Efficient total synthesis of naturally occurring anti-TMV compound gramniphenol G

Article abstract of DOI:10.1080/00397911.2016.1207782

An efficient synthesis of Gramniphenol G identified as 2-(4′-Methoxyphenyl)-7,7-dimethyl-7H-furo[3,2-g]chromene and originally isolated from the plant Arundina gramnifolia belonging to orchidaceae family was accomplished starting from resorcinol. The key

Full text of DOI:10.1080/00397911.2016.1207782

Synthetic Communications
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An Efficient Total Synthesis of Naturally Occurring
anti-TMV Compound Gramniphenol G
Raju M. Walunj, Arun D. Natu, Madhusudan V. Paradkar & Supada R.
Rojatkar
To cite this article: Raju M. Walunj, Arun D. Natu, Madhusudan V. Paradkar & Supada R.
Rojatkar (2016): An Efficient Total Synthesis of Naturally Occurring anti-TMV Compound
Gramniphenol G, Synthetic Communications, DOI: 10.1080/00397911.2016.1207782
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1207782
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Date: 02 August 2016, At: 04:57

An efficient total synthesis of naturally occurring anti-TMV compound
Gramniphenol G
Raju M. Walunj1, Arun D. Natu1, Madhusudan V. Paradkar1, Supada R. Rojatkar2
1Post graduate and Research Centre, Department of Chemistry, MES Abasaheb Garware
College, Pune, India, 2R & D Centre in Pharmaceutical Sciences and Applied Chemistry,
Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune, Maharashtra,
India
GRAPHICAL ABSTRACT
O
OH
HO
OH
O
O
O
O
Resorcinol
Gramniphenol G
INTRODUCTION
Benzofurans and their analogues constitute a major group of naturally occurring
compounds.[1] Many 2-arylbenzofurans exhibit broad range of biological activities
including anticancer,[2] antiviral,[3] immunosuppressive,[4] antioxidative,[5] and anti-
inflammatory.[6] Recently, several new compounds were isolated [7] from the plant
Arundina gramnifolia belonging to orchidaceae family which is used in Chinese folkloric
medicine as a detoxifying and diuretic agent, as well as for the treatment of arthritis and
inflammation.[8] Two compounds namely Gramniphenol G (1) and Gramniphenol F (2)
from this plant belong to a new class of compounds wherein a pyran ring is fused to a
benzofuran ring system. The structures of Gramniphenol G (1) and Gramniphenol F (2)
1

as depicted below comprising of a pyranobenzofuran ring system were elucidated on the
basis of NMR and Mass analysis.[7]
Prompted by the unique structures of (1) and (2) and their potential in vitro anti-tobacco
mosaic virus activity (anti-TMV)[7] we decided to undertake total synthesis of (1).
Retrosynthetic analysis (Scheme 1) indicated that (1) can originate from resorcinol
involving the oxidative cyclization of ortho-vinyl phenol as a key step.
RESULTS AND DISCUSSION
On the basis of this retrosynthetic analysis, following synthetic route (Scheme 2) was first
planned for the key intermediate (10) starting from resorcinol (3).
We started the synthesis with Friedel-Crafts acylation of resorcinol (3) using 3,3-
dimethyl acrylic acid (4) in presence of zinc chloride and phosphorous oxychloride as per
the methods reported in literature.[9] After completion of reaction, usual work up gave
crude compound (5) which on subsequent heterocyclization in alkaline medium provided
a pink solid of 2,2-dimethyl-7-Hydroxy chroman-4-one (6) in 86% overall yield.
Subsequent reduction of (6) using amalgamated zinc in dilute HCl provided phenol (7) in
85% yield.[10] Synthesis of (10) further involved condensation of phenol (7) and phenyl
acetic acid (8) followed by Fries rearrangement. Condensation of phenol (7) with phenyl
acetic acid (8) to provide (9) was accomplished by condensation of acyl chloride of
phenyl acetic acid (8) and phenol (7) to provide an oil which on column chromatographic
purification provided ester (9) in 95% yield. Subsequently, Fries rearrangement of ester
2

(9) using anhydrous aluminium chloride at 150 to 180°C provided required intermediate
(10) in 50% yield.
With Fries product (10) in hand we decided to transform it first in to key intermediate
(12), followed by intermediate (13) which on dehydrogenation should provide the target
molecule Gramniphenol G (1) (Scheme 3).
Reduction of carbonyl group in compound (10) using sodium borohydride in methanol as
solvent at ambient temperature gave benzylic alcohol (11) in 95% yield. Dehydration of
alcohol (11) in N,N-dimethylformamide as solvent at reflux temperature provided ortho-
vinylphenol (12) in 85% yield. Now formation of compound (13) involved oxidative
cyclization of ortho-vinylphenol (12) following the reported method.[11] This was
achieved using iodine as an oxidative reagent and potassium carbonate as base in 40%
yield. During the course of this reaction, formation of (13) involves an intermediate
which was isolated and characterized as 2-aryl-3- iodo dihydropyranobenzofuran (14).
Finally, synthesis of Gramniphenol G namely 2-(4'-methoxyphenyl)-7,7-dimethyl-7H-
furo[3,2-g]chromene (1) was achieved by dehydrogenation of (13) with 2,3-dicyno-5-6-
dichloro-p-benzoquinone (DDQ) in 1,4-dioxane as solvent and at reflux temperature in
95% yield.
Gramniphenol G (1) thus obtained was an orange solid having m. p. 179-181°C.
However, as mentioned earlier Gramniphenol G was originally isolated from Arundina
3

gramnifolia (orchidaceae family) and was reported to be an orange gum [7] may be due to
small impurities. Moreover, recently total synthesis of Gramniphenol G (1) obtained as a
solid with m. p. 181-183°C has been reported.12
The reported IR spectrum showed a peak at 3342 cm-1. [7] There is no hydroxyl group in
the synthetically prepared Gramniphenol G and does not contain this peak. Gramniphenol
F isolated from the same plant contains a hydroxyl group and showed a band at 3344 cm-1
in IR.[7] It is quite possible that isolated Gramniphenol G might be contaminated with
Gramniphenol F. The mass analysis showed the molecular ion peak at [M+Na] = 329.1
suggesting the molecular formula C20H18O3. Its 1H, 13C, and DEPT NMR spectral data
(Table 1) exhibited signals for all 20 carbons and 18 protons, suggesting the presence of
the following partial structures: a 2-arylbenzofuran system bearing seven aromatic
protons, a gem-dimethylchromene moiety and a methoxy group. Observation of long-
range correlations (Fig. 2) of H-1″ with C-4, C-6, and C-3", as well as those of H-2″ with
C-3" and C-5 led to the proposal of an angularly fused gemdimethylchromene at C-5 and
C-6. The location of the methoxy group at C-4′ was established on the basis of HMBC
correlation (Fig. 2) of methoxy protons with C-4′ and further confirmed by NOESY
correlation (Fig.3), the methoxy group showed the NOE correlation between methoxy
group with H-3′ and H-5′.
The relationships of the olefinic protons H-1″/H-2″ and the aromatic proton signals H-2′
/H-3′ and H-5′ /H-6′ were well displayed in the 1H-1H COSY correlations (Fig, 2). Thus,
the structure (1) was established as Gramniphenol G namely 2-(4'-methoxyphenyl)-7, 7-
4

dimethyl-7H-furo[3,2-g]chromene on the basis of the above discussed physical and 1D,
2-D NMR spectral data.
CONCLUSION
In conclusion, we have described an efficient total synthesis of Gramniphenol G namely
2-(4'-methoxyphenyl)-7,7-dimethyl-7H-furo[3,2-g]chromene (1) starting with resorcinol
and using easily accessible reagents.
EXPERIMENTAL
All solvents were purified and dried by standard procedures prior to use. Thin-layer
chromatography (TLC) was performed on Merck 60 F254 silica-gel plates and
visualization was accomplished by ultraviolet (UV) irradiation or iodine. Melting points
were determined using open capillary tubes and are uncorrected. Crude products were
purified by column chromatography on 100- to 200-mesh silica gel or neutral alumina.
The yields reported are the yields obtained after the column chromatographic separation.
Mass spectra were recorded on a Perkin-Elmer instrument. Infrared (IR) spectra were
recorded on a Perkin-Elmer BX 2 Fourier transform (FT)–IR instrument as a thin film or
KBr pellets and are expressed in cm-1. 1H and 13C NMR spectra are recorded on Varian
Mercury spectrometer on 400 and 100MHz respectively using CDCl3 as solvent.
Chemical shifts are reported in δ ppm with reference to tetramethylsilane (TMS) as an
internal standard.
5

PREPARATION OF 1-(7-HYDROXY-2,2-DIMETHYLCHROMAN-6-YL)-2-(4'-
METHOXYPHENYL) ETHANONE (10)
A homogeneous mixture of (9) (10.0 g, 0.030 mol) and anhydrous AlCl3 (7.3 g, 0.054
mol) was heated at 150-180°C for one hour. The course of the reaction was monitored by
TLC. The reaction mixture was then cooled and decomposed over HCl (1:1) which
provided an oily product. It was extracted with diethyl ether, washed with water and dried
over anhydrous Na2SO4. Removal of solvent gave thick oil which was further purified by
column chromatography using hexane- ethyl acetate gradient as eluent to provide (10) as
an off white solid. Yield: 5.0 g (50%); mp: 134-136°C; IR (KBr): ʋ max; 2976, 1637,
1147 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 1.36 (s, 6H, CH3), 1.81-1.85 (t, 2H,
CH2), 2.73-2.76 (t, 2H, CH2), 3.80 (s, 3H, OCH3), 4.15 (s, 2H, CH2), 6.33 (s, 1H, aryl H),
6.88-6.91 (broad d, 2H, aryl H), 7.19-7.21 (d, J = 8.0 Hz, 2H, aryl H), 7.58 (s, 1H, aryl
H), 12.35 (s, 1H, aryl OH); 13C NMR (100 MHz, CDCl3): δ ppm 21.70 (CH2), 26.90
(CH3), 32.63 (CH2), 43.70 (CH2), 55.18 (OCH3), 75.90 (C), 104.73, 112.76, 114.09,
126.47, 130.33, 131.84, 158.55 (aryl C-OH), 161.38, 163.30, (aryl C and CH), 201.97
(carbonyl); Mass: [M+1] = 327.1; Anal. calcd. for C20H22O4: C, 73.60; H, 6.79; O, 19.61.
Found: C, 73.61; H, 6.87; O, 19.52.
PREPARATION OF 2-(4'-METHOXYPHENYL)-7,7-DIMETHYL-6,7-DIHYDRO-
5H-FURO[3,2-G] CHROMENE (13)
To the solution of stilbene (12) (5.0 g, 0.0161 mol) in THF (250 ml) was added
anhydrous K2CO3 (13.3 g, 0.096 mol), iodine (24.5 g, 0.096 mol) and the contents were
stirred at ambient temperature until (12) was consumed. The course of reaction was
6

monitored by TLC. The mixture was poured into saturated aqueous NaHCO3 and treated
with saturated aqueous NaHSO3 to consume the excess iodine. The mixture was extracted
with dichloromethane, washed with water and the organic layer was dried over anhydrous
sodium sulphate. Removal of solvent provided a residue which on column
chromatography using hexane-ethyl acetate gradient as eluent provided (13) as an off
white solid.
Compound (13) ; Yield: 2.0 g (40%); mp: 201-202°C; IR (KBr): ʋ max 2972, 2945,
1147 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 1.38 (s, 6H, CH3), 1.84-1.87 (t, 2H,
CH2), 2.88-2.92 (t, 2H, CH2), 3.86 (s, 3H, OCH3), 6.75 (s, 1H, aryl H), 6.94-6.95 (d, J =
4.0 Hz, 2H, aryl H), 6.97 (s, 1H, aryl H), 7.20 (s, 1H, aryl H), 7.74-7.76 (d, J = 8.0 Hz,
2H, aryl H); 13C NMR (100 MHz, CDCl3): δ ppm 22.76 (CH2), 26.87 (CH3), 33.02
(CH2), 55.32 (OCH3), 74.30 (C), 99.06, 99.19, 114.13, 117.05, 119.84, 122.54, 123.76,
125.92, 151.82, 154.47, 155.01, 159.49 (aryl C and CH); Mass: [M+1] = 309.1; Anal.
calcd. for C20H20O3: C, 77.90; H, 6.54; O, 15.57. Found: C, 77.85; H, 6.70; O, 15.45.
PREPARATION OF GRAMNIPHENOL G (1)
Chroman (13) (0.5 g, 0.0016 mol) was dissolved in 1, 4-dioxane (50 ml). To the resulting
solution, DDQ (0.40 g, 0.0017 mol) was added and the mixture was refluxed for 6 hrs
until (13) was completely consumed as evident from TLC. Solvent was evaporated under
vacuum and the yellow residue obtained was purified by column chromatography using
hexane-ethyl acetate gradient as eluent to provide an orange solid which was caracterized
as Gramniphenol G (1).
7

Gramniphenol G (1); Yield: 0.47 g (94%); mp: 179-181°C (lit.[12] mp: 181-183°C); IR
(KBr): ʋ max; 2978, 2933, 1587, 1462, 1126, 1033 cm-1; 1H NMR (400 MHz, CDCl3): δ
ppm 1.47 (s, 6H, CH3), 3.83 (s, 3H, OCH3), 5.64 (d, J = 10.0 Hz, 1H, =CH), 6.43 (d, J =
10.0 Hz,1H, =CH), 6.76 (s, 1H, aryl H), 6.96 (broad d, 2H, aryl H), 6.97 (s, 1H, aryl H)
7.12 (s, 1H, aryl H), 7.74 (broad d, 2H, aryl H); 13C NMR (100 MHz, CDCl3): δ ppm
27.76 (CH3), 55.32 (OCH3), 76.20 (C), 99.46, 114.18, 117.27, 118.12, 122.83, 123.53,
125.92, 129.87, 151.04, 155.31, 159.58 (aryl C and CH); Mass: [M+23] = 329.1; Anal.
calcd. for C20H18O3: C, 78.41; H, 5.92; O, 15.67. Found: C, 78.21; H, 5.80; O, 15.99.
(spectral data are in accordance with Reference 7).
ACKNOWLEDGMENTS
Authors are grateful to Principal Dr. S. G. Gupta, Abasaheb Garware College and Dr. R.
C. Chikate, Head, Department of chemistry for providing the necessary facilities, Dr. D.
G. Naik, Agharkar Research Institute, Pune, for providing spectral analysis and valuable
discussions.
SUPPORTING INFORMATION
Full experimental details and 1H and 13C NMR spectra for all the intemediates and final
compound can be accessed via supplementary information section of this article’s
webpage.
8

REFERENCES
[1] Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford.
Comprehensive Heterocyclic Chemistry II 1996, 2, 259.
[2] (a) Navarro, E.; Alonso, S. J.; Trujillo, J.; Jorge, E.; Perez, C. J. Nat. Prod. 2001, 64,
134. (b) Lambert, J. D.; Meyers, R. O.; Timmermann, B. N.; Dorr, R. T. Cancer Lett.
2001, 171, 47.
[3] Craigo, J.; Callahan, M.; Huang, R. C. C.; DeLucia, A. L. Antiviral Res. 2000, 47, 19.
[4] Cho, J. Y.; Kim, A. R.; Yoo, E. S.; Baik, K. U.; Park, M. H. J. Pharm. Pharmacol
1999, 51, 1267.
[5] Silva, D. H. S.; Pereira, F. C.; Zanoni, M. V. B.; Yoshida, M. Phytochemistry 2001,
57, 437.
[6] Day, S. H.; Chiu, N. Y.; Tsao, L. T.; Wang, J. P.; Lin, C. N. J. Nat. Prod. 2000, 63,
1560.
[7] Qiu-Fen Hu, Bin Zhou, Jian-Ming Huang, Xue-Mei Gao, Li-Dan Shu,Guang-Yu
Yang and Chun-Tao Che, J. Nat. Prod. 2013, 76, 292−296.
[8] Hong, D. Y.; Y. Lian, S.; Shen, L. D. Flora of China; Chinese Science Press: Beijing
1983, 73, 320.
[9] Seboek, Peter; Jekoe Jozsef; Timar, Tibor; Jaszberenyi, Joseph Cs. Heterocycles
1994, 38 (9), 2099-3114.
[10] Bridge et al. J. Chem. Soc. 1937, 1530-1534.
[11] Duan, Xin-Fang; Zeng, Jing; Zhang, Zhan-Bin; Zi, Guo-Fu, J.Org. Chem. 2007, 72
(26), 10283-10286.
[12] Kongara Damodar, Jin-Kyung Kim, Jong-Gab Jun, Tetrahedron Lett. 2016, 57,
1183–1186.
9

Table 1. 1H, 13C NMR, and HMBC Correlations Data of Compound 1(δ in ppm, in
CDCl3)
Position
δH (J in Hz)
δC
HMBC
2
-
155.31 (s)
99.46 (d)
117.27 (d)
118.12 (s)
151.04 (s)
99.46 (d)
122.83 (s)
155.31 (s)
123.53 (s)
125.92 (d)
114.18 (d)
159.58 (s)
122.84 (d)
129.87 (d)
76.20 (s)
27.76 (q)
55.33 (q)
3
6.76 (s)
122.83, 155.31
4
7.12 (s)
99.46, 122.83, 151.04,155.31
5
-
-
6
-
-
7
6.97 (s)
151.04
3a
7a
1'
-
-
-
-
-
-
2', 6'
3', 5'
4'
7.74 (br d)
125.92, 155.31, 159.58
6.96 (br d)
114.18, 123.53, 159.58
-
-
1"
6.43 (d, J= 10Hz)
5.64 (d, J= 10Hz)
-
76.20, 117,27, 151.04
76.20, 118.12
-
2"
3"
4", 5"
-OMe
1.47 (s)
27.76, 76.20, 129.87
159.58
3.83 (s)
10

Scheme 1. Retrosynthetic analysis of Gramniphenol G
O
OH
O
O
O
O
O
O
O
HO
O
O
OH
O
O
OH
HO
OH
+
OH
OH
O
O
O
O
11

Scheme 2. Reagents and conditions: (a) ZnCl2, POCl3, ambient temperature (b) 2 % aq.
NaOH, 5-10°C (c) Zn, conc. HCl, HgCl2, water (d) i. Thionyl chloride, reflux
temperature ii. Distillation, 60-70°C (e) Anhydrous AlCl3, 150-180°C
HO
OH
HO
OH
O
OH
6
O
b
a
+
OH
O
O
5
3
4
c
O
OH
7
O
OH
e
O
O
d
+
O
OH
O
O
O
O
9
10
O
8
12

Scheme 3. Reagents and conditions: (a) NaBH4, methanol, ambient temperature (b) N,N-
dimethylformamide, 150°C (c) Iodine, K2CO3, THF, ambient temperature (d) DDQ,
dioxane.
O
OH
O
OH
O
OH
a
b
OH
11
O
O
O
O
12
10
14
c
O
O
I
O
O
O
O
d
O
O
O
13
1
13

Figure1. Structures of Gramniphenol G (1) and Gramniphenol F (2)
14

Figure 2. 1H-1H COSY (
) and 1H-13C HMBC (
) correlations of compound (1)
15

Figure 3. NOESY (
) correlations of compound (1)
16