New synthesis of arcyriaflavin-A via silyl enol ether-mediated and Fischer indolisations

Article abstract of DOI:10.1016/j.tetlet.2005.05.075

A new synthesis of the natural product arcyriaflavin-A is described. It was brought about through Diels-Alder cycloaddition and two indolisations based on silyl enol ether nucleophilic attack and Fischer processes.

Full text of DOI:10.1016/j.tetlet.2005.05.075

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4839–4841
New synthesis of arcyriaflavin-A via silyl enol ether-mediated
and Fischer indolisations
*
Dulce Alonso, Esther Caballero, Manuel Medarde and Fernando Tome
*
´
´ ´ ´
Laboratorio de Quımica Organica y Farmaceutica, Facultad de Farmacia, 37007 Salamanca, Spain
Received 21 April 2005; revised 16 May 2005; accepted 18 May 2005
Available online 4 June 2005
Abstract—A new synthesis of the natural product arcyriaflavin-A is described. It was brought about through Diels–Alder cyclo-
addition and two indolisations based on silyl enol ether nucleophilic attack and Fischer processes.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Some time ago, we began a research project aimed at the
synthesis of indolocarbazole alkaloid1 analogues, taking
arcyriaflavin-A as the simplest model. We have already
described the preparation of a broad variety of this fam-
ily of compounds, some of them displaying an interest-
ing cytotoxic profile.2 The synthetic methodology used
for this purpose was a combination of a Diels–Alder
reaction between aryl-siloxy-butadienes and a male-
imide derivative followed by a Fischer indolisation.
ether 2, which can readily be prepared3 from o-nitro-
benzaldehyde through a Diels–Alder reaction between
the nitrophenylsiloxydiene 1 and maleimide (Scheme
2).
To our knowledge, there are no references describing the
use of a silyl enol ether as a substrate for the reductive
cyclisation of aromatic nitro compounds. While there
are examples of nitrene-mediated insertions on silyl enol
ethers, all reported cases involve the generation of the
nitrene species from azide derivatives.5–7
During the course of those studies, we performed a new
synthesis3 of arcyriaflavin-A, in which the last indole
unit of the indolocarbazole system was assembled by a
triethylphosphite-mediated formal nitrene insertion
(Cadogan and SundbergÕs procedure).4
When the cycloadduct 2 was reacted with neat tri-
ethylphosphite at 160 ꢁC, compound 3a was obtained
in 75% yield. If nitrene insertion is taken into consider-
ation as the cyclisation process, the expected reaction
product, 3b, would have the 2,3-dihydroindole moiety
(Scheme 3a). Accordingly, an alternative cyclisation
mechanism, instead of a simple nitrene insertion, must
be involved.
Since one drawback arising from that synthesis was the
decrease in yield due to the formation of two regioiso-
mers in the key Fischer indolisation process, we decided
to overcome this problem by changing the synthetic
approach. For this purpose, we planned to build the
indolocarbazole skeleton by reductive cyclisation of
the cycloadduct 2 followed by the Fischer reaction of
the resulting ketone 3, as shown in Scheme 1.
The cyclisation process during the treatment of olefins
and nitroaromatic derivatives is usually explained in
terms of the formation of a nitrene intermediate under
P(OEt)3 reducing conditions.4 This explanation, valid
for most cases,4,8 is not satisfactory for the formation
of our synthetic intermediate towards arcyriaflavin-A.
As depicted in Scheme 3a, the nucleophilic attack by
the silyl enol ether on the electrophilic nitrene would
result in a dihydroindole moiety (compound 3b), which
requires a further oxidation process to yield 3a.
In order to obtain pyrrolocarbazoletrione 3, it was nec-
essary to explore the reductive cyclisation of silyl enol
Keywords: Arcyriaflavin-A; Indolocarbazoles; Silyl enol ether;
Indolisation.
*
As stated by Sundberg, while this type of reductive
cyclisations can formally be considered to be nitrenoid
Corresponding authors. Tel.: +34 923 294528; fax: +34 923
294515; e-mail: frena@usal.es
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.075

4840
D. Alonso et al. / Tetrahedron Letters 46 (2005) 4839–4841
O
O
O
OTBDMS
D-A
OTBDMS
NO2
NH
NH
O
P(OEt)3
Fischer
HN
HN
HN
NH
O
O
NO2
O
2
1
3a: With indole moiety
3b: With dihydroindole moiety
Arcyriaflavin-A
Scheme 1.
O
O
O
H
H
OTBDMS
Toluene, r.t.
OTBDMS
NO2
CHO
HN
TBDMSOTf
Ph3P
NO2
NO2
NO2
O
HN
O
96%
O
Et3N / CH2Cl2
r.t. 100%
Toluene,
reflux 86%
1
2
P(OEt)3
160º C
75%
MeO
O
HN
O
O
HN
O
H
H
3a
NH
NH
O
O
PhNHNH2
NH
NH
AcOH/EtOH/H2O
Reflux, 57%
NH
HN
O
Arcyriaflavin-A
p-MeO-PhNHNH2
AcOH/EtOH/H2O Reflux, 64%
3-Methoxyarcyriaflavin-A
Scheme 2.
in character, several observations suggest this to be an
oversimplification.9 It seems more likely that each of
the reductants would generate a specific electrophilic
nitrogen intermediate that would attack the adjacent
double bond, such that the structure of the reactive
intermediate could vary with the reducing agent.
vin-A. When 3a was subjected to Fischer indolisation,
arcyriaflavin-A was isolated directly by crystallisation
(57% yield), thus implying that an aromatisation process
to generate an indole ring occurs readily under the reac-
tion conditions. An unsymmetrical analogue of arcyria-
flavin-A (3-methoxy-derivative) was obtained following
a similar procedure, but in this case using p-meth-
oxyphenylhydrazine for the indolisation reaction (see
Scheme 2, for the complete synthesis).11
In the present case, an intermediate product in the
P(OEt)3 treatment of the nitro group, which could
maintain the electrophilic character together with a
not fully reduced state, would explain the formation
of 3a. The generally accepted formation of a nitroso
derivative during this kind of reduction10 could ac-
count for this, as depicted in Scheme 3b. The appear-
ance of an oxy-amino intermediate as a consequence
of cyclisation mediated by the nitroso group, would
only require an elimination step in order to produce
the observed product, being compatible with the reac-
tion conditions.
In conclusion, the sequence described here (aryl-siloxy-
diene Diels–Alder reaction, and nitro-reductive silyl enol
ether-mediated and Fischer indolisations) provides a
new high-yielding synthesis of the alkaloid arcyriafla-
vin-A and its 3-substituted unsymmetrical analogue
(35% and 40% overall yields from o-nitrobenzaldehyde,
respectively), thus representing a noticeable improve-
ment to our previous procedure (12% overall yield).
The pyrrolocarbazoletrione 3a has a very interesting
structure as a possible synthetic intermediate for the
preparation of other natural or unnatural fused poly-
heterocyclic products.
With compound 3a in hand, two synthetic steps re-
mained in order to complete the synthesis of arcyriafla-

D. Alonso et al. / Tetrahedron Letters 46 (2005) 4839–4841
(a) Nitrene intermediate
4841
O
O
O
O
O
OX
P(OEt)3
160º C
NO2
OX
N
OX
O
O
[O]
HN
HN
HN
HN
HN
N
NH
NH
O
O
O
O
O
3a
3b
(b) Nitroso intermediate
O
O
O
O
O
OX
OX
O
O
O
-XOH
HN
HN
HN
HN
HN
N O
N OX
N
NH
O
O
O
O
O
N
O
3a
X = TBDMS
Scheme 3.
8. So¨derberg, B. C. J. Curr. Org. Chem. 2000, 4, 727–764,
and references cited therein.
Acknowledgements
9. Sundberg, R. J. Indoles; Academic Press: London, 1996,
pp 24–26.
Financial support came from the following institutions:
Spanish MCyT (PPQ2000-1179), Junta de Castilla y
10. (a) Brown, P. K.; Herbert, R. B.; Holliman, F. G.
Tetrahedron Lett. 1973, 14, 761–764; (b) Ref. 8; (c)
Kimbaris, A.; Varvounis, G. Tetrahedron 2000, 56, 9675–
9682; (d) Moody, C. J.; Whitham, G. H. Reactive Interme-
diates; Oxford University Press: New York, 1992, pp 52–56.
11. All the analytical data for the compounds synthesised are
consistent with their structure, as for instance: 3a: Yellow
´
Leon (SA048/03), Spanish MEC (CTQ2004-00369) and
European FEDER Funds.
References and notes
1
solid, mp 294 ꢁC (CHCl3). H NMR (400 MHz, DMSO)
(d ppm) 11.95 (1H, s, N–H), 11.31 (1H, s, N–H), 8.01 (1H,
d, J = 8.0 Hz, H-10), 7.41 (1H, d, J = 8.0 Hz, H-7), 7.34
(1H, t, J = 8.0 Hz, H-8), 7.14 (1H, t, J = 8.0 Hz, H-9), 4.54
(1H, d, J = 7.4 Hz, H-10c), 3.90 (1H, m, H-3a), 2.90 (2H,
m, H-4). 13C NMR (d ppm) 186.5, 178.1, 175.7, 138.5,
130.3, 126.7, 125.2, 123.2, 120.5, 119.7, 112.9, 40.3, 39.9,
34.1. MS found for C14H10N2O3 m/z: 254. 3-Methoxy-
arcyriaflavin-A: Brown solid, mp 320 ꢁC (CHCl3). 1H
NMR (400 MHz, DMSO) (d ppm) 11.76 (1H, s, N–H),
11.59 (1H, s, N–H), 10.95 (1H, s, N–H), 8.96 (1H, d,
J = 7.4 Hz, H-8), 8.55 (1H, s, H-4), 7.76 (1H, d,
J = 7.4 Hz, H-11), 7.68 (1H, d, J = 8.6 Hz, H-1), 7.52
(1H, t, J = 7.4 Hz, H-10), 7.32 (1H, t, J = 7.4 Hz, H-9),
7.17 (1H, d, J = 8.6 Hz, H-2), 3.41 (3H, s, OMe). 13C
NMR (d ppm) 171.4 (·2), 153.8, 140.2, 135.2, 129.6, 129.1,
126.6, 124.3, 122.1, 121.7, 120.2, 120.0, 119.5, 116.0, 115.6,
115.3, 112.7, 112.0, 106.6, 55.5. HRMS (FAB) m/z calcd
for C21H13N3O3 355.0957, found 355.1001. Arcyriaflavin-
A: the analytical data agree with those reported in
Gribble, G. W.; Berthel, S. J. Tetrahedron 1992, 48,
8869–8880.
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