Unprecedented total synthesis of bruceolline D, E, and H

Article abstract of DOI:10.1080/00397911.2020.1795199

Single pot strategy of wittig olefination-Claisen rearrangement has been employed to obtain 3-prenylated indoles. The resulting indoles on the consecutive sequence of epoxidation, cyclization and further oxidation afforded short, protecting group free tot

Full text of DOI:10.1080/00397911.2020.1795199

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Unprecedented total synthesis of bruceolline D, E,
and H
Dnyaneshwar Gaikwad
To cite this article: Dnyaneshwar Gaikwad (2020): Unprecedented total synthesis of bruceolline D,
E, and H, Synthetic Communications, DOI: 10.1080/00397911.2020.1795199
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https://doi.org/10.1080/00397911.2020.1795199
Unprecedented total synthesis of bruceolline D, E, and H
Dnyaneshwar Gaikwad
Department of Chemistry, B.P.H.E. Society’s Ahmednagar College, Ahmednagar, India
ABSTRACT
ARTICLE HISTORY
Single pot strategy of wittig olefination-Claisen rearrangement has
been employed to obtain 3-prenylated indoles. The resulting indoles
on the consecutive sequence of epoxidation, cyclization and further
oxidation afforded short, protecting group free total synthesis of bru-
ceolline D, E and H.
Received 5 June 2020
KEYWORDS
Claisen rearrangement;
consecutive sequence;
3
-prenyl indole; wittig
GRAPHICAL ABSTRACT
olefination
O
PPh
3
Cl
O
O
CHO
1
.
O
TFPAA
2
+
R
R
NO
2
t-BuOK, THF
. FeSO , NH
Diglyme
DDQ, H O
N
H
N
H
N
H
R
R
2
4
3
,
R =H; Bruceolline D
R = H; Bruceolline E
R = OH; Bruceolline H
Introduction
Effective construction of densely oxygenated cyclopenta[b]indole framework with a qua-
ternary carbon center has been of pivotal issues in indole based alkaloids. This could
probably be not only due to the presence of this scaffold in many bioactive compounds
but also synthetically challenging among the heterocycles. A number of natural products
possessing this unique functionality proved to be involved in various biological activ-
[
1]
ities ranging from cyto-toxicity against HCl-H460 cell lines, Eg5 inhibiter, antifertility
to estrogenic effect. Because of the importance of this class, in the last three decades,
several research groups attempted to construct this framework in various natural prod-
ucts synthesis. This included some of the recent and familiar methods like Fischer
[
2]
[3]
[4]
indole strategy, intramolecular Friedel-Crafts reaction, Pauson-Khand reaction,
[
5a]
[5b]
and palladium
as well as rhodium
catalyzed cyclization. All of these synthetic
routes with few exceptions involved structural and/or functional group modification in
readymade indole ring.
Among these cyclopenta[b]indoles, a group of bruceollines is of particular interest
[
6]
due to their potential in the treatment of malaria and other parasitic diseases. Since
[
7]
the isolation of bruceollines (Figure 1) came into picture, literature survey revealed
limited number of reports for their synthesis. Most of these approaches restricted to the
tandem cyclizations in indole moiety as such with few exceptions. For instance,
CONTACT Dnyaneshwar Gaikwad
dshwar@gmail.com
Department of Chemistry, B.P.H.E. Society’s Ahmednagar
College, Ahmednagar 414001, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
D. GAIKWAD
O
O
O
N
H
N
R
H
Bruceolline D (1)
R = H, Bruceolline E (2)
R = OH, Bruceolline H (3)
O
O
OH
OGlu
N
H
R
N
H
R = H, Bruceolline J (4)
Bruceolline K (6)
R = OH, Bruceolline I (5)
Figure 1. Chemical structures of bruceollines from Brucea mollis Wall.
Badenock and Gribble reported two separate methods for the synthesis of bruceolline
[
6a]
D, E, and J. The first approach
used tandem acylation/Nazarov cyclization of ethyl
indol-1-carboxylate followed by oxidation with selenium dioxide to synthesize bruceol-
[
8]
line E. Their second route comprised the use of chiral borane and baker’s yeast to
[
9]
afford enantioselective synthesis of natural as well as unnatural bruceolline J. Dethe
and Kumar reported racemic as well as asymmetric approach through dihydroxylation
for the synthesis of bruceolline D, E and J. Tandem N-alkylation-Aza-Cope rearrange-
[
10]
ment reaction has been used by Wei Wang et al.
to achieve the synthesis of bruceol-
line D. So far only one synthesis has been reported each for bruceolline H and I
[
6b,11]
respectively by Occhiato
and coworkers. Gold catalyzed Nazarov cyclization of
propargylic acetate has been successfully employed for the synthesis of these
bruceollines.
Results and discussion
Herein, we report a short and protecting group free total synthesis of bruceolline family
D, E and H through single pot preparation of 3-prenylated indole 9 followed by a con-
secutive sequence of epoxidation, cyclization and oxidation. The protocol for the prep-
[
12]
aration of 3-allylindole
has previously been successfully employed by our group. This
time we envisioned that bruceollines D, E and H could be easily accessed without the
[
13]
need of protection through wittig olefination and Claisen rearrangement.
The synthe-
sis began with the preparation of 3-prenylated indole 9 by wittig olefination of
[
12,13]
o-nitrobenzaldehyde 7 with phosphorane 8 under standard conditions
followed by
a Claisen rearrangement resulting 69% yield of 9 over three steps. The resulting
[
14]
3
-prenyl indole 9 (intermediate with identical NMR data ) was then subjected to

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SYNTHETIC COMMUNICATIONS
3
CHO
NO2
O
8
PPh Cl
3
+
a
O
Ref. 12
N
H
7
NO2
9
O
O
c
O
X
b
+
OH
N
H
N
H
Bruceolline D (1)
Bruceolline E (2)
N
H
1
0
ꢀ
Scheme 1 Reagents and conditions: (a) t-BuOK (1.5 eq.), Dry THF, 0 C, 1 h; (b) TFPAA (1.5 eq.),
ꢀ
1
,4-Dioxane, DDQ (4.2 eq.), H O, 7 h; (c) TFPAA (1.5 eq.), DCM, 40 C, 12 h.
2
trifluoroperacetic acid in dichloromethane to obtain desired cyclopent[b]indole frame-
[
15]
work 10.
We intended from the above strategy to oxidize alcohol in possible inter-
mediate 10 to furnish synthesis of bruceolline D. Miserably, our attempts to get the
desired product or any kind of intermediate moiety under varying reaction conditions
remained unsuccessful. These findings led us to employ in situ cyclization-oxidation to
form ketone or a-diketone directly. Accordingly, compound 9 was treated with trifluor-
[
16]
operacetic acid followed by oxidation with DDQ
reflux for 7 h. Fortunately to our surprise, a mixture of desired bruceolline D and E
1.3:1) was obtained. This clearly implied that a sequence of epoxidation, cyclization
in 1,4-dioxane-water (5:1) under
(
and oxidation has been affected altogether one after the other (Scheme 1). Attempts to
increase the reaction duration upto 18 h, moles of oxidizing reagent as well as additives
has resulted no significant change in yield of either bruceolline D or E. We also wish to
note that none of the intermediate products like cyclopenta[b]indole, cyclopenta[b]in-
dol-2-ol 10, cyclopenta[b]indol-1-one or bruceolline J were observed on quenching of
reaction at any stage right before its completion.
These results encouraged further research to accomplish the synthesis of bruceolline
H. Accordingly, 4-acetoxy-2-nitrobenzaldehyde 11 was subjected to phosphorane 8
under the same conditions. The resulting crude aryl vinyl ether as such was then heated
[
12]
[17]
under standard condition
indole 12 was then allowed to react with trifluoroperacetic acid and DDQ in
,4-dioxane-water (5:1) to furnish bruceolline H (3) and its deoxy analogue 13 in 0.7:1
proportion (Scheme 2). The spectral data of bruceolline D, E, and H are in accordance
to afford 7-hydroxy prenyl indole
12. This prenylated
1
[
7–9]
to that of reported in literature.
Conclusion
In conclusion, a short, two stage and protecting group free total synthesis of bruceolline
D, E, and H has been achieved. The key steps of the synthesis comprised two separate
consecutive sequences involving single pot preparation of 3-prenyalted indoles followed
by Nazarov type cyclization and further oxidation. This strategy afforded easy access of

4
D. GAIKWAD
CHO
NO2
O
O
PPh Cl
O
+
3
O
a
O
O
NO2
8
11
O
O
O
Ref. 12
b
+
N
H
HO
N
H
HO
N
HO
H
12
13
3
ꢀ
Scheme 2. Reagents and conditions: (a) t-BuOK (1.5 eq.), Dry THF, 0 C, 1.5h; (b) TFPAA (1.5 eq.), 1,4-
Dioxane, DDQ (4.5 eq.), H O, 10 h.
2
cyclopenta[b]indolone framework to be useful for the synthesis of indole based nat-
ural products.
Experimental procedure
Materials and methods
All reactions were carried out using reagents and solvents having highest commercial
quality and used without further purification, unless otherwise stated. Anhydrous THF
and 1,4-dioxane were distilled from sodium-benzophenone. Reactions were monitored
by thin-layer chromatography (TLC) using 0.25 mm Merck silica gel plates (60 F-254).
Purification of crude products was carried out by column chromatography using Merck
silica gel (100–200 mesh). Isolated yields refer to chromatographically pure material.
1
13
Characterization of all products and intermediates include H NMR, C NMR and
high resolution mass spectroscopy.
1
13
H NMR and C NMR spectra were recorded at 400, 300 and 101 and 75 MHz,
respectively, in the specified deuterated solvent. Solvent reference lines were set at 7.26
and 77.00 (CDCl ), 2.05 and 29.84 (Acetone-D ), 2.50 and 39.52 ppm (DMSO- D ) in
3
6
6
1
13
H and C NMR spectra, respectively using tetramethylsilane (TMS) as internal stand-
ard. Mass spectra were recorded by direct inlet of solution in CH OH with an electro-
3
spray ionization (ESI) interface in the positive mode.
General experimental procedure
[
14]
3
-(3-Methylbut-2-enyl)-1H-indole (9)
2
-Nitrobenzaldehyde 7 (3 g, 19.8 mmol) and phosphorane from 8 (11.8 g, 29.7 mmol, 1.5
[
13]
eq.) were allowed to react under standard condition
to form intermediate allyl vinyl
ether. The crude product so obtained after normal aqueous extractive workup was
found to be unfit for chromatographic separation as well as spectral characterization.
Hence this intermediate as such without any further treatment was heated in diglyme/
[
12]
water (1:1) under standard condition.
After refluxing the reaction mixture for 18 h,

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5
(
TLC check, R 0.4, n-hexane/EtOAc, 8:2) the reaction mixture is mixed with 5 mL
f
brine. The crude product was extracted with ethyl acetate (5 mL Â 3), and organic
phase was dried over anhydrous sodium sulfate. The solvent was removed under
reduced pressure to get yellow mass. The crude product was chromatographed by
means of silica gel (eluent n-hexane/EtOAc, 95:5) to afford 69% (2.53 g, 13.6 mmol) of
3-(3-Methylbut-2-enyl)-1H-indole 9 as a pale yellow viscous oil.
9
9
Bruceolline D (1) and bruceolline E (2)
Compound 9 (1.9 g, 10.2 mmol) was dissolved in 45 mL 1,4-dioxane. To this was added
dropwise trifluoroperacetic acid (2.0 g, 15.3 mmol, 1.5 eq.) over a period of 10 min at rt.
To this stirred solution, DDQ (9.79 g, 43.12 mmol, 4.2 eq.) in 9 mL water was added in
one portion. The resulting mixture was refluxed for 7 h (TLC check) to get reddish
orange mass. It was then stirred with 10 mL 20% Na CO at rt for 10 min and 30 mL
2
3
brine was added. The products were extracted with ethyl acetate (10 mL Â 3), dried
over anhydrous sodium sulfate and concentrated under reduced pressure. The impure
products were purified by silica column chromatography (20–40% ethyl acetate in pet
9
9
ether) to afford 0.68 g, bruceolline D (1) and 0.52 g, bruceolline E (2) in
.3:1 proportion.
1
3
-(3-Methylbut-2-en-1-yl)-1H-indol-6-ol (12)
4
-Acetoxy-2-nitrobenzaldehyde 11 (4 g, 19.1 mmol) and wittig salt 8 (11.3 g, 28.7 mmol)
ꢀ
was mixed with 120 mL dry THF at 0 C in an inert atmosphere of nitrogen. To this
stirred solution, t-BuOK (4.7 g, 40.1 mmol, 1.5 eq.) was added in one portion. The
resulting mixture was stirred for 1.5 h (TLC check) at the same temperature so as to
change it to yellowish in color. The solvent was stripped out by means of vacuum. The
resulting crude allyl vinyl ether without any further purification was treated under
[
13]
standard condition
to give compound 12. Thus, after refluxing the reaction mixture
in diglyme: water for 26 h (TLC check, R , 0.25, Ethyl acetate/pet ether, 2:3) 20 mL brine
f
was added. The crude product was chromatographed using silica gel and 10% ethyl
acetate in pet ether as an eluent to afford 12 in 60.5% yield as a pale yellow solid.
11
Bruceolline H (3) and 6-Hydroxy-3, 3-dimethyl-1H, 2H, 3H, 4H-
cyclopenta[b]indol-2-one (13)
To a stirred solution of compound 11 (2.0 g, 9.9 mmol) in 50 mL dioxane, TFPAA
(1.94 g, 14.9 mmol, 1.5 eq.) was added dropwise over the period of 10 min. The resulting
solution was stirred at rt for further 20 min. To this DDQ (10.16 g, 44.7 mmol, 4.52 eq.)
in 10 mL water was added in one portion. The resulting mixture was refluxed for 10 h
(
TLC check) to get orange mass. It was then stirred with 10 mL 20% Na CO at rt for
2 3
10 min and 25 mL brine was added. The products were extracted with ethyl acetate
(
10 mL Â 3), dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The crude products were purified by silica column chromatography (eluent,

6
D. GAIKWAD
11
ethyl acetate/pet ether, 1:1) to afford 0.54 g bruceolline H (3) and 0.65 g its deoxy ana-
logue 13 as a yellow solid.
1
13
Full experimental detail, H and C NMR spectra, HRMS. This material can be
found via the “Supplementary Content” section of this article’s webpage.
Acknowledgments
Author thanks Central Instrumentation Facility, Savitribai Phule Pune University, Pune and
SAIF, Punjab University, Chandigarh for spectral analysis. He is grateful to the Principal, Dr. R.
J. Barnabas, Ahmednagar College, Ahmednagar for providing all necessary lab facility.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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[
17] Due to strong alkaline condition, prolonged reaction duration under reflux, the acetate
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