Total synthesis of the marine pyrroloiminoquinone alkaloid tsitsikammamine A

Article abstract of DOI:10.1016/j.tetlet.2008.12.078

A concise route to the marine pyrroloiminoquinone alkaloid tsitsikammamine A and a regioisomer was developed. The synthesis was based on a Michael reaction between the indole dione 6 and 2′-amino-1-(4-methoxyphenyl)ethanol.

Full text of DOI:10.1016/j.tetlet.2008.12.078

Tetrahedron Letters 50 (2009) 1128–1130
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Tetrahedron Letters
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Total synthesis of the marine pyrroloiminoquinone alkaloid tsitsikammamine A
*
Arnaud Rives, Tamara Delaine, Laurent Legentil, Evelyne Delfourne
Université Paul Sabatier, UMR CNRS 5068, Laboratoire de Synthèse et Physicochimie de Molécules d’Intérêt Biologique, 118 route de Narbonne, 31062 Toulouse Cédex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise route to the marine pyrroloiminoquinone alkaloid tsitsikammamine A and a regioisomer was
developed. The synthesis was based on a Michael reaction between the indole dione 6 and 20-amino-1-(4-
methoxyphenyl)ethanol.
Received 24 October 2008
Revised 15 December 2008
Accepted 16 December 2008
Available online 24 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
Marine alkaloid
Pyrroloiminoquinone
Tsitsikammamine
Marine organisms provide a valuable source for natural prod-
ucts. In the past several years, many new pyrroloiminoquinone
alkaloids have been isolated mainly from sponges.1 This class of
compounds consisting of prianosins, discorhabdins, batzellins,
ity against human colon tumor (HCT-116) when compared with
their parent alkaloids.6 Despite different works by our group7
and by others8 to propose analogues of wakayin and tsitsikamm-
amines with potential antitumor activity, and thought that these
alkaloids have been isolated for quite a while now, no synthesis
of these marine metabolites has been reported to date. We de-
scribe herein the first total synthesis of tsitsikammamine A and
one of its regioisomers.
wakayin, damirone, and makaluvamines possesses
a pyrrol-
o[4,3,2-de]quinoline skeleton. Due to their remarkable biological
activities, a number of synthetic methodologies have been devel-
oped to prepare the natural products2 and analogues.3
Tsitsikammamines A (1) and B (2)4, two alkaloids closely struc-
turally related to wakayin 35 and isolated from a Latrunculid
sponge, have been reported to exhibit cytotoxicity and topoiso-
merase I inhibition.
The initial retrosynthetic pathway investigated was based on a
Michael addition between the previously described indole dione
67b and 40-methoxy-2-aminoacetophenone 7.
MeO
MeO
HO
NHBoc
NHBoc
H
N
O
O
O
O
R2
N
+
+
O
HN
O
+
1
N
N
NH2
N
H
Ts
Ts
N
H
N
H
N
R1
N
H
O
7
6
8a
O
3
1, R1= R2 = H
2, R1= Me, R2 = H
4, R1= H, R2 = OH
5, R1= Me, R2 = OH
This last b-ketoamine was synthesized in one step according to
Grayson and Heyes’ method9 involving anisole which was reacted
with gaseous HCl in the presence of AlCl3. Compound 7 was ob-
tained as a hydrochloride salt in 50% yield. The coupling reaction
of this salt with compound 6 did not give the expected adduct 8a
whatever the experimental conditions used, but afforded mainly
(41% yield) one of regioisomers 9a or 9b. It is noteworthy that the
same reaction was observed when the methoxyphenyl group was
.
Recently, reinvestigation of extracts of the same sponge search-
ing for minor pyrroloiminoquinone metabolites yielded N-18
oxime analogues of tsitsikammamine A and B, 4 and 5, respec-
tively. These compounds exhibited significantly reduced cytotoxic-
* Corresponding author. Tel.: +33 561 55 62 93; fax: +33 561 55 60 11.
E-mail address: delfourn@chimie.ups-tlse.fr (E. Delfourne).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.078

A. Rives et al. / Tetrahedron Letters 50 (2009) 1128–1130
1129
replaced by a phenyl group (77% yield) or by an indole group (58%
yield).
Surprisingly, the formation of the second five-membered nitro-
gen ring was achieved by direct cyclization of the hydroxy-deriva-
tives 11a and 11b in trifluoroacetic acid and CH2Cl2, and was
concomitant with the cleavage of the Boc protective group leading
to compounds 12a and 12b.
NHBoc
NHBoc
MeO
O
O
O
H
N
O
O
MnO2 oxidation of these compounds gave the bispyrroloquinone
derivatives 13a and 13b which were subsequently cyclized into
the corresponding iminoquinones 14a and 14b. The overall yields
of these three steps were 16% and 22%, respectively. It has to be
noted that few amounts (<4%) of compounds 14a and 14b were also
formed during the cyclization step involving trifluoroacetic acid
when the reaction was conducted in the absence of solvent. The to-
syl group of 14a and 14b was removed by action of 1 N NaOH in
dioxane leading to compounds 15a and 15b (46% and 40% yield,
respectively), together with secondary compounds 16a and 16b.
The free base of tsitsikammamine A 17b was readily obtained by
demethylation of compound 15b using BBr3, whereas the same
reaction conditions applied on compound 15a afforded the non-nat-
ural regioisomer 17a.11
N
N
N
H
Ts
Ts
9a
O
O
O
MeO
MeO
9b
OMe
An alternative route to prepare intermediate 8 relied on the reduc-
tion of the carbonyl function of 7 prior to the Michael addition. This
reduction effected by NaBH4 provided b-hydroxyamine 10 in 72%
yield. Reaction of 10 with quinone 6 in absolute ethanol gave two
regioisomers 11a and 11b (57% and 19%, respectively, a and b refer
to the order of elution during the purification by silica gel flash
chromatography). Dess–Martin periodinane oxidation of these alco-
hols provided the two corresponding b-keto-adducts 8a and 8b.10
Attempts to cyclize these products failed.
The spectroscopic data of the trifluoroacetic salt of 17b were
shown to be identical with those reported for tsitsikammamine A
(1).4 Investigations are currently in progress to apply this synthetic
route to the other marine metabolite wakayin 3.
MeO
NHBoc
MeO
NHBoc
O
O
H
N
O
OH
OH
a
N
+
6
+
OH
NH2
10
Ts
N
N
H
11a
Ts
O
O
MeO
NH2
b
11b
MeO
NH2
b
NH2
O
O
O
H
H
N
N
c
N
N
N
N
H
Ts
Ts
Ts
13a
12b
O
O
12a
d
MeO
MeO
c
MeO
N
O
N
NH2
H
N
H
N
f
O
O
N
N
H
Ts
+
O
N
N
H
Ts
17a
13b
MeO
e
N
O
HO
H
N
14a R = Ts
15a R = H
HO
d
N
H
N
O
MeO
16a
N
MeO
f
N
N
H
H
17b
N
N
H
MeO
Ts
O
N
O
14b R = Ts
15b R = H
e
+
N
H
N
H
16b
a- abs EtOH, rt, 2h. b- TFA, CH Cl , rt, 4h. c- MnO , CH Cl , rt, overnight. d- abs EtOH, 4Α molecular sieve,
2
2
2
2
2
reflux, 3h. e- 1N NaOH, dioxane, rt, overnight. f- BBr , CH Cl , N , 4h.
3
2
2
2

1130
A. Rives et al. / Tetrahedron Letters 50 (2009) 1128–1130
8. (a) Zhang, L.; Cava, M. P.; Rogers, R. D.; Rogers, L. M. Tetrahedron Lett. 1998, 39,
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J = 7.8 Hz), 6.74 (d, 2H, J = 8.4 Hz), 6.96 (d, 1H, J = 2.1 Hz), 7.16 (d, 1H,
J = 3.0 Hz), 7.68 (d, 2H, J = 8.4 Hz), 9.37 (br s, 1H), 12.15 (br s, 1H), 12.44 (br
s, 1H). 13C (DMSO-d6) 18.35, 49.07, 115.07 (3C), 118.13, 121.84, 122.18, 122.52,
123.51, 125.27, 125.49, 130.16 (2C), 133.83, 154.96, 156.71, 167.99. (17a)
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6.82 (s, 1H), 6.95 (s, 1H), 7.47 (d, 2H, J = 8.7 Hz), 7.60 (br s, 1H), 7.70 (br s, 1H),
11.81 (br s, 1H). 13C (DMSO-d6) 18.92, 49.05, 11.83 (2C), 115.04, 116.13,
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