Diastereoselective Total Synthesis of Raputindole A

Article abstract of DOI:10.1021/acs.orglett.8b02349

The first diastereoselective total synthesis of the bisindole alkaloid raputindole A is reported. After Au(I)-catalyzed assembly of the cyclopenta[f]indole tricycle, it was possible to hydrogenate the indene double bond regio- A nd diastereoselectively through iridium catalysis, guided by a preinstalled hydroxy function. Attempted HWE reaction led to formal elimination of formaldehyde from an α-quaternary cyclopentane carbaldehyde, which was circumvented by Takai olefination. After Suzuki-Miyaura cross coupling and deprotection/oxidation, (±)-raputindole A was obtained in 13 linear steps in 18% overall yield.

Full text of DOI:10.1021/acs.orglett.8b02349

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diastereoselective Total Synthesis of Raputindole A
Mario Kock and Thomas Lindel*
TU Braunschweig, Institute of Organic Chemistry, Hagenring 30, 38106 Braunschweig, Germany
S
* Supporting Information
ABSTRACT: The first diastereoselective total synthesis of the bisindole
alkaloid raputindole A is reported. After Au(I)-catalyzed assembly of the
cyclopenta[f ]indole tricycle, it was possible to hydrogenate the indene
double bond regio- and diastereoselectively through iridium catalysis,
guided by a preinstalled hydroxy function. Attempted HWE reaction led
to formal elimination of formaldehyde from an α-quaternary cyclopentane
carbaldehyde, which was circumvented by Takai olefination. After
Suzuki−Miyaura cross coupling and deprotection/oxidation, ( )-rapu-
tindole A was obtained in 13 linear steps in 18% overall yield.
he unique terpenoid bisindole alkaloid raputindole A (1,
Figure 1) was isolated from the rutaceous tree Raputia
OH groups mainly concerns the mono reduction of 1,4-
dienes,9 in addition to 1,2-10 and remote alkenes.11 The
literature regarding 1,3-dienes is surprisingly scarce.12 Even
simple 1-hydroxymethyl-1H-indene derivatives have not been
subjected to diastereoselective homogeneous hydrogenation.
The synthesis of raputindole A (1) starts from N-TIPS-6-
iodoindoline (2, Scheme 1),13 which underwent quantitative
Sonogashira coupling with ynol 3, synthesized by O-TIPS-
protection of hydroxyacetone and a Grignard reaction with
ethynyl magnesium bromide.14 The obtained 6-alkynylindoline
T
Figure 1. Bisindole alkaloid raputindole A (1) from the Amazonian
tree Raputia simulans Kallunki.
Scheme 1. Synthesis of the Tricyclic Core of Raputindole A
(1) and Introduction of the Isobutenyl Side Chain
simulans Kallunki in 2010.1 The rare cyclopenta[f]indole core
of 1 can also be found in nodulisporic acids,2 shearinines,3 and
janthitrems,4 which exhibit a fully substituted indole enamine
section. An unsubstituted enamine section can be found in the
trikentrines5 and herbindoles.6 Cyclopenta[f ]indole systems
have been accessed synthetically from indene-based starting
materials involving late-stage indole synthesis.7
Recently, we reported the first total synthesis of raputindole
A (1) that featured a regioselective Au(I)-catalyzed cyclization
of a 6-alkynylindole precursor to the cyclopenta[f]indole
system of 1. The resulting indanone moiety had to be
functionalized further by conversion to the alkenyltriflate,
followed by installation of the isobutenyl side chain by Pd-
catalyzed cross coupling with potassium isobutenyl tetrafluor-
oborate. A critical step remained the reduction of the resulting
indene to the indane moiety in the presence of a conjugated
isobutenyl side chain and an isolated monosubstituted double
bond.8 While the regioselectivity of that step was convincing
and complementary to that of catalytic heterogeneous
hydrogenation, the diastereoselectivity was low, requiring
separation by chromatography. Thus, we decided to investigate
a diastereoselective total synthesis of raputindole A (1).
We envisaged a tethered homogeneous hydrogenation that
would guide both hydrogen atoms onto the indene double
bond syn to a preinstalled hydroxymethyl moiety. Regio and
diastereoselective hydrogenation of dienes exploiting directing
Received: July 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02349
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
was acetylated to give cyclization precursor 4. Employing the
“preactivated” Au(I)-catalyst Au(PPh3)NTf2,15 followed by
methanolysis afforded the desired cyclopenta[f]indoline 5 in
pleasing quantitative yield.
As described by Pfaltz et al., the more stable BARF-analogue
([Ir(COD)py(PCy3)]BARF) was envisioned to be more
susceptible toward the coordination by the OH-group than
the original Crabtree catalyst.18 Unfortunately, in our case, this
catalyst was too active, leading to an increased amount of fully
reduced product 10 and decreased de’s. Thus, we investigated
the temperature dependence of the OH-directed hydro-
genation reaction. As expected, the reaction of diene 8 with
H2 under Ir-catalysis (entries 5−8, Table 1) proceeds much
slower at lower temperatures showing no conversion at −45
°C. Full conversion was achieved after 2 days at −20 °C,
affording the desired isobutenyl product 9 in 63% yield and
96% de and a decreased amount of undesired isobutyl product
10. At 0 °C the reaction proceeded within 18 h giving an even
better product ratio and an isolated yield of isobutenyl product
9 of 63% and 99% de (Scheme 2). Control experiments
employing Wilkinson’s catalyst ([Rh(PPh3)3]Cl) and [Ru((R)-
BINAP)](OAc)2 did not result in product formation.
Reduction using Pd/C or Pd(OH)2/C as catalyst gave fully
reduced product 10 in quantitative yield and 20% de. N-
Unprotected indolines suffered from poor yield in the OH-
directed hydrogenation, probably due to competing catalyst
coordination.
A sequence of α-deprotonation, triflation of the enolate
(PhNTf2, LHMDS), N-TIPS deprotection (2 N HCl), N-
tosylation (TsCl, DMAP), and O-TIPS deprotection (p-
TsOH) was performed on gram-scale with only one chromato-
graphic workup at the end to give alkenyl triflate 6 in an overall
yield of 85% (Scheme 1). This swap of protecting groups
became necessary as the Suzuki−Miyaura cross-coupling did
not proceed in the presence of the bulky N-TIPS protecting
group. On the other hand, the N-tosyl protected derivative of
propargyl acetate 4 underwent Au(I)-catalyzed cyclization very
slowly affording the cyclopenta[f ]indoline in moderate yield
and the intermediate allene (see the Supporting Information
(SI)). The desilylation step required acidic conditions because
fluoride sources led to decomposition. Suzuki−Miyaura cross-
coupling of alkenyl triflate 6 with isobutenyl trifluoroborate 7
yielded the desired diene 8 (95%). Exceeding 50 °C had to be
avoided because of protodetriflation to the indene.
With diene 8 in hand, we investigated the regio- and
diastereoselectivity of the envisioned OH-directed hydro-
genation (Scheme 2). Preliminary experiments employing
[Rh(dppb)(NBD)]BF4 as catalyst gave promising results
affording a mixture of products (see the SI) with 64% de
(Table 1).16
When employing D2 instead of H2, we observed that both
deuterium atoms were added to the same face of the indene
double bond (bisdeuterated product 9-d2, 72%), as indicated
by NOESY correlations of 6-H to the vicinal methyl and
isobutenyl groups (Scheme 3). The formation of an
Scheme 2. Ir-Catalyzed OH-Directed Hydrogenation of 1,3-
Diene 8 and IBX Oxidation
Scheme 3. Deuterium Labeling Study
A variety of Rh- and Ir-catalysts were synthesized by ligand
exchange reactions (Table 1).17 Rh-catalysts in all cases gave de
values of about 65% of the desired product 9 (as judged by 1H
NMR data), as part of an inseparable mixture of products. Ir-
catalysts had a superior performance in all cases studied,
reaching up to 99% de. In addition, only the desired product 9
and the fully reduced product 10 were formed that were
separable by column chromatography.
intermediate Ir(V) complex such as 13 would be in agreement
with DFT calculations and a kinetic study by Brandt and co-
workers19 that has been widely accepted.9e,20 Interestingly, we
Table 1. Rh- or Ir-Catalyzed OH-Directed Hydrogenation of Diene 8
c
c
entry
catalyst
time [h]
temp [°C]
yield [%] 9:10
de (9)
a
1
2
3
4
5
6
7
8
9
[Rh(NBD)(dppb)]BF4
2
2
5
rt
rt
rt
rt
68:5
64%
66%
88%
99%
99%
96%
86%
94%
20%
a
[Rh(COD)(dppb)]BARF
59:21
23:61
54:46
74:25
66:26
23:75
62:25
0:100
b
[Ir(COD)(dppb)]BARF
[Ir(COD)py(PCy3)]PF6
[Ir(COD)py(PCy3)]PF6
[Ir(COD)py(PCy3)]PF6
a
1
b
b
18
48
8
24
0.25
0 °C
−20 °C
rt
−10 °C
rt
b
b
[Ir(COD)py(PCy3)]BARF
[Ir(COD)py(PCy3)]BARF
a
Pd/C (5%)
a
b
c
1
10 mol % catalyst used. 5 mol % catalyst used. Determined by H NMR spectroscopy
B
DOI: 10.1021/acs.orglett.8b02349
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
found a 1:1 ratio of 11-epimers in the doubly reduced side
product 10-d4, which could be explained by a rather free
rotation around the C7−C11 bond. In addition, only 83%
deuteration was found at C12, whereas complementary 17%
deuteration occurred at the methyl groups of the isobutyl side
chain. Apparently, 1,2-hydrogen migration took place to a
minor extent.21
For installing the second indole moiety of 1, alcohol 9 was
oxidized to aldehyde 11 (IBX, 90%, Scheme 2). We also
prepared the saturated analogue 12 by oxidation of 10 (IBX,
89%). Unexpectedly, HWE reaction of aldehyde 12 with indol-
6-yl methylphosphonate 14 (for the synthesis, see the SI)22 led
to formal elimination of formaldehyde to give indene 15 in
35% yield as the sole product after dehydration in CDCl3
(Scheme 4).
On reaction of 19 (for the synthesis, see the SI) with
Ph3PMeBr/LHMDS in THF we did observe the expected
Wittig olefination forming vinyl product 20 (Scheme 4). The
key difference between starting materials 12 and 19 is the
presence of an α-hydrogen in ester 19. We assume that in the
case of 19 reprotonation of the lithium alkoxide takes place
that allows for the formation of an oxaphosphetane leading to
20.
To obtain raputindole A (1), Takai olefination of aldehyde
11 proved to be successful (Scheme 5). At room temperature,
Scheme 5. Final Steps toward Raputindole A (1)
Scheme 4. Unexpected Formal Elimination of
Formaldehyde on Attempted HWE and Wittig Reactions of
Aldehyde 12
elimination product 22 was still formed as minor component
of a mixture with the desired (E)-iodoalkene 21 (21:22 = 5:2).
Employing 10 equiv of CrCl2 and stirring at 0 °C suppressed
the formation of the elimination product 22 (<5%) and
increased the yield of (E)-iodoalkene 21 to 87%.
The second indole moiety was introduced via Suzuki−
Miyaura cross coupling using commercially available boronic
acid 23 to afford bisindole 24 (84%, Scheme 5). The reaction
had to be strictly protected from light and temperatures
exceeding 50 °C to prevent side product formation (e.g.,
hydroxydeborylation). Detosylation of indoline 24 was
achieved with Na/naphthalene at −78 °C, followed by
dehydrogenation using Pd/C at 85 °C to give ( )-raputindole
A (rac-1) in 53% yield over two steps.
In summary, the bisindole alkaloid raputindole A (1) was
synthesized diastereoselectively via Au(I)-catalyzed cyclization
and a regio- and diastereoselective reduction of a 1,3-diene
employing Ir-catalyzed OH-directed hydrogenation. ( )-Ra-
putindole A (rac-1) was obtained in 13 linear steps and in 18%
overall yield.
Starting from propargylacetate 4, we also tried to perform an
enantioselective cyclopentannulation to 5, but failed miserably.
A variety of chiral Au(I)- and Pt(II)-catalysts23 (e.g., (R)-
DTBM-SEGPhos-(AuCl)2, (−)-DIOP-(AuCl)2, (R)-MONO-
Phos-AuCl, (R)-TRIP-AuPPh3, (R)-DTBM-SEGPhos-PtCl2)
did not result in any enantioinduction on cyclization of
propargyl acetate 4. Chiral phase HPLC analysis (ChiralPakIA,
see the SI) always showed equal concentration of the
enantiomers. It appears that an entirely different synthetic
strategy will have to be developed to achieve enantioselectivity.
The same observation was made on reaction of 12 with
Ph3PMeBr/LHMDS that afforded the indene derivative 15
(76%). Here, we were able to isolate tertiary alcohol 18 (22%)
that underwent rapid dehydration in CDCl3. Starting from 12,
a betaine is formed which, as in the Schlosser−Wittig reaction,
does not cyclize the oxaphosphetane in the presence of excess
LHMDS, but instead forms oxidoylide 16. On workup with
aqueous NH4Cl, protonation takes place, followed by
fragmentation with formation of stabilized phenyl-substituted
tertiary carbenium ion 17 and loss of acetaldehyde and PPh3.
The reaction appears to be unprecedented. Applying only
LHMDS to aldehyde 12 did not result in any reaction. Formal
elimination of formaldehyde did not occur when the isobutenyl
or isobutyl groups were replaced by a methoxycarbonyl moiety.
C
DOI: 10.1021/acs.orglett.8b02349
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02349.
■
S
All relevant experimental procedures, characterization
data, and NMR spectra (PDF)
̈
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7448−7451.
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Corresponding Author
*E-mail: th.lindel@tu-bs.de
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Thomas Lindel: 0000-0002-7551-5266
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DOI: 10.1021/acs.orglett.8b02349
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