Synthesis of pentalongin and C(1)- and C(3)-substituted pentalongin using intramolecular Heck reaction

Article abstract of DOI:10.1016/j.tetlet.2012.03.061

An efficient and high yielding route for the synthesis of pentalongin and 1-alkyl, 1-aryl, and 3-alkyl substituted pentalongin has been demonstrated using intramolecular Heck reaction as a key step.

Full text of DOI:10.1016/j.tetlet.2012.03.061

Tetrahedron Letters 53 (2012) 2659–2661
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Tetrahedron Letters
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Synthesis of pentalongin and C(1)- and C(3)-substituted pentalongin
using intramolecular Heck reaction
⇑
Sukla Nandi, Raju Singha, Shubhankar Samanta, Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and high yielding route for the synthesis of pentalongin and 1-alkyl, 1-aryl, and 3-alkyl
substituted pentalongin has been demonstrated using intramolecular Heck reaction as a key step.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 8 February 2012
Revised 16 March 2012
Accepted 20 March 2012
Available online 24 March 2012
Keywords:
Intramolecular Heck reaction
Pentalongin
1-Methylpentalongin
1-Phenylpentalongin
3-Methylpentalongin
Pyranonaphthoquinones are widely distributed in plants, ani-
mals, bacteria, fungi, and algae, and are often associated with anti-
tumor, antibacterial, and antiprotozoan activities.1 The family of
the pyranonaphthoquinones and 1H-naphtho-[2,3-c]pyran-5,10-
dione derivatives is found in various natural products.2 A particular
group of pyranonaphthoquinone antibiotics bearing a C(3)–C(4)
double bond that is 3,4-dehydro-pyranonaphthoquinone scaffolds
include pentalongin (1),3 dehydroherbarin (2),4 anhydrofusarubin
(3),5 and 1,3-disubstituted-3,4-dehydro-pyranonaphthoquinones
(4, Fig. 1),6 also show significant antimicrobial activities.7 Pent-
alongin is an unsubstituted, tricyclic 3,4-dehydro-pyranonaphtho-
quinone, which is used in Rwanda and Kenya as a traditional
medicine for the treatment of malaria and skin diseases.8
Knowing these interesting biological activities of 3,4-dehydro-
pyranonaphthoquinone series, we wish to develop a general
synthetic route to pentalongin-based natural products. Several
methods are available in the literature for the synthesis of pent-
alongin (1)9,10 such as dehydration of psychorubrin,9a photochem-
ical [2+2] addition of 2-chloro-1,4-naphthoquinone and acrolein
dimethyl acetal, and subsequent treatment of the resulting 1,4-
dimethoxymethyl-1,2-dihydrocyclobuta[b]naphthalene-3,8-dione
with p-toluenesulfonic acid.10a De Kimpe and co-workers first re-
ported the total synthesis of the naturally occurring pyranonaph-
thoquinone antibiotic pentalongin in 14% overall yield, they also
reported the synthesis of 1-methylpentalongin by this procedure
but they have failed to synthesize 3-methylpentalongin and they
have proposed another pathway for the synthesis of 1-phenyl-
pentalongin in overall 7% yield. Next they have reported another
approach toward pentalongin by ring closure metathesis using
Grubbs’ first-generation catalyst in good yield.11
Recently our group reported a general methodology regarding
pyran chemistry12 and this prompted us toward the synthesis of
pentalongin and its analogues by using intra-molecular Heck reac-
tion13 with 2-allyloxy compounds.
The synthesis of pentalongin (1), 1-methylpentalongin (14), and
1-phenylpentalongin (15) is presented in Schemes 1 and 2, starting
from 1,4-dimethoxynaphthalene (5), which is readily available
from 1,4-naphthoquinone through reductive methylation by means
of Na2S2O4 and methyl iodide.14 The aldehyde group in 6 was intro-
duced by dichloromethyl methyl ether formylation of the dime-
thoxynaphthalene. The 3-bromo substituent in 7 was introduced
by electrophilic bromination of 615 and here the disappearance of
one of the aromatic C–H proton signals confirmed the formation
of product 7. Using this aromatic bromoaldehyde as the starting
material we can synthesize a series of pentalongin-based antibiotics.
Alcohol 8a16 was prepared by the reduction of compound 7
with sodium borohydride in CH3CN but alcohols 8b and 8c, were
prepared from bromoaldehyde 7 using Grignard reaction. The allyl
moiety was introduced using allyl bromide, in basic condition to
give 9a–c17 in 87–92% yield. When these compounds 9a–c were
subjected to intramolecular Heck reaction afforded only com-
pounds 10a–c with exocyclic double bond in 79–84% yield12 and
no regioisomeric product possessing the endocyclic doublebond
was formed during this Heck-type ring closure. Compounds
10a–c on reaction with catalytic osmium(VIII) tetroxide and excess
⇑
Corresponding author.
E-mail address: jkray@chem.iitkgp.ernet.in (J.K. Ray).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.061

2660
S. Nandi et al. / Tetrahedron Letters 53 (2012) 2659–2661
O
O
O
O
R1
OMe O
OH
OH
O
1
4
O
3
O
O
O
R2
MeO
MeO
O
O
3
4 R1 = Me, Ph;
2
1
R2 = Me, Ph
Figure 1. Some biologically active 3,4-dehydro-pyranonaphthoquinones.
O
O
OMe
OMe
OMe
OMe
CHO
CHO
Br
a
b
c
OMe
OMe
5
7
6
Scheme 1. Synthesis of the aromatic bromoaldehyde 7. Reagents and conditions: (a) 5.0 equiv Na2S2O4, Et2O/EtOAc/H2O, 10:1:10, 25 °C, 30 min; 2.1 equiv NaH, 2.2 equiv
MeI, DMF, À15 °C, 1 h, 82%; (b) 1.1 equiv TiCl4, 1.1 equiv CHCl2OCH3, CH2Cl2, 0 °C, 4 h, 94%; (c) 1.1 equiv Br2, CH2Cl2, 25 °C, 1 h, 75%.
OMe R
OMe R
OMe R
OH
a
c
O
b
O
7
Br
Br
OMe
OMe
9a-c
OMe
8a R = H
10a-c
8b R = Me
8c R = Ph
d
O
R
O
R
OMe R
OMe R
O
g
O
O
f
O
e
O
O
O
O
13b-c
OH
OMe OH
12b-c
OMe O
11a-c
O
14 R = Me
15 R = Ph
1 R = H
Scheme 2. Synthesis of pentalongin 1 and its C(1)-substituted derivatives 14 and 15. Reagents and conditions: (a) (i) R = H; 2 equiv NaBH4, CH3CN, 25 °C, 3 h, 96%; (ii) R = Me;
1.2 equiv MeMgBr, Et2O, 0 °C, 4 h, 81%; (iii) R = Ph; 1.2 equiv PhMgBr, Et2O, 0 °C, 4 h, 82%; (b) 2 equiv allyl bromide, 3 equiv NaH, THF, 0 °C, 5 h, 87–92%; (c) 0.25 equiv PPh3,
1.2 equiv Cs2CO3, 10 mol % Pd(OAc)2, DMF, 85–90 °C, 2 h, 79–84%; (d) 0.01 equiv OsO4, 2.4 equiv NaIO4, THF–H2O (2:1), 70 °C, 18 h, 82–85%; (e) 1.1 equiv NaBH4, MeOH–
CH2Cl2 (1:1), 25 °C, 16 h, 74–78%; (f) 3 equiv CAN, CH3CN–H2O (1:2), 0 °C, 15 min, 25 °C, 15 min, 93–94%; (g) Catalytic p-TsOH, benzene, reflux, 1 h, 76–78%.
OMe
OMe
OMe
OMe
OMe
OH
O
Br
a
b
O
c
Me
Br
Me
Br
Br
OMe
O
OMe
d
OMe
O
8a
22
18
16
17
OMe
OMe
g
O
O
e
O
O
f
Me
Me
Me
Me
O
O
OH
OMe OH
21
OMe O
20
19
Scheme 3. Synthesis of 3-methylpentalongin 22. Reagents and conditions: (a) 0.5 equiv PBr3, CCl4, 25 °C, 1 h, 66%; (b) (i) 3 equiv NaH, 2 equiv but-3-en-2-ol, THF, 40 °C,
30 min; (ii) 1 equiv 16, 40 °C, 3 h, 79%; (c) 0.25 equiv PPh3, 1.2 equiv Cs2CO3, 10 mol % Pd(OAc)2, DMF, 85–90 °C, 2 h, 83%; (d) 0.01 equiv OsO4, 2.4 equiv NaIO4, THF–H2O (2:1),
70 °C, 18 h, 81%; (e) 1.1 equiv NaBH4, MeOH–CH2Cl2 (1:1), 25 °C, 16 h, 76%; (f) 3 equiv CAN, CH3CN–H2O (1:2), 0 °C, 15 min, 25 °C, 15 min, 91%; (g) Catalytic p-TsOH, benzene,
reflux, 1 h, 67%.
of sodium periodate lead to the formation of ketones 11a–c. From
the keto compound 11a we can easily synthesize our targeted mol-
ecule pentalongin 1, which is reported in the literature.18 Sodium
borohydride reduction followed by oxidation with cerium(IV)
ammonium nitrate of the ketones 11b,c afforded the pyranonaph-
thoquinone derivatives 13b and 13c. Finally dehydration of com-
pounds 13b,c using p-toluenesulfonic acid in benzene under
reflux condition gave 1-methylpentalongin 14 and 1-phenylpent-
alongin 15 as sole products in overall 25–27% yield (Scheme 2)
which are known compounds.11a
For the synthesis of 3-methylpentalongin (22) we used alcohol
8a which was first brominated with phosphorus tribromide in
carbon tetrachloride to yield dibromonaphthalene 16 in 66%
overall yield, which is the literature known compound.17 This

S. Nandi et al. / Tetrahedron Letters 53 (2012) 2659–2661
2661
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In short we have designed an efficient and general strategy for
the synthesis of pentalongin and C(1)-and C(3)-substituted pent-
alongin. The advantage of using our synthetic strategy is that all
these products can be synthesized from the same aromatic bromo-
aldehyde using intramolecular Heck reaction as a key step. We are
gratified to prove that this methodology has the potential to be of
great benefit in the convergent synthesis of a number of pyrano-
naphthoquinone-based natural products.
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Acknowledgements
S.N. thanks the CSIR, New Delhi, for the fellowships and we also
thank D.S.T. for providing funds for the project and creating
400 MHz NMR facility under the IRPHA program.
Supplementary data
Supplementary data (detailed experimental procedures and
spectral data for all the unknown compounds) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.03.061.
12. Jana, R.; Samanta, S.; Ray, J. K. Tetrahedron Lett. 2008, 49, 851.
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