Synthesis of gingerol and diarylheptanoids

Article abstract of DOI:10.1016/j.tetasy.2011.11.010

The synthesis of gingerol 1 and related compounds 2-5 along with diarylheptanoids 6-8 has been accomplished using a Keck allylation, Crimmins' aldol reaction, aldehyde coupling with acetylene, and chelation controlled reductions as the key reactions. The absolute configuration of these molecules was confirmed by preparing their acetonide derivatives and by comparison of the NMR data with natural compounds.

Full text of DOI:10.1016/j.tetasy.2011.11.010

Tetrahedron: Asymmetry 22 (2011) 2124–2133
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Tetrahedron: Asymmetry
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Synthesis of gingerol and diarylheptanoids
Gowravaram Sabitha a, , Chitti Srinivas a, Teega Rammohan Reddy a, Kurra Yadagiri a, Jhillu Singh Yadav a,b
⇑
a Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500007, India
b Bee Research Chair, College of Food and Agriculture Science, King Saud University, Riyadh, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of gingerol 1 and related compounds 2–5 along with diarylheptanoids 6–8 has been accom-
plished using a Keck allylation, Crimmins’ aldol reaction, aldehyde coupling with acetylene, and chelation
controlled reductions as the key reactions. The absolute configuration of these molecules was confirmed
by preparing their acetonide derivatives and by comparison of the NMR data with natural compounds.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 7 November 2011
Accepted 21 November 2011
Available online 7 January 2012
1. Introduction
2. Results and discussion
Gingerol 1 (Fig. 1) was initially isolated by Nakatani et al. in
19921 from rhizomes of Zingiber officinale. In 2007 the same com-
pound was isolated by Liang et al.2 from ‘Gui-Zhi’ decoction. The
‘Gui-Zhi’ decoction consists of five traditional Chinese medicines,
which have a long history of usage in traditional medicine in China
to treat colds, coughs, fevers, and asthma for thousands of years.3
Upon the investigation of Gui-Zhi decoction, several compounds
were isolated2 by chromatography methods. Their structures were
identified as 1, 2, and 3 (Fig. 1) based on their chemical and spec-
troscopic analyses. Compounds 2 and 3 were synthesized from
gingerol 1 and their structures were established based on their ace-
tonide derivatives. Other related compounds 4 and 51 (Fig. 1) were
also isolated along with gingerol.
The synthesis of gingerol 1 and compounds 2–5 started from
hexanal 9. At first, hexanal 9 was treated with an allyltitanium
complex (R,R)-Ti9 to afford the corresponding allylic alcohol 10
with good enantiomeric excess (ee >95%) (Scheme 1). After protec-
tion of 10 as a TBS ether, compound 11 was isolated in a 95% yield.
The oxidative cleavage of the terminal olefin in 11 produced the
corresponding aldehyde 12 in an 86% yield over two steps.
The desired alkynes 15a and 15b10 were prepared from 13a and
13b via dibromoolefins 14a and 14b as shown in Scheme 2. The
dibromoolefins 14a and 14b were prepared from the correspond-
ing aldehydes 13a and 13b following the Corey–Fuchs protocol.11
Aldehyde 12 and alkyne 15b were used for the synthesis of
gingerol 1 and its related compounds 2–5.
Compounds similar to gingerol having an aliphatic C7 chain
with aromatic substituents, often phenols, at the termini are called
diarylheptanoids. Such compounds are common in the ginger fam-
ily, Zingiberaceae, which has a history of medicinal use in the sys-
tems of traditional medicine as anti-inflammatory, antitumor,
and chemopreventive,4 bactereostatic,5 and nematocidal6 agents.
Recently, a new diarylheptanoid 67 (Fig. 1) has been isolated from
the rhizomes of Zingiber mekongense. The structure elucidation was
mainly based on spectroscopic analysis and the stereochemistry
was proved through chemical conversion. Compound 6 exhibited
anti HIV-1 activity. Two other diarylheptanoids 7 and 8 were iso-
lated from Z. officinale.8 Based on their important biological activi-
ties and our continuing interest in the total synthesis of naturally
isolated compounds, we herein report the synthesis of gingerol 1
and its related compounds 2–5 along with three other diarylhepta-
noids 6–8.
Alkenylation of compound 12 with substituted phenyl acety-
lene 15b and n-BuLi in THF at ꢀ78 °C to room temperature gave
a diastereomeric mixture, which without separation was converted
into a keto compound using IBX in DMSO to give keto compound
16 in a 94% yield. Under hydrogenation of compound 16 using
Pd(OH)2 in benzene, the triple bond was reduced in addition to
deprotection of the benzyl group in one-pot to give compound
17. Finally, the deprotection of TBS group using TBAF in THF affor-
ded gingerol 1 in an 87% yield. The physical and spectral data of 1
were in full agreement with the natural compound.
Next, the two natural syn and anti 1,3-diols 2 and 3 were
prepared from gingerol 1 by stereoselective reduction of keto
group. Thus, treatment of gingerol 1 with diethylmethoxyborane12
afforded syn diol 2 in an 80% yield (95:5 dr). To confirm the stere-
oselectivity, 2 was converted into an acetonide 18 by treating with
2,2-DMP in CH2Cl2 in the presence of a catalytic amount of pTSA.
Similarly gingerol 1 was converted into anti diol 3 by the treatment
with tetramethylammonium triacetoxyborohydride13 in CH3CN:
AcOH (1:1) at ꢀ40 °C in an 85% yield (96:4 dr). To confirm its
stereoselectivity it was also converted into acetonide 19. The
⇑
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.2011.11.010

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2124–2133
2125
O
OH
OH
OH
MeO
HO
MeO
HO
2
6-gingerol 1
OH
OH
OAc OAc
MeO
HO
MeO
HO
3
4
OAc OAc
OAc OAc
MeO
MeO
OMe
OMe
MeO
MeO
6
5
7
OMe
OMe
OH
OH
OH
OH
MeO
HO
OMe
OH
MeO
HO
OMe
OH
8
Figure 1. Gingerol and diaryl heptanoids.
OP
OTBS
a
c
CHO
O
9
10 P = H
b
12
11 P = TBS
Scheme 1. Reagents and conditions: (a) (R) BINAL, allyltributyltin, Ti(OiPr)4, dry CH2Cl2, ꢀ78 °C to ꢀ20 °C, 72 h, 80%, (95 ee%); (b) TBSCl, imidazole, dry CH2Cl2, 0 °C-rt, 2 h,
95%; (c) (i) OsO4, NMO acetone:H2O (4:1) overnight. (ii) NaIO4 THF:H2O (4:1) 0 °C, 1 h, 86% for two steps.
preparation of 2 and 3 and study of their derivatives (18 and 19)
spectral data1 allow us to reconfirm their structures. Therefore
the configuration of syn and anti 1,3 diols 2 and 3 confirmed by
preparing the respective acetonides 18 and 19 and their 13C NMR
studies by using Rychnovsky’s method.14
The aldehydes 30a and 30b required for the synthesis of diaryl-
heptanoids 6–8 were obtained from 13a and 13b. The aldehydes
13a and 13b were subjected to 2C-Wittig homologation with (car-
boethoxymethylene)triphenylphosphorane in benzene at reflux to
afford the a,b-unsaturated esters 25a and 25b. Esters 25a and 25b
Two diacetate derivatives 4 and 5 isolated from the same plant
were prepared from 18 as shown in Scheme 4. Accordingly, pheno-
lic OH group was protected as benzyl ether 20 followed by the
hydrolysis of acetonide group provided diol compound 21. The diol
was converted into diacetate 22 using acetic anhydride, triethyl-
amine in the presence of DMAP in CH2Cl2. Removal of benzyl group
furnished the natural product 4 in a 94% yield. Similarly natural
diacetate derivative 5 was obtained from 18. Thus treatment of
18 with MeI in the presence of NaH afforded compound 23, which
on deprotection of acetonide group produced diol 24. The diol 24
was converted into diacetate 5 using acetic anhydride, triethyl-
amine in the presence of DMAP in dry CH2Cl2 in a 93% yield. Spec-
tral data of 4 and 5 matched with the natural products.1
were reduced by using LiAlH4 in THF to give the saturated alcohols
26a and 26b. Oxidation of compounds 26a and 26b using IBX in
DMSO/CH2Cl2 gave aldehydes 27a and 27b.
Aldehyde 27a was subjected to a Crimmins aldol15 reaction
with chiral (S)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethanone16
in the presence of TiCl4 and N,N-diisopropylethylamine (DIPEA)
in dry CH2Cl2 to give a b-hydroxy amide 28a (85:15 dr). The hydro-
xy group in compound 28a was protected as its corresponding TBS
ether 29a in a 93% yield by using t-butyldimethylsilyltrifluorome-
thane sulfonate and 2,6-lutidine in dry CH2Cl2. Amide 29a was
treated with DIBAL-H to give the aldehyde 30a. Similarly, the alde-
hyde 30b was prepared from aldehyde 13b (Scheme 5), during
Br
Br
MeO
b
CHO
MeO
RO
MeO
RO
a
RO
R1
R1
R1
13a R = Me, R1 = OMe
13b R = Bn, R1 = H
15a R = Me, R1 = OMe, 92%
15b R = Bn, R1 = H, 91%
14a R = Me, R1 = OMe, 91%
14b R = Bn, R1 = H, 90%
Scheme 2. Reagents and conditions: (a) PPh3, CBr4, dry CH2Cl2, 0.5 h, 0 °C-rt; (b) EtMgBr, dry THF, 0 °C-rt, 1 h.

2126
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2124–2133
O
OTBS
C5H11
O
OTBS
C5H11
MeO
BnO
MeO
HO
b
a
c
15b + 12
1
16
17
O
O
OH
OH
OH
MeO
HO
MeO
d
C5H11
C5H11
f
95%
18
Br
2
1
O
O
OH
MeO
HO
MeO
HO
C5H11
f
C5H11
e
94%
19
3
Scheme 3. Reagents and conditions: (a) (i) n-BuLi, dry THF,-78 °C-rt, 5 h, 86%, (ii) IBX, DMSO, dry CH2Cl2, 0 °C-rt, 2 h, 94%; (b) Pd(OH)2, H2, benzene, 5 h, 93%; (c) TBAF, dry
THF, 0 °C-rt, 6 h, 87%; (d) Et2BOMe, NaBH4, anhydrous THF–MeOH (1:4), ꢀ78 °C, 8 h, 80%; (e) Me4NBH(OAc)3, CH3CN/AcOH (1:1), ꢀ40 °C, 4 h, 85%; (f) 2, 2 DMP, pTSA, Dry
CH2Cl2, 0 °C-rt, 2 h.
O
O
O
OP
OP
MeO
BnO
MeO
BnO
a
c
e
C5H11
C5H11
4
20
90%
21 P = H
22 P = Ac, 94%
d
18
OH OH
C5H11
24
O
c
MeO
MeO
d
MeO
MeO
C5H11
5
b
23
89%
93%
Scheme 4. Reagents and conditions: (a) NaH, BnBr, THF, 0 °C-rt, 4 h, 95%; (b) NaH, MeI, THF, 0 °C-rt, 4 h, 94%; (c) pTSA, MeOH, 0 °C-rt, 1 h; (d) Ac2O, TEA, DMAP, dry CH2Cl2,
0 °C-rt, 0.5 h; (e) Pd(OH)2, H2, Benzene, 4 h, 93%.
which the alcohol within compound 28b (85:15 dr) was protected
as corresponding MOM ether 29b.
78% yield (95:5 dr). Similarly, treatment of 33b with tetramethyl-
ammonium triacetoxyborohydride13 in CH3CN:AcOH (1:1) at
ꢀ40 °C gave anti-diol 8 in an 84% yield (96:4 dr).
Similarly, aldehydes 30a and 30b and alkynes 15a and 15b were
coupled (as shown in Scheme 3) for the synthesis of diarylhepta-
noids 6–8 (Scheme 6). Alkenylation of compounds 30a and 30b
with substituted phenyl acetylenes 15a and 15b and n-BuLi in
THF at ꢀ78 °C to room temperature gave a diastereomeric mixture,
which without separation was converted into a keto compound
using IBX in DMSO to give compounds 31a and 31b. Under the
hydrogenation of compound 31a and 31b using Pd(OH)2 in ben-
zene, the triple bond was reduced in addition to the deprotection
of the benzyl group occurring in one-pot. The deprotection of
TBS group in 32a using TBAF in THF afforded compound 33a in
an 86% yield. The deprotection of the MOM group in 32b using
pTSA in MeOH afforded 33b in an 80% yield.
3. Conclusion
In conclusion, gingerol and its derivatives and three other
diarylheptanoids were synthesized using a Keck allylation, Crim-
mins aldol, aldehyde coupling with acetylene, and chelation con-
trolled reductions as the key reactions.
4. Experimental
4.1. General
Next, the natural anti-1,3-diol 6 was prepared from 33a via ster-
eoselective reduction of the keto group. Thus, treatment of 33a
with tetramethylammonium triacetoxyborohydride13 in CH3CN:A-
cOH (1:1) at ꢀ40 °C afforded anti-1,3-diol 34 in an 85% yield (96:4
dr). Diol 34 was converted into diacetate 6 using acetic anhydride,
and triethylamine in the presence of DMAP in CH2Cl2 to furnish the
natural product 6 in a 93% yield. Similarly, the two natural syn- and
anti-1,3-diols 7 and 8 were prepared from 33b by stereoselective
reduction of the keto group. Thus, treatment of 33b with diet-
hylmethoxyborane12 in THF:MeOH (1:4) at ꢀ78 °C gave 7 in a
Reactions were conducted under N2 in anhydrous solvents such
as CH2Cl2, THF, benzene, toluene, DMSO, and MeOH. All reactions
were monitored by TLC (silica-coated plates and visualized under
UV light). Light petroleum ether (bp 60–80 °C) was used. Yields re-
fer to chromatographically 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

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2124–2133
2127
O
MeO
RO
MeO
RO
MeO
RO
OEt
OH
a
c
b
O
R1
R1
R1
25a R = Me, R1 = OMe, 90%
25b R = Bn, R1 = H, 91%
13a R = Me, R1 = OMe
13b R = Bn, R1 = H
26a R = Me, R1 = OMe, 87%
26b R = Bn, R1 = H, 88%
S
O
OP
OP
MeO
OMe
OR
OMe
OR
O
g
S
N
d
O
RO
R1
R1
R1
Ph
30a R = Me, R1 = OMe, P = TBS, 85%
30b R = Bn, R1 = H, P = MOM, 86%
28a R = Me, R1 = OMe, P = H, 79%
29a R = Me, R1 = OMe, P = TBS
27a R = Me, R1 = OMe, 87%
27b R = Bn, R1 = H, 86%
e
28b R = Bn, R1 = H, P = H, 80%
29b R = Bn, R1 = H, P = MOM
f
Scheme 5. Reagents and conditions: (a) Ph3P@CHCO2Et, benzene, reflux, 4 h; (b) LAH, dry THF, reflux, 4 h; (c) IBX, DMSO, dry CH2Cl2, 0 °C-rt, 2 h; (d) (S)-1-(4-benzyl-2-
thioxothiazolidin-3-yl)ethanone, TiCl4, i-Pr2NEt, dry CH2Cl2, ꢀ78 °C, 1 h; (e) TBSOTf, 2,6-lutidine, dry CH2Cl2, 0 °C to rt, 2 h, 93%; (f) MOMCl, i-Pr2NEt, dry CH2Cl2, 0 °C to rt, 4 h,
80%; (g) DIBAL-H, dry CH2Cl2, ꢀ78 °C, 0.5 h.
O
OP
OMe
OR
O
OP
30a-b
MeO
RO
OMe
OR
MeO
RO
a
b
+
R1
15a-b
R1
32a R = Me, R1 = OMe, P = TBS, 92%
33a
R1
R1
R = Me, R1 = OMe, P = TBS, 86%
31a
31b
c
1
R = Me, R1 = OMe, P = H
R = Bn, R = H, P = MOM, 87%
32b R = H, R1 = H, P = MOM, 93%
33b R = H, R1 = H, P = H
d
OH
OH
OAc OAc
OMe
MeO
MeO
MeO
OMe
OMe
e
f
33a
85%
OMe
MeO
34
6
OMe
OMe
OH
OMe
OMe
OH
OH
OH
OMe
OH
OMe
MeO
HO
MeO
HO
g
e
33b
84%
OH
7
8
Scheme 6. Reagents and conditions: (a) (i) n-BuLi, dry THF, ꢀ78 °C-rt, 5 h; (ii) IBX, DMSO, dry DCM, 0 °C-rt, 2 h; (b) Pd(OH)2, H2, Benzene, 5 h; (c) TBAF, dry THF, 0 °C-rt, 6 h;
86%; (d) pTSA, MeOH, 0 °C-rt, 6 h; 80%; (e) Me4NBH(OAc)3, CH3CN/AcOH (1:1), ꢀ40 °C, 4 h; (f) Ac2O, TEA, DMAP, Dry DCM, 0 °C-rt, 0.5 h; 93%; (g) Et2BOMe, NaBH4, dry THF–
MeOH (1:4), ꢀ78 °C, 8 h, 78%.
FT-200 MHz (Gemini) and Bruker UXNMR FT-300 MHz (Avance)
spectrometers. Chemical shifts (d) are reported relative to TMS
(d = 0.0) as an internal standard. Mass spectra were recorded under
E1 conditions at 70 eV on an LC–MSD (Agilent technologies) spec-
trometers. All high resolution spectra were recorded on QSTAR XL
hybrid ms/ms system (Applied Bio systems/MDS sciex, foster city,
USA), equipped with an ESI source (IICT, Hyderabad). Column chro-
matography was performed on silica gel (60–120 mesh) supplied
by Acme Chemical Co., India. TLC was performed on Merck 60
F-254 silica gel plates. Optical rotations were measured with JASCO
DIP-370 Polarimeter at 25 °C.
4.1.1. (S)-Non-1-en-4-ol 10
A mixture of (R,R)-BINOL (0.457 g, 1.59 mmol) and Ti(OiPr)4
(2.83 mL, 9.59 mmol) in dry CH2Cl2 (20 mL) in the presence of
4 Å molecular sieves was stirred at reflux. After 1 h, the reaction

2128
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2124–2133
mixture was cooled to room temperature and then aldehyde 9
(0.80 g, 7.99 mmol) in dry CH2Cl2 (10 mL) was added and stirred
for a further 10 min. The reaction mixture was then cooled to
ꢀ78 °C and allyl tri-n-butyltin (0.25 mL, 7.99 mmol) was added.
After 10 min, this mixture was placed in a refrigerator at ꢀ20 °C
for 70 h. After completion of the reaction, it was quenched by add-
ing a saturated solution of NaHCO3 and the product was extracted
with CH2Cl2. The organic phase was washed with water, brine, and
dried over anhydrous Na2SO4; the solvent was removed in vacuo.
The residue was purified by silica gel column chromatography
(EtOAc/pet-ether, 1:9) to afford the pure compound 10 (0.90 g,
uct was purified by silica gel column chromatography (EtOAc/pet-
ether, 1:9) to afford the alcohol as a diastereomeric mixture
(1.79 g, 86%). The obtained alcohol (1.6 g, 3.22 mmol) in dry CH2Cl2
(20 mL) was added dropwise at 0 °C to an ice-cooled solution of 2-
iodoxybenzoic acid (1.17 g, 4.187 mmol) in DMSO (1.372 mL,
19.37 mmol). The mixture was stirred at room temperature for
2 h and then filtered through a Celite pad and washed with ether.
The combined organic filtrates were washed with water and brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The
crude product was purified by column chromatography (EtOAc/
pet-ether, 1:19) to afford keto 16 (1.49 g, 94%) as a viscous liquid.
80%) as a viscous liquid. ½a D25
ꢁ
¼ ꢀ10:7 (c 2, CHCl3); IR (neat): mmax
½
a 2D5
ꢁ
¼ ꢀ12:7 (c 1, CHCl3); IR (neat): mmax 3447, 2935, 2859, 2187,
3388, 2957, 2929, 2860, 1640, 1461, 1028, 995, 914 cmꢀ1
;
1H
1664, 1510, 1247, 1130, 1078 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
;
NMR (CDCl3, 500 MHz): d 5.84–5.75 (m, 1H), 5.11 (dd, J = 14.7,
2.9 Hz, 2H), 3.64–3.56 (m, 1H), 2.31–2.23 (m, 1H), 2.15–2.07 (m,
1H), 1.47–1.24 (m, 8H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 134.8, 117.9, 70.7, 41.9, 36.7, 31.8, 25.3, 22.6, 14.0.
7.41–7.28 (m, 5H), 7.10 (dd, J = 8.3, 1.5 Hz, 1H), 7.03 (d, J = 1.5 Hz,
1H), 6.82 (d, J = 8.3 Hz, 1H), 5.15 (s, 2H), 4.32–4.24 (m, 1H), 3.89
(s, 3H), 2.80 (dd, J = 15.1, 6.8 Hz, 1H), 2.68 (dd, J = 15.1, 5.3 Hz,
1H), 1.56–1.46 (m, 2H), 1.38–1.24 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H),
0.87 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (CDCl3, 75 MHz):
d 186.4, 150.7, 149.3, 136.2, 128.6, 128.1, 127.2, 115.8, 113.2,
112.1, 91.9, 88.2, 70.8, 69.2, 56.0, 53.2, 37.6, 31.8, 25.8, 24.6,
22.6, 18.0, 14.0, ꢀ4.5, ꢀ4.7; ESI: m/z = 495 [M+H]+. HRMS (ESI):
[M+Na]+ m/z calcd for C30H42O4Si: 517.2750, found: 517.2740.
4.1.2. (S)-tert-Butyldimethyl(non-1-en-4-yloxy)silane 11
To a stirred solution of alcohol 10 (0.8 g, 5.62 mmol) in dry
CH2Cl2 (20 mL) was added imidazole (1.148 g, 16.87 mmol), fal-
lowed by TBDMS-Cl (0.93 g, 6.18 mmol) at 0 °C. The reaction mix-
ture was stirred at the same temperature for 2 h. The reaction
mixture was quenched with a saturated solution of NH4Cl and ex-
tracted with CH2Cl2. The extract was washed with water and brine,
dried over anhydrous Na2SO4, solvent was removed in vaccuo. The
residue was purified by silica gel column chromatography (EtOAc/
pet-ether, 1:19) to afford pure compound 11 (1.37 g, 95% yield) as a
colorless liquid.
4.1.5. (S)-5-(tert-Butyldimethylsilyoxy)-1-(4-hydroxy-3-meth
oxyphenyl)decan-3-one 17
To a stirred solution of compound 16 (1.4 g, 2.83 mmol) in ben-
zene (20 mL) was added Pd(OH)2 and stirred under an H2 atmo-
sphere for 5 h at room temperature. After completion of the
reaction, the catalyst was removed by filtration, and the solvent
was removed in vacuo. The residue was purified by silica gel column
chromatography (EtOAc/pet-ether, 1:9) to afford the pure com-
½
a 2D5
ꢁ
¼ ꢀ15:7 (c 2, CHCl3); IR (neat):
mmax 3451, 2931, 2859, 1641,
1465, 1252, 1056, 834 cmꢀ1; 1H NMR (CDCl3, 500 MHz): d 5.83–5.73
(m, 1H), 5.01 (dd, J = 15.7, 4.9 Hz, 2H), 3.70–3.64 (m, 1H), 2.23–2.15
(m, 2H), 1.46–1.22 (m, 8H), 0.88–0.92 (m, 12H) 0.05 (s, 3H) 0.04
(s, 3H); 13C NMR (CDCl3, 50 MHz): d 135.5, 116.5, 72.1, 41.9, 36.8,
32.0, 25.9, 25.0, 22.6, 18.2, 14.0, ꢀ4.4, ꢀ4.5; ESI: m/z = 279 [M+Na]+.
pound 17 (1.075 g, 93%) as a viscous liquid. ½a D25
¼ þ13:5 (c 2,
ꢁ
CHCl3); IR (neat): mmax 3447, 2931, 2857, 1711, 1515, 1261,
834 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 6.76 (d, J = 7.9 Hz, 1H),
;
6.63 (d, J = 2.4 Hz, 1H), 6.61 (dd, J = 8.1, 2.4 Hz, 1H), 5.32 (s, 1H),
4.17–4.06 (m, 1H), 3.87 (s, 3H), 2.85–2.65 (m, 4H), 2.53 (dd,
J = 15.1, 7.2 Hz, 1H), 2.36 (dd, J = 15.1, 4.9 Hz, 1H), 1.45–1.21 (m,
8H), 0.90 (t, J = 6.2 Hz, 3H), 0.86 (s, 9H), 0.05 (s, 3H), ꢀ0.01 (s, 3H);
13C NMR (CDCl3, 75 MHz): d 209.3, 146.3, 143.8, 133.0, 120.7,
114.3, 110.9, 69.2, 55.8, 50.2, 46.6, 37.7, 31.8, 29.1, 25.8, 24.6, 22.6,
18.0, 14.0, ꢀ4.6, ꢀ4.7; ESI: m/z = 409 [M+H]+. HRMS (ESI): [M+Na]+
m/z calcd for C23H40O4NaSi: 431.2593, found: 431.2601.
4.1.3. (S)-3-(tert-Butyldimethylsilyloxy)octanal 12
To a solution of 11 (1.3 g, 5.07 mmol) in acetone:water (10 mL,
4:1) was added OsO4 (0.0196 M) in toluene (2.58 mL, 0.05 mmol),
and NMO (0.77 g, 6.59 mmol) was added and the mixture was stir-
red at rt overnight. The reaction mixture was quenched with a sat-
urated solution of Na2SO3, then extracted with ethylacetate. The
combined organic layers were washed with brine, dried over anhy-
drous Na2SO4 and concentrated under reduced pressure to obtain a
residue, which was used directly for the next reaction.
4.1.6. (S)-5-Hydroxy-1-(4-hydroxy-3-methoyphenyl)decane-3-
one 1
To a solution of the above obtained diol THF:H2O (10 mL, 4:1)
was added NaIO4 (1.54 g, 7.22 mmol) and stirred for 1 h. After
completion of the reaction, the mixture was filtered through a Cel-
ite pad and washed with ethyl acetate. The filtrate was dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (EtOAc/
pet-ether, 1:9) to afford compound 12 (1.12 g, 86% for two steps) as
a brown liquid. The unstable aldehyde was used immediately for
the next reaction.
To a solution of 17 (1.04 g, 2.54 mmol) in THF (20 mL) was
added TBAF (3.82 ml, 3.82 mmol, a 1 M solution in THF) at 0 °C.
The reaction mixture was stirred for 6 h and then diluted with
water and extracted with EtOAc. The organic layer was washed
with water, brine, dried over anhydrous Na2SO4, and the solvent
was removed in vacuo. The residue was purified by silica gel col-
umn chromatography (EtOAc/pet-ether, 2:8) to afford pure com-
pound 1 (0.651 g, 87%) as a viscous liquid. ½a D25
¼ þ22:7 (c 2,
ꢁ
CHCl3); IR (neat): mmax 3442, 2929, 2860, 1705, 1515, 1269, 1152,
1033 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 6.77 (d, J = 7.5 Hz, 1H),
;
4.1.4. (S)-1-(4-(Benzyloxy)-3-methoxyphenyl)-5-(tert-butyldi
methylsilyloxy)dec-1-yn-3-one 16
6.63 (d, J = 4.1 Hz, 1H), 6.60 (d, J = 8.8, 1.5 Hz, 1H), 5.33 (s, 1H),
4.01–3.90 (m, 1H), 3.87 (s. 3H), 2.81 (t, J = 6.9 Hz, 2H), 2.69 (t,
J = 6.9 Hz, 2H), 2.55–2.40 (m, 2H), 1.49–1.10 (m, 8H), 0.89 (t,
J = 6.8 Hz, 3H); 13C NMR (CDCl3, 50 MHz): d 211.4, 146.5, 144.1,
132.7, 120.7, 114.4, 110.9, 67.6, 55.8, 49.3, 45.3, 36.4, 31.7, 29.2,
25.1, 22.5, 14.0; ESI: m/z = 317 [M+Na]+. HRMS (ESI): [M+Na]+ m/
z calcd for C17H26O4Na: 317.1728, found: 317.1738.
To a stirred solution of alkyne 15b (1.0 g, 4.19 mmol) in dry THF
(10 mL) was slowly added n-BuLi (2.5 M solution) in hexanes
(3.93 mL, 6.29 mmol) at ꢀ78 °C under N2. The reaction mixture
was stirred for 30 min at ꢀ78 °C, and a solution of compound 12
(1.08 g, 4.19 mmol) in dry THF (15 mL) was added dropwise with
stirring. The mixture was kept at ꢀ78 °C for 2 h and then allowed
to warm to rt for 2 h. The reaction was quenched with a saturated
solution of NH4Cl and extracted with EtOAc, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude prod-
4.1.7. (3R,5S)-1-(4-Hydroxy-3-methoxyphenyl)decane-3,5-diol 2
To a solution of hydroxyketone compound 1 (0.5 g, 1.27 mmol)
in anhydrous THF:MeOH (15 mL; 4:1) at ꢀ78 °C under N2 was

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2124–2133
2129
added diethylmethoxyborane (1.52 mL, 1.52 mmol, 1 M in THF),
as a light yellow liquid. ½a D25
ꢁ
¼ þ17:9 (c 1, CHCl3); IR (neat): mmax
and the resulting mixture was stirred for 30 min. Next, solid NaBH4
(0.057 mg, 1.52 mmol) was added in one portion. The mixture was
stirred for 6 h at ꢀ78 °C, and a mixture of 30% H2O2 (6 mL), phos-
phate buffer (pH 7, 12 mL), and methanol (12 mL) was added. Al-
most all of the organic solvent was removed under reduced
pressure, and the residual aqueous solution was extracted with
CH2Cl2. The extract was dried over anhydrous Na2SO4 and concen-
trated. To the residue was added glacial AcOH (1 mL) in EtOAc
(15 mL) and stirred for 2 h to completely decompose the boric acid
ester of the diols. Then the reaction was quenched by saturated
NaHCO3 (5 mL). The organic layer was separated, and the aqueous
layer was again extracted with EtOAc and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure. The res-
idue was purified by silica gel column chromatography (EtOAc/pet-
ether, 3:7) to afford the pure compound 2 (0.402 g, 80%) as a vis-
3434, 2934, 2861, 1514, 1458, 1376, 1267, 1198, 1035 cmꢀ1 1H
;
NMR (CDCl3, 300 MHz):
d 6.76 (d, J = 8.3 Hz, 1H), 6.62 (d,
J = 1.5 Hz, 1H), 6.61 (dd, J = 5.3, 1.5 Hz, 1H), 5.29 (s, 1H), 3.87 (s,
3H), 3.79–3.65 (m, 2H), 2.64 (ddd, J = 13.4, 8.3, 5.3 Hz, 1H), 2.56
(td, J = 13.6, 7.5 Hz, 1H), 1.75 (ddd, J = 13.6, 8.3, 5.3 Hz, 1H), 1.60
(dddd, J = 13.6, 9.1, 7.5, 3.7 Hz, 1H), 1.51–1.21 (m, 10H), 1.38 (s,
3H), 1.37 (s, 3H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3,
50 MHz): d 146.3, 143.5, 134.1, 121.1, 114.3, 111.0, 98.4, 69.1,
67.9, 65.8, 38.4, 37.0, 36.4, 31.8, 30.8, 30.3, 24.6, 22.6, 19.9, 14.0;
ESI: m/z = 359 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for
C20H32O4Na: 359.2198, found: 359.2199.
4.1.10. 4-(2-((4S,6S)-2,2-Dimethyl-6-pentyl-1,3-dioxan-4-yl)
ethyl)-2-methoxyphenol 19
Compound 3 (0.035 g, 0.118 mmol) was converted into com-
pound 19 (0.037 g, 94%) following the procedure adopted for the
cous liquid. ½a 2D5
ꢁ
¼ þ8:1 (c 2, CHCl3); IR (neat): mmax 3447, 2928,
2853, 1608, 1517, 1457, 1273, 1157, 1037 cmꢀ1
;
1H NMR (CDCl3,
preparation of compound 18. ½a D25
¼ þ19:0 (c 1, CHCl3); IR (neat):
ꢁ
300 MHz): d 6.77 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 7.5 Hz, 2H), 5.32
(s, OH, 1H), 3.89 (s, 3H), 3.86–3.76 (m, 2H), 2.67 (ddd, J = 14.3,
9.8, 6.7 Hz, 1H), 2.60 (ddd, J = 13.6, 10.5, 5.3 Hz, 1H), 1.75 (ddd,
J = 14.3, 9.0, 6.8 Hz, 1H), 1.71 (dddd, J = 13.6, 9.0, 7.5, 4.5 Hz, 1H),
1.57 (dt, J = 14.3, 3.0 Hz, 1H), 1.49–1.23 (m, 9H), 0.90 (t,
J = 6.8 Hz, 3H); 13C NMR (CDCl3, 50 MHz): d 146.4, 143.6, 133.8,
120.8, 114.2, 111.0, 73.2, 72.3, 55.8, 42.8, 40.0, 38.2, 31.7, 31.3,
25.0, 22.5, 14.0; ESI: m/z = 319 [M+Na]+. HRMS (ESI): [M+Na]+ m/
z calcd for C17H28O4Na: 319.1885, found: 319.1892.
mmax 3434, 2934, 2861, 1514, 1458, 1376, 1267, 1198, 1035 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 6.76 (d, J = 8.3 Hz, 1H), 6.65–6.60
(m, 2H), 5.30 (s, 1H), 3.87 (s, 3H), 3.79–3.64 (m, 2H), 2.66 (ddd,
J = 13.6, 9.1, 5.3 Hz, 1H), 2.53 (ddd, J = 14.4, 9.0, 7.5 Hz, 1H), 1.75
(dtd, J = 13.6, 8.3, 5.3 Hz, 1H), 1.63 (dddd, J = 13.6, 9.0, 6.8, 3.9 Hz,
1H), 1.54 (td, J = 9.0, 6.1 Hz, 1H), 1.43–1.19 (m, 10H), 1.33 (s, 3H),
1.31 (s, 3H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d
146.3, 143.5, 134.0, 120.9, 114.1, 110.9, 100.1, 66.6, 65.8, 55.7,
38.8, 37.8, 35.9, 31.7, 31.3, 25.0, 24.9, 24.7, 22.5, 14.0; ESI: m/
z = 359 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C20H32O4Na:
359.2198, found: 359.2199.
4.1.8. (3S,5S)-1-(4-Hydroxy-3-methoxyphenyl)decane-3,5-diol 3
To a stirred solution of tetramethylammonium triacetoxyboro-
hydride (0.128 g, 0.484 mmol) in anhydrous acetonitrile (2.0 mL)
was added acetic acid (2.0 mL) and the mixture was stirred at room
temperature for 30 min. The mixture was cooled to ꢀ40 °C, and a
solution of compound 1 (0.12 g, 0.407 mmol) in 1.0 mL of acetoni-
trile was added. The mixture was stirred at the same temperature
for 3 h. The reaction was quenched with 0.5 N aqueous sodium
potassium tartrate and the mixture was diluted with CH2Cl2, and
washed with saturated aqueous NaHCO3 solution. The aqueous
layer was back extracted with CH2Cl2, and the combined organic
layers were washed with a saturated aqueous NaHCO3 solution.
The aqueous layer was back extracted with CH2Cl2, and the com-
bined organic layers were dried over anhydrous Na2SO4. The sol-
vent was removed under reduced pressure, after which the
residue was purified by silica gel column chromatography
(EtOAc/pet-ether, 7:3) to afford pure compound 3 (0.102 g, 85%)
4.1.11. (4R,6S)-4-(4-(Benzyloxy)-3-methoxyphenethyl)-2,2-
dimethyl-6-pentyl-1,3-dioxane 20
To
a
stirred suspension of sodium hydride (0.024 g,
1.010 mmol) in dry THF (3 mL) at 0 °C, alcohol 18 (0.17 g,
0.505 mmol) in dry THF (3 mL) was added dropwise. After stirring
for 30 min, BnBr (0.061 mL, 0.505 mmol) was added. After comple-
tion of the reaction, the reaction mixture was quenched with a sat-
urated solution of NH4Cl and extracted with EtOAc. The organic
layer was washed with water and brine solution, dried over anhy-
drous Na2SO4, and concentrated in vacuo. The residue was purified
by silica gel column chromatography (EtOAc/pet-ether, 1:19) to af-
ford the pure compound 20 (0.204 g, 95%) as a light yellow liquid.
½
a 2D5
ꢁ
¼ þ8:6 (c 1, CHCl3); IR (neat): mmax 2991, 2932, 2861, 1510,
1457, 1378, 1262, 1147, 1029 cmꢀ1 1H NMR (CDCl3, 500 MHz): d
;
7.40 (d, J = 7.9 Hz, 2H), 7.32 (t, J = 7.9 Hz, 2H), 7.27–723 (m, 1H),
6.74 (d, J = 7.9 Hz, 1H), 6.67 (s, 1H), 6.59 (d, J = 7.9 Hz, 1H), 5.07
(s, 2H), 3.86 (s, 3H), 3.75–3.67 (m, 2H), 2.64 (ddd, J = 13.8, 8.9,
4.9 Hz, 1H), 2.55 (q, J = 13.8, 7.9 Hz, 1H), 1.81–1.71 (m, 1H), 1.66–
1.56 (m, 1H), 1.37 (s, 3H), 1.36 (s, 3H), 1.50–1.22 (m, 10H), 0.89
(t, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d 149.4, 146.2,
137.4, 135.4, 128.4, 127.7, 127.2, 120.3, 114.1, 112.3, 98.3, 71.1,
69.0, 67.9, 55.9, 38.1, 37.0, 36.4, 31.8, 30.7, 30.3, 24.6, 22.6, 19.9,
14.0; ESI: m/z = 449 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for
as a white sold. ½a D25
ꢁ
¼ ꢀ1:0 (c 3, CHCl3); IR (neat): mmax 3447,
2928, 2853, 1608, 1517, 1457, 1273, 1157, 1037 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz): d 6.76 (d, J = 7.9 Hz, 1H), 6.64 (d, J = 6.9 Hz,
2H), 5.33 (s, OH, 1H), 3.97–3.85 (m, 2H), 3.88 (s, 3H), 2.69 (ddd,
J = 13.8, 9.9, 5.9 Hz, 1H), 2.58 (ddd, J = 13.8, 8.9, 6.9 Hz, 1H), 1.81
(ddd, J = 13.8, 8.9, 5.9 Hz, 1H), 1.70 (dddd, J = 13.8, 10.8, 6.9,
3.9 Hz, 1H), 1.61–1.57 (m, 2H), 1.45–1.37 (m, 8H), 0.90 (t,
J = 6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz): 146.5, 143.7, 134.0,
120.9, 114.2, 111.0, 69.4, 68.8, 55.8, 42.4, 39.3, 37.4, 31.8, 25.4,
22.7, 13.9; ESI: m/z = 319 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd
for C17H28O4Na: 319.1885, found: 319.1892.
C27H38O4Na: 449.2667, found: 449.2660.
4.1.12. (3R,5S)-1-(4-(Benzyloxy)-3-methoxyphenyl)decane-3,5-
diol 21
4.1.9. 4-(2-((4R,6S)-2,2-Dimethyl-6-pentyl-1,3-dioxan-4-yl)
ethyl)-2-methoxyphenol 18
To a stirred solution of compound 20 (0.17 g, 0.398 mmol) in
MeOH (5 mL) at 0 °C was added a catalytic amount of pTSA. The
reaction mixture was stirred at room temperature for 1 h. After
completion of the reaction, the reaction mixture was quenched
with solid NaHCO3 under ice cooling, and the solvent was removed
in vacuo. The residue was purified by silica gel column chromatog-
raphy (EtOAc/pet-ether, 2:8) to afford the pure compound 21
To a solution of triol 2 (0.32 g, 1.08 mmol) in dry CH2Cl2
(10 mL), 2,2-DMP (1.32 mL, 2.16 mmol) and a catalytic amount of
pTSA were added. The mixture was stirred at ambient temperature
for 2 h. After completion of the reaction, solid NaHCO3 was added
to neutralize the pTSA. The solvent was removed in vacuo and the
residue was purified by silica gel column chromatography (EtOAc/
pet-ether, 1:9) to afford the pure mono-acetonide 18 (0.345 g, 95%)
(0.138 g, 90%) as a light yellow liquid. ½a D25
¼ þ5:3 (c 1, CHCl3);
ꢁ
IR (neat): mmax 3392, 2928, 2859, 1511, 1456, 1262, 1136,

2130
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2124–2133
1028 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 7.43–7.25 (m, 5H), 6.70
ether, 1:19) to afford the pure compound 23 (0.137 g, 94%) as a
(d, J = 1.5 Hz, 1H), 6.62 (dd, J = 7.5, 1.5 Hz, 1H), 5.08 (s, 2H), 3.87
(s, 3H), 3.85–3.76 (m, 2H), 2.67 (ddd, J = 13.6, 9.0, 6.0 Hz, 1H),
2.63 (dd, J = 14.4, 6.0 Hz, 1H), 1.72 (ddd, J = 15.1, 9.0, 6.8 Hz, 1H),
1.56 (dt, J = 14.3, 3.0 Hz, 1H), 1.49–1.22 (m, 8H), 0.90 (t,
J = 6.8 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d 149.5, 146.3, 137.4,
135.2, 128.5, 127.7, 127.2, 120.1, 114.2, 112.3, 73.3, 72.4, 71.1,
55.6, 42.9, 39.8, 38.3, 31.7, 31.3, 24.9, 22.6, 14.0; ESI: m/z = 409
[M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C24H34O4Na:
409.2354, found: 409.2350.
light yellow liquid. ½a D25
ꢁ
¼ þ8:9 (c 1.5, CHCl3); IR (neat): mmax
2991, 2933, 2859, 1514, 1461, 1379, 1262, 1157, 1032; cmꢀ1
;
1H
NMR (CDCl3, 500 MHz): d 6.72 (d, J = 8.9 Hz, 1H), 6.67–6.63 (m,
2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.76–3.67 (m, 2H), 2.65 (ddd,
J = 13.8, 8.9, 4.9 Hz, 1H), 2.56 (ddd, J = 13.8, 7.9, 6.8 Hz, 1H), 1.81–
1.71 (m, 1H), 1.65–1.56 (m, 1H), 1.38 (s, 3H), 1.37 (s, 3H), 1.51–
1.22 (m, 10H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (CDCl3, 50 MHz):
d 148.7, 147.1, 134.7, 120.3, 114.8, 111.2, 98.4, 69.0, 67.9, 55.9,
55.8, 38.2, 37.0, 36.4, 31.8, 30.7, 30.3, 24.6, 22.6, 19.9, 14.0; ESI:
m/z = 373 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for
4.1.13. (3R,5S)-1-(4-(Benzyloxy)-3-methoxyphenyl)decane-3,5-
diyl diacetate 22
C21H34O4Na: 373.2354, found: 373.2352.
Anhydrous Et3N (0.098 mL, 0.698 mmol), Ac2O (0.066 mL,
0.698 mmol), and a catalytic amount of DMAP were added to a
solution of diol 21 (0.09 g, 0.232 mmol), in dry CH2Cl2 (4 mL), un-
der N2 atmosphere at room temperature. The mixture was stirred
at room temperature for 30 min. The solvent was removed under
reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc/pet-ether, 1:19) to afford the pure com-
4.1.16. (3R,5S)-1-(3,4-Dimethoxyphenyl)decane-3,5-diol 24
Compound 23 (0.1 g, 0.258 mmol) was converted into com-
pound 24 (0.079 g, 90%) following the procedure adopted for the
preparation of compound 21. ½a D25
ꢁ
¼ þ9:8 (c 3, CHCl3); IR (neat):
mmax 3380, 2931, 2858, 1514, 1460, 1261, 1150, 1030 cmꢀ1
;
1H
NMR (CDCl3, 500 MHz): d 6.73 (d, J = 8.9 Hz, 1H), 6.69–6.66 (m,
2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.84–3.77 (m, 2H), 2.68 (ddd,
J = 13.8, 8.9, 5.9 Hz, 1H), 2.61 (pent, J = 13.8, 8.9 1H), 1.80–1.65
(m, 2H), 1.59–1.22 (m, 8H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR (CDCl3,
50 MHz): d 148.8, 147.1, 134.6, 120.1, 111.7, 111.3, 73.2, 72.3, 55.9,
55.8, 42.9, 39.9, 38.2, 37.7, 31.3, 24.9, 22.5, 14.0; ESI: m/z = 333
[M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C18H30O4Na:
333.2041, found: 333.2035.
pound 22 (0.103 g, 94%) as a light yellow liquid. ½a D25
¼ ꢀ3:2 (c 1,
ꢁ
CHCl3); IR (neat): mmax 2926, 2860, 1732, 1510, 1456, 1371, 1233,
1023 cmꢀ1 1H NMR (CDCl3, 500 MHz): d 7.39 (d, J = 7.0 Hz, 2H),
;
7.32 (t, J = 8.0 Hz, 2H), 7.27–722 (m, 1H), 6.74 (d, J = 8.0 Hz, 1H),
6.66 (d, J = 2.0 Hz, 1H), 6.57 (d, J = 7.0 Hz, 1H), 5.07 (s, 2H), 4.92–
4.82 (m, 2H), 3.87 (s, 3H), 2.55 (td, J = 14.0, 7.0 Hz, 1H), 2.49 (td,
J = 14.0, 7.0 Hz, 1H), 2.02 (s, 3H), 1.96 (s, 3H), 1.85 (td, J = 14.0,
7.0 Hz, 1H), 1.68 (td, J = 12.0, 6.0 Hz, 1H), 1.53–1.44 (m, 2H),
1.42–1.20 (m, 8H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (CDCl3,
50 MHz): d 170.6, 170.6, 149.5, 146.3, 137.3, 134.5, 128.4, 127.7,
127.2, 120.0, 114.1, 112.1, 78.8, 70.1, 55.9, 38.4, 35.6, 34.1, 31.5,
31.1, 24.7, 22.4, 21.2, 14.0; ESI: m/z = 493 [M+Na]+. HRMS (ESI):
[M+Na]+ m/z calcd for C28H38O6Na: 493.2566, found: 493.2583.
4.1.17. (3R,5S)-1-(3,4-Dimethoxyphenyl)decane-3,5-diyl
diacetate 5
Compound 24 (0.04 g, 0.128 mmol) was converted into com-
pound 5 (0.047 g, 94%) following the procedure adopted for the
preparation of compound 22. ½a D25
¼ ꢀ1:2 (c 3, CHCl3). IR (neat):
ꢁ
mmax 3450, 2927, 2859, 1732, 1637, 1530, 1455, 1370, 1236,
1026 cmꢀ1 1H NMR (CDCl3, 500 MHz): d 6.73 (d, J = 7.9 Hz, 1H),
;
4.1.14. (3R,5S)-1-(4-Hydroxy-3-methoxyphenyl)decane-3,5-diyl
diacetate 4
6.66–6.61, (m, 2H), 4.92–4.83 (m, 2H), 3.86 (s, 3H), 3.83 (s, 3H),
2.57 (td, J = 7.9, 14.8 Hz, 1H), 2.50 (td, J = 7.9, 14.8 Hz, 1H), 2.03
(s, 3H), 1.97 (s, 3H), 1.86 (td, J = 6.9, 14.8 Hz, 1H), 1.69 (td, J = 6.9,
14.8 Hz, 1H), 1.52–1.46 (m, 2H), 1.42–1.34 (m, 2H), 1.33–1.19 (m,
8H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d 170.6,
170.5, 148.7, 147.1, 133.8, 120.0, 111.5, 111.1, 71.0, 70.8, 55.8,
55.7, 38.3, 35.7, 34.1, 31.5, 31.0, 24.7, 22.4, 21.1, 20.1, 13.8; ESI:
m/z = 417 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for
C22H34O6Na: 417.2253, found: 417.2248.
To a solution of compound 22 (0.06 g, 0.127 mmol) in benzene
(5 mL) was added a catalytic amount of Pd(OH)2 and stirred under
an H2 atmosphere for 4 h. After completion of the reaction, the cat-
alyst was removed by filtration, washed with ethylacetate, and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc/pet-ether,
1:9) to afford the pure compound 4 (0.045 g, 93%) as a light yellow
liquid. ½a 2D5
ꢁ
¼ ꢀ3:6 (c 1, CHCl3); IR (neat): mmax 3449, 2928, 2858,
1733, 1515, 1371, 1242, 1030 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d
4.1.18. (E)-Ethyl-3-(3,4,5-trimethoxyphenyl)acrylate 25a
6.76 (d, J = 7.5 Hz, 1H), 6.64–6.56 (m, 2H), 5.32 (s, OH, 1H), 4.93–
4.80 (m, 2H), 3.89 (s, 3H), 2.56 (td, J = 14.5, 7.5 Hz, 1H), 2.49 (td,
J = 14.5, 7.5 Hz, 1H), 2.04 (s, 3H), 1.97 (s, 3H), 1.85 (td, J = 14.9,
6.7 Hz, 1H), 1.69 (td, J = 13.9, 5.8 Hz, 1H), 1.54–1.44 (m, 2H),
1.42–1.35 (m, 2H), 1.34–1.19 (m, 8H), 0.89 (t, J = 6.3 Hz, 3H). 13C
NMR (CDCl3, 50 MHz): d 170.6, 170.5, 146.2, 143.7, 133.1, 120.8,
114.2, 110.9, 71.1, 70.8, 55.8, 38.4, 35.8, 34.1, 31.5, 31.2, 24.7,
22.4, 21.1, 21.0, 13.9; ESI: m/z = 403 [M+Na]+. HRMS (ESI):
[M+Na]+ m/z calcd for C21H32O6Na: 403.2096, found: 403.2088.
Ethyl(triphenylphosphoranylidene)acetate (1.55 g, 4.46 mmol)
was added to a stirred solution of 3,4,5-trimethoxy benzaldehyde
13a (0.73 g, 3.72 mmol) in benzene (10 mL). Then the reaction
mixture was refluxed for 4 h. The solvent was removed in vacuo,
and the residue was purified by silica gel column chromatography
(EtOAc/pet-ether, 1:19) to afford the pure compound 25a (0.89 g,
90%) as a white solid. IR (neat): mmax 2999, 2974, 2942, 1702,
1633, 1583, 1505, 1453, 1314, 1278, 1123, 991 cmꢀ1 1H NMR
;
(CDCl3, 300 MHz): d 7.60 (d, J = 15.6 Hz, 1H), 6.76 (s, 2H), 6.35 (d,
J = 16.5 Hz, 1H), 4.27 (q, J = 14.6, 6.8 Hz, 2H), 3.89 (s, 6H), 3.88 (s,
3H), 1.34 (t, J = 6.8 Hz, 3H); ESI: m/z = 289 [M+Na]+.
4.1.15. (4R,6S)-4-(3,4-Dimethoxylphenetyl)-2,2-dimethyl-6-
pentyl-1,3-dioxane 23
To
a
stirred suspension of sodium hydride (0.019 g,
4.1.19. 3-(3,4,5-Trimethoxyphenyl)propan-1-ol 26a
0.832 mmol) in dry THF (5 mL) at 0 °C, alcohol 18 (0.14 g,
0.416 mmol) in dry THF (5 mL) was added dropwise. After stirring
for 30 min, MeI (0.038 mL, 0.624 mmol) was added. After comple-
tion of the reaction, the reaction mixture was quenched with a sat-
urated aqueous NH4Cl solution and extracted with EtOAc. The
organic layer was washed with water and brine, and dried over
anhydrous Na2SO4. The solvent was removed in vacuo, and the res-
idue was purified by silica gel column chromatography (EtOAc/pet-
To a stirred suspension of LiAlH4 (0.303 g, 7.98 mmol) in dry
THF (10 mL) at 0 °C, a solution of
a,b unsaturated ester 25a
(0.85 g, 3.19 mmol) in dry THF (10 mL) was added drop wise. Then
the reaction mixture was refluxed for 4 h and cooled to 0 °C, di-
luted with ether and quenched by the dropwise addition of satu-
rated aqueous Na2SO4. The solid material was filtered and
washed thoroughly with hot ethyl acetate several times. The com-
bined organic layers were dried over anhydrous Na2SO4. The

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2124–2133
2131
solvent was removed in vacuo and the residue was purified by
silica gel column chromatography (EtOAc/pet-ether, 3:7) to afford
pure compound 26a (0.628 g, 87%) as a viscous liquid.
3.33 (dd, J = 10.0, 6.6 Hz, 1H), 3.29–3.16 (m, 2H), 3.02 (dd, J = 12.6,
10.9 Hz, 1H), 2.87 (d, J = 11.5 Hz, 1H) 2.61 (t, J = 7.4 Hz, 2H) 1.90–
1.79 (m, 2H) 0.89 (s, 9H), 0.11 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3,
75 MHz): d 201.2, 172.0, 153.1, 137.9, 136.4, 135.9, 129.4, 128.9,
127.2, 105.1, 68.6, 60.8, 56.0, 45.7, 39.4, 36.5, 32.1, 31.6, 25.8,
18.0, ꢀ4.4, ꢀ4.6; ESI: m/z = 612 [M+Na]+. HRMS (ESI): [M+Na]+ m/
z calcd for C34H43NO5S2SiNa: 612.2249, found: 612.2275.
IR (neat): mmax 3371, 2941, 1711, 1613, 1514, 1446, 1366, 1228,
1147, 1033 cmꢀ1; 1H NMR (CDCl3, 300 MHz): d 6.36 (s, 2H), 3.84 (s,
6H), 3.78 (s, 3H), 3.66 (t, J = 5.9 Hz, 2H), 2.63 (t, J = 7.9 Hz, 2H),
1.89–1.82 (m, 2H), 1.40 (br s, OH, 1H); ESI: m/z = 249 [M+Na]+.
4.1.20. 3-(3,4,5-Trimethoxyphenyl)propanal 27a
4.1.23. (S)-3-(tert-Butyldimethylsilyloxy)-5-(3,4,5-trimeth oxy-
phenyl)pentanal 30a
To an ice-cooled solution of 2-iodoxybenzoic acid (0.876 g,
3.129 mmol) in DMSO (1.11 mL, 15.64 mmol) was added a solution
of alcohol 26a (0.59 g, 2.607 mmol) in dry CH2Cl2 (10 mL). The mix-
ture was stirred at room temperature for 2 h and then filtered
through a Celite pad and washed with ether. The combined organic
filtrates were washed with water, brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified by sil-
ica gel column chromatography (EtOAc/pet-ether, 1:9) to afford
the pure compound 27a (0.508 g, 87%) as a viscous liquid. The
unstable aldehyde used immediately for the next reaction.
To a solution of 29a (0.7 g, 1.186 mmol) in dry CH2Cl2 at ꢀ78 °C,
was added DIBAL (1.7 M in toluene, 1.39 mL, 2.37 mmol). The
bright yellow color solution was stirred until the color faded. Then
the reaction mixture was diluted with CH2Cl2 and quenched with a
saturated aqueous Na/K tartrate solution, and allowed to warm to
rt, and stirred for 2 h. After separation of the layers, the aqueous
layer was further extracted with CH2Cl2. The combined organic lay-
ers were dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(EtOAc/pet-ether, 1:19) to afford the pure compound 30a
(0.385 g, 85%) as a brown viscous liquid.
4.1.21. (S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-3-hydroxy-
5-(3,4,5-trimethoxyphenyl)pentan-1-one 28a
To a solution of thiazolidinethione acetate (0.49 g, 1.87 mmol)
in dry CH2Cl2 (20 mL) was added TiCl4 (1 M in CH2Cl2, 1.91 mL,
1.91 mmol) at ꢀ78 °C, forming a red-orange slurry. After 5 min, DI-
PEA (0.358 mL, 2.09 mmol) was slowly added, forming the charac-
teristic enolate color (deep red). After 30 min at ꢀ78 °C aldehyde
27a (0.46 g, 2.06 mmol) in dry CH2Cl2 (10 mL) was added. Within
5 min, the color had faded to a pale brown color, indicating the
consumption of the enolate. The reaction mixture was quenched
with a saturated solution of NH4Cl, and diluted with CH2Cl2. The
product was extracted with CH2Cl2 and washed with brine. The
combined organic layers were dried over anhydrous Na2SO4 and
the solvent was removed under reduced pressure. The residue
was purified by silica gel column chromatography (EtOAc/pet-
ether, 1:9) to afford the pure compound 28a (0.704 g, 79%) as a
4.1.24. (S)-5-(tert-Butyldimethylsilyloxy)-1,7-bis(3,4,5-trimeth
oxyphenyl)hept-1-yn-3-one 31a
Aldehyde 30a (0.358 g, 0.937 mmol) was converted into com-
pound 31a (0.461 g, 86%, for two steps) using alkyne 15a (0.18 g,
0.937 mmol) following the procedure adopted for the preparation
of compound 16. ½a D25
ꢁ
¼ ꢀ3:3 (c 0.6, CHCl3); IR (neat): mmax 2934,
2855, 2191, 1666, 1580, 1503, 1461, 1241, 1128 1005 cmꢀ1
;
1H
NMR (CDCl3, 300 MHz): d 6.76 (s, 2H), 6.35 (s, 2H), 4.40–4.29 (m,
1H), 3.86 (s, 9H), 3.82 (s, 6H), 3.77 (s, 3H), 2.89 (dd, J = 15.3,
6.4 Hz, 1H), 2.77 (dd, J = 15.3, 5.8 Hz, 1H), 2.63 (t, J = 7.5 Hz, 2H)
1.85 (td, J = 14.4, 7.7 Hz, 2H) 0.91 (s, 9H), 0.10 (s, 3H), 0.08 (s,
3H); 13C NMR (CDCl3, 75 MHz): d 185.9, 153.2, 153.1, 137.7,
114.4, 110.4, 105.1, 68.5, 61.0, 60.8, 56.2, 56.0, 52.9, 39.3, 31.6,
25.8, 18.1, ꢀ4.6, ꢀ4.9; ESI: m/z = 595 [M+Na]+. HRMS (ESI):
[M+Na]+ m/z calcd for C31H44O8SiNa: 595.2703, found: 595.2728.
yellow viscous liquid. ½a D25
¼ þ16:6 (c 0.9, CHCl3); IR (neat): mmax
ꢁ
3453, 2935, 2837, 1697, 1589, 1503, 1458, 1238, 1125,
1006 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 7.37–7.20 (m, 5H), 6.39
4.1.25. (S)-5-(tert-Butyldimethylsilyloxy)-1,7-bis(3,4,5-trimeth
oxyphenyl)heptan-3-one 32a
(s, 2H), 5.36 (dddd, J = 10.7, 6.9, 4.1, 0.7 Hz, 1H), 4.15–4.05 (m,
1H), 3.82 (s, 6H), 3.78 (s, 3H), 3.68 (dd, J = 17.9, 1.9 Hz, 1H), 3.30
(dd, J = 11.7, 7.2 Hz, 1H), 3.21 (dd, J = 13.2, 3.6 Hz, 1H), 3.14–2.97
(m, 2H), 2.89 (d, J = 11.5 Hz, 1H), 2.84–2.71 (m, 1H), 2.69–2.57
(m, 1H), 1.95–1.70 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 201.4,
173.1, 153.0, 137.4, 136.2, 129.3, 129.1, 128.9, 128.8, 127.4,
127.2, 105.2, 68.2, 64.9, 60.8, 56.0, 45.8, 41.0, 40.0, 36.7, 32.1;
ESI: m/z = 498 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for
Compound 31a (0.34 g, 0.593 mmol) was converted into com-
pound 32a (0.315 g, 92%) following the procedure adopted for
preparation of compound 17. ½a D25
¼ ꢀ12:8 (c 0.7, CHCl3); IR (neat):
ꢁ
mmax 2933, 2855, 1712, 1589, 1506, 1459, 1421, 1238, 1127,
1009 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 6.33 (s, 2H), 6.32 (s,
;
2H), 4.25–4.15 (m, 1H), 3.84 (s, 6H), 3.82 (s, 6H), 3.78 (s, 3H),
3.77 (s, 3H), 2.84–2.66 (m, 4H), 2.65–2.39 (m, 4H), 1.80–1.68 (m,
2H), 0.89 (s, 9H), 0.07 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3,
75 MHz): d 208.7, 153.1, 137.8, 136.7, 105, 68.6, 60.8, 55.9, 50.1,
46.3, 39.4, 31.8, 29.8, 25.8, 18.0, ꢀ4.6, ꢀ4.7; ESI: m/z = 599
[M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C31H48O8SiNa:
599.3016, found: 599.3028.
C24H29NO5S2Na: 498.1384, found: 498.1400.
4.1.22. (S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-3-(tert-
butyldimethylsilyloxy)-5-(3,4,5-trimethoxyphenyl)pentan-1-
one 29a
To a stirred solution of 28a (0.66 g, 1.38 mmol) in dry CH2Cl2
(20 ml) were sequentially added 2,6-lutidine (0.32 ml, 2.77 mmol)
and t-butyldimethylsilyltrifluoromethane sulfonate (0.35 ml,
1.52 mmol). After completion of the reaction, it was quenched with
a saturated solution of NH4Cl. After separation of the layers, the
aqueous layer was further extracted with CH2Cl2. The combined or-
ganic layers were dried over anhydrous Na2SO4, and concentrated
in vacuo. The residue was purified by silica gel column chromatog-
raphy (EtOAc/pet-ether, 1:19) to afford the pure compound 29a
4.1.26. (S)-5-Hydroxy-1,7-bis(3,4,5-trimethoxyphenyl)heptan-3-
one 33a
To a solution of 32a (0.25 g, 0.433 mmol) in THF (10 mL) was
added TBAF (0.520 ml, 0.520 mmol, 1 M solution in THF) at 0 °C.
The reaction mixture was stirred for 6 h and then diluted with
water and extracted with EtOAc. The organic layer was washed
with water, and brine, dried over anhydrous Na2SO4, and concen-
trated in vacuo. The crude product was purified by silica gel col-
umn chromatography (EtOAc/pet-ether, 2:8) to afford pure
(0.760 g, 93%) as a yellow viscous liquid. ½a D25
¼ þ133:2 (c 0.8,
ꢁ
CHCl3); IR (neat): mmax 2930, 2855, 1696, 1588, 1506, 1459, 1241,
compound 33a (0.172 g, 86%) as
¼ ꢀ2:4 (c 1.2, CHCl3); IR (neat): mmax 3453, 2936, 2836,
1707, 1589, 1505, 1458, 1421, 1237, 1124, 1006 cmꢀ1 1H NMR
(CDCl3, 300 MHz): d 6.35 (s, 2H), 6.32 (s, 2H), 4.04–3.95 (m, 1H),
a brown viscous liquid.
1129 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 7.36–7.21 (m, 5H), 6.35
½ ꢁ
a 2D5
(s, 2H), 5.30–5.19 (dddd, J = 10.4, 7.2, 3.9, 0.9 Hz, 1H), 4.43–4.34
(m, 1H), 3.85 (s, 6H), 3.78 (s, 3H), 3.56 (dd, J = 16.8, 7.5 Hz, 1H),
;

2132
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2124–2133
3.83 (s, 6H), 3.81 (s, 6H), 3.78 (s, 3H), 3.77 (s, 3H), 2.80 (t, J = 7.1 Hz,
4H), 2.69 (t, J = 7.1 Hz, 4H), 2.74–2.66 (m, 1H), 2.62–2.45 (m, 3H),
1.79–1.69 (m, 1H), 1.65–1.55 (m, 1H); 13C NMR (CDCl3, 75 MHz):
d 211.0, 153.1, 153.0, 137.5, 136.4, 105.2, 105.1, 66.8, 60.7, 55.9,
49.3, 45.1, 38.1, 32.1, 29.8; ESI: m/z = 485 [M+Na]+. HRMS (ESI):
[M+Na]+ m/z calcd for C25H34O8Na: 485.2151, found: 485.2144.
6.79 (d, J = 12.3 Hz, 1H), 6.74 (d, J = 4.5 Hz, 1H), 6.65 (dd, J = 8.1,
2.1 Hz, 1H), 5.36 (dddd, J = 10.7, 6.9, 3.9, 0.7 Hz, 1H), 5.09 (s, 2H),
4.17–4.03 (m, 1H), 3.88 (s, 3H), 3.65 (dd, J = 17.9, 2.3 Hz, 1H),
3.39 (dd, J = 11.1, 7.2 Hz, 1H), 3.20 (dd, J = 13.0, 3.4 Hz, 1H), 3.10
(dd, J = 17.9, 9.2 Hz, 1H), 3.02 (dd, J = 12.8, 10.4 Hz, 1H), 2.88 (d,
J = 11.5 Hz, 1H), 2.83–2.57 (m, 2H), 1.97–1.68 (m, 2H); 13C NMR
(CDCl3, 75 MHz): d 201.3, 173.1, 149.5, 146.3, 137.3, 136.3, 134.9,
129.3, 128.9, 128.4, 127.7, 127.2, 120.2, 114.2, 112.3, 71.1, 68.2,
67.0, 55.9, 45.8, 37.9, 36.8, 31.9, 31.4; ESI: m/z = 544 [M+Na]+.
4.1.27. (3S,5S)-1,7-Bis(3,4,5-trimethoxyphenyl)heptane-3,5-diol
34
Compound 32a (0.11 g, 0.237 mmol) was converted into com-
pound 34 (0.095 g, 85%) following the procedure adopted for the
4.1.33. (S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-5-(4-
(benzyloxy)-3-methoxyphenyl)-3-(methoxymethoxy)pentan-1-
one 29b
preparation of compound 3. ½a D25
ꢁ
¼ þ3:1 (c 0.5, CHCl3); IR (neat):
mmax 3443, 2924, 2852, 1590, 1505, 1459, 1237, 1125 cmꢀ1
;
1H
NMR (CDCl3, 300 MHz): d 6.35 (s, 4H), 4.03–3.90 (m, 2H), 3.83 (s,
12H), 3.78(s, 6H), 2.76–2.51 (m, 4H), 1.89–1.55 (m, 6H); 13C NMR
(CDCl3, 75 MHz): d 153.1, 137.6, 136.0, 105.2, 68.8, 60.8, 56.0,
42.6, 39.1, 32.6; ESI: m/z = 487 [M+Na]+. HRMS (ESI): [M+Na]+ m/
z calcd for C25H36O8Na: 487.2307, found: 487.2297.
To a stirred solution of alcohol 28b (1.0 g, 1.918 mmol) in dry
CH2Cl2 (30 mL) at 0 °C under N2, Pr2NEt (0.655 mL, 3.83 mmol)
i
was added followed by the dropwise addition of MOMCl
(0.230 mL, 2.87 mmol). After stirring for 4 h at room temperature,
the reaction mixture was diluted with water, and washed with a
saturated solution of NH4Cl, and brine. The combined organic lay-
ers were dried over anhydrous Na2SO4 and the solvent was re-
moved under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/pet-ether, 1:9) to afford
4.1.28. (3S,5S)-1,7-Bis(3,4,5-trimethoxyphenyl)heptane-3,5-diyl
diacetate 6
Compound 34 (0.04 g, 0.861 mmol) was converted into com-
pound 6 (0.043 g, 93%) following the procedure adopted for the
the pure compound 29b (0.86 g, 80%) as
¼ þ97:9 (c 2.9, CHCl3); IR (neat): mmax 3027, 2935, 1696,
1511, 1456, 1262, 1142, 1031 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
a yellow liquid.
preparation of compound 22. ½a D25
ꢁ
¼ þ4:7 (c 0.5, CHCl3); IR (neat):
½ ꢁ
a 2D5
mmax 2926, 2853, 1734, 1663, 1589, 1506, 1459, 1423, 1240, 1127,
;
1012 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 6.34 (s, 4H), 4.99 (quint,
7.45–7.14 (m, 10H), 6.74 (d, J = 12.6 Hz, 1H), 6.72 (d, J = 6.2 Hz,
1H), 6.63 (dd, J = 8.1, 1.5 Hz, 1H), 5.24 (dddd, J = 11.1, 6.9, 3.9,
0.7 Hz, 1H), 5.07 (s, 2H), 4.65 (ABq, J = 20.0, 7.0 Hz, 2H), 4.19–
4.03 (m, 1H), 3.87 (s, 3H), 3.53 (t, J = 7.7 Hz, 2H), 3.37 (s, 3H),
3.35–3.15 (m, 2H), 3.06–2.78 (m, 2H), 2.77–2.53 (m, 2H), 1.96–
1.80 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 200.1, 171.6, 149.4,
146.2, 137.2, 136.3, 134.9, 129.3, 128.7, 128.4, 128.3, 127.6,
127.1, 120.0, 114.1, 112.1, 96.7, 74.5, 71.0, 68.5, 55.8, 55.7, 44.2,
36.9, 36.5, 32.0, 31.0; ESI: m/z = 588 [M+Na]+. HRMS (ESI):
[M+Na]+ m/z calcd for C31H35NO5S2Na: 588.1854, found: 588.1866.
J = 5.3 Hz, 2H), 3.84 (s, 12H), 3.78 (s, 6H), 2.57–2.46 (m, 4H), 2.01
(s, 6H), 1.98–1.68 (m, 6H); 13C NMR (CDCl3, 75 MHz): d 170.7,
153.1, 137.0, 136.1, 105.1, 70.5, 60.8, 56.0, 38.7, 35.7, 32.0, 21.1;
ESI: m/z = 571 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for
C29H40O10Na: 571.2519, found: 571.2515.
4.1.29. (E)-Ethyl-3-(4-(benzyloxy)-3-methoxyphenyl)acrylate
25b
Compound 13b (1.2 g, 4.95 mmol) was converted into com-
pound 25b (1.67 g, 91%) following the procedure adopted for the
preparation of compound 25a. IR (neat): mmax 2938, 1707, 1631,
4.1.34. (S)-5-(4-(Benzyloxy)-3-methoxyphenyl)-3-(methoxy
methoxy)pentanal 30b
1591, 1507, 1460, 1375, 1255, 1161, 1137, 1030 cmꢀ1 1H NMR
;
(CDCl3, 400 MHz): d 7.61 (d, J = 16.0 Hz, 1H), 7.50–7.29 (m, 5H),
7.07 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 6.30
(d, J = 16.0 Hz, 1H), 5.19 (s, 2H), 4.25 (q, J = 14.0, 7.0 Hz, 2H), 3.91
(s, 3H), 1.33 (t, J = 7.0 Hz, 3H); ESI: m/z = 335 [M+Na]+.
Compound 29b (0.8 g, 1.41 mmol) was converted into com-
pound 30b (0.436 g, 86%) following the procedure adopted for
the preparation of compound 30a.
4.1.35. (S)-1,7-Bis(4-(benzyloxy)-3-methoxyphenyl)-5-(methoxy
methoxy)hept-1-yn-3-one 31b
4.1.30. 3-(4-(Benzyloxy)-3-methoxyphenyl)propan-1-ol 26b
Compound 25b (1.3 g, 4.16 mmol) was converted into com-
pound 26b (0.997 g, 88%) following the procedure adopted for
the preparation of compound 26a. IR (neat): mmax 3397, 2936,
Aldehyde 30b (0.391 g, 1.09 mmol) was converted into com-
pound 31b (0.56 g, 87%, for two steps) using alkyne 15b (0.26 g,
1.09 mmol) following the procedure adopted for the preparation
2869, 1596, 1511, 1457, 1263, 1226, 1146, 1030 cmꢀ1
;
1H NMR
of compound 16. ½a D25
ꢁ
¼ ꢀ6:2 (c 0.8, CHCl3); IR (neat): mmax 2934,
(CDCl3, 300 MHz): d 7.42–7.25 (m, 5H), 6.74 (d, J = 8.3 Hz, 1H),
6.69 (d, J = 2.3 Hz, 1H), 6.61 (dd, J = 8.3, 2.3 Hz, 1H), 5.07 (s, 2H),
3.86 (s, 3H), 3.63 (t, J = 6.0 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 1.89–
1.78 (m, 2H); ESI: m/z = 295 [M+Na]+.
2185, 1661, 1594, 1511, 1457, 1245, 1141, 1025 cmꢀ1 1H NMR
;
(CDCl3, 500 MHz): d 7.43–7.24 (m, 10H), 7.05 (dd, J = 8.0, 2.0 Hz,
1H), 7.01 (bs, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H),
6.70 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 5.11 (s, 2H), 5.04
(s, 2H), 4.66 (ABq, J = 7.0 Hz, 2H), 4.21–4.14 (m, 1H), 3.87 (s, 3H),
3.84 (s, 3H), 3.37 (s, 3H), 2.96 (dd, J = 16.0, 7.0 Hz, 1H), 2.73 (dd,
J = 15.0, 5.0 Hz, 1H), 2.65 (ddd, J = 16.0, 9.0, 6.0 Hz, 2H), 1.96–1.82
(m, 2H); 13C NMR (CDCl3, 75 MHz): d 185.3, 150.7, 149.4, 146.4,
136.0, 134.8, 128.6, 128.4, 128.1, 127.7, 127.2, 127.1, 120.1,
115.7, 114.1, 113.1, 112.1, 96.1, 92.5, 87.8, 73.7, 71.1, 70.7, 56.0,
55.9, 55.6, 50.8, 36.7, 31.0; ESI: m/z = 617 [M+Na]+. HRMS (ESI):
[M+Na]+ m/z calcd for C37H38O7Na: 617.2515, found: 617.2532.
4.1.31. 3-(4-(Benzyloxy)-3-methoxyphenyl)propanal 27b
Compound 26b (0.94 g, 3.45 mmol) was converted to com-
pound 27b (0.802 g, 86%) following the procedure adopted for
preparation of compound 27a.
4.1.32. (S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-5-(4-
(benzyloxy)-3-methoxyphenyl)-3-hydroxypentan-1-one 28b
Aldehyde 27b (0.773 g, 2.86 mmol) was converted into com-
pound 28b (1.08 g, 80%) using thiazolidinethione acetate (0.68 g,
2.60 mmol) following the procedure adopted for the preparation
4.1.36. (S)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-5-(methoxy
methoxy)heptan-3-one 32b
of compound 28a. ½a D25
ꢁ
¼ þ131:8 (c 1.1, CHCl3); IR (neat): mmax
Compound 31b (0.45 g, 0.756 mmol) was converted into com-
pound 32b (0.294 g, 93%) following the procedure adopted for
3448, 2924, 2860, 1683, 1513, 1328, 1257, 1225, 1135,
1037 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 7.46–7.21 (m, 10H),
the preparation of compound 17. ½a D25
¼ þ5:7 (c 1.4, CHCl3); IR
ꢁ

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2124–2133
2133
(neat): mmax 3420, 2929, 2852, 1709, 1606, 1515, 1458, 1369,
1270, 1151, 1031 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 6.77 (d,
4.1.39. (3S,5S)-1,7-Bis(4-hydroxy-3-methoxyphenyl)heptane-
3,5-diol 8
;
J = 2.7 Hz, 1H), 6.75 (d, J = 2.7 Hz, 1H), 6.60 (d, J = 8.3 Hz, 4H),
5.33 (s, OH, 1H), 5.32 (s, OH, 1H), 4.58 (ABq, J = 16.6, 6.8 Hz,
2H), 4.05–3.96 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.32 (s, 3H),
2.78 (t, J = 6.8 Hz, 2H), 2.67 (t, J = 6.8 Hz, 2H) 2.64–2.37 (m,
4H), 1.80–1.69 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 208.2,
146.4, 143.9, 143.7, 133.6, 132.8, 120.8, 114.3, 114.2, 111.0,
110.9, 96.3, 73.9, 55.8, 55.6, 48.3, 45.6, 37.0, 31.2, 29.2; ESI: m/
z = 441 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C23H30O7Na:
441.1889, found: 441.1895.
Compound 33b (0.06 g, 0.160 mmol) was converted into com-
pound 8 (0.050 g, 84%) following the procedure adopted for the
preparation of compound 3. ½a D25
¼ ꢀ13:5 (c 0.5, EtOH); IR (neat):
ꢁ
mmax 3443, 2931, 2860, 1604, 1514, 1457, 1265, 1165, 1032 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 6.77 (d, J = 8.3 Hz, 2H), 6.67–6.60
(m, 4H), 5.33 (bs, OH, 2H), 4.10–4.01 (m, 1H), 3.97–3.89 (m, 1H),
3.88 (s, 6H), 2.79–2.49 (m, 4H), 1.92–1.52 (m, 6H); 13C NMR (CDCl3,
75 MHz): d 146.4, 143.7, 133.6, 120.9, 114.2, 110.9, 68.9, 55.8, 43.8,
40.1, 31.8; ESI: m/z = 399 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd
for C21H28O6Na: 399.1783, found: 399.1793.
4.1.37. (S)-5-Hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)
heptan-3-one 33b
Acknowledgments
To a stirred solution of compound 32b (0.25 g, 0.597 mmol) in
methanol (20 mL) was added a catalytic amount of pTSA. The reac-
tion mixture was stirred at room temperature for 6 h. Solid NaH-
CO3 was added to neutralize the pTSA and filtered. The filtrate
was concentrated under reduced pressure and purification by silica
gel column chromatography (EtOAc/pet-ether, 8:2) and afforded
C.H.S., T.R.M.R. and K.Y.G. thank UGC-New Delhi for the award
of fellowship. Author acknowledges the partial support by King
Saud University for Global Research Network for Organic Synthesis
(GRNOS).
33b (0.178 g, 80%) as a liquid. ½a D25
ꢁ
¼ þ4:0 (c 1, CHCl3); IR (neat):
References
mmax 3428, 2931, 1704, 1604, 1515, 1457, 1267, 1163, 1032 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 6.86 (d, J = 8.3 Hz, 1H), 6.76 (d,
J = 8.3 Hz, 2H), 6.62 (d, J = 8.3 Hz, 3H), 5.35 (br s, OH, 1H), 5.33
(br s, OH, 1H), 4.03–3.91 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.80
(t, J = 6.8 Hz, 2H), 2.67 (t, J = 6.8 Hz, 2H), 2.62–2.44 (m, 4H), 1.77–
1.52 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 211.4, 146.3, 144.1,
133.6, 132.5, 129.6, 120.8, 120.7, 115.8, 114.3, 114.2, 111.0,
110.9, 66.8, 55.8, 49.3, 45.4, 38.3, 31.3, 29.2; ESI: m/z = 397
[M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C21H26O6Na:
397.1627, found: 397.1645.
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Compound 33b (0.07 g, 0.186 mmol) was converted into com-
pound 7 (0.054 g, 78%) following the procedure adopted for the
preparation of compound 2. ½a D25
¼ 0:0 (c 0.5, EtOH); IR (neat):
ꢁ
mmax 3443, 2931, 2860, 1604, 1514, 1457, 1265, 1165,
;
1032 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 6.77 (d, J = 9.1 Hz,
2H), 6.66–6.61 (m, 4H), 5.36 (bs, OH, 2H), 3.99–3.88 (m, 1H),
3.87 (s, 6H), 3.86–3.77 (m, 1H), 2.74–2.50 (m, 4H), 1.88–1.35
(m, 6H); 13C NMR (CDCl3, 75 MHz):
d 146.4, 143.7, 133.4,
120.8, 114.2, 110.9, 71.6, 55.8, 43.6, 40.7, 31.3; ESI: m/z = 399
[M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C21H28O6Na:
399.1783, found: 399.1793.
16. For the synthesis of the N-acetylthiazolidinethione complex see: Yadav, J. S.;
Naveen Kumar, V.; Srinivasa Rao, R.; Srihari, P. Synthesis 2008, 1938–1942.