Oxidative dearomatization in the synthesis of erythrina, oxindole and hexahydropyrrolo[2,3-b]indole skeletons

Article abstract of DOI:10.1039/c001465f

New synthetic strategies leading to highly functional erythrina, oxindole and pyrrolidinoindoline skeletons have been developed and an efficient formal syntheses of (±)-demethoxyerythratidinone reported.

Full text of DOI:10.1039/c001465f

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Oxidative dearomatization in the synthesis of erythrina, oxindole and
hexahydropyrrolo[2,3-b]indole skeletonsw
Jixuan Liang, Jingbo Chen, Jianping Liu, Liang Li and Hongbin Zhang*
Received 21st January 2010, Accepted 23rd March 2010
First published as an Advance Article on the web 16th April 2010
DOI: 10.1039/c001465f
New synthetic strategies leading to highly functional erythrina,
oxindole and pyrrolidinoindoline skeletons have been developed
and an efficient formal syntheses of (Æ)-demethoxyerythratidinone
reported.
aromatization occurred, and afforded oxindole 11a in good
yield. To the best of our knowledge, there have been no reports
of this kind of transformation as exemplified by the sequential
alkylation and re-aromatization of intermediate 10 under
basic condition.3 It is noteworthy that a complex mixture
was produced when strong bases such as sodium hydride or
potassium tert-butoxide were used.
Over the past two years, our laboratory has been involved in a
research program concerned with the synthesis of bioactive
alkaloids. We are especially interested in developing a general
and flexible strategy towards the synthesis of natural product-
like compounds with erythrina, oxindole and pyrrolidino-
indoline ring systems. Recently we reported a process towards
the synthesis of spiro-cyclohexyldienonyl b-lactams from
amide derivatives of 4-aminophenol, with a new oxidative
formation of a carbon–carbon bond being the key feature.1
The potential of 4-aminophenol derived amides as a building
block for the synthesis of more complex alkaloid structures
was not fully explored in our previous research. We envisaged
that the same phenolic amide derivative might be used as a
starting material in the synthesis of stereochemically and
skeletally different frameworks such as highly functional
erythrina, oxindole and hexahydropyrrolo[2,3-b]indole ring
systems through an oxidative dearomatization strategy.
Herein, we report our results for the synthesis of erythrina
and oxindole skeletons from the same phenolic amide (1, see
Scheme 1), and spiro-oxindole and hexahydropyrrolo[2,3-b]-
indole ring systems from the same phenolic amide (1a).
A formal syntheses of (Æ)-demethoxyerythratidinone based
on our new method is also presented in this communication.
We began our research by treatment of 4-aminophenol, a
commercially cheap starting material (Aldrich 1kg/$157USD),
with homoveratroyl chloride.2 The product, amide 8, was then
converted to amine by a reduction with lithium aluminium
hydride. By treatment of amine 9 with ethyl 3-chloro-3-
oxopropanoate, the amide (1) was obtained in 50% yield over
three steps. The oxidative dearomatization process was then
conducted by treatment of amide 1 with iodobenzene diacetate
(IBD) in methanol. The tandem process, involving an oxidative
dearomatization followed by an intramolecular Michael
addition, led to cyclohexenone 10 (see Scheme 2). Without
further purification, compound 10 was then treated with allyl
bromide in THF in the presence of potassium carbonate at
70 1C (oil bath). To our pleasure, alkylation as well as
To get further insight of this process, a number of oxindoles
were then synthesized and the results are summarized in
Table 1. In comparison with our previous procedure,3 this
method is more flexible and efficient, and could also be applied
to the synthesis of oxindoles with acid sensitive functionalities
(Table 1, 11d).
Based on this new method, we then initiated the synthesis of
spirooxindole and pyrrolidinoindoline related skeletons,
with the aim of creating diverse core structures for medicinal
chemistry. Amide 1a was converted to compound 12
(53% yield over two steps) by an oxidative dearomatization–
conjugate addition with IBD in methanol followed by an
4
alkylation with tert-butyl-2-iodoethyl carbamate
in the
presence of potassium carbonate. Methylation of phenol 12
with dimethyl sulfate resulted in compound 13 in 88% yield.
With intermediate 13 in hand, we decided to remove the
protecting group (Boc) and conduct a lactamization. To our
surprise, treatment of carbamate 13 with HCl followed by
potassium carbonate in methanol under nitrogen resulted in
an unprecedented rearrangement, with oxindole 14 being
obtained (Scheme 3). In the presence of oxygen, however, this
process could lead directly to the formation of 3-hydroxy-
oxindole 15 in high yield (see Scheme 4).
Key Laboratory of Medicinal Chemistry for Natural Resource,
Ministry of Education, School of Chemical Science and Technology,
Yunnan University, Kunming, Yunnan 650091, PR China.
E-mail: zhanghb@ynu.edu.cn, zhang_hongbin@hotmail.com
w Electronic supplementary information (ESI) available: 1H NMR,
13C NMR spectra of all key intermediates and experimental details.
See DOI: 10.1039/c001465f
Scheme 1 Speculation for the synthesis of erythrina, oxindole and
pyrrolidinoindoline skeletons.
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Scheme 3 Rearrangement of oxindole 13.
Scheme 2 Synthesis of oxyindole with a full carbon quaternary
center.
Table 1 Oxindoles prepared under basic conditionsa
Substrate
R
Product
R1
Yield (%)
11a
11b
11c
Allyl
CH2Ph
i-Bu
52.6
48.0
46.9
10
Scheme
4
Synthesis of spiro-oxindole and pyrrolidinoindoline
10a
CH2Ph
11d
11e
51.3
related skeletons.
54.8
36.8
11f
n-Bu
a
b
Reaction conditions: see ESIw. Yields represent isolated yields over
two steps (average of two runs).
After rearrangement, oxidation of the enolate intermediate
led to the formation of 3-hydoxyloxindole 15. Reduction of 15
with lithium aluminium hydride afforded a C-3a hydroxy-
pyrrolidinoindoline (16) in 61% yield (Scheme 5). It is note-
worthy that compound 16 is a mimic of the natural alkaloid
CPC-1.5 The spirooxindole 17, might be used as an advanced
precursor for the total synthesis of horsfiline,6 was obtained by
treatment of compound 13 with trimethyl aluminium in
toluene.
Having successfully established the new method for the
synthesis of core structures for horsfoline and CPC-1, we then
turned our attention to the construction of a highly functional
erythrina skeleton from amide 1. The initial oxidative
dearomatization was carried out in dichloromethane, using
IBD as an oxidant. This reaction conditions unfortunately led
to a complex mixture. We then tried the oxidation with IBD in
Scheme 5 Synthesis of erythrina alkaloid.
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trifluoroethanol at À40 1C.7 To our delight, we were able to
access the desire product in 15% yield. Finally, an optimized
‘‘one pot’’ procedure was established, the erythrina type
compound (3) was obtained in 82% isolated yield after an
oxidative carbon–carbon coupling (PIFA) followed by a
Michael addition (K2CO3) in trifluoroethanol (Scheme 5).8
Only one diastereomer was isolated in this sequential step
and the relative stereochemistry, shown in Scheme 5, was
established by a NOE experiment.
Notes and references
1 J. Liang, J. Chen, F. Du, X. Zeng, L. Li and H. Zhang, Org. Lett.,
2009, 11, 2820.
2 The homoveratroyl chloride was generated by treatment of homo-
veratric acid with oxalic chloride in dichloromethane in the presence
of DMF, for examples, see: C. D. Gilmore, K. M. Allan and
B. M. Stoltz, J. Am. Chem. Soc., 2008, 130, 1558.
3 Although we have reported a procedure leading to oxindoles with a
quaternary carbon center, introduction of an alkyl substituent to the
a-position of the two carbonyl groups in amide (1, or 1a) before
conducting the oxidative dearomatization is obviously a drawback
and decreases the flexibility of the method (see ref. 1).
4 tert-Butyl-2-iodoethylcarbamate was prepared by following
literature procedure: C. Hunter, R. F. W. Jackson and H. K. Rami,
J. Chem. Soc., Perkin Trans. 1, 2000, 219.
5 M. Kitajima, I. Mori, K. Arai, N. Kogure and H. Takayama,
Tetrahedron Lett., 2006, 47, 3199.
6 A similar intermediate has been used for the synthesis of horsfiline,
see: B. M. Trost and M. K. Brennan, Org. Lett., 2006, 8, 2027.
7 Oxidative coupling with IBD or PIFA in trifluoroethanol at À40 1C
was well documented in Kita’s synthesis of maritidine and Node’s
synthesis of galanthamine. See (a) Y. Kita, T. Takada, M. Gyoten,
H. Tohma, M. H. Zenk and J. Eichhorn, J. Org. Chem., 1996, 61,
5857; (b) S. Kodama, Y. Hamashima, K. Nishida and M. Node,
Angew. Chem., Int. Ed., 2004, 43, 2659.
8 Characteristic NMR peaks for compound 3 are a doublet signal
(J = 11.7 Hz) at 3.38 ppm (proton signal at C7 position) in the H
NMR spectrum and a quaternary carbon resonance at 59.5 ppm
(carbon signal at C5 position) in the 13C NMR spectrum.
9 (a) Y. Tsuda, A. Nakai, K. Ito, F. Suzuki and M. Haruna, Hetero-
cycles, 1984, 22, 1817. For selective synthesis of erythrina alkaloids,
see: (b) F. Zhang, N. S. Simpkins and C. Wilson, Tetrahedron Lett.,
2007, 48, 5942; (c) W. H. Pearson, J. E. Kropf, A. L. Choy, I. Y. Lee
and J. W. Kampf, J. Org. Chem., 2007, 72, 4135; (d) S. Gao,
Y. Q. Tu, X. Hu, S. Wang, R. Hua, Y. Jiang, Y. Zhao, X. Fan
and S. Zhang, Org. Lett., 2006, 8, 2373; (e) Q. Wang and A. Padwa,
Org. Lett., 2006, 8, 601; (f) A. Padwa and Q. Wang, J. Org. Chem.,
2006, 71, 7391; (g) G. Kim, J. H. Kim and K. Y. Lee, J. Org. Chem.,
2006, 71, 2185; (h) P. C. Stanislawski, A. C. Willis and
M. G. Banwell, Org. Lett., 2006, 8, 2143; (i) S. M. Allin,
G. B. Streetley, M. Slater, S. L. James and W. P. Martin, Tetrahedron
Lett., 2004, 45, 5493; (j) A. Padwa, H. I. Lee, P. Rashatasakhon and
M. Rose, J. Org. Chem., 2004, 69, 8209; (k) S. A. A. El Bialy,
H. Braun and L. F. Tietze, Angew. Chem., Int. Ed., 2004, 43, 5391;
(l) Y. Yasui, K. Suzuki and T. Matsumoto, Synlett, 2004, 619.
This cyclization established the tricyclic ring system and
provided a highly functional Erythrina skeleton in an efficient
way (four steps for Erythrina derivative 3). Compound 3 was
further manipulated, hydrogenation followed by decarboxyla-
tion, to a known intermediate for the synthesis of natural
erythrina alkaloid (Æ)-demethoxyerythratidinone (Scheme 5),
thus furnished a formal synthesis.9
a
In conclusion, we have explored in this research new
approaches towards the synthesis of structurally diverse
molecules starting from phenolic amide derivatives (1, 1a).
With an oxidative dearomatization as the key step, we have
developed a practical, efficient and flexible method for the
synthesis of oxindoles, hexahydropyrrolo[2,3-b]indole ring
and erythrina skeletons. We also disclosed an interesting
rearrangement in this research for the first time. Based on
the new methodology, we have completed a formal synthesis
of natural demethoxyerythratidinone. The highly functional
erythrina and pyrrolidinoindoline derivatives generated in this
research could be used not only as intermediates for the
synthesis of natural alkaloids, but also as building blocks in
the synthesis of natural product-like compounds for the inter-
ests of medicinal chemistry.
1
This work was supported by grants from Natural Science
Foundation of China (20832005, 20925205), National Basic
Research Program of China (973 Program 2009CB522300)
and Natural Science Foundation of Yunnan Provincial
Science & Technology Department (2006B0003M).
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This journal is The Royal Society of Chemistry 2010
3668 | Chem. Commun., 2010, 46, 3666–3668