Rapid assembly of the tetracyclic core of subincanadine F by a 7- exo heck cyclization

Article abstract of DOI:10.1055/s-0029-1219545

An efficient approach to the tetracyclic bridged framework of the indole alkaloid subincanadine F by a 7-exo Heck cyclization of a 2-iodoindole upon a double bond included in a tetrahydropyridine system is described. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219545

944
LETTER
Rapid Assembly of the Tetracyclic Core of Subincanadine F by a 7-exo Heck
Cyclization
Rapid
Assembly
o
a
f
the
T
etrac
n
yclic Core
o
i
Subin
e
canadine
F
l Solé,* M.-Lluïsa Bennasar, Iván Jiménez
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institut de Biomedicina (IBUB), University of Barcelona,
Av. Joan XXIII, sn, Barcelona 08028, Spain
Fax +34(93)4024539; E-mail: dsole@ub.edu
Received 15 January 2010
N
Abstract: An efficient approach to the tetracyclic bridged frame-
work of the indole alkaloid subincanadine F by a 7-exo Heck cy-
clization of a 2-iodoindole upon a double bond included in a
tetrahydropyridine system is described.
N
7-exo
I
Heck
reaction
N
N
R
R
PG
PG
Key words: indoles, cyclization, palladium, Heck reaction, alka-
loids
Scheme 1 Synthetic strategy
We centered our investigation on the Heck reactions of
tetrahydropyridines 3a and 3b, which are unfunctional-
ized at the double bond (Scheme 2). They were synthe-
sized from 2-iodotryptopholes 1a and 1b,10 respectively,
following a classical sequence of reactions.11 Thus, treat-
ment of tryptophol 1a with p-toluenesulfonyl chloride af-
forded the corresponding sulfonic acid ester, which on
reaction with pyridine gave pyridinium salt 2a. Reduction
of the latter with sodium borohydride in methanol yielded
tetrahydropyridine 3a12 in 53% overall yield. Similarly,
tetrahydropyridine 3b13,14 was prepared in 56% overall
yield from tryptophol 1b.
Indolo-fused, medium-sized nitrogen heterocycles are the
basic structural units of a variety of natural products, in-
cluding apparicine, ervaticine, subincanadine E (also
known as pericine), and subincanadine F (Figure 1). De-
spite their diverse biological properties and challenging
structural complexities, these alkaloids have received lit-
tle attention from the synthetic point of view. In fact, only
apparicine1 and subincanadine F2,3 have, very recently,
been produced by total synthesis.
N
N
n
TsO
OH
N
N
H
N
O
X
1. TsCl
H
I
I
subincanadine F
apparicine, n = 1, X = CH2
ervaticine, n = 1, X = O
2. py, 80 °C
N
R
N
R
subincanadine E, n = 2, X = CH2
(pericine)
1a R = Me
1b R = SO2Ph
2a R = Me (59%)
2b R = SO2Ph (76%)
Figure 1 Alkaloids with indolo-fused, medium-sized nitrogen hete-
rocycles
N
NaBH4
Heck
I
see Table 1
N
Our continuing interest in the study of palladium-based
methodologies for the synthesis of indole derivatives4 led
us to consider intramolecular Heck reactions5 for the con-
struction of indolo-fused bridged heterocyclic systems.1,6
We have focused now on the unique tetracyclic skeleton
of subincanadine F, an alkaloid which displays interesting
in vitro cytotoxicity against murine lymphoma and human
epidermoid carcinoma cells.7
R
3a R = Me (90%)
3b R = SO2Ph (74%)
N
N
N
R
N
R
4a R = Me
5a R = Me
4b R = SO2Ph
5b R = SO2Ph
Our strategy for the assembly of the bridged tetracyclic
core of subincanadine F hinges on the closure of the aze-
pino ring by means of a 7-exo intramolecular Heck
reaction8,9 of a 2-iodoindole upon a double bond included
in a tetrahydropyridine system (Scheme 1).
NaOH
MeOH–H2O
4c R = H
Scheme 2
Once an efficient route for the preparation of the tetrahy-
dropyridine substrates had been established, we carried
out a detailed study of the Heck reaction, whose most sig-
nificant results are summarized in Table 1. The optimiza-
SYNLETT 2010, No. 6, pp 0944–0946
x
x.
x
x.
2
0
1
0
Advanced online publication: 23.02.2010
DOI: 10.1055/s-0029-1219545; Art ID: G00410ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Rapid Assembly of the Tetracyclic Core of Subincanadine F
945
Table 1 Heck Cyclization of Aryl Halides 3a,b
Entry
Substrate
3a
Reaction conditions
Products (yield, %)
1
2
3
4
5
6
7
8
Pd(OAc)2 (0.2 equiv), Et3N (2 equiv), MeCN, 100 °C, sealed tube, 18 h
Pd(PPh3)4 (0.1 equiv), K2CO3 (3 equiv), toluene, 80 °C, 24 h
3a,a 5a (10)
3a (35), 4a (30)
3a + 4a (3:1)b
3aa
3a
3a
Pd2(dba)3 (0.05 equiv), BINAP (0.15 equiv), K2CO3 (3 equiv), toluene, 80 °C, 48 h
Pd2(dba)3 (0.05 equiv), BINAP (0.15 equiv), Ag3PO4 (3 equiv), DMF, 80 °C, 24 h
Pd2(dba)3 (0.1 equiv), dppe (0.3 equiv), K2CO3 (3 equiv), toluene, 80 °C, 22 h
Pd2(dba)3 (0.1 equiv), dppp (0.3 equiv), K2CO3 (3 equiv), toluene, 80 °C, 18 h
Pd2(dba)3 (0.1 equiv), dppp (0.3 equiv), K2CO3 (3 equiv), toluene, 80 °C, 24 h
Pd2(dba)3 (0.1 equiv), dppe (0.3 equiv), K2CO3 (3 equiv), toluene, 80 °C, 24 h
3a
3a
3a (5), 4a (60), 5a (10)
4a (68)
3a
3b
4b (76), 5b (8)
4b (20)
3b
a Not quantified.
b 1H NMR analysis of the crude reaction mixture.
tion assays were performed with N-methyl derivative 3a. References and Notes
Ligand-free conditions [Pd(OAc)2 and Et3N in MeCN]8a
(1) (a) Bennasar, M.-L.; Zulaica, E.; Solé, D.; Alonso, S. Chem.
Commun. 2009, 3372. (b) Bennasar, M.-L.; Zulaica, E.;
Solé, D.; Roca, T.; García-Díaz, D.; Alonso, S. J. Org.
Chem. 2009, 74, 8359.
resulted in the formation of only minor amounts of the hy-
drodehalogenation product 5a (entry 1), while the use of
Pd(PPh3)4 as the catalyst in toluene at 80 °C gave a 1:1
mixture of the starting product 3a and tetracycle 4a (entry
2). Changing the ligand from Ph3P to BINAP resulted in
low reaction rates (entry 3) or no conversion (entry 4), de-
pending on the reaction solvent. Better results were ob-
tained using two- and three-atom bridged diphosphines.15
Thus, when dppe was used as the ligand, tetracycle 4a was
obtained in 60% yield together with small amounts of the
reduction compound 5a (entry 5). The results were im-
proved by using the long-chain ligand dppp, which in-
creased the cyclization yield to 68% (entry 6).16
(2) Gao, P.; Liu, Y.; Zhang, L.; Xu, P.-F.; Wang, S.; Lu, Y.; He,
M.; Zhai, H. J. Org. Chem. 2006, 71, 9495.
(3) Chen, P.; Cao, L.; Li, C. J. Org. Chem. 2009, 74, 7533.
(4) (a) Solé, D.; Serrano, O. J. Org. Chem. 2008, 73, 2476.
(b) Solé, D.; Serrano, O. J. Org. Chem. 2008, 73, 9372.
(5) General reviews: (a) Trepohl, V. T.; Oestreich, M. In
Modern Arylation Methods; Lutz, A., Ed.; Wiley-VCH:
Weinheim, 2009, 221. (b) Zeni, G.; Larock, R. C. Chem.
Rev. 2006, 106, 464. (c) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442. (d)Bräse,
S.; de Meijere, A. In Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
New York, 2004, 217.
Similar results were obtained in the Heck reactions of N-
benzenesulfonyl indole 3b. Once again, the most effective
ligand for the Heck cyclization was dppp, which allowed
tetracycle 4b17 to be obtained in 76% yield (entry 7).
However, the use of dppe resulted in a complex reaction
mixture from which 4b was isolated in only 20% yield
(entry 8). Finally, removal of the indole protecting group
of 4b by treatment with NaOH in hydromethanolic solu-
tion smoothly afforded tetracycle 4c18 (Scheme 1).
(6) Bennasar, M.-L.; Zulaica, E.; Solé, D.; Alonso, S. Synlett
2008, 667.
(7) Kobayashi, J.; Sekiguchi, M.; Shimamoto, S.; Shigemori,
H.; Ishiyama, H.; Ohsaki, A. J. Org. Chem. 2002, 67, 6449.
(8) For the synthesis of azepino[4,5-b]indoles by Heck reactions
of 2- and 3-haloindoles, see: (a) Sundberg, R. J.; Cherney,
R. J. J. Org. Chem. 1990, 55, 6028. (b) Stewart, S. G.;
Heath, C. H.; Ghisalberti, E. L. Eur. J. Org. Chem. 2009,
1934.
(9) For related processes promoted by Pd(II), see: (a) Trost,
B. M.; Genêt, J. P. J. Am. Chem. Soc. 1976, 98, 8516.
(b) Trost, B. M.; Godleski, S. A.; Genêt, J. P. J. Am. Chem.
Soc. 1978, 100, 3930.
In conclusion, the Heck cyclization strategy reported here
opens a new short synthetic route for the construction of
the bridged tetracyclic system of subincanadine F from
easily accessible precursors. The application of this ap-
proach for the completion of the total synthesis of the nat-
ural product and the implementation of the Heck
methodology to prepare other indolo-fused, medium-
sized nitrogen heterocycles is being pursued in our labo-
ratory.
(10) Kuethe, J. T.; Wong, A.; Davies, I. W.; Reider, P. J.
Tetrahedron Lett. 2002, 43, 3871.
(11) Elderfield, R. C.; Fischer, B.; Lagowski, J. M. J. Org. Chem.
1957, 22, 1376.
(12) Tetrahydropyridine 3a
1H NMR (300 MHz, CDCl3): d = 2.25 (m, 2 H), 2.63 (m, 2
H), 2.71 (t, J = 5.7 Hz, 2 H), 3.01 (m, 2 H), 3.14 (m, 2 H),
3.73 (s, 3 H), 5.71 (dm, J = 9.9 Hz, 1 H), 5.79 (dm, J = 9.9
Hz, 1 H), 7.07 (ddd, J = 7.8, 7.2, 1.2 Hz, 1 H), 7.15 (ddd,
J = 8.1, 7.2, 1.2 Hz, 1 H), 7.28 (dd, J = 8.1, 1.2 Hz, 1 H),
7.56 (dd, J = 7.8, 1.2 Hz, 1 H). 13C NMR (75.5 MHz,
CDCl3): d = 25.4 (CH2), 26.2 (CH2), 34.1 (Me), 50.0 (CH2),
52.6 (CH2), 58.5 (CH2), 87.4 (C), 109.6 (CH), 118.1 (CH),
119.0 (C), 119.2 (CH), 121.8 (CH), 125.2 (CH), 125.3 (CH),
Acknowledgment
We thank the ‘Ministerio de Educación y Ciencia’, Spain, for finan-
cial support (projects CTQ2006-00500/BQU and CTQ2009-
07175).
Synlett 2010, No. 6, 944–946 © Thieme Stuttgart · New York

946
D. Solé et al.
LETTER
127.6 (C), 138.5 (C). ESI-HRMS: m/z calcd for C16H20IN2
J = 7.5, 6.9, 1.2 Hz, 1 H), 7.15 (ddd, J = 8.1, 6.9, 1.2 Hz, 1
H), 7.24 (dd, J = 8.1, 1.2 Hz, 1 H), 7.45 (dd, J = 7.5, 1.2 Hz,
1 H). 13C NMR (75.5 MHz, CDCl3): d = 22.9 (CH2), 29.5
(Me), 31.2 (CH), 49.7 (CH2), 51.0 (CH2), 56.2 (CH2), 109.0
(CH), 112.7 (C), 117.5 (CH), 119.0 (CH), 120.6 (CH), 125.2
(CH), 126.1 (CH), 127.5 (C), 135.9 (C), 139.0 (C). ESI-
HRMS: m/z calcd for C16H19N2 [M + H]+: 239.1543; found:
239.1545.
[M + H]+: 367.0666; found: 367.0664.
(13) Tetrahydropyridine 3b
1H NMR (300 MHz, CDCl3): d = 2.22 (m, 2 H), 2.52 (m, 2
H), 2.65 (t, J = 5.7 Hz, 2 H), 2.93 (m, 2 H), 3.08 (m, 2 H),
5.68 (dm, J = 9.9 Hz, 1 H), 5.77 (dm, J = 9.9 Hz, 1 H), 7.20–
7.31 (m, 2 H), 7.36–7.55 (m, 4 H), 7.84 (m, 2 H), 8.30 (m, 1
H). 13C NMR (75.5 MHz, CDCl3): d = 25.8 (CH2), 26.1
(CH2), 49.9 (CH2), 52.5 (CH2), 56.8 (CH2), 79.4 (C), 115.9
(CH), 118.5 (CH), 123.7 (CH), 125.0 (CH), 125.2 (CH),
127.0 (CH), 129.0 (2 CH), 130.4 (C), 130.7 (C), 133.8 (CH),
138.0 (C), 139.2 (C). ESI-HRMS: m/z calcd for
(17) Tetracycle 4b
1H NMR (300 MHz, CDCl3): d = 2.65 (ddd, J = 15.6, 3.9,
1.8 Hz, 1 H), 2.95–3.27 (m, 5 H), 3.37 (dd, J = 14.1, 4.8 Hz,
1 H), 3.74 (dm, J = 18.3 Hz, 1 H), 4.16 (m, 1 H), 5.64 (dm,
J = 9.9 Hz, 1 H), 5.82 (dm, J = 9.9 Hz, 1 H), 7.21–7.47 (m,
5 H), 7.55 (tt, J = 7.5, 1.2 Hz, 1 H), 7.71 (m, 2 H), 8.23 (dm,
J = 8.1 Hz, 1 H). 13C NMR (75.5 MHz, CDCl3): d = 22.7
(CH2), 31.4 (CH), 49.6 (CH2), 50.7 (CH2), 54.6 (CH2), 115.1
(CH), 117.8 (CH), 122.7 (C), 123.4 (CH), 124.3 (CH), 125.1
(CH), 125.8 (CH), 126.1 (CH), 129.3 (CH), 130.3 (C), 133.7
(CH), 136.2 (C), 138.4 (C), 139.4 (C). ESI-HRMS: m/z calcd
for C21H21N2O2S [M + H]+: 365.1318; found: 365.1319.
C21H22IN2O2S [M + H]+: 493.0441; found: 493.0439.
(14) It should be noted that in the reduction of 2b with NaBH4
(MeOH, 0 °C) the hydrodehalogenated product 5b was also
obtained (13%). This side product was formed even when
the reduction was carried out at –10 °C.
(15) For a review on the bite angle effects of diphosphines in
C–C coupling reactons, see: Birkholz, M.-N.; Freixa, Z.;
van Leeuwen, P. W. N. M. Chem. Soc. Rev. 2009, 38, 1099.
(16) Heck Cyclization of 3a (Table 1, Entry 6)
(18) Tetracycle 4c
Pd2(dba)3 (17 mg, 0.019 mmol), dppp (24 mg, 0.058 mmol),
and K2CO3 (79 mg, 0.57 mmol) were successively added to
a solution of iodoindole 3a (70 mg, 0.19 mmol) in toluene
(10 mL), and the resulting mixture was heated at 80 °C for
18 h. The reaction mixture was poured into H2O and
extracted with Et2O (3 × 50 mL). The organic extracts were
washed with brine, dried, and concentrated. The resulting
residue was chromatographed (SiO2, flash, from CH2Cl2 to
CH2Cl2–MeOH 8%) to give tetracycle 4a; 31 mg (68%). 1H
NMR (300 MHz, CDCl3): d = 2.81 (ddd, J = 15.6, 4.2, 3.3
Hz, 1 H), 3.10 (dq, J = 15.6, 6.9 Hz, 1 H), 3.25 (m, 2 H), 3.31
(dm, J = 18.0 Hz, 1 H), 3.39 (br, 1 H), 3.50 (m, 2 H), 3.71 (s,
3 H), 3.82 (dm, J = 18.0 Hz, 1 H), 5.84 (m, 2 H), 7.07 (ddd,
1H NMR (400 MHz, CDCl3): d = 2.75 (ddd, J = 15.6, 4.0,
2.4 Hz, 1 H), 3.08 (ddd, J = 15.6, 12.0, 3.2 Hz, 1 H), 3.14 (br
s, 1 H), 3.22 (ddd, J = 13.6, 12.0, 2.0 Hz, 1 H), 3.29–3.40 (m,
2 H), 3.48 (m, 2 H), 3.83 (dm, J = 18.8 Hz, 1 H), 5.83 (dm,
J = 10.0 Hz, 1 H), 5.89 (dm, J = 10.0 Hz, 1 H), 7.06–7.13
(m, 2 H), 7.28 (m, 1 H), 7.45 (dd, J = 6.0, 2.0 Hz, 1 H), 7.89
(br, 1 H). 13C NMR (100.5 MHz, CDCl3): d = 23.0 (CH2),
34.7 (CH), 49.3 (CH2), 51.3 (CH2), 56.3 (CH2), 110.5 (CH),
112.8 (C), 117.5 (CH), 119.4 (CH), 120.8 (CH), 125.4 (CH),
126.0 (CH), 129.0 (C), 134.3 (C), 137.8 (C). ESI-HRMS:
m/z calcd for C15H17N2 [M + H]+: 225.1386; found:
225.1384.
Synlett 2010, No. 6, 944–946 © Thieme Stuttgart · New York