Total synthesis of two naphthoquinone antibiotics, psychorubrin and pentalongin, and their C(1)-substituted alkyl and aryl derivatives

Article abstract of DOI:10.1021/jo9811975

The synthesis of 1-alkyl- and 1-aryl-1H-naphtho[2,3-c]pyran-5,10- diones, bearing a C(3)-C(4) double bond, was performed by two alternative cyclization strategies of 2,3-disubstituted 1,4-naphthoquinones. Lemieux- Johnson oxidation of 2-allyl-3-hydroxymethyl-1,4-dimethoxynaphthalenes and subsequent oxidative demethylation of the intermediate 3,4-dihydro-5,10- dimethoxy-1H-naphtho[2,3-c]pyran-3-oles to the corresponding 3,4-dihydro-3- hydroxy- 1H-naphtho[2,3-c]pyran-5,10-diones gave, after acid-catalyzed dehydration, the desired 1H-naphtho[2,3-c]pyran-5,10-diones. Alternatively, the pyranonaphthoquinone ring system was constructed by intramolecular acid- catalyzed condensation of (3-hydroxymethyl-1,4-naphthoquinone-2- yl)acetaldehyde acetals. Using this synthetic approach, the synthesis of two naturally occurring naphthoquinone antibiotics, pentalongin and psychorubrin, is reported.

Full text of DOI:10.1021/jo9811975

J . Org. Chem. 1999, 64, 1173-1179
1173
Tota l Syn th esis of Tw o Na p h th oqu in on e An tibiotics, P sych or u br in
a n d P en ta lon gin , a n d Th eir C(1)-Su bstitu ted Alk yl a n d Ar yl
Der iva tives
Bart Kesteleyn, Norbert De Kimpe,* and Luc Van Puyvelde
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences,
University of Gent, Coupure Links 653, B-9000 Gent, Belgium
Received J une 19, 1998
The synthesis of 1-alkyl- and 1-aryl-1H-naphtho[2,3-c]pyran-5,10-diones, bearing a C(3)-C(4) double
bond, was performed by two alternative cyclization strategies of 2,3-disubstituted 1,4-naphtho-
quinones. Lemieux-J ohnson oxidation of 2-allyl-3-hydroxymethyl-1,4-dimethoxynaphthalenes and
subsequent oxidative demethylation of the intermediate 3,4-dihydro-5,10-dimethoxy-1H-naphtho-
[2,3-c]pyran-3-oles to the corresponding 3,4-dihydro-3-hydroxy-1H-naphtho[2,3-c]pyran-5,10-diones
gave, after acid-catalyzed dehydration, the desired 1H-naphtho[2,3-c]pyran-5,10-diones. Alterna-
tively, the pyranonaphthoquinone ring system was constructed by intramolecular acid-catalyzed
condensation of (3-hydroxymethyl-1,4-naphthoquinone-2-yl)acetaldehyde acetals. Using this syn-
thetic approach, the synthesis of two naturally occurring naphthoquinone antibiotics, pentalongin
and psychorubrin, is reported.
In tr od u ction
ture,5 a particular group of pyranonaphthoquinone an-
tibiotics bearing a C(3)-C(4) double bonds has received
much less attention.6 Examples of this group of 3,4-
dehydro-pyranonaphthoquinones include dehydroherbar-
in (4),7 anhydrofusarubin (5),8 and pentalongin (6),9 and
The synthesis of naturally occurring pyranonaphtho-
quinones such as frenolycin B (1),1 eleutherin (2),2 and
nanaomycin A (3)3 has been of great interest for many
also these pyranonaphthoquinones show significant
antimicrobial activities.10 Pentalongin (6) for example,
which was isolated from Pentas longiflora Oliv. (Rubi-
aceae), shows antifungal and antiparasital activity, and
the powder from the roots of P. longiflora is used by the
years because these compounds have been found to show
important physiological activities against Gram-positive
bacteria, fungi, and mycoplasmas. Furthermore, it has
been suggested that these pyranonaphthoquinones may
exhibit antitumor activity because their proposed mech-
anism of action, namely as “bioreductive dialkylating
agents”, resembles that of alkylating antibiotics such as
the mitomycins.4
(5) Naruta, Y.; Maruyama, K. Recent Advances in the Synthesis of
Quinonoid Compounds. In The Chemistry of Quinonoid Compounds;
Patai, S., Rappoport, Z., Eds.; J ohn Wiley: New York, 1988; Vol. II, p
241.
(6) Aldersley, M. F.; Dean, F. M.; Hamzah, A. S. Tetrahedron Lett.
1986, 27, 255. (b) Aldersley, M. F.; Chishti, S. H.; Dean, F. M.; Douglas,
M. E.; Ennis, D. S. J . Chem. Soc., Perkin Trans. 1 1990, 2163.
(7) Kadkol, M. V.; Golpalkrishnan, K. S.; Narasimhachari, N. J .
Antibiot. 1971, 24, 245. (b) Nagarajan, R.; Narasimhachari, N.; Kadkol,
M. V.; Gopalkrishnan, K. S. J . Antibiot. 1971, 24, 249.
(8) Tatum, J . H.; Baker, R. A. Phytochemistry 1983, 22, 543. (b)
Parisot, D.; Devys, M.; Fe´re´zou, J .-P.; Barbier, M. Phytochemistry 1983,
22, 1301.
(9) Hari, L.; De Buyck, L. F.; De Pooter, H. L. Phytochemistry 1991,
30, 1726. (b) De Kimpe, N.; Van Puyvelde, L.; Schripsema, J .; Erkelens,
C.; Verpoorte, R. Magn. Reson. Chem. 1993, 31, 329.
(10) Baker, R. A.; Tatum, J . H.; Nemec, S., J r. Phytopathology 1981,
71, 951. (b) Baker, R. A.; Tatum, J . H.; Nemec, S., J r. Mycopathologia
1990, 111, 9.
Although the synthesis of various pyranonaphtho-
quinones has been extensively investigated in the litera-
* Author to whom correspondence should be addressed. Phone: 32
9 264.59.51. Fax: 32 9 264.62.43.
(1) Iwai, Y.; Kora, A.; Takahashi, Y. J . Antibiot. 1978, 31, 959.
(2) Schmid, H.; Ebno¨ther, A. Helv. Chim. Acta 1951, 64, 1041.
(3) (a) Omura, S.; Tanaka, H.; Koyama, Y.; Katagiri, M. J . Antibiot.
1974, 27, 363. (b) Tanaka, H.; Koyama, Y.; Marumo, H.; Oiwa, R.;
Katagiri, M.; Nagai, T.; Omura, S. J . Antibiot. 1975, 28, 860. (c)
Tanaka, H.; Koyama, Y.; Nagai, T.; Omura, S. J Antibiot. 1975, 28,
868.
(4) Moore, H. W. Science 1977, 197, 527.
10.1021/jo9811975 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/26/1999

1174 J . Org. Chem., Vol. 64, No. 4, 1999
Kesteleyn et al.
Sch em e 1
Sch em e 2
traditional healers of the Dispensary of Traditional
Medicine of Curphametra (Butare, Rwanda) to treat the
skin disease pityriasis versicolor.9
In view of the interesting physiological activities of
pentalongin (6) and other pyranonaphthoquinones of the
3,4-dehydro series, we wanted to develop a general
synthetic strategy allowing the synthesis of a series of
pentalongin-based antibiotics for SAR studies. Pental-
ongin (6) was obtained before by dehydration of psycho-
rubrin (7), another natural naphthoquinone antibiotic
with significant antitumor activity, isolated from Psy-
chotria rubra.11 Pentalongin was also synthesized by a
photochemical [2+2] addition of 2-chloro-1,4-naphtho-
quinone and acrolein dimethyl acetal and subsequent
treatment of the resulting 1-dimethoxymethyl-1,2-dihy-
drocyclobuta[b]naphthalene-3,8-dione with p-toluene-
sulfonic acid,12 but this photochemical procedure was
completely unsuccessful in our hands, despite several
attempts. Therefore, in this paper, we present the first
total synthesis of two naturally occurring pyranonaph-
thoquinone antibiotics, pentalongin (6) and psychorubrin
(7), by a new synthetic route, as a general strategy for
the synthesis of 1H-naphtho[2,3-c]pyran-5,10-diones. Us-
ing this synthetic approach, a series of unnatural ana-
logues of pentalongin (6) bearing alkyl and aryl substit-
uents at the C(1) and C(3) positions of pentalongin will
be synthesized.
The resulting 2-allyl-3-bromo-1,4-naphthoquinone (9) was
subjected to a conventional reductive methylation by
means of tin(II) chloride and dimethyl sulfate to yield
2-allyl-3-bromo-1,4-dimethoxynaphthalene (10).
Direct conversion of this bromonaphthalene 10 to
alcohol 13 via condensation with anhydrous formalde-
hyde was attempted by reaction of 10 with 1 equiv of
n-butyllithium in tetrahydrofuran at -78 °C and treat-
ment of the intermediate lithium salt with anhydrous
formaldehyde (by bubbling formaldehyde gas, generated
by heating anhydrous paraformaldehyde, through the
solution) (Scheme 2). Unfortunately, the reaction gave
only the debrominated 2-allyl-1,4-dimethoxynaphthalene
(11) which was obtained in 94% yield from the reaction
mixture, indicating, however, under these circumstances,
the complete conversion of 10 into its lithium salt by
bromine-lithium exchange. The desired alcohol 13 was
obtained via the introduction of a methoxycarbonyl group
and subsequent reduction of this functional group with
lithium aluminum hydride. Methoxycarbonylation of
bromonaphthalene 10 to 12 was carried out by bromine-
lithium exchange and subsequent condensation of the
transient anion formed with methyl choroformate or
methyl cyanoformate, the latter providing a better yield
of 52%. With methyl choroformate, compound 12 was
obtained only in 33% yield. In either case, the 2-allyl-
1,4-dimethoxynaphthalene (11) was a side product (up
to 25%) from the methoxycarbonylation reaction, but it
could be separated easily from ester 12 by flash chroma-
Resu lts a n d Discu ssion
The synthesis of pentalongin (6) and psychorubrin (7)
is presented in Schemes 1 and 2, starting from 2-bromo-
1,4-naphthoquinone (8), which is readily available from
1-hydroxynaphthalene through oxidative bromination
with N-bromosuccinimide.13 Radical allylation of this
naphthoquinone 8 with vinylacetic acid, using ammo-
nium persulfate and silver nitrate in aqueous acetonitrile,
allowed the introduction of an allyl side chain at C(2).
(11) Hayashi, T.; Smith, F. T.; Lee, K. H. J . Med. Chem. 1987, 30,
2005.
(12) Naito, T.; Makita, Y.; Yazaki, S.; Kaneko, C. Chem. Pharm. Bull.
1986, 34, 1505.
(13) Heinzman, S. W.; Grunwell, J . R. Tetrahedron Lett. 1980, 21,
4305.

Synthesis of Psychorubin and Pentalongin
J . Org. Chem., Vol. 64, No. 4, 1999 1175
Sch em e 3
Sch em e 4
were formed in a ratio of ca. 2:1. Lactol 16 underwent
spontaneous dehydration in anhydrous solvents and was
therefore immediately oxidized with cerium(IV) am-
monium nitrate to afford the pyranonaphthoquinone
1-methylpsychorubrin (17) as a mixture of stereoisomers
in a ratio of 31:69, in an overall yield of 79% from alcohol
15. The cis- and trans-isomers were not separated but
were reacted with p-toluenesulfonic acid in benzene
under reflux to give 1-methylpentalongin (18) as the sole
product in 66% yield (Scheme 3).
Finally, the possibility of introducing a phenyl group
at C(1) of pentalongin using the same synthetic route was
investigated (Scheme 4). Therefore, the naphthyl anion
derived from 2-allyl-3-bromo-1,4-dimethoxynaphthalene
(10), obtained by bromine-lithium exchange utilizing
n-butyllithium, was condensed with benzaldehyde at -78
°C, resulting in alcohol 19. Unfortunately, lactol 20 could
not be obtained by Lemieux-J ohnson oxidation of the
alcohol 19, which resulted only in a complex reaction
mixture, and thus the introduction of an aryl group at
C(1) of pentalongin necessitated another synthetic ap-
proach (vide infra).
The synthesis of 1,3-dimethylpentalongin (23) is out-
lined in Scheme 5. Isomerization of the double bond in
alkenol 15 to the conjugated vinylic position was per-
formed with potassium tert-butoxide in dry tetrahydro-
furan. It was found that oxidative demethylation of
alcohol 21 with 4 equiv of cerium(IV) ammonium nitrate
not only oxidized the dimethyl ether to the 5,10-quinonoid
system but induced simultaneous oxidative cyclization
of the alkenol moiety, resulting in a mixture of stereoi-
someric 4-hydroxypyranonaphthoquinones 22 in a total
yield of 66%.15 Elimination of water from the stereoiso-
mers 22 could not be performed with p-toluenesulfonic
acid and necessitated the use of 5 equiv of anhydrous
oxalic acid in benzene under reflux for 36 h. The resulting
1,3-dimethylpentalongin (23) was isolated in 47% yield
after flash chromatography (Scheme 5).
tography. No efforts were made to improve the yields of
the conversion of 10 to 12, because the difficulties for
introducing the methoxycarbonyl group were thought to
be mainly of steric origin. Lemieux-J ohnson oxidation
of the alcohol 13 with catalytic osmium(VIII) tetroxide
and excess of sodium periodate resulted in lactol 14 as
the sole product. Because this acetal was found to
undergo spontaneous elimination of water in anhydrous
solvents, it was reacted immediately with cerium(IV)
ammonium nitrate to afford psychorubrin (7) in an
overall yield of 82% yield from alkenol 13. The spectral
data of the synthetic psychorubrin were in complete
accordance with those of the natural product.11 Finally,
pentalongin (6) was obtained by treatment of psychoru-
brin (7) with p-toluenesulfonic acid in benzene under
reflux for 30 min.11 After recrystallization from methanol,
pentalongin (6) was obtained as red needles with physical
and spectral data identical to the natural product.9 This
is the first report on the total synthesis of pentalongin,
obtained in 14% overall yield from 2-bromo-1,4-naphtho-
quinone (8).
For the preparation of 1-methylpentalongin (18) using
the same synthetic pathway, the bromonaphthalene
10 was treated with 1 equiv of n-butyllithium in dry
tetrahydrofuran at -78 °C, and condensation of the
intermediate anion with acetaldehyde at the same tem-
perature gave alcohol 15 in 28% yield after flash chro-
matography. Lemieux-J ohnson oxidation of alkenol 15
with catalytic osmium(VIII) tetroxide and excess of
sodium periodate lead to the formation of lactol 16 as a
mixture of stereoisomers.14 The cis- and the trans-isomers
In analogy with the former synthesis, treatment of
alkenol 13 with potassium tert-butoxide in dry tetrahy-
(14) Kometani, T.; Takeuchi, Y.; Yoshii, E. J . Chem. Soc., Perkin
Trans. 1 1981, 1197.
(15) Chorn, T.A.; Giles, R. G. F.; Green, I. R.; Mitchell, P. R. K. J .
Chem. Soc., Perkin Trans. 1 1983, 1249.

1176 J . Org. Chem., Vol. 64, No. 4, 1999
Kesteleyn et al.
Sch em e 5
Sch em e 7
Sch em e 6
treatment with p-toluenesulfonic acid or flash chroma-
tography on silica gel resulted in the formation of
naphthopyranes 29. In an attempt to oxidize these
pyranonaphthalenes 29 to the desired pyranonaphtho-
quinones 31, using the common oxidizing agents cerium-
(IV) ammonium nitrate or silver(II) oxide, only complex
reaction mixtures were obtained. Therefore, in an alter-
native approach, oxidative demethylation was carried out
prior to the acid-catalyzed cyclization and elimimation
of water. The intermediate acetals 28 were treated first
with 3 equiv of cerium(IV) ammonium nitrate, but the
intermediate acetals 30 could not be purified; elution over
silica, as well as treatment of the crude acetals 30 with
p-toluenesulfonic acid, allowed the desired 1-alkyl- or
1-phenyl-1H-naphtho[2,3-c]pyran-5,10-diones 31 to be
isolated in 42% (31a , R ) Me), 34% (31b, R ) n-Pr), and
7% (31c, R ) Ph) yield (Scheme 7).
drofuran induced the allylic double bond to isomerize to
the conjugated vinylic position in alcohol 24, as il-
lustrated in Scheme 6. Oxidative cyclization and simul-
taneous oxidative demethylation of the alcohol 24 by the
use of 4 equiv of cerium(IV) ammonium nitrate afforded
a complex reaction mixture from which only one epimer,
namely, the cis-isomer 25, could be isolated in a yield of
16% by means of flash chromatography. The small
coupling constant of 2 Hz between H(3) and H(4) implies
that H(3) is axial and H(4) is pseudoequatorial; the C(3)
methyl is therefore equatorial, and the C(4) hydroxy
group pseudoaxial. Curiously, when the alcohol 25 was
reacted with an excess of anhydrous oxalic acid, under
the same conditions as those used for the dehydration of
alcohols 22, the desired 3-methylpentalongin (26) could
not be detected in the reaction mixture (Scheme 6).
In Scheme 7, the use of an acetal protected aldehyde
27 is demonstrated as an alternative synthetic approach
for the synthesis of C(1)-substituted alkyl- or aryl-1H-
naphtho[2,3-c]pyran-5,10-diones. Acetal 27, as a starting
material, is available in an overall yield of 34% from
1-hydroxynaphthalene in six steps.16 The use of 1.05
equiv of n-butyllithium in dry tetrahydrofuran at -78
°C caused bromine-lithium exchange, and condensation
of the transient anion with an aldehyde afforded alcohols
28. These intermediates 28 were not purified, and
In conclusion, the synthesis of a series of C(1)- and
C(3)-substituted alkyl- and aryl-1H-naphtho[2,3-c]pyran-
5,10-diones was performed by two alternative synthetic
pathways. Using this methodology, the first total syn-
thesis of two naturally occurring naphthoquinones, pen-
talongin and psychorubrin, was completed.
Exp er im en ta l Section
1
Gen er a l Meth od s. H NMR (270 MHz) and 13C NMR (68
MHz) peak assignments were performed with the aid of the
DEPT technique, 2D-COSY spectra, and HETCOR spectra.
Dry tetrahydrofuran (THF) was obtained by distillation from
sodium-benzophenone ketyl. Diethyl ether was dried and
(16) J oshi, B. S.; J iang, Q.; Rho, T.; Pelletier, S. J . Org. Chem. 1994,
59, 8220.

Synthesis of Psychorubin and Pentalongin
J . Org. Chem., Vol. 64, No. 4, 1999 1177
distilled from sodium. Other solvents were used without
further purification.
239(100). Anal. Calcd for C17H18O4: C 71.31, H 6.34. Found C
71.34, H 6.57. 2-Allyl-3-(1-h yd r oxyeth yl)-1,4-d im eth ox-
yn a p h th a len e (15): yield, 76 mg, 28% (ethyl acetate/hexane,
20/80). 2-Allyl-3-(1-h yd r oxyp h en ylm et h yl)-1,4-d im et h -
oxyn a p h th a len e (19): yield: 193 mg, 58% (ethyl acetate/
hexane, 10/90).
2-Allyl-3-br om o-1,4-n a p h th oqu in on e (9). To a stirred
suspension of 2-bromo-1,4-naphthoquinone (8)13 (500 mg, 2.10
mmol), silver nitrate (110 mg, 1.05 mmol), and vinylacetic acid
(270 mg, 3.15 mmol) in acetonitrile (50 mL) was added
dropwise over 15 min a solution of ammonium persulfate (860
mg, 3.78 mmol) in water (25 mL). Stirring was continued for
7 h at 60-70 °C, and then the reaction mixture was poured
into cold water and extracted with ethyl acetate. The extract
was washed with aqueous sodium hydrogen carbonate and
brine, dried (MgSO4), and evaporated at reduced pressure.
Recrystallization from methanol gave pure 2-allyl-3-bromo-
1,4-naphthoquinone (9) (410 mg, 71%), mp 79 °C.
2-Allyl-3-h yd r oxym et h yl-1,4-d im et h oxyn a p h t h a len e
(13). To a solution of methyl (3-allyl-1,4-dimethoxynaphtha-
lene-2-yl)carboxylate (12) (570 mg, 2 mmol) in dry ether (20
mL) was added lithium aluminum hydride (91 mg, 2.4 mmol)
at 0 °C. The suspension was stirred overnight at room
temperature, poured into a diluted hydrochloric acid solution,
and extracted with ether. The combined extracts were washed
with brine, dried (MgSO4), and evaporated at reduced pres-
sure. Flash chromatography on silica gel with 20% ethyl
acetate in hexane gave 2-allyl-3-hydroxymethyl-1,4-dimethox-
ynaphthalene (13) (495 mg, 96%), mp 83 °C. 1H NMR (CDCl3):
δ 2.56 (1H, s broad, OH), 3.73 (2H, dt, J ) 5.2 Hz, 1.8 Hz,
CH2-CHdCH2), 3.86 (3H, s, MeO), 3.94 (3H, s, MeO), 4.83
(2H, s, CH2OH), 4.90 (1H, dd, J ) 17.2 Hz, 1.8 Hz, CHd
CHAHB), 5.05 (1H, dd, J ) 10.1 Hz, 1.8 Hz, CHdCHAHB), 6.11
(1H, ddt, J ) 17.2 Hz, 10.1 Hz, 5.2 Hz, CHdCH2), 7.43-7.52
(2H, m, H-6 and H-7), 8.02-8.07 (2H, m, H-5 and H-8). 13C
NMR (CDCl3): δ 30.32 (CH2-CHdCH2), 57.16 (CH2OH), 62.23
(MeO), 63.18 (MeO), 115.27 (CHdCH2), 122.37 and 122.52 (d
CH-5 and dCH-8), 125.73 and 126.29 (dCH-6 and dCH-7),
127.67 (dCquat), 128.63 (dCquat), 129.11 (dCquat), 138.01 (CHd
CH2), 150.49 (dC-OMe), 151.48 (dC-OMe). IR (NaCl, cm-1):
3400 (OH), 1590, 1450, 1355, 1270, 1100, 915, 775, 735. MS
m/z (%): 258(M+, 100), 225(98). Anal. Calcd for C16H18O3: C
74.40, H 7.02. Found C 74.03, H 6.78.
3,4-Dih yd r o-5,10-d im eth oxy-1H-n a p h th o[2,3-c]p yr a n -
3-ol (14). To a solution of 2-allyl-3-hydroxymethyl-1,4-
dimethoxynaphthalene (13) (100 mg, 0.4 mmol) in water (5
mL) and dioxane (15 mL) was first added a catalytic amount
of osmium(VIII) tetroxide (10 mg), and then sodium periodate
(170 mg, 0.8 mmol) was added portionwise over a period of 1
h. The suspension formed was stirred for 3 days, poured into
water, extracted with ether, washed with brine, dried (MgSO4),
and evaporated at reduced pressure. Flash chromatography
on silica gel with 40% ethyl acetate in hexane gave 3,4-dihydro-
5,10-dimethoxy-1H-naphtho[2,3-c]pyran-3-ol (14) (20 mg, 19%).
Compound 14 was found to eliminate water rapidly when
dissolved in CDCl3. The crude product (purity about 90%) was
used as such in the next step. 1H NMR (CDCl3): δ 2.97 (1H,
dd, J ) 16.8 Hz, 5.3 Hz, CHAHB), 3.29 (1H, dd, J ) 16.8 Hz,
4.0 Hz, CHAHB), 3.89 (3H, s, MeO), 3.90 (3H, s, MeO), 4.99
and 5.19 (each 1H, each d, J ) 15.5 Hz, CH2-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-Allyl-3-br om o-1,4-d im eth oxyn a p h th a len e (10). To a
solution of 2-allyl-3-bromo-1,4-naphthoquinone (9) (500 mg, 1.8
mmol) in 95% ethanol (20 mL) at 50 °C was added a solution
of tin(II) chloride (1.2 g, 6.34 mmol) in concentrated hydro-
chloric acid (1.2 mL). After 30 min at the same temperature,
cold water (100 mL) was added. A white solid precipitated and
was isolated by filtration. The precipitate was mixed with
dimethyl sulfate (3.42 g, 27 mmol), and to the resulting
suspension was added dropwise at 0 °C a 50% potassium
hydroxide solution (10 mL). Stirring was continued for 3 h at
65 °C, and then the reaction mixture was poured into cold
water, extracted with ether, washed with aqueous sodium
hydrogen carbonate and brine, dried (MgSO4), and evaporated
at reduced pressure. Flash chromatography on silica gel with
20% chloroform in pentane as eluent gave 2-allyl-3-bromo-1,4-
dimethoxynaphthalene (10) (430 mg, 78%), mp 57 °C.
2-Allyl-1,4-d im eth oxyn a p h th a len e (11). A 2.5 M solution
of n-butyllithium in hexane (0.4 mL, 1 mmol) was added
dropwise at -78 °C to a solution of 2-allyl-3-bromo-1,4-
dimethoxynaphthalene (10) (0.307 g, 1 mmol) in tetrahydro-
furan (10 mL) under a nitrogen atmosphere, and stirring was
continued at the same temperature for 1 h. Then, anhydrous
formaldehyde gas (generated by heating paraformaldehyde at
100-150 °C) was bubbled through the solution along with a
nitrogen stream during 30 min, and the solution was allowed
to warm to room temperature over a period of 2 h. The mixture
was poured into 2 N HCl, extracted with ether, dried (MgSO4),
and evaporated at reduced pressure. Flash chromatography
(chloroform/pentane, 2/8) gave pure 2-allyl-1,4-dimethoxynaph-
thalene (11) (0.21 g, 94%) as a colorless liquid.
Met h yl (3-Allyl-1,4-d im et h oxyn a p h t h a len e-2-yl)ca r -
boxyla te (12), 2-Allyl-3-(1-h yd r oxyeth yl)-1,4-d im eth oxy-
n a p h th a len e (15), a n d 2-Allyl-3-(h yd r oxyp h en ylm eth yl)-
1,4-d im et h oxyn a p h t h a len e (19). A 2.5
M solution of
n-butyllithium in hexane (0.4 mL, 1 mmol) was added dropwise
at -78 °C to a solution of 2-allyl-3-bromo-1,4-dimethoxynaph-
thalene (10) in dry THF (5 mL) under a nitrogen atmosphere,
and stirring was continued at the same temperature for 30
min. A solution of acetaldehyde (88 mg, 2 mmol), methyl
cyanoformate (102 mg, 1.2 mmol), or benzaldehyde (130 mg,
1.2 mmol), respectively, in dry THF (2 mL) was then added,
and the resultant mixture was stirred for 10 min at -78 °C
and then allowed to warm to room temperature over a period
of 2 h. The mixture was poured into 2 N hydrogen chloride,
extracted with ether, dried (MgSO4), and evaporated at
reduced pressure. Compounds 12, 15, and 19 were isolated
after flash chromatography on silica gel with ethyl acetate/
hexane as the eluent. Side products were not isolated or
identified.
P sych or u br in (7). A solution of cerium(IV) ammonium
nitrate (610 mg, 1.14 mmol) in water (5 mL) was added
dropwise to a solution of crude 3,4-dihydro-5,10-dimethoxy-
1H-naphtho[2,3-c]pyran-3-ol (14) (100 mg, 0.38 mmol) in
acetonitrile (10 mL) and water (10 mL) at 0 °C. The stirred
mixture was allowed to warm to room temperature over a
period of 30 min, poured into water, and extracted with ethyl
acetate. The combined extracts were washed with brine, dried
(MgSO4), and evaporated at reduced pressure. Flash chroma-
tography (eluent ethyl acetate 50% in hexane) gave psycho-
rubrin (7) (80 mg, 82% from 13) as a yellow powder, mp 149
°C (lit.11 150-152 °C). Spectral data were in accordance with
those available in the literature.11
Met h yl (3-a llyl-1,4-d im et h oxyn a p h t h a len e-2-yl)ca r -
boxyla te (12): yield, 150 mg, 52% (ethyl acetate/hexane, 5/95).
1H NMR (CDCl3): δ 3.62-3.65 (2H, m, CH2), 3.89 (3H, s, MeO),
3.93 (3H, s, MeO), 3.98 (3H, s, MeO), 5.02-5.09 (2H, m, CHd
CH2), 5.87-6.02 (1H, m, CHdCH2), 7.47-7.58 (2H, m, H-6 and
H-7), 8.06-8.11 (2H, m, H-5 and H-8). 13C NMR (CDCl3): δ
31.48 (CH2), 52.22 (OMe), 62.46 (MeO), 63.52 (MeO), 115.88
(CHdCH2), 122.62 and 122.98 (dCH-5 and dCH-8), 125.21
(dCquat), 125.48 (dCquat), 126.27 and 127.37 (dCH-6 and dCH-
7), 127.56 (dCquat), 129.54 (dCquat), 136.40 (CHdCH2), 150.28
()C-OMe), 150.38 ()C-OMe), 168.23 (CdO). IR (NaCl,
cm-1): 1730 (CdO). MS m/z (%): 286(M+, 90), 255(14), 240(20),
P en ta lon gin (6). A solution of psychorubrin (7) (330 mg,
1.4 mmol) in benzene (20 mL) was heated under reflux for 30
min with a catalytic amount of p-toluenesulfonic acid. The
reaction mixture was allowed to cool to room temperature,
dried (MgSO4), and evaporated at reduced pressure. Flash
chromatography (eluent 10% ethyl acetate in hexane) afforded
pentalongin (6) (190 mg, 64%) as a red powder, mp 160-161
°C (methanol) (lit.9 160-161 °C). Spectral data were in
accordance with those available in the literature.9
3,4-Dih yd r o-5,10-d im eth oxy-1-m eth yl-1H-n a p h th o[2,3-
c]p yr a n -3-ol (16). To a solution of 2-allyl-3-(1-hydroxyethyl)-
1,4-dimethoxynaphthalene (15) (109 mg, 0.4 mmol) in water

1178 J . Org. Chem., Vol. 64, No. 4, 1999
Kesteleyn et al.
(2 mL) and dioxane (6 mL) was first added a catalytic amount
of osmium(VIII) tetroxide (10 mg). Then, sodium periodate (170
mg, 0.8 mmol) was added portionwise over a period of 1 h.
After 3 days, the suspension was poured into water, extracted
with ether, washed with brine, dried (MgSO4), and evaporated
at reduced pressure. Flash chromatography on silica gel with
40% ethyl acetate in hexane as eluent gave 3,4-dihydro-5,10-
dimethoxy-1-methyl-1H-naphtho[2,3-c]pyran-3-ol (16) as a
mixture of cis- and trans-isomers in a ratio of ca. 2:1 (53 mg,
48%). Compound 16 rapidly eliminated water when dissolved
in CDCl3. The crude product (purity about 90%) was im-
mediately used as such in the next step.
3,4-Dih yd r o-3-h yd r oxy-1-m eth yl-1H-n a p h th o[2,3-c]p y-
r a n -5,10-d ion e (17). A solution of crude 3,4-dihydro-5,10-
dimethoxy-1-methyl-1H-naphtho[2,3-c]pyran-3-ol (16) (70 mg,
0.26 mmol) in acetonitrile (2 mL) was added dropwise to a
solution of cerium(IV) ammonium nitrate (430 mg, 0.78 mmol)
in water (5 mL) at 0 °C. The stirred suspension was allowed
to warm to room temperature over a period of 30 min, poured
into water, and extracted with ethyl acetate. The combined
extracts were washed with brine, dried (MgSO4), and evapo-
rated at reduced pressure. Recrystallization from dry ether
gave 3,4-dihydro-3-hydroxy-1-methyl-1H-naphtho[2,3-c]pyran-
5,10-dione (17) (50 mg, 79% from 15) as a mixture of cis- and
trans-isomers in a ratio of 69:31. 1H NMR (CDCl3): δ (cis-
stereoisomer) 1.56 (3H, d, J ) 6.9 Hz, CH3), 2.77-2.79 (2H,
m, CH2), 3.83 (1H, broad s, OH), 5.07 (1H, q, J ) 6.9 Hz,
CHCH3), 5.55 (1H, m, CHOH); (trans-stereoisomer) 1.63 (3H,
d, J ) 6.6 Hz, CH3), 2.58 (1H, ddd, J ) 18.6 Hz, 6.7 Hz, 3.3
Hz, CHAHB), 3.01 (1H, dt, J ) 18.3 Hz, 3.0 Hz, CHAHB), 4.00
(1H, broad s, OH), 4.96-5.13 (1H, m, CHCH3), 5.16 (1H, dd,
J ) 6.7 Hz, 3.0 Hz, CHOH), (both) 7.67-7.74 (2H, m, H-7 and
H-8), 8.00-8.10 (2H, m, H-6 and H-9). 13C NMR (CDCl3): δ
(cis-stereoisomer) 20.20 (CH3), 28.75 (CH2), 65.07 (CHCH3),
88.80 (CHOH), 126.27 (dCH-6 and dCH-9), 131.77 (dCquat),
132.09 (dCquat), 133.67 and 133.80 (dCH-7 and dCH-8), 139.10
(dCquat), 145.23 (Cquat), 183.18 (CdO), 183.75 (CdO); (trans-
stereoisomer) 21.29 (CH3), 29.70 (CH2), 69.18 (CHCH3), 91.97
(CHOH), 126.27 (dCH-6 and dCH-9), 131.71 (dCquat), 132.16
(dCquat), 133.74 and 133.89 (dCH-7 and dCH-8), 139.87 (d
1,3-Dim eth ylp en ta lon gin (23). A solution of stereoiso-
meric 4-hydroxypyranonaphthoquinones 2215 (120 mg, 0.47
mmol) in benzene (15 mL) was heated under reflux for 36 h
in the presence of an excess of oxalic acid (210 mg, 2.4 mmol).
Then the reaction mixture was poured into aqueous sodium
hydrogen carbonate, and the organic layer was separated. The
water phase was extracted twice with dichloromethane, and
the combined extracts were dried (MgSO4) and evaporated at
reduced pressure. Flash chromatography (eluent 5% ethyl
acetate in hexane) afforded 1,3-dimethylpentalongin (23) (50
1
mg, 47%) as a red powder, mp 74-75 °C. H NMR (CDCl3): δ
1.41(3H, d, J ) 6.6 Hz, CH3-1), 2.02 (3H, d, J ) 0.7 Hz, CH3-
3), 5.70 (1H, q, J ) 6.6 Hz, CH), 5.89 (1H, q, J ) 0.7 Hz, CHd
C-O), 7.65-7.73 (2H, m, H-7 and H-8), 8.04-8.09 (2H, m, H-6
and H-9). 13C NMR (CDCl3): δ 18.11 (CH3), 20.97 (CH3), 69.72
(CH), 93.15 (CHdC-O), 125.82 and 126.34 (dCH-6 and dCH-
9), 126.43 (dCquat), 131.69 (dCquat), 132.63 (dCquat), 133.03 and
133.83 (dCH-7 and dCH-8), 136.13 (dCquat), 162.73 (CHdC-
O), 181.99 (CdO), 182.69 (CdO). IR (NaCl, cm-1): 1670 (Cd
O), 1650 (CdO), 1580 (CdC), 1560 (CdC). MS m/z (%): 240(M+,
34), 225(100). Anal. Calcd for C15H12O3: C 74.99, H 5.03. Found
C 74.73, H 4.99.
tr a n s-2-(Hydr oxym eth yl)-1,4-dim eth oxy-3-(1-pr open yl)-
n a p h th a len e (24). To a solution of 2-allyl-3-(hydroxymethyl)-
1,4-dimethoxynaphthalene (13) (200 mg, 0.78 mmol) in dry
THF (10 mL) under a nitrogen atmosphere was added potas-
sium tert-butoxide (0.35 g, 3.12 mmol). The suspension was
allowed to react for 3 h, poured into a saturated solution of
ammonium chloride, extracted with ether, dried (MgSO4), and
evaporated at reduced pressure. Flash chromatography (eluent
20% ethyl acetate in hexane) afforded trans-2-(hydroxymethyl)-
1,4-dimethoxy-3-(1-propenyl)naphthalene (24) (190 mg, 95%),
mp 71-72 °C.
cis-3,4-Dih yd r o-4-h yd r oxy-3-m eth yl-1H-n a p h th o[2,3-c]-
p yr a n -5,10-d ion e (25). To a solution of trans-2-(hydroxym-
ethyl)-1,4-dimethoxy-3-(1-propenyl)naphthalene (24) (200 mg,
0.78 mmol) in acetonitrile (15 mL) and water (10 mL) was
added dropwise a solution of cerium(IV) ammonium nitrate
(1.69 g, 3.12 mmol) in water (5 mL) at 0 °C. The reaction
mixture was allowed to warm to room temperature and, after
30 min, was poured into water and extracted with ethyl
acetate. The combined extracts were washed with brine, dried
(MgSO4), and evaporated at reduced pressure. Flash chroma-
tography on silica gel with 50% ethyl acetate in hexane gave
cis-3,4-dihydro-4-hydroxy-3-methyl-1H-naphtho[2,3-c]pyran-
5,10-dione (25) (30 mg, 16%), mp 139-140 °C. Side products
C
quat), 145.57 (dCquat), 183.37 (CdO), 183.61 (CdO). IR (KBr,
cm-1): 3370 (OH), 1660 (CdO), 1590 (CdC). MS m/z (%): 244-
(M+, 12), 226(72), 211(100). Anal. Calcd for C14H12O4: C 68.85,
H 4.95. Found C 69.17, H 4.92.
1-Meth ylp en ta lon gin (18). A solution of 3,4-dihydro-3-
hydroxy-1-methyl-1H-naphtho[2,3-c]pyran-5,10-dione (17) (30
mg, 0.12 mmol) in benzene (5 mL) was heated under reflux
with a catalytic amount of p-toluenesulfonic acid. After 1 h,
the reaction mixture was allowed to cool to room temperature,
dried (MgSO4), and evaporated at reduced pressure. Recrys-
tallization from ether/pentane gave 1-methylpentalongin (18)
1
were neither isolated nor identified. H NMR (CDCl3): δ 1.45
(3H, d, J ) 6.3 Hz, CH3), 2.53 (1H, s broad, OH), 3.66 (1H, qd,
J ) 6.3 Hz, 2.0 Hz, CH-CH3), 4.47 (1H, dd, J ) 19.1 Hz, 1.6
Hz, CHAHB), 4.56 (1H, m, CHOH), 4.87 (1H, d, J ) 19.1 Hz,
CHAHB), 7.71-7.78 (2H, m, H-7 and H-8), 8.05-8.13 (2H, m,
H-6 and H-9). 13C NMR (CDCl3): δ 16.05 (CH3), 61.47 (CH-
OH), 63.52 (CH2), 73.57 (CH-CH3), 126.22 and 126.59 (dCH-6
and dCH-9), 131.75 (dCquat), 131.80 (dCquat), 134.03 and
134.19 (dCH-7 and dCH-8), 141.07 (dCquat), 143.32 (dCquat),
183.84 (CdO), 184.06 (CdO). IR (KBr, cm-1): 3400 (OH), 1660
(CdO), 1590 (CdC). MS m/z (%): no M+, 226(M+ - H2O, 8),
201(15), 200(100), 172(75). Anal. Calcd for C14H12O4: C 68.85,
H 4.95. Found C 68.64, H 4.73.
1
(20 mg, 66%), mp 92-93 °C. H NMR (CDCl3): δ 1.45 (3H, d,
J ) 6.6 Hz, CH3), 5.69 (1H, q, J ) 6.6 Hz, CHCH3), 6.04 (1H,
d, J ) 5.6 Hz, CH)CH-O), 6.85 (1H, d, J ) 5.6 Hz, CHdCH-
O), 7.68-7.73 (2H, m, H-7 and H-8), 8.04-8.10 (2H, m, H-6
and H-9). 13C NMR (CDCl3): δ 18.08 (CH3), 68.66 (CHCH3),
96.33 (CHdCH-O), 125.95 and 126.45 (dCH-6 and dCH-9),
128.53 (dCquat), 131.61 (dCquat), 132.47 (dCquat), 133.31 and
133.94 (dCH-7 and dCH-8), 134.88 (dCquat), 152.07 (CH)CH-
O), 182.29 (2 × CdO). IR (KBr, cm-1): 1670 (CdO), 1650 (Cd
O), 1580 (CdC), 1540 (CdC). MS m/z (%): 226(M+, 48),
211(100). Anal. Calcd for C14H10O3: C 74.33, H 4.46. Found C
74.02, H 4.57.
The synthesis of 1-alkyl- and 1-phenyl-5,10-dimethoxy-1H-
naphtho[2,3-c]pyrans 29 is exemplified by the synthesis of
1-m eth yl-5,10-d im eth oxy-1H-n a p h th o[2,3-c]p yr a n (29a ).
A 2.5 M solution of n-butyllithium in hexane (0.6 mL, 1.4
mmol) was added dropwise at -78 °C to a solution of 2-(3-
bromo-1,4-dimethoxy-2-naphthylmethyl)-1,3-dioxolane (27)16
(500 mg, 1.4 mmol) in dry THF (5 mL) under a nitrogen
atmosphere, and stirring was continued at the same temper-
ature for 10 min. A solution of acetaldehyde (0.12 g, 2.8 mmol)
in dry THF (2 mL) was then added, and the resultant mixture
was stirred for another 30 min at -78 °C and then allowed to
warm to room temperature over a period of 2 h. The reaction
mixture was then poured into 2 N hydrogen chloride, extracted
with ether, dried (MgSO4), and evaporated at reduced pres-
sure. The intermediate acetal 28a could not be purified. An
attempted flash chromatography on silica gel with 50% ethyl
tr a n s-2-(1-Hydr oxyeth yl)-1,4-dim eth oxy-3-(1-pr open yl)-
n a p h th a len e (21). To a solution of 2-allyl-3-(1-hydroxyethyl)-
1,4-dimethoxynaphthalene (15) (620 mg, 2.3 mmol) in dry THF
(20 mL) under a nitrogen atmosphere was added potassium
tert-butoxide (1.03 g, 9.2 mmol). The suspension was stirred
at room temperature for 2 h, poured into a saturated solution
of ammonium chloride, extracted with ether, dried (MgSO4),
and evaporated at reduced pressure. Flash chromatography
(eluent 20% ethyl acetate in hexane) afforded trans-2-(1-
hydroxyethyl)-1,4-dimethoxy-3-(1-propenyl)naphthalene (21)
(600 mg, 97%) as an oil. Spectral data were in accordance with
those available in the literature.15

Synthesis of Psychorubin and Pentalongin
J . Org. Chem., Vol. 64, No. 4, 1999 1179
acetate in hexane as eluent led only to the isolation of a
mixture of the cyclization product 16, together with the
elimination product 29a . The crude acetal 28a was therefore
heated under reflux for 16 h in benzene (20 mL) in the
presence of a catalytic amount of p-toluenesulfonic acid. The
reaction mixture was allowed to cool to room temperature,
dried (MgSO4), and evaporated at reduced pressure. Recrys-
tallization from dry ether gave 1-methyl-5,10-dimethoxy-1H-
naphtho[2,3-c]pyran 29a (140 mg, 39%) as the sole product,
30 min at -78 °C, the reaction mixture was allowed to warm
to room temperature over a period of 2 h. The mixture was
then poured into 2 N hydrochloric acid, extracted with ether,
and evaporated at reduced pressure. To the crude product
dissolved in acetonitrile (10 mL) was added dropwise a solution
of cerium(IV) ammonium nitrate (1.38 g, 2.55 mmol) at 0 °C.
The reaction mixture was allowed to warm to room temper-
ature for 30 min, poured into water, and extracted with ethyl
acetate. The combined extracts were washed with brine and
evaporated at reduced pressure. The crude product was heated
under reflux for 1 h in benzene in the presence of a catalytic
amount of p-toluenesulfonic acid, dried (MgSO4), and evapo-
rated at reduced pressure. Flash chromatography (eluent 5%
ethyl acetate in hexane) afforded 1-methylpentalongin (31a )
(80 mg, 42%) as a red powder, mp 95 °C (methanol). For
spectrometric data of 31a , see compound 18 (vide supra). 1-n -
P r op yl-p en ta lon gin (31b): yield, 34%, after flash chroma-
tography (eluent 5% ethyl acetate in hexane), mp 98.5-99.5
°C (methanol). 1-P h en yl-p en ta lon gin (31c): yield, 7%, after
flash chromatography (eluent 5% ethyl acetate in hexane), mp
121 °C (methanol).
1
mp 135 °C. H NMR (CDCl3): δ 1.51 (3H, d, J ) 6.6 Hz, CH3),
3.89 (3H, s, MeO), 3.95 (3H, s, MeO), 5.75 (1H, q, J ) 6.6 Hz,
CHCH3), 6.14 (1H, d, J ) 5.9 Hz, CHdCH-O), 6.57 (1H, d, J
) 5.9 Hz, CHdCH-O), 7.39-7.49 (2H, m, H-6 and H-7), 7.96-
8.06 (2H, m, H-5 and H-8). 13C NMR (CDCl3): δ 20.66 (CH3),
62.16 (MeO), 62.21 (MeO), 69.34 (CHCH3), 98.53 (CHdCH-
O), 118.47 (dCquat), 122.33 (dCH-5 and dCH-8), 123.65
(dCquat), 125.25 and 126.13 (dCH-6 and dCH-7), 127.87 (d
Cquat), 128.87 (dCquat), 143.88 (CHdCH-O), 144.85 (dC-
OMe), 146.59 (dC-OMe). IR (KBr, cm-1): 1625 (CdC), 1590,
1450, 1350, 1230, 1075, 1030, 780. MS m/z (%): 256(M+, 97),
241(100), 227(21), 226(22). Anal. Calcd for C16H16O3: C 74.98,
H 6.29. Found C 74.87, H 6.38.
1-P r opyl-5,10-dim eth oxy-1H-n aph th o[2,3-c]pyr an (29b):
yield, 30%, after flash chromatography (eluent 40% chloroform
in pentane), mp 71-73 °C. 1-P h en yl-5,10-d im eth oxy-1H-
n a p h th o[2,3-c]p yr a n (29c): yield, 27%, after flash chroma-
tography (eluent 5% ethyl acetate in hexane), mp 78-79 °C.
The synthesis of 1-alkyl- and 1-phenyl-1H-naphtho[2,3-c]-
pyran-5,10-diones (31) is exemplified by the synthesis of
1-m eth ylp en ta lon gin (31a ). To a solution of 2-(3-bromo-1,4-
dimethoxy-2-naphthylmethyl)-1,3-dioxolane (27)16 (300 mg,
0.85 mmol) in dry THF (5 mL) at -78 °C under a nitrogen
atmosphere was added a 2.5 M solution of n-butyllithium (0.36
mL, 0.89 mmol). After 10 min, a solution of acetaldehyde (70
mg, 1.7 mmol) in dry THF (2 mL) was added, and after another
Ack n ow led gm en t. The authors are indebted to the
J anssen Research Foundation, Beerse, Belgium, for
financial support.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
(1H NMR, 13C NMR, IR, and MS) and elementary analyses of
compounds 9-10, 11, 15, 16, 19, 24, 29b,c, and 31b,c (4
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O9811975