Total Synthesis and Absolute Configuration of Raputindole A

Article abstract of DOI:10.1021/acs.orglett.7b03014

The first total synthesis of the bisindole alkaloid raputindole A from the rutaceous plant Raputia simulans is reported. The key step is a Au(I)-catalyzed cyclization that assembles the cyclopenta[f]indole tricycle from a 6-alkynylated indoline precursor. The isobutenyl side chain was installed by Suzuki-Miyaura cross-coupling, followed by a regioselective reduction employing LiDBB. Starting from 6-iodoindole, the sequence needs nine steps and provided (±)-raputindole A in 6.6% overall yield. The absolute configuration of the natural product (+)-raputindole A was determined by quantum chemical calculation of the ECD spectrum.

Full text of DOI:10.1021/acs.orglett.7b03014

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Total Synthesis and Absolute Configuration of Raputindole A
Mario Kock, Peter G. Jones, and Thomas Lindel*
TU Braunschweig, Institute of Organic Chemistry, Hagenring 30, 38106 Braunschweig, Germany
S
* Supporting Information
ABSTRACT: The first total synthesis of the bisindole alkaloid raputindole A from the
rutaceous plant Raputia simulans is reported. The key step is a Au(I)-catalyzed
cyclization that assembles the cyclopenta[f ]indole tricycle from a 6-alkynylated indoline
precursor. The isobutenyl side chain was installed by Suzuki−Miyaura cross-coupling,
followed by a regioselective reduction employing LiDBB. Starting from 6-iodoindole, the
sequence needs nine steps and provided ( )-raputindole A in 6.6% overall yield. The
absolute configuration of the natural product (+)-raputindole A was determined by
quantum chemical calculation of the ECD spectrum.
mong alkaloids derived from prenylated indole-based
precursors, the raputindoles (1−4, Figure 1) from the
and allenyl acetates via one 3,3-shift or two consecutive 1,2-
shifts of the acetoxy group.8 In the area of natural product
synthesis, Lee et al. published the formal synthesis of the
cyclopenta[g]indole derivative herbindole B via Au(I)-catalyzed
cyclization of an N-tosylindoline-derived propargylacetate.9
Scarpi, Occhiato, and co-workers achieved the Au(I)-catalyzed
pentannulation at an enamine moiety, obtaining cyclopenta-
[b]indolones that were converted to the bruceollines H and I.10
Our total synthesis of ( )-raputindole A (rac-1) was to start
from N-TIPS-6-iodoindoline (5, Scheme 1).6 Four C−C
A
Scheme 1. Synthesis of the Tricyclic Core of Raputindole A
and Introduction of the Isobutenyl Side Chain
Figure 1. Bisindole alkaloids raputindole A−D (1−4) from the
Amazonian tree Raputia simulans.
rutaceous tree Raputia simulans Kallunki are unique because
they are dimeric and feature a rare cyclopenta[f]indole tricyclic
partial structure.1 In addition to compounds 1−4, nodulisporic
acids,2 the shearinines3 and janthitrems4 also contain a
cyclopenta[f ]indole partial structure. Cyclopenta[f ]indole
systems have been accessed from indene-based starting
materials.5 We felt that a different strategy exploiting indole
derivatives should be developed.
Recently, we reported the synthesis of cyclopenta[f ]indolin-
7-ones from propargyl acetates employing Au(I) catalysis,
which proved to be more efficient than the Lewis acid induced
cyclization of 6-hydroxyallylated indoles.6
Cyclopentannulation starting from propargyl acetates had
first been described by Nolan and co-workers in 2006, who
obtained indene derivatives and also found acetoxyallenes
behaving in a similar manner.7 Cavallo, Nolan, and co-workers
showed that Au(I) catalyzes the interconversion of propargyl
couplings were planned, beginning with the alkynylation at
C6, followed by Au(I)-catalyzed cyclopentannulation, intro-
duction of the isobutenyl side chain, and incorporation of the
second indole unit. Sonogashira coupling of commercially
available enynol 6 with N-TIPS-6-iodoindoline (5) and
subsequent acetylation of the alcohol gave cyclization precursor
Received: September 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03014
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Organic Letters
Letter
7 in excellent yield over two steps (Scheme 1). Handling of the
resulting allyl acetate 7 had to strictly avoid heating over 30 °C
in order to prevent Claisen rearrangement to the conjugated
enyne.
Cyclization of propargyl acetate 7 under optimized
conditions,11 including sonication to activate the Au(I)-catalyst
and filtration through Celite to remove excess silver salts,
followed by methanolysis afforded cyclopenta[f]indoline 8 in
very good yield (85%, Scheme 1) and complete regioselectivity.
This regioselectivity is retained even without the bulky N-TIPS
group. However, electron-deficient N-tosylindoline only gave a
tosylindolinyl cyclopentenone in poor yield (see the Supporting
Information).
The cyclization is initiated by Au(I) activation of alkyne 7,
followed by either a 3,3-migration or two consecutive 1,2-
migrations of the acetoxy group to give an allene intermediate,
as investigated by Cavallo, Nolan, and co-workers for the case
of 2-methylbut-3-yn-2-yl acetate.8 Nucleophilic attack of the
indoline 5-position at the Au(I)-activated allene would lead to
cyclization, followed by rearomatization and protodeauration
affording product 8.
analyses, indicating that the configuration of the secondary
stereogenic center had remained unchanged. The overall
replacement of the acetoxy by the aryl group at the quaternary
center had proceeded largely with inversion of configuration. In
both experiments, the de values of the products were lower
than that of the noncyclized precursors. The mirror-like
product ratios suggest that the stereochemical outcome of the
Au(I)-catalyzed cyclization depended only on the configuration
of the quaternary center.
The formation of diastereomers 10a and 10b is in agreement
with competing reaction pathways, of which one involves a
stereospecific 3,3-acetoxy shift, whereas the other proceeds in a
nonstereospecific manner via two consecutive 1,2-acetoxy shifts
(Scheme 3).8 In the latter case, an allyl cation (11) should be
Scheme 3. Proposed First Steps of the Mechanism of the
Au(I)-Catalyzed Cyclization, Outlined for Diastereomer 9b
Scheme 2 shows an experiment that supports the existence of
both pathways in our case. Diastereomeric propargyl acetates
Scheme 2. Au(I)-Catalyzed Cyclization of Diastereomeric
Propargyl Esters 9a and 9b Affording
Cyclopenta[f]indolines 10a and 10b and X-ray Structure of
a
Diastereomer 10a
formed after the first 1,2-acetoxy shift that leaves room for the
formation of the two diastereomeric intermediates 12 and 13,
which could undergo Nazarov-type cyclizations to the tricyclic
vinyl acetates preceding 10a and 10b, respectively.
Toward raputindole A (1), the isobutenyl side chain had to
be introduced (Scheme 4). Attempts to utilize the carbonyl
function of ketone 8 by reaction with organometallic species,
Wittig-type reactions, reduction followed by Mitsunobu
reaction, Corey−Chaykovsky reaction, or conversion to the
benzyl bromide12 failed due to poor reactivity or product
lability. However, vinyl triflate 14 was accessible by α-
deprotonation with LHMDS and trapping of the enolate with
PhNTf2. In the event, it turned out that the subsequent cross
coupling required the removal of the bulky TIPS protecting
group. Desilylation with aqueous HCl during workup gave the
unprotected indoline vinyl triflate 15 in very good yield.
Suzuki−Miyaura coupling of 15 with isobutenyl tetrafluor-
oborate (16)13 at 70 °C afforded the desired indoline-based
triene 17 in good yield and short reaction time. The internal
indene double bond of 17 had to be reduced selectively in the
presence of the isobutenyl and vinyl side chains. Under
conditions of heterogeneous catalytic hydrogenation the order
of reactivity proved to be opposite.
a
Hydrogens omitted for clarity.
9a and 9b were obtained via nucleophilic addition of lithiated
N-TIPS-6-ethynylindoline to (S)-3-(benzyloxy)butan-2-one,
followed by acetylation and separation by chromatography
(9a:9b 10:1 and 1:23, respectively; see the Supporting
Information). Au(I)-catalyzed cyclization of each of the
diastereomers 9a and 9b, followed by methanolysis, afforded
diastereomeric cyclopenta[f ]indolinones 10a and 10b in ratios
of 5:2 and 2:5, respectively. The relative (and absolute)
configurations of 10a and 10b were determined by X-ray
There are reports that Birch reaction with lithium metal had
been selective toward benzylic double bonds.14 Indeed,
treatment of triene 17 with lithium 4,4′-di-tert-butyldiphenylide
(LiDBB) and 2,6-di-tert-butylphenol as a sterically demanding
proton source15 in THF at −78 °C gave the desired product 19
in 73% yield (dr = 1:1, Scheme 4). The diastereomers were not
separable by column chromatography at this stage. In addition,
B
DOI: 10.1021/acs.orglett.7b03014
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Letter
measured (MeOH) and gave expected mirror image spectra
(see the Supporting Information).
Scheme 4. Regioselective Reduction of
Cyclopenta[f]indoline 17 and Access to ( )-Raputindole A
(rac-1)
We performed a quantum-chemical calculation of the ECD
spectrum of (+)-raputindole A (1). MMFF calculations showed
that 19 conformers possessed a relative energy within a 3 kcal/
mol range with respect to the most stable one. The conformers
were then optimized by DFT calculations at the CAM-B3LYP/
LanL2DZ level in methanol (PCM) using Gaussian 09.16 The
resulting eight remaining conformers (3 kcal/mol range, not
identical) were submitted to TDDFT calculations at the CAM-
B3LYP/LanL2DZ level followed by plotting of their UV and
ECD spectra utilizing SpecDis v1.70.1.17 The eight ECD
spectra were Boltzmann-weighted, summed, and UV-corrected
to give the spectrum depicted in Figure 2. The calculated
spectrum is in good agreement with the experimental one. We
conclude that the absolute configuration of (+)-raputindole A
(1) is (5R,7R).
Figure 2. Experimental (black) and calculated (red, 5R,7R-
configuration, graph scaled) ECD spectra of (+)-raputindole A (1)
in methanol.
side products were observed in the 10% range that resulted
from protonation of the intermediate benzyl radical anion 18 at
the allylic position and from a subsequent reduction of the
incipient exocyclic benzylic double bond (see the Supporting
Information).
The total synthesis of ( )-raputindole A (rac-1) was
completed by a phosphine-free Heck reaction of alkene 19
with unprotected 6-iodoindole. Spontaneous oxidation of the
indoline to the indole took place during column chromatog-
raphy on silica gel to give ( )-raputindole A (rac-1) and its
diastereomer rac-20 in 56% overall yield. Final purification
required reversed-phase column chromatography on LiChro-
prep RP-18. Pure rac-1 was isolated. However, rac-20 was
difficult to purify due to contamination (about 10%) with the
regioisomeric Heck product. Overall, ( )-raputindole A (rac-1)
was obtained in 6.6% yield over nine linear steps from N-TIPS-
6-iodoindoline (5).
To obtain enantiomerically pure natural product we
separated both enantiomers of ( )-raputindole A (rac-1) via
semipreparative chiral HPLC (ChiralpakIA 250 × 10 mm, 5 μm
particle size, 5 mL/min n-hexane/THF (88:12), isocratic, UV-
detection at 291 nm). The optical rotatory power of synthetic
(+)-raputindole A ([a]2D1.9 (MeOH, c = 0.105) +90.5) was in
good agreement with the literature value ([α]D (MeOH, c =
0.105) +82.8). ECD spectra of both enantiomers were
In summary, the bisindole alkaloid raputindole A (1) was
synthesized in the racemic form for the first time. The
cyclopenta[f]indole tricycle was assembled by Au(I)-catalyzed
cyclization from a 6-alkynylated indoline precursor, which
probably proceeds via competing stereospecific 3,3-acetoxy and
nonstereospecific consecutive 1,2-acetoxy shifts. Regioselective
reduction employing LiDBB gave access to the indane moiety.
The sequence requires nine steps and provided ( )-raputindole
A in 6.6% overall yield. The absolute configuration of the
natural product (+)-raputindole A was determined as (5R,7R).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03014.
Relevant experimental procedures, characterization data,
and NMR spectra (PDF)
Accession Codes
CCDC 1576393−1576394 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
C
DOI: 10.1021/acs.orglett.7b03014
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: th.lindel@tu-bs.de.
ORCID
Thomas Lindel: 0000-0002-7551-5266
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.7b03014
Org. Lett. XXXX, XXX, XXX−XXX