 6). Probing the effect of solvent
(Table 1, entries 6, and 10–13) revealed that polar dimethyl-
ACHTUNGTRENNUNGacetamide (DMA) was optimal for the process (Table 1,
entry 10). Finally, an acidic additive, PhCO2H, was found to
be beneficial to the enantioselectivity of the Henry reaction
(91% ee, Table 1, entry 15). We found that pure product 3a
could be obtained in a high yield without column chroma-
tography after workup. Moreover, the enantioselectivity
could be further improved (99% ee) by washing the product
with CH2Cl2 (Table 1, entry 15).
Having established a standard reaction protocol, we then
probed a variety of isatins (1) and nitroalkanes (2) to deter-
7792
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Chem. Eur. J. 2011, 17, 7791 – 7795

Enantioselective Henry Reactions of Istatins
COMMUNICATION
nism underlying the biological
activities of phytoalexins. For
example, (À)-4, as a representa-
tive cruciferous phytoalexin, is
a useful model for the study of
a plantꢁs chemical and biochem-
ical defense mechanisms.[16]
Herein, we present the first
asymmetric synthesis of this
target
in
four
steps
(Scheme 3).[19]
A related approach to that of
the non-asymmetric version re-
ported by Kutschy, Monde, and
co-workers[19b] was explored to
find an asymmetric synthesis by
taking advantage of highly
enantioenriched adduct 3a. The
Figure 1. The X-ray crystal structure of compound 3j.
stereochemistry of the nitroaldol adducts was determined by
single crystal X-ray analysis of compound 3j (Figure 1).[13]
A transition state (TS) model was proposed to rationalize
the high enantioselectivity and the observed absolute config-
uration (R) of the cupreine-catalyzed Henry reaction
(Scheme 2). Bifunctional catalyst I enables the simultaneous
Scheme 3. A concise synthesis of (S)-(À)-spirobrassinin; py=pyridine.
nitro group in 3a (99% ee) was reduced by Pd-catalyzed hy-
drogenation to give amine 5 in 92% yield. Conversion of
the amino group to form dithiocarbamate 6 was achieved in
74% yield. No racemization was observed in this two-step
transformation. Finally, an intramolecular nucleophilic sub-
stitution reaction by treatment of (+)-dioxibrassinin (6) with
MsCl (Ms=mesylate) afforded the target (S)-(À)-spirobras-
sinin in 45% yield. A high enantioselectivity (88% ee) was
obtained for this nucleophilic substitution reaction at a ter-
Scheme 2. A proposed transition state for the reaction.
activation of nucleophile 1a through a base–acid interaction
and of electrophile 2a through the stronger double-hydro-
gen-bonding activation of the 6’- and 9-OH groups to deliv-
er product 3a with a high level of enantioselectivity, as ob-
served in the investigation. Moreover, the amino group di-
rects nitromethane 2a to a Re-face attack of isatin 1a to
give adduct 3a with the obtained R configuration.
To illustrate the synthetic utility of this methodology, we
undertook the total synthesis of (S)-(À)-spirobrassinin (4;
Scheme 3), a natural product isolated from Pseudomonas ci-
chorii inoculated Chinese cabbages and Japanese radishes in
1987.[14] The compound displays various biological properties
including plant defense,[15] antifungal,[16] and antitumor activ-
ities,[17] as well as oviposition stimulation.[18]. Therefore, a
concise total synthesis of this natural product could provide
a tool for access to analogues that may be valuable in bio-
medical studies that aim to elucidate the molecular mecha-
AHCTUNGTREGtNNNU iary carbon atom. Its optical purity can be increased to
99% ee by recrystallization. The spectral data for 4 are in
full agreement with those described in the literature ([a]2D5 =
À135.58 (c=0.4 in CH2Cl2); m.p. 140–1428C; literature:[19b]
[a]2D0 =À143.6 (c=0.25 in CH2Cl2, 92% ee); m.p.: 142–
1448C).
In conclusion, motivated by the “privileged” status of 3-
substitiuted 3-hydroxyoxindoles, we have developed the first
enantioselective synthesis of these compounds by using
Henry reactions employing readily available isatins and ni-
troalkanes. The process is efficiently catalyzed by a simple
natural product, cupreine, to give the aldol adducts in high
yields and with good to high enantioselectivities under mild
reaction conditions. This much less explored strategy[3o] rely-
Chem. Eur. J. 2011, 17, 7791 – 7795
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7793

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Experimental Section
General Procedure (Table 2): Compound 2 (5.0 mmol) was added to a
solution of 1 (1.0 mmol) and PhCO2H (12 mg, 0.1 mmol) in DMA (2 mL)
in the presence of catalyst I (30 mg, 0.1 mmol) at À158C. The mixture
was stirred at À158C for a specified time, monitored by utilizing the
color change to light yellow and by TLC until these indicated reaction
completion. An HCl solution (1n, 10 mL) was added to the reaction mix-
ture, which was then extracted with EtOAc (3ꢂ5 mL). The combined or-
ganic extracts were dried (Na2SO4), filtered, and concentrated in vacuo
to provide a light yellow solid (for products 3a–j and n Table 2, en-
tries 1–10 and 14) or oil (for products 3k–m Table 2, entries 11–13). The
product was sufficiently pure (>95% purity) for yield calculation, char-
acterization, and chiral HPLC analysis. Interestingly, it was found in
some cases that, when a product was obtained as a solid (Table 2, en-
tries 1–10 and 14), if it was washed with CH2Cl2 (3 mL) and then filtered
the collected solid had a higher enantiopurity based on chiral HPLC
analysis than prior to the washing (e.g., products 3a–c, e, f, i, j and n, ee
values shown in parenthesis in Table 2). However, in case of 3d, g, and h,
the filtrate exhibited a higher enantiopurity than the solid.
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Chem. Eur. J. 2008, 14, 8087; f) N. Hara, S, Nakamura, K. Kubo, N.
Shibata, T. Toru, Chem. Eur. J. 2009, 15, 6790; for some recent ex-
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Acknowledgements
We are grateful for financial support from the China 111 Project (Grant
B07023) and the “Thousand Talents” program of China.
Keywords: Henry reaction · isatins · natural products ·
organocatalysis · oxindoles
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Received: April 4, 2011
Published online: May 30, 2011
Chem. Eur. J. 2011, 17, 7791 – 7795
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7795