Synthesis of oxacalothrixin B and its analogues involving iodine/TBHP-mediated electrocyclization

Article abstract of DOI:10.1016/j.tetlet.2017.06.036

The total synthesis of oxacalothrixins, an isostere of biologically important carbazoloquinone alkaloid, calothrixin B was achieved from 2-acetyl-3-methylbenzofuran. An iodine/TBHP-mediated oxidative cyclization of benzofuranyl-enamine has been employed as a key step to synthesize, the crucial intermediate 1-hydroxy dibenzofurancarbaldehyde. The latter upon reductive cyclization followed by PIDA-mediated oxidation furnished oxacalothrixin B and its analogues.

Full text of DOI:10.1016/j.tetlet.2017.06.036

Accepted Manuscript
Synthesis of Oxacalothrixin B and its Analogues Involving Iodine/TBHP-Medi-
ated Electrocyclization
Bose Muthu Ramalingam, Arasambattu K. Mohanakrishnan
PII:
S0040-4039(17)30758-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.036
TETL 49028
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 May 2017
11 June 2017
12 June 2017
Please cite this article as: Ramalingam, B.M., Mohanakrishnan, A.K., Synthesis of Oxacalothrixin B and its
Analogues Involving Iodine/TBHP-Mediated Electrocyclization, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.06.036
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Synthesis of Oxacalothrixin B and its Analogues
Involving Iodine/TBHP-Mediated Electrocyclization
Bose Muthu Ramalingam, Arasambattu K. Mohanakrishnan *

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of Oxacalothrixin B and its Analogues Involving Iodine/TBHP-
Mediated Electrocyclization
Bose Muthu Ramalingam, Arasambattu K. Mohanakrishnan*
Department of Organic Chemistry, School of Chemical Sciences, University of Madras, Guindy Campus, Chennai - 600 025, Tamil Nadu, India
Email: mohanakrishnan@unom.ac.in/mohan_67@hotmail.com
ARTICLE INFO
ABSTRACT
The total synthesis of oxacalothrixins, an isostere of biologically important carbazoloquinone
alkaloid, calothrixin B was achieved from 2-acetyl-3-methylbenzofuran. An iodine/TBHP-
mediated oxidative cyclization of benzofuranyl-enamine has been employed as a key step to
synthesize, the crucial intermediate 1-hydroxy dibenzofurancarbaldehyde. The latter upon
reductive cyclization followed by PIDA-mediated oxidation furnished oxacalothrixin B and its
analogues.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
I2/TBHP
2017 Elsevier Ltd. All rights reserved.
Calothrixin B
Electrocyclization
methylbenzofuran 69 using (CH3)2SO4, 2M NaOH in dioxane for
2 h afforded 5-methoxy-3-acetyl-2-methylbenzofuran 7.
Calothrixin
A
1
and
B
2
are novel indolo[3,2-
j]phenanthridine alkaloids isolated from calothrix cyanobateria
in 1999.1 These natural product exhibit important biological
activities such as antimalarial, anticancer and they inhibit
bacterial RNA polymerase2 and poison DNA topoisomerase I.3
Calothrixin A is also known to induce the intracellular formation
of reactive oxygen species.4 The highly promising biological
activity of calothrixins led to the development of several
synthetic strategies.5
O
Me
SnCl4/CH3COCl
Me
DCM, 0 oC,
O
Me
O
O
4
30 min, 85%
5
O
HO
MeO
The development of more potent as well as more selective
analogues of calothrixin may well lead to a suitable clinical
candidate. Recently, our group reported
2 M NaOH
(CH3)2SO4
Me
Me
Me
a synthesis of
dioxane, 2 h
74%
O
Me
O
thiacalothrixin B 3 involving Lewis acid- mediated domino
reaction protocol. Both thia analogues of calothrixin displayed
comparable cytotoxicity with that of the parent calothrixin.6 In a
further continuation on the synthesis of calothrixin analogues,
oxacalothrixins, the isostere of calothrixin B is planned using an
established Lewis acid-mediated domino reaction strategy.7
6
7
Scheme 1. Synthesis of 2-acetyl-3-methylbenzofurans 5 and 7.
As expected an allylic bromination of compound 5/7 using
NBS and a catalytic amount of AIBN in CCl4 at reflux for 4 h
afforded respective bromo compound 8a/8b in good yield. Next,
the reaction of bromo compound 8a/8b with PPh3 in dry THF
upon reflux followed by Wittig reaction of resulting
phosphonium salt 9a/9b with 2-nitroarylaldehydes 10a-c using
K2CO3 as a base in DCM at room temperature led to the
formation of 3-acetyl-2-nitroarylvinyl-benzo[b]furan 11a-f (E
and Z mixture) as yellow-orange/yellow solid in good yields. A
subsequent reaction of 3-acetyl-2-nitroarylvinylenes (E:Z) 11a-f
with DMF.DMA in the presence of 50 mol% glycocyamine as a
catalyst at 100 °C for 2 h followed by aqueous workup furnished
only E-enamines 12a-f as yellow-orange/yellow solid in 84-86%
yields.
O
O
O
O
N
N
N
N
H
N
H
S
O
O
O
3
1
2
Fig. 1. Bioactive calothrixins and thiacalothrixins B.
The synthetic work started with the preparation of 3-acetyl-2-
methylbenzofuran and 5-hydroxy-3-acetyl-2-methylbenzofuran.
Friedel-Crafts acylation of 2-methylbenzofuran 48 using
o
CH3COCl in the presence of SnCl4 in dry DCM at 0 C for 30
min afforded 3-acetyl-2-methylbenzo[b]furan 5 in good yield.
Next,
a
routine o-methylation of 5-hydroxy-3-acetyl-2-

2
Tetrahedron
O
O
R1
R1
Most likely, the relatively electron withdrawing nature of
NBS/CCl4
AIBN (Cat.)
Me
CH3
PPh3/THF
reflux, 3 h
benzofuran oxygen atom of 12a compared to the sulfur as well as
N-phenylsulfonyl units may disfavor the LA-mediated oxidative
cyclization reaction.
5 7
/
86-88%
CH2Br
CH2PPh3 Br
O
O
9a/9b
8a/8b
1
1
8a
8b
R = H
1
9a
9b
R = H
1
The formation of 1-hydroxydibenzofuran-2-carboxaldehyde
14a in low yield prompted us to explore an alternative strategy
for conversion of enamine 12a into the required 1-
hydroxydibenzofuran carbaldehyde 14a. Hence, based on the
literature survey, an iodine-mediated cyclization10 was planned.
However, as expected the reaction of enamine 12a with 1 equiv.
of I2 in DCM at reflux failed to induce any cyclization.
Surprisingly, the reaction of 12a with iodine (0.5 equiv.) in the
presence of TBHP (2 equiv.) as co-oxidant in DCM at room
temperature for 2 h afforded desired compound 14a in 30% yield.
R = OMe
R = OMe
OHC
O2N
R2
O
R1
CH3
10a-c
9a 9b
/
R2
K2CO3, DCM
8 h, 79-83%
O
O2N
11a-f
E:Z - 90:10
11/12 R1 R2
O
NMe2
a
b
c
d
e
f
H
DMF.DMA
glycocyamine
(50 mol %)
H
Cl
F
R1
H
11a-f
H
Next, we turned our attention to investigate the role of iodine
and TBHP-mediated oxidative cyclization of enamine 12a. As
expected, the reaction of the enamine 13a could be performed
with different conditions and the results obtained are summarized
in Table 1.
100 oC, 2 h
82-86%
R2
O
OMe
OMe
OMe
H
Cl
F
12a-f
O2N
E - isomer
Scheme 2. Synthesis of benzofuranyl enamines 12a-f.
Table 1. Condition optimization on cyclization of enamine 12a
Unfortunately, the reaction of enamine 12a using established
procedure,6 i.e., with 3 equiv. of FeCl3 in DMF at reflux for 3 h
followed by workup and column chromatographic purification
afforded oxacalothrixin B 13a only in a 10% yield. To improve
the yield of 13a, the enamine 12a was refluxed with 3 equiv. of
FeCl3 in DMF for 1 h without any success. Indeed, only a trace
amount of product formation could be monitored only by the
TLC. Since, the FeCl3-mediated domino reaction of the enamine
12a was found to be problematic; a slightly detoured route for
accessing oxacalothrixin B 13a via 1-hydroxydibenzofuran-2-
carbaldehyde 14a was planned. Unexpectedly, the reaction of
enamine 12a with 1 equiv. of CuBr2 in DMF at reflux for 1 h
followed by workup led to the formation of 1-
hydroxydibenzofuran-2-carbaldehyde 14a only in a 20% yield.
Reducing the reaction time for 30 min instead of 1 h also
afforded the carbaldehyde 14a in a trace amount. While changing
the solvent as 1,2-DCE instead of DMF also failed to give the
desired compound 14a in a reasonable yield. Even though, the
corresponding N-phenylsulfonylindole enamines were smoothly
transformed into the respective 4-hydroxy-2-nitroarylcarbazole-
3-carbaldehydes by using CuBr2 in good yields,7 in the present
case, when the similar conditions were employed, transformation
of benzofuran based enamine 12a into the respective aldehyde
14a was found to be difficult.
Entry Catalyst
Oxidant
Solvent
T
°C
Time Yield
(%)a
(h)
1
2
I2 (1 equiv.)
DCM
DCM
DCM
DCM
ACN
DCM
DCM
DCM
ACN
DCM
rt
rt
rt
rt
rt
6
2
NA
30
I2 (0.5 equiv.)
I2 (1 equiv.)
I2 (2 equiv.)
I2 (2 equiv.)
I2 (2 equiv.)
I2 (2 equiv.)
TBHP (3 equiv.)
TBHP (3 equiv.)
TBHP (5 equiv.)
TBHP (5 equiv.)
K2S2O8 (5 equiv.)
m-CPBA (5 equiv.)
TBHP (5 equiv.)
TBHP (5 equiv.)
TBHP (2 equiv.)
3
2
52
4
2
80
5
6
72
6
50
6
25
7
rt
rt
rt
rt
6
65
8
NIS (2 equiv.)
NaI (2 equiv.)
PIDA (2 equiv.)
12
6
70
9
NA
NA
10
2
a
Isolated yields of 1-hydroxydibenzofuran-2-carbaldehyde 14a
In order to optimize the reaction condition for facile
transformation of enamine 12a into the required aldehyde 14a,
the oxidative cyclization was performed by varying the
equivalents of iodine as well as TBHP (Table 1, entries 2-4). An
increase in the amount of iodine (2 equiv.) and TBHP (5 equiv.)
greatly enhanced the formation of 14a. When the reaction was
performed in acetonitrile (ACN) instead of DCM, resulted in a
slightly reduced the yield of 14a (Table 1, entry 5). Use of other
oxidant such as K2S2O8 inplace of TBHP furnsihed low yield of
dibenzofuran-2-carbaldehyde 14a (Table 1, entry 6). However,
when m-CPBA was employed as co-oxidant led to the formation
of 14a in a moderate yield (Table 1, entry 7). The exploration of
iodine source as NIS has slightly decreased the yield of 14a
(Table 1, entry 8). However, the replacement of iodine by NaI,
failed to induce any cyclization. The replacement I2-TBHP
condition with PIDA/TBHP also failed to produce the expected
aldehyde 14a (Table 1, entry 10), instead a complex mixture was
obtained.
O
NMe2
O
N
3 equiv. FeCl3
reflux, 3 h, 10%
O
O
13a
O
12a
O2N
HO
CHO
CuBr2, DMF
12a
reflux,1 h
20%
O
O2N
14a
The optimised reaction condition for the facile transformation
of enamine 13a into the dibenzofuran aldehyde 14a was found to
involve I2 (2 equiv.), TBHP (5 equiv.) in DCM at room
temperature for 2 h (entry 6).
Having established a facile transformation of the enamine
12a into dibenzofuran aldehyde 14a using I2 and TBHP, adopting
the similar conditions, rest of the enamines 12b-f were also
converted into the respective 1-hydroxydibenzofuran 14b-f in
excellent yields.
Scheme 3. LA-mediated domino reaction of enamine 12a
It should be noted that the N-phenylsulfonylindole as well as
benzo[b]thiophene based enamines underwent a facile LA-
mediated domino reaction to afford the corresponding aldehydes
as well as calothrixin analogues in good yields.7 The obtainment
of low yield for LA-mediated transformation of enamine 12a into
oxacalothrixin B 13a/dibenzofuran-2-carbaldehyde 14a might be
due to the poor co-ordination ability of enamine-carbonyl group.

3
HO
CHO
O2N
HO
R1
R1
N
I2 (2 equiv.)
TBHP (5 equiv.)
Fe (10 equiv.)
14a-f
R2
AcOH, Ethanol
reflux, 4 h, 78-84%
12a-f
R2
DCM, 2 h, 77-80%
O
O
20a-f
14a-f
R1
R2
14
a
H
Scheme 7. Synthesis of quinodibenzofurans 20a-f.
H
Cl
F
b
H
c
H
To complete the total synthesis of oxacalaothrixin B, 13-
hydroxyquinodibenzofuran 20a was initially subjected to CAN
oxidation11 in acetone–water mixture to afford product 13a only
in a low yield. Finally, after considerable experimentations, a
smooth oxidation of 13-hydroxyquinodibenzofuran 20a was
performed by using 5 equiv. of PhI(OAc)2 in CH3CN–H2O at rt
for 12 h to furnish oxacalothrixin B 13a in 74% yield.11
Adopting the similar conditions, rest of the 13-
hydroxyquinodibenzofurans 20b-f were also converted into the
respective oxacalothrixin B 13b-f in good yields.
d
OMe
H
Cl
F
e
f
OMe
OMe
Scheme 4. Synthesis of dibenzofurancarbaldehydes 14a-f.
The probable mechanism for the smooth transformation of
the enamines 12a-f into the respective aldehydes 14a-f using I2
/TBHP is depicted in Scheme 5. The reaction of iodine with
TBHP may generate highly reactive trivalent iodine compounds,
which upon co-ordination with the enamine carbonyl group led to
the formation of triene intermediate 15. The triene 15 upon
electrocyclization followed by aromatization may lead to
aldehydes 14a-f.
O
R1
13 R1
R2
H
N
PhI(OAc)2
a
b
c
d
e
f
H
20a-f
CH3CN/H2O
rt, 12 h, 69-74%
H
Cl
F
R2
O
H
O
13a-f
OMe
OMe
OMe
H
I
I O
or
I
+ t-BuOH
I2 + t-BuOOH
Cl
F
O
I O
I
O
O
I
I
O
O
NMe2
-I
NMe2
Scheme 8. Synthesis of oxacalothrixin B 13a-f.
After completion of oxacalothrixin B, next, the synthesis of
12a-f
R1
O
O
O2N
R1
16
O2N
oxaisocalothrixin is planned from the 2-acetyl-3-
B
15
methylbenzofuran.12 As expected, a routine allylic bromination
of compound 21 using NBS and a catalytic amount of AIBN in
CCl4 at reflux for 4 h afforded bromo compound 22 in 84% yield.
Next, the reaction of bromo compound 22 with PPh3 in dry THF
upon reflux for 3 h followed by the Wittig reaction of resulting
phosphonium salt 23 with 2-nitrobenzaldehyde 10a using K2CO3
as a base in DCM at rt gave 2-acetyl-3-nitroarylvinyl-
benzo[b]furan 24 (E and Z; 90:10) as a yellow solid in 78% yield.
Next, the reaction of 2-acetyl-3-nitroarylvinylene 24 with
DMF.DMA in the presence of 50 mol% glycocyamine at 100 °C
for 2 h followed by aqueous workup furnished enamine (E:Z;
80:20) 25 as a yellow solid.
O
NMe2
H
14a-f
-HOI
R1
O
O2N
17
Scheme 5. Mechanistic hypothesis for aldehydes 14a-f.
To our delight, a representative indole as well as
benzo[b]thiophene based enamines 18a/18b could be smoothly
transformed into respective carbazole/dibenzo[b]thiophene
carbaldehyde 19a/19b using iodine-TBHP protocol in good
yields. Thus, this protocol was found to be applicable for smooth
transformation of indole as well as benzo[b]thiophene based
enamines. Upon comparison with Lewis acid-mediated
electocyclization of enamine, the iodine/TBHP-mediated
oxidative cyclization protocol seems to involve mild reaction
condition.
Me
PPh3 Br
Me
Br
Me
NBS, AIBN
PPh3/THF
reflux, 3 h
Me
CCl4, reflux
4 h, 84%
O
O
O
O
21
O
22
O
23
O2N
OHC
O2N
DMF.DMA
glycocyamine
(50 mol %)
O
HO
NMe2
CHO
I2 (2 equiv.)
TBHP (5 equiv.)
NO2
10a
NMe2
Me
100 oC, 2 h
K2CO3, DCM
8 h, 78%
O
DCM, rt, 2 h
O
X
X
24
O
25
O
O2N
O2N
X = N-SO2Ph
O2N
19a
X = N-SO2Ph (84%)
19b X = S (86%)
18a
18b X = S
I2 (2 equiv.)
CuBr2/DMF
X
TBHP (5 equiv.)
X
DCM, rt, 2 h
25
CHO
reflux
Scheme 6. I2/TBHP-mediated cyclization of enamines 18a and
18b
Initially, 2-
O
OH
26
Scheme 9. Attempted oxidative cyclization of enamine 25.
the
reductive
cyclization
of
nitrophenyldibenzofuran aldehydes 14a-f using Raney-Ni in THF
failed to give the required 13-hydroxyquinodibenzofuran.
Unfortunately, the expected oxidative cyclization of the
isomeric benzofuran enamine 25 with I2 (2 equiv.)/TBHP (5
equiv.) conditions in DCM at room temperature failed to give
expected dibenzofuran-3-carbaldehyde 26. Further, the CuBr2-
mediated electrocyclization of enamine 25 also failed to give the
expected product 26.
Subsequently,
a
smooth reductive cyclization of these
compounds 14a-f was carried out in the presence of Fe (10
equiv.) in acetic acid-ethanol at reflux for 4 h to afford 13-
hydroxyquinodibenzofurans 20a-f in very good yields.

4
Tetrahedron
In summary, synthesis of oxacalothrixins and its analogues
are achieved involving a novel iodine/TBHP-mediated domino
reaction of the enamines as a key step followed by reductive
cyclization and PIDA-mediated oxidation. However, the
synthesis of oxaisocalothrixin B could not be completed due to
the electrocyclization problems encountered with respective
enamine using iodine/TBHP as well as CuBr2 conditions. Studies
on anticancer activities of oxacalothrixins and their analogues are
in progress and the results will be reported in due course.
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Acknowledgments
Financial assistance from CSIR (02(0214)/14-EMR-II), New
Delhi is acknowledged. B.M.R thanks CSIR, New Delhi for
fellowship. The authors thank DST-FIST for high-resolution
NMR and HRMS facilities.
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5
Highlights of the Manuscript
•
Total synthesis of oxacalothrixins, an
isostere of anticancer indole alkaloid,
calothrixin B
•
Crucial
intermediate
1-hydroxy
dibenzofurancarbaldehyde achieved through
Iodine/TBHP-mediated
cyclization
oxidative
•
PIDA-mediated
oxidation
of
led
13-
to
hydroxyquinodibenzofurans
oxacalothrixins