Lewis Acid Catalyzed Displacement of Trichloroacetimidates in the Synthesis of Functionalized Pyrroloindolines

Article abstract of DOI:10.1021/acs.orglett.6b02024

The pyrroloindoline core is found in many natural products. These structures often differ at the C3a position, which may be substituted with an oxygen, nitrogen, or sp³- or sp²-hybridized carbon. Utilizing a trichloroacetimidate leaving group, a diversity-oriented approach to these structures has been developed. The trichloroacetimidate intermediate allows for the rapid incorporation of anilines, alcohols, thiols, and carbon nucleophiles. This method was applied in the synthesis of arundinine and a formal synthesis of psychotriasine.

Full text of DOI:10.1021/acs.orglett.6b02024

Letter
pubs.acs.org/OrgLett
Lewis Acid Catalyzed Displacement of Trichloroacetimidates in the
Synthesis of Functionalized Pyrroloindolines
Arijit A. Adhikari and John D. Chisholm*
Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, New York 13244, United States
S
* Supporting Information
ABSTRACT: The pyrroloindoline core is found in many
natural products. These structures often differ at the C3a
position, which may be substituted with an oxygen, nitrogen,
or sp3- or sp2-hybridized carbon. Utilizing a trichloroacetimi-
date leaving group, a diversity-oriented approach to these
structures has been developed. The trichloroacetimidate
intermediate allows for the rapid incorporation of anilines,
alcohols, thiols, and carbon nucleophiles. This method was
applied in the synthesis of arundinine and a formal synthesis of psychotriasine.
flexible intermediates that allow for the rapid variation of
he pyrroloindoline ring system is found in many well-
1
Tknown alkaloids and cyclic peptides. These systems have functionality at this position. This expedites diversity-oriented
approaches to both natural and unnatural pyrroloindolines,
allowing for rapid synthesis and facilitating biological evaluation.
While selenides8 and sulfonium salts9 have been employed, the
bromide is most commonly utilized as a leaving group at the C3a
position with a number of approaches to pyrroloindoline natural
products taking advantage of this leaving group. Displacement of
C3a-bromo pyrroloindolines can be achieved with the use of
stoichiometric base, but these reactions typically only function
well when an ester is present at C2.10 Otherwise, silver salts are
often utilized,11 but these conditions often require the use of
superstoichiometric amounts of these expensive reagents. Single-
electron-transfer conditions have also been explored for
substitution of the bromide with carbon nucleophiles.12
become popular targets for total synthesis efforts that are driven
by the unusual structures and promising bioactivity presented in
many of these natural products.2 In assessing pyrroloindoline
natural products, the structures may be classified by the
substituent at the C3a position, which may be an sp3- or an
sp2-hybridized carbon (as in flustramine B (1)3 or asperazine
(2)4), an indole or indoline nitrogen (as in psychotriasine (3)5 or
kapakahine C (4)6) or the oxygen of an ether (like arundinine
57) (Figure 1).
Given that the C3a position is an important point of diversity
in these structures, significant effort has been directed toward
Our recent interest in the substitution chemistry of
trichloroacetimidates with oxygen, sulfur, and nitrogen nucleo-
philes13 led to the hypothesis that a C3a-trichloroacetimidate
pyrroloindoline could be utilized to synthesize a diverse library of
pyrroloindoline-based structures from a common starting
material.14 Relevant to this hypothesis, Sunazuka has recently
shown that a C3a-hydroxyfuroindoline trichloroacetimidate was
a competent electrophile under Lewis acid promoted con-
ditions.15 In order to explore this chemistry, a C3a-hydroxy
pyrroloindoline was required. While a number of methods have
been reported for the synthesis of C3a-hydroxypyrroloindoline-
s,8e,f,12a,16 the oxidation reported by Takayama and co-workers17
that employs m-CPBA and TFA seemed to provide the most
direct access. When protected tryptamine 6 was exposed to these
conditions, a 59% yield of pyrroloindoline 7 was obtained.
Protection of the indoline nitrogen and formation of the
trichloroacetimidate provided the C3a-trichloroacetimidate
pyrroloindoline 9 (Scheme 1).
Received: July 11, 2016
Figure 1. Some representative pyrroloindoline natural products.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02024
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Letter
Scheme 1. Synthesis of Imidate Pyrroloindoline 9
Table 2. Addition of Oxygen, Sulfur, and Carbon
Nucleophiles to Imidate 9
With an efficient route to imidate 9 established, nucleophilic
substitution at the C3a position of the pyrroloindoline (Table 1)
Table 1. Substitution of Imidate 9 with 4-Bromophenol 10a
a
entry
conditions
yield (%)
1
2
3
4
5
6
7
8
9
CSA, DCM, rt, 24 h
63
75
65
71
75
0
CSA, DCE, reflux, 1 h
TfOH, DCE, rt, 15 min
Cu(OTf)2, DCE, rt, 15 min
BF3·OEt2, DCE, rt, 10 min
BF3·OEt2, THF, rt, 10 min
BF3·OEt2, DME, rt, 10 min
BF3·OEt2, CH3CN, rt, 10 min
BF3·OEt2, MeNO2, rt, 10 min
31
29
47
a
10 mol % acid catalyst was used in all cases.
was explored. 4-Bromophenol (10a) was chosen as the
nucleophile for optimizing the displacement conditions since it
could serve as a model system for the synthesis of arundinine 5.
Brønsted acids were first utilized as catalysts for the displacement
reaction. Use of CSA at room temperature provided a sluggish
reaction, but heating to reflux in DCE provided 75% yield after 1
h. Using the more powerful TfOH provided an even faster
reaction at rt, but numerous side products were seen in the crude
1H NMR. The switch was then made to the Lewis acid
Cu(OTf)2, which was found to provide good yields of product.
Moving to the more powerful Lewis acid BF3·OEt2 provided an
even more rapid reaction giving 75% isolated yield of the desired
product, and these conditions were adopted for evaluating other
nucleophiles. Other solvents proved to be less effective,
providing lower yields of product.
a
Some apparent Friedel−Crafts products (∼14% for 13b, ∼33% for
b
1
14b) were observed in the crude H NMR. Reaction was performed
at reflux for 30 min. Reaction performed at reflux for 2 h.
c
Several other nucleophiles were then evaluated in substitution
reactions with imidate 9 (Table 2). Electron-poor phenols were
excellent substrates in this system, with more electron-rich
phenols giving more side products. At least some of these side
products were due to competing Friedel−Crafts alkylation
reactions. Aliphatic alcohols like 2-nitrobenzyl alcohol, meth-
anol, and allyl alcohol also proved to be excellent nucleophiles
and provided the corresponding ethers with very high yields
(Table 2, entries 6−8). Even the sterically encumbered dimethyl
propargyl alcohol 18a participated in the substitution, providing
18b in excellent yield. Thiol-based nucleophiles 19a and 20a also
yielded the corresponding thioethers with very high yields.
Given the presence of aryl, prenyl, and tert-prenyl groups at the
pyrroloindoline C3a position, some carbon nucleophiles that can
provide similar functionality were also evaluated. Dimethox-
ybenzene (21a) provided the Friedel−Crafts alkylation product
in 79% yield at room temperature in 10 min. Allyltributyltin 22a
had to be heated to reflux for 2 h to afford the alkylated product.
Prenyltributyltin 23a provided the reverse prenylated product
23b, a common motif in pyrroloindoline natural products, in
48% yield under similar reaction conditions. The moderate yield
in this case may be due to sterics, as the new carbon−carbon
bond is formed between two quaternary centers.
B
DOI: 10.1021/acs.orglett.6b02024
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Letter
Nitrogen-based nucleophiles were also evaluated (Table 3).
The displacement of imidate 9 with electron-poor anilines was
difficult to purify. Similar systems have been reported to be
unstable by other researchers.9a However, when 5-bromoindo-
line 31a or 5,7-dibromoindoline 32a was employed, satisfactory
yields were obtained (entries 8 and 9), as the bromine atoms
block the undesired alkylation of the aromatic ring and slow
oxidation of the indoline to the indole. Employing an indole
instead of the indoline provided a complex mixture of products.
After significant reoptimization, a 25% yield of the N-alkylated
product 33b could be isolated from the reaction mixture when
Cu(OTf)2 was used as the catalyst in mesitylene solvent. The
improved yield using Cu(OTf)2 may be attributed to a more
selective reaction with the weaker Lewis acid.
Table 3. Addition of Nitrogen Nucleophiles to Imidate 9
Access to aniline 29b and indole 33b led to a formal synthesis
of psychotriasine (3, Figure 1). Following a route similar to that
of Baran,18 aniline 29b was subjected to the Larock indole
synthesis affording indole 33b in 67% yield (Scheme 2). Removal
Scheme 2. Formal Synthesis of Psychotriasine 3
of the Cbz group then provided indoline 35, which intersected
Baran’s route to psychotriasine, completing a formal synthesis.
While utilizing the 2-iodoaniline as a nucleophile followed by
Larock indole synthesis results in higher yields, the direct
addition of indole 33a to imidate 9 provides a more expeditious
route.
This new method was also utilized in a synthesis of
arunidinine. Arunidinine (5) was first isolated by Abdullaev
and co-workers in 1998 from the giant reed Arundo donax.7 Key
to the synthesis of arunidinine is the formation of the ether
linkage at the C3a position of the pyrroloindoline, which may be
formed from imidate 9. As electron-poor phenols provided
higher yields, protected indole 36 was synthesized as the phenol
coupling partner (see the Supporting Information for the
synthesis of 36). Protection of the both tryptamine nitrogens
as 2-nitrophenylsulfonamides was anticipated to prevent N-
alkylation and deactivate the aromatic system, limiting side
products from Friedel−Crafts-type reactions. Reaction of phenol
36 with imidate 9 utilizing BF3·OEt2 gave only trace amounts of
product due to side reactions. Evidently, the Ns group was not
effective at deactivating the indole toward electrophilic side
reactions. Better results were obtained with Cu(OTf)2, and this
afforded the etherified product 37 in 47% yield. The nosyl groups
were then removed, with methylation of the aliphatic nitrogen to
providing 38 in 75% yield over two steps. Conversion of 38 into
arunidinine 5 was completed by removal of the Cbz group and
reduction of the methyl carbamate (Scheme 3). The product of
these transformations provided material that matched data
reported for the natural product.
a
b
Reaction was performed at reflux for 30 min. Some apparent
Friedel−Crafts products were observed in the crude 1H NMR (∼20%
c
for 28b, ∼26% for 30b, ∼19% for 31b). Excess imidate 9 was used
d
(1.3 equiv). Copper(II) triflate (30 mol %) was used in mesitylene
solvent for 22 h at rt.
rapid and high yielding at room temperature using BF3·OEt2
(entries 1−3). More electron-rich anilines had to be refluxed in
dichloroethane to provide the desired product, and the yields
tended to be more moderate. In some cases, using a slight excess
of the imidate provided an improved yield. Anilines with an
ortho-halogen substitution or an o-nitro group were well
tolerated. N-Methylaniline 30a provided a moderate yield of
the N-substituted product, with the N-substitution blocking the
nitrogen and leading to competitive Friedel−Crafts alkylation
reactions. Indoline was a competent nucleophile under these
conditions; however, the product decomposed readily and was
In summary, a convenient route to differentially substituted
pyrroloindolines at the C3a position using a common
trichloroacetimidate precursor has been demonstrated. Anilines,
alcohols, thiols, phenols, and carbon-based nucleophiles
provided moderate to high yields using only a catalytic amount
of a Lewis acid. A formal synthesis of psychotriasine and a total
synthesis of arundinine were also achieved using this new
C
DOI: 10.1021/acs.orglett.6b02024
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02024.
Full experimental procedures (including the synthesis of
indole 36) and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jdchisho@syr.edu.
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Hamza, D.; Kaiser, M. Bioorg. Med. Chem. 2015, 23, 2636. (b) For a
similar strategy with oxindole-based trichloroacetimidates, see:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Institute of
General Medical Sciences (R15-GM116054). NMR spectra were
obtained at Syracuse University using instrumentation acquired
with the assistance of the National Science Foundation (CHE-
1229345).
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