Synthesis of pyranonaphthoquinone antibiotics involving the phthalide annulation strategy

Article abstract of DOI:10.1055/s-2006-926248

The synthesis of the pyranonaphthoquinone antibiotic pentalongin was performed using the phthalide annulation strategy. Annulation of the cyanophthalide onto 6H-pyran-3-one resulted in a hongconin analogue, which upon further elaboration was converted into the natural product. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926248

LETTER
621
Synthesis of Pyranonaphthoquinone Antibiotics Involving the Phthalide
Annulation Strategy
a
b
b
c
d
Synthesisof
P
v
e
ntalongin en Claessens, Dashnie Naidoo, Dulcie Mulholland, Luc Verschaeve, Johannes van Staden,
a
Norbert De Kimpe*
a
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
b
c
d
School of Chemistry, University of KwaZulu-Natal, Howard College Campus, 4041 Durban, South Africa
Department of Environmental Toxicology, Vito (Flemish Institute for Technological Research), Boeretang 200, 2400 Mol, Belgium
Research Centre for Plant Growth and Development, School of Botany and Zoology, University of Natal, Pietermaritzburg, Private Bag
X01, Scottsville 3209, South Africa
Received 24 November 2005
In the past years, our department has managed to syn-
thesise a particular group of pyranonaphthoquinones such
Abstract: The synthesis of the pyranonaphthoquinone antibiotic
pentalongin was performed using the phthalide annulation strategy.
Annulation of the cyanophthalide onto 6H-pyran-3-one resulted in
a hongconin analogue, which upon further elaboration was convert-
ed into the natural product.
as pentalongin (1),8 dehydroherbarin (2) 1,3-disub-
,9
10
1
1
stituted-3,4-dehydropyranonaphthoquinones
3
tetra-
1
2
cyclic pentalongin derivatives 4 and harounoside (5,
Figure 1).13
Key words: annulations, natural products, quinones, phthalide,
pentalongin
The naphtho[2,3-c]pyran skeleton was constructed before
by ring closure of 2-allyl-3-hydroxymethyl-1,4-
1
0
dimethoxynaphthalenes and 2-allyl-3-hydroxymethyl-
Pyranonaphthoquinone antibiotics are a diverse family of 1,4-naphthoquinones,14 by intramolecular base-catalysed
naturally occurring 1H-naphtho[2,3-c]pyran-5,10-diones condensation of 3-bromomethyl-1,4-dimethoxy-2-naph-
1
15
found in bacteria, fungi, aphides and higher plants. Due thaleneacetic acid, by palladium-catalysed intramolecu-
2
,3
to their promising biological activities, they attracted lar cyclisation of 2-bromo-3-aryloxymethyl-1,4-naph-
considerable synthetic attention. Among these pyrano- thoquinone, by ring-closing metathesis of a vinyl ether,
naphthoquinones, pentalongin is of special interest. It is a by using chloromethylation of substituted-2-naphthylace-
4
,5
12
9
1
6
natural product isolated from the Central East African tic acid and by reaction of 2-(1-hydroxyalkyl)-l,4-naph-
medicinal plant Pentas longiflora, which is used in thoquinones with enamines or imines.17 In this report, a
Rwanda and Kenya in the traditional medicine for the novel efficient route towards pentalongin is described,
6
treatment of malaria and skin diseases. Pentalongin was utilising a phthalide annulation strategy, which allows the
found to be responsible for the antifungal properties of the synthesis of novel pyranonaphthoquinone derivatives
7
plant extract. In addition, it reveals the tricyclic backbone which are not accessible by other routes.
of many other pyranonaphthoquinone antibiotics.
A brief look at the retrosynthetic scheme reveals the ne-
cessity of the construction of the Michael acceptor 6H-py-
O
OMe O
ran-3-one (9). The annulated compound 7 is a hongconin
analogue, a compound from traditional Chinese medicine
shown to exhibit antianginal activity.18 Further elabora-
tion via pyranonaphthoquinone 6 will result in pentalon-
gin (1, Scheme 1). Firstly, it was necessary to construct
O
O
MeO
O
O
pentalongin (1)
dehydroherbarin (2)
R1
O
O
6
H-pyran-3-one (9). The literature revealed an existing
O
synthesis of the 6H-pyran-3-one using palladium cou-
pling of tri-n-butylvinyltin with allyloxyacetyl chloride
and subsequent ring-closing metathesis in a total yield of
R2
R1
3
O
O
OGlc
O
19
1
7% and a synthesis using a Hg(II) ring closure from the
O
20
appropriate alkyne in 21% yield. In an attempt to avoid
the toxic tin or mercury reagent and the low yielding re-
sults, an alternative pathway was devised (Scheme 2). In
the first step, the nucleophilic attack of allyl alcohol at
butadiene monoxide 10 resulted in the desired 1-allyloxy-
but-3-en-2-ol (11). The alcohol 11 could easily be ring-
closed by using Grubbs’ second-generation catalyst
towards dihydropyranol (12) in 73% yield.
OGlc
4
R2
harounoside (5)
Figure 1
SYNLETT 2006, No. 4, pp 0621–0623
0
2.
0
3.
2
0
0
6
Advanced online publication: 20.02.2006
DOI: 10.1055/s-2006-926248; Art ID: G35605ST
Georg Thieme Verlag Stuttgart · New York
©

6
22
S. Claessens et al.
LETTER
methodology is developed by Kraus et al. and Hauser et
21
O
O
O
OH
2
2
al. and became an often used procedure in the synthesis
2
3
of naphthoquinones. In spite of its usefulness, the reac-
tion products are often difficult to characterise due to
solubility problems and due to their capacity to form sta-
bilised radicals, which make it impossible to run NMR
O
O
O
1
6
24
OH
O
O
spectra. The only way to characterise these so-called ‘si-
lent NMR quinones’ is to protect the naphthalene diols in
order to avoid formation of radicals. The cyanophthalide
annulation reaction was carried out using LiOt-Bu as the
base and in the presence of LiCl to catalyse the reaction,
resulting in the hongconin analogue 7. All attempts to re-
duce the keto function in compound 7 to the correspond-
ing alcohol failed. In view of the encountered problems it
was necessary to protect the aromatic diol 7 as its double
O
O
+
O
O
CN
OH
7
8
9
Scheme 1
1.2 equiv NaH,
OH
O
1
equiv allylalcohol,
O
25
methyl ether 13 using dimethyl sulfate and potassium
THF, –20 °C, 1 h,
r.t., 16 h, sealed vessel
carbonate in acetone. Subsequent reduction of 13 using
sodium borohydride resulted in alcohol 14. The problem-
atic oxidation of the pyranonaphthalene 15 was already
1
0
11, 43%
0.01 equiv Grubbs' (II)
10
26
catalyst, CH2Cl2, r.t., 24 h
observed by us and by others. Therefore, the decision
was made firstly to oxidise compound 14 towards the
27
O
OH
quinone 6. The oxidative demethylation was realised us-
ing cerium(IV) ammonium nitrate in aqueous acetonitrile
and afforded the 4-hydroxynaphthoquinone 6 in 95%
yield. Exceeding the reaction time of 15 minutes resulted
in complex reaction mixtures. The final dehydration
applying p-toluenesulfonic acid in benzene under reflux
for three hours resulted in the target pentalongin (1) in
1
.5 equiv PCC
O
CH Cl , r.t., 24 h
O
2
2
9
, 69%
12, 73%
Scheme 2
3
7% yield.
The subsequent oxidation towards 6H-pyran-3-one (9)
was accomplished using a PCC-oxidation in dichloro-
methane to give the 6H-pyran-3-one (9) in 69% yield. The
next step to work out was the phthalide annulation reac-
tion (Scheme 3) with the heterocyclic compound 9. This
In conclusion, by using the phthalide annulation strategy,
the naturally occurring pentalongin (1) was synthesised.
Applying this synthetic pathway opens the door for new
pentalongin derivatives and new naphthoquinone anti-
biotics, with the required cyclic enol ether moiety.
O
1.1 equiv n-BuLi
.1 equiv t-BuOH
LiCl (cat)
OH
O
OMe
O
O
1
5 equiv K2CO3
2
2.2 equiv Me SO
4
O
+
O
O
acetone, ∆, 2 h
O
THF, –78 °C,
4
h, r.t., 16 h
CN
OH
OMe
50% (13)
8
9
88% (7)
1.1 equiv NaBH4,
MeOH–CH2Cl2 (1:1),
r.t., 16 h
O
O
O
O
OH
OMe OH
p-TsOH, benzene,
, 3 h
3 equiv CAN,
CH3CN–H2O (1:2)
∆
O
O
O
0
°C, 15 min,
r.t., 15 min
OMe
pentalongin, 37% (1)
95% (6)
52% (14)
OMe
3
equiv CAN,
CH3CN–H2O (1:2)
p-TsOH, benzene
O
15
OMe
Scheme 3
Synlett 2006, No. 4, 621–623 © Thieme Stuttgart · New York

LETTER
Synthesis of Pentalongin
623
Acknowledgment
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2
H, s, CH O), 7.62 (1 H, ddd, J = 8.4, 7.0, 1.4 Hz, CH-7), 7.73
2
(
1
1 H, ddd, J = 8.4, 7.0, 1.4 Hz, CH-8), 8.11 (1 H, dd, J = 8.4,
.4 Hz, CH-9), 8.34 (1 H, dd, J = 8.4, 1.4 Hz, CH-6). C
1
3
(
NMR (acetone-d ): d = 62.13 (OCH ), 63.14 (OCH ), 64.46
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3
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2
2
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(
(
(
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(
(
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1
C
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quat
+
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(
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(
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1
dione (6): H NMR (CDCl ): d = 3.86 (1 H, dd, J = 12.2, 3.8
(
3
Hz, CHCH H ), 4.03 (1 H, dd, J = 12.2, 3.5 Hz, CHCH H ),
2001, 57, 4213.
a
b
a
b
4
.49 (1 H, dd, J = 18.9, 1.65 Hz, OCH H ), 4.76 (1 H, dd,
(
(
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a
b
1
3
m, CH –CH ), 8.09 (2 H, m, CH –CH ). C NMR (CDCl3):
7
8
6
9
d = 60.18 (CH O), 63.23 (CHOH), 69.51 (CH ), 126.38 (C-
2
2
6
7
1
or C-9), 126.63 (C-9 or C-6), 131.83 (2 × Cquat), 134.28 (C-
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(
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max
–
1
+
+
cm . MS (ES ): m/z (%) = 231 (15) [M + H ], 213 (100)
+
[
M – H O].
1999, 1881.
2
Synlett 2006, No. 4, 621–623 © Thieme Stuttgart · New York