Synthesis of diarylheptanoids, (5S)-5-acetoxy-1,7-bis(4-hydroxy-3- methoxyphenyl)-3-heptanone and (3S,5S)-3,5-diacetoxy-1,7-bis(4-hydroxy-3- methoxyphenyl)heptane

Article abstract of DOI:10.1016/j.tetasy.2011.09.012

The total syntheses of the first examples of diarylheptanoid natural products (5S)-5-acetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-3-heptanone 1, and (3S,5S)-3,5-diacetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptane 2 isolated from the rhizomes of Zingiber officinale were accomplished using Sharpless epoxidation and cross-metathesis reactions as the key steps.

Full text of DOI:10.1016/j.tetasy.2011.09.012

Tetrahedron: Asymmetry 22 (2011) 1729–1735
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of diarylheptanoids, (5S)-5-acetoxy-1,7-bis(4-hydroxy-3-methoxy-
phenyl)-3-heptanone and (3S,5S)-3,5-diacetoxy-1,7-bis(4-hydroxy-3-
methoxyphenyl)heptane
Gowravaram Sabitha a, , Gajangi Chandrashekhar a, Kurra Yadagiri a, Jhillu Singh Yadav a,b
⇑
a Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500007, India
b King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
The total syntheses of the first examples of diarylheptanoid natural products (5S)-5-acetoxy-1,7-bis(4-
hydroxy-3-methoxyphenyl)-3-heptanone 1, and (3S,5S)-3,5-diacetoxy-1,7-bis(4-hydroxy-3-methoxy-
phenyl)heptane 2 isolated from the rhizomes of Zingiber officinale were accomplished using Sharpless
epoxidation and cross-metathesis reactions as the key steps.
Received 26 August 2011
Accepted 16 September 2011
Available online 21 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of (5S)-5-acetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)
-3-heptanone
1 and (3S,5S)-3,5-diacetoxy-1,7-bis(4-hydroxy-3-
In recent years, there have been considerable efforts to search
for naturally occurring substances for the treatment of carcinogen-
esis. Many components from medicinal or dietary plants have been
identified to possess potential chemopreventive properties. The
diarylheptanoids having an aliphatic C7 chain with aromatic sub-
stituents, often phenols, at the termini are common in the ginger
family, Zingiberaceae, which has a history of medicinal use in sys-
tems of traditional medicine.
The best known example of a diarylheptanoid is curcumin (dif-
eruloylmethane), a yellow coloring agent from turmeric (Curcuma
longa L., Zingiberaceae), which has been studied extensively for its
wide-ranging pharmacological properties such as antioxidant,
anti-inflammatory, antitumor, and chemopreventive activities.1–3
Related diarylheptanoids are known from the genera Curcuma,4
Zingiber,5–8 Alpinia,9 and Renealmia10 are very often bactereostat-
ic11 or nematocidal12 agents. Recently, two new diarylheptanoids
1 and 213 (Fig. 1), which are structurally related to curcumin have
been isolated from the rhizomes of Zingiber officinale. The structure
elucidation was mainly based on 2D-NMR spectroscopy and mass
spectral analysis. Some of the related methods14 exist in the liter-
ature for the synthesis of other diarylheptanoids.
methoxyphenyl)heptane 2 via a cross-metathesis reaction.
The retrosynthetic analysis is shown in Scheme 1. The synthesis
of target molecules 1 and 2 could be achieved by cross-metathesis
reaction of two units 4 and 5. The compound 4 in turn could be
prepared from (3-hydroxy-4-methoxy)-3-phenyl propanal 6 using
Sharpless epoxidation as the key step, whereas compound 5 could
be made from vanillin.
The synthesis of subunit 4 started by the protection of (3-hydro-
xy-4-methoxy)-3-phenyl propanal16
6
as its benzyl ether
(Scheme 2). Wittig olefination using a two-carbon-stabilized ylide
produced the ,b-unsaturated ester 8, which on selective reduction
7
a
of the ester group using DIBAL-H gave the allyl alcohol 9, which
was subjected to Sharpless epoxidation conditions using (+)-DIPT,
TBHP to give epoxy alcohol 10 (95% ee). Opening of epoxide with
Red-Al furnished 1,3-diol 11, which was converted to acetal 12 in
85% yield using PMB dimethyl acetal and a catalytic amount of p-
TSA in CH2Cl2. The regioselective reductive ring opening of the cyc-
lic PMP acetal with DIBAL-H and oxidation of the resulting alcohol
13 using IBX afforded aldehyde 14. Vinylation of the aldehyde
using vinylmagnesium bromide in THF gave allyl alcohol 15 as a
diastereomeric mixture. The free hydroxy group was converted
to a ketone using IBX in DMSO to afford 4.
The styryl compound 5 was made from vanillin in two steps,
benzyl protection followed by one carbon Wittig olefination
(Scheme 3). With both subunits 4 and 5 in hand, our next task
was to couple them. Thus, a cross-metathesis (CM) reaction
between 4 and 5 using Grubbs’ 2nd generation catalyst17 in CH2Cl2
at reflux gave the desired coupled product 18 in 70% yield for 48 h.
PMB deprotection in compound 18 using DDQ afforded the second-
ary alcohol 19, which was acetylated under normal conditions to
2. Results and discussion
Earlier we had reported the synthesis of the diarylheptanoids
centrolobine, and diospongin A and B.15 As a continuation of our
interest in this series of compounds, we herein report the first
⇑
Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.09.012

1730
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 1729–1735
OAc
O
OAc
OAc
1
1
MeO
HO
OMe
OH
OMe
OH
MeO
HO
3
5
3
5
1
2
O
O
OMe
OH
MeO
HO
curcumin
OH
H
H
HO
O
O
O
OH
diospongin A
diospongin B
H
H
(-)-centrolobine
Figure 1.
OAc
O
OAc
O
OMe
OH
MeO
HO
OMe
OBn
MeO
BnO
1
3
OAc OAc
OMe
OH
MeO
2
HO
PMBO
O
OMe
MeO
BnO
+
OBn
4
5
Scheme 1. Retrosynthetic analysis.
give acetate 3 in 92% yield. Finally, reduction of the double bond
was achieved using Pd/C, H2 in dry EtOAc at room temperature
to afford the saturated compound, simultaneously deprotecting
two benzyl groups affording the target molecule 1 in 82% yield
(Scheme 4). The prepared synthetic (5S)-5-acetoxy-1,7-bis(4-hy-
droxy-3-methoxyphenyl)-3-heptanone 1 is identical (IR, 1H and
13C NMR) with the natural product and also its specific rotation
3. Conclusion
In conclusion, this Letter describes the first synthesis of (5S)-5-
acetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-3-heptanone 1 and
(3S,5S)-3,5-diacetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hep-
tane 2.
½
a 2D5
ꢀ
¼ þ5:0 (c 0.5, CHCl3) which is in good agreement with the lit-
4. Experimental
4.1. General
erature value {lit.13
½ ꢀ
a 2D5
¼ þ3:0 (c 0.6, CHCl3)}.
To obtain compound 2, a reagent-controlled reduction was car-
ried out with the (R)-Me-CBS reagent18 to give excellent selectivity
(92% de) in setting the desired configuration at C-3, leading to the
allylic alcohol 20 in 88% yield (Scheme 5). Now, the allyl alcohol 20
was converted to the corresponding acetate 21 and reduction of
the double bond using Pd/C, H2 in dry EtOAc at room temperature
simultaneously deprotecting two benzyl groups afforded the target
molecule 2 in 82% yield. The prepared synthetic (3S,5S)-3,5-diacet-
Reactions were conducted under N2 in anhydrous solvents such
as CH2Cl2, THF, and EtOAc. All reactions were monitored by TLC
(silica-coated plates and visualizing under UV light). Light petro-
leum ether (bp 60–80 °C) was used. Yields refer to chromatograph-
ically and spectroscopically (1H, 13C NMR) homogeneous material.
Air-sensitive reagents were transferred by syringe or double-ended
needle. Evaporation of solvents was performed at reduced pressure
on a Buchi rotary evaporator. 1H and 13C NMR spectra of samples in
CDCl3 were recorded on Varian FT-200 MHz (Gemini) and Bruker
UXNMR FT-300 MHz (Avance) spectrometers. Chemical shifts (d)
oxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptane
2 is identical
(IR, 1H and 13C NMR) with the natural product and its specific rota-
tion ½a 2D5
ꢀ
¼ þ8:5 (c 1.25, CHCl3) which is in good agreement with
the literature value {lit.13
½ ꢀ
a 2D5
¼ þ7:0 (c 0.68, CHCl3)}.

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 1729–1735
1731
CO2Et
MeO
BnO
MeO
HO
CHO
MeO
BnO
CHO
a
b
8
6
7
O
MeO
MeO
BnO
OH
10
OH
c
e
d
BnO
OMe
9
OH
O
O
MeO
BnO
MeO
g
OH
f
12
BnO
11
OPMB
OPMB
MeO
MeO
OH
i
h
O
14
BnO
13
BnO
PMBO
O
PMBO
OH
MeO
BnO
MeO
BnO
j
15
4
Scheme 2. Reagents and conditions: (a) K2CO3, acetone, BnBr, reflux, 3 h, (b) PPh3@CHCO2Et, benzene, rt, 3 h, (72% over two steps); (c) DIBAL-H, dry CH2Cl2, 0 °C, 30 min.,
82%; (d) (+) DIPT, Ti(iOPr)4, TBHP, dry CH2Cl2, 3 h, 90%; (e) Red-Al, dry THF, 1 h, 92%; (f) PMB dimethyl acetal, p-TsOH, CH2Cl2, 0 °C–rt, 1 h, 85%; (g) DIBAL-H, dry CH2Cl2, 0 °C–
r.t., 1 h, 83%; (h) IBX, dry CH2Cl2, dry DMSO, 0 °C–rt, 10 h; (i) CH2@CHMgBr, THF, 0 °C–rt, 2 h, (71% over two steps); (j) IBX, dry CH2Cl2, dry DMSO, 0 °C–rt, 12 h, 78%.
MeO
HO
OMe
OBn
MeO
BnO
a
b
O
O
5
16
17
Scheme 3. Reagents and conditions: (a) K2CO3, acetone, BnBr, reflux, 3 h, 88%; (b) CH3 PPh3+Brꢁ, n-BuLi, dry THF, 0 °C, 3 h, 78%.
are reported relative to TMS (d = 0.0) as the internal standard. Mass
To a solution of the above aldehyde in C6H6 (40 mL) was added
Ph3P@CHCOOEt (5.9 g, 16.9 mmol) and the reaction mixture was
stirred for 3 h at room temperature. After completion of the reac-
tion, monitored by TLC, C6H6 was removed under reduced pressure,
the residue was dissolved in ether, and petroleum ether was added
to it. The triphenylphosphine oxide crystallized out was filtered off
and the filtrate was concentrated to dryness. The crude product
was purified by column chromatography (eluent: PE–EtOAc,
spectra were recorded in E1 conditions at 70 eV on LC-MSD (Agi-
lent technologies) spectrometers. All high resolution spectra were
recorded on QSTAR XL hybrid ms/ms system (Applied Bio sys-
tems/MDS sciex, foster city, USA), equipped with an ESI source
(IICT, Hyderabad). Column chromatography was performed on sil-
icagel (60–120 mesh) supplied by Acme Chemical Co., India. TLC
was performed on Merck 60 F-254 silica gel plates. Optical rota-
tions were measured with a JASCO DIP-370 Polarimeter at 25 °C.
8.5:1.5) to afford the pure
yield from two steps) as a semi solid. IR (Neat): 2933, 1715,
1651, 1511, 1456, 1311, 1265, 1146, 1033 cmꢁ1 1H NMR: (CDCl3,
a,b-unsaturated ester 8 (4.06 g, 72%
4.1.1. Ethyl (E)-5-[4-(benzyloxy)-3-methoxyphenyl]-2-
pentenoate 8
;
300 MHz): d 7.42–7.22 (m, 5H), 7.01–6.89 (m, 1H), 6.75 (d, 1H,
J = 8.1 Hz), 6.66 (d, 1H, J = 1.7 Hz), 6.60 (dd, 1H, J = 1.8, 8.1 Hz),
5.79 (d, 1H, J = 15.6 Hz), 5.08 (s, 2H), 4.16 (q, 2H, J = 7.1, 14.3 Hz),
3.86 (s, 3H), 2.70 (t, 2H, J = 8.1 Hz), 2.53–2.43 (m, 2H), 1.28 (t,
3H, J = 7.1 Hz); ESI-MS: 363 [M+Na]+.
Benzylbromide (1.8 mL, 14.97 mmol) was added to a mixture of
3-(4-hydroxy-3-methoxyphenyl) propanal (3 g, 16.66 mmol) and
potassium carbonate (4.6 g, 33.33 mmol) in acetone (40 mL). The
mixture was stirred for 3 h at reflux condition. TLC indicated con-
sumption of the starting material. The mixture was filtered
through Celite and the filter cake was washed well with acetone.
The filtrate was concentrated under vacuo. The resulting residue
was redissolved in ethyl acetate, transferred to a separatory funnel,
washed with sodium carbonate (satd), HCl (3 M) and brine, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure. The crude aldehyde 7 was used for the next step.
4.1.2. (E)-5-[4-(Benzyloxy)-3-methoxyphenyl]-2-penten-1-ol 9
DIBAL-H (16.8 mL, 1.4 M solution in toluene, 23.52 mmol) was
added to a stirred solution of ester 8 (4 g, 11.76 mmol) in anhy-
drous CH2Cl2 (50 mL) at 0 °C and the mixture was allowed to stir
at the same temperature for 1 h. After monitoring with TLC, the
reaction was quenched with aq MeOH (1 mL) at 0 °C. Then a

1732
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 1729–1735
PMBO
O
MeO
BnO
PMBO
O
4
OMe
OBn
MeO
BnO
a
b
+
OMe
18
OBn
OH
5
OAc
O
O
OMe
OBn
MeO
OMe
OBn
MeO
c
BnO
BnO
19
3
OAc
O
OMe
MeO
HO
d
1
OH
Scheme 4. Reagents and conditions: (a) Grubbs II catalyst, dry CH2Cl2, reflux, 48 h, 70%, b) DDQ, CH2Cl2/H2O (9:1), 0 °C, 30 min., 78%; (c) Ac2O, DMAP, Et3N, CH2Cl2, 30 min.,
92%; (d) Pd/C, H2, dry EtOAc, 6 h, 82%.
OAc
O
OAc OH
OMe
OBn
OMe
OBn
MeO
BnO
MeO
BnO
a
20
3
OAc OAc
OAc OAc
OMe
OH
OMe
OBn
MeO
HO
MeO
BnO
c
b
2
21
Scheme 5. Reagents and conditions: (a) (R)-CBS, BH3DMS, dry toluene, 0 °C, 30 min, 88%; (b) Ac2O, DMAP, Et3N, CH2Cl2, 30 min., 92%; (c) Pd/C, H2, dry EtOAc, 6 h, 82%.
saturated solution of sodium potassium tartrate (25 mL) was
added, and stirred for 1 h. The aqueous phase was extracted with
CH2Cl2 and the combined organic extracts were dried over anhy-
drous Na2SO4, concentrated, and purified by column chromatogra-
phy (eluent: PE–EtOAc, 6:4) on silica gel to afford the desired
allylic alcohol 9 (2.87 g, 82%) as a white solid. mp = 48–49 °C; IR
(KBr): 3323, 2918, 2849, 1590, 1513, 1458, 1384, 1259, 1223,
quenched with 0.5 mL of water, and stirred for 1 h at room temper-
ature. After that 30% aqueous NaOH solution saturated with NaCl
(2 mL) was then added and the reaction mixture was stirred vigor-
ously for another 0.5 h at room temperature. The resulting mixture
was then filtered through Celite rinsing with CH2Cl2. The organic
phase was separated and the aqueous phase was extracted with
CH2Cl2. The combined organic phases were washed with brine
and dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure and purified by silica gel column chromatogra-
phy (eluent: PE–EtOAc, 5:5) to afford 10 (2.65 g, 90%) as a white so-
1134, 1085, 1003 cmꢁ1 1H NMR: (CDCl3, 300 MHz): d 7.44–7.22
;
(m, 5H), 6.74 (d, 1H, J = 8.3 Hz), 6.66 (d, 1H, J = 2.2 Hz), 6.59 (dd,
1H, J = 1.5, 7.5 Hz), 5.74–5.52 (m, 2H), 5.07 (s, 2H), 4.03 (d, 2H,
J = 4.5 Hz), 3.86 (s, 3H), 2.62 (t, 2H, J = 8.3 Hz), 2.37–2.28 (m, 2H);
ESI-MS: 321 [M+Na]+.
lid. mp = 51 °C; ½a D25
ꢀ
¼ ꢁ23:0 (c 1, CHCl3); IR (KBr): 3374, 2933,
2857, 1590, 1514, 1457, 1262, 1137, 1022 cmꢁ1
;
1H NMR (CDCl3,
300 MHz): d 7.42–7.22 (m, 5H), 6.74 (d, 1H, J = 7.9 Hz), 6.68 (d,
1H, J = 1.1, 8.1 Hz), 6.61 (d, 1H, J = 1.5 Hz), 5.08 (s, 2H), 3.86 (s,
3H), 3.81–3.74 (m, 1H), 3.54–3.46 (m, 1H), 2.95–2.89 (m, 1H),
2.79–2.75 (m, 1H), 2.74–2.57 (m, 2H), 1.88–1.78 (m, 2H); 13C
NMR (CDCl3, 75 MHz): 149.5, 146.4, 137.2, 134.2, 128.3, 127.6,
127.1, 120.1, 114.2, 112.2, 71.1, 61.5, 58.5, 55.9, 55.2, 33.4, 31.7;
ESI-MS: 337 [M+Na]+; HRMS calcd for C19H22O4Na: 337.1415;
found: 337.1406.
4.1.3. (2S,3S)-3-[4-(Benzyloxy)-3-methoxyphenethyl]oxiran-2-
ylmethanol 10
In a 100 mL two-necked round-bottom flask, 15 mL of anhy-
drous CH2Cl2 was added to 4 Å powdered activated molecular
sieves and the suspension mixture was cooled to ꢁ20 °C, Ti(OiPr)4
(0.6 mL, 1.87 mmol) and L-(+) DIPT (0.44 g, 1.87 mmol) in anhy-
drous CH2Cl2 (8 mL) were subsequently added with stirring and
the resulting mixture was stirred for 0.5 h at ꢁ24 °C. Compound
9 (2.8 g, 9.39 mmol) in anhydrous CH2Cl2 (20 mL) was then added
and the resulting mixture was stirred for another 0.5 h at ꢁ24 °C
followed by the addition of TBHP (5 M solution in CH2Cl2, 2.4 mL,
12.2 mmol) was added and the resulting mixture was stirred at
the same temperature for 3 h. It was then warmed to 0 °C,
4.1.4. (3S)-5-[4-(Benzyloxy)-3-methoxyphenyl]pentane-1,3-diol
11
A solution of compound 10 (2.6 g, 8.28 mmol) in anhydrous THF
(30 mL) was cooled to 0 °C and Red-Al (3.9 mL, 3.2 M solution in
toluene, 12.42 mmol) was added to it over a period of 1 h. The

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 1729–1735
1733
mixture was quenched with NH4Cl. The organic layer was washed
with brine, dried over anhydrous Na2SO4, and purified by column
chromatography (eluent: PE–EtOAc, 4:6) to give the required diol
(25 mL).The mixture was stirred at room temperature for 10 h
and then filtered through a Celite pad and washed with Et2O
(2 ꢂ 30 mL).The combined organic filtrates were washed with
H2O (3 ꢂ 5 mL) and brine (2 ꢂ 5 mL), dried over anhydrous Na2SO4
(2 g), and concentrated in vacuo. The unstable crude aldehyde 14
was used for the next reaction.
11 (2.40 g, 92%) as a white solid. mp = 48–50 °C; ½a D25
¼ ꢁ9:0 (c 1,
ꢀ
CHCl3); IR (KBr): 3360, 2936, 1590, 1514, 1457, 1262, 1140,
1030 cmꢁ1 1H NMR (CDCl3, 500 MHz): d 7.39 (d, 2H, J = 6.6 Hz),
;
7.31 (t, 2H, J = 6.6 Hz), 7.27–7.22 (m, 1H), 6.75–6.68 (m, 2H), 6.60
(d, 1H, J = 8.5 Hz), 5.05 (s, 2H), 3.86–3.78 (m, 2H), 3.83 (s, 3H),
3.76–3.71 (m, 1H), 2.71–2.63 (m, 1H), 2.61–2.52 (m, 1H,), 1.79–
1.62 (m, 4H); 13C NMR (CDCl3, 75 MHz): 149.4, 146.2, 137.2,
135.1, 128.4, 127.6, 127.2, 120.1, 114.2, 112.2, 71.2, 71.1, 61.4,
55.9, 39.3, 38.2, 31.4; ESI-MS: 339 [M+Na]+; HRMS calcd for
To a solution of the above aldehyde 14 in THF (20 mL) was
added dropwise vinylmagnesium bromide (5.4 mL, 1 M in THF,
5.4 mmol) at 0 °C. The mixture was stirred at room temperature
for 2 h. Then saturated NH4Cl solution was added and the mixture
extracted with Et2O (50 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (eluent: PE–
EtOAc, 7.5:2.5) to afford 15 (1.43 g, 71% over two steps) as a pale
yellow liquid.
C19H24O4Na: 339.1572; found: 339.1578.
4.1.5. (4S)-4-[4-(Benzyloxy)-3-methoxyphenethyl]-2-(4-meth-
oxyphenyl)-1,3-dioxane 12
To an ice-cold solution of 2-iodoxybenzoic acid (1.27 g,
4.54 mmol) in anhydrous DMSO (2.1 mL, 30.30 mmol) was added
a solution of vinyl alcohol 15 (1.4 g, 3.03 mmol) in anhydrous
CH2Cl2 (20 mL).The mixture was stirred at room temperature for
12 h and then filtered through a Celite pad and washed with
Et2O (40 mL).The combined organic filtrates were washed with
H2O (2 ꢂ 5 mL) and brine (2 ꢂ 5 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo. The crude keto product was purified by
column chromatography on silica gel (eluent: PE–EtOAc, 8:2) to af-
A solution of diol compound 11 (2.35 g, 7.43 mmol) in anhy-
drous CH2Cl2 (30 mL) was cooled to 0 °C and a catalytic amount
of p-TsOH followed by PMB acetal (1.5 mL, 8.9 mmol) was added
to it and stirred for 1 h. The mixture was quenched with sodium
bicarbonate. The organic layer was washed with brine, dried over
anhydrous Na2SO4, and purified by column chromatography (elu-
ent: PE–EtOAc, 8:2) to give the required alcohol 12 (2.73 g, 85%)
as a white solid. mp = 56 °C; ½a D25
ꢀ
¼ ꢁ38:0 (c 1, CHCl3); IR (KBr):
1H
7.42–7.22 (m, 7H), 6.84 (d, 2H,
2927, 2859, 1613, 1515, 1459, 1372, 1252, 1134, 1030 cmꢁ1
;
ford 4 (1.08 g, 78%) as a gummy liquid. ½a D25
¼ þ8:6 (c 0.75, CHCl3);
ꢀ
NMR (CDCl3, 300 MHz):
d
IR (Neat): 2928, 2860, 1678, 1611, 1512, 1458, 1251, 1144,
J = 8.8 Hz), 6.74 (d, 1H, J = 8.1 Hz), 6.69 (d, 1H, J = 1.7 Hz), 6.61
(dd, 1H, J = 1.7, 8.1 Hz), 5.38 (s, 1H), 5.08 (s, 2H), 4.21 (dd, 1H,
J = 4.1, 10.9 Hz), 3.92–3.82 (m, 2H), 3.84 (s, 3H), 3.79 (s, 3H),
2.79–2.60 (m, 2H), 2.01–1.70 (m, 4H,); 13C NMR (CDCl3, 75 MHz):
159.8, 149.5, 146.3, 137.3, 135.1, 131.4, 128.4, 127.6, 127.2,
120.2, 114.2, 113.5, 112.4, 100.9, 76.0, 71.2, 66.9, 55.9, 55.2, 37.5,
31.2, 30.7; ESI-MS: 457 [M+Na]+; HRMS calcd for C27H31O5:
435.2171; found: 435.2152.
1031 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 7.39 (d, 2H, J = 7.6 Hz),
;
7.32 (t, 2H, J = 6.6 Hz), 7.25 (t, 1H, J = 7.6 Hz), 7.17 (d, 2H,
J = 7.6 Hz), 6.80 (d, 2H, J = 8.5 Hz), 6.72 (d, 1H, J = 8.5 Hz), 6.65–
6.64 (m, 1H), 6.57 (d, 1H, J = 8.5 Hz), 6.33 (dd, 1H, J = 10.5,
18.1 Hz), 6.18 (d, 1H, J = 18.1 Hz), 5.79 (d, 1H, J = 10.5 Hz), 5.07 (s,
2H), 4.40 (ABq, 2H, J = 11.4, 26.7 Hz), 3.96–3.91 (m, 1H), 3.84 (s,
3H), 3.78 (s, 3H), 2.92 (dd, 1H, J = 5.7, 15.2 Hz), 2.69–2.52 (m,
3H), 1.83–1.77 (m, 2H); 13C NMR (CDCl3, 75 MHz): 199.3, 159.1,
149.5, 146.2, 137.3, 136.9, 135.1, 130.4, 129.4, 128.6, 128.4,
127.6, 127.2, 120.1, 114.2, 113.7, 112.2, 74.8, 71.4, 71.1, 55.9,
55.2, 44.5, 36.6, 31.2; ESI-MS: 483 [M+Na]+; HRMS calcd for
4.1.6. (3S)-5-[4-(Benzyloxy)-3-methoxyphenyl]-3-[(4-methoxy-
benzyl)oxy]pentan-1-ol 13
A solution of PMB acetal 12 (2.67 g, 6.15 mmol) in anhydrous
CH2Cl2 (35 mL) was treated with diisobutylaluminum hydride
(5.3 mL, 7.38 mmol) at 0 °C. The mixture was stirred at room tem-
perature for 1 h. After monitoring with TLC, the reaction was
quenched with aq. MeOH (1 mL) at 0 °C. Then the satd soln of so-
dium potassium tartrate (20 mL) was added, and extracted with
CH2Cl2 (3 ꢂ 30 mL). The org. layer was washed with brine
(20 mL) and H2O (20 mL). The combined org. layer was dried over
anhydrous Na2SO4, concentrated under vacuum, and the crude
alcohol was purified by column chromatography on silica gel (elu-
ent: PE–EtOAc, 6.5:3.5) to afford 13 (2.20 g, 83%) as a colorless li-
C29H32O5Na: 483.2147; found: 483.2140.
4.1.8. 1-(Benzyloxy)-2-methoxy-4-vinylbenzene 5
Benzylbromide (0.42 mL, 3.54 mmol) was added to a mixture of
4-hydroxy-3-methoxy benzaldehyde (0.6 g, 3.94 mmol) and potas-
sium carbonate (1.08 g, 7.88 mmol) in acetone (15 mL). The mix-
ture was stirred for 3 h at reflux condition. TLC indicated the
consumption of the starting material. The mixture was filtered
through Celite and the filter cake was washed well with acetone.
The filtrate was concentrated under vacuo. The resulting residue
was redissolved in ethyl acetate, transferred to a separatory funnel,
washed with sodium carbonate (satd), HCl (3 M) and brine, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure. The crude aldehyde was purified by column chromatog-
raphy on silica gel (eluent: PE–EtOAc, 8:2) to afford 17 (0.84 g, 88%)
as a colorless solid.
quid. ½a 2D5
ꢀ
¼ þ14:6 (c 0.75, CHCl3); IR (Neat): 3446, 2937, 2866,
1610, 1512, 1457, 1250, 1140, 1033 cmꢁ1
;
1H NMR (CDCl3,
300 MHz): d 7.42–7.15 (m, 7H), 6.82 (d, 2H, J = 8.6 Hz), 6.74 (d,
1H, J = 8.1 Hz), 6.64 (d, 1H, J = 1.7 Hz), 6.57 (dd, 1H, J = 1.7,
8.1 Hz), 5.08 (s, 2H), 4.44 (ABq, 2H, J = 11.3, 23.9 Hz), 3.85 (s, 3H),
3.78 (s, 3H), 3.76–3.71 (m, 1H), 3.70–3.58 (m, 2H), 2.58 (t, 2H,
J = 7.9 Hz), 1.96–1.66 (m, 4H); 13C NMR (CDCl3, 75 MHz): 159.2,
149.5, 146.3, 137.3, 135.2, 130.2, 129.4, 128.4, 127.7, 127.2,
120.0, 114.2, 113.8, 112.2, 77.4, 71.1, 70.6, 60.6, 55.9, 55.2, 35.7,
35.4, 31.0; ESI-MS: 459 [M+Na]+; HRMS calcd for C27H32O5Na:
459.2147; found: 459.2148.
To a mixture of methyltriphenylphosphonium bromide (2.47 g,
6.60 mmol) in 20 mL of anhydrous THF was added 1.6 M solution
of n-BuLi in hexanes (2.5 mL, 3.96 mmol) at 0 °C. After stirring
for 1 h at 0 °C, a solution of 17 (0.8 g, 3.30 mmol) in 10 mL of anhy-
drous THF was added. After stirring for 3 h at 0 °C, the reaction
mixture was quenched with saturated aqueous NH4Cl, extracted
with ether, washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by Col-
umn Chromatography on silica gel (eluent: PE–EtOAc, 9:1) to
afford the desired product 5 (0.61 g, 78%) as a white solid.
mp = 59–60 °C; IR (KBr): 3063, 3034, 2936, 2873, 1580, 1511,
4.1.7. (5S)-7-[4-(Benzyloxy)-3-methoxyphenyl]-5-[(4-methoxy-
benzyl)oxy]-1-hepten-3-one 4
To an ice-cold solution of 2-iodoxybenzoic acid (2.07 g,
7.4 mmol) in anhydrous DMSO (3.5 mL, 49.3 mmol) was added a
solution of alcohol 13 (2.15 g, 4.93 mmol) in anhydrous CH2Cl2
1458, 1330, 1264, 1139, 1028 cmꢁ1 1H NMR: (CDCl3, 300 MHz):
;

1734
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 1729–1735
d 7.42–7.22 (m, 5H), 6.92 (d, 1H, J = 1.7 Hz), 6.84–6.75 (m, 2H), 6.58
(dd, 1H, J = 10.7, 17.5 Hz), 5.55 (d, 1H, J = 17.5 Hz), 5.13–5.07 (m,
1H), 5.11 (s, 2H), 3.89 (s, 3H); ESI-MS: 263 [M+Na]+.
110.2, 71.1, 70.7, 70.5, 55.9, 55.9, 44.8, 35.7, 31.2, 21.1; ESI-MS:
617 [M+Na]+; HRMS calcd for C37H39O7: 595.2695; found:
595.2713.
4.1.9. (E,5S)-1,7-Di[4-(benzyloxy)-3-methoxyphenyl]-5-[(4-meth-
oxybenzyl)oxy]-1-hepten-3-one 18
4.1.12. (5S)-5-Acetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-3-
heptanone 1
A mixture of compound 4 (1 g, 2.17 mmol), compound 5 (0.52 g,
2.17 mmol), and Grubbs second generation catalyst (10 mol %) in
anhydrous CH2Cl2 (20 mL) was stirred for 48 h at 50 °C. After com-
pletion of the reaction, and concentration of the reaction mixture
under the reduced pressure, the residue was subjected to column
chromatography (eluent: PE–EtOAc, 8:2) to give pure 18 (1.02,
To a stirred solution of 3 (0.15 g, 0.25 mmol) in anhydrous
EtOAc (5 mL) was added a catalytic amount of 10% Palladium ad-
sorbed on carbon and stirred under H2 atmosphere for 6 h. The
reaction mixture was filtered through Celite and the filtrate was
concentrated under reduced pressure. The reaction mixture was
purified by column chromatography (eluent: PE–EtOAc, 7:3) to ob-
70%) as a gummy liquid. ½a D25
ꢀ
¼ þ5:0 (c 1, CHCl3); IR (Neat):
tain 1 (0.08 g, 82%) as a colorless oil. ½a D25
¼ þ5:0 (c 0.5, CHCl3); IR
ꢀ
2923, 2855, 1648, 1594, 1510, 1457, 1258, 1139, 1029 cmꢁ1
;
1H
(Neat): 3433, 2925, 2853, 1722, 1605, 1515, 1458, 1370, 1267,
NMR (CDCl3, 300 MHz): d 7.43–7.26 (m, 16H), 7.17 (d, 2H,
J = 8.3 Hz), 7.01–6.97 (m, 2H), 6.85–6.52 (m, 2H), 5.14 (s, 2H),
5.06 (s, 2H), 4.43 (d, 2H, J = 2.2 Hz), 4.00–3.91 (m, 1H), 3.88 (s,
3H), 3.83 (s, 3H), 3.74 (s, 3H), 2.97 (dd, 1H, J = 6.7, 15.1 Hz), 2.72–
2.54 (m, 3H), 1.89–1.79 (m, 2H); 13C NMR (CDCl3, 75 MHz):
198.7, 159.1, 150.4, 149.7, 149.5, 146.3, 143.1, 137.3, 136.4,
135.2, 130.5, 129.4, 128.6, 128.4, 128.0, 127.6, 127.6, 127.2,
127.1, 124.9, 122.9, 120.1, 114.2, 113.7, 113.3, 112.2, 110.2, 75.4,
71.5, 71.1, 70.8, 55.9, 55.9, 55.2, 45.7, 36.8, 31.2; ESI-MS: 695
[M+Na]+; HRMS calcd for C43H45O7: 673.3165; found: 673.3195.
1153, 1032 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 6.75 (dd, 2H,
;
J = 2.2, 7.5 Hz), 6.62 (d, 2H, J = 2.2 Hz), 6.59 (d, 2H, J = 7.9 Hz)
5.42–5.32 (br s, OH), 5.20–5.13 (m, 1H), 3.87 (s, 3H), 3.84 (s, 3H),
2.79–2.74 (m, 2H), 2.68–2.60 (m, 2H), 2.58–2.44 (m, 4H), 1.97 (s,
3H), 1.87–1.77 (m, 2H); 13C NMR (CDCl3, 75 MHz): 206.9, 170.4,
146.3, 143.9, 143.8, 132.9, 132.7, 120.7, 114.2, 111.0, 110.8, 69.9,
55.8, 55.8, 47.2, 45.0, 35.9, 31.2, 29.2, 21.0; ESI-MS: 439 [M+Na]+;
HRMS calcd for C23H28O7Na: 439.1732; found: 439.1742.
4.1.13. (1S,3R,4E)-1-[4-(Benzyloxy)-3-methoxyphenethyl]-5-[4-
(benzyloxy)-3-methoxyphenyl]-3-hydroxy-4-pentenyl acetate
20
4.1.10. (E,5S)-1,7-Di[4-(benzyloxy)-3-methoxyphenyl]-5-hydr-
oxy-1-hepten-3-one 19
To a stirred solution of (R)-Me-CBS-oxazaborolidine catalyst
(1 M in toluene, 0.12 mL) in anhydrous toluene (3 mL), BH3.DMS
(2 M in THF, 0.35 mL) was added at 0 °C and stirred for 0.5 h. Then
a concentrated solution of keto compound 3 (0.35 g, 0.59 mmol) in
anhydrous toluene (5 mL) was added and the mixture was stirred
for 0.5 h at 0 °C. After monitoring with TLC, the reaction mixture
was quenched with MeOH (1 mL) and followed to warm to room
temperature. The solvent was removed under reduced pressure
and purified by silica gel column chromatography (eluent: PE–
To a solution of 18 (0.95 g, 1.41 mmol) in CH2Cl2/H2O (9:1,
20 mL) was added dichlorodicynoquinone (DDQ) (0.38 g,
1.69 mmol) at 0 °C. The solution was stirred for 0.5 h. After the
reaction was complete, the solution was filtered through a pad of
Celite. The Celite pad was washed with CH2Cl2 (50 mL). The com-
bined filtrate was concentrated and purified by column chroma-
tography (eluent: PE–EtOAc, 7:3) to provide 19 as a pale yellow
solid (0.6 g, 78%). mp = 107 °C; ½a D25
¼ þ78:0 (c 0.25, CHCl3); IR
ꢀ
(KBr): 3482, 3033, 2927, 1624, 1592, 1458, 1262, 1139,
EtOAc, 7:3) to afford 20 (0.3 g, 88%) as
¼ þ4:5 (c 1, CHCl3); IR (Neat): 3497, 2924, 2855, 1730,
1589, 1512, 1458, 1376, 1261, 1139, 1026 cmꢁ1 1H NMR (CDCl3,
a viscous liquid.
1028 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): d 7.45–7.26 (m, 11H),
½ ꢀ
a 2D5
7.04–6.99 (m, 2H), 6.83 (d, 1H, J = 9.0 Hz), 6.76–6.72 (m, 2H),
6.63 (dd, 1H, J = 2.2, 8.3 Hz), 6.52 (d, 1H, J = 15.8 Hz), 5.14 (s, 2H),
5.07 (s, 2H), 4.12–4.01 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 2.83–
2.57 (m, 4H), 1.89–1.61 (m, 2H); 13C NMR (CDCl3, 75 MHz):
200.7, 150.7, 149.7, 149.5, 146.3, 143.7, 137.3, 136.3, 135.2,
128.6, 128.4, 128.0, 127.7, 127.3, 127.2, 127.1, 124.3, 123.0,
120.2, 114.1, 113.3, 112.3, 110.2, 71.1, 70.7, 67.2, 55.9, 55.9, 46.5,
38.3, 31.4; ESI-MS: 575 [M+Na]+; HRMS calcd for C35H36O6Na:
575.2409; found: 575.2428.
;
300 MHz): d 7.42–7.20 (m, 10H), 6.90–6.37 (m, 7H), 6.03–5.85
(m, 1H), 5.56–5.46 (m, 1H), 5.09 (s, 2H), 5.05 (s, 2H) 4.33–4.25
(m, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.61–2.47 (m, 2H), 2.05–1.84
(m, 2H), 1.96 (s, 3H) 1.83–1.65 (m, 2H); 13C NMR (CDCl3,
75 MHz): 171.1, 149.6, 149.5, 148.2, 146.3, 137.3, 136.9, 134.6,
133.0, 129.7, 128.4, 128.4, 127.8, 127.7, 127.2, 125.1, 120.0,
119.7, 114.2, 113.8, 112.2, 109.5, 71.4, 71.1, 70.9, 70.3, 55.9, 39.4,
36.4, 31.4, 31.2, 21.2; ESI-MS: 619 [M+Na]+; HRMS calcd for
C37H40O7Na: 619.2671; found: 619.2656.
4.1.11. (1S,4E)-1-[4-(Benzyloxy)-3-methoxyphenethyl]-5-[4-
(benzyloxy)-3-methoxyphenyl]-3-oxo-4-pentenyl acetate 3
Anhydrous Et3N (0.3 mL, 2 mmol), Ac2O (0.1 g, 1 mmol), and a
catalytic amount of DMAP were added to a solution of 19 (0.55 g,
1 mmol) in CH2Cl2 (12 mL) under nitrogen atmosphere at room
temperature. The mixture was stirred at room temperature for
0.5 h. The solvent was removed under reduced pressure, and the
mixture was purified by silica gel column chromatography (eluent:
PE–EtOAc, 9:1) to afford 3 (0.54 g, 92%) as a yellow viscous liquid.
4.1.14. (1S,3R,4E)-3-(Acetyloxy)-1-[4-(benzyloxy)-3-methoxy
phenethyl]-5-[4-(benzyloxy)-3-methoxyphenyl]-4-pentenyl
acetate 21
Anhydrous Et3N (0.12 mL, 0.84 mmol), Ac2O (0.04 g, 0.42 mmol),
and a catalytic amount of DMAP were added to a solution of 20
(0.25 g, 0.42 mmol) in CH2Cl2 (5 mL) under nitrogen atmosphere at
room temperature. The mixture was stirred at room temperature
for 0.5 h. The solvent was removed under reduced pressure, and
the mixture was purified by silica gel column chromatography
(eluent: PE–EtOAc, 9:1) to afford 21 (0.24 g, 92%) as a colorless li-
½
a 2D5
ꢀ
¼ þ7:2 (c 0.9, CHCl3); IR (Neat): 1736, 1654, 1593, 1512, 1453,
1232, 1140 cmꢁ1; 1H NMR (CDCl3, 500 MHz): d 7.47–7.26 (m, 11H),
7.04–7.00 (m, 2H), 6.83 (d, 1H, J = 8.9 Hz), 6.72 (d, 1H, J = 7.9 Hz),
6.70–6.67 (m, 1H), 6.60 (dd, 1H, J = 1.9, 7.9 Hz), 6.52 (d, 1H,
J = 16.8 Hz), 5.30–5.24 (m, 1H), 5.14 (s, 2H), 5.04 (s, 2H), 3.91 (s,
3H), 3.86 (s, 3H), 2.98 (dd, 1H, J = 5.9, 14.8 Hz), 2.74 (dd, 1H,
J = 6.9, 14.8 Hz), 2.67–2.53 (m, 2H), 2.00 (s, 3H), 1.96–1.90 (m,
2H); 13C NMR (CDCl3, 75 MHz): 196.7, 170.5, 150.5, 149.7, 149.5,
146.3, 143.5, 137.3, 136.3, 134.4, 128.6, 128.4, 128.0, 127.7,
127.4, 127.1, 127.1, 124.2, 122.9, 120.0, 114.2, 113.3,, 112.1,
quid. ½a 2D5
ꢀ
¼ ꢁ14:5 (c 1, CHCl3); IR (Neat): 2923, 2854, 1733, 1510,
1457, 1372, 1233, 1139, 1024 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): d
7.43–7.24 (m, 10H), 6.90–6.66 (m, 5H), 6.58 (dd, 1H, J = 1.5,
8.3 Hz), 6.48 (d, 1H, J = 15.8 Hz), 5.89 (dd, 1H, J = 7.5, 15.8 Hz), 5.39
(q, 1H, J = 6.7, 13.5 Hz), 5.12 (s, 2H), 5.07 (s, 2H), 5.00–4.92 (m,
1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.63–2.48 (m, 2H), 2.08–1.97 (m,
2H), 2.02 (s, 3H), 2.01 (s, 3H), 1.92–1.80 (m, 2H); 13C NMR (CDCl3,
75 MHz): 170.5, 170.0, 149.6, 149.6, 148.2, 146.4, 137.3, 136.9,

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 1729–1735
1735
134.5, 132.8, 129.6, 128.5, 128.4, 127.8, 127.7, 127.2, 127.2, 124.8,
References
120.0, 119.7, 114.3, 113.8, 112.2, 109.6, 71.9, 71.1, 70.9, 70.5, 55.9,
39.0, 36.0, 31.1, 29.6, 21.2, 21.1; ESI-MS: 661 [M+Na]+; HRMS calcd
for C39H42O8Na: 661.2777; found: 661.2763.
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4.1.15. (3S,5S)-3,5-Diacetoxy-1,7-bis(4-hydroxy-3-methoxy-
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To a stirred solution of 21 (0.18 g, 0.28 mmol) in anhydrous
EtOAc (5 mL) was added a catalytic amount of 10% palladium ad-
sorbed on carbon and stirred under H2 atmosphere for 6 h. The
reaction mixture was filtered through Celite and the filtrate was
concentrated under reduced pressure. The reaction mixture was
purified by column chromatography (eluent: PE–EtOAc, 7:3) to ob-
tain 2 (0.1 g, 82%) as a colorless oil. ½a D25
¼ þ8:5 (c 1.25, CHCl3); IR
ꢀ
(Neat): 3440, 2925, 2853, 1730, 1606, 1515, 1431, 1372, 1240,
1153, 1030 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): d 6.76 (d, 2H,
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J = 7.5 Hz), 6.60–6.55 (m, 4H), 5.36–5.32 (br s-OH, 2H), 4.92–4.82
(m, 2H), 3.87 (s, 6H), 2.59–2.40 (m, 4H), 1.98 (s, 6H), 1.95–1.64
(m, 6H); 13C NMR (CDCl3, 75 MHz): 170.6, 146.3, 143.7, 133.0,
120.8, 114.2, 110.9, 70.6, 55.8, 38.4, 35.9, 31.1, 21.1; ESI-MS: 478
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G.C. and K.Y. thank the UGC, New Delhi, for the award of fellow-
ship. Author acknowledges the partial support by King Saud Uni-
versity for Global Research Network for Organic Synthesis
(GRNOS).