Synthesis of pyranonaphthoquinone antibiotics involving the ring closing metathesis of a vinyl ether

Article abstract of DOI:10.1016/j.tetlet.2004.03.008

The synthesis of two antibiotic pyranonaphthoquinones was performed by a straightforward synthetic route utilizing ring closing metathesis. Vinylation of 3-(1-propenyl)-2-hydroxymethyl-1,4-dimethoxynaphthalene under iridium catalysis and subsequent ring closing metathesis of 3-(1-propenyl)-2-vinyloxymethyl-1,4- dimethoxynaphthalene with Grubbs' catalyst paved the way to the natural antibiotics pentalongin and psychorubrin.

Full text of DOI:10.1016/j.tetlet.2004.03.008

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3443–3446
Synthesis of pyranonaphthoquinone antibiotics involving the ring
closing metathesis of a vinyl ether
Tuyen Nguyen Van and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure links 653,
B-9000 Ghent, Belgium
Received 2 January 2004; revised 20 February 2004; accepted 3 March 2004
Abstract—The synthesis of two antibiotic pyranonaphthoquinones was performed by a straightforward synthetic route utilizing ring
closing metathesis. Vinylation of 3-(1-propenyl)-2-hydroxymethyl-1,4-dimethoxynaphthalene under iridium catalysis and sub-
sequent ring closing metathesis of 3-(1-propenyl)-2-vinyloxymethyl-1,4-dimethoxynaphthalene with Grubbs’ catalyst paved the way
to the natural antibiotics pentalongin and psychorubrin.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
attracted considerable synthetic attention.4;5 The syn-
thesis of a particular smaller group of naturally occur-
ring pyranonaphthoquinones, such as pentalongin 1,6;7
psychorubrin 2,6;7 dehydroherbarin 3,8 1,3-disubsti-
Pyranonaphthoquinone antibiotics are a diverse family
of naturally occurring 1H-naphtho[2,3-c]pyran-5,10-
diones, which are found in bacteria, fungi, aphides and
higher plants.1 Some pyranonaphthoquinones have been
found to possess antimicrobial, antiparasitical and
anticancer properties.2;3 Accordingly, they have recently
tuted-3,4-dehydropyranonaphthoquinones
49
and
harounoside 5,10 was accomplished by us in efforts
towards the discovery of biologically active pyrano-
naphthoquinone derivatives (Fig. 1).
OR1
O
O
O
O
O
O
R2O
OH
O
O
O
3 R1= Me, R2 = Me
(dehydroherbarin)
1 (pentalongin)
2 (psychorubrin)
O
HO
OH
OH
OH
O
O
O
O
O
R1
O
HO
HO
O
HO
OH
R2
4 R1= Me, Ph; R2 = Me, Ph
5 (harounoside)
Figure 1.
Keywords: Pentalongin; Psychorubrin; Iridium-catalyzed vinylation; Ring closing metathesis (RCM).
* Corresponding author. Tel.: +32-092645951; fax: +32-092646243; e-mail: norbert.dekimpe@UGent.be
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.008

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T. Nguyen Van, N. De Kimpe / Tetrahedron Letters 45(2004) 3443–3446
Pentalongin 1 is a natural product from the Central-East
African medicinal plant Pentas longiflora, which is used
in Rwanda and Kenya in the traditional medicine for
the treatment of malaria and skin diseases.11 Also psy-
chorubrin is a naturally occurring pyranonaphthoqui-
none with significant antitumour activity, which was
isolated from Psychotria rubra (Fig. 1).12
was converted into compound 9 by ring closing
metathesis.
Treatment of compound 8 with 7% mol of Grubbs’ first
generation catalyst in toluene at room temperature for
12 h under nitrogen, and then at 100 °C for an additional
12 h afforded compound 97;16 in good yield (86%), cul-
minating in the synthesis of this pyranonaphthoquinone
precursor 9 in three efficient steps. It was found that
these conditions were most appropriate for this con-
version despite the known thermal lability of the cata-
lyst. To our knowledge, the use of Grubbs’ first
generation catalyst for the ring closing reaction of enolic
ethers is limited and known to be problematic.17–20
Attempts were initially made to employ ruthenium
catalysts for the ring closure of vinyl ethers, but these
reactions failed and gave only dimerization products.
However, the ring closing reaction of such vinyl ethers
was successful by using the Schrock molybdenum cata-
lyst.18 It has been suggested that the carbene resulting
from the rapid reaction between the vinyl ether moiety
and the ruthenium catalyst is inert towards further
metathesis.21 However recently, the ring closing reaction
of vinyl ethers containing alkoxy substituents by using
Grubbs’ first generation catalyst was performed suc-
cessfully by Wong. Probably, the neighbouring alkoxy
groups may exert an influence on the chemoselectivity of
the metathesis process between the ruthenium catalyst
and the olefin.22 Very recently, de Koning has also
succeeded in achieving the ring closing metathesis reac-
tion of phenolic vinyl ethers containing neighbouring
alkoxy groups by using Grubbs’ second generation
catalyst.23
The known syntheses of pentalongin 1 and psychorubrin
2 are based upon the construction of the 1H-naph-
tho[2,3-c]pyran skeleton by ring closure of 2-allyl-3-hy-
droxymethyl-1,4-dimethoxynaphthalenes6 and 2-allyl-3-
hydroxymethyl-1,4-naphthoquinones13 by oxidative
olefin cleavage or by intramolecular base-catalyzed
condensation
of
3-bromomethyl-1,4-dimethoxy-2-
naphthaleneacetic acid followed by selective reduction.7
In continuation of our interest in the efficient synthesis
of this class of compounds, we now report a new syn-
thetic pathway for pyranonaphthoquinones, using
Grubbs’ first generation catalysts for the ring closing
step.
The synthesis of precursors of pentalongin 1 and psy-
chorubrin 2 starting from 2-allyl-3-hydroxymethyl-1,4-
dimethoxynaphthalene 66 and proceeding to the reduced
and protected form of pentalogin (9) is outlined in
Scheme 1. Isomerization of the allylic double bond in
the easily accessible compound 66 was carried out by
treatment with potassium tert-butoxide in tetrahydro-
furan to give 2-hydroxymethyl-1,4-dimethoxy-3-(1-pro-
penyl)-naphthalene 7 in 95% yield as the (E)-isomer,
exclusively.8 Vinylation of compound 7 at the oxygen
atom was carried out with vinyl acetate in the presence
of chloro(1,5-cyclootadiene)iridium(I) dimer ([IrCl-
(cod)]2) as catalyst.14 For example, a mixture of com-
pound 7,vinyl acetate, sodium carbonate and
[IrCl(cod)]2 (molar ratio 1:5:0.6:0.001) was stirred in
toluene at 100 °C for 12 h to afford vinyl ether 815 in
excellent yield (96%) as the (E)-isomer. This compound
As outlined in Scheme 2, 5,10-dimethoxy-1H-naph-
tho[2,3-c]pyran 9 was hydrated by treatment with
p-toluenesulfonic acid in aqueous acetonitrile at 100 °C
for 3 h, affording hemiacetal 107;24 in 75% yield after
purification by flash chromatography on silica gel.
OMe
OH
OMe
3 equiv. KOtBu
OH
THF, rt, 3 h
OMe
7 (95%)
OMe
6
5 equiv. vinyl acetate
0.6 equiv. Na2CO3
0.001 equiv. [IrCl(cod)]2
100°C, 12 h
PCy3
Cl
Cl
OMe
OMe
OMe
O
Ru
Ph
PCy3
7%mol
O
toluene, rt, 12 h, N2
then 100°C, 12 h
OMe
8 (96%)
9 (86%)
Scheme 1.

T. Nguyen Van, N. De Kimpe / Tetrahedron Letters 45(2004) 3443–3446
3445
OMe
OMe
2 equiv. p-TsOH
O
O
CH3CN, H2O (1:1)
OH
100°C, 3 h
OMe
10 (75%)
OMe
9
3 equiv. CAN
CH3CN, H2O (1:1)
rt, 30 min
O
O
O
p-TsOH (catalyst)
O
O
benzene, 80°C
20 min
OH
O
1 (72%)
2 (91%)
Scheme 2.
6. Kesteleyn, B.; De Kimpe, N.; Van Puyvelde, L. J. Org.
Chem. 1999, 64, 1173–1179.
7. Kesteleyn, B.; De Kimpe, N.; Van Puyvelde, L. Synthesis
1999, 1881–1883.
8. Kesteleyn, B.; De Kimpe, N. J. Org. Chem. 2000, 65, 640–
644.
9. Tuyen Nguyen, V.; Kesteleyn, B.; De Kimpe, N. Tetra-
hedron 2001, 57, 4213–4219.
10. De Kimpe, N.; Kesteleyn, B.; Tuyen Nguyen, V.; Van
Puyvelde, L. 18th International Congress of Heterocyclic
Chemistry, Yokohama, Japan, July 29–August 3, 2001,
p 120.
Psychorubrin 2 was prepared in 91% yield by treatment
of hemiacetal 10 with cerium(IV) ammonium nitrate
(CAN) in aqueous acetonitrile at room temperature for
30 min.6 Finally, pentalongin 1 was obtained in 72%
yield by treatment of psychorubrin 2 with p-toluene-
sulfonic acid in benzene at 80 °C for 20 min.7;12;13 All
attempts to carry out the direct oxidation of compound
9 to pentalongin 1 by using several oxidative reagents
such as CAN, AgO, HNO3 and CrO3 failed. This
problematic oxidation of certain pyranonaphthalene
derivatives was already observed by us6 and others.25
11. Van Puyvelde, L.; Hakizayezu, D.; Brioen, P.; De Kimpe,
N.; De Vroey; C.; Bogaerts, J.; Hakizamungu, E.,
Presented at the International Congress on Natural
Products Research, Halifax, Nova Scotia, Canada, July
31–August 4, 1994.
12. Hayashi, T.; Smith, F. T.; Lee, K.-H. J. Med. Chem. 1987,
30, 2005–2008.
13. Pialat, J.-P.; Hoffmann, P.; Moulis, C.; Fouraste, I.;
Labidalle, S. Nat. Prod. Lett. 1998, 12, 23–30.
14. Okimoto, Y.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc.
2002, 124, 1590–1591.
In conclusion, by using a new synthetic approach, that
is, a RCMstrategy, the naturally occuring antibiotics
pentalogin 1 and psychrubrin 2 were synthesized
in high yield. This protocol now opens a new way
for the synthesis of other pyranonaphthoquinone
antibiotics.
15. (E)-3-(1-Propenyl)-2-vinyloxymethyl-1,4-dimethoxynaph-
1
Acknowledgements
thalene 8. H NMR (CDCl3, 270 MHz): d 1.97 (3H, dd,
J ¼ 6:6 and 1.6 Hz, CH3), 3.82 (3H, s, OMe), 3.86 (3H, s,
OMe), 4.14 (1H, dd, J ¼ 6:9 and 2.3 Hz, CH@CHaHb),
4.40 (1H, dd, J ¼ 6:9 and 2.0 Hz, CH@CHaHb), 4.93 (2H,
s, OCH2), 6.25–6.34 (1H, m, CH3CH@CH), 6.56–6.68
(2H, m, overlap., MeACH@CHA), 7.48–7.54 (2H, m, H-6
and H-7), 8.07–8.13 (2H, m, H-5 and H-8). 13C NM R
(CDCl3, 67 MHz): d 19.7 (Me), 60.6 (OMe), 62.7 (CH2O),
63.7 (OMe), 87.0 (OCH@CH), 122.6 (CH@), 122.7
(CH@), 123.8 (@Cquat), 123.9 (CH@), 126.0 (@Cquat),
126.7 (CH@), 127.4 (CH@), 128.3 (@Cquat), 129.4 (CH@),
132.8 (@Cquat), 150.0 (OACH@CH), 151.4 (@CAOMe),
152.4 (@CAOMe). IR (NaCl): 2916; 2854:1640 (C@C),
1607 (C@C), 1451; 1354:1191, 1061, 1051 cmÀ1. M Sm=z
(%): no Mþ, 257 [(M)vinyl)þ, 20], 242 (20), 241 (100), 210
(14), 149 (10). Anal. Calcd for C18H20O3: C 76.03, H 7.09;
found C 76.12, H 7.20.
The authors are indebted to Johnson and Johnson
(Beerse, Belgium), divison of Janssen Pharmaceutica,
for financial support.
References and notes
1. Thomson, R. H. Naturally Occuring Quinones, 2nd ed.;
Academic: London, 1971; p 282 see also p 597.
2. Wang, W.; Li, T.; Milburn, R.; Yates, J.; Hinnant, E.;
Luzzio, M. J.; Noble, S. A.; Attardo, G. Bioorg. Med.
Chem. Lett. 1998, 8, 1579–1584.
3. Lee, H.; Hong, S. S.; Kim, Y. H. Bioorg. Med. Chem. Lett.
1996, 6, 933–936.
4. Brimble, M. A.; Nairn, M. R.; Prabaharan, H. Tetrahe-
dron 2000, 56, 1937–1992.
5. Naruta, Y.; Maruyama, J. Recent Advances in the
Synthesis of Quinoid Compounds. In The Chemistry of
Quinoid Compounds; Patai, S., Rappoport, Z., Eds.; John
Wiley: New York, 1988; Vol. II, p 241.
16. 5,10-Dimethoxy-1H-naphtho[2,3-c]pyran 9. White pow-
der, mp 138–139 °C, 1H NMR, 13C NMR and MS data
were identical to data reported in the literature.7
17. (a) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38,
123–126; (b) Clark, J. S.; Kettle, J. G. Tetrahedron Lett.
1997, 38, 127–130.

3446
T. Nguyen Van, N. De Kimpe / Tetrahedron Letters 45(2004) 3443–3446
18. Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem.
1994, 59, 4029–4031.
19. Gurjar, M. K.; Krishna, L. M.; Reddy, B. S.; Chorghade,
M . S.Synthesis 2000, 557–560.
20. Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs,
R. H. J. Am. Chem. Soc. 2002, 122, 3783–3784.
21. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
22. Sturino, C. F.; Wong, J. C. Y. Tetrahedron Lett. 1998, 39,
9623–9629.
23. (a) Van Otterlo, W. A. L.; Ngidi, E. L.; Coyanis, E. M.; de
Koning, C. B. Tetrahedron Lett. 2003, 44, 311–313; (b)
Van Otterlo, W. A. L.; Ngidi, E. L.; de Koning, C. B.
Tetrahedron Lett. 2003, 44, 6483–6486.
5.3 Hz, ArCHaHb), 3.29 (1H, dd, J ¼ 16:8 and 4.0 Hz,
ArCHaHb), 3.89 (3H, s, OMe), 3.90 (3H, s, OMe), 4.99
and 5.19 (each 1H, each d, J ¼ 15:5 Hz, CH2–O), 5.42
(1H, dd, J ¼ 5:3 and 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). 13C NM R
(CDCl3, 67 MHz): d 29.6 (C-4), 60.2 (C-1), 61.3 (OMe),
61.5 (OMe), 92.4 (C-3), 121.4 (@Cquat), 121.9 (@CH),
122.1 (@CH), 123.5 (@Cquat), 125.8 (2 ꢀ @Cquat), 127.0
(@Cquat), 127.7 (@Cquat), 147.1 (@CAOMe), 149.9
(@CAOMe). IR (NaCl): 3390 (OH), 1590; 1450:1355,
1265, 1068 cmÀ1. M Sm=z (%): 260 (Mþ, 10), 243 (17), 229
(20), 215 (100), 216 (15), 200 (10). Anal. Calcd for
C15H16O4: C 69.22, H 6.20; found C 69.12, H 6.09.
25. Giles, R. G. F.; Green, I. R.; Taylor, C. P. Tetrahedron
Lett. 1999, 40, 4871–4872.
24. 3,4-Dihydro-5,10-dimethoxy-1H-naphtho[2,3-c]pyran-3-ol
1
10. H NMR (CDCl3, 270): d 2.97 (1H, dd, J ¼ 16:8 and