Chiron approach to the synthesis of yashabushidiol B, (3S,5S)-1-(4′- hydroxyphenyl)-7-phenylheptane-3,5-diol, and its 4′-methoxy analogue

Article abstract of DOI:10.1016/j.tetasy.2010.12.015

The total synthesis of yashabushidiol B 4, a linear diarylheptanoid containing a 1,3-diol system and its analogues 5 and 6 has been achieved by utilizing intermediate 7, which was derived from d-glucose. The Wittig reaction is the key step of our syntheti

Full text of DOI:10.1016/j.tetasy.2010.12.015

Tetrahedron: Asymmetry 22 (2011) 8–11
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journal homepage: www.elsevier.com/locate/tetasy
Chiron approach to the synthesis of yashabushidiol B, (3S,5S)-1-
(40-hydroxyphenyl)-7-phenylheptane-3,5-diol, and its 40-methoxy analogue
⇑
Vishwas U. Pawar, Vaishali S. Shinde
Garware Research Centre, Department of Chemistry, University of Pune, Pune 411 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of yashabushidiol B 4, a linear diarylheptanoid containing a 1,3-diol system and its
analogues 5 and 6 has been achieved by utilizing intermediate 7, which was derived from D-glucose.
The Wittig reaction is the key step of our synthetic strategy.
Received 22 October 2010
Accepted 15 December 2010
Available online 25 January 2011
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
masked aldehyde in a Wittig reaction to obtain the required hepta-
noid chain with a 1,3-diol functionality. For this reaction, we tested
various temperatures (Scheme 1), but in all cases, we observed a
complex reaction mixture. Varying the equivalents of base and
Wittig salt, were also unsuccessful.
Diarylheptanoids constitute an important class of natural plant
metabolites due to their interesting biological and pharmacological
properties, such as antiiinflammatory, antioxidant, anticancer,
inhibition of nitric oxide production, DPPH-radical scavenging
activity.1 The linear diarylheptanoids are characterized by a linear
seven carbon chain flanked by two aromatic rings. More than 70
linear diarylheptanoids have been isolated from Nature.2 In addi-
tion to the aforementioned biological activities, linear diarylhepta-
noids with a 1,3-diol system also exhibit hepatoprotective and
antiemetic activities.1i,3 Yashabushidiol, A 1 and B 2 (Fig. 1), linear
diarylheptanoids containing a 1,3-diol system, were first isolated
in 1986 from the male flowers of Alnus sieboldiana.4
Antiemetic compounds 3 and 6 were isolated by Takahashi
et al.5 from Alpinia katsumadai Hayata and from the rhizomes of
Alpinia officinarum,6 respectively. Recently, Narsimhulu et al.7 have
synthesized compounds 4 and 6, which are the antipodes of the
natural products, along with other isomers via alkynylation of
Although Wittig reactions with similar anomers were reported9
with other reagents, our reaction was unsuccessful probably due to
the free –OH group at the C2 position, which can interfere in beta-
ine intermediate formation leading to a complex mixture. There-
fore, we thought to protect the C2 hydroxyl group as a benzyl
ether so that it could be deprotected during the reduction of the
olefin after the Wittig reaction in a single step.
The synthesis of target molecules 4, 5, and 6 can be visualized as
shown in the retrosynthesis (Scheme 2). The chiral 1,3-diol func-
tionality in these diarylheptanoids can be seen in the anomers
13. These C2 benzyl protected anomers can be extended to diaryl-
heptanoids using suitable Wittig reagents. This anomeric mixture
could be obtained by anomeric methyl deprotection of C2 benzy-
lated compound 12. This compound could be derived in two steps
the
D-mannitol derivative 3-hydroxy-5-phenyl pentanal with
from 7, which was synthesized from D-glucose.
substituted phenyl acetylenes and their anticancer activity was
tested. Compound 6 showed potent anticancer activity with an
IC50 of 12.82 lg/mL on a THP-1 leukemia cell line while negligible
To achieve the synthesis of C2 benzyl protected anomers 13,
compound 7 was treated with acidic resin in methanol at room
temperature (Scheme 3) to afford methoxy protected 11 in quanti-
activity was observed for compound 4.
Herein we report the first total synthesis of yashabushidiol B 4
and its analogues 5 and 6 from compound 7 (1,2-O-isopropylidene-
tative yield as a mixture of anomers (a/b = 17:83) as evident from
1H NMR spectrum. The C2 hydroxy group of this mixture was then
protected as a benzyl ether using NaH and BnBr in THF with 93%
yield to give 12. The anomeric methoxy group was deprotected
with an acidic resin in the presence of cat. H2SO4 under reflux
conditions to give compound 13 in 71% yield. Our next task was
to perform the Wittig olefination on compound 13. We repeated
the same reaction conditions for Wittig reaction as discussed in
Scheme 1. This time, we observed the formation of Wittig products
14 and 15 only under reflux conditions in 76% and 79% yield,
respectively, as a diastereomeric mixture of olefins. Reduction of
the olefin and benzyl deprotection was carried out under hydroge-
nation conditions using 10% Pd/C in ethyl acetate at 80 psi; the
yashabushidiol B 4 and methoxy derivative 5 were obtained in
3,5,6-trideoxy-6-phenyl-
a-D-gulo-1,4-furanose), which has been
synthesized from
D
-glucose.8
2. Results and discussion
Treatment of compound 7 with cat. H2SO4 at 65 °C afforded 8 as
a 1:1 mixture of a
,b-anomers (determined by 1H NMR) which can
be visualized as a masked aldehyde. We planned to utilize this
⇑
Corresponding author. Tel.: +91 20 25601395; fax: +91 20 25691728.
E-mail address: vsshinde@chem.unipune.ac.in (V.S. Shinde).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.12.015

V. U. Pawar, V. S. Shinde / Tetrahedron: Asymmetry 22 (2011) 8–11
9
OH OH
OH OH
(+)-Yashabushidiol B 2
Yashabushidiol A 1
OH OH
OH OH
3
R
4
(−)-Yashabushidiol B , R = H
(−)-5, R = OMe
(−)-6, R = OH
Figure 1. Yashabushidiol A, B, and other linear diarylheptanoids.
OH OH
O
O
b)
a)
X
OH
O
9, R = H
10, R = OMe
R
8
7
O
OH
Scheme 1. Reagents and conditions: (a) cat. H2SO4, THF/H2O (4:1), 65 °C, 2.5 h, 85%; (b) Ph3P+CH2Ph(40-R)Brꢀ, n-BuLi, THF. Temperature conditions: (i) ꢀ78 °C to rt; (ii) 0 °C to
rt; (iii) 0 °C to reflux; (iv) rt to reflux.
OH OH
O
O
OH
OMe
R
4; R = H
OBn
13
12
OBn
5; R = OMe
6; R = OH
O
D-glucose
O
O
7
Scheme 2. Retrosynthesis.
O
b)
O
c)
O
Ref.8
a)
OMe
OMe
D-glucose
O
OH
11, α:β = 17:83
OBn
7
O
12
OH OH
OH OBn
7
1
2'
6"
1"
2"
1'
6'
e)
d)
5
3
O
OH
4"
4'
R
R
OBn
14
4, R = H, (−)-Yashabushidiol B, 96%
5, R = OMe, 98%
, R = H, Z:E = 64:36,
13
15, R = OMe, Z:E = 61:39
OH OH
OH OH
7
1
2'
7
1
2'
6"
6"
f)
1"
2"
1"
2"
1'
6'
1'
6'
5
3
5
3
4"
4"
4'
4'
OH
OMe
6
5
Scheme 3. Reagents and conditions: (a) DowexÒ 50WX4-200 (H+ form), MeOH, rt, 12 h, quant.; (b) NaH, BnBr, THF, 0 °C to rt, 2 h, 93%; (c) DowexÒ 50WX4-200 (H+ form), cat.
H2SO4, reflux, 12 h, 71%; (d) Ph3P+CH2Ph(40-R)Brꢀ, n-BuLi, THF, 0 °C to reflux, 4 h; 76% for 14, and 79% for 15; (e) H2, Pd/C, ethyl acetate, 80 psi, rt, 12 h; 96% for 4, 98% for 5; (f)
AlCl3, EtSH, 0 °C to rt, 1 h, 99%.

10
V. U. Pawar, V. S. Shinde / Tetrahedron: Asymmetry 22 (2011) 8–11
96% and 98% yield, respectively. Our initial attempts at the
demethylation of compound 5 by using BBr3 were unsuccessful,
due to the interference of free 1,3-diol functionality. Therefore,
demethylation was carried out using Fujita’s protocol10 with AlCl3
in EtSH/CH2Cl2 (2.0:0.5, v/v) which afforded phenolic diarylhepta-
noid 6 in quantitative yield.
added dropwise and stirred for 10 min. To this, benzyl bromide
(0.46 mL, 3.87 mmol) was added. The reaction was quenched with
a satd solution of NH4Cl. The solvent was evaporated and the reac-
tion mixture was extracted in ethyl acetate to give a mixture of C-2
benzylated methoxy anomers 12 as a thick liquid; (0.562 g, 93%).
Rf: 0.70 (ethyl acetate/hexane = 3:7). Elem. Anal. Calcd for
C20H24O3: C, 76.89; H, 7.74. Found: C, 76.71; H, 7.52.
3. Conclusion
4.1.3. 2-O-Benzyl-3,5,6-trideoxy-6-phenyl-D-gulo-1,4-furanose
13
In conclusion, a new, efficient and straightforward total synthe-
sis of (ꢀ)-yashabushidiol B 4 and other diarylheptanoids 5 and 6
A solution of 12 (0.55 g, 1.76 mmol) in THF/H2O (9:1; 10 mL)
was refluxed in the presence of DOWEXÒ 50WX4-200 (H+ form,
0.3 g) and cat. H2SO4 for 12 h. The reaction was cooled to rt, care-
fully neutralized with solid NaHCO3. Next, the THF was evaporated
under vacuum and the reaction mixture was extracted in ethyl ace-
tate to give a mixture of anomers 13 as a thick liquid; (0.373 g,
71%). Rf: 0.46 (ethyl acetate/hexane = 4:6). Elem. Anal. Calcd for
has been demonstrated via a chiron approach from
D-glucose
derivative 7. The target molecules 4 and 5 were obtained in five
steps with 48% overall yield and compound 6 in six steps with
51% overall yield. It is noteworthy that there is only one known re-
port7 for the synthesis of compounds 4 and 6, our strategy utilizes
simple, non-hazardous reagents and high yielding steps. Further
efforts are currently in progress for the synthesis of other diaryl-
heptanoids by utilizing this methodology.
C19H22O3: C, 76.48; H, 7.43. Found: C, 76.61; H, 7.62.
4.1.4. (3R,5S)-1-(40-Methoxyphenyl)-3-benzyloxy-7-phenylhept-
1-ene-5-ol 14
4. Experimental
4.1. General
A suspension of Wittig salt (0.451 g, 1.039 mmol) and n-BuLi
(0.65 ml, 1.039 mmol) in dry THF (10 mL) was cooled to 0 °C to
give a clear, dark red solution. To this, a solution of 13 (0.16 g,
0.519 mmol) in THF (10 ml) was added slowly at the same temper-
ature. The reaction mixture was refluxed for 5 h, cooled to rt, after
which THF was vacuum evaporated. The 1H NMR of crude product
showed mixture of olefins. Column purification with hexane/ethyl
acetate (9.5:0.5) on silica gel (100–200 mesh) afforded a mixture of
14 (0.152 g, 76%). Rf: 0.83 (ethyl acetate/hexane = 4:6). 1H NMR
(300 MHz, CDCl3, d): 1.64–1.96 (m, 4H, H-4, and H-6), 2.61–2.93
(m, 2H, H-7, and 1H, –OH, D2O Ex.), 3.91–4.03 (m, 2H, H-3, and
H-5), 4.15 (d, J = 11.7 Hz, 1H, –OCHH-Ph), 4.53 (d, J = 11.7 Hz, 1H,
–OCHH-Ph), 5.75 (dd, J = 9.6, 11.7 Hz, 1H, H-2), 6.72 (d,
J = 11.7 Hz, 1H, H-1), 7.17–7.41 (m, 15H, 3 ꢁ ArH). Elem. Anal.
Calcd for C26H28O2: C, 83.83; H, 7.58. Found: C, 83.67; H, 7.62.
Melting points were recorded with Thomas Hoover Capillary
melting point apparatus and are uncorrected. IR spectra were
recorded with Shimadzu FTIR-8400 as a thin film or using KBr pel-
lets and are expressed in cmꢀ1 1H (300 MHz) and 13C (75 MHz)
.
NMR spectra were recorded with a Varian Mercury instrument
using CDCl3 as a solvent. Chemical shifts were reported in d unit
(ppm) with reference to TMS as the internal standard and J
values are given in hertz. 1H–1H COSY and decoupling experiments
confirmed the assignments of the signals wherever required.
Elemental analyses were carried out with Thermo-Electron
Corporation CHNS analyzer Flash-EA 1112. Optical rotations were
measured using Jasco P1020 polarimeter with sodium light
(589.3 nm) at 25 °C. Thin layer chromatography was performed
on pre-coated plates (0.25 mm, silica gel 60 F254). Visualization
was made by absorption of UV light or by thermal development
after spraying with 3.5% solution of 2,4-dinitrophenylhydrazine
in methanol/H2SO4 or with basic aqueous potassium permanga-
nate solution or with 10% solution of phosphomolybdic acid
(PMA) in ethanol.
4.1.5. (3R,5S)-3-Benzyloxy-1,7-diphenylhept-1-ene-5-ol 15
The same procedure as used for 14, was adopted for the synthe-
sis of 15; (0.171 g, 79%). Rf: 0.73 (ethyl acetate/hexane = 4:6).1H
NMR (300 MHz, CDCl3, d): 1.69–1.88 (m, 4H, H-4, and H-6), 2.58–
2.82 (m, 2H, H-7, and 1H, –OH, D2O Ex.), 3.76 (s, 3H, –OCH3),
3.96–4.01 (m, 2H, H-3, and H-5), 4.13 (d, J = 11.6 Hz, 1H, –OCHH-
Ph), 4.51 (d, J = 11.6 Hz, 1H, –OCHH-Ph), 5.69 (dd, J = 9.5, 11.8 Hz,
1H, H-2), 6.70 (d, J = 11.8 Hz, 1H, H-1), 6.82 (d, J = 8.4 Hz, 2H, H-
30, and H-50), 7.11 (d, J = 8.4 Hz, 2H, H-20, and H-60), 7.15–7.31 (m,
10H, 2 ꢁ ArH). Elem. Anal. Calcd for C27H30O3: C, 80.56; H, 7.51.
Found: C, 80.61; H, 7.82.
4.1.1. 1-O-Methyl-3,5,6-trideoxy-6-phenyl-D-gulo-1,4-furanose
11
To a solution of 7 (0.205 g, 0.826 mmol) in methanol (5 mL) was
added DOWEXÒ 50WX4-200 (H+ form, 0.5 g) at room temperature.
After stirring for 12 h, the reaction mixture was filtered through a
pad of Celite and washed with methanol (40 mL). The filtrate was
concentrated in vacuo to give 11 (0.183 g, 99%) as a colorless oil.
Rf: 0.23 (ethyl acetate/hexane = 3:7). 1H NMR showed a mixture
4.1.6. (3S,5S)-Yashabushidiol B 4
A solution of 14 (0.1 g, 0.3 mmol) in ethyl acetate (20 mL) and
10% Pd/C (0.03 g) was hydrogenated at 80 psi for 12 h at 25 °C.
After completion of the reaction, it was filtered through a Celite
pad, washed with ethyl acetate and concentrated on a rotavapor
to give 4 as a white crystalline solid (0.073 g, 96%). Mp: 93–
of anomers (a/b = 17:83). Further reactions were carried out on
this anomeric mixture. 1H NMR (300 MHz, CDCl3, d): 1.44–1.52
(m, 1H, H-5a), 1.82–1.94 (m, 1H, H-5b), 1.98–2.10 (m, 1H, H-3a),
2.33–2.42 (m, 1H, H-3b), 2.59–2.75 (m, 2H, H-6, and 1H, –OH,
D2O Ex.), 3.29 (s, 3H, –OCH3), 3.99–4.17 (m, 1H, H-4), 4.15 (dd,
J = 2.7, 6.3 Hz, 1H, H-2), 4.81 (s, 1H, H-1), 7.11–7.26 (m, 5H, ArH).
Elem. Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C,
70.51; H, 8.22.
95 °C; Rf: 0.57 (ethyl acetate/hexane = 4:6); ½a D25
ꢂ
¼ ꢀ7:3 (c 1,
CHCl3), IR (KBr): 3374 (OH), 2934 (CH), 1048 (C–O) cmꢀ1
;
1H
NMR (300 MHz, CDCl3, d): 1.68 (t, J = 5.4 Hz, 2H, H-4), 1.73–1.88
(m, 4H, H-2, and H-4), 2.64–2.81 (m, 4H, H-1, H-7, and 2H, 2 ꢁ
–OH, D2O Ex.), 3.97–4.01 (m, 2H, H-3, and H-5), 7.12 (m, 10H,
2 ꢁ ArH); 13C NMR (75 MHz, CDCl3, d): 32.2 (C-1, C-7), 39.0 (C-2,
C-6), 42.6 (C-4), 68.9 (C-3, C-5), 125.9, 128.4, 128.5, 141.8, Ar-C).
Elem. Anal. Calcd for C19H24O2: C, 80.24; H, 8.51. Found: C,
80.31; H, 8.42.
4.1.2. 1-O-Methyl-2-O-benzyl-3,5,6-trideoxy-6-phenyl-D-gulo-
1,4-furanose 12
To an ice cooled suspension of NaH (0.093 g, 3.87 mmol) in THF
(15 mL), a solution of 11 (0.43 g, 1.93 mmol) in THF (10 mL) was

V. U. Pawar, V. S. Shinde / Tetrahedron: Asymmetry 22 (2011) 8–11
11
4.1.7. (3S,5S)-1-(40-Methoxyphenyl)-7-phenylheptane-3,5-diol 5
A solution of 15 (0.09 g, 0.23 mmol) in ethyl acetate (20 mL) and
10% Pd/C (0.03 g) was hydrogenated at 80 psi for 12 h at 25 °C.
After completion of the reaction, it was filtered through a Celite
pad, washed with ethyl acetate and concentrated on a rotavapor
to give 5 as a white crystalline solid (0.068 g, 98%). Mp: 71–
125.9 (C-400), 128.3 (C-200 and C-300), 128.4 (C-500 and C-600), 129.4
(C-20 and C-60), 133.5 (C-10), 141.8 (C-100), 154.0 (C-40). Elem. Anal.
Calcd for C19H24O3: C, 75.97; H, 8.05. Found: C, 75.78; H, 8.12.
Acknowledgments
73 °C; Rf: 0.51 (ethyl acetate/hexane = 1:1); ½a D25
ꢂ
¼ ꢀ7:7 (c 0.7,
We gratefully acknowledge University of Pune, Pune for finan-
cial support (BCUD/OSD/184-2009). We are grateful to Professor
M. S. Wadia and Professor D. D. Dhavale, for insightful discussions.
V.U.P. is thankful to UGC (New Delhi, INDIA) for a fellowship in the
form of SRF.
CHCl3); IR (KBr, disk, cmꢀ1): 3352 (OH), 2928 (CH), 1068 (C–O);
1H NMR (300 MHz, CDCl3, d): 1.65 (t, J = 5.4 Hz, 2H, H-4), 1.70–
1.87 (m, 4H, H-2, and H-6), 2.59–2.78 (m, 4H, H-1, H-7, and 2H,
2 ꢁ –OH, D2O Ex.), 3.77 (s, 3H, –OCH3), 3.95–4.01 (m, 2H, H-3,
and H-5), 6.82 (d, J = 8.4 Hz, 2H, H-30, and H-50), 7.10 (d,
J = 8.4 Hz, 2H, H-20, and H-60), 7.17–7.30 (m, 5H, ArH); 13C NMR
(75 MHz, CDCl3, d): 31.2 (C-1), 32.2 (C-7), 39.0 (C-2), 39.2 (C-6),
42.4 (C-4), 55.3 (–OCH3), 68.7 (C-3 and C-5), 113.9 (C-30 and C-
50), 125.9 (C-400), 128.4 (C-200 and 300), 128.5 (C-500 and 600), 129.3
(C-20 and C-60), 133.9 (C-10), 141.9 (C-100), 157.8 (C-40). Elem. Anal.
Calcd for C20H26O3: C, 76.40; H, 8.33. Found: C, 76.51; H, 8.22.
References
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4.1.8. (3S,5S)-1-(40-Hydroxyphenyl)-7-phenylheptane-3,5-diol 6
To a mixture of ethanethiol (0.2 mL) and dichloromethane
(1 mL) was added AlCl3 (0.064 g, 0.48 mmol) at 0 °C. A solution of
5 (0.05 g, 0.16 mmol) in CH2Cl2 (2 mL) was added at the same tem-
perature and stirred for 1 h at rt. Excess AlCl3 was quenched by
methanol (2 mL). The solvent was evaporated to obtain thick resi-
due, which was extracted in ethyl acetate. Column purification
(ethyl acetate/hexane, 1:3) afforded demethylated product 6 as a
thick liquid (0.047 g, 99%). Rf: 0.45 (ethyl acetate/hexane = 1:1);
½
a 2D5
ꢂ
¼ ꢀ8:4 (c 1.5, CHCl3); IR (KBr): 3352 (OH), 2928 (CH), 1068
(C–O) cmꢀ1 1H NMR (300 MHz, CDCl3, d): 1.65 (t, J = 5.3 Hz, 2H,
;
H-4), 1.69–1.87 (m, 4H, H-2, and H-6), 2.57–2.79 (m, 4H, H-1, H-
7, and 2H, 2 ꢁ –OH, D2O Ex.), 3.94–4.00 (m, 2H, H-3, and H-5),
6.73 (d, J = 8.2 Hz, 2H, H-30, and H-50), 7.01 (d, J = 8.2 Hz, 2H, H-20,
and H-60), 7.16–7.19 (m, 3H, ArH), 7.25–2.31 (m, 2H, ArH); 13C
NMR (75 MHz, CDCl3, d): 31.2 (C-1), 32.1 (C-7), 39.0 (C-2), 39.1
(C-6), 42.4 (C-4), 68.9 (C-3), 69.0 (C-5), 115.3 (C-30 and C-50),
7. Narasimhulu, M.; Reddy, T. S.; Mahesh, K. C.; Krishna, A. S.; Rao, J. V.;
Venkateswarlu, Y. Bioorg. Med. Chem. Lett. 2009, 19, 3125.
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