Synthesis of two naphthoquinone antibiotics pentalongin and psychorubrin

Article abstract of DOI:10.1055/s-1999-3613

The synthesis of two naturally occurring pyranonaphthoquinone antibiotics, pentalongin (1) and psychombrin (2), is reported.

Full text of DOI:10.1055/s-1999-3613

SHORT PAPER
1881
Synthesis of Two Naphthoquinone Antibiotics Pentalongin and Psychorubrin
Bart Kesteleyn, Norbert De Kimpe,* Luc Van Puyvelde
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, University of Gent, Coupure Links 653,
B-9000 Gent, Belgium
Fax +32(9) 2646243; E-mail: norbert.dekimpe @rug.ac.be
Received 29 January 1999; revised 15 June 1999
The synthesis of pentalongin (1) and psychorubrin (2) is
Abstract: The synthesis of two naturally occurring pyranonaphtho-
presented in Scheme 1, using ethyl 3-methyl-1,4-dioxo-2-
quinone antibiotics, pentalongin (1) and psychorubrin (2), is report-
10
naphthylacetate (3) as starting material. Reduction of the
naphthoquinone ester 3 with tin(II) chloride in concentrat-
ed hydrochloric acid and subsequent methylation of the
intermediate hydroquinone ester with dimethyl sulfate in
the presence of excess potassium hydroxide gave the
naphthylacetic acid (4) in 78% yield. Upon treatment of
the acid 4 with N-bromosuccinimide (NBS) and a catalyt-
ic amount of benzoyl peroxide in carbon tetrachloride,
radical bromination occurred selectively and quantitative-
ly at the methyl group. The bromomethylnaphthylacetic
acid (5) thus obtained, was then cyclised to lactone 6 in
virtually quantitative yield using potassium carbonate in
acetone under reflux. Partial reduction of lactone 6 using
ed.
Key words: pyranonaphthoquinone, Pentas longiflora, 1H-naph-
tho[2,3-c]pyran-5,10-dione, pentalongin, psychorubrin
Pentalongin (1) (1H-naphtho[2,3-c]pyran-5,10-dione) has
been isolated from Pentas longiflora Oliv. (Rubiaceae).1
The dry powder from the roots of P. longiflora is used as
a folk remedy (Rwanda) to treat pityriasis versicolor, a
2
fungal infection disease of the skin. In a bioassay-guided
phytochemical study of the roots, pentalongin was identi-
fied as the physiologically active compound, responsible
2
for the antimycotic activity of the dry plant material. Pen-
1
equivalent of diisobutylaluminium hydride in benzene
talongin was obtained before by acid-catalysed dehydra-
tion of psychorubrin (2), another naturally occurring
pyranonaphthoquinone with significant antitumor activi-
gave the hemi-acetal 7 which was found to spontaneously
eliminate water in anhydrous solvents such as chloroform.
An attempted flash chromatography on silica gel using
3
ty, isolated from Psychotria rubra.
5
% ethyl acetate in hexane as eluent also led to the isola-
tion of elimination product 8 as the sole product. Curious-
ly, in an attempt to oxidize this naphthopyran 8 to
pentalongin (1), using the common oxidizing agents ceri-
um(IV) ammonium nitrate or silver(II) oxide, only com-
plex reaction mixtures were obtained. Therefore, in an
alternative approach, pentalongin (1) was synthesized by
oxidation of the crude lactol 7 and subsequent acid cata-
lyzed elimination of water. Thus, psychorubrin (2) was
prepared by treatment of the crude lactol 7 with ceri-
um(IV) ammonium nitrate in aqueous acetonitrile, in an
Figure 1
Pentalongin (1) and psychorubrin (2) are both so-called overall yield of 87% from lactone 6. Dehydration of psy-
pyranonaphthoquinone antibiotics. This particular group chorubrin (2) with p-toluenesulfonic acid in benzene un-
of microbial and plant metabolites with a characteristic der reflux gave pentalongin (1) in a yield of 64% after
1
H-naphtho[2,3-c]pyran-5,10-dione nucleus which in- flash chromatography. After recrystallisation from meth-
4
5
cludes examples such as nanaomycin A, frenolycin B
anol, pentalongin (1) was obtained as red needles with
6
and eleutherin, is known to possess a variety of physio- physical and spectral data in complete accordance with
logical activities. Several synthetic efforts have been those reported for the natural product.1 In this way, pen-
,2
7
made toward their synthesis. Never before has much at- talongin (1) was synthesized in an overall yield of 43%
tention been paid to the synthesis of those pyranonaphtho- from ethyl 3-methyl-1,4-dioxo-2-naphthylacetate (3).
quinones, such as pentalongin, having a double bond in
8
the pyran ring. In a previous paper we already described
1H NMR spectra (270 MHz) and 13C NMR spectra (68 MHz) were
a strategy that allows the introduction of this C(3)-C(4)
run with a Jeol JNM-EX 270 NMR spectro-meter. Peak assign-
ments were performed with the aid of the DEPT technique, 2D-
COSY spectra and HETCOR spectra. IR spectra were obtained
double bond in the pyranonaphthoquinone ring-system.9
Unfortunately, this methodology allowed pentalongin
9
only to be obtained in an overall yield of 14%. Therefore, from a Perkin Elmer model 1310 spectrophotometer while mass
in this paper, we present the total synthesis of pentalongin spectra were measured with a Varian MAT 112 spectrometer (70
eV). Melting points were measured with a Büchi 535 apparatus.
(
1) as well as its closely related pyranonaphthoquinone
Flash chromatography was carried out using a glass column with
antibiotic psychorubrin (2), using a new, improved and
straightforward synthetic approach.
Synthesis 1999, No. 11, 1881–1883 ISSN 0039-7881 © Thieme Stuttgart · New York

1
882
B. Kesteleyn et al.
SHORT PAPER
Scheme 1
Acros silica gel (particle size 0.035–0.07 mm, pore diameter ca. 6
nm).
126.97 (=Cquat), 128.46 (=Cquat), 150.26 (=C-OMe), 150.82 (=C-
OMe), 177.25 (C=O).
+
EIMS m/z (%): 260 (M , 100), 245(18), 213(30), 201(48), 199(13),
1
,4-Dimethoxy-3-methyl-2-naphthylacetic Acid (4)
To a solution of ethyl 3-methyl-1,4-dioxo-2-naphthylacetate (3)
40 mmol, 10.3 g) in 95% EtOH (200 mL) was added dropwise a so-
1
85(22), 157(22), 141(11), 129(12), 128(18), 115(12).
1
0
Anal. calcd. for C H O : C 69.22%, H 6.20%, found C 69.20%, H
1
5
16
4
(
6
.05%.
lution of SnCl (140 mmol, 26.6 g) in concentrated HCl (25 mL).
2
Stirring was continued for 0.5 h and the reaction mixture was con-
centrated in vacuo until most of the EtOH was evaporated. Upon the
3
-Bromomethyl-1,4-dimethoxy-2-naphthylacetic Acid (5)
A stirred mixture of 1,4-dimethoxy-3-methyl-2-naphthylacetic acid
addition of cold H O (500 mL) to the resulting mixture, a white sol-
2
(
(
4) (8 mmol, 2.08 g), NBS (8.4 mmol, 1.5 g) and benzoyl peroxide
0.8 mmol, 0.2 g) in CCl (100 mL) was heated under reflux for 2 h.
id precipitated and after 30 min the precipitate was isolated by fil-
tration and mixed together with dimethyl sulfate (800 mmol, 100.8
4
The mixture was allowed to cool to r.t. and, after filtration of suc-
cinimide and evaporation of the solvent in vacuo, 3-bromomethyl-
1
tained as an orange solid, mp 133–134 °C. This compound was used
as such in the next reaction step (purity > 96%).
IR (KBr) νmax = 2900 (OH), 1700 (C=O) cm-1.
g). Then a solution of KOH (1.6 mol, 89.6 g) in H O (200 mL) was
2
added at 0 °C over a period of 1 h. Stirring was continued for 2 h at
,4-dimethoxy-2-naphthylacetic acid (5) (2.7 g, 100%) was ob-
7
0–80 °C and then the mixture was poured in ice-water (800 mL).
The aqueous solution was acidified with concentrated HCl until pre-
cipitation of the naphthylacetic acid derivative was completed. The
precipitate was obtained by filtration and dissolved in acetone (150
mL), dried (MgSO ) and evaporated in vacuo to give 1,4-
4
1
H NMR (CDCl ): δ = 3.93 (3H, s, MeO), 4.06 (3H, s, MeO), 4.13
3
dimethoxy-3-methyl-2-naphthylacetic acid (4) (8.12 g, 78%). The
crude product (purity about 98%) was used without further purifica-
tion in the next step. An analytical sample was purified by means of
(2H, s, CH -COOH), 4.84 (2H, s, CH Br), 7.50–7.57 (2H, m, H-6
2
2
and H-7), 8.02–8.10 (2H, m, H-5 and H-8), 11.20 (1H, br s, COOH).
13C NMR (CDCl
flash chromatography on silica gel with 2% MeOH in CHCl as elu-
3
): δ = 26.80 (CH COOH), 31.72 (CH Br), 62.30
2
2
3
ent, mp 124–125 °C.
(MeO), 62.53 (MeO), 122.23 (=Cquat), 122.71 and 123.05 (=CH-5
and =CH-8), 126.18 (=Cquat), 126.65 and 127.11 (=CH-6 and =CH-
-
1
IR (KBr): νmax = 1695 (C=O) cm .
7
), 128.23 (=Cquat), 128.82 (=Cquat), 151.55 (=C-OMe), 151.71 (=C-
1
H NMR (CDCl ): δ = 2.37 (3H, s, CH ), 3.87 (3H, s, MeO), 3.91
3
3
OMe), 177.55 (C=O).
(3H, s, MeO), 3.95 (2H, s, CH ), 7.46–7.50 (2H, m, H-6 and H-7),
2
+
EIMS m/z (%): 338/40 (M , 12), 259 (100), 258 (44), 243(11),
31(38), 215(17), 214(12), 213(29), 201(40), 200(28), 199(47),
186(38), 185(23), 183(18), 171(21), 163(16), 157(19), 143(17),
41(34), 139(21), 129(17), 128(43), 127(23), 115(39), 105(21),
104(16), 82(15), 80(16), 77(29), 76(31), 51(22), 43(19).
8
.01–8.08 (2H, m, H-5 and H-8), 10.8 (1H, broad s, COOH).
2
1
3
C NMR (CDCl ): δ = 12.70 (CH ), 32.72 (CH ), 61.47 (MeO),
3
3
2
6
2.35 (MeO), 122.32 and 122.46 (=CH-5 and =CH-8), 123.25
1
(=Cquat), 125.62 and 126.22 (=CH-6 and =CH-7), 126.47 (=Cquat),
Synthesis 1999, No. 11, 1881–1883 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Two Naphthoquinone Antibiotics Pentalongin and Psychorubrin
Psychorubrin (2)
1883
Anal. Calcd. for C H BrO : C 53.12%, H 4.46%; found C 53.37%,
15
15
4
H 4.34%.
Under N , a solution of 3,4-dihydro-5,10-dimethoxy-1H-naph-
2
tho[2,3-c]pyran-3-one (6) (1.7 mmol, 430 mg) in benzene (10 mL),
was treated with a solution of 1 M DIBALH in hexane (2 mmol, 2
mL). After stirring for 1 h, the mixture was poured in 4 M HCl. The
organic layer was separated and the aqueous phase was extracted
3
,4-Dihydro-5,10-dimethoxy-1H-naphtho[2,3-c]pyran-3-one
(
6)
To a solution of 3-bromomethyl-1,4-dimethoxy-2-naphthylacetic
acid (5) (2 mmol, 0.68 g) in acetone (50 mL) was added K CO (10
twice with CH Cl . The combined organic extracts were washed
2
3
2
2
with aq NaHCO , evaporated in vacuo and dissolved again in
mmol, 1.38 g) and the mixture was heated under reflux for 2 h. Then
the precipitate was removed by filtration and evaporation of the fil-
trate in vacuo gave pure 3,4-dihydro-5,10-dimethoxy-1H-naph-
tho[2,3-c]pyran-3-one (6) (0.51 g, 99%). An analytical sample was
obtained after recrystallization from MeOH, mp 126 °C.
3
MeCN (10 mL). Then, a solution of Ce(NH
.76 g) in water (10 mL) was added at 0 °C and the reaction was al-
lowed to warm to r.t. for 30 min. The mixture was poured in H O,
) (NO ) (5.1 mmol,
4 2 3 6
2
2
extracted with EtOAc, washed with brine, dried and evaporated in
vacuo. Flash chromatography on silica gel with EtOAc/hexane 1:1
as eluent gave psychorubrin (2) (340 mg, 87%) as a pale yellow sol-
-
1
IR (KBr): νmax = 1745 (C=O) cm .
1
3
H NMR (CDCl ): δ = 3.90 (2H, s, CH C=O), 3.92 (3H, s, MeO),
id, mp 149 °C (lit., mp 150–152 °C).
3
2
3
.93 (3H, s, MeO), 5.53 (2H, s, CH O), 7.54–7.58 (2H, m, H-7 and
2
H-8), 8.08–8.12 (2H, m, H-6 and H-9).
Pentalongin (1)
1
3
A solution of psychorubrin (2) (330 mg, 1.4 mmol) in benzene (20
mL) was heated under reflux for 30 min with a catalytic amount of
p-HOTs. The mixture was cooled to r.t., dried (MgSO ) and evapo-
rated in vacuo. Flash chromatography (eluent 10% EtOAc in hexa-
ne) afforded pentalongin (1) (190 mg, 64%) as a red powder, mp
C NMR (CDCl ): δ = 30.80 (CH C=O), 62.43 (MeO), 63.02
3
2
(
MeO), 65.28 (CH O), 119.55 (=Cquat), 120.57 (=Cquat), 122.39 and
2
1
8
22.57 (=CH-6 and =CH-9), 126.63 and 126.92 (=CH-7 and =CH-
), 127.78 (=Cquat), 128.89 (=Cquat), 148.23 (=C-OMe), 148.91 (=C-
4
OMe), 170.51 (C=O).
1
1
60–161 °C (MeOH) (lit., mp 160–161 °C).
+
EIMS m/z (%):258(M , 100), 243(18), 215(15), 199(26), 171(11),
41(12), 128(17), 115(16).
Anal. calcd. for C H O : C 69.76%, H 5.46%; found C 69.52%, H Acknowledgement
1
1
5
14
4
5
.36%.
The authors are indebted to the Janssen Research Foundation for fi-
nancial support. The authors especially wish to thank Dr. V. Sipido
and Mr. W. Van Laerhoven of the Janssen Research Foundation for
their valuable suggestions throughout this work.
3
,4-Dihydro-5,10-dimethoxy-1H-naphtho[2,3-c]pyran-3-ol (7)
and 5,10-Dimethoxy-1H-naphtho[2,3-c]pyran (8)
Under N , a solution of 3,4-dihydro-5,10-dimethoxy-1H-naph-
2
tho[2,3-c]pyran-3-one (6) (0.39 mmol, 100 mg) in benzene (5 mL),
was treated with a solution of 1 M DIBALH in hexane (0.47 mmol,
References
0
.47 mL) and after stirring for 1 h the mixture was poured in 2 M
(
(
(
1) Hari, L.; De Buyck, L. F.; De Pooter, H. L. Phytochemistry
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2) De Kimpe, N.; Van Puyvelde, L.; Schripsema, J.; Erkelens,
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HCl. The organic layer was separated and the aqueous phase was
extracted twice with CH Cl . The combined organic extracts were
1
2
2
dried (MgSO ) and evaporated in vacuo to give 3,4-dihydro-5,10-
4
dimethoxy-1H-naphtho[2,3-c]pyran-3-ol (7) (70 mg, 69%) together
with traces of the elimination product 8.
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-
1
IR (NaCl): νmax = 3390 (OH), 1590, 1450, 1355, 1265, 1068 cm .
(4) Omura, S.; Tanaka, H.; Koyama, Y.; Katagiri, M.; Awaya, J.;
Nagai,T.; Hata, T. J. Antibiot. 1974, 27, 363.
1
H NMR (CDCl ): δ 2.97 (1H, dd, J = 16.8 Hz, 5.3 Hz, ArCH H ),
3
a
b
b) Tanaka, H.; Koyama, Y.; Awaya, J.; Maruma, H.; Oiwa, R.;
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S. J. Antibiot. 1975, 28, 868.
3
3
.29 (1H, dd, J = 16.8 Hz, 4.0 Hz, ArCH H ), 3.89 (3H, s, MeO),
.90 (3H, s, MeO), 4.99 and 5.19 (each 1H, each d, J = 15.5 Hz,
a b
CH -O), 5.42 (1H, dd, J = 5.3 Hz, 4.0 Hz, CH-OH), 7.45-7.51 (2H,
m, H-7 and H-8), 8.01-8.08 (2H, m, H-6 and H-9).
2
(
5) Iwai, Y.; Kora, A.; Takahashi, Y.; J. Antibiot. 1978, 31, 959.
This compound was found to eliminate H O rapidly when dissolved
in anhyd solvents (CDCl ). Flash chromatography of the crude lac-
tol 7 on silica gel with 5% EtOAc in hexane as eluent gave 5,10-
dimethoxy-1H-naphtho[2,3-c]pyran (8) (30 mg, 32%) as an oil.
2
(6) Schmid, H.; Ebnöther, A. Helv. Chim. Acta 1951, 64, 1041.
(7) Naruta, Y.; Maruyama, K. Recent Advances in the Synthesis
of Quinonoid Compounds. In The Chemistry of Quinonoid
Compounds; Patai, S.; Rappoport, Z. Eds.; Wiley: New York
1988; Vol. II., p. 241.
3
1
H NMR (CDCl ): δ = 3.89 (3H, s, MeO), 3.90 (3H, s, MeO), 5.29
3
(
8) Aldersley, M. F.; Dean, F. M.; Hamzah, A. S. Tetrahedron
Lett. 1986, 27, 255.
(2H, s, CH O), 6.19 (1H, d, J = 5.9 Hz, CH = CH-O), 6.70 (1H, d,
2
J = 5.9 Hz, CH = CH-O), 7.41-7.51 (2H, m, H-7 and H-8), 8.00–
8
b) Aldersley, M. F.; Chishti, S. H.; Dean, F. M.; Douglas, M.
E.; Ennis, D. S. J. Chem. Soc. Perkin Trans. I 1990, 2163.
c) Naito, T.; Makita, Y.; Yazaki, S.; Kaneko, C. Chem. Pharm.
Bull. 1986, 34, 1505.
.06 (2H, m, H-6 and H-9).
1
3
C NMR (CDCl ): δ = 62.17 (MeO), 63.25 (MeO), 99.98
3
(
(
CH=CH-O), 119.15 (=Cquat), 119.50 (=Cquat), 122.28 and 122.32
=CH-6 and =CH-9), 125.44 and 126.31 (=CH-7 and =CH-8),
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1
28.08 (=Cquat), 128.84 (=Cquat), 144.74 (=C-OMe), 146.57 (=C-
OMe), 146.99 (CH=CH-O).
(
+
EIMS m/z (%): 242 (M , 67), 228(16), 227(100), 212(48), 184(11),
1
(
10) Aldersley, M. F.; Dean, F. M.; Nayyir-Mazhir, R. J. Chem.
39(11), 128(17).
Soc. Perkin Trans. I 1983, 1753.
Anal. calcd. for C H O : C 74.36%, H 5.82%; found C 73.98%, H
1
5
14
3
5
.72%.
Article Identifier:
437-210X,E;1999,0,11,1881,1883,ftx,en;Z00799SS.pdf
1
Synthesis 1999, No. 11, 1881–1883 ISSN 0039-7881 © Thieme Stuttgart · New York