Synthesis of β- And γ-carbolines via ruthenium and rhodium catalysed [2+2+2] cycloadditions of yne-ynamides with methylcyanoformate

Article abstract of DOI:10.1039/c1cc11298h

A flexible approach towards substituted β- and γ-carbolines based on transition metal catalysed [2+2+2] cycloaddition reactions between functionalised yne-ynamides and methylcyanoformate is described. The versatility of this new reaction sequence is demon

Full text of DOI:10.1039/c1cc11298h

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COMMUNICATION
Synthesis of b- and c-carbolines via ruthenium and rhodium catalysed
[2+2+2] cycloadditions of yne-ynamides with methylcyanoformatew
Felix Nissen,a Vincent Richard,b Carole Alayracab and Bernhard Witulski*ab
Received 4th March 2011, Accepted 30th March 2011
DOI: 10.1039/c1cc11298h
A flexible approach towards substituted b- and c-carbolines
based on transition metal catalysed [2+2+2] cycloaddition
reactions between functionalised yne-ynamides and methylcyano-
formate is described. The versatility of this new reaction
sequence is demonstrated by its application in the total synthesis
of the marine natural product eudistomin U.
Scheme 1 The A - ABC ring formation strategy to b- and/or
g-carbolines.
Pyrido[3,4-b]indoles, commonly known as b-carbolines, are
in natural product syntheses when methylcyanoformate
the key structural motif of a variety of biologically important
(R3 = CO2Me in Scheme 1) is used as the nitrile component.
alkaloids of natural and synthetic origin.1 Natural products
The synthesis of a set of substituted diyne precursors needed
containing a b-carboline unit have been isolated from
terrestrial plants and various marine invertebrates and their
for this study started with the readily available yne-ynamide 1
that was obtained through our previously reported method of
biological properties range from interactions with the benzo-
the direct N-ethynylation of tosylanilides with ethynyl-
diazepine receptor to potent antitumor, antiviral and anti-
iodonium triflate (Scheme 2).8b,10 Methylation of the ynamide
microbial activities.2 The occurrence of the pyrido[4,3-b]indole
unit in 1 provided compound 2 (97% yield) and a subsequent
or g-carboline motif in natural products is less well documented.3
desilylation with tetrabutylammonium fluoride (TBAF)
However, a number of reports have shown that g-carbolines
possess significant antitumor properties based on their structural
similarity to the natural products ellipticine and olivacine.4
afforded yne-ynamide 3 (90% yield). Thereafter, the bismethylated
diyne 4 (92% yield) became available through a second
methylation sequence starting from 3.
Due to their biological importance synthetic methodologies
A
simple and flexible way to further functionalise
for the b- and the g-carboline framework received considerable
attention. The Pictet–Spengler reaction followed by
yne-ynamide 1 was found in the Negishi reaction.11 Palladium
catalysed cross-couplings of 1 with various iodobenzenes and
iodopyridines provided the yne-ynamides 5a–d already at
room temperature and their subsequent desilylation with
TBAF afforded the desired yne-ynamides 6a–d in a short
overall synthetic sequence (Scheme 2).
a
dehydrogenation reaction is the most widely studied method
to access b-carbolines.5 More recently, palladium catalysed
cross-coupling and iminoannulation reactions,6 as well as
gold(III)-catalysed cycloisomerisation sequences were reported
for the construction of b- and g-carbolines.7
We disclose here an expedient method for the synthesis of
b- and g-carbolines that is based on an A - ABC ring
formation strategy by transition metal catalysed [2+2+2]
cycloaddition reactions of functionalised yne-ynamides with
nitriles (Scheme 1).8,9
Such a straightforward assembly via a consecutive formation
of three bonds in a single reaction step should allow diversity as
well as target oriented syntheses of either b- or g-carbolines.
Furthermore, this approach should be relevant for applications
a University of Mainz, Mainz, Germany
b Laboratoire de Chimie Mole´culaire et Thio-organique, UMR CNRS
´
6507, INC3M, FR 3038, ENSICAEN & Universite de Caen,
6 Boulevard du Marechal Juin, 14050 Caen, France.
E-mail: bernhard.witulski@ensicaen.fr
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, 1H NMR, 13C NMR and analytical data
for all new compounds. See DOI: 10.1039/c1cc11298h
Scheme 2 Reagents and conditions: (a) LiHMDS, THF, MeI, À40 1C
to rt, 12 h (97% yield for 2); (b) TBAF, THF, 0 1C, 15 min (90% yield
for 3); (c) LiHMDS, THF, MeI, À40 1C to rt, 12 h (92% yield for 4);
(d) LiHMDS, ZnBr2, Pd2dba3 (5 mol%), PPh3 (20 mol%), THF, rt,
12 h; (e) TBAF, THF, 0 1C.
´
c
6656 Chem. Commun., 2011, 47, 6656–6658
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Next, [2+2+2] cycloaddition reactions of yne-ynamides
with methylcyanoformate were investigated.12,13 Catalysts
for the co-cyclisation of tethered diynes with electron deficient
nitriles to provide annelated pyridines were reported by Itoh
and Tanaka utilising the Cp*RuCl(cod) complex or cationic
rhodium complexes, respectively.14,15 Therefore, co-cyclisations
of yne-ynamides with methylcyanoformate as the electron
deficient nitrile component were carried out with either
Cp*RuCl(cod) at 35 1C (method A, Table 1) and 120 1C
(method B, Table 1), or with a cationic rhodium catalyst
generated from 3 mol% [Rh(cod)2]BF4 and 3 mol% BINAP
at room temperature (method C, Table 1).
Table 1 Synthesis of b-carbolines and g-carbolines
Ratio Yield
b : g (%)
Entry Yne-ynamide
Method Product
Gratifyingly, the [2+2+2] cycloaddition of yne-ynamides
with an excess of methylcyanoformate led to the successful
synthesis of either b- or g-carbolines as the major products with
the following details: compounds 3, 6a, and 6b provided the
b-carbolines 7, 8a, and 8b, respectively, as single regioisomers
when Cp*RuCl(cod) was used as a catalyst and b-carbolines
were obtained as the major regioisomers, when the cationic
rhodium catalyst generated by method C was applied (Table 1,
entries 1–5). The 2-pyridyl substituted yne-ynamide 6c and
methylcyanoformate underwent a co-cyclisation neither in the
presence of the Cp*RuCl(cod), nor in the presence of the
cationic rhodium complex following method C. Presumably
the bipyridyl moiety in product 8c inhibits the catalytic cycle by
complexation to the Rh- or Ru-based catalyst. In strong
contrast, the b-carboline 8d was obtained in 70% yield
as a single regioisomer when Cp*RuCl(cod) mediated the
co-cyclisation of the 3-pyridyl substituted yne-ynamide 6d with
methylcyanoformate (Table 1, entry 8), whereas the cationic
rhodium catalyst was again unproductive (entry 9).
1
2
3
3
A
C
7
7
100 : 0 92
75 : 25 84
3
4
5
6a R = H
6a R = H
6b R = OMe
A
C
A
8a R = H
8a R = H
8b R = OMe
100 : 0 61
92 : 8 95
100 : 0 60
6
7
6c
6c
A
C
8c
8c
—
—
0
0
Mixtures of regioisomeric b- and g-carbolines were obtained
when symmetrically substituted yne-ynamides were subjected
to the [2+2+2] cycloaddition reaction (Table 1, entries 10–13).
These results strongly indicate that the regioselective outcome
of the co-cyclisation is directed by the substitution pattern on
the starting yne-ynamide. Indeed, with the cycloaddition
precursors 12, 14, and 16 both catalysts now provided
g-carbolines. The Cp*RuCl(cod) complex afforded the
g-carbolines 13, 15, and 17 as a single isomer in 46%, 52%
and 67% yield respectively (Table 1, entries 14, 16, and 17).
Here, the cationic Rh-catalysts gave the corresponding
g-carbolines as the major products, and with a steric increase
of the substituent on the alkyne moiety the ratio of regio-
isomers was significantly raised (Table 1, entries 15 and 18).
These results are in agreement with other studies concerning
the regioselective outcome of [2+2+2] cycloadditions of
tethered diynes with nitriles.16 In all examples studied within
the carboline series reported here, the Cp*RuCl(cod) catalyst
was less reactive but more selective than the cationic rhodium-
based catalyst generated from [Rh(cod)2]BF4 and BINAP.
With the aim to underline the applicability of this new atom-
and step economic approach towards either b- or g-carbolines,
the total synthesis of the b-carboline eudistomin U (22) was
targeted (Scheme 3). Eudistomin U was isolated from the
Caribbean ascidian Lissoclinum fragile and showed DNA
binding and antimicrobial properties.17,18
8
9
6d
6d
A
C
8d
8d
100 : 0 70
—
0
10
11
12
13
9 R1 = R2 = H
9 R1 = R2 = H
4 R1 = R2 = CH3
4 R1 = R2 = CH3
A
C
B
C
10 R1 = R2 = H 30 : 70 70
10 R1 = R2 = H 40 : 60 40
11 R1 = R2 = CH3 50 : 50 87
11 R1 = R2 = CH3 60 : 40 84
14
15
16
17
18
12 R1 = CH3
12 R1 = CH3
14 R1 = C5H11
16 R1=C6H5
16 R1=C6H5
B
C
B
B
C
13 R1 = CH3
13 R1 = CH3
15 R1 = C5H11
17 R1=C6H5
17 R1=C6H5
0 : 100 46
40 : 60 83
0 : 100 52
0 : 100 67
7 : 93 65
1 via three steps including a Sonogashira coupling with
trimethylsilyl acetylene and the N-ethynylation of the tosyl-
amide moiety with ethynyliodonium triflate (Scheme 3). The
Negishi reaction of 1 with 3-iodo-N-tosylindole was followed
Our synthesis commenced with commercially available
2-iodoaniline (18) that was transformed into the yne-ynamide
c
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Chem. Commun., 2011, 47, 6656–6658 6657

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Scheme 3 Application of this new b-carboline synthesis in the total synthesis of eudistomin U (22).
by a desilylation with TBAF to provide the yne-ynamide 19
(78% yield over two steps). The Cp*RuCl(cod) catalysed
[2+2+2] cycloaddition of 19 with methylcyanoformate
(7 equiv.) gave rise to the b-carboline ester 20 (94% yield)
that was thereafter saponificated with simultaneous removal
of the N-carboline and N-indolyl tosyl groups to provide the
b-carboline carboxylic acid 21 (96% yield). Finally, decarboxy-
lation of 21 with the help of copper powder under microwave
irradiation afforded eudistomin U (22, 88% yield) whose
spectroscopic data were identical to that of natural material.17
In conclusion an expedient method for the synthesis of
either b- or g-carbolines based on ruthenium or rhodium-
catalysed [2+2+2] cycloaddition reactions was developed.
This new method for the construction of the b-carboline
framework was applied in the total synthesis of the marine
natural product eudistomin U that was achieved within 8 steps
and with 49% overall yield starting from commercially
available 2-iodoaniline.
(b) J. H. Wynne and W. M. Stalick, J. Org. Chem., 2003, 68,
4845 and references cited therein.
5 (a) E. D. Cox and J. Cook, Chem. Rev., 1995, 95, 1797;
(b) J. D. Panarese and S. P. Waters, Org. Lett., 2010, 12, 4086;
(c) J. Dong, X.-X. Shi, J.-J. Yan, J. Xing, Q. Zhang and S. Xiao,
Eur. J. Org. Chem., 2010, 6982.
6 (a) S. Ding, Z. Shi and N. Jiao, Org. Lett., 2010, 12, 1540;
(b) Z. Shi, Y. Cui and N. Jiao, Org. Lett., 2010, 12, 2908;
(c) H. Zhang and R. C. Larock, J. Org. Chem., 2002, 67, 7048;
(d) S. Chiba, Y.-J. Xu and Y.-F. Wang, J. Am. Chem. Soc., 2009,
131, 12886.
7 G. Verniest, D. England, N. De Kimpe and A. Padwa, Tetrahedron,
2010, 66, 1496.
8 For the synthesis of indolines, carbazoles, and 3-aminopyridines
via [2+2+2] cycloadditions with ynamides, see: (a) B. Witulski
and T. Stengel, Angew. Chem., Int. Ed., 1999, 38, 2426;
(b) B. Witulski and C. Alayrac, Angew. Chem., Int. Ed., 2002, 41,
3281; (c) C. Alayrac, D. Schollmeyer and B. Witulski, Chem.
Commun., 2009, 1464; (d) P. Garcia, S. Moulin, Y. Miclo,
D. Leboeuf, V. Gandon, C. Aubert and M. Malacria, Chem.–Eur.
J., 2009, 15, 2129.
9 For reviews on ynamides, see: (a) K. A. deKorver, H. Li,
A. G. Lohse, R. Hayashi, Z. Lu, Y. Zhang and R. P. Hsung,
Chem. Rev., 2010, 110, 5064; (b) G. Evano, A. Coste and
K. Jouvin, Angew. Chem., Int. Ed., 2010, 49, 2840;
(c) B. Witulski and C. Alayrac, N-Acyl and N-Sulfonyl Alk-1-yn-
1-amines, in Science of Synthesis, Compounds with Four and Three
Carbon-Heteroatom Bonds, ed. A. de Meijere, Georg Thieme,
Stuttgart, 2005, vol. 24, ch. 4.4.2, pp. 1031–1058.
This work was supported by CNRS and the ANR (ANR 08-
CEXC). The ‘‘Region Basse-Normandie’’ and ERDF funding
´
(ISCE-Chem & INTERREG IVa program) are gratefully
acknowledged for financial support. We thank Dr G. Paulay
(Florida Museum of Natural History, USA) for the
permission to use the picture of Lissoclinum fragile in our
graphical abstract.
10 B. Witulski and T. Stengel, Angew. Chem., Int. Ed., 1998, 37, 489.
11 For Sonogashira reactions with ynamides, see: M. R. Tracey,
Y. Zhang, M. O. Frederick, J. A. Mulder and R. P. Hsung, Org.
Lett., 2004, 6, 2209.
12 For reviews on [2+2+2] cycloadditions, see: (a) P. R. Chopade
and J. Louie, Adv. Synth. Catal., 2006, 348, 2307; (b) B. Heller and
M. Hapke, Chem. Soc. Rev., 2007, 36, 1085; (c) K. Tanaka, Synlett,
Notes and references
1 (a) T. Ohmoto and K. Koike, in The Alkaloids, ed. A. Brossi,
Academic Press, San Diego, 1989, vol. 36, pp. 135–170; (b) R. Cao,
W. Peng, Z. Wang and A. Xu, Curr. Med. Chem., 2007, 14, 479;
(c) E. Magnier and Y. Langlois, Tetrahedron, 1998, 54, 6201.
2 For examples, see: (a) B. S. Davidson, Chem. Rev., 1993, 93, 1771;
(b) W. D. Inman, W. M. Bray, N. C. Gassner, R. S. Lokey,
K. Tenney, Y. Y. Shen, K. TenDyke, T. Suh and P. Crews, J. Nat.
Prod., 2010, 73, 255; (c) W. Wang, S.-J. Nam, B.-C. Lee and
H. Kang, J. Nat. Prod., 2008, 71, 163; (d) S. Pedpradab, R. Edrada,
R. Ebel, V. Wray and P. Proksch, J. Nat. Prod., 2004, 67, 2113;
(e) J. Kobayashi, G. C. Harbour, J. Gilmore and K. L. Rinehart,
Jr., J. Am. Chem. Soc., 1984, 106, 1526; (f) M. Cain, R. W. Weber,
F. Guzman, J. M. Cook, S. A. Barker, K. C. Rice, J. N. Crawley,
S. M. Paul and P. Skolnick, J. Med. Chem., 1982, 25, 1081;
(g) R. Sakai and T. Higa, J. Am. Chem. Soc., 1986, 108, 6404.
3 S. Dvorackova, P. Sedmera, H. Potesilova, F. Santavy and
V. Simanek, Collect. Czech. Chem. Commun., 1984, 49, 1536.
4 (a) J. Chen, X. Dong, T. Liu, J. Lou, C. Jiang, W. Huang, Q. He,
B. Yang and Y. Hu, Bioorg. Med. Chem., 2009, 17, 3324;
2007, 1977; (d) J. A. Valera and C. Saa, Synlett, 2008, 2571.
´
13 Noteworthy, cobalt complexes are the most frequently used
catalysts for pyridine syntheses via [2+2+2] cycloaddition of
diynes (or two alkynes) with alkyl or aryl substituted nitriles.
However, electron deficient nitriles are less suitable for cobalt
catalysed reactions.
14 Y. Yamamoto, S. Okuda and K. Itoh, Chem. Commun., 2001, 1102.
15 K. Tanaka, N. Suzuki and G. Nishida, Eur. J. Org. Chem., 2006, 3917.
16 (a) Y. Yamamoto, K. Kinpara, T. Saigoku, H. Takagishi,
S. Okuda, H. Nishiyama and K. Itoh, J. Am. Chem. Soc., 2005,
127, 605; (b) Y. Komine, A. Kamisawa and K. Tanaka, Org. Lett.,
2009, 11, 2361.
17 A. Badre, A. Boulanger, E. Abou-Mansour, B. Banaigs,
G. Combaut and C. Francisco, J. Nat. Prod., 1994, 57, 528.
18 For previous syntheses of eudistomin U, see: (a) P. Rocca,
F. Marsais, A. Godard, G. Queguiner, L. Adams and B. Alo,
´
Tetrahedron Lett., 1995, 36, 7085; (b) P. Molina, P. M. Fresneda
and S. Garcia-Zafra, Tetrahedron Lett., 1995, 36, 3581; and ref. 5b.
c
6658 Chem. Commun., 2011, 47, 6656–6658
This journal is The Royal Society of Chemistry 2011