Silver catalyzed cascade synthesis of alkaloid ring systems: Concise total synthesis of fascaplysin, homofascaplysin C and analogues

Article abstract of DOI:10.1039/c001350a

A silver catalyzed and microwave assisted one-pot cascade synthesis provides efficient access to diverse alkaloid-inspired scaffold classes, and a concise and efficient total synthesis of homofascaplysin C and fascaplysin.

Full text of DOI:10.1039/c001350a

View Online / Journal Homepage / Table of Contents for this issue
This article is part of the
2010 ‘Enzymes & Proteins’
web themed issue
This issue showcases high quality research in the field of enzymes and
proteins.
Please visit the website to access the other papers in this issue:-
http://www.rsc.org/chemcomm/enzymesandproteins

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Silver catalyzed cascade synthesis of alkaloid ring systems: concise total
synthesis of fascaplysin, homofascaplysin C and analogueswz
Herbert Waldmann,*ab Luc Eberhardt,a Kathrin Wittsteinab and Kamal Kumar*a
Received 20th January 2010, Accepted 18th March 2010
First published as an Advance Article on the web 13th April 2010
DOI: 10.1039/c001350a
A silver catalyzed and microwave assisted one-pot cascade
synthesis provides efficient access to diverse alkaloid-inspired
scaffold classes, and a concise and efficient total synthesis of
homofascaplysin C and fascaplysin.
In initial exploring experiments, we investigated different
reaction conditions using 2-(phenylethynyl)benzaldehyde 1a
and di-tert-butyl-2-(2-aminophenyl)malonate 2a as substrates
and Au(III), Au(I) and Ag-salts as catalysts (see Table 1). While
the use of Au(I) did not lead to product formation, AuCl3
either alone or in the presence of a silver co-catalyst induced
formation of decarboxylated product 3a (Scheme 2). The
expected intermediate 6 could be isolated in low yield
(o10%) and converted into 3a in a separate transformation.
Further experiments revealed that AuCl3 or AgOTf alone in
dichloroethane or ethanol give only relatively low yields of 3a
(Table 1, entries, 2, 4, 5 and 7). Combination of AuCl3 with a
silver co-catalyst in dichloroethane resulted in a higher yield
whereas in ethanol such a promoting effect was recorded only
at higher temperature (Table 1, entries 3 and 6). A significant
increase in yield was observed when 20 mol% of AgOTf was
used at 60 1C in ethanol along with an excess of a nitrogen-
base like proline or lutidine (Method A, Table 1, entries 8 and 9).
Under these conditions the final product was formed in yields
up to 84%. If the catalyst loading was lowered, the reaction
did not go to completion even after two days. Finally, we
explored whether microwave heating would accelerate the
reaction sequence, and, gratifyingly, the desired product 3a
was isolated in 95% yield after irradiation at 150 1C (150 W)
for 45 min in the presence of 2.5 mol% AgOTf and 10 mol%
of lutidine (Method B; entry 1, Table 2). Under the optimized
reaction conditions either with normal heating or with micro-
wave heating, acetylenes carrying electron rich aromatic
substituents and alkyl groups (Table 2, entries 2–4, and 6)
yielded the corresponding indoloisoquinolines in high yields.
In general microwave heating enhanced the yields by up to
25% in these cases (3a–3d). Microwave heating proved to be
particularly efficient if the acetylene was substituted with an
aromatic ring carrying an electron-withdrawing group
(Table 2, entries 5, 9, 12 and 16) or if the aniline carried
electron-donating substituents (Table 2, entries 10–12). The
most striking reactions were those between electron-rich
aldehydes and electron-rich anilines which proceeded only
under microwave heating (Table 2, entries 14–16). These
results demonstrate that the developed Ag+-catalyzed cascade
sequence provides an efficient access to tetracyclic indolo-
isoquinolines 3 in a one-pot, four-step transformation. This
heterocycle class is of particular importance due to its
pronounced antitumor activity.8
Compound libraries based on natural product core scaffolds are
an important source of bioactive molecules for medicinal
chemistry and chemical biology research.1 Efficient reaction
sequences that give flexible access to scaffold and stereochemical
diversity and complexity preferably employing catalytic multi-
step synthesis sequences are in high demand.2 In this respect the
core scaffolds of alkaloid classes are particularly important
since numerous alkaloids display diverse biological activities.
Consequently the synthesis of alkaloid-inspired compound
collections has received considerable attention.3–4 Here we report
the development of a silver-catalyzed cascade reaction sequence
that gives access to different alkaloid-inspired polycyclic scaffold
classes in an efficient one-pot process, including fascaplysin-type
alkaloids and analogs thereof. For the development of the
sequence we reasoned that an imine formed from an acetylenic
benzaldehyde (I) and an aniline with a pendant nucleophile (II)
would undergo cycloisomerization in the presence of Ag/Au ions
as catalysts that activate the alkyne for nucleophilic attack to
yield the isoquinolinium intermediate (III).5,6 This cation
would be subject to a nucleophilic attack from the pendant
1,3-dicarbonyl group to form scaffold IV (Scheme 1).
Structural variation of the acetylenic aldehyde and the
nucleophile attached to the aniline would give rise to diverse
ring systems fused to a common isoquinoline motif, which
defines the core structure of a large group of biologically and
medicinally relevant compounds.7
Scheme 1 Design of a cascade route to diverse alkaloid scaffolds.
a Max Planck Institut fur molekulare Physiologie, Otto-Hahn Strasse 11,
¨
44227-Dortmund, Germany.
E-mail: Herbert.Waldmann@mpi-dortmund.mpg.de,
Kamal.Kumar@mpi-dortmund.mpg.de; Fax: (+)49-231-133-2499;
Tel: (+)49-231-133-2401
b Technische Universitat Dortmund, Fachbereich Chemie,
¨
44221-Dortmund, Germany
In order to extend the scope of the cascade synthesis and to
expand the scaffold diversity accessible by means of this
method we employed indole- and furan-derived acetylenic
aldehydes 7 (Scheme 3) in the silver catalyzed transformation.
In these cases regular heating and microwave heating in the
w This article is part of the ‘Enzymes and Proteins’ web-theme issue for
ChemComm.
z Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data of the new products. See DOI: 10.1039/
c001350a
ꢀc
This journal is The Royal Society of Chemistry 2010
4622 | Chem. Commun., 2010, 46, 4622–4624

Table 1 Cascade synthesis of indolo[2,1-a]isoquinolinesa
Entry
Catalystb (mol%)
Co-catalyst or base (mol%)
Solvent
T/1C
Time/h
Yield (%)c
1
2
3
4
5
6
7
8
9
Au(PPh3)Cl (10)
AuCl3 (10)
AuCl3 (10)
AgOTf (10)
AgOTf (10)
AuCl3 (10)
AgOTf (10)
AgOTf (20)
AgOTf (20)
—
—
DCE
DCE
DCE
DCE
DCE
EtOH
EtOH
EtOH
EtOH
rt
rt
rt
rt
80
60
60
60
60
72
72
72
72
18
24
18
18
24
n.r.
11
40
8
21
33
33
74
84
AgSbF6 (10)
—
—
AgOTf (10)
—
L-Proline (100)
2,6-Lutidine (100)
a
b
For details of catalyst and reaction conditions screening, see the ESI. No product was formed in the absence of any catalyst. Isolated yields.
c
Scheme 3 Cascade synthesis of complex benzoindolizines.
eight minutes followed by treatment of the crude reaction
mixtures with 20% formic acid at room temperature to induce
the decarboxylation.
Scheme 2 Cascade synthesis of indolo[2,1-a]isoquinolines.
Table 2 Silver catalyzed synthesis of indolo[2,1-a]isoquinolines
Since aromatization appears to be the driving force for the
decarboxylation to yield compounds 3 and 8, we reasoned that
increasing the length of the linker between the pendant nucleo-
phile and the phenyl ring would prevent aromatization and lead
to formation of larger ring systems with different scaffolds. To
explore this possibility, aniline 10 with a substituted ethyl
malonate moiety was treated with acetylenic benzaldehydes
under the optimized reaction conditions for the silver catalyzed
cascade cyclization. Gratifyingly, both alkyl and aryl substi-
tuted acetylenes including quinoline derivative 9c (Table 3,
entry 3) yielded the desired benzazepino[2,1-a]isoquinolines as
single diastereomers in moderate to high yields (Table 3). The
relative cis-configuration of 11a was established by means of a
clear nOe interaction between the two benzylic protons.
Yielda
Entry No. R1
R2
R3
R4
(%, A/B)b,c
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
Ph
3-Thiophene
n-Pr
3-OMe-Ph
4-CF3-Ph
4-OMe-Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
84/95
81/92
54/81
64/85
13/56
60/83
50/78
n.i./86
n.r./52
The successful implementation of the silver catalyzed
cascade reaction sequence to skeletally diverse alkaloid-
inspired ring systems encouraged us to apply this methodology
to natural product synthesis. The fascaplysin- and homo-
fascaplysin class of marine natural products9 has a characteristic
12H-pyrido[1,2-a;3,4-b0]diindole pentacyclic framework which
could readily be accessed using the silver catalyzed cascade
cyclization reaction described above, thereby providing a
concise synthesis of these natural products and possible
analogues. The characteristic architecture of these molecules
has previously inspired both total synthesis10 endeavours and
investigations into their biological activities.11
OMe Ph
OMe n-Pr
OMe 4-CF3-Ph
9
10
11
12
13
14
15
16
17
3j
3k
3l
3m
3n
3o
3p
3q
H
H
H
H
Ph
n-Pr
4-CF3-Ph
Ph
OMe OMe 21/65
OMe OMe 17/60
OMe OMe 18/59
OMe
H
n.i./87
OMe Ph
OMe n-Pr
OMe 4-CF3-Ph
OMe OMe n.r./50
OMe OMe n.r./73
OMe OMe n.r./67
H
H
H
H
77/n.i.
a
b
Isolated yields (n.r = no reaction; n.i. = not investigated). Method A:
AgOTf (20 mol%), 2,6-lutidine (1.0 equiv.), ethanol, 60 1C, 24 h; Method B:
AgOTf (2.5 mol%), 2,6-lutidine (10 mol%), ethanol, MW-150 W, 150 1C,
45 min. c In isolated cases, remaining intermediate (tlc, LC-MS) was
decarboxylated by treating the crude reaction mixture with 20% HCO2H
under reflux overnight to obtain the indolo[2,1-a]isoquinolines 3.
Boc-protected 3-ethynyl-indole-2-carbaldehyde (12) was
employed as a common precursor for the natural product targets
fascaplysin and homofascaplysin C. The microwave assisted silver
catalyzed cascade cyclization of 12 with aniline 2 yielded the
pentacyclic core 13 in high yield after acidic work-up (see the
ESIz). Partial reduction of the tert-butyl ester (B60% conversion)
by means of in situ generated lithium diisobutylpiperidino-
hydroaluminate12 provided the natural product homofascaplysin
C (14) in 48% overall yield over four steps from 12 (Scheme 4).
presence of 2.5 mol% catalyst were ineffective. But the desired
polycyclic products 8 were obtained in up to 50% overall yield
in the presence of 10 mol% of the catalyst at a reaction time of
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 4622–4624 | 4623

Table 3 Silver catalyzed synthesis of benzazepeno[2,1-a]isoquinolines
2 Reviews: (a) D. Enders, C. Grondal and M. R. M. Huttl, Angew.
¨
Chem., Int. Ed., 2007, 46, 1570–1581; (b) D. G. Rivera,
O. E. Vercillo and L. A. Wessjohann, Org. Biomol. Chem.,
2008, 6, 1787–1795; (c) L. F. Tietze and N. Rackelmann, Pure
Appl. Chem., 2004, 76, 1967–1983; (d) A. Ulaczyk-Lesanko and
D. G. Hall, Curr. Opin. Chem. Biol., 2005, 9, 266–276;
(e) L. F. Tietze, Chem. Rev., 1996, 96, 115–136.
3 For reviews on selected examples see e.g.: (a) D. A. Horton,
G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103,
893–930; (b) S. Brase, C. Gil and K. Knepper, Bioorg. Med. Chem.,
¨
2002, 10, 2415–2437.
4 Selected examples from our labs: (a) A. Noren-Muller, W. Wilk,
¨
¨
Yielda
K. Saxena, H. Schwalbe, M. Kaiser and H. Waldmann, Angew.
Chem., Int. Ed., 2008, 47, 5973–5977; (b) A. Noren-Muller,
I. Reis-Correa, Jr., H. Prinz, C. Rosenbaum, K. Saxena,
´
Entry
No.
R1
X
R2
R3
(%, A/B)b
¨
¨
1
2
3
4
5
6
7
11a
11b
11c
11d
11e
11f
11g
H
H
–Ph–
H
H
CH
CH
N
CH
CH
CH
CH
Ph
H
H
H
Et
Et
Et
Et
72/89
58/82
42/72
75/90
68/87
59/n.i.
n.i./69
nPr
Ph
H. J. Schwalbe, D. Vestweber, G. Cagna, S. Schunk, O. Schwarz,
H. Schiewe and H. Waldmann, Proc. Natl. Acad. Sci. U. S. A., 2006,
103, 10606–10611; (c) C. Rosenbaum, P. Baumhof, R. Mazitschek,
Ph
O. Muller, A. Giannis and H. Waldmann, Angew. Chem., Int. Ed.,
¨
3-OMe-Ph
H
4-CF3-Ph
2004, 43, 224–228; (d) H. Waldmann, G. V. Karunakar and
K. Kumar, Org. Lett., 2008, 10, 2159–2162.
H
OMe
5 For selected examples see: (a) S. Su and J. A. Porco, Jr., J. Am.
Chem. Soc., 2007, 129, 7744–7745; (b) S. Su and J. A. Porco, Jr.,
Org. Lett., 2007, 9, 4983–4986; (c) N. Asao, S. Yudha, T. Nogami
and Y. Yamamoto, Angew. Chem., Int. Ed., 2005, 44, 5526–5528;
(d) N. Asao, K. Iso and S. Yudha, Org. Lett., 2006, 8, 4149–4151;
(e) Q. Ding and J. Wu, Org. Lett., 2007, 9, 4959–4962; (f) Q. Ding,
X. Yu and J. Wu, Tetrahedron Lett., 2008, 49, 2752–2755;
(g) W. Sun, Q. Ding, X. Sun, R. Fan and J. Wu, J. Comb. Chem.,
2007, 9, 690–694; (h) R. Yanada, S. Obika, H. Kono and
Y. Takemoto, Angew. Chem., Int. Ed., 2006, 45, 3822–3825;
(i) K. Gao and J. Wu, J. Org. Chem., 2007, 72, 8611–8613;
(j) S. Obika, H. Kono, Y. Yasui, R. Yanada and Y. Takemoto,
J. Org. Chem., 2007, 72, 4462–4468; (k) M. Yu, Y. Wang, C.-J. Li
and X. Yao, Tetrahedron Lett., 2009, 50, 6791–6794.
a
b
= not investigated). Method A: AgOTf
Isolated yields (n.i.
(20 mol%), 2,6-lutidine (1.0 equiv.), ethanol, 60 1C, 24 h; Method B:
AgOTf (2.5 mol%), 2.6-lutidine (10 mol%), ethanol, MW (150 W),
150 1C, 45 min.
6 Reviews: (a) E. Jimenez-Nunez and A. M. Echavarren, Chem.
´
Rev., 2008, 108, 3326–3350; (b) V. Michelet, P. Y. Toullec and
J. P. Genet, Angew. Chem., Int. Ed., 2008, 47, 4268–4315; (c) A. S. K.
Hashmi, Chem. Rev., 2007, 107, 3180–3211; (d) S. F. Kirsch,
Synthesis, 2008, 3183–3204; (e) N. T. Patil and Y. Yamamoto, Chem.
Rev., 2008, 108, 3395–3442; (f) P. Belmont and E. Parker, Eur. J. Org.
Chem., 2009, 6075–6089.
7 (a) K. W. Bentley, The Isoquinoline Alkaloids, Harwood Academic,
Australia, 1998, vol. 1; (b) K. W. Bentley, Nat. Prod. Rep., 2006,
23, 444–463; (c) M. Chrzanowska and M. D. Rozwadowska,
Chem. Rev., 2004, 104, 3341–3370.
8 M. I. Goldbrunner, G. Loidl, T. Polossek, A. Mannschreck and
E. von Angerer, J. Med. Chem., 1997, 40, 3524–3533.
9 (a) D. M. Roll, C. M. Ireland, H. s. M. Lu and J. Clardy,
´ ´
J. Org. Chem., 1988, 53, 3276–3278; (b) C. Jimenez, E. Quinoa,
M. Adamczeski, L. M. Hunter and P. Crews, J. Org. Chem., 1991,
56, 3403–3410.
Scheme 4 Synthesis of homofascaplysin C and fascaplysin.
To overcome the difficult reduction of the tert-butyl ester 13
to final product 14, aniline 15 was employed in the cascade
synthesis of pentacyclic core 16 which was obtained in 61%
yield.13 Formylation of 16 with POCl3 cleanly provided homo-
fascaplysin C with an overall yield of 53%.10a In addition, the
pentacyclic core 16 was efficiently transformed to the natural
product fascaplysin by oxidation with peracetic acid, followed
by salt formation in 52% overall yield (Scheme 4).10a
10 Selected syntheses efforts: (a) G. W. Gribble and B. Pelcman,
J. Org. Chem., 1992, 57, 3636–3642; (b) D. S. Carter and D. L. Van
Vranken, J. Org. Chem., 1999, 64, 8537–8545; (c) C. Aubry,
P. R. Jenkins, S. Mahale, B. Chaudhuri, J.-D. Marechalc and
´
In conclusion we have developed an efficient one-pot, four-
step silver catalyzed cascade sequence that gives ready access to a
variety of skeletally diverse natural product inspired compound
classes including fascaplysin-type alkaloids. This method will
facilitate the synthesis and biological investigation of skeletally
and structurally diverse alkaloid-based compound collections.
M. J. Sutcliffe, Chem. Commun., 2004, 1696–1697;
(d) S. V. Dubovitskii, Tetrahedron Lett., 1996, 37, 5207–5208;
(e) M. E. Zhidkov, O. V. Baranova, N. N. Balaneva,
S. N. Fedorov, O. S. Radchenkob and S. V. Dubovitski,
Tetrahedron Lett., 2007, 48, 7998–8000.
11 Selected reports on biological activities: (a) C. Aubry, A. J. Wilson,
D. Emmerson, E. Murphy, Y. Y. Chan, M. P. Dickens,
M. D. Garcı
Med. Chem., 2009, 17, 6073–6084; (b) S. Mahale, C. Aubry,
A. J. Wilson, P. R. Jenkins, J.-D. Marechal, M. J. Sutcliffec and
´
a, P. R. Jenkins, S. Mahale and B. Chaudhuri, Bioorg.
Notes and references
´
1 (a) K. Kumar and H. Waldmann, Angew. Chem., Int. Ed., 2009, 48,
3224–3242; (b) J. P. Nandy, M. Prakesch, S. Khadem, P. T. Reddy,
U. Sharma and P. Arya, Chem. Rev., 2009, 109, 1999–2060;
(c) G. M. Cragg, P. G. Grothaus and D. J. Newman, Chem.
Rev., 2009, 109, 3012–3043; (d) R. Breinbauer, I. R. Vetter and
H. Waldmann, Angew. Chem., Int. Ed., 2002, 41, 2878–2890; (e) for
a diversity oriented synthesis (DOS) approach see: R. J. Spandl,
M. Diaz-Gavilan, M. G. K. O’Connell, G. L. Thomas and
D. R. Spring, Chem. Rec., 2008, 8, 129–142 and references therein.
B. Chaudhuri, Bioorg. Med. Chem. Lett., 2006, 16, 4272–4278;
(c) J. Lin, X.-J. Yan and H.-M. Chen, Cancer Chemother.
Pharmacol., 2007, 59, 439–445; (d) A. Huwe, R. Mazitschek and
A. Giannis, Angew. Chem., Int. Ed., 2003, 42, 2122–2138;
(e) A. M. Senderowicz, Oncogene, 2003, 22, 6609–6620.
12 J. H. Ahn, J. I. Song, J. E. Ahn and D. K. An, Bull. Korean Chem.
Soc., 2005, 26, 377–378.
13 Treatment of 13 with TFA led to decomposition and only 10% of
16 could be obtained.
ꢀc
This journal is The Royal Society of Chemistry 2010
4624 | Chem. Commun., 2010, 46, 4622–4624