Total synthesis and assignment of the absolute stereochemistry of xanthoangelol J: Development of a highly efficient method for Claisen-Schmidt condensation Dedicated to Late (Dr.) Jadab C. Sarma on his 55th birthday on first May 2013

Article abstract of DOI:10.1016/j.tet.2013.11.106

The first total synthesis of cancer chemopreventive terpenyl hydroxychalcone xanthoangelol J isolated from Angelica keiskei was accomplished with asymmetric epoxidation, aromatic C-alkylation and Claisen-Schmidt condensation via enol mode as key steps. The crucial Claisen-Schmidt condensation has been accomplished by a novel green method using KHSO ₄-SiO₂ as a recyclable catalyst under microwave activation. The absolute configuration of the molecule was also determined.

Full text of DOI:10.1016/j.tet.2013.11.106

Tetrahedron 70 (2014) 637e642
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis and assignment of the absolute stereochemistry of
xanthoangelol J: development of a highly efficient method for
ClaiseneSchmidt condensation
*
Dwipen Kakati , Nabin C. Barua
Natural Products Chemistry Division, CSIR North East Institute of Science & Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of cancer chemopreventive terpenyl hydroxychalcone xanthoangelol J isolated
from Angelica keiskei was accomplished with asymmetric epoxidation, aromatic C-alkylation and Clai-
seneSchmidt condensation via enol mode as key steps. The crucial ClaiseneSchmidt condensation has
been accomplished by a novel green method using KHSO4eSiO2 as a recyclable catalyst under microwave
activation. The absolute configuration of the molecule was also determined.
Received 19 September 2013
Received in revised form 28 November 2013
Accepted 30 November 2013
Available online 7 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Dedicated to Late (Dr.) Jadab C. Sarma on his
55th birthday on first May 2013
Keywords:
Chalcone
Green synthesis
Xanthoangelol J
KHSO4
Total synthesis
1. Introduction
effects on the induction of EpsteineBarr virus early antigen (EBV-
EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells.1
In their search for potential cancer chemopreventive agents
from natural sources, Akihisa et al. isolated xanthoangelol J (1)
from Angelica keiskei stem exudates along with 11 other com-
pounds like xanthoangelol I (2) and deoxydihydroxanthangelol H
(3).1 Its gross structure was determined on the basis of detailed
spectral analysis but the stereochemistry of the 300-C was not
assigned. In preliminary screening for cancer chemopreventive
potential this compound was found to possess potent inhibitory
EpsteineBarr virus (EBV) a human herpes virus that causes in-
fectious mononucleosis and is associated with many malignant
diseases including nasopharyngeal carcinoma, B-cell and T-cell
lymphomas2 and post transplant lymphoproliferative diseases.3
The title compound also showed potent inhibitory effect
against activation of (ꢀ)-(E)-methyl-2-[(E)-hydroxyimino]-5-
nitro-6-methoxy-3-hexemide (NOR 1), a nitrogen oxide (NO)
donor.1
OH
OH
OH
HO
MeO
5'
4'
HO
6'
4''
6''
2''
1'
3''
3'
7''
O
O
2'
1''
O
O
5''
OH
OH O
3
1
2
In a project on bioactive molecules we studied the synthesis and
* Corresponding author. Present address: Department of Chemistry, Rajiv Gandhi
University, Rono Hills, Doimukh, Itanagar 791112, Arunachal Pradesh, India. Tel.:
þ91 9678004037; fax: þ91 360 2277889; e-mail addresses: kakatid@hotmail.com,
dwipen_kakati@yahoo.co.in (D. Kakati).
bioactivity of a variety of chalconoids.4 Working on terpenylated
chalcones, the promising cytotoxic potential, very low isolation
yield (0.067%)1 and interesting structural features of the molecule
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.106

638
D. Kakati, N.C. Barua / Tetrahedron 70 (2014) 637e642
xanthoangelol J attracted us to develop a route for its synthesis.
Both the (R)- and (S)-isomers of the molecule were prepared for
biological studies and from comparison of their analytical data the
natural isomer was identified to be (S)-(þ)-xanthoangelol J. A key
step involved in the synthetic scheme is the ClaiseneSchmidt
condensation between the chiral arylketone (11a/b) and 4-
hydroxybenzaldehyde. When hydroxybenzaldehyde is a substrate,
acid catalysed methods are preferred over base catalysed versions
of ClaiseneSchmidt condensation as prior protection of the hy-
droxy groups is a prerequisite via the later.5 But in this very case it
was not possible to realise the condensation using reported
methods with catalysts like BF3eEt2O,6 I2,7 SOCl2eEtOH,8
I2eAl2O3,4a etc. It prompted us for the development of a new
method of ClaiseneSchmidt condensation with wide applicability.
KHSO4 is considered as a green catalyst9 and has been successfully
utilised in many organic transformations in supported form over
SiO2.10 Our premeditated efforts resulted in the development of
new rapid method of ClaiseneSchmidt condensation using
KHSO4eSiO2 as a reusable catalyst under microwave activation in
green reaction conditions.
products. To avoid a possible loss of the chiral fragment (9a/b) we
studied a reaction using geranyl bromide as the alkyl halide to set
the reaction conditions to get the desired alkylation occurred at 30-
C of 10. Following a literature report11 we tried the reaction using
K2CO3 in acetone and two products were isolated. However, pres-
ence of three protons in the region between
NMR spectra of the products confirms them to be O-alkylated
products.
In their studies on the synthesis of prenylated natural products,
Lee et al.12 used DBU in THF for C-prenylation of 20,40,60-trihy-
droxyacetophenone with 40% product yield. We followed the same
procedure for our reaction here and the 30-C-alkylated product was
formed in 34% isolated yield. Complete conversion of the starting
materials could not be achieved even after 52 h of reaction time.
With increasing time, formation of a non-polar mixture of products
was observed in TLC analysis.
d
6.0 and 7.0 in the 1H
Now we attempted the reaction between 9a and 10 using same
reaction conditions. After continuous stirring of 60 h the desired
product 11a was isolated in 29% yield. Presence of a singlet at d 12.9
for 20-OH in 1H NMR supported by 13C NMR data for aromatic
carbons nullifies the occurrence of O-alkylation in the product.
Further, presence of a pair of doublets in the aromatic region in-
tegrating for two protons confirms that the alkylation occurred at
30-C of 20,40-dihydroxyacetophenone.
2. Results and discussions
The retrosynthetic analysis of xanthoangelol J (1) is outlined in
Scheme 1. The molecule can be broken down to two main frag-
mentsdfragment 11a/b and 4-hydroxybenzaldehyde (12). Frag-
ment 11a/b can be obtained from 20,40-dihydroxyacetophenone
(10) and nerol (4).
We tried different Lewis acids for the ClaiseneSchmidt con-
densation between 11a and 12 but ended up with disappointing
results. Interestingly with the use of SOCl2/EtOH as a source of in
situ generated HCl,8 the starting materials got consumed with the
formation of 11% of the desired product along with a complex
mixture (TLC). This signifies that instead of Lewis acids, the con-
HO
OH
€
densation may be best induced using a mild Bronsted acid.
1
+
Therefore we studied the catalytic ability of a general laboratory
reagent KHSO4 to bring about the condensation between aceto-
phenone and benzaldehyde in ethanol. To our delight, 44% product
formation was observed after 12 h of room temperature stirring
with 20 mol % catalyst. With the same substrates we tried to find
the optimal reaction conditions in different solvents with catalytic
amount of KHSO4. Maximum product formation was observed in
the reaction in PEG compared to the reactions in the lower alcohols
or in water (Table 1). But it took as long as 42 h for completion with
91% of isolated product yield. To reduce the reaction time, the re-
action was carried out under microwave irradiation. Use of mi-
crowave at different powers (200e350 W) in different time
(1e7 min) durations could enhance the yield only up to 73%. Fur-
ther enhancement of microwave power or reaction time resulted in
the decomposition of the product formed. Then we tried the re-
action using KHSO4 in supported form. For this KHSO4 was sup-
ported over silica gel for column chromatography and used in
catalytic amount to catalyse the model reaction in PEG. This time
100% conversion was achieved after 6 min of microwave irradiation.
Presence of the solvent was found obligatory since a reaction car-
ried out without solvent keeping other reaction conditions un-
changed resulted only traces of the product. To study the necessity
of supporting KHSO4 over silica, the reaction was carried out with
same amount of KHSO4 and silica gel as a mixture, but only traces of
the product was formed. This suggests the existence of a synergistic
effect between the two when silica gel is used as a support. It may
be understood that the solid support provides a very high surface
area for the catalysis making the reaction faster.
OH O
OTBS
O
12
11a (3''S)
11b (3''R)
HO
OTBS
+
Br
OH O
10
9a (1S)
9b (1R)
4
OH
Scheme 1. Retrosynthetic analysis of xanthoangelol J.
Our approach is to design a synthetic strategy using chiral in-
termediates of known configuration that will allow us to determine
the absolute configuration of the molecule unambiguously. We
planned to synthesise two enantiomeric epoxides 5a and
b (Scheme 2) of known configuration corresponding to the terpenyl
side chain of 11a and b, respectively. Commercially available nerol
(4) was subjected to asymmetric epoxidation for this stereo-
selective synthesis to get 5a with 86% ee and 5b with 91% ee
Regioselective opening of the epoxides and subsequent conversion
of the primary eOH group to its bromide gave the fragments 9a and
b. With the requisite chiral terpenyl fragments in hand, we next
focused on the 30-C-alkylation of 20,40-dihydroxyacetophenone (10)
with these. It was presumed that the presence of a couple of hy-
droxy groups and another two perspective aryl carbons (50 and 60-
C) in 10 may lead to both C- and O- as well as mixture of C-alkylated
With this excellent catalytic system in hand we studied the
applicability of the same with a variety of substituted aryl alde-
hydes and aryl ketones (Table 2). Irrespective of the nature of
substituents in the aryl rings, chalcones were synthesised in
moderate to excellent yields without any side product using this
protocol. Products were purified by simple recrystallisation, found
to be geometrically pure and configured trans.13

D. Kakati, N.C. Barua / Tetrahedron 70 (2014) 637e642
639
OH
OTBS
OTBS
O
a/b
c
d
OH
OH
HO
OH
7a (6S)
6a (3S)
6b (3R)
5a (2R,3S)
5b (2S,3R)
4
7b (6R)
e
HO
g
OTBS
Br
OTBS
f
+
OH O
OTBS
OH O
OH
8a (3S)
8b (3R)
9a (1S)
11a (3''S)
10
9b (1R)
11b (3''R)
+
HO
OH
HO
h
i
(S)-(+)-1
H
OH O
OTBS
O
13a (3''S)
12
13b (3''R)
i
i
ꢀ
ꢀ
Scheme 2. Synthetic scheme of (S)-(þ)-1. Reagents and conditions: (a) Ti(O- Pr)4, (ꢃ)-DET, TBHP, DCM, 4 A mol. Sieves, 91.5%; (b) Ti(O- Pr)4, (þ)-DET, TBHP, DCM, 4 A mol. Sieves,
89%; c) LiAlH4, THF, ꢃ40 ꢁC, 87%; (d) tBuMe2SiOTf, 2,6-Lutidine, DCM, ꢃ20 ꢁC, 76.9%; (e) p-TsOH, MeOH, 87.4%; (f) CBr4, Ph3P, DCM, 87.0%; (g) DBU, THF, 60h, 29%; (h) KHSO4eSiO2,
MW, 56.5%; (i) TBAF, DMPU, 4 A mol. sieves, 80 ꢁC, 8 h, 92%.
ꢀ
Table 1
consecutive cycles. Although a marginal decrease of product for-
mation was observed in the sixth cycle, no appreciable loss of
catalytic activity was observed up to the fifth cycle (Fig. 1).
Optimisation of solvent and catalyst loading
Entry
Catalyst loading
(mol %)
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
30
10
20
EtOH
MeOH
H2O
12
12
12
12
12
12
12
6
44
22
NRb
47
PEG
EtOHeH2O
MeOHeH2O
PEG-H2O
d
43
39
43
Tracec
47
9
10
11
PEG
PEG
PEG
12
12
42
32
91
a
Isolated pure yield.
No reaction.
Reaction mixture was grinded and kept in a mechanical shaker.
b
c
Fig. 1. Catalyst activity for six cycles.
Table 2
KHSO4eSiO2 catalysed synthesis of chalcones
Successful application of this new method in synthesising a va-
riety of chalcones including polyhydroxychalcones encouraged us
to apply the same for realising the condensation between 11a and
12. Equimolar amounts of the compounds 11a and 12 were irradi-
ated in MW in presence of 20 mol % catalyst. After 5 min of irra-
diation at 200 W power, TLC showed no further conversion of the
starting material. Work up followed by column chromatography
resulted in the isolation of 13a in 56.5% yield. Finally removal of the
KHSO4-SiO2
MW, PEG
R'
R
+
R'
R
H
O
O
O
Entry
R0
R
Time (min)
Yielda (%)
1
2
H
2-OH
H
H
6
7
6
8
8
7
6
7
8
5
8
8
8
7
93
91
82
81
91
92
82
80
79
85
79
80
78
82
3
4
5
6
4-OMe
3-OH
4-OH
H
4-OMe
2-NO2
4-OH
TBS group by TBAF furnished (S)-(þ)-1 {½a D23
þ28.8 (c 0.5, MeOH)}
ꢂ
in 94% yield with 7.21% overall yield. (R)-(ꢃ)-1 {½a D23
ꢃ24.0 (c 0.5,
ꢂ
4-OH
MeOH)} was also prepared in the same way by taking (þ)-DET in
the asymmetric epoxidation step of the synthetic scheme (Scheme
2). Comparison of the optical rotation values suggests the absolute
7
8
4-OH
H
4-OMe
4-NO2
9
2-OH
3-OMe, 4-OH
4-OMe
2-NO2
4-OH
3,4-OH
4-OMe
configuration of xanthoangelol J {[
a
]
25 þ6.0 (c 0.1, MeOH)} to be (S)-
D
10
11
12
13
14
4-OCH2CH]CH2
2,4-OMe
2,4-OH
4-OH
2,4-OMe
(þ)-xanthoangelol J.
3. Conclusion
a
Isolated pure yield.
Thus we developed the first synthetic route for the total syn-
thesis of xanthoangelol J along with the determination of its ab-
solute configuration. The synthesis was accomplished in eight steps
with 7.2% overall yield. A new, green method was also developed
for the synthesis of chalcones with wide applicability. The final step
i.e., the ClaiseneSchmidt condensation involved in the synthetic
scheme of xanthoangelol J was realised using this green method.
In order to study the reusability of the catalyst it was separated
from the reaction mixture by filtration through a sintered funnel,
washed properly with EtOH and oven dried at 150 ꢁC for 2 h.
Thereafter it was used to catalyse the reaction between acetophe-
none and benzaldehyde and the process was repeated for six

640
D. Kakati, N.C. Barua / Tetrahedron 70 (2014) 637e642
Inexpensive and reusable catalyst, short reaction time, use of
a green solvent PEG and use of microwave irradiation as energy
source render this new endeavour as a potential alternative over
the available methods of ClaiseneSchmidt condensation.
to get (2.01 g, 11.8 mmol, 91.5%, 86% ee)15 of 5a as a colourless oil.
25
[a
]
þ18.3 (c 1.6, CHCl3); IR (CHCl3, cmꢃ1) 3427, 2968, 1672, 1647,
D
1450, 1380, 1257, 1218, 1033, 913; 1H NMR (300 MHz, CDCl3)
d
5.12e5.07 (m, 1H, 6CH), 3.84e3.80 (m, 1H, 1CHH), 3.69e3.63 (m,
1H, 1CHH), 2.99 (dd, J¼6.84, 4.47 Hz, 1H, 2CH), 2.13e2.08 (m, 2H,
5CH2), 1.84 (br s, 1H, OH), 1.69 (s, 3H, 7CH3), 1.62 (s, 3H, 7CH3),
1.53e1.45 (m, 2H, 4CH2), 1.34 (s, 3H, 3CH3); 13C NMR (75 MHz,
4. Experimental
4.1. General remarks
CDCl3) d 132.3 (C-7), 123.2 (C-6), 64.4 (C-2), 61.5 (C-1), 61.2 (C-3),
33.1 (C-4), 25.6 (7CH3), 19.5 (C-5), 17.6 (3CH3),16.9 (7CH3); MS (ESI):
All commercially available chemicals and reagents were pur-
chased from Aldrich and used without further purification. Melting
points were determined with a Buchi B 540 apparatus in open
capillaries and are uncorrected. IR spectra were recorded on a Per-
kineElmer 1640 FT-IR instrument. The 1H and 13C NMR spectra
were recorded on Bruker DPX-300 NMR machine with TMS as the
internal standard in solvents. Mass spectra were recorded on
a WATERS Micro-mass ZQ 4000 (ESI Probe) spectrometer. Optical
rotations were measured using a PerkineElmer 343 polarimeter.
Elemental analyses were carried out using a PerkineElmer series II
CSNS/O Model 2400 analyzer.
m/z 171 (MþH)þ.
4.5. (3S)-3,7-Dimethyl-oct-6-ene-1,3-diol (6a)16
LiAlH4 (0.908 g, 23.9 mmol) was slowly added to anhydrous THF
(40 mL) under argon cooled to ꢃ40 ꢁC and stirred for 5 min.
Compound 5a (1.7 g, 9.98 mmol) dissolved in THF (5 mL) was added
drop wise to this solution. The reaction mixture was maintained at
ꢃ40 ꢁC for 4 h, then was allowed to warm to room temperature and
stirred overnight. The reaction was quenched with saturated tar-
taric acid (25 mL) and stirred for 1 h. After filtration through Celite,
it was extracted with EtOAc (3ꢄ40 mL). The organic layer was dried
over anhydrous Na2SO4. Chromatography over silica gel
4.2. Preparation of the catalyst
(100e200 mesh, EtOAc/hexane) yielded 6a as a colourless oil (1.5 g,
24
KHSO4 (1.0 g) was dissolved in 200 mL of distilled water. Silica
gel for column chromatography (4.0 g, 60e120 mesh) was slowly
added to the solution with continuous swirling. Then the mixture
was kept in a hot air oven at 150 ꢁC for 6 h and stored in a dessicator.
8.7 mmol, 87%); [
a
]
þ1.61 (c 1.5, CHCl3); IR (CHCl3, cmꢃ1) 3536,
D
3382, 2969, 2928, 2883, 1557, 1451, 1376, 1342, 1216, 1116, 1067; 1H
NMR (300 MHz, CDCl3)
d
5.12 (t, J¼6.9 Hz, 1H, 6CH), 3.87e3.84 (m,
2H, 1CH2), 2.05e2.01 (m, 2H, 5CH2), 1.68 (s, 3H, 7CH3), 1.62 (s, 3H,
7CH3), 1.56 (t, J¼7.3 Hz, 2H, 2CH2), 1.52e1.49 (m, 4H, 4CH2, 1,3OH),
4.3. Representative procedure for synthesis of chalcones
(Table 2)
1.24 (s, 3H, 3CH3); 13C NMR (75 MHz, CDCl3)
d 131.6 (C-7), 124.1 (C-
6), 73.7 (C-3), 59.5 (C-1), 42.2 (C-2), 41.3 C-4), 26.4 (3CH3), 25.6
(7CH3), 17.5 (C-5), 16.8 (7CH3); MS (ESI): m/z 173 (MþH)þ.
In a typical reaction acetophenone (0.2 g, 1.66 mmol) and
benzaldehyde (0.176 g, 1.66 mmol) was dissolved in PEG (8 mL) and
to this solution was added 0.225 g KHSO4eSiO2 (20 mol % KHSO4).
Then the mixture was transferred to a sealed reaction vessel of
Anton Paar Synthos 3000 microwave reactor and irradiated for
6 min at 250 W power. Maximum internal temperature observed
was 92e99 ꢁC and pressure 5.3e5.7 bar. After cooling to room
temperature ethanol (10 mL) was added to the reaction mixture
and filtered through a sintered funnel to separate the solid catalyst.
The filtrate was concentrated under reduced pressure and the
product was recrystallised from the ethanol.
4.6. (6S)-6,8-Bis-(tert-butyldimethylsilanyloxy)-2,6-dimethyl-
oct-2-ene11 (7a)
To an ice cold stirred solution of 6a (1.4 g, 8.12 mmol) in CH2Cl2
(50 mL), 2,6-lutidine (3.47 g, 32.4 mmol) and TBSOTf (5.15 g,
19.5 mmol) were added at 0 ꢁC. The resulting mixture was warmed
to room temperature and stirred for 12 h, and then water (40 mL)
was added. The aqueous layer was extracted with CH2Cl2
(3ꢄ40 mL). Combined organic phase was washed with brine, dried
(Na2SO4), and concentrated under reduced pressure. The crude
mixture was purified by column chromatography over silica gel
(100e200 mesh) using EtOAc/hexane as the mobile phase to get the
4.4. (2R,3S)-3-Methyl-3-((4-methylpent-3-enyl)oxiran-2-yl)
methanol (5a)14
product 7a as a colourless oil (2.5 g, 6.25 mmol, 76.9%). ½a D23
þ0.68
ꢂ
(c 1.5, CHCl3), IR (KBr, cmꢃ1) 2998, 2962, 2919, 2903, 1609, 1540,
To a stirred suspension of crushed molecular sieves (4 A, 0.4 g) in
1493, 1464, 1409, 1360, 1238, 1098, 991; 1H NMR (300 MHz, CDCl3)
ꢀ
anhydrous CH2Cl2 (40 mL),
L
-(ꢃ)-DET (0.409 g, 1.98 mmol) and
d
5.09 (t, J¼6.71 Hz, 1H, 3CH), 3.71 (t, J¼7.13 Hz, 2H, 8CH2),
Ti(OiPr)4 (0.366 g, 1.29 mmol) were added. The suspension was
then cooled to ꢃ20 ꢁC, TBHP (3.51 mL, 19.3 mmol, 5.5 M in CH2Cl2)
was slowly added to it and the mixture was stirred for 40 min at
ꢃ20 ꢁC. Then the suspension was further cooled to ꢃ25 ꢁC before
2.0 g (12.9 mmol) of 3,7-dimethyl-octa-2,6-dien-1-ol (4) was added
drop wise as a 50% solution in anhydrous CH2Cl2. The suspension
was stirred for another 3 h atꢃ25 ꢁC. Then the temperature of the
suspension was raised to 0 ꢁC, 30 mL of water was added and
allowed to reach room temperature. Now aqueous NaOH (30 mL,
30% solution in water, saturated with NaCl) was added to the sus-
pension and stirred for 25 min until a clear phase separation ob-
served. The suspension was then filtered through a sintered funnel
to separate the residues of the molecular sieves from the solution.
Liquid phases were separated and the aqueous phase was extracted
with CH2Cl2 (3ꢄ40 mL). Combined organic phases were dried over
Na2SO4 and the solvent was removed under reduced pressure.
Resulting thick oil was purified by column chromatography over
silica gel (100e200 mesh) using EtOAc/hexane as the mobile phase
2.08e1.89 (m, 2H, 4CH2),1.81e1.66 (m, 2H, 7CH2), 1.64 (s, 3H, 2CH3),
1.61 (s, 3H, 2CH3), 1.48e1.33 (m, 2H, 5CH2), 1.22 (s, 3H, 6CH3), 0.89
(s, 9H, C(CH3)3), 0.86 (s, 9H, C(CH3)3), 0.07 (s, 6H, Si(CH3)2), 0.05 (s,
6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3)
d 131.4 (C-2), 124.7 (C-3),
74.9 (C-6), 60.1 (C-8), 44.9 (C-7), 43.1 (C-5), 28.1 (6CH3), 26.1
(SiC(CH3)), 26.0 (SiC(CH3)), 25.8 (2CH3), 23.3 (C-4), 18.4 (SiC(CH3)3),
17.1 (2CH3), ꢃ1.9 (Si(CH3)2), ꢃ5.5 (Si(CH3)2); MS (ESI): m/z 401
(MþH)þ.
4.7. (3S)-3-(tert-Butyldimethylsilanyloxy)-3,7-dimethyl-oct-
6-en-1-ol (8a)
To a cooled (0 ꢁC) solution of the bis-TBS-ether 7a (2.4 g,
5.98 mmol) in MeOH (40 mL), p-TsOH (0.123 g, 0.71 mmol) was
added as a solid. The reaction mixture was stirred at the same
temperature for 30 min. Then it was quenched with solid NaHCO3
and filtered. The filtrate was concentrated under reduced pressure
and purified by column chromatography over silica gel

D. Kakati, N.C. Barua / Tetrahedron 70 (2014) 637e642
641
(100e200 mesh) using EtOAc/hexane as the mobile phase to isolate
temperature, ethyl acetate (15 mL) was added to the reaction mixture
and filtered through a sintered funnel to separate the solid catalyst.
After aqueous washing (1ꢄ15 mL), the organic layer was dried over
Na2SO4 and concentrated under reduced pressure. Column chro-
matography over silica gel (100e200 mesh) using EtOAc/hexane as
the solvent system afforded 13a as a yellow oil (0.204 g, 0.39 mmol,
8a as a colourless oil (1.50 g, 5.23 mmol, 87.4%); ½a D23
þ2.13 (c 1.55,
ꢂ
CHCl3); IR (KBr, cmꢃ1) 3407, 3080, 2967, 2438, 2868, 1630, 1460,
1377, 1358, 1148,1096; 1H NMR (300 MHz, CDCl3)
d
5.08 (t, J¼7.1 Hz,
1H, 6CH), 3.80 (t, J¼5.71 Hz, 2H, 1CH2), 2.71 (m, 2H, 5CH2), 1.96 (m,
2H, 2CH2), 1.69 (s, 3H, 7CH3), 1.60 (s, 3H, 7CH3), 1.56 (t, J¼5.72 Hz,
2H, 4CH2), 1.22 (s, 3H, 3CH3), 0.87 (s, 9H, C(CH3)3), 0.12 (s, 6H,
56.5%); ½a 2D3
ꢂ
þ26.7 (c 0.51, MeOH); IR (KBr, cmꢃ1) 3378, 2965, 2926,
Si(CH3)2); 13C NMR (75 MHz, CDCl3)
d
132.1 (C-7), 124.3 (C-6), 77.1
1619, 1605, 1558, 1448, 1375, 1231, 1157, 1056, 916; 1H NMR
(C-3), 60.2 (C-1), 44.5 (C-2), 42.6 (C-4), 27.8 (3CH3), 25.7 (7CH3),
25.4 (SiC(CH3), 25.3 (SiC(CH3), 23.1 (C-5), 18.2 (SiC(CH3)3), 17.7
(7CH3), ꢃ1.3 (SiCH3). MS (ESI): m/z 287 (MþH)þ.
(300 MHz, CD3OD)
(d, J¼15.3 Hz, 1H,
d
13.9 (s,1H, 20OH), 7.90 (d, J¼8.7 Hz,1H, 60H), 7.78
a
-H), 7.68 (d, J¼15.3 Hz, 1H, -H), 7.65 (d, J¼8.32 Hz,
b
2H, 2H, 6H), 6.86 (d, J¼8.38 Hz, 2H, 3H, 5H), 6.44 (d, J¼8.4 Hz,1H, 5H),
5.10e5.06 (m, 1H, 600CH), 2.70e2.64 (m, 1H, 100CH2), 2.09e2.04 (m,
2H, 500CH2), 1.66e1.60 (m, 2H, 200CH2), 1.61 (s, 3H, 700-CH3), 1.58 (s, 3H,
700-CH3), 1.50e1.42 (m, 2H, 400CH2), 1.19 (s, 3H, 300-CH3), 0.87 (s, 9H,
4.8. (1S)[1-(20-Bromo-ethyl)-1,5-dimethyl-hex-4-enyloxy]-
tert-butyldimethylsilane (9a)
SiC(CH3)3), 0.12 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CD3OD)
d
191.0
CBr4 (2.26 g, 6.83 mmol) was added under N2 at room temper-
ature to a solution of 8a (1.4 g, 4.88 mmol) in anhydrous CH2Cl2
(50 mL). After stirring for 10 min the solution was cooled to 0 ꢁC and
Ph3P (3.59 g, 13.7 mmol) was added. The mixture was stirred
overnight and passed through a silica gel (60e120 mesh) column to
separate the highly polar coloured by-products to get 9a as brown
(CO), 165.6 (C-40), 163.6 (C-20), 161.8 (C-4), 145.4 (C- ), 132.4 (C-700),
b
131.8 (C-60),130.1(C-1),128.1(C-2, C-6),126.5 (C-600),119.0 (C-10),117.9
(C-3, C-5), 114.8 (C-30), 75.0 (C-300), 46.0 (C-200), 41.3 (C-400), 29.1
(3CH3), 27.9 (700CH3), (SiC(CH3)), 25.6 (SiC(CH3)), 25.3 (SiC(CH3)), 18.3
(700CH3), 7.3 (C-100), ꢃ1.3 (Si(CH3)2). MS (ESI): m/z 524 (M)þ.
a 23
oil (1.48 g, 4.25 mmol, 87.0%); ½ ꢂD þ1.9 (c 1.51, CHCl3); IR (KBr,
4.11. (E)-1-[20,40-Dihydroxy-(300S)-(300-hydroxy-300,700-dimethy-
loct-600-enyl)-phenyl]-3-(4-hydroxyphenyl)-propenone [(S)-
(D)-1]
cmꢃ1) 2969, 2858, 1650, 1444, 1384, 1369, 1202, 1110, 840; 1H NMR
(300 MHz, CDCl3)
d
5.11 (t, J¼7.10 Hz, 1H, 4CH), 3.67 (t, J¼5.70 Hz,
2H, 20CH2), 2.68 (t, J¼5.73 Hz, 2H, 10CH2), 1.95e1.87 (m, 2H, 3CH2),
1.68 (s, 3H, 5CH3), 1.61 (s, 3H, 5CH3), 1.59e1.49 (m, 2H, 2CH2), 1.20
(s, 3H, 1CH3), 0.86 (s, 9H, SiC(CH3)3), 0.32 (s, 6H, Si(CH3)2); 13C NMR
Compound 13a (0.15 g, 0.36 mmol) was added to a 1.0 M solu-
tion of tetra butyl ammonium fluoride in THF (1.43 mL, 1.43 mmol)
and the solution was concentrated in vacuo. The residual oil was
dissolved in DMPU (1.5 mL) and crushed activated molecular sieves
(75 MHz, CDCl3)
d 132.9 (C-5), 124.6 (C-4), 77.4 (C-1), 41.9 (C-2),
30.5 (1CH3), 27.8 (5CH3), 26.1 (C-20), 25.8 (SiC(CH3)), 25.5
(SiC(CH3)), 25.3 (SiC(CH3)), 23.0 (C-3), 18.2 (5CH3), 18.1 (SiC(CH3)3),
ꢃ1.3 (Si(CH3)2). MS (ESI): m/z 350 (MþH)þ.
ꢀ
(4 A, 0.15 g) were added to it. The resulting suspension was heated
at 80 ꢁC for 8 h. Then the reaction mixture was cooled to room
temperature, diluted with ethyl acetate (10 mL) and poured on to
cold water. The solution was extracted with EtOAc (3ꢄ10 mL), dried
over Na2SO4, filtered and concentrated under reduced pressure.
The resulting oil was washed with hexane to remove any residual
DMPU and subjected to column chromatography over silica gel
(100e200 mesh) using EtOAc/hexane as the mobile phase to afford
(S)-(þ)-1 as a yellow solid (0.136 g, 0.331 mmol, 92%); mp
4.9. 1-{(300S)-[300-(tert-Butyl-dimethyl-silanyloxy)-300,700-di-
methyl-oct-6-enyl]-20,40-dihydro-xyphenyl}-ethanone (11a)
A mixture of 9a (1.01 g, 2.9 mmol), 20,40-dihydroxyacetophenone
(10, 0.45 g, 2.9 mmol) and DBU (0.441 g, 2.9 mmol) in dry THF
(30 mL) was stirred at room temperature for 20 h. Addition of 2 N
HCl (15 mL), extraction with EtOAc (3ꢄ30 mL), washing with brine
(1ꢄ30 mL) and removal of the solvent followed by column chro-
matography over silica gel (100e200 mesh) using EtOAc/hexane as
the mobile phase resulted in the isolation of 11a as a thick brown oil
121e123 ꢁC [lit. 120e123 ꢁC];1
½
a 2D3
ꢂ
þ28.8 (c 0.5, MeOH); IR (KBr,
cmꢃ1) 3370, 2969, 2929, 1615, 1605, 1562, 1512, 1444, 1370, 1236,
1167, 1107, 980, 833, 796; 1H NMR (300 MHz, CD3COCD3)
d
13.9 (s,
-H),
1H, 20OH), 7.91 (d, J¼8.8 Hz, 1H, 60H), 7.78 (d, J¼15.3 Hz, 1H,
b
(0.353 g, 0.84 mmol, 29%); ½a D23
ꢂ
þ6.9 (c 0.5, CHCl3); IR (KBr, cmꢃ1
)
7.70 (d, J¼15.3, 1H, -H), 7.67 (d, J¼8.4 Hz, 2H, 2H, 6H), 6.87 (d,
a
3381, 2960, 1629, 1606, 1455, 1376, 1357, 1150, 1058, 916, 712; 1H
J¼8.4 Hz, 2H, 3H, 5H), 6.45 (d, J¼8.8 Hz, 1H, 50H), 5.10e5.05 (m, 1H,
600CH), 2.71e2.68 (m, 1H, 100CH2), 2.08e2.04 (m, 2H, 500CH2),
1.65e1.60 (m, 2H, 200CH2), 1.61 (s, 3H, 700CH3), 1.58 (s, 3H, 700CH3),
1.50e1.42 (m, 2H, 400CH2), 1.19 (s, 3H, 3CH3); 13C NMR (75 MHz,
NMR (300 MHz, CDCl3)
d
13.1 (s, 1H, 20OH); 7.57 (d, J¼8.8 Hz, 1H,
60H); 6.39 (d, J¼8.6, 1H, 50H), 5.11 (t, J¼7.41 Hz, 1H, 600CH), 2.75 (t,
J¼5.81 Hz, 2H, 100CH2), 2.62e2.40 (m, 2H, 500CH2), 2.48 (s, 3H,
COCH3), 1.69 (s, 3H, 700CH3), 1.61 (s, 3H, 700CH3), 1.82e1.54 (m, 2H,
400CH2), 1.20 (s, 3H, 300CH3), 0.87 (s, 9H, SiC(CH3)3), 0.12 (s, 6H,
CD3COCD3)
(C-
), 132.2 (C-2, C-6), 131.8 (C-700), 130.6 (C-60), 128.1 (C-1), 126.5
(C-600),119.0 (C-
d
193.6 (CO), 165.7 (C-20), 163.4 (C-40), 161.4 (C-4), 145.4
b
Si(CH3)2); 13C NMR (75 MHz, CDCl3)
d
190.9 (CO), 161.4 (C-40), 159.2
a
),117.9 (C-30),117.3 (C-3, C-5),114.8 (C-10),108.8 (C-
(C-20), 132.2 (C-700), 129.1 (C-60), 124.3 (C-600), 119.0 (C-10), 117.8 (C-
30), 107.9 (C-50), 77.2 (C-300), 45.6 (C-200) 41.9 (C-400), 30.5 (300CH3),
27.8 (700CH3), 7.1 (C-100), 25.7 (SiC(CH3)), 25.5 (SiC(CH3)), 25.3
(SiC(CH3)), 23.1 (C-300), 18.2 (700CH3), 18.1 (SiC(CH3)3), ꢃ1.3
(Si(CH3)2). MS (ESI): m/z 421 (MþH)þ.
50), 73.0 (C-300), 43.0 (C-400), 41.3 (C-200), 27.9 (300-CH3), 26.3 (7-CH3),
23.9 (C-500), 18.4 (C-100), 18.1 (7-CH3). MS (ESI): m/z 411 (MþH)þ.
Anal. calcd for C25H30O5: C, 73.15; H, 7.37. Found: C, 73.11; H, 7.39.
Acknowledgements
4.10. (E)-1-{(300S)-[300-(tert-Butyl-dimethyl-silanyloxy)-300,700-
dimethyl-oct-600-enyl]-20,40-dihydroxyphenyl}-3-(4-
hydroxyphenyl)-propenone (13a)
The authors are thankful to the Director, CSIR NEIST for pro-
viding necessary facilities, CSIR New Delhi for funding the project
(NWP-0037), the Analytical Chemistry Division, CSIR NEIST for re-
cording the spectra and the reviewers for their valuable
suggestions.
11a (0.29 g, 0.69 mmol), 4-hydroxybenzaldehyde (12, 0.084 g,
0.69 mmol), PEG-400 (5 mL) and KHSO4eSiO2 (0.326 g) was mixed in
a reaction vessel of Anton Paar Synthos 3000 MW reactor. Then the
mixture was irradiated at 200 W power for 5 min (TLC showed
completion of the reaction). Maximum internal temperature ob-
served was 72 ꢁC and pressure 5.2e5.4 bar. After cooling to room
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.11.106.

642
D. Kakati, N.C. Barua / Tetrahedron 70 (2014) 637e642
9. Baghernejad, B.; Oskooie, H. A.; Heravi, M. M.; Beheshtiha, Y. S. Chin. J. Chem.
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