Efficient assembly of 3-substituted oxindole-based isoxazolines leading to the synthesis of (±)-flustraminol-B and related natural product building blocks

Article abstract of DOI:10.1016/j.tetlet.2012.07.005

An efficient synthesis of oxindole-based isoxazolines has been developed and the resulting spirocyclic intermediates have been elaborated to synthetically versatile 3-hydroxy-3-alkyl oxindole building blocks such as the 3-hydroxy-3-methylenecyano-2-oxindo

Full text of DOI:10.1016/j.tetlet.2012.07.005

Tetrahedron Letters 53 (2012) 4889–4891
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Tetrahedron Letters
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Efficient assembly of 3-substituted oxindole-based isoxazolines leading
to the synthesis of ( )-flustraminol-B and related natural product building
blocks
⇑
Anand Singh, Gregory P. Roth
Sanford-Burnham Medical Research Institute at Lake Nona, 6400 Sanger Road, Orlando, FL 32827, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of oxindole-based isoxazolines has been developed and the resulting spirocyclic
intermediates have been elaborated to synthetically versatile 3-hydroxy-3-alkyl oxindole building blocks
Received 15 June 2012
Accepted 2 July 2012
Available online 11 July 2012
such as the 3-hydroxy-3-methylenecyano-2-oxindoles (6) and
c-amino alcohols (12). Utility of this
methodology is demonstrated through the synthesis of pyrrolo[2,3-b]indolines including the marine
natural product ( )-flustraminol-B.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
[3+2] Cycloaddition
Isoxazoline
3-Hydroxy oxindole
Amino alcohols
Pyrrolo[2,3-b]indolines
Functionalized oxindole-based small molecules represent an
important natural product scaffold cluster by virtue of their bioac-
tivity and as intermediates for generating further molecular
complexity (Fig. 1).1 Isoxazolines are prevalent as biologically inter-
esting molecules and our goal was to develop an efficient and con-
venient synthesis of oxindolyl spiro-isoxazolines and explore their
utility as synthetic intermediates.2 Herein, we demonstrate the
application of a [3+2] cycloaddition reaction toward the synthesis
of novel oxindole-based spirocyclic derivatives with subsequent
elaboration to 3,3-disubstituted oxindoles and pyrrolo[2,3-b]indo-
line-based natural product scaffolds. In order to exemplify a meth-
H
N
O
OH
HN
N
HO
HN
NH
H
N
O
O
HO
O
O
N
O
O
O
N
H
CONH2
N
2
O
NH
HO
O
N
H
H
O
Cl
NH
N
H
H
N
H
OH
OMe
O
TMC-95A
Chloptosin
HO
Br
odology involving 3-hydroxy-disubstituted oxindoles,
a
total
HO
AcO
COMe
O
synthesis of the marine bryophyte metabolite ( )-flustraminol-B3
has been accomplished.
N
H
NH
Me
N
Br
Flustraminol-B
N
H
N H
Br
Our preliminary investigation of [3+2] cycloaddition reactions
between nitrile oxide precursor 2 and substituted 3-methylene-
oxindoles revealed that the primary challenge was to engage the
two very reactive precursors in a predictable and productive man-
ner. Generation of the dipole prior to its introduction in the reaction
using Amberlyst A21™ (basic resin) provided higher yields than the
use of Et3N or Hünig’s base in the reaction flask. While the use of a
basic resin provided initial utility, it was determined to be inconve-
nient, impractical, and expensive for scale-up. We envisioned that
performing the reaction in a biphasic medium with a water soluble
base might result in an equally effective reaction which would also
H
Convolutamydine A
HKI00504
Figure 1. Natural products featuring motifs derived from 3-hydroxy oxindoles.
be amenable to scale-up. Indeed, a reaction performed with NaHCO3
under biphasic conditions (CH2Cl2/H2O) afforded the product in
significantly improved yields even as the stoichiometry of the di-
pole was decreased (Table 1).
A comparative examination of the scope of this cycloaddition,
with respect to the dipolarophile, revealed that yields were consis-
tently higher under the biphasic conditions. Substitutions at all
positions of the oxindole were tolerated well and high yields and
⇑
Corresponding author. Tel.: +1 407 745 2062; fax: +1 407 745 2001.
E-mail address: groth@sanfordburnham.org (G.P. Roth).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.005

4890
A. Singh, G. P. Roth / Tetrahedron Letters 53 (2012) 4889–4891
Table 1
CN
Nitrile oxide cycloaddition: reaction optimization
KOAc
OH
MeOH-H2O
EtO C
2
EtO2C
R
O
100 °C, µW
(R = H; 83%)
(R = 6-Br; 81%)
HO
N
O
N
H
N
O
N
CH Cl (0.2 M)
2
2
6
O
base
N
H
Cl
CO Et
2
O
EtO2C
O
N
H
1
2
3
NHBoc
OH
N
H
NiCl2, NaBH4
(Boc)2O
MeOH
0 °C to rt
(74%)
Entrya
Dipole Eq.
Base
Time (h)
Yieldb (%)
3a
O
1
2
3
4
5
1
3
1
2
3
Amberlyst A21
Amberlyst A21
NaHCO3
NaHCO3
NaHCO3
15
15
15
15
15
33
80
61
92
97
N
H
7
Scheme 1. Isoxazoline ring opening.
a
For entries 1 and 2, a solution of the dipole precursor was added to the reaction
through a syringe filled with Amberlyst 21.
b
Isolated yields.
CONH2
OH
1.
N
Br
Cs2CO3
CH3CN, DMF, rt
Table 2
OH
O
N
Scope of the nitrile oxide [3+2] cycloaddition reaction
O
Br
H2O2, Cs2CO3
EtOH, H2O, rt
(63% overall)
2.
R2
N
H
Br
8
9
Amberlyst A21
HO
N
O
N
CH2Cl2, rt
R1
O
or
R2
O
N
H
R1
O
Cl
NaHCO3
HO
N
CH2Cl2/H2O, rt
1
2
3
AlH3•Me2NEt
H
AlH3•Me2NEt
NH
THF, rt
(69%)
THF, -15 °C
(73%)
N
H
Entry
Ra
Rb
Yielda,b (%)
Yielda,c (%)
rrd
Br
10a
1
2
3
4
5
6
7
8
9
10
H
CO2Et 3a
CO2Et 3b
CO2Et 3c
CO2Et 3d
CO2Et 3e
CO2Et 3f
Ph 3g
4-BrPh 3h
4-CF3Ph 3i
3-OMePh 3j
80
66
50
82
84
72
81
77
79
73
93
89
86
91
92
83
89
88
86
90
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
4-Br
5-Cl
6-Br
7-Br
HO
HO
N
NMe
NH HCHO, MeOH
4,6-di-Br
N
H
H
H
H
H
then
H
Br
Br
NaBH3CN
10b
11
(77%)
a
b
c
Isolated yields.
( )−Flustraminol-B
Using Amberlyst resin as base.
Using NaHCO3 base.
Scheme 2. Synthesis of ( )-flustraminol-B.
d
Regioisomer ratios (rr) were measured using 1H NMR.
hydrolysis followed by a decarboxylative elimination affording
3-hydroxy-3-cyanomethyl oxindoles 6. An alternative reductive
ring opening pathway can be accessed by employing the NiCl2–
NaBH4 system to furnish the amino alcohol 7 in good yield. Con-
comitant protection of the aminoester can be achieved by perform-
ing the reduction in the presence of (Boc)2O. The use of NiCl2–
NaBH4 provides a critical control of reducing ability such that the
ester and oxindole functionality are unaffected.
We envisioned the b-hydroxynitriles as a gateway to access
oxindole and pyrrolidinoindoline derivatives featuring different
oxidation states. These transformations, as applied to a synthesis
of ( )-flustraminol-B, are illustrated in Scheme 2. Base mediated
prenylation of hydroxynitrile 8 afforded the desired precursor for
cyclization. The presence of the bromine substituent precludes
the use of strong hydride donors to reduce the cyano moiety. In-
deed, attempts to synthesize the pyrrolidinoindoline, using a direct
reduction–cyclization sequence using LiAlH4 or Red-Al, resulted in
aromatic debromination. To circumvent this problem, we em-
ployed carefully controlled peroxide promoted hydrolysis of the
nitrile to yield the primary amide 9.6 This hydrolysis could also
be achieved using a protocol employing sodium peroxide (Na2O2)
but the yields obtained were inconsistent.7 Amide 9 was then
cyclized to the tricyclic derivative 10a using AlH3–Me2NEt
(alane–amine complex).
excellent regioselectivity were obtained. The 4,6-dibromo-substi-
tuted derivative, found in certain natural products,1a also per-
formed well (entry 6; Table 2). Reactions typically performed on
up to a gram scale provided the spiro-isoxazoline in 90% yield
(entry 1). To further the reaction scope we synthesized and evalu-
ated various hydroxyiminoyl chlorides in order to access additional
novel oxindole based isoxazolines.4 As depicted in Table 2, elec-
tronically distinct nitrile oxides provided the corresponding isox-
azoline derivatives with good yields and as single regioisomers. A
comparative analysis of reactions performed using Amberlyst™
resin and NaHCO3 (biphasic conditions) as bases revealed that
yields were higher for the latter.
Having established a convenient method for the synthesis of
novel oxindolyl isoxazolines, we sought to functionalize these spi-
rocycles to generate high value natural product building blocks.
Although simple isoxazolines can be functionalized using a wide
array of reagents, presence of the oxindole moiety limits the
choices due to chemoselectivity concerns. Indeed, the use of com-
monly used reagents such as H2/Pd, boranes, and samarium iodide
either afforded undesired products or led to complex mixtures.2a
We have demonstrated that these spiro-isoxazolines can be elabo-
rated to useful motifs using two distinct pathways (Scheme 1).5
The first transformation is a one-pot sequence involving ester

A. Singh, G. P. Roth / Tetrahedron Letters 53 (2012) 4889–4891
4891
R
Acknowledgments
R
N
O
NHBoc
We thank SBMRI for financial support to GPR and Dr. David
Terry (SBMRI) for obtaining accurate mass data.
NiCl2, NaBH4, (Boc)2O
MeOH, 0 °C to rt
OH
O
O
N
N
R1
12
3
R1
Supplementary data
dr1
CO2Et 12a 2.3:1
Yield2 (%)
entry
R1
R
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.
005.
1
2
3
4
5
H
Me
H
H
H
74
79
80
76
75
12b
CO2Et
Ph
2.1:1
12c 2.5:1
4-CF3Ph 12d
12e
3:1
2.0:1
References and notes
3-OMePh
1
1
2
Diastereomer ratios were measured using H NMR. Isolated Yieds.
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Cyclization of Aminoalcohol 12b to the Pyrrolidinoindoline 13
EtO2C
CO2Et
NBoc
NHBoc
HO
AlH3•Me2NEt
THF, -15 °C
(73%)
OH
O
N
H
N
Me
Me
12b
13
Scheme 3. Conversion of isoxazolines to amino alcohols and the pyrrolo[2,3-
b]indoline scaffold.
Subjecting the tricyclic amide 10a to alane reduction again at a
higher temperature afforded the desired pyrrolidinoindoline core
in 69% yield. The requisite N-methyl group was installed by reduc-
tive amination to provide ( )-flustraminol-B. The amenability of
the nitrile functionality to undergo a plethora of redox transforma-
tions renders these building blocks suitable for the generation of
small libraries of natural product derivatives.
The conversion of isoxazolines to the corresponding amino alco-
hols was further explored by synthesizing various substituted oxi-
dized tryptophan derivatives (Scheme 3). The reduction worked
reliably for a variety of substituted isoxazolines and produced a
separable mixture of diastereomers. Streamlined access to oxin-
dole-based amino alcohols has provided us with an opportunity
to develop further transformations such as a reductive cyclization
to access the pyrrolo[2,3-b]indoline moiety featuring a pendant
carboxylic ester group (13). This work represents a stepping stone
for future applications that include analog synthesis of natural
products chloptosin and NW-G01 while avoiding inefficient syn-
thesis of substituted tryptophan starting materials.8 As a prelimin-
ary example, subjecting amino alcohol 12b to AlH3–Me2NEt
resulted in a smooth cyclization leading to the tricyclic derivative
13.
In summary, the [3+2] cycloaddition reaction platform was used
to develop a practical, efficient, and scalable synthesis of novel
oxindole-based spiro-isoxazolines. Application of these heterocy-
cles toward generating an ensemble of synthetic building blocks
is demonstrated. Efforts to apply these transformations to generate
a diverse array of advanced natural product derivatives are
underway.
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