A simple and efficient total synthesis of anticancer indole alkaloids TMC-205 and its analogues

Article abstract of DOI:10.1016/j.tetlet.2021.153137

A concise synthesis of TMC-205 was accomplished in two steps via a protecting-group-free (PGF) and redox-economical strategy. In this approach, a high yield Pinnick oxidation and a practical Heck-dehydration reaction with high atom economy as well as a high regio- and stereo-selectivity (E-isomer) were used and further applied to the total synthesis of its active analogues. This newly established route would be beneficial for future structure–activity relationship (SAR) and biological studies. The synthetic strategy and methodologies demonstrated in this paper could be extended to related biologically active natural products.

Full text of DOI:10.1016/j.tetlet.2021.153137

Journal Pre-proofs
A Simple and Efficient Total Synthesis of Anticancer Indole Alkaloids
TMC-205 and Its Analogues
Tao Li, Jinjie Song, Lihua Wang, Ting Lei, Shizhi Jiang, Fusheng Wang
PII:
S0040-4039(21)00346-4
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2021.153137
TETL 153137
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 March 2021
20 April 2021
26 April 2021
Please cite this article as: Li, T., Song, J., Wang, L., Lei, T., Jiang, S., Wang, F., A Simple and Efficient Total
Synthesis of Anticancer Indole Alkaloids TMC-205 and Its Analogues, Tetrahedron Letters (2021), doi: https://
doi.org/10.1016/j.tetlet.2021.153137
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
©
2021 Published by Elsevier Ltd.

Graphical Abstract.
A Simple and Efficient Total Synthesis of
Anticancer Indole Alkaloids TMC-205 and Its
Analogues
Leave this area blank for abstract info.
a
a
a
a
a,
a,
Tao Li , Jinjie Song , Lihua Wang , Ting Lei , Shizhi Jiang , Fusheng Wang 
O
O
H
OH
Heck
Pinnick
-dehydration oxidation
+
E
TMC-205
HO
N
N
Br
Gram-Scale, 91% overall yield
H
H
2
5
Steps
VS
Steps



Cheap and readily available feed stock
Protecting-group-free and redox-economy
Excellent regio- and stereo-selectivity
(
First total synthesis)

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A Simple and Efficient Total Synthesis of Anticancer Indole Alkaloids TMC-205
and Its Analogues
a
a
a
a
a,
a,
Tao Li , Jinjie Song , Lihua Wang , Ting Lei , Shizhi Jiang  and Fusheng Wang 
aCollege of Pharmacy, Dali University, Dali 671000, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise synthesis of TMC-205 was accomplished in two steps via a protecting-group-free (PGF)
and redox-economical strategy. In this approach, a high yield Pinnick oxidation and a practical
Heck-dehydration reaction with high atom economy as well as a high regio- and stereo-selectivity
(E-isomer) were used and further applied to the total synthesis of its active analogues. This newly
established route would be beneficial for future structure-activity relationship (SAR) and
biological studies. The synthetic strategy and methodologies demonstrated in this paper could be
extended to related biologically active natural products.
Available online
Keywords:
Anticancer
Indole alkaloid
Heck reaction
Protecting-group-free
Pinnick oxidation
2
009 Elsevier Ltd. All rights reserved.

Corresponding author. E-mail address:jiangshizhi@dali.edu.cn (S.-Z. Jiang);
wfsyn@163.com (F.-S. Wang).

2
Tetrahedron Letters
In recent years, protecting-group-free (PGF), step-economical
our outlined synthesis was found to be the coupling of an indole
moiety and an olefin side chain. In this context, Heck coupling [12]
appeared to be the most attractive reaction for introducing a trans-
alkene, without the participation of the indole enamine moiety and
the aldehyde group. Retrosynthetic analysis revealed 6-
bromoindole derivative 2 and allyl alcohol 3 as suitable starting
materials to install the desired carbon skeleton 5 upon Heck-
dehydration reaction [11].
and redox-economical methods have received considerable
attention as strategies to improve the efficiency of total synthesis.
In addition, this approach provides an “opportunity for invention,”
as the development of a novel synthesis strategies and synthetic
methodologies is essential [1-6]. Herein, we report the successful
application of these principles to the total synthesis of TMC-205
and its analogues.
TMC-205 (Scheme 1), an unusual structurally simplified
indole-3-carboxylic acid derivative bearing an isoprene-like side
chain at the 6-position, is a secondary metabolite of an unidentified
fungal strain, TC 1630, which was isolated in 2001 by the Masaaki
Sakurai group [7]. TMC-205 shows antiproliferative activity
against various human cancer cell lines and also activates the
SV40 promoter [7,8]. However, only 3.3 mg of TMC-205 was first
isolated from the fermentation broth of TC 1630, and such a small
amount of the extract could not be used for SAR and biological
studies. The fascinating structural features of TMC-205, along
with its potential pharmacological activity and our ongoing
interest in the total synthesis of biologically active indole natural
products [9-11], prompted us to develop a practical approach to
synthesize this attractive indole alkaloid.
Our synthetic efforts commenced with the use of 6-
bromoindole-3-carboxaldehyde 2 as the key starting material. This
compound is commercially available and can also be prepared
easily from the inexpensive 6-bromoindole via Vilsmeier-Haack
formylation [12-15]. Notably, after initial extraction of the crude
material, 2 could be purified conveniently by recrystallization on
a 10 g scale (See Supporting Information for details).
With substrate 2 in hand, we focused on the Heck-dehydration
reaction. Initially, we used CH
3
CN as the solvent and treated
in the presence of Et N as
bromide 2 with Pd(OAc) and P(o-tol)
2
3
3
a base in a sealed tube at 115°C. After 5 h, the desired diene 5 was
obtained in 81% yield with high regio- and stereo-selectivity [11]
(
Table 1, entry 1). The geometry of the double bond was
1
ascertained as the E-isomer by H NMR spectroscopy.
Thus far, only one group has achieved the total synthesis of
TMC-205 in early 2014; the product was obtained in 5 steps via
the longest linear sequence reported (6 total steps) and in 64%
overall yield by adopting Friedel-Crafts acylation, esterification
Inspired by the recent systematic investigations of this reaction
by our group [11], we attempted to further improve the yield. We
began our investigation by screening several readily available
palladium catalysts. A slightly increased yield was observed when
(using TMSCHN
2
), and Suzuki-Miyaura coupling as the key steps
Pd
low reaction rate. When PdCl
both the reaction rate and yields were unsatisfactory (entries 2, 4).
Therefore, Pd(OAc) was chosen as the optimal catalyst.
2
(dba)
3
was employed (entry 3), but this was accompanied by a
[8]. In the first total synthesis, an obvious convergent approach
2
and Pd (dba) ·CHCl were used,
2
3
3
was used for the C6−C9 bond formation via the Suzuki-Miyaura
cross-coupling reaction. However, the reported methods required
the independent preparation of the isoprene portion and involved
multiple steps for finally constructing the 3-carboxy group; in
addition, they had inherent limitations such as the requirement of
harsh reaction conditions as well as expensive and toxic reagents
and starting materials. Hence, the previous synthesis methods are
complicated. Here we reveal an effective two-step procedure
toward the concise synthesis of TMC-205 from inexpensive and
readily available starting materials under mild conditions.
2
Other phosphorus ligands, PPh , P(2-furyl) , DPEphos, and
3
3
Xantphos, were also evaluated (entries 5-8), but P(o-tol) was
3
superior to all of them.
Examination of other trialkylamines, including DIPEA, and (n-
C
3
H
7
)
3
N, (n-C
8
H
17
)
3
N, indicated that they all performed well
N, the
(entries 9-11). In particular, in the presence of (n-C H )
3 7 3
yield of product 5 reached 87% and the reaction time was
shortened to 3 h (entry 10). These observations are consistent with
those in our previous studies that a tertiary amine base is necessary
for an efficient Heck-dehydration reaction [11].
O
O
First total synthesis
OMe
OMe
Suzuki-Miyaura
coupling
(5 steps,ref.8)
+
N
Br
N
O
H
hydrolysis
B
O
H
H
O
OH
After ascertaining that tripropylamine was the best base for the
reaction, we next investigated the role of the solvent. A screening
various solvents such as DMF, THF, 1,4-dioxane, DCE, and
toluene, we found that polar solvents led to the formation of diene
5 in good yield (entries 1, 12-14). In particular, the yield of 5
reached 85% in the presence of 1,4-dioxane (entry 14). A slightly
decreased yield were observed when DCE and toluene was
employed (entries 15, 16).
TMC-205 (1)
N
H
O
Heck-Mizoroki
coupling
O
H
H
oxidation
-dehydration
+
HO
N
Br
N
This work
2 steps)
Protecting-group-free
Redox-economy
H
2
H
3
5
(
cheap and readily available
Scheme 1. Retrosynthetic analysis of TMC-205.
Various additives (polymerization inhibitor) were further
screened to boost the transformation (entries 17-19). All of them
had a positive effect on this reaction; especially, the addition of
BHT led to an improved yield of up to 86% (entry 17).
Early-stage installation of the 3-carboxy group was not
advisable because of the difficulties in controlling the troublesome
acidic group. As illustrated in Scheme 1, our retrosynthetic
analysis of TMC-205 calls for a late-stage construction of the 3-
carboxy group by the oxidation of aldehyde 5. The crucial step in
Table 1. Investigating the Effect of the Catalyst, Ligand, Base, Solvent and Additives.
O
H
O
H
3
(4.5 eq.), Pd(OAc)2 (0.08 eq.),
HO
4
P(o-tol)3 (0.2 eq.), Et3N (1.0 eq.)
CH3CN (2ml), sealed tube, 115 o
C
N
H
N
Br
H
5
2
(1.0 eq.)
100mg, 0.45mmol
Entry
variable
t [h]
5
R.S.M. 2%a
yield 4%a
yield 5%a
1
2
3
None
-
-
81
60
83
PdCl
2
8
22
-
15
7
b
2
Pd (dba)
3
8

3
b
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
Pd
PPh
P(2-furyl)
2
(dba)
3
CHCl
3
8
8
8
8
6
8
3
5
8
8
8
5
8
8
8
8
-
10
75
3
8
24
32
3
12
9
6
35
DPEphosc
Xantphosd
DIPEAe
21
65
8
4
45
-
9
86
0
1
2
3
4
5
6
7
8
9
(n-C
(n-C
3
8
H
7
)
3
N
-
3
87
H
17
)
3
N
6
9
82
DMF
THF
12
8
4
82
10
80
1,4-dioxane
DCEf
7
0
85
25
22
6/8/6
3
2
72
Toluene
-
51
g
BHT (0.1/0.3/0.03eq.)
5/15/5
86/70/81
83
h
TBX (0.1 eq.)
5
3
i
TBC (0.1 eq.)
7
84
R.S.M.=Recovered Starting Material.
-” = Not Detected
“
a
b
c
d
e
f
Isolated yield.
.04 eq.
Bis(2-diphenylphosphinophenyl)ether
,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene
0
9
N,N-diisopropylethylamine.
Dichloroethane.
g
h
i
2
2
,6-di-tert-butyl-p-cresol.
-tert-butyl-4,6-dimethylphenol.
p-tert-butylcatechol..
Table 2. Further Study in the Synthesis of diene 5.
O
O
H
H
3
(4.5 eq.), Pd(OAc)2 (0.08 eq.),
HO
4
5
P(o-tol)3 (0.2 eq.), (n-C3H7)3N (1.0 eq.)
CH3CN (2ml), sealed tube, 115 o
BHT (0.1 eq.)
C
N
H
N
Br
H
2
(1.0 eq.)
100mg, 0.45mmol
Entry
variable
t [h]
5(7b)
5(10b)
5
R.S.M. 2%a
Yield 4%a
Yield 1%a
94(93b)
91(94b)
91
1
None (CH
3
CN as solvent)
4(3b)
12(4b)
8
-(-b)
-(- b)
-
2
1,4-dioxane
3
DMF
4
DMF;atmospheric pressure
8(10b)
5
15(11b)
5
3(4b)
2
80(82b)
92
5c
2
Pd(OAc) (0.04eq.)
a
b
c
Isolated yield.
gram-scale (1.34 g).
3
P(o-tol) (0.1 eq.).
Table 3. Study on Pinnick-oxidation of 5.
O
NaClO2 (4.0 eq.)
-methyl-2-butene (50.0 eq.)
O
H
OH
2
THF-t-BuOH-H2O (4:4:1.5, 9.5 mL)
NaH2PO4 (10.0 eq.)
TBC (1.5 eq.), resorcinol (1.5 eq.)
protect form light, r.t., 18h
N
N
H
H
5
(1.0 eq.)
TMC-205 (1)
42 mg, 0.2 mmol
Entry
1
Optimization of ref. [16]b,e
None
t [h]
20
R.S.M. 5%a
yield 1%a
20
14
21
34
2c
NaClO
(4.0 eq.); + resorcinol
11
2

4
Tetrahedron
3d
NaClO
(4.0 eq.); + resorcinol; + THF
8
23(21e)
33
42(30e)
62
2
4
“Entry 3”; at -18 ℃
“Entry 3” ; + TBX
48
5
18
33
66
6
“Entry 3” ; + TBX; at -18 ℃
“Entry 3” ; + BHT
48
35
64
7
18
36
62
18(27f)
19(21f)
g
78 (76f, g)
8
“Entry 3” ; + TBC
a
b
c
d
e
f
Isolated yield.
NaClO
NaClO
NaClO
2
(20.0 eq.), 2-methyl-2-butene (250.0 eq.), THF-t-BuOH-H
2
O (0:4:2.0, 6.0 mL), NaH
2
PO
4
(20.0 eq.).
2
( 4.0 eq. ), 2-methyl-2-butene ( 50.0 eq. ), THF-t-BuOH-H
2
O (0:4:1.5, 5.5 mL), NaH
2
PO
PO
4
(10.0 eq.).
(10.0 eq.).
2
( 4.0 eq. ), 2-methyl-2-butene ( 50.0 eq. ), THF-t-BuOH-H
2
O (4:4:1.5, 9.5 mL), NaH
2
4
Without premixing.
Gram-scale (1.27 g)
g
9
7% yield, based on recovered starting material (brsm) .
R1
R1
Considering the above findings, a high yield of diene 5 (Table
, 94%, entry 1; 91%, entries 2, 3) was obtained in 5 h when
adopting tripropylamine as the base, BHT as the additive, and
CH CN as the solvent (or 1,4-dioxane, DMF). To evaluate the
3 (4.5 eq.), Pd(OAc)2 (0.08 eq.),
P(o-tol)3 (0.2 eq.), (n-C3H7)3N (1.0 eq.) HO
2
CH3CN (2ml), sealed tube, 115 o
C
Br
N
N
BHT (0.1 eq.)
(1.0 eq.) R2
.45mmol
R2
0
3
O
O
efficiency of this reaction on a larger-scale, we performed the
CF3
CF3
OH
reaction using 1.34 g of substrate 2. Pleasingly, 5 was isolated in
N
N
H
N
N
excellent yield (93%, CH
3
CN; 94%, 1,4-dioxane) without loss of
H
H
H
HO
HO
HO
HO
4a
4b
4c
4d
efficiency, as opposed to the small-scale reaction. Nevertheless,
we were dissatisfied with the use of a sealed tube, which is not
ideal for large-scale synthesis. Therefore, we further attempted to
(
natural product)
one step, 94% yield
one step, 95% yield
one step, 96% yield
O
one stepa, 97% yield
(aby direct reduction of 5)
O
CF3
CF3
OH
develop
a more practical method. Process development
demonstrated that the reaction could also performed at
atmospheric pressure in DMF (80% or 82% on a gram scale, entry
N
H
N
H
N
Me
N
H
5a
5b
5c
5d
one step, 78% yield
one step, 88% yield
one step, 75% yield
one stepa, 80-90% yield
(aby direct reduction of TMC-205)
4
), without the need for higher temperatures to compensate for the
reduction in reaction pressure. Furthermore, good performance
was achieved by using only 4 mol% of the catalyst (92%, entry 5).
As shown above, the Heck-dehydration reaction is a more efficient
and reliable method than previous reaction [8] for introducing a
isoprene unit toward the synthesis of TMC-205.
O
O
O
H
H
OH
N
H
N
H
N
H
HO
4
5
TMC-205 (1)
one step, 96% yield
one step, 94% yield
91% overall yield
compound 5a-5d, 4b, 1: Antiproliferative Activity against HCT-116 Colon Cancer cells[8]
compound 4a, 4c, 4d, 4, 5: Potential active analogues
Having assembled the desired carbon skeleton, we turned our
attention to oxidizing the 3-aldehyde group into a carboxyl group
en route to the desired TMC-205. Oxidation of the aldehyde group
of 5 via Pinnick oxidation under the literature conditions [16]
afforded TMC-205 in 21% yield along with the starting material
in 20% yield, after flash column chromatography. The
spectroscopic data for the synthetic TMC-205 were in agreement
with those reported for the natural product [7]. To achieve an
efficient transformation, we decided to explore a high-yield
Pinnick oxidation. After many experimental trials [17] (Table 3),
we achieved the desired result with resorcinol [18] and TBC as the
ref.19
R
H
R
N
N
H
PhO2S
6, -Me, Caulindole A
N
(
R = H)
H
7, -Me, Caulindole B
8, -Me, Caulindole C
9, -Me, Caulindole D
(
R =
)
OH
ref.20
OH
O
2
additives in a mixed solvent system (THF-t-BuOH-H O) and
OH
O
O
OH
O
H
H
H
obtained TMC-205 in 78% yield (or 97% brsm, entry 8). The
reaction also performed well on the gram scale. The Pinnick
oxidation reported in this paper is beneficial and valuable for
further application of this reaction in the field of organic synthesis.
The two-step synthesis of TMC-205 was finally realized via a
practical Heck-dehydration reaction, followed by a well-studied
Pinnick oxidation on a gram scale, in excellent yield without the
need for protecting groups.
O
MeO
OMe
HO
O
OH
HO
OH
OH
OH
10, Griffipavixanthone
etc.
Following the above optimized Heck-dehydration reaction, we
decided to embark on the synthesis of the active analogues of
TMC-205 so that its pharmacological activity could be better
examined and the synthetic utility of this reaction could be
demonstrated. As shown in Scheme 2, the reaction proceeded well
with a wide range of substrates, furnishing a series of the desired
tertiary allylic alcohol or isoprene products in good yields (4a-4d
or 5a-5d, 4, 5). Although 5a−5d, 4b, 1 have been previously
synthesized [8], the synthetic route was not as efficient as that
employed by our group. The yields of 5d were variable due to the
instability of the butadiene and enol. Additionally, attempts to
Scheme 2. Synthesis of active analogues.

5
synthesize 4d and 5d via the Heck-dehydration reaction proved
difficult due to the unstable nature of (6-bromo-1H-indol-3-yl)
methanol. Further application of this methodology to the total
syntheses of other natural products (such as 6-10 [19, 20] and so
on) are under investigation and will be reported in due course.
16. Y. Fumio, M. Yoshihiko, S. Masanori, Heterocycles, 2007, 72,
99-620.
1
5
7. A. Raach, O. Reiser, J. Prakt. Chem. 2000, 342, 605-608 and
references therein.
8. B. O. Lindgren, T. Nilsson, Acta. Chem. Scend., 1973, 27, 888-890.
19. D. H. Dethe, R. D. Erande, B. D. Dherange, Org. Lett. 2014, 16,
764-2767.
0. M. J. Smith, K. D. Reichl, R. A. Escobar, T. Heavey, D. F. Coker,
1
2
In summary, a concise and practical total synthesis of TMC-
2
2
05 (on a gram scale) was achieved in two steps and in 91% overall
S. E. Schaus, J. A. Porco, J. Am. Chem. Soc. 2019, 141, 148-153.
yield from simple, readily available starting materials and
reagents. The short and efficient synthesis features a successful
PGF and a redox-economical strategy, thus demonstrating the
pursuing values of modern organic synthesis. Through
optimization of the reaction parameters, a high-yield Pinnick
oxidation has been achieved. The trans-(3-methyl-l, 3-butadienyl)
unit is effectively introduced via a novel Heck-dehydration
reaction, with high atom economy as well as high regio- and
stereo-selectivity. Based on the key reaction, a series of active
analogues of TMC-205, including another natural product, have
Declaration of interests
☒ The authors declare that they have no known
also
been
synthesized in
good yields.
Moreover, the
strategy and
methodologies adopted in this synthesis would be beneficial for
the preparation of other relevant natural products. The gram-scale
synthesis of TMC-205 will facilitate the testing of its biological
properties and SAR studies. Efforts related to these aspects will be
the focus of our future studies.
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐
The authors declare the following financial
Acknowledgments
interests/personal relationships which may be
considered as potential competing interests:
S.-Z. J. thanks Basic Joint Project of Yunnan Provincial
Science and Technology Department (grant number 2017FH001-
0
19, 2019FH001-087) and the Innovation Team Project of Dali
University for Development and Utilization of Characteristic
Medicinal Plants in Western Yunnan & Bai Nationality Medicines
(grant number ZKLX2019106) for financial support.
References and notes
1
2
3
.
.
.
J. B. Hendrickson, J. Am. Chem. Soc., 1975, 97, 5784-5800.
R. W. Hoffmann, Synthesis, 2006, 21, 3531-3541.
N. Z. Burns, P. S. Baran, R. W. Hoffmann, Angew. Chem. Int. Ed.
2
009, 48, 2854-2867.
4
5
6
7
.
.
.
.
I. S. Young, P. S. Baran, Nature Chem., 2009, 1, 193-205.
R. N.Saicic, Tetrahedron, 2014, 70, 8183-8218.
C. Hui, F. Chen, F. Pu, J. Xu, Nat. Rev. Chem. 2019, 3, 85-107.
M. Sakurai, J. Kohno, M. Nishio, K. Yamamoto, T. Okuda, K.
Kawano, N. Nakanishi, J. Antibiot, 2001, 54, 628-634.
8
9
1
1
1
1
1
1
.
.
Y. Gao, S. Osman, K. Koide, ACS Med. Chem. Lett., 2014, 5, 863- Highlights
8
67.
S. Z. Jiang, X. Y. Zeng, X. Liang, T. Lei, K. Wei, Y. R. Yang,
Angew. Chem. Int. Ed., 2016, 55, 4044-4048.



A concise and efficient total synthesis of TMC-
05 is achieved.
0. X. Liang, S. Z. Jiang, K. Wei, Y. R. Yang, J. Am. Chem. Soc., 2016,
38, 2560−2562.
1. L. H. Wang, T. Lei, F. S. Wang, S. Z. Jiang, G. Y. Yan, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2021.152822.
2
1
A protecting-group-free and redox-economical
strategy has been used.
This practical reaction was further applied to the
synthesis of TMC-205 analogues.
2. M. Oestreich, The Mizoroki-Heck Reaction. Wiley: Chichester,
2
009.
3. B. Jiang, J. M. Smallheer, C. Amaral-Ly, M. A. Wuonola, J. Org.
Chem., 1994, 59, 6823-6827.
4. D. Schäfer, P. Weiß, J. Ermert, J. C. Meleán, F. Zarrad, B.
Neumaier, Eur. J. Org. Chem. 2016, 4621-4628.
5. S. Gandhi, B. Baire, J. Org. Chem. 2019, 84, 3904−3918.