Dioxindole in asymmetric catalytic synthesis: Routes to enantioenriched 3-substituted 3-hydroxyoxindoles and the preparation of maremycin A

Article abstract of DOI:10.1002/anie.201107443

Taming the reactivity: Understanding the nucleophilicity of dioxindole under different reaction conditions is key to a direct and easy access to valuable spiro oxindole ? butyrolactones and 3-substituted 3-hydroxyoxindole derivatives in excellent yields and enantioselectivities (see scheme). The preparation of maremycin A serves as an example for the potential usefulness of this previously unexplored reactivity in natural product synthesis. Copyright

Full text of DOI:10.1002/anie.201107443

Angewandte
Chemie
DOI: 10.1002/anie.201107443
Synthetic Methods
Dioxindole in Asymmetric Catalytic Synthesis: Routes to
Enantioenriched 3-Substituted 3-Hydroxyoxindoles and the
Preparation of Maremycin A**
Giulia Bergonzini and Paolo Melchiorre*
Dedicated to Professor Giuseppe Bartoli
Many biologically active compounds and natural products
possess an oxindole framework with a hydroxy-bearing
tetrasubstituted stereogenic center at C3 (Scheme 1).[1] It
tively construct tetrasubstituted carbon stereocenters at the
C3 position of oxindole.[2,5,6] In contrast, dioxindole 1, which
would directly install the valuable hydroxy moiety at C3, has
never been used as a competent nucleophile in analogous
reaction pathways.[7] This is rather surprising, because the
electron induction of the hydroxy moiety could be expected to
increase the acidity of the hydrogen atom at C3 and the
propensity toward an alkylation pathway. Although such
reactions have not been reported,[8] we believed that dioxin-
dole could probably alkylate equally or more readily than 3-
alkyloxindoles. We thus investigated the reactivity profile of
compound 1 (easily derived from isatin by simple reduction)
under different reaction conditions in order to evaluate our
reasoning. Extensive studies are reported in Tables S1–S5 in
the Supporting Information, with selected results summarized
in Table 1. Scheme 2 provides a rationalization of our efforts,
which eventually allowed us to tame the inherently strong
nucleophilic character of dioxindole 1.
Scheme 1. Naturally occurring and biologically active 3-hydroxyoxindole
derivatives.
has been shown that a defined three-dimensional spatial
arrangement of this structural element greatly influences the
biological activity.[1a] This observation has provided the
impetus to develop highly stereoselective routes to this
particular target structure.
In the last few years, different catalytic asymmetric
methodologies have been reported, including metal-based
and organocatalytic methods.[2] These strategies mainly relied
on 1) nucleophilic additions to isatins,[3] 2) intramolecular
arylation reactions,[4] and 3) the direct hydroxylation of 3-
alkyl-substituted oxindoles.[5] Herein, we describe an unpre-
cedented synthetic strategy to access 3-substituted 3-hydroxy-
oxindole derivatives in excellent yields and enantioselectivi-
ties. At the heart of the study is the use of dioxindole 1 and the
possibility to channel its inherently high nucleophilicity
toward a productive reaction pathway.
Table 1: Understanding the dioxindole reactivity: selected optimization
studies.[a]
Entry
A
Additive
2
Yield [%][b]
ee [%][d]
[mol%] ([mol%])
[equiv] isatide[c] 3a+4a 3a/4a
1
2
3
4
5
6
–
–
5
5
5
1
0.5
1
DABCO (5)
quinine (5)
–
–
–
–
1.2
1.2
1.2
1.2
1.2
39[c]
37[c]
11[c]
6
<5
–
–
–
–
24
85
99
81
<5
–
–
–
The deprotonative activation of racemic 3-alkyl- or 3-aryl-
substituted oxindoles under basic conditions and the subse-
quent asymmetric addition to a number of electrophiles has
recently been identified as a versatile strategy to stereoselec-
–
96/97
97/97
97/97
97/97
n.d.
2-FBA (5)
2-FBA (50)
2-FBA (50)
2-FBA (1)
[*] Prof. Dr. P. Melchiorre
7
–
8[e]
12[c]
ICREA–Instituciꢀ Catalana de Recerca i Estudis AvanÅats
Passeig Lluꢁs Companys 23, 08010 Barcelona (Spain)
[a] Reactions performed on a 0.05 mmol scale using 1.2 equiv of 2 with
[2]0 =0.6m in acetone. All reactions afforded a poor diastereomeric
distribution (ranging from 1.4:1 to 1:1). A Michael addition/hemi-
acetalization sequence led to a mixture of the two anomers of hemiacetal
B. Oxidation of the crude mixture with PCC (3 equiv; CH2Cl2, 16 h) gave
the corresponding products 3a and 4a. [b] Yield determined by 1H NMR
analysis of the crude reaction mixture with 2,5-dimethylfuran as internal
standard. [c] The maximum yield for isatide is 50%, because two
oxindole units are merged. [d] ee values of isolated compounds 3a and
4a, n.d.=not determined. [e] [2]0 =0.06m in acetone. DABCO=1,4-
diazabicyclo [2.2.2]octane, 2-FBA=ortho-fluorobenzoic acid, PCC=
pyridine chlorochromate, TMS=trimethylsilyl.
G. Bergonzini, Prof. Dr. P. Melchiorre
ICIQ–Institute of Chemical Research of Catalonia
Avenida Paꢂsos Catalans 16, 43007 Tarragona (Spain)
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.es/portal/862/Melchiorre.aspx
[**] Support from the Institute of Chemical Research of Catalonia (ICIQ)
Foundation and from MICINN (grant CTQ2010-15513) is gratefully
acknowledged. G.B. is grateful to the MEC for an FPU predoctoral
fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107443.
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prevents reagent degradation.[13] The addition of an acid could
probably induce the formation of the more soluble enediol
intermediate III (Scheme 2, path b),[14] thus assuring a con-
stant yet low amount of nucleophile in the organic solvent.
Attempts to dilute the mixture to a concentration of 0.06m in
order to enhance the dioxindole solubility and avoid the large
excess of 2-FBA resulted in an incomparably lower reactivity
(Table 1, entry 8). For this reason, we selected the conditions
reported in Table 1, entry 6 (A: 1 mol%; 2-FBA: 50 mol%)
to evaluate the scope of the reaction.
A wide range of b-substituted enals are well-tolerated,
including differently substituted aryl groups as well as
heteroaryl, alkenyl, and alkyl moieties (Table 2). The spiro
oxindole g butyrolactones 3 and 4 were isolated in good to
high chemical yields with high to excellent enantiomeric
excess. As a limitation of the system, an ester moiety led to a
moderate level of enantioselectivity (Table 2, entry 11).
Although the conjugate addition proceeds with poor control
over the relative configuration,[15] the possibility to easily
isolate the two diastereoisomers for almost all of the adducts 3
and 4 by column chromatography testifies to the synthetic
utility of the process. The absolute and relative configuration
of the stereogenic centers of compound 3e was unambigu-
ously determined by anomalous dispersion X-ray crystallo-
graphic analysis.[16]
Scheme 2. Taming the dioxindole 1 reactivity: an oxidative enolate
coupling in the presence of a tertiary amine and traces of oxygen leads
to the formation of the dimeric isatide (path a). Milder reaction
conditions (i.e., the use of a secondary amine) preserve the intrinsic
high nucleophilic power of 1 (path b). B=base.
Exposure of a solution of dioxindole 1 in acetone to an
aerobic atmosphere in the presence of a base (e.g., a tertiary
amine such as DABCO or quinine, see entries 1 and 2 in
Table 1) led to the fast and almost quantitative formation of
isatide, the dimeric form of 1.[7b,9] This oxidative dimerization
pathway under basic conditions has already been report-
ed,[9a,b] and is driven by oxidation of the enolate intermediate I
to form an isatin radical II (Scheme 2, path a).[9]
With the aim of minimizing the oxidative coupling
pattern, we evaluated the compatibility of dioxindole with a
milder, less basic organic catalyst. We found that the chiral
secondary amine A[10] can indeed coexist with 1 (Table 1,
entry 3),[8] which is a necessary condition to preserve the
intrinsically nucleophilic character of dioxindole. This obser-
vation provided the foundation for the design of an unpre-
cedented direct catalytic asymmetric route to enantioen-
riched 3-substituted 3-hydroxyoxindoles.
Further investigations of the conjugate addition reaction
were carried out to delineate the scope of the nucleophilic
component. Dioxindole derivatives that bear different sub-
Table 2: Aldehyde substrate scope.[a]
Given the established ability of catalyst A to promote the
stereoselective conjugate addition of a variety of nucleophiles
to a,b-unsaturated aldehydes[10c] under iminium ion activa-
tion, we focused on the reaction between 1 and cinnamalde-
hyde 2.[11] The addition was followed by a fast hemiacetaliza-
tion, which led to a mixture of the two anomers of hemiacetal
B. Direct oxidation of the crude mixture with pyridine
chlorochromate (PCC) gave the corresponding spiro oxindole
g butyrolactones[12] 3a and 4a with high optical purity
(Table 1, entry 4). Rather unexpectedly, we observed that
use of ortho-fluorobenzoic acid (2-FBA) as a co-catalyst
induced a tremendous acceleration of the Michael addition,
while completely minimizing the amount of isatide, which was
formed through the oxidative pathway (Table 1, entries 5 and
6, and Tables S3 and S4). A large excess of 2-FBA (50 mol%
with regard to amine A) allowed us to reduce the amine
catalyst loading to 1 mol%, while maintaining high enantio-
selectivity and reactivity (the reaction reaches completion
over 16 h; Table 1, entry 6). Experimental observations
suggest that this uncommon reaction acceleration mainly
depends on solubility issues (see Figure S1 and Table S6 in the
Supporting Information). Indeed, under the reaction condi-
tions (initial concentration of aldehyde 2 is 0.6m in acetone)
the dioxindole is only partially soluble, a condition that
Entry
R1
Products
Yield [%][b]
total (3/4)
ee [%][c]
3/4
1
2
3
4
5
6
7
Ph
3a, 4a
3b, 4b
3c, 4c
3d, 4d
3e, 4e
3 f, 4 f
3g, 4g
98 (43/55)
63 (24/39)
89 (47/42)
92 (43/49)
93 (39/54)
65 (30/35)
91 (38/53)
97/97
97/98
88/92
94/98
97/98
96/97
99/99
4-MeO-C6H4
4-NO2-C6H4
2-NO2-C6H4
4-Cl-C6H4
2-furanyl
3-thiophenyl
8
3h, 4h
74 (39/35)
96/97
=
9
CH CHCH3
pentyl
CO2Et
3i, 4i
3j, 4j
3k, 4k
79 (29/50)
63
72
89/97
98/86
66/70
10[d]
11
[a] Reactions performed on a 0.2 mmol scale using 1.2 equiv of enal with
[2]0 =0.6m in acetone (ACS-grade reagent). All reactions afforded a poor
diastereomeric distribution (ranging from 1.5:1 to 1:1). [b] The total yield
of the spiro g butyrolactones (obtained by oxidation of the crude with
PCC) is reported; the values in brackets refer to the yield of isolated
diastereomerically pure compounds 3 and 4, which can be easily
separated by column chromatography on silica gel. The yields reflect the
degree of conversion. [c] Determined by HPLC analyses of isolated
compounds 3 and 4 on chiral stationary phases. [d] 5 mol% of both the
catalyst A and of 2-FBA was used. Boc=tert-butoxycarbonyl.
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stituents at the C5 and C7 positions performed well under the
reaction conditions (Table 3, entries 1–4), while the presence
of a substituent at the nitrogen atom slightly lowered the
Table 3: Scope of dioxindole derivatives.[a]
Entry
R1
R2
X
Product
Yield [%][b]
total (3/4)
ee [%][c]
3/4
1
2
3
4
Me
CF3O
Br
H
H
H
H
H
Br
H
N-H
N-H
N-H
N-H
N-Me
N-Bn
O
3l, 4l
89 (32/57)
92 (44/48)
64 (24/40)
93
67 (39/28)
92
97/97
97/93
96/96
95/95
90/94
95/95
96/97
3m, 4m
3n, 4n
3o, 4o
3p, 4p
3q, 4q
3r, 4r
5[d]
6[d]
7[d]
H
tBu
H
tBu
72 (30/42)
[a] Reactions carried on a 0.2 mmol scale using 1.2 equiv of cinnamal-
dehyde with [2]0 =0.6m in acetone. [b] The total yield of the spiro
g butyrolactones (obtained by oxidation of the crude with PCC) is
reported; the values in brackets refer to the yield of the isolated
diastereomerically pure compounds 3 and 4, which can be easily
separated by column chromatography on silica gel, see the Supporting
Information for details. [c] Determined by HPLC analyses of the isolated
compounds 3 and 4 on chiral stationary phases. [d] 5 mol% of the
catalyst A and of 2-FBA was used.
Scheme 3. DMAP=4-dimethylaminopyridine, pTSA=para-toluenesul-
fonic acid, THP=tetrahydropyranyl.
reactivity of the catalytic system, but preserved the high
enantioselectivity (Table 3, entries 5 and 6). Finally, we
demonstrated that a 3-hydroxy-substituted benzofuranone
derivative is also a competent substrate for the present
reaction (Table 3, entry 7).
The synthesized spiro oxindole g butyrolactones 3 and 4
are valuable, complex compounds.[12] However, the central
goal of our studies was to devise a novel and versatile strategy
to stereoselectively access 3-substituted 3-hydroxyoxindole
derivatives. Standard manipulations of the products easily led
to the target compounds 5 and 6 (Scheme 3a,b). A comple-
mentary approach to 3-hydroxyoxindoles 6a,b can be envis-
aged through the use of an O-protected dioxindole derivative
as the nucleophile[7] in the Michael addition, followed by a
simple reduction/deprotection sequence (Scheme 3c).
The application of a new synthetic strategy to streamline
the preparation of complex natural products is generally
considered an important validation of its synthetic potential
and usefulness. By exploiting the dioxindole reactivity, we
Scheme 4. Stereocontrolled synthesis of maremycin A. DIPEA=N,N-
diisopropylethylamine, HATU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetra-
methyluronium hexafluorophosphate, LDA=lithium diisopropylamide.
was followed by condensation with N-Boc-S-methyl-l-cystei-
ne.[17b] After purification, this reaction afforded compound 12
as a single stereoisomer. Maremycin A was finally accessed
after removal of the Boc protective group and formation of
the diketopiperazine ring[18b] in 15% overall yield starting
from dioxindole 7.
Understanding the reactivity of dioxindole under differ-
ent reaction conditions has allowed us to channel its
inherently high nucleophilicity toward a productive reaction
pathway. We believe that this previously unexplored reac-
tivity will rapidly find applications in the design of other
catalytic asymmetric transformations, thus opening new
envisioned a straightforward access to maremycin A,[17]
a
diketopiperazine alkaloid that was recently isolated from the
culture broth of marine Streptomyces species B 9173. Our
synthetic plan started with the addition of N-Me dioxindole 7
to crotonaldehyde on a gram scale (Scheme 4). After
oxidation with PCC, the major diastereoisomer of the spiro
oxindole g butyrolactone 9 was isolated by chromatography
in good yield and with 95% ee. Formation of the correspond-
ing lithium enolate and treatment with trisylazide gave azide
10,[18a] which has the desired three-dimensional arrangement,
as the major isomer (d.r. = 6.3:1). The Staudinger reaction
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[9] a) G. A. Russell, C. L. Myers, P. Bruni, F. A. Neugebauer, R.
Blankespoor, J. Am. Chem. Soc. 1970, 92, 2762; b) E. Ziegler, T.
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opportunities to access enantioenriched 3-substituted 3-
hydroxyoxindole derivatives.
Received: October 21, 2011
Published online: December 15, 2011
Keywords: asymmetric synthesis · molecular complexity ·
.
organocatalysis · oxindoles · spiro compounds
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was used as the solvent, a fast oxidative coupling occurred and
led to the formation of isatide as the main product (conditions:
[2]0 = 0.6m in DMSO, A (5 mol%), 2-FBA (5 mol%), 3 h, 22%
conversion to isatide; no hemiacetal product B detected).
[14] Both a tertiary amine and an acid are able to reduce the optical
purity of enantioenriched dioxindole 1 by promoting keto – enol
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