Radical Cyclizations for the Synthesis of Pyrroloindoles: Progress toward the Flinderoles

Article abstract of DOI:10.1021/acs.orglett.6b00768

Under the influence of Lewis acid catalysis, donor/acceptor cyclopropanes underwent nucleophilic ring opening by indolines. The resulting N-alkyl indolines bearing a pendant malonyl moiety oxidatively cyclized to 1,2-pyrroloindoles. This method was showcased by the preparation of the skeletal structure of the flinderoles.

Full text of DOI:10.1021/acs.orglett.6b00768

Letter
pubs.acs.org/OrgLett
Radical Cyclizations for the Synthesis of Pyrroloindoles: Progress
toward the Flinderoles
Joanne E. Curiel Tejeda, Bryan K. Landschoot, and Michael A. Kerr*
Department of Chemistry, The University of Western Ontario, London, Ontario, Canada, N6A 5B7
*
S Supporting Information
ABSTRACT: Under the influence of Lewis acid catalysis, donor/acceptor cyclopropanes underwent nucleophilic ring opening
by indolines. The resulting N-alkyl indolines bearing a pendant malonyl moiety oxidatively cyclized to 1,2-pyrroloindoles. This
method was showcased by the preparation of the skeletal structure of the flinderoles.
he pyrroloindole moiety is a substructure common to a
number of naturally occurring molecules of biological and
piperidine-fused products, two examples were included in
which a three carbon unit was installed on the nitrogen via a
cyclopropane ring opening.
In the context of a total synthesis of members of the
flinderoles, we sought to develop this chemistry further.
Scheme 1 shows a brief retrosynthesis of Flinderole C showing
T
medicinal importance. Perhaps the most notable of these is
Mitomycin C, a potent and clinically used chemotherapeutic
1
agent. The Flinderoles A−C are recently isolated antimalarial
2
bis-indoles, which have as a key structural feature a 1,2-
pyrroloindole (Figure 1). Several elegant syntheses of these
natural products have been reported.
3
Scheme 1. Retrosynthesis of Flinderole C
Figure 1. Representative 1,2-pyrrolindole derived compounds.
as a key sequence the ring opening of a cyclopropane 4 at a 4°
carbon by indoline nucleophile 3 and subsequent radical
cyclization of the adduct 2 to the pyrroloindole 1. In this letter
we report the success of this general strategy in the synthesis of
highly substituted 1,2-pyrroloindoles and the synthesis of the
complete heterocyclic framework of Flinderole C.
In this letter, we marry two research themes from our lab and
direct them to the development of an efficient pyrroloindole
synthesis: namely nucleophilic ring opening of donor−acceptor
4
5
cyclopropanes and the radical functionalization of indoles.
Several years ago we reported that indolines bearing a malonic
ester moiety tethered to the nitrogen underwent dehydrogen-
ation to an indole, oxidation to a malonic radical, and
subsequent cyclization onto the indole 2-position in a single
Figure 2 shows indolines 3a,b which were used as
8
nucleophiles in reaction with cyclopropanes 4a−h. The
optimum conditions were found to use Yb(OTf) (5 mol %)
3
6
operation. This was showcased in that report by preparing a
series of 1,2-annulated indoles and later by application to the
total synthesis of mersicarpine. While most examples were
Received: March 16, 2016
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©
XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b00768
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
If this method was to be useful in accessing targets such as
the flinderoles, cyclopropanes bearing a 4° center vicinal to the
diester moiety would be required (see Scheme 1). To this end,
we prepared a series of cyclopropanes 4i−m and treated them
with several indolines (3a,c,d) under Lewis acid catalysis. In
addition to Yb(OTf) as the catalyst, Sc(OTf) also emerged as
3
3
a viable promoter of this reaction. Figure 4 shows the results.
Figure 2. Nucleophilic ring opening of cyclopropanediesters by
indolines.
as the Lewis catalyst, in toluene at 110 °C. The reactivity of the
cyclopropanes toward nucleophilic ring opening is, to a large
degree, influenced by the ability of the group vicinal to the
diesters to stabilize a developing positive charge on the attached
carbon. This is reflected in the variation of the reaction times as
well as the yields in some cases. For example cyclopropane 4h,
in reaction with indoline 3a, required 24 h to undergo
consumption and resulted in a yield of only 24%. The steric
effect of the isopropyl moiety seems to override any electronic
benefit. Otherwise the yields were consistently good over a
range of aryl, heteroaryl, and vinyl substituents.
Figure 4. Nucleophilic ring opening of cyclopropanediesters at a 4°
center.
Using conditions previously found to be effective, attention
was turned to the cyclization of substrates 5−13 (Figure 3).
Based on our retrosynthesis of the flinderoles, acetylenic
cyclopropanes were studied; however, vinyl and phenyl
substituents were also tolerated. The vinyl cyclopropane 4m
underwent competitive polymerization and resulted in lower
yields. Indolines bearing a side chain capable of elaboration in
the context of flinderole synthesis also performed well in this
reaction yielding a 1:1 mixture of diastereomers. Since the
indolines were to be oxidized to indoles in the next step, this
was inconsequential.
Treatment with 5 equiv of Mn(OAc) in methanol at 70 °C
3
effected the tandem indoline to indole/oxidative malonic
radical cyclization to produce pyrroloindoles 14−22.
As expected, indolines 23−29 performed well in the
oxidative radical cyclization event yielding 1,2-pyrroloindoles
3
0−36. Figure 5 shows the results. It was worrisome to us at
the outset that the malonic radical may react in some way with
the pendant alkynyl moiety; however, this was unfounded. For
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the most part the yields paralleled their less substituted
counterparts.
In order to showcase this method in the milieu of total
synthesis, we targeted the heterocyclic substructure of the
flinderoles. To this end, the alkynyl moiety of 35 was
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hydrostannylated to yield vinylstannane 37 in 85% yield
(
Scheme 2). This compound was subjected to Stille coupling
conditions with N-tosylated 2-bromoindole to yield the
bisindolyl compound 38. With the skeletal structure of the
flinderoles secured in four steps, a series of functional group
manipulations (admittedly nontrivial) are necessary to convert
38 to the target molecule.
Figure 3. Oxidative radical cyclization of 5−13.
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DOI: 10.1021/acs.orglett.6b00768
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Letter
AUTHOR INFORMATION
■
*
Corresponding Author
E-mail: makerr@uwo.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council of Canada for funding. We are grateful to Mr. Doug
Hairsine of the University of Western Ontario Mass
spectrometry facility for performing MS analyses.
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ASSOCIATED CONTENT
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*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00768.
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Full experimental details and spectroscopic data for all
new compounds (PDF)
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