A new method for the synthesis of the marine alkaloid fascaplysin based on the microwave-assisted Minisci reaction

Article abstract of DOI:10.1016/j.tetlet.2013.04.113

A new two-step method for the synthesis of the marine alkaloid fascaplysin has been developed, via homolytic benzoylation (Minisci reaction) of β-carboline under microwave irradiation followed by intermolecular quaternization.

Full text of DOI:10.1016/j.tetlet.2013.04.113

Tetrahedron Letters 54 (2013) 3530–3532
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A new method for the synthesis of the marine alkaloid fascaplysin based on
the microwave-assisted Minisci reaction
⇑
Maxim E. Zhidkov , Vladimir A. Kaminskii
Department of Chemistry, School of Natural Sciences, Far Eastern Federal University, 8 Sukhanov Str., Vladivostok 690950, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A new two-step method for the synthesis of the marine alkaloid fascaplysin has been developed, via
homolytic benzoylation (Minisci reaction) of b-carboline under microwave irradiation followed by inter-
molecular quaternization.
Received 2 January 2013
Revised 13 April 2013
Accepted 26 April 2013
Available online 3 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
Fascaplysin
b-Carboline
Minisci reaction
Microwave irradiation
The marine alkaloid fascaplysin (1), which was isolated initially
from the sponge Fascaplysinopsis sp. in 1988, was the first natural
It was previously shown that intermolecular quaternization of
o-substituted 1-benzoyl-b-carbolines was the most effective strat-
egy for the formation of the fascaplysin skeleton. This simple and
practical approach to these starting materials makes use of the
Minisci homolytic acylation of b-carboline (3) with o-substituted
benzoyl radicals. These intermediates are usually generated
0
representative of the pyrido[1,2-a:3,4-b ]diindole ring system (2)
(
Fig. 1).1 This compound exhibits a broad range of bioactivity
including antibacterial, antifungal, antiviral, HIV-1-RT, p56 tyro-
sine kinase, antimalarial, and also suppresses proliferation of
numerous cancer cell lines.2 In addition, fascaplysin inhibits the
growth of S180 cell-implanted tumors and has anti-angiogenesis
4
in situ by addition of the FeSO —t-BuOOH redox system to the cor-
responding aldehydes, or by silver-catalyzed decarboxylation of
a
-
3
,4
12
properties. The mechanisms of its action include the selective
inhibition of cyclin-dependent kinase 4, which regulates the G
/S checkpoint of the cell cycle, the intercalation of DNA, and
keto acids with sodium persulfate in a two-phase system. The
selective acetylation of b-carboline at C-1 under both these condi-
tions was described earlier, and it was found that the second meth-
0
–
G
1
5–7
13
the induction of apoptosis.
Detailed information on fascaplysin,
od was ineffective. Initially, the reaction of b-carboline (3) with
its natural and synthetic analogs, and their properties are de-
scribed in a review. Investigations on fascaplysin derivatives can
o-fluorobenzaldehyde (4) was investigated under the reaction
8
13,14
conditions described in the literature.
As a result, 1-(2-fluor-
form the starting point for elaboration of novel lead compounds,
and therefore necessitates the development of effective procedures
for their syntheses. Several methods to prepare fascaplysin have
obenzoyl)-b-carboline (5) was isolated after flash chromatography
in 10% yield. The reaction was accompanied by methylation of
b-carboline at C-1 resulting in the formation of harmine (6).15
Further addition of radical precursors was ineffective leading to
accumulation of diacylation product 7, substituted at both C-1
and C-3 (Scheme 1).
9
been described in the literature. One such example was optimized
for the total syntheses of natural bromo-substituted derivatives of
1
0
fascaplysin, but it utilized difficult to obtain starting materials.
An approach for the preparation of various fascaplysin derivatives
substituted on ring A has been elaborated.1 In this Letter, a novel
two-step method for the synthesis of compound 1 is described.
This approach could be used to obtain fascaplysin derivatives
substituted on the E ring.
1
6
4
Cl-
7
5
3
8
N+
O
N
E
9
2
A
NH
10
NH
1
1
3
1
1
12
1
2
Figure 1. Structures of the natural product fascaplysin (1), and pyrido[1,2-a:3,4-
b ]diindole (2).
⇑
Corresponding author. Tel.: +7 4232 429510; fax: +7 4232 429510.
E-mail address: mzhidkov@rambler.ru (M.E. Zhidkov).
0
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.113

M. E. Zhidkov, V. A. Kaminskii / Tetrahedron Letters 54 (2013) 3530–3532
3531
o-F-C H -CHO (4),
6
4
a
1
0% of 5
F
O
O
O
F
,
a
N
F
8
N
N
N
+
+
3
5% of 5
N
H
N
H
N
H
N
H
O
O
3
5
6
7
F
o-F-C H -CHO
6
4
(
4), b
6
5% of 5
Scheme 1. Reagents and conditions: (a) 70% t-BuOOH, FeSO
times.
4
ꢀ7H
2
O, CF
3
COOH, CH
3
COOH, H
2
O, 4 °C, 30 min, twice; (b) 70% t-BuOOH, MW, 10 W, CF
3
COOH, 40 min, several
During subsequent investigations 2-(2-fluorophenyl)-1,3-
the possibility of the cyclization of compound 5 at the indole nitro-
gen we specifically synthesized the appropriate product 9 from
bromo-substituted b-carboline 10 by the action of DBU in refluxing
DMF in 68% yield. The structure of compound 9 was proved by
dioxolane (8) was examined as the radical precursor because the
1
6
corresponding radical has more active nucleophilic properties.
As a result, the yield of the target product 5 was 35% after hydro-
lysis of the reaction mixture, but further addition of the compo-
nents of the redox system proved ineffective. This necessitated a
search for other methods to generate benzoyl radicals from benz-
aldehyde 4. Heating was applied for t-BuOOH homolytic decompo-
sition, but this procedure was not effective for benzoylation of b-
carboline. Microwave irradiation is often used for the heating
and activation of various reactions, thus it was examined for t-
BuOOH decomposition. Reaction of a mixture of 3, 4, and t-BuOOH
in acetic acid under microwave irradiation afforded the target
compound 5 in 65% yield along with trace amounts of by-products
1
8
COSY, HMBC, HSQC, and NOESY experiments. The spectral char-
acteristics of the product of pyꢀHCl catalyzed cyclization of com-
pound 5 differed considerably from those of compound 9 and at
the same time they were similar to those of natural fascaplysin.19
In conclusion, the described chemistry represents the simplest
and shortest approach for the synthesis of fascaplysin. In combina-
1
1
tion with an earlier elaborated method, it generates the founda-
tion for obtaining various fascaplysin derivatives, that, in turn,
should open new opportunities for detailed studies of structure
activity relationships among these potentially physiologically ac-
tive substances. The activation of the homolytic benzoylation
(Minisci reaction) of b-carboline by microwave irradiation also re-
quires additional investigation. At present, the substitution of a
wide range of heterocyclic systems (pyridines, pyrazines, quino-
lines, quinoxalines, etc.) with nucleophilic radicals under micro-
wave irradiation is the subject of detailed investigations.
1
7
6
and 7. To the best of our knowledge, there is no previous report
on the microwave-assisted Minisci reaction.
In an attempt to convert b-carboline 5 into fascaplysin, it was
heated at 220 °C as described in Radchenko’s approach, but unfor-
9
d
tunately the desired product was not obtained (Scheme 2). Using
microwave irradiation also failed to yield compound 1. An attempt
to synthesize a bromo-substituted analog of compound 5 via acyl-
ation of b-carboline with o-bromobenzaldehyde proved ineffective,
a result which can be explained by the steric influence of the large
bromine atom at C-2 of the benzaldehyde. Heating of 5 with pyrid-
inium chloride at 200–220 °C, followed by work-up, allowed isola-
tion of a product of cyclization that could have involved the indole
Acknowledgments
This research was made possible in part by Grants from the
Russian Ministry of Education and Science (No. 3.2354.2011) and
an award from the CRDF (No. RUXO-003-VL-06).
9b,9c
nitrogen or the pyridine nitrogen (see Scheme 2).
To exclude
References and notes
1. Roll, D. M.; Ireland, C. M.; Lu, H. S.; Clardy, J. J. Org. Chem. 1988, 53, 3276–3278.
Cl
2. For example, see: (a) Jimenez, C.; Quinoa, E.; Adamczeski, M.; Hunter, L. M.;
Crews, P. J. Org. Chem. 1991, 56, 3403–3410; (b) Schmidt, E. W.; Faulkner, D. J.
Tetrahedron Lett. 1996, 37, 3951–3954; (c) Kirsch, G.; Konig, G. M.; Wright, A.
D.; Kaminsky, R. J. Nat. Prod. 2000, 63, 825–829; (d) Charan, R. D.; McKee, T. C.;
Gustafson, K. R.; Pannell, L. K.; Boyd, M. R. Tetrahedron Lett. 2002, 43, 5201–
+
5
: X=F, a
0%
N
8
N
H
5
204; (e) Popov, A. M.; Stonik, V. A. Antibiot. Khimioter. 1991, 36, 12–14.
3. Yan, X.; Chen, H.; Lu, X.; Wang, F.; Xu, W.; Jin, H.; Zhu, P. Eur. J. Pharm. Sci. 2011,
3, 251–259.
1
O
N
X
4
4.
Zheng, Y. L.; Lu, X. L.; Lin, J.; Chen, H. M.; Yan, X. J.; Wang, F.; Xu, W. F. Biomed.
Pharmacother. 2010, 64, 527–533.
6
N
H
N
N
5. Soni, R.; Muller, L.; Furet, P.; Schoepfer, J.; Stephan, C.; Zunstein-Mecker, S.;
O
5
O
Fretz, H.; Chaudhuri, B. Biochem. Biophys. Res. Commun. 2000, 275, 877–884.
8
6. Hormann, A.; Chaudhuri, B.; Fretz, H. Bioorg. Med. Chem. 2001, 9, 917–921.
1
0:X=Br, b
8%
4
9
7. Lu, X. L.; Zheng, Y. L.; Chen, H. M.; Yan, X. J.; Wang, F.; Xu, W. F. Yao Xue Xue Bao
2009, 44, 980–986.
3
6
1
0
8.
Bharate, S. B.; Manda, S.; Mupparapu, N.; Battini, N.; Vishwakarma, R. A. Mini
Rev. Med. Chem. 2012, 12, 650–664.
2
12
1
11
9
9.
(a) Gribble, G. W.; Pelcman, B. J. Org. Chem. 1992, 57, 3636–3642; (b) Rocca, P.;
Marsais, F.; Godart, A.; Quéguiner, G. Tetrahedron Lett. 1993, 34, 7917–7918; (c)
Molina, P.; Fresneda, M.; Garciazafra, S.; Almendros, P. Tetrahedron Lett. 1994,
Scheme 2. Reagents and conditions: (a) pyꢀHCl, 200–220 °C, 40 min; (b) DBU, DMF,
reflux, 3 h.

3
532
M. E. Zhidkov, V. A. Kaminskii / Tetrahedron Letters 54 (2013) 3530–3532
3
5, 8851–8854; (d) Radchenko, O. S.; Novikov, V. L.; Elyakov, G. B. Tetrahedron
J
1
= 8.2 Hz,
J
2
= 7.2 Hz, 1H), 7.22 (dd,
J
1
= 7.8 Hz,
J
2
= 7.2 Hz, 1H), 6.98 (t,
) d: 193.5,
1
3
Lett. 1997, 38, 5339–5342; (e) Waldmann, H.; Eberhardt, L.; Wittstein, K.;
Kumar, K. Chem. Commun. 2010, 4622–4624.
0. Zhidkov, M. E.; Baranova, O. V.; Balaneva, N. N.; Fedorov, S. N.; Radchenko, O.
S.; Dubovitskii, S. V. Tetrahedron Lett. 2007, 48, 7998–8000.
1. Zhidkov, M. E.; Baranova, O. V.; Kravchenko, N. S.; Dubovitskii, S. V. Tetrahedron
Lett. 2010, 51, 6498–6499.
J = 8.9 Hz, 2H), 6.89 (d, J = 8.2 Hz, 1H); C NMR (100 MHz, CDCl
167.1, 163.7, 140.9, 137.9, 137.3, 136.1, 134.0, 133.9, 131.7, 129.3, 123.6, 121.8,
120.8, 118.5, 115.2, 114.9, 111.9; MS (EI) m/z = 290 (M , 100), 262 (84), 167 (7),
145 (13), 140 (20), 123 (31), 95 (51). Anal. Calcd for C18
3
+
1
1
1
2
H11FN O: C, 74.48; H,
3.82; N, 9.65. Found: C, 74.52; H, 3.74; N, 9.55.
18. 8H-Benzo[b]indolo[3,2,1-ij]-1,5-naphthyridin-8-one (9): A mixture of 10 (50 mg,
2. For example, see: (a) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28,
0.14 mmol), DBU (85 mg, 0.56 mmol) and DMF (3 mL) was heated at reflux for
4
89; (b) Minisci, F. Synthesis 1973, 1–24; (c) Caronna, T.; Fronza, G.; Minisci, F.;
3 h. After cooling the mixture was poured into
extracted with EtOAc (3 ꢁ 20 mL). The combined organic layer was washed
with brine (2 ꢁ 50 mL), dried over Na SO , and evaporated under reduced
pressure. Compound 9 was isolated by flash column chromatography (EtOAc)
(26 mg, 68%) as a yellow solid; mp 169–170 °C. IR (KBr) max: 3078, 3014, 1698,
) d: 9.05 (d, J = 4.7 Hz, 1H, H-
= 1.4 Hz, 1H, H-9), 8.40 (d, J = 8.3 Hz, 1H, H-12), 8.32
(d, J = 8.5 Hz, 1H, H-1), 8.26 (d, J = 7.7 Hz, 1H, H-4), 8.21 (d, J = 4.7 Hz, 1H, H-5),
7.90 (td, J = 8.0 Hz, J = 1.9 Hz, 1H, H-11), 7.78 (td, J = 8.0 Hz, J = 1.4 Hz, 1H,
H-2), 7.52 (m, 2H, H-3, H-10); C NMR (100 MHz, CDCl ) d: 177.9 (C-8), 145.0
2
H O (100 mL) and then
Porta, O. J. Chem. Soc., Perkin Trans. 2 1972, 2035; (d) Fontana, F.; Minisci, F.;
Nogueira Barbosa, M. C.; Vismara, E. J. Org. Chem. 1991, 56, 2866.
2
4
1
1
3. Bracher, F.; Daab, J. Synth. Commun. 1995, 25, 1557–1562.
4. b-Carboline was obtained from tryptophan in one step, see: Kermack, W. O.;
Perkin, W. H.; Robinson, R. J. Chem. Soc., Trans. 1921, 119, 1602–1642. A very
pure product was obtained by sublimation at 220 °C in vacuo (5 mm).
5. Bracher, F.; Puzik, A. J. Heterocycl. Chem. 2004, 41, 173–176.
6. Li, T.-S.; Li, S.-H.; Li, J.-T.; Li, H.-Z. J. Chem. Res. 1997, 1, 26–27.
7. Procedure for the microwave-assisted Minisci reaction: A mixture of b-carboline
m
ꢂ1
1
1652, 1596, 1460 cm
; H NMR (400 MHz, CDCl
3
6), 8.75 (dd, J = 8.0 Hz, J
1
2
1
1
1
1
2
1
2
13
3
(
(
3) (100 mg, 0.6 mmol), o-fluorobenzaldehyde (4) (3.5 g, 28 mmol), t-BuOOH
70% solution in H O, 0.25 mL, 1.8 mmol), and AcOH (2.5 mL) was placed in a
(C-6), 139.9 (C-13a), 138.9 (C-12a), 135.7 (C-7b), 135.4 (C-7a), 134.4 (C-11),
132.3 (C-4b), 130.8 (C-2), 129.7 (C-9), 126.4 (C-8a), 124.6 (C-4a), 123.9 (C-10),
123.6 (C-3), 123.2 (C-4), 118.0 (C-5), 115.4 (C-12), 114.2 (C-1); MS (ESI) m/
z = 271 (M+H) , 293 (M+Na) . Anal. Calcd for C18H N O: C, 77.99; H, 3.73; N,
10 2
10.36. Found: C, 79.75; H, 3.86; N, 10.16.
2
Ò
sealed 10 mL vial and irradiated using
system (CEM Corporation, www.cem.com) at 10 W for 40 min. The addition of
t-BuOOH (70% solution in H O, 0.25 mL, 1.8 mmol) and microwave irradiation
was repeated until there was no starting material left (TLC monitoring). The
mixture was poured into H O (100 mL) and then neutralized with K CO and
extracted with EtOAc (3 ꢁ 50 mL). The combined organic layer was washed
with brine (2 ꢁ 100 mL), dried over Na SO , and evaporated under reduced
pressure. Compound 5 was isolated by flash column chromatography (EtOAc/
hexanes 1:50) (172 mg, 65%) as yellow solid; mp 172–173 °C. IR (CHCl
a Discover microwave synthesis
+
+
2
19. Compound 1: water-soluble red powder. IR (KBr)
m
max: 3402, 3068, 1718, 1621,
ꢂ1
1
2
2
3
1508, 1467, 1451, 1083, 1065 cm
;
H NMR (400 MHz, MeOH-d ) d: 9.40 (d,
4
J = 6.2 Hz, 1H), 8.98 (d, J = 6.2 Hz, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.36 (d, J = 7.8 Hz,
1H), 8.10 (d, J = 7.8 Hz, 1H), 8.02 (t, J = 7.0 Hz, 1H), 7.94 (t, J = 7.0 Hz, 1H), 7.86
(d, J = 8.4 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H); 13C NMR
2
4
3
)
m
max
:
4
(100 MHz, MeOH-d ) d: 183.7, 149.5, 149.2, 143.5, 139.4, 136.6, 133.7, 133.5,
ꢂ1
1
3
(
8
443, 3070, 3000, 1642, 1623, 1600, 1506, 1493, 1156, 669 cm
400 MHz, C ) d: 10.35 (br s, 1H, NH), 8.71 (dd, J = 8.9 Hz, J = 4.0 Hz, 2H),
.52 (d, J = 4.9 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 4.9 Hz, 1H), 7.39 (dd,
; H NMR
128.3, 127.6, 126.1, 125.8, 125.4, 124.2, 121.9, 121.8, 117.4, 115.3; MS (ESI) m/
+
6
D
6
1
2
11 2
z = 271 (M ); HRMS calcd for C18H N O: 271.0871; found 271.0862.