Total Synthesis of (+)-Raputindole A: An Iridium-Catalyzed Cyclization Approach

Article abstract of DOI:10.1021/acs.orglett.0c01943

This work describes the total synthesis of raputindole A (1) through a convergent approach that features (1) an iridium-catalyzed cyclization to assemble the tricyclic core of the northern part, (2) enzymatic resolution to secure the preparation of an enantiomerically pure benzylic alcohol intermediate, and (3) the installation of the isobutenyl side chain via methallylation of the corresponding benzylic carbocation and coupling of the northern and southern parts via the Heck reaction. (+)-Raputindole A (1) was prepared in 10 steps (longest linear sequence) in 3.3% overall yield.

Full text of DOI:10.1021/acs.orglett.0c01943

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Letter
Total Synthesis of (+)-Raputindole A: An Iridium-Catalyzed
Cyclization Approach
Juliana L. L. F. Regueira, Luiz F. Silva, Jr., and Ronaldo A. Pilli*
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ABSTRACT: This work describes the total synthesis of raputindole A (1) through a convergent
approach that features (1) an iridium-catalyzed cyclization to assemble the tricyclic core of the
northern part, (2) enzymatic resolution to secure the preparation of an enantiomerically pure
benzylic alcohol intermediate, and (3) the installation of the isobutenyl side chain via methallylation
of the corresponding benzylic carbocation and coupling of the northern and southern parts via the
Heck reaction. (+)-Raputindole A (1) was prepared in 10 steps (longest linear sequence) in 3.3%
overall yield.
C (5) is another member of this family, which was isolated in
2011 from Raputia praetermissa, collected in the Brazilian
Amazon forest.2 Structurally, this is a rare new class of indole
alkaloid as it features unsubstituted N-1, C-2, and C-3
positions.1 Other natural products containing the 1,2,3-
unsubstituted pattern are trikentrin A3 and the alkaloids
from the herbindole family.4 Another feature of some of the
representatives of this rare alkaloid class is the presence of a
linear 1,5,6,7-tetrahydrocyclopenta[f ]indole scaffold, as in
shearinine D5 and in (+)-nodulisporic acid A.6 A third
structural feature of raputindole A (1) is the presence of a bis-
prenylated bisindole core, as in the antimalarial alkaloids
flinderoles A−C7 which can conceivably be traced back to the
cyclization of two isoprenyl groups. Other examples of
bisindole alkaloids include spongotine A,8 caulindoles,9 and
dragmacidin D,10 which, unlike raputindoles, have their indole
moieties connected via the C-3 (spongotine A and
dragmacidin D) or C-5 (caulindoles) position. Because of
these unusual structural features, the raputindoles have
attracted the attention of natural product and synthetic
chemists.11
aputindole A (1) was isolated in 2010 from Raputia
Rsimullans kalunki, a tree found in the Peruvian Amazon
rainforest, along with raputindoles B (2), C (3), and D (4) and
displayed moderate inhibitory activity of CDK2, GSK-3B, and
DYRK1 kinases (IC50 > 10 μM, Figure 1).1 Deoxiraputindole
The absolute stereochemistry of raputindole A (1) was
determined in 2017, with its first total synthesis accomplished
by Lindel and coworkers.12 Their synthetic route involved a
Received: June 10, 2020
Figure 1. Bisindole alkaloids of the raputindole family.
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Au(I)-catalyzed cyclization to access the linear tricycle and a
Pd-catalyzed installation of the isobutenyl side chain. However,
low diastereoselectivity was observed in the indene catalytic
hydrogenation to install the stereogenic center at C-7. To solve
this critical step, in 2018, the same group published a
diastereoselective total synthesis of raputindole A (1).13 In
addition to the Au(I)-catalyzed assembly of the cyclo-
pentaneindole moiety, this second approach featured an
iridium-catalyzed asymmetric hydrogenation of the indene
double bond guided by a preinstalled hydroxyl function, a
Suzuki−Miyaura cross-coupling to join the two indole
moieties, and the final oxidation of the indoline precursor.
Our total synthesis of raputindole A (1) aimed to avoid the
use of an indoline as a surrogate of the indole ring because it
would require additional steps, including a late-stage oxidation
of an indoline intermediate. Instead, our strategy features the
use of N-tosyl indoles in both the northern and southern parts
of the structure, an iridium-catalyzed diastereoselective
cyclization,14 a methallylation reaction to install the isobutenyl
side chain at C-7, and a Heck cross-coupling reaction to build
the raputindole A (1) scaffold. It is noteworthy that our
approach incorporates an enzymatic resolution step that allows
us to obtain (+)-raputindole A (1).
could also allow for the total syntheses of raputindole B (2)
and deoxiraputindole C (5).
The commercially available 5,6-disubstituted indole 8 was
protected as the corresponding N-tosyl derivative, followed by
the diisobutylaluminium hydride (DIBAL-H) reduction of the
methyl ester and benzylic oxidation with manganese dioxide,
en route to aldehyde 11 (three steps, 95% overall yield,
Scheme 2). To install the necessary boronic acid, a Miyaura
Scheme 2. Iridium-Catalyzed Preparation of Linear
Tricyclic Indole ( )-6 and Its Enzymatic Resolution
a
Our disconnection relies on a convergent approach where
the northern and southern parts are connected via a Heck
coupling reaction (Scheme 1). The isobutenyl side chain
Scheme 1. Retrosynthetic Analysis for Raputindole A (1)
a
(a) TEBAC (0.1 equiv), NaOH (1.75 equiv), TsCl (1.10 equiv),
DCM, rt, 2.5 h, 95%. (b) DIBAL-H (2.0 equiv), DCM, 4.5 h, 0 °C −
rt, >99%. (c) MnO2 (18.0 equiv), DCM, rt, 5 h, >99%. (d)
Pd(Cl)2(dppf) (0.05 equiv), KOAc (3.0 equiv), B2(pin)2 (1.2 equiv),
dioxane, 80 °C, 16 h, 95%. (e) H2O (10.0 equiv), THF/toluene (1:1),
[Ir(Cl)(COD)]2 (0.05 equiv), Et3N (1.25 equiv), isoprene (10.0
equiv), THF/toluene (1:1), 80 °C, 24 h, 94%. (f) Vinyl acetate (4.0
equiv), CALB (2:1 mass ratio g/g), toluene/MTBE (8:2 v/v), 64 °C,
34 h, 30% of (S,S)-13 and 36% of (R,R)-6, ee >99%.
borylation was employed using Pd(Cl)2(dppf) and bis-
(pinacolato)diboron, which provided pinacol ester 12 in 95%
yield after silica gel chromatography.17 In 2007, Hayashi and
coworkers disclosed an iridium-catalyzed [3 + 2]-annulation of
dienes with ortho-carbonylated phenylboronic acids.14 We
decided to apply this methodology, which, to the best of our
knowledge, has so far not been applied to the total synthesis of
a natural product. Initial attempts to use boronic acid 7 as the
substrate in this cyclization provided indole 6 in 36% yield, and
we then decided to explore the in situ generation of boronic
acid 7 via the hydrolysis of pinacol ester 12. It is worth noting
that this one-pot approach proceeded regio- and diastereose-
lectively, providing the racemic linear tricyclic indole ( )-6 in
94% yield as the key synthetic intermediate in our approach.18
According to the mechanistic proposal put forth by Hayashi
and coworkers,14 the formation of indolyliridium(I) species B
is followed by the coordination of isoprene to the metallic
would be installed by the methallylation of the linear tricyclic
indole 6 with methallyltrimethylsilane.15 The northern part
would come from boronic acid 7, to be prepared from
commercially available bromoindole 8. An iridium-catalyzed
cyclization with isoprene would provide the linear tricyclic N-
tosyl indole 6, according to the methodology described by
Hayashi and coworkers for representative boronic acids.14 The
southern part required the use of indole 9 to be prepared via a
Batcho−Leimgruber protocol.16 This convergent approach
B
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center (intermediate C) and the addition of the electron-rich
terminal double bond to the activated carbonyl, leading to the
π-allyliridium(III) complex D (Scheme 3). Reductive elimi-
nation affords iridium(I) alkoxide E, which is hydrolyzed to
cyclopenta[f ]indole ( )-6 with the regeneration of the
catalytic species. The relative stereochemistry depicted for
( )-6 was confirmed later on at the stage of the bisindole 15
(Scheme 4) through the irradiation of its carbinolic proton (δ
5.38), which led to an increment in the signal of the methyl
group at C-5 (δ 1.47; see the SI). Overall, the implemented six-
step route afforded the racemic tricyclic N-tosyl indole 6 in
85% overall yield from commercially available 5,6-disubstituted
indole 8.
Scheme 3. Mechanistic Proposal for the Hayashi [3 + 2]
Annulation
To secure indole 6 in enantiomerically pure form, we
devised the use of the enzymatic resolution of racemic ( )-6
with lipase B from Candida antarctica (CALB-Novozym 435),
which is known to be very selective for the hydrolysis and
transesterification of secondary alcohols, particularly in the
acetylation of benzylic alcohols, as reported by Ferraz and
coworkers (Scheme 2).19 After solvent screening and
optimization of enzyme loading, we found that by using a
toluene/MTBE mixture (8:2 v/v) as the solvent and increasing
the amount of CALB to a 2:1 mass ratio compared with the
substrate, treatment of benzylic alcohol ( )-6 with vinyl
acetate provided the corresponding enantiomerically pure
acetate (5S,7S)-13 (30% yield) and enantiomerically pure
alcohol (5R,7R)-6 (36% yield, >99% ee, as determined by
chiral HPLC; see the SI).20,21
To complete our synthetic approach to (+)-raputindole A
(1), the isobutenyl side chain and the southern indole moiety
needed to be installed. The former was planned to be
introduced via the methallylation of the benzylic carbocation
to be derived from (5R,7R)-6 with methallyltrimethylsilane,
̈
which required the screening of different Bronsted and Lewis
acids. To establish the best experimental conditions,
allyltrimethylsilane was employed as a model nucleophile.
a
Scheme 4. Methallylation and Final Steps in the Total Synthesis of Raputindole A (1)
a
(a) BiBr3 (0.2 equiv), methallyltrimethylsilane (2.0 equiv), DCE, rt, 1 h, 69%, 14a/14b (1:2 ratio). (b) 17 (2.0 equiv), (5R,7R)-6 (1.0 equiv),
Pd(OAc)2 (0.1 equiv), NaOAc (2.0 equiv), nBu4NBr (0.2 equiv), N,N-dimethylacetamide/H2O (9:1), 100 °C, 24 h, 48%. (c) TsOH (1.2 equiv),
toluene, 80 °C, 4 h, 98%, 18a/18b (1:2 ratio). (d) 18a/18b (2.0 equiv), 17 (1.0 equiv), Pd(OAc)2 (0.1 equiv), NaOAc (2.0 equiv), nBu4NBr (0.2
equiv), N,N-dimethylacetamide/H2O (9:1), 100 °C, 24 h, 71%, 19a/19b (1:2 ratio). (e) NaOH (10.0 equiv), MeOH/THF (2:1), 64 °C, 67%,
raputindole A (1)/7-epi-raputindole A (1:2 ratio).
C
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Whereas the use of FeCl3 in dichloroethane at room
temperature only led to a complex mixture, the desired
allylation product could be isolated both with InCl3 (52%
The approach described herein should also be amenable for
the preparation of ( )-raputindole A (1) in nine steps from
the commercially available 6-iodo indole (9) in a comparable
yield as that reported in its first synthesis12 and at the same
time offering a much shorter route than the one reported in the
second synthesis of ( )-raputindole A (1).13
Despite the still unresolved control of the stereochemistry at
C-7, the originality of our approach stems from the efficient
preparation of the tricyclic indole ( )-6 in 85% overall yield
from the commercially available indole 8 and its versatility
from the availability of a chiral version of the iridium catalyst to
develop an asymmetric synthesis of raputindole A (1).18
Additionally, with minor adaptations, our route is amenable to
the total synthesis of other members of the raputindole family
such as raputindole B (2) and deoxiraputindole C (5) as well
as to derivatives thereof to support structure−biological
activity relationship studies.
1
yield) and with BiBr3 (66% yield). Inspection of the H NMR
spectra of the products revealed that a 4:1 and 3:1 mixture of
products, respectively, was formed.22,23 Considering the best
yields observed with bismuth tribromide in dichloroethane at
room temperature, these conditions were employed with
methallyltrimethylsilane as the nucleophile, and a mixture of
methallyl-substituted indoles (5R,7S)-14a and (5R,7R)-14b
was isolated in 69% yield as a 1:2 molar ratio. In an attempt to
improve the ratio in favor of the required (5R,7S)-14a, a
second approach was also investigated where the order of the
two key steps was reversed. A Heck reaction of (5R,7R)-6 with
N-tosyl 6-iodoindole (17), prepared according to the literature
procedure,24 provided bisindole (5R,7R)-15 in 48% yield.
Unfortunately, attempts to perform the bismuth-tribromide-
mediated methallylation were unsuccessful, providing only a
complex mixture containing the desired product 16 (Scheme
4).
ASSOCIATED CONTENT
* Supporting Information
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Despite the poor diastereoselectivity observed in the
installation of the isobutenyl side chain, we moved forward
with the 1:2 mixture of (5R,7S)-14a and (5R,7R)-14b and
proceeded to the isomerization to convert the exo double bond
to the required isobutenyl side chain. Treatment with p-TsOH
in toluene at 80 °C afforded a 1:2 mixture of (5R,7R)-18a and
(5R,7S)-18b in >99% yield.25 With the northern and southern
moieties secured, the mixture of indoles 18a and 18b was
submitted to the Heck reaction conditions already employed
for (5R,7R)-6 to provide a 1:2 mixture of (5R,7R)-19a and
(5R,7S)-19b in 71% yield. The removal of both tosyl groups,
which have served well for the assembly of the key bisindole
precursor, was a challenging undertaking. Initially, we
attempted to use TBAF in THF, thioglycolic acid, as well as
LiOH in THF to remove the tosyl groups, but we only
observed product degradation. The use of KOH and CTAB in
THF-H2O under phase-transfer catalysis made the depro-
tection possible, but an inseparable mixture of raputindole A
(1) and its monotosyl derivative was obtained.25−30 An
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01943.
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Ronaldo A. Pilli − Institute of Chemistry, University of
Campinas, 13083-970 Campinas, Sao Paulo, Brazil;
̃
orcid.org/0000-0002-5919-7763; Email: pilli@
iqm.unicamp.br
Authors
Juliana L. L. F. Regueira − Institute of Chemistry, University of
Sao Paulo (USP), 05508-000 Sao Paulo, Sao Paulo, Brazil;
Institute of Chemistry, University of Campinas, 13083-970
Campinas, Sao Paulo, Brazil
§Luiz F. Silva, Jr. − Institute of Chemistry, University of Sao
Paulo (USP), 05508-000 Sao Paulo, Sao Paulo, Brazil
̃
̃
̃
̃
1
̃
inspection of the H NMR spectrum of the crude mixture,
̃
̃
revealed the presence of a multiplet at δ 6.51 to 6.53, which
correlates with the one observed in 6-iodo-indole (9),
suggesting the deprotection of the southern indole moiety.
This conclusion was also corroborated by nuclear Overhauser
effect spectroscopy (NOESY) analysis of the crude mixture.
After extensive experimentation, we found out that NaOH in
THF/MeOH at 64 °C was the best condition to remove both
tosyl groups, providing a 1:2 mixture of raputindole A (1) and
its C-7 epimer in 67% yield, which were separated by
preparative chiral HPLC (Chiralpak IA column) to afford
(+)-raputindole A (1), which was spectroscopically identical to
the natural product. (See the SI.)
In summary, we have accomplished the diastereoselective
total synthesis of (+)-raputindole A (1) through stereoselective
iridium-catalyzed cyclization, enzymatic resolution, and meth-
allylation promoted by bismuth tribromide followed by
isomerization, which allowed the northern part of raputindole
A (1) to be obtained as a 1:2 mixture of (5R,7R)-18a and
(5R,7S)-18b. After merging it with the southern part,
represented by N-tosyl 6-iodo-indole (17), via the Heck
reaction and the removal of both tosyl groups, (+)-raputindole
A (1) was isolated in 10 steps (longest linear sequence) in
3.3% overall yield after preparative chiral HPLC separation.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01943
Author Contributions
L.F.S. conceived the original synthetic proposal. R.A.P.
conceived the revised synthetic approach and supervised the
experimental work and the writing of this Letter. J.L.L.F.R.
carried out all the experimental work and wrote the Letter.
Notes
The authors declare no competing financial interest.
§L.F.S.: In memoriam.
ACKNOWLEDGMENTS
We thank the Conselho Nacional de Desenvolvimento
■
́
́
Cientifico e Tecnologico (CNPq, no. 141855/2015-0) for
̀
research support and the Fundaca̧ o de Amparo a Pesquisa do
̃
Estado de Sao Paulo (FAPESP) for research grants (nos.
2016/12096-0 and 2019/13104-5). We thank and dedicate
this work to the memory of Professor Luiz Fernando da Silva,
Jr. for his dedication to this project during his life. We thank
the colleagues from the Pilli group for fruitful discussions that
̃
D
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(18) Nishimura, T.; Yasuhara, Y.; Nagaosa, M.; Hayashi, T. C2-
Symmetric tetrafluorobenzobarrelenes as highly efficient ligands for
the iridium-catalyzed asymmetric annulation of 1,3-dienes with 2-
formylphenylboron reagents. Tetrahedron: Asymmetry 2008, 19 (15),
1778−1783.
(19) Ferraz, H. M.; Bianco, G. G.; Teixeira, C. C.; Andrade, L. H.;
Porto, A. L. M. Enzymatic Resolution of α-tetralos by CALB-catalyzed
acetylation. Tetrahedron: Asymmetry 2007, 18, 1070−1076.
(20) Ribeiro, S. S.; Raminelli, C.; Porto, A. L. M. Enzymatic
Resolution by CALB of Organofluorine Compounds Under Conven-
tional Condition and Microwave Irradiation. J. Fluorine Chem. 2013,
154, 53−59.
(21) Bandeira, P. T.; Thomas, J. C.; de Oliveira, A. R. M.; Piovan, L.
Lipase-Mediated Kinetic Resolution: An Introductory Approach to
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contributed to the final route. We thank Professor Leandro H.
Andrade (USP) for kindly providing the enzyme CALB and
allowing the access to GC-MS equipment, Professor Fernando
̂
Antonio Santos Coelho (UNICAMP) for providing the
preparative Chiralpak column, and Professor Helio Alexandre
Stefani (USP) for allowing access to preparative HPLC. R.A.P.
dedicates this work to his former Ph.D. advisor, Professor
Albert J. Kascheres, for his mentoring, guidance, and example.
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