Access to 1-indolyltetrahydro-β-carbolines: via metal-free cross-dehydrogenative coupling: The total synthesis of eudistomin U, isoeudistomin U and 19-bromoisoeudistomin U

Article abstract of DOI:10.1039/d0cc06958b

A highly selective and captivating metal-free cross-dehydrogenative coupling for the cross-coupling of two reactive nucleophiles such as tetrahydro-β-carboline and indoles is developed. A series of 1-indolyltetrahydro-β-carboline derivatives were synthesized in excellent to moderate yields. Temperature, time and concentration control resulted in mono indolylation selectively. Moreover, the total synthesis of eudistomin U and isoeudistomin U and the first total synthesis of 19-bromoisoeudistomin U were accomplished.

Full text of DOI:10.1039/d0cc06958b

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Access to 1-Indolyltetrahydro--carbolines via Metal-Free Cross-
Dehydrogenative Coupling: Total Synthesis of Eudistomin U,
Isoeudistomin U and 19-Bromoisoeudistomin U†
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Ganapathy Ranjani and Rajagopal Nagarajan
A
highly selective and captivating metal-free cross- and non-reactive. Combinations of transition-metal catalysts,
dehydrogenative coupling for the cross-coupling of two oxidants, and mostly high temperatures are generally needed
reactive nucleophiles such as tetrahydro- -carboline and to activate the non-reactive C-H bonds (C-H activation).
indoles is developed. A series of 1-indolyltetrahydro- The oxidation of the C-H bond becomes easy when it


-
carboline derivatives were synthesized in excellent to accompanies a hetero-atom (O, N, S) at the adjacent position
moderate yields. Temperature, time and concentration (reactive nucleophiles). In oxidative coupling reactions, one of
control resulted in mono indolylation selectively. Moreover, the two nucleophiles involved in the C-C bond formation is in
total synthesis of Eudistomin U, Isoeudistomin U and first situ converted into electrophile by means of oxidizing reagents
t
total synthesis of 19-Bromoisoeudistomin
U
were (NCS, NBS, BuOCl, DDQ, TEMPO salts, transition metal
accomplished using the same strategy with good overall catalysts). On the other hand, such reactions are highly prone
yield.
to side reactions (homocoupling, the coupling of oxidizing
reagents with one of the reactants, over-oxidation, etc.) and
The construction of a carbon-carbon bond plays an exemplary poor selectivity. The situation becomes very tough to handle
role in organic synthesis and serves as the heart of classical when both the nucleophiles involved in the oxidative cross-
1
and modern synthetic organic chemistry. For many years, coupling are highly reactive. The specific choice of reagents
transition metal-catalysed traditional cross-couplings were and reaction conditions may solve the issues experienced
2
mainly used for making C-C bond formation. Conventional during the coupling of highly reactive nucleophiles.
metal-catalysed coupling reactions employ pre-functionalized
electrophiles, nucleophiles, and results in stoichiometric
amounts of waste during the transmetalation step. Besides,
pre-functionalized electrophiles used in the traditional
coupling reactions are either directly or indirectly obtained
from the corresponding C-H nucleophiles.
Figure 1. Examples of 1-Indolyl--Carboline alkaloids
To minimize the waste production and address
environmental issues, scientists started developing more
3
greener, and environmentally benign synthetic reactions. If
two C-H nucleophiles are coupled directly without any pre-
functionalization then, the by-product would be hydrogen, and
also the waste production will be minimized. The coupling of
two nucleophiles was seemed to be highly imaginary until
3
oxidative cross-coupling strategies were developed. The
future of organic synthesis relies on such oxidative cross- Figure 2. Previous reports for the synthesis of 1-indolyl THCs
coupling strategies as they possess the potential to make
synthetic organic chemistry more economical and eco-
Tetrahydro--carboline (THC) (1) is an annulated indole,
friendlier. C-H bonds can generally be classified as reactive highly reactive, and presents in many biologically active
4
a-c
alkaloids.
literature with the combination of TH
). Developing cross-dehydrogenative coupling (CDC) for the
coupling of reactive nucleophiles such as indoles and TH C will
address the problems associated with the CDC reaction of
Also, many exciting alkaloids were known in the

C (1) and indole (2) (Fig.
School of Chemistry, University of Hyderabad, Hyderabad - 500046, Telangana,
India. E-mail: nagarajan@uohyd.ac.in
1

†
Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
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Journal Name
reactive nucleophiles and also afford biologically important 1- (1). In literature, only two reports were found in which CDC is
View Article Online
DOI: 10.1039/D0CC06958B
indolyltetrahydro-

-carboline (6) derivatives. Though the employed for the coupling of tetrahydro-

-carboline with
6
oxidation of secondary amine is relatively difficult, reactivity of alkenyl/aryl boronates , and to the best of our knowledge, no
indole allows the substrate to undergo further oxidation reports were found on the direct CDC of two reactive
5
a
followed by coupling with one more molecule of indole.
nucleophiles such as simple TH

C (1) and indole (2) to afford
-carbolines selectively.
Keeping the literature gap in mind, we started reaction
optimization with different oxidizing reagents, solvents at
various temperature and time (Table 1). N-Chlorosuccinimide
mono indolyl tetrahydrotetrahydro-

Table 1. Optimization of reaction conditions
(NCS) (five minutes of stirring after the addition of NCS and
then indole (2a) was added, followed by 10 minutes of stirring
before quenching the reaction) resulted in only 10 % of the
cross-coupled product 6a (Table 1, entry 1). By decreasing the
reaction time to 5 minutes (two minutes of stirring after
adding NCS and then indole (2a) was added, followed by 3
minutes of stirring before quenching the reaction), we could
get the aimed coupled product selectively without any over
oxidation but the conversion was only about 50 % (Table 1,
S.
Oxidizing
reagent
Solvent
dioxane
T
Time
Yield (%) f
6a
10 60 20
a
o
No
( C) (min)
7
8
b
1
NCS
(1.0 1,4-
rt
rt
rt
rt
rt
rt
15.0
5.0
equiv.)
NCS
equiv.)
2b
3b
4b
5b
6b
(1.0 1,4-
dioxane
50
-
-
-
t
BuOCl (1.3 EtOAc-
5.0
70 20
equiv.)
NaOCl (2.0 DCM-
2
H O
t
entry 2). When BuOCl, NaOCl and DIB were employed as an
120
60
-
-
-
-
-
-
-
oxidizing agent, no mono indolyl product 6a formation was
observed (Table 1, entries 3, 4, 5). With DDQ in DCM (after
adding DDQ 1.5 h of stirring and then indole (2a) addition,
followed by 30 minutes of stirring before quenching the
reaction), 40 % of the coupled product was formed (Table 1,
entry 6). During the course of optimization, we understood
equiv.)
DIB
2
H O
(1.0 DCM
-
equiv.)
DDQ (1.0 DCM
equiv.)
120
40
b, c
b, c
c, d
+
-
-
-
7
8
9
1
1
1
1
1
1
1
T BF
4
4
4
DCM
DCM
DCM
DCM
DCM
DME
THF
toluene -20
EtOAc
1,4-
0
2.5
2.5
2.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
25 75
50 50
-
-
-
-
-
that the time required for the oxidization of TH
crucial. We carried out many reactions by increasing the time
for initial oxidation of TH C 1a, using DDQ, none of our
C 1a is also
+
T BF
-20
-20
-20
-20
-20
-20
+
T BF
82
85
88
70
72
60
58
24
-
-
-

0e Ph
C PF
+
-
3
3
3
3
3
3
3
6
attempts improved the yield of the reaction. Then we
prepared a Bobbitt salt and employed it as an oxidizing
reagent, 25 % and 50 % of coupled product 6a was obtained at
e
+
-
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
C BF
4
e
e
e
e
e
+
-
-
-
-
-
C BF
4
+
C BF
4
4
4
4
-
-
-
-
-
-
-
-
o
o
0
C and -20 C within 150 seconds respectively (Table 1,
+
C BF
entries 7, 8). Surprisingly, the yield of the coupled product 6a
was increased to 82 % when the concentration of the reaction
is decreased to 0.06 M (Table 1, entry 9). When we employed
triphenylcarbenium salts as oxidizing agents, fortunately the
yield of the reaction was further improved.
Hexafluorophosphate salt of trityl cation afforded 85 % of 6a
whereas the tetrafluoroborate salt of the same furnished 88 %
of 6a in 180 seconds (Table 1, entries 10, 11). By screening
various solvents, we understood that DCM is the best solvent
to achieve the targeted compound 6a as a major compound
+
C BF
-20
-20
+
C BF
dioxane
7e Ph
8
C BF
+
-
-
CHCl
DCE
-20
-20
3.0
3.0
45
54
-
-
-
-
1
1
3
3
4
4
3
e
+
Ph
C BF
a
where T = temperature, Reaction conditions: 1a (0.18 mmol,
1
mmol, 1.2 equiv.) unless otherwise mentioned, solvent (3 mL).
T = TEMPO. Reaction concentration is 0.2 M. 2 minutes of
stirring after adding oxidizing reagent and 30 seconds of
equiv.), 2a (0.2 mmol, 1.1 equiv.), oxidizing reagent (2.2
b
c
(Table 1, entries 11-18).
After completing the optimization of reaction conditions for
d
stirring after adding indole 2a. Reaction concentration is 0.06
M. 2.5 minutes of stirring after adding oxidizing reagent and
the synthesis of 6a, we started the investigation of substrate
scope of trityl salt mediated CDC of Boc protected TH C (1a)
e

30 seconds of stirring after adding indole 2a, reaction
with different indoles (2a-q) possessing electron donating and
electron withdrawing substitutions (Scheme 1). Indoles with
EDGs reacted extremely faster and afforded good to excellent
yield of the products (6b-f), the structure of 6c was confirmed
using X-ray crystallography (CCDC number: 1973061). Indoles
with EDGs at the second position reacted very fast and also
resulted in excellent yield of the products and just 10 seconds
after adding indole are sufficient to get the coupled product in
major amount (6e, 6f). Due to the combined effect of electron
donating and electron withdrawing nature of halogens,
moderate yields of the product was obtained when halogens
f
concentration is 0.06 M. Isolated yields.
Hence it will be highly difficult to obtain the mono indolyl
products selectively. Since TH
possibility of cleavage of the ring under oxidative conditions.
Due to which no direct CDC methodologies were explored with
the combination of TH C and indole. Preparation of 1-indolyl
TH C rely on Pictet-Spengler reaction or less selective
chloroindolenine intermediates (Fig. 2). Hence, we aimed to
develop a CDC reaction for the coupling of indole (2) and TH
C is also reactive, there is a
5
b


5
c-d

C
2
| J. Name., 2012, 00, 1-3
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a,b
were present on indole (6g-j). As expected, indoles with strong Scheme 2: Oxidative cleavage of tetrahydro-
EWGs further resulted in decreased conversion and therefore

-carboline
View Article Online
DOI: 10.1039/D0CC06958B
gave only moderate yield of the coupled products (6k-n).
Scheme 1: Substrate Scope (Synthesis of derivatives of 6a) a,b
:
a
Reaction conditions: Tetrahydro-

-carboline 1a (0.185 mmol,
1
.0 equiv.), Trityl salt (0.222 mmol, 1.2 equiv.), NuH (0.204
b
mmol, 1.1 equiv.), & DCM (3.0 mL, 0.06 M), Isolated yields.
In addition, rotamers were found in most of the cases and
can be differentiated only at the aliphatic region of the THC
and the Boc group of the coupled products. To prove the
rotamer formation, we have conducted high temperature
NMR by taking 6c as a model substrate, delightedly, at higher
temperature, multiple peaks those formed at room
temperature were merged. Besides, indoles with bulky groups
at the 2- and 4-position did not show rotamer formation (6e,
6f, 6m and 6o). After deprotecting the Boc group of 6a, the
rotamers were disappeared (10, see the ESI) and confirms that
the rotamers are formed due to the presence of Boc group.
a
Reaction conditions: Tetrahydro--carboline 1a-c (0.185
Figure 3. Proposed mechanism of the reaction
mmol, 1.0 equiv.), Trityl salt (0.222 mmol, 1.2 equiv.), indoles
a-q (0.204 mmol, 1.1 equiv.), & DCM (3.0 mL, 0.06 M), 30
2
Proposed mechanism for the trityl salt mediated CDC of
tetrahydro--carboline 1a with indole 2a and oxidative ring
seconds. For substrates 2e and 2f, the reaction time is 10
b
seconds after addition of indole. Isolated yields.
opening by water is described in Fig. 2. Trityl cation oxidizes
the compound 1a and affords intermediate (i) which on the
nucleophilic attack of indole furnishes the product 6a. When
the nucleophilicity of indole is not sufficient enough to couple,
attack of water followed by in situ acidic ring opening results in
oxidative cleavage of 6a to give compound 9 (Fig. 3).
Increasing the time of the reaction (to improve the
conversion), resulted in further decrease in yield of the
product in the case of indole having EWGs (6k-n). Gratifyingly,
when an EDG was introduced at the second position of the
indole possess EWG already on its ring, the conversion and
yield of the reaction was further improved (6o). Moreover,
protection of indole N-H with electron releasing groups also
resulted in good yield of the coupled products (6p, q). In case
After analysing the substrate scope of the reaction, we
attempted the total synthesis of alkaloid Eudistomin U (3)
(Scheme 3). Eudistomin U (3) is an 1-indolyl--carboline
alkaloid (Fig. 1) and exhibit a wide spectrum of biological
of N-benzyl protected TH
observed and when both the N-H of tetrahydro-
1c) were protected with Boc groups, trace amounts of

C (1b), no coupled product was
7
properties. Eudistomin U (3) and isoeudistomin U (4) were

-carboline
isolated from the marine ascidian Lissoclinum fragile by
(
7
a
Francisco et al. in the year 1994. 19-Bromoisoeudistomin U
5) was isolated from the marine ascidian Eudistoma along
coupled product 6s was obtained (confirmed by TLC). As the
nucleophilicity is not sufficient enough to undergo CDC
reaction, no coupled product was observed when 7-azaindole,
(
7
b
with isoeudistomin U (4) in the year 1996. Structural revision
of isoeudistomin U (4) was reported by its synthesis in the year
1
3
-methylindole, ethyl indole-2-carboxylate, and 5-benzyloxy-
ethyl indole-2-carboxylate were used and only oxidative
cleavage of tetrahydro- -carboline (1a) was observed in such
7
c
995 whereas the synthesis of alkaloid 5 is not known till
date. In 1995, Molina & co-workers successfully completed the

8
a
first total synthesis of Eudistomin U (3). Later a couple of
cases to afford compound 9 (Scheme 2). Also, a gram scale
synthesis of 6a was performed and resulted in 82 % of yield
5
d, 8b-m
reports were reported for the synthesis of 3.
We would
like to apply the trityl salt mediated CDC reaction followed by
oxidation/ aromatization strategy for the total synthesis of 3, 4
(see the ESI).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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5. Compound 6a on Boc deprotection using HCl in 1,4-
Journal Name
&
Angew. Chem., Int. Ed., 2013, 52, 2082–2086. (e) S. A.
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Girard, T. Knauber and C.-J. Li, Angew. Chem., Int. Ed., 2014,
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dioxane, afforded compound 10 and which on further
5
3, 74–100. (f) M. K. Lakshman and P. K. Vuram, Chem. Sci.,
o
aromatization using 10 % Pd/C in xylene at 140 C for 6 hours
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017, 8, 5845–5888. (g) R. Narayan, K. Matcha and A. P.
furnished the target alkaloid Eudistomin U (3) in 66 % of yield
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afforded the Isoeuditomin U in 56 % (over 2 steps) and
compound 6j, on deprotection followed by partial oxidation
with IBX furnished 19-Bromoisoeudistomin U in 60 % (over 2
steps) (Scheme 3, see the ESI, Table S1).
(
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1
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(
1
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To conclude, a highly selective and rapid metal-free cross-
dehydrogenative coupling strategy for the coupling of very
reactive nucleophiles such as tetrahydro--carboline and
indoles was demonstrated successfully. Insights into
the factors governing the reactivity and reaction’s selectivity
opened the door for solving the puzzles in the chemistry of
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excellent to moderate yields. In addition, total synthesis of
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U (5) were
%
We acknowledge SERB, India for financial support
EEQ/2017/000422) and GR thanks DST, India for fellowship.
(
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DOI: 10.1039/D0CC06958B
A highly selective metal-free cross-dehydrogenative-coupling approach for the synthesis of 1-
indolyltetrahydro-β-carbolines is developed. Total synthesis of biologically important alkaloids,
Eudistomin U, Isoeudistomin U and the first total synthesis of 19-Bromoisoeudistomin U were
accomplished using the developed strategy.