Simple synthesis of two naphthoquinone antibiotics psychorubrin and pentalongin

Article abstract of DOI:10.1081/SCC-120015812

1H-Naphtho[2,3-c]pyran-5,10-dione derivatives were synthesized using chloromethylation of substituted-2-naphthylacetic acid as the key step. The utility of this method was demonstrated in the synthesis of two-pyranonaphthoquinone antibiotics psychorubrin (1) and pentalongin (2).

Full text of DOI:10.1081/SCC-120015812

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Simple Synthesis of Two Naphthoquinone Antibiotics
Psychorubrin and Pentalongin
a
a
a
a
Vivek J. Bulbule , Priti S. Koranne , Yogesh S. Munot , Hanumant B. Borate & Vishnu H.
a
Deshpande
a
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune, India
Available online: 16 Aug 2006
To cite this article: Vivek J. Bulbule, Priti S. Koranne, Yogesh S. Munot, Hanumant B. Borate & Vishnu H. Deshpande
2003): Simple Synthesis of Two Naphthoquinone Antibiotics Psychorubrin and Pentalongin, Synthetic Communications: An
(
International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:4, 587-594
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 4, pp. 587–594, 2003
Simple Synthesis of Two Naphthoquinone
Antibiotics Psychorubrin and Pentalongin
Vivek J. Bulbule, Priti S. Koranne, Yogesh S. Munot,
Hanumant B. Borate, and Vishnu H. Deshpande*
Division of Organic Chemistry: Technology,
National Chemical Laboratory, Pune, India
ABSTRACT
1H-Naphtho[2,3-c]pyran-5,10-dione derivatives were synthesized
using chloromethylation of substituted-2-naphthylacetic acid as the
key step. The utility of this method was demonstrated in the synthesis
of two-pyranonaphthoquinone antibiotics py sc horubrin ( 1) and
pentalongin (2).
The physiological properties exhibited by naturally occurring
H-naphtho[2,3-c]pyranoquinoneshave alwayskept the organic
1
chemists interested in their studies. Thisfamily of antibioticshas
[
1]
*
Correspondence: Vishnu H. Deshpande, Division of Organic Chemistry:
Technology, National Chemical Laboratory, Pune 411 008, India; Fax: þ91 20
893614.
5
5
87
DOI: 10.1081/SCC-120015812
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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5
88
Bulbule et al.
been shown to exhibit activity against a variety of gram-positive bacteria,
pathogenic fungi and yea st saswell asantitumor and antiviral activity.
[2]
Psychorubrin (1), a natural naphthoquinone antibiotic with peculiar
structural features and significant antitumor activity, isolated from
Psychotria rubra, isan important member of thisfamily. Other examples
[
3]
[4]
[5]
of such nucleus include nanaomycin A, frenolycin B and eluetherin.
[6]
Pentalongin (2), which was oi slated from Pentas longiflora Oliv.
(Rubiaceae), shows antifungal and antiparasitic activity and is a represen-
tative example of a growing family of 3,4-dehydropyranonaphtho-
quinone antibioticsbearing C(3)–C(4) double bond in the pyran ring.
[
7]
[8]
Examplesof thisgroup include dehydroherbarin,
anhydrofusarubin
etc. Thiscombination of st ructural featuresand diver se biological activi-
tieshasmade the pyranonaphthoquinone antibioticsinteret si ng and
worthwhile synthetic targets and numerous publications have appeared
[
9a]
describing construction of naphthopyran ring. De Kimpe et al. accom-
plished synthesis of psychorubrin and pentalongin using two alternative
cyclisation strategies of 2,3-disubstituted 1,4-naphthoquinones. Ethyl-
[
9b]
3
1
-methyl-1,4-dioxo-2-naphthylacetate
H-naphtho[2,3-c]pyran-5,10-diones. Both these methods involve
was also used to construct
multisteps and expensive reagents coupled with overall low yields.
These authors also described the synthesis of 1H-2-naphtho[2,3-c]
[
9c]
thiapyran-5,10-dione-2,2-dioxide, a sulfone derivative of pentalongin.
Synthesis of 1,3-disubstituted naphtho[2,3-c]pyran-5,10-diones, which
involve the introduction of an acylmethyl group onto 2-(1-hydroxy-
ethyl)-1,4-naphthoquinones and subsequent base and acid induced ring
[9d]
closure
was also developed recently by the same group.
We wish to report herein, a more efficient and convenient method to
construct the naphthopyran ring, using inexpensive reagents. Thus in this
paper synthesis of psychorubrin (1) and pentalongin (2) by using a
chloromethylation reaction as a key step is described.
[
9e]
1
,4-Dimethoxy-2-naphthylacetic acid (8) was chosen as a starting
material for the synthesis of 1H-naphtho[2,3-c]pyran-5,10 diones
which wasprepared as hs own in Sch. 1. The 2-formyl-1,4-dimethoxy-
naphthalene (4), prepared by the Vilsmeier-Haack formylation of
1,4-dimethoxynaphthalene (3), wasreduced to alcohol 5 using sodium
borohydride in methanol. Further, thisalcohol was sm oothly converted
into 1,4-dimethoxy-2-naphthylacetic acid (8) by one carbon homologa-
tion using a standard set of reactions. The formylation of the acid 8 at the
ortho position to methoxy group gave aldehyde 9 (Sch. 2), which was
then reduced to the alcohol 10 by sodium borohydride. It was expected
[
10]
that the desired naphthopyran 11 would form during acidic workup.
However, the desired naphthopyran 11 could not be obtained. The

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Synthesis of Psychorubrin and Pentalongin
589
ꢀ
Scheme 1. (a) DMF–POCl
ꢀ
3
, 80 C, 4 h, 93%; (b) NaBH
4
, MeOH, r.t. 94%;
c) PBr , CCl , 0 C, 30 min 96%; (d) KCN, EtOH, reflux, 3 h 75%; (e) 2.5 N
(
NaOH, reflux, 18 h 90%.
3
4
ꢀ
3 4
Scheme 2. (a) DMF–POCl , 80 C, 4 h 76%; (b) NaBH , MeOH, r.t. 73%; (c) 1 N
HCl; (d) TsOH, benzene, reflux, 30 min.
alcohol 10 wasrefluxed in benzene employing Dean-Stark water
separator with a catalytic amount of p-toluenesulfonic acid but that
also failed to give 11 as sh own in Sch. 2.
An alternative approach to construct the naphthopyran ring was
[
11]
employed in which chloromethylation
of 1,4-dimethoxy-2-naphthyla-
cetic acid (8) using 37% formalin solution and concentrated hydrochloric
acid in glacial acetic acid afforded naphthopyran 11 in 82% yield (Sch. 3).
Partial reduction of the naphthopyran 11 using 1 equivalent of diisobutyl-
aluminum hydride gave the required hemiacetal 12 in 77% yield along
with over reduced product diol 13 in 11% yield. Oxidation of the hemi-
acetal 12 using cerium(IV) ammonium nitrate in aqueous acetonitrile
gave psychorubrin (1) in 81% yield. Further dehydration of psychorubin
with p-toluenesulfonic acid in benzene under reflux gave pentalongin (2)
in 88% yield as red needles. Physical and spectral data were found
[
12]
identical to the natural (1) and (2).

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5
90
Bulbule et al.
ꢀ
Scheme3. (a)37%Formalinsolution, AcOH, HCl, 90 C,1 h, 82%;(b)DIBAL-H,
ꢀ
ꢀ
toluene, 0 C-r.t., 30 min, 77%; (c) 2 equivalentsof CAN, CH CN, H O, 0 C-r.t.,
3
2
3
0 min, 81%; (d) TsOH, benzene, reflux, 30 min, 88%.
In conclusion, the synthesis of psychorubrin (1) and pentalongin (2)
having 1H-naphtho[2,3-c]pyran-5,10-dione wasperformed involving
chloromethylation of 1,4-dimethoxy-2-naphthylacetic acid asa key st ep.
EXPERIMENTAL
Progress of the reactions was followed by TLC using silica gel with
fluorescent indicator coated on aluminum sheets. Column chromatogra-
phy was performed on silica gel (60–120 mesh). Melting points were
determined on a Buchi B-540 capillary melting point apparatusand are
1
13
uncorrected. H and C NMR spectra were recorded on the AC 200 or
MSL 300 MHz Bruker instrument in CDCl with TMS asan internal
3
standard. Chemical shifts are reported in ppm (ꢀ). IR spectra were
recorded on a Perkin–Elmer infrared model 137-E spectrometer. Mass
spectra were recorded on an automated Finnigan MAT-1020C Mass
spectrometer using ionization energy of 70 eV.
3,4-Dihydro-5,10-dimethoxy-1H-naphtho[2,3-c]-
pyran-3-one (11)
A 50 mL round bottom flask was charged with 1,4-dimethoxy-
naphthylacetic acid (8) (0.5 g, 2 mmol) and acetic acid (2.5 mL).
ꢀ
The solution was stirred and heated at 80 C in an oil bath, while
8.6 mL of conc. HCl wasadded rapidly and followed immediately by

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Synthesis of Psychorubrin and Pentalongin
591
6
1
.17 mL of 37% formalin. The yellow solution was stirred and heated for
ꢀ
h, during which time reaction temperature reached to 90 C and solution
assumed a dark colour. After cooling to room temperature the solution
waspoured into a mixture of 100 g chipped ice and 100 mL of cold water.
The mixture wasextracted with chloroform (100 mL), chloroform layer
waswa hs ed with 5% aqueous os dium bicarbonate until neutral, then
with water and dried over sodium sulfate. Evaporation of the solvent
gave crude lactone which waspurified by meansof column chromato-
graphy using 5% acetone in pet ether as an eluent to afford pure 11
ꢀ
[9b]
ꢀ
(
0.433 g, 82.63%) asa white so lid, m.p. 126 C [Lit.
ꢁ
m.p. 126 C].
1
1
IR (CHCl ): 1745 cm (C¼O). H NMR (CDCl ): ꢀ 3.90 (s, 2H,
3
3
CH C¼O), 3.93 (s, 3H, OMe), 3.94 (s, 3H, OMe), 5.53 (s, 2H, CH O),
2
2
1
3
7
.50–7.60 (m, 2H), 8.03–8.15 (m, 2H). C NMR (CDCl ): ꢀ 30.51
3
(
(
(
CH C¼O), 62.01 (OMe), 62.60 (OMe), 64.88 (CH O), 119.32, 120.38
2
2
¼C quat), 122.15, 122.57, 126.30, 126.60, 127.55 (¼C quat), 128.69
¼C quat), 147.99 (¼C–OMe), 148.69 (¼C–OMe), 169.79 (–C¼O).
þ
MS (m/z): 258 (M , 100), 243 (15), 215 (15), 199 (36), 171 (12), 141
18), 128 (32), 115 (28), 91 (10) and 76 (18).
(
3,4-Dihydro-5,10-dimethoxy-1H-naphtho[2,3-c]pyran-3-ol (12)
Under nitrogen atmosphere,
,10-dimethoxy-1H-naphtho[2,3-c]pyran-3-one (11) (0.126 g, 0.4 mmol)
a
solution of 3,4-dihydro-
5
in toluene (6 mL) wastreated with a os lution of 2.5 M DIBAL-H in
ꢀ
toluene (0.057 g, 0.16 mL, 0.4 mmol) at 0 C and after stirring for 1 h at
room temperature the mixture waspoured in 2 M HCl. The organic layer
was separated and the aqueous phase was extracted with ethyl acetate.
The combined organic extractswere wa hs ed with brine, dried over
sodium sulfate and evaporated under reduced pressure to give a residue
which wasa mixture of two product s. It was se parated by column chro-
matography over silica gel using acetone in pet ether as an eluent. Elution
with 30% acetone in pet ether gave 3,4-dihydro-5,10-dimethoxy-1H-
naphtho[2,3-c]pyran-3-ol (12) asa colorle ss oil (0.098 g, 77.87%). IR
ꢁ
1
1
(
4
CHCl ): 3390 cm
3
(OH). H NMR (CDCl ): ꢀ 2.95 (dd, J ¼ 16 Hz,
3
Hz, 1H), 3.28 (dd, J ¼ 16 Hz, 4 Hz, 1H), 3.89 (s, 3H, OMe), 3.90 (s, 3H,
OMe), 4.97 (d, J ¼ 16 Hz, 1H), 5.19 (d, J ¼ 16 Hz, 1H), 5.41 (t, J ¼ 4 Hz,
þ
1
H), 7.40–7.60 (m, 2H), 7.95–8.15 (m, 2H). MS (m/z): 260 (M , 88),
242 (24), 228 (30), 214 (71), 199 (100), 171 (20), 141 (22), 128 (35), 115
(
30) and 77 (14). Further elution with 40% acetone in pet ether afforded
2
1
-(3-hydroxymethyl-1,4-dimethoxy-naphthalen-2-yl)-ethanol (13) (0.014g,
ꢀ
ꢁ1
1
1%) aswhite needlesm.p. 152 C. IR (CHCl ): 3187 cm . H NMR
3

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92
Bulbule et al.
(
(
CDCl ): ꢀ 3.12 (t, J ¼ 4 Hz, 2H), 3.90 (s, 3H), 3.98 (t, J ¼ 4 Hz, 2H), 3.99
3
1
s, 3H), 4.88 (s, 2H), 7.45–7.55 (m, 2H), 7.99–8.12 (m, 2H). C NMR
3
(
CDCl ): ꢀ 29.80 (–CH –CH –OH), 56.38 (–CH –CH –OH), 61.71
3
2
2
2
2
(
–CH –OH), 62.96 (–OCH ), 63.62 (–OCH ), 122.29, 122.95, 125.89,
2 3 3
1
26.44, 128.02 (¼C quat), 128.09 (¼C quat), 128.53 (¼C quat), 129.64
þ
(
¼C quat), 150.92 (–C–OMe), 151.47 (–C–OMe). MS (m/z): 262 (M ,
1
00), 244 (3), 229 (7), 214 (28), 199 (42), 186 (22), 171 (17), 157 (9), 140
17), 128 (38), 115 (40), 105 (12), 91 (9) and 77 (15). Anal. calcd. for
C H O : C ¼ 68.70, H ¼ 6.87%; Found: C ¼ 68.29, H ¼ 6.96%.
(
1
5
18
4
Psychorubrin (1)
3,4-Dihydro-5,10-dimethoxy-1H-naphtho[2,3-c]pyran-3-ol (12)
0.055 g, 0.2 mmol) was dissolved in acetonitrile (3 mL). Then a solution
(
of cerium(IV) ammonium nitrate (0.600 g, 1.07 mmol) in water (3 mL)
ꢀ
wasadded at 0 C and the reaction wasallowed to warm to room
temperature for 30 min. The mixture waspoured into water, extracted
with ethyl acetate, washed with brine, dried and evaporated in vacuo.
Column purification of the residue using 30% acetone in petroleum ether
afforded psychorubrin (1) (0.039 g, 81.25%) asa pale yellow so lid; m.p.
ꢀ ꢀ
53 C. [Lit. m.p. 150–152 C]. IR (CHCl ): 3410 (OH), 1660 (quinone
3
[2]
1
ꢁ1 1
C¼O), 1640 (quinone C¼O), 1590 cm . H NMR (CDCl ): ꢀ 2.65–2.94
3
(
m, 2H), 4.60–4.90 (m, 2H), 5.50 (t, J ¼ 4 Hz, 1H), 7.68–7.80 (m, 2H,
3 2
1
3
Ar H), 8.02–8.16 (m, 2H, ArH). C NMR (CDCl ): ꢀ 27.97 (CH O),
5
1
1
1
7.67 (CH CHOH), 90.64 (–CHOH), 126.15, 126.44, 132.0 (¼C quat),
2
32.03 (¼C quat), 133.75, 133.78, 139.23 (¼C quat), 141.29 (¼C quat),
þ
83.01 (quinone), 183.49 (quinone). MS (m/z): 230 (M , 13), 212 (42),
84 (100), 156 (20), 128 (40), 115 (12) and 76 (40).
Pentalongin (2)
A solution of psychorubrin (1) (0.030 g, 0.01 mmol) in benzene
5 mL) washeated under reflux for 30 min with a catalytic amount of
(
p-toluenesulfonic acid. The mixture was cooled to room temperature,
diluted with ethyl acetate, washed with water, dried over sodium sulfate
and evaporated in vacuo. Chromatographic separation using 15%
acetone in petroleum ether afforded pentalongin (2) (0.024 g, 88.88%)
ꢀ
[6]
ꢀ
asred needle ;s m.p. 162 C [Lit. m.p. 160–161 C]. IR (CHCl ): 1670
3
ꢁ
1
(
quinone C¼O), 1651 (quinone C¼O), 1596 (C¼C), 1553 cm
.
1
H NMR (CDCl ): ꢀ 5.18 (s, 2H, CH O), 6.13 (d, J ¼ 6 Hz, 1H), 6.99
3
2

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Synthesis of Psychorubrin and Pentalongin
593
(
d, J ¼ 6 Hz, 1H), 7.65–7.80 (m, 2H, ArH), 8.05–8.17 (m, 2H, ArH).
3 2
1
3
C NMR (CDCl ): ꢀ 62.20 (CH O), 98.06, 124.49, 126.04, 126.56,
1
1
31.75, 132.61, 133.31, 133.89, 136.64, 154.18, 181.59 (quinone –C¼O),
þ
82.06 (quinone –C¼O). MS (m/z): 212 (M , 100), 183 (28), 155 (12), 128
(
32), 104 (8), 76 (10).
ACKNOWLEDGMENTS
VJB thanks LTMT (Mumbai) for financial assistance in the form of
Senior Research Fellowship. PSK thanks Director, NCL for allowing to
carry out experimentsin the laboratory.
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5
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Received in the UK October 8, 2001