Synthesis of (+)-varitriol analogues via novel and versatile building blocks based on julia olefination

Article abstract of DOI:10.1002/ejoc.200901012

The synthesis of (+)-varitriol (1) analogues was achieved through, the use of Julia olefination. The potential anticancer properties of 1 coupled with, our interest in developing building blocks that enable olefin formation under the Julia protocol constitute the basis of our research project. Efforts are aimed at the synthesis of building blocks 2 and 3 and to explore their use towards the synthesis of (+)-varit:riol analogues. Herein, we would, like to present the synthesis of building block 3 and its ability to react with variety of substituted aromatic-, heterocyclic- and carbohydrate-derived aldehydes to yield alkene 6 in moderate to good yields with E as the major isomer. The successful, coupling of 2 with (furanoside moieties) aldehydes 5k, 5m and 5n in particular and the obtainment of compound 23 reflect the promise associated with the new strategy.

Full text of DOI:10.1002/ejoc.200901012

FULL PAPER
DOI: 10.1002/ejoc.200901012
Synthesis of (+)-Varitriol Analogues via Novel and Versatile Building Blocks
Based on Julia Olefination
Annamalai Senthilmurugan[a] and Indrapal Singh Aidhen*[a]
Dedicated to Professor G. C. Kulkarni on the occasion of his 60th birthday
Keywords: Natural products / Varitriol analogues / Julia olefination / Sulfones
The synthesis of (+)-varitriol (1) analogues was achieved
through the use of Julia olefination. The potential anticancer
properties of 1 coupled with our interest in developing build-
building block 3 and its ability to react with variety of substi-
tuted aromatic-, heterocyclic- and carbohydrate-derived al-
dehydes to yield alkene 6 in moderate to good yields with E
ing blocks that enable olefin formation under the Julia proto- as the major isomer. The successful coupling of 2 with
col constitute the basis of our research project. Efforts are
aimed at the synthesis of building blocks 2 and 3 and to ex-
plore their use towards the synthesis of (+)-varitriol ana-
logues. Herein, we would like to present the synthesis of
(furanoside moieties) aldehydes 5k, 5m and 5n in particular
and the obtainment of compound 23 reflect the promise asso-
ciated with the new strategy.
logues of 1 and evaluated their cytotoxicity. In the absence
of detailed investigations, initial studies indicated that too
much variation in the aromatic ring was unfavourable.
Introduction
(+)-Varitriol (1, Figure 1), a natural product isolated
from the marine strain of the fungus Emericella variecolor
in 2002,[1] has attracted the attention of synthetic organic
chemists due to its potential anticancer properties.[2] Jen-
nings[3] first synthetic efforts towards 1, using -ribose for
the furanoside part of 1, led to the synthesis of its enantio-
mer, which not only established the configuration of the
natural product but also laid the basis for their argument
towards the possible synthesis of 1 through the use of ex-
pensive -ribose. Subsequent to this, Taylor[4] also achieved
the synthesis of 1 along with other analogues by making
use of the Ramberg–Backlund reaction for the C–C bond
formation between the aromatic and furanoside parts. The
first total synthesis of 1 was presented by Shaw,[5] and it
involved the use of olefin cross metathesis for the same C–
C connectivity between the aromatic and furanoside parts.
Although the elegant use of methyl α--mannopyranoside
as the starting material for the furanoside part of 1 obviated
the need for expensive -ribose, the synthetic route became
lengthy and the yield in the olefin cross metathesis step was
modest. Simultaneously, Nagarapu[6] also used the olefin
cross metathesis strategy for the synthesis of novel ana-
Figure 1. Structure of (+)-varitriol (1).
Given the fact that (+)-varitriol (1) has an impressive
biological activity against several tumours and awaits eluci-
dation of its mode of action, synthetic pursuits towards an-
alogues in particular becomes necessary and justified. In
this context, a synthetic strategy based on the disconnection
X was envisaged (Figure 2). The conceived synthetic route
was designed to retain the aromatic residue needed in natu-
ral product 1, while allowing the flexibility of altering the
furanoside part by coupling with a variety of functionalized
aldehydes, particularly from the domain of carbohydrates.
The proposed synthetic equivalent for synthon A towards
this objective was 2. The envisaged C–C bond formation
for the proposed disconnection was based on the efficiency
of the Julia olefination in the literature (Figure 2).[7] While
this exploration was underway, another synthesis of (+)-
varitriol (1) by Gracza appeared, wherein the requisite
[a] Department of Chemistry, Indian Institute of Technology
Madras,
Chennai 600036, India
Fax: +91-44-22574202
E-mail: isingh@iitm.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901012.
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furanoside part of the natural product had been synthesized
With the use of anhydrous K2CO3 as base in dry DMF
from dimethyl -tartrate and appended to the aromatic al- at 70 °C, the benzylic carbanion was formed and treated
dehyde through the Kocien´ski–Julia protocol.[8]
with a variety of substituted aromatic and heterocyclic alde-
hydes 5a–h in excellent yields over a 10–12 h reaction period
(Scheme 2). Olefinated products 6a–h were formed either
exclusively as the E isomer or as an E/Z mixture (Table 1).
1
All the products were characterized by H and 13C NMR
spectroscopy and mass spectrometry. To preclude any pos-
sible decomposition of sensitive carbohydrate-derived alde-
hydes under the reaction conditions, which involved heating
at 70 °C, the use of sodium hydride as a base in dry DMF
at ambient or low temperature was explored (Scheme 2). To
our satisfaction and delight, a clean reaction ensued with a
variety of carbohydrate-derived aldehydes 5i–n[10] at 0 °C
(Table 1). Successful synthesis of sulfone 3 and its facile re-
action with a variety of aldehydes offered proof of concept
for the proposed new strategy towards the synthesis of (+)-
varitriol (1) analogues through the disconnection X. The
focus and objective of this new strategy for analogues is to
bring variation into the furanoside part while retaining the
aromatic structural features of the natural product intact.
Figure 2. Retroanalysis of (+)-varitriol (1) and novel building
blocks 2 and 3.
Results and Discussion
Towards model studies, synthesis of ester sulfone 3 and
its reaction with the aldehyde functionality was planned.
Sulfone 3, hitherto unknown in the literature, could be eas-
ily synthesized in three steps from methyl o-toluate (4). It
involved bromination of the benzylic site in 4 with N-bro-
mosuccinimide (NBS) to give known ester bromide 4a.[9]
Nucleophilic substitution of benzyl bromide 4a with 2-mer-
captobenzothiazole (HS–BT) occurred in the presence of
anhydrous K2CO3 in acetone at reflux to furnish sulfide 4b
in 70% yield. Sulfide 4b was then oxidized to sulfone 3 by
30% H2O2 in the presence of sodium tungstate at 0 °C in
81% yield (Scheme 1).
Scheme 2. Model studies on the reactivity of building block 3.
With successful model studies in the background, the
synthesis of the key building block 2 was initiated by using
the same protocol as that described for the synthesis of 3.
This demanded ester 7 as the necessary starting material.
Although commercially available, it is prohibitively expens-
ive and therefore merited an efficient and convenient syn-
thetic route from cheap starting materials as an alternative.
A literature survey (Scheme 3) revealed the use of 2,3-di-
methyl anisole (8) or 3-methylanisole (9) as the starting ma-
terial towards this end. The use of the former[11] involves
regioselective oxidation of the methyl group at the C-2 posi-
tion and the latter[12] uses heteroatom-directed lithiation for
introduction of the carboxyl group at the C-2 position.
Stringent reaction conditions and nonexclusive lithiation at
C-2 with nBuLi for subsequent carboxylation by using car-
bon dioxide as the electrophile made the use of 3-methyl-
anisole as the starting material deter. The regioselective oxi-
dation of 8 is based on exclusive benzylic bromination at
the C-2 methyl with 1 equivalent of NBS, under the influ-
ence of a 200-W light source and AIBN (azobisisobutyro-
nitrile) as the radical initiator. Further oxidation of benzylic
bromide intermediate 10 to aldehyde 11 by using AgNO3 as
an oxidant, followed by second oxidation with NBS under
radical conditions paves the way for 7. Recently, regioselec-
tive lithiation[13] of o-anisic acid with the use of lithium
Scheme 1. Synthesis of building block 3 for model studies.
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Synthesis of (+)-Varitriol Analogues via Julia Olefination
Table 1. Formation of olefins 6a–n by reaction of sulfone 3 with
aldehydes 5a–n.
Scheme 3. Literature procedures for the synthesis of starting mate-
rial 7.
Due to the ready availability of 2,3-dimethylanisole (8),
our initial efforts banked on its use. Unfortunately, in our
hands, despite utmost care in replicating the reaction condi-
tions,[11] compound 8 underwent ring bromination in ad-
dition to benzylic bromination (Scheme 4) during the imple-
mentation of the two-step procedure for the synthesis of
compound 11 en route to the synthesis of desired starting
material 7. The new product was isolated in 30% yield, and
besides recovery of starting material 8, a 1:1 mixture of
compounds 11 and 13 was obtained through the intermedi-
acy of 10 and 12, respectively. This was evident by analysis
1
of the H NMR spectra, which showed a set of peaks in
the aldehyde region at δ = 10.53 and 10.63 ppm. As antici-
pated, there were two doublets centred at δ = 6.80 (J =
8.0 Hz) and 6.83 ppm (J = 8.4 Hz) and a triplet at δ =
7.37 ppm (J = 8.0 Hz) for the aromatic protons in desired
compound 11. In addition to these signals there were two
doublets centred at δ = 6.74 (J = 8.8 Hz) and 7.66 ppm (J
= 8.8 Hz) in the aromatic region, which were ascribed to
ring brominated product 13. Two sharp singlets at δ = 3.88
and 3.89 ppm and also at δ = 2.56 and 2.63 ppm correspond
to the requisite –OCH3 and –CH3 groups in compounds
11 and 13. Exploring the use of 2 equivalents of NBS to
circumvent the incomplete consumption of starting mate-
rial 8, to our disappointment, led to the predominant for-
mation of 13 in 50% yield over two steps. In another at-
tempt to prevent the observed ring bromination, benzylic
bromination with 1 equivalent of NBS was carried out un-
der reduced intensity of light by using a 100 W bulb instead
of a 200 W bulb. To our delight, under this slight variation,
no ring bromination was observed and the two-step pro-
cedure of benzylic bromination at the C-2 methyl group fol-
lowed by oxidation of the benzylic bromide afforded the
[a] Conditions A: K2CO3, DMF, 70 °C. [b] Conditions B: NaH,
DMF, 0 °C. [c] Ratio calculated on the basis of the H NMR spec-
tra of each compound.
1
2,2,6,6-tetramethylpiperidine (LiTMP) or sBuLi/TMEDA exclusive formation of aldehyde 11, however, in 50% yield.
(N,N,NЈ,NЈ-tetramethyl-1,2-ethylenediamine) for intro- The attempted conversion of aldehyde 11 into desired ester
duction of the methyl group was reported for synthesis of 7 with the reported use of NBS was once again marred with
ester 7 under stringent reaction conditions and on a milli- undesired ring bromination and led to the exclusive forma-
gram scale.
tion of ring brominated ester 14.
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was carried out by using conditions B, that is, NaH as a
base in DMF at 0 °C, and the products were obtained after
purification by silica-gel chromatography in good yields
(Table 2).
Table 2. Julia olefination of aldehydes 5k, 5m and 5n with sulfone
2.
Scheme 4. Synthesis of intermediates 7 and 14.
Because the use of NBS for the regioselective oxidation
of the C-2 methyl group in compound 8 into an aldehyde
group or its subsequent oxidation to an ester functionality
was troublesome, we resorted to other available alternatives
in the literature for the desired conversion. Besides the use
of NBS, regioselective oxidation of the C-2 methyl group in
2,3-dimethylanisole (11) was achieved by using K2S2O8 on
a ca. 10-g scale.[14] To our satisfaction, the conversion of 8
into 11 could be easily effected in 70–75% yield by using
this method with good consistency and reproducibility. Al-
dehyde 11 was subsequently converted into acid by CuBr-
mediated oxidation[15] with tBuOOH, and the acid was con-
verted into ester 7 by using Me2SO4 and 1,8-diazabicy-
cloundec-7-ene (DBU) in acetone with good yields.[16] Ester
7 was then converted into building block 2 in three steps as
described for compound 3 in Scheme 1. This includes (a)
the benzylic bromination with NBS to furnish 15, (b) reac-
tion of the crude bromide with 2-mercaptobenzothiazole in
the presence of K2CO3 as base in acetone to afford sulfide
16 in 60% yield (over 2 steps) and finally (c) the oxidation
of sulfide 16 with 30% H2O2 in the presence of sodium
tungstate in MeOH. Sulfone 2 was obtained in 70% yield
as a crystalline solid (Scheme 5).
[a] Conditions B: NaH, DMF, 0 °C. [b] Ratio calculated on the ba-
sis of the H NMR spectra of each compound.
1
Finally, to establish the new strategy, Julia olefinated
product 22 was taken further to the triol stage. Compound
22 was subjected to reduction of the ester functionality by
lithium aluminium hydride (LAH) at 0 °C in dry THF. TLC
analysis affirmed the complete consumption of the starting
material and the appearance of a new polar spot. The crude
product from LAH reduction was further subjected to de-
protection by 1  aqueous HCl at room temperature
(Scheme 6). Triol 23 was successfully isolated in 62% yield
(2 steps). The 1H and 13C NMR spectroscopic analysis con-
firmed the presence of benzylic (–C6H3CH2OH) protons at
1
δ = 4.76 ppm as a singlet in the H NMR spectrum and at
δ = 55.8 ppm in the 13C NMR spectrum; also, the deprotec-
tion was confirmed by the disappearance of two singlets at
1
δ = 1.31 and 1.50 ppm in H NMR spectrum and at δ =
24.9 and 26.1 ppm in the 13C NMR spectrum, correspond-
ing to the acetonide methyl groups.
Scheme 6. Synthesis of triol 23.
Scheme 5. Synthesis of building block 2.
Building block 2 was then treated with aldehydes 5k, 5m
While our objective of synthesizing (+)-varitriol ana-
and 5n containing the furanoside ring to achieve the synthe- logues focused on maintaining the aromatic part identical
sis of closely related analogues of (+)-varitriol. The reaction as required in the natural product and varying only the
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Synthesis of (+)-Varitriol Analogues via Julia Olefination
furanoside part, the availability of aromatic ester 14 con- has been demonstrated that the furanoside part can be
taining a bromine substituent tempted its use for demon- replaced by a pyranoside ring system in search for more
strating the versatility of the developed strategy. Besides analogues.
this, the presence of an aryl bromide functionality in 14
provides a means for further derivatization in the aromatic
part of the natural product. Ester 14 was converted into
sulfone 26 via sulfide 25 (Scheme 7) by following the same
sequence of reaction as that described for 2 and 3. The crys-
Conclusions
In conclusion, convenient syntheses of three new build-
talline nature of 26 allowed its X-ray diffraction analysis,[17]
which fully confirmed the presence of bromine at the para
position with respect to the methoxy group in the aromatic
ring. Sulfone 26 reacted efficiently with carbohydrate-de-
rived aldehydes 5l and 5n as representative examples under
reaction conditions B to furnish 27 and 28 in 77 and 54%
yield, respectively (Scheme 8), which are valuable precur-
sors of (+)-varitriol analogues. With the synthesis of 27, it
ing blocks 2, 3 and 26 from simple aromatic substrates have
been realized in good yields with convenient preparative
procedures. These new building blocks have enabled highly
efficient coupling with a variety of aldehydes towards the
synthesis of various analogues of (+)-varitriol containing
the furanoside and pyranoside ring systems with varying
configurations at the stereocentres therein. Further use of
these building blocks demonstrating their versatility and
utility in other synthetic endeavours is currently underway.
Experimental Section
General Information: All reactions were carried out in oven-dried
glassware. Dry DMF was prepared by stirring in calcium hydride
and kept under 4 Å molecular sieves after downward distillation.
Solvents used for chromatography were LR grade. Anhydrous
K2CO3 was prepared by keeping it in a hot-air oven for 24 h at
100 °C. Thin-layer chromatography was performed on aluminium
plates coated with silica gel 60. Visualization was observed by UV
light irradiation or by dipping into a solution of cerium(IV) sulfate
(2.5 g) and ammonium molybdate (6.25 g) in 10% sulfuric acid
(250 mL) followed by charring on a hot plate. Melting points were
determined in capillaries and are uncorrected. 1H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded with CDCl3 as the
solvent and tetramethylsilane (TMS) as the reference. The proton
numbering for the spectral assignment (1H chemical shift) follows
the numbering of the carbon atoms in the corresponding name of
the compound. Mass spectra were recorded with a MICRO-Q TOF
mass spectrometer by using the ESI technique at 10 eV. Optical
rotations were measured with an Autopol IV polarimeter at room
temperature.
General Procedure for the Preparation of Bromides 4a, 15 and 24
from 4, 7 and 14, Respectively: To a solution of the ester (1 mmol,
1 equiv.) in CCl4 (15 mL) was added fresh NBS (1 equiv.) added.
To this solution was added a catalytic amount of AIBN (5 wt.-
%). The reaction mixture was heated at reflux for 2–4 h. After the
disappearance of starting material (TLC), the reaction mixture was
cooled and filtered. The resulting crude bromide was used as such
for further reactions.
Scheme 7. Synthesis and ORTEP structure of sulfone 26. Reagents
and conditions: (a) NBS, AIBN, CCl4, reflux; (b) 2-mercapto-
benzothiazole, K2CO3, acetone, reflux, 10 h, 65%; (c) 30% H2O2,
Na2WO4·2H2O, MeOH, 0 °C to r.t., 6 h, 83%.
General Procedure for the Preparation of Ester Sulfides 4b, 16 and
25: To a solution of bromide (1 mmol, 1 equiv.) in dry acetone
(10 mL) was added anhydrous K2CO3 (2 equiv.) and 2-mercapto-
benzothiazole (1.1 equiv.), and the resulting suspension was heated
at reflux for 8–12 h. After complete consumption of the starting
material, the solvent was evaporated under reduced pressure. The
resulting mass was added with water (50 mL) and extracted with
ethyl acetate (3ϫ15 mL). The collected organic layer was dried
with anhydrous Na2SO4, filtered, concentrated and subjected to pu-
rification by silica gel column chromatography.
Methyl 2-{(Benzo[d]thiazol-2-ylthio)methyl}benzoate (4b): 72%
yield; Rf = 0.43, (ethyl acetate/hexanes, 1:9); colourless oil. IR
Scheme 8. Synthesis of analogues of (+)-varitriol from building
block 26.
(CH Cl ): ν = 1077, 1263, 1426, 1456, 1712 cm–1. 1H NMR
˜
2
2
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3
3
(400 MHz, CDCl3): δ = 3.92 (s, 3 H, COOCH3), 5.00 (s, 2 H,
(d, JH,H = 7.6 Hz, 1 H, 5-H), 6.94 (d, JH,H = 8.4 Hz, 1 H, 3-H),
3
4
3
SCH2Ar), 7.27 (t, JH,H = 7.6 Hz, 1 H, 5-H), 7.31–7.34 (td, JH,H
7.30 (t, JH,H = 8.0 Hz, 1 H, 4-H), 7.56–7.60 (m, 1 H, 5Ј-H), 7.62–
3
3
3
= 0.8 Hz, JH,H = 7.6 Hz, 1 H, 4-H), 7.38–7.46 (m, 2 H, 5Ј, 6Ј-H),
7.67 (td, 4JH,H = 0.8 Hz, JH,H = 8.4 Hz, 1 H, 6Ј-H), 7.95 (d, JH,H
3
3
7.67 (d, JH,H = 7.6 Hz, 1 H, 3-H), 7.71 (d, JH,H = 8.0 Hz, 1 H,
= 8.0 Hz, 1 H, 4Ј-H), 8.25 (d, 3JH,H = 8.0 Hz, 1 H, 7Ј-H) ppm. 13
C
3
6-H), 7.90 (d, JH,H = 8.0 Hz, 1 H, 7Ј-H), 7.98–8.00 (m, 1 H, 4Ј- NMR (100 MHz, CDCl3): δ = 52.6, 56.2, 57.9, 109.9, 112.5, 122.3,
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 36.0, 52.2, 120.9, 121.4,
124.4, 125.5, 126.0, 127.6, 128.0, 131.2, 137.2, 152.6, 157.6, 164.9,
124.1, 125.9, 127.8, 128.8, 131.2, 131.7, 132.4, 135.5, 139.3, 153.1,
167.2 ppm. HRMS (EI): calcd. for C17H15NO5S2 [M + H]+
167.0, 167.4 ppm. HRMS (EI): calcd. for C16H13NO2S2 [M + H]+ 378.0470; found 378.0473.
316.0466; found 316.0461.
Methyl 2-{(Benzo[d]thiazol-2-ylsulfonyl)methyl}-3-bromo-6-meth-
Methyl 2-{(Benzo[d]thiazol-2-ylthio)methyl}-6-methoxybenzoate (16):
69% yield; Rf = 0.3, (CH2Cl2/hexanes, 1:1, 2ϫ elusion), colourless
oxybenzoate (26): 83% yield; Rf = 0.3, (ethyl acetate/hexanes, 3:7),
colourless crystals; m.p. 156–160 °C. IR (CH Cl ): ν = 1072, 1153,
˜
2
2
1288, 1337, 1435, 1465, 1578, 1717 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 3.76 (s, 3 H, OCH3), 3.80 (s, 3 H, COOCH3), 5.24 (s,
2 H, SO2CH2Ar), 6.81 (d, 3JH,H = 9.2 Hz, 1 H, 5-H), 7.48 (d, 3JH,H
= 8.8 Hz, 1 H, 5Ј-H), 7.51–7.59 (m, 2 H, 4Ј-H, 6Ј-H), 7.90–7.92
(m, 1 H, 7Ј-H), 8.15–8.17 (m, 1 H, 4Ј-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 52.8, 56.4, 57.9, 114.3, 117.9, 122.2, 125.6,
126.2, 126.7, 127.6, 128.0, 135.3, 137.5, 152.7, 156.9, 165.3,
166.8 ppm. HRMS (EI): calcd. for C17H14BrNO5S2 [M + Na]+
455.9575; found 455.9579.
oil. IR (CH Cl ): ν = 1070, 1113, 1260, 1427, 1465, 1585,
˜
2
2
1727 cm–1. H NMR (400 MHz, CDCl3): δ = 3.73 (s, 3 H, OCH3),
1
3
3.82 (s, 3 H, COOCH3), 4.54 (s, 2 H, ArCH2S), 6.76 (d, JH,H
=
3
8.4 Hz, 1 H, 5-H), 7.05 (d, JH,H = 7.6 Hz, 1 H, 3-H), 7.16–7.22
(m, 2 H, 5Ј, 6Ј-H), 7.29–7.33 (m, 1 H, 4-H), 7.63 (d, 3JH,H = 8.0 Hz,
3
1 H, 4Ј-H), 7.80 (d, JH,H = 7.6 Hz, 1 H, 7Ј-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 35.1, 52.4, 56.1, 110.9, 121.0, 121.5, 122.4,
123.3, 124.3, 126.0, 131.0, 135.4, 135.6, 153.1, 157.0, 166.2,
167.7 ppm. HRMS (EI): calcd. for C17H15NO3S2 [M + H]+
346.0572; found 346.0577.
General Procedure for the Julia Olefination of Sulfones with Alde-
hydes
Methyl
2-{(Benzo[d]thiazol-2-ylthio)methyl}-3-bromo-6-methoxy-
benzoate (25): 65% yield; Rf = 0.3, (CH2Cl2/hexanes, 1:1); colour-
Conditions A: To a suspension of sulfone 3 (0.2 g, 0.5757 mmol,
1 equiv.) and anhydrous K2CO3 (0.239 g, 1.73 mmol, 3 equiv.) in
dry DMF (3 mL) was added a solution of aldehyde (1 equiv.) in
dry DMF (2 mL), and the reaction mixture was heated at 70 °C
for 10–12 h. After complete consumption of the starting material,
the reaction mixture was quenched with water (10 mL) and ex-
tracted with ethyl acetate (3ϫ15 mL). The collected organic layer
was dried with anhydrous Na2SO4, filtered, concentrated and sub-
jected to purification by silica gel column chromatography.
less oil. IR (CH Cl ): ν = 1071, 1091, 1271, 1292, 1426, 1456, 1575,
˜
2
2
1731 cm–1. H NMR (400 MHz, CDCl3): δ = 3.81 (s, 3 H, OCH3),
1
3
3.84 (s, 3 H, COOCH3), 4.80 (s, 2 H, SCH2Ar), 6.78 (d, JH,H
=
9.2 Hz, 1 H, 5-H), 7.30 (t, 3JH,H = 8.0 Hz, 1 H, 4-H), 7.41–7.44 (m,
3
3
1 H, 6Ј-H), 7.58 (d, JH,H = 8.8 Hz, 1 H, 5Ј-H), 7.75 (d, JH,H
=
8.0 Hz, 1 H, 7Ј-H), 7.92 (d, JH,H = 8.4 Hz, 1 H, 4Ј-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 36.0, 52.7, 56.2, 112.5, 116.2, 121.0,
121.5, 124.4, 125.8, 126.1, 133.7, 134.8, 135.3, 152.7, 156.0, 166.2,
166.7 ppm. HRMS (EI): calcd. for C17H14BrNO3S2 [M + Na]+
445.9496; found 445.9492.
3
Conditions B: To a suspension of NaH (0.026 g, 0.6333 mmol,
1.1 equiv.) in dry DMF (2 mL) was added a solution of sulfone 3
(0.2 g, 0.5757 mmol, 1 equiv.) at 0 °C. The solution turned to a red-
dish orange colour, which indicated the formation of the carbanion.
After 10 min, a solution of aldehyde (1 equiv.) in dry DMF (1 mL)
was added to the reaction mixture. The disappearance of the red-
dish orange colour was observed. The reaction mixture was allowed
to attain room temperature and maintained for further 30 min to
1 h. After complete consumption of the starting material, the reac-
tion mixture was quenched with water (10 mL) and extracted with
ethyl acetate (3ϫ15 mL). The collected organic layer was dried
with anhydrous Na2SO4, filtered, concentrated and subjected to pu-
rification by silica gel column chromatography.
General Procedure for the Oxidation of Sulfides 4b, 16 and 25 into
Sulfones 3, 2 and 26, Respectively: To a solution of sulfide (1 mmol,
1 equiv.) in MeOH (2 mL) at 0 °C was added Na2WO4·2H2O
(0.5 equiv.). After 5 min of stirring, 30% H2O2 (4 equiv.) was
added, and the reaction mixture was allowed to attain room tem-
perature and stirred for 5–6 h. After complete consumption of the
starting material, MeOH from the reaction mixture was evaporated
under reduced pressure. The resulting mass was quenched with a
saturated solution of sodium metabisulfite until the effervescence
stopped. The resulting solution was then extracted with ethyl ace-
tate (3ϫ15 mL). The collected organic layer was dried with anhy-
drous Na2SO4, filtered, concentrated and subjected to purification
by silica gel column chromatography.
(E)-Methyl 2-[2-(Pyridin-2-yl)vinyl]benzoate (6a): 87% yield, (E
only); Rf = 0.32 (ethyl acetate/hexanes, 2:8), colourless oil. IR
Methyl 2-{(Benzo[d]thiazol-2-ylsulfonyl)methyl}benzoate (3): 86%
yield; Rf = 0.3 (ethyl acetate/hexanes, 2:8); colourless crystals, m.p.
(CH Cl ): ν = 1076, 1248, 1431, 1583, 1715 cm–1. 1H NMR
˜
2
2
(400 MHz, CDCl3): δ = 3.95 (s, 3 H, COOCH3), 7.13–7.21 (m, 2
104–108 °C. IR (CH Cl ): ν = 1078, 1118, 1268, 1332, 1469,
˜
2
2
3
1715 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.74 (s, 3 H, CO-
H, 1-H, 2Ј-H), 7.38 (t, JH,H = 7.6 Hz, 1 H, 4Ј-H), 7.53–7.58 (m, 2
3
3
H, 6-H, 8-H), 7.71 (t, JH,H = 7.6 Hz, 1 H, 7-H), 7.78 (d, JH,H
=
OCH3), 5.47 (s, 2 H, SCH2Ar), 7.32–7.34 (m, 1 H, 5-H), 7.42–7.44
3
3
7.6 Hz, 1 H, 3Ј-H), 7.96 (d, JH,H = 7.6 Hz, 1 H, 5-H), 8.41 (d,
(m, 2 H, Ar-H, BT-H), 7.57 (t, JH,H = 8.0 Hz, 1 H, 5-H), 7.64 (t,
3JH,H = 16.4 Hz, 1 H, ArCHCHPy), 8.63 (d, JH,H = 4.4 Hz, 1 H,
3
3JH,H = 7.2 Hz, 1 H, 4-H), 7.94–7.96 (m, 2 H, BT-H), 8.23 (d, 3JH,H
= 8.0 Hz, 1 H, 7Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.2,
58.1, 122.2, 125.5, 127.5, 127.6, 127.9, 129.3, 131.2, 131.3, 132.2,
133.5, 137.2, 152.6, 165.4, 167.2 ppm. HRMS (EI): calcd. for
C16H13NO4S2 [M + Na]+ 370.0184; found 370.0190.
6Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.2, 121.7, 122.3,
127.4, 127.9, 129.0, 130.2, 130.7, 132.3, 132.4, 137.0, 138.4, 148.9,
155.5, 167.6 ppm. HRMS (EI): calcd. for C15H13NO2 [M + H]+
240.1025; found 240.1028.
Methyl 2-{(Benzo[d]thiazol-2-ylsulfonyl)methyl}-6-methoxybenzoate tert-Butyl 3-[2-(Methoxycarbonyl)styryl]-1H-indole-1-carboxylate
(2): 75% yield; Rf = 0.3, (ethyl acetate/hexanes, 2:8), colourless
(6b): 75% yield, (E:Z = 4:1); Rf = 0.5 (ethyl acetate/hexanes, 2:8);
crystals. m.p. 134–137 °C. IR (CH Cl ): ν = 1070, 1154, 1273, 1334,
yellow oil. IR (CH Cl ): ν = 1093, 1154, 1237, 1452, 1720 cm–1. 1H
˜
˜
2
2
2
2
1470, 1589, 1718 cm–1. H NMR (400 MHz, CDCl3): δ = 3.80 (s,
NMR (400 MHz, CDCl3): δ = 1.61 (s, 9 H, tBu), 3.86 (s, 3 H,
1
3
3 H, OCH3), 3.81 (s, 3 H, COOCH3), 4.96 (s, 2 H, ArCH2S), 6.92 COOCH3), 7.07 (d, JH,H = 16.4 Hz, 1 H, ArCHCHIn), 7.23–7.29
560
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 555–564

Synthesis of (+)-Varitriol Analogues via Julia Olefination
3
(m, 4 H, Ar-H), 7.42–7.47 (m, 1 H, Ar-H), 7.68 (t, 3JH,H = 3.2 Hz,
CDCl3): δ = 3.86 (s, 3 H, COOCH3), 6.84 (d, JH,H = 16.0 Hz, 1
4
3
2 H, 4-H), 7.85–7.87 (dd, JH,H = 1.2 Hz, JH,H = 7.6 Hz, 1 H, H, ArCHCHArCl), 7.15–7.23 (m, 2 H, 2Ј, 5Ј-H), 7.25–7.29 (m, 1
3
7Ј-H), 7.91–7.93 (m, 1 H, Ar-H), 8.05 (d, JH,H = 16.4 Hz, 1 H,
H, 5-H), 7.34 (d, 3JH,H = 7.6 Hz, 1 H, 6Ј-H), 7.43–7.47 (m, 1 H, 4-
3
3
4
ArCHCHIn), 8.12 (d, JH,H = 8.0 Hz, 1 H, 6-H) ppm. Non-over-
H), 7.61 (d, JH,H = 7.6 Hz, 1 H, 3-H), 7.86–7.88 (dd, JH,H =
0.8 Hz, JH,H = 7.6 Hz, 1 H, 4Ј-H), 7.92 (d, JH,H = 16.0 Hz, 1 H,
ArCHCHArCl) ppm. Non-overlapped peaks of Z-isomer: δ = 3.82
3
3
lapped peaks of Z-isomer: δ = 1.48 (s, 9 H, tBu), 3.79 (s, 3 H,
3
COOCH3), 6.65 (d, JH,H = 12.4 Hz, 1 H, ArCHCHIn) ppm. 13C
3
NMR (100 MHz, CDCl3): δ = 28.2, 55.1, 83.9, 115.3, 119.2, 120.2,
122.9, 123.0, 124.8, 126.4, 126.9, 127.4, 128.2, 128.6, 130.7, 132.1,
132.2, 136.0, 139.5, 149.5, 167.9 ppm. Non-overlapped peaks of Z-
isomer: δ = 28.0, 52.0, 83.5, 114.9, 122.8, 124.6, 124.7, 130.6, 130.7,
149.6, 167.4 ppm. HRMS (EI): calcd. for C23H23NO4 [M + Na]+
400.1525; found 400.1534.
(s, 3 H, COOCH3), 6.55 (d, JH,H = 12 Hz, 1 H, ArCHCHArCl)
ppm. 13C NMR (100 MHz, CDCl3): δ = 52.1, 124.9, 126.7, 127.1,
127.5, 127.7, 128.6, 129.0, 129.8, 129.9, 130.7, 132.2, 134.6, 138.8,
139.3, 167.7 ppm. Non-overlapped peaks of Z-isomer: δ = 127.9,
129.3, 130.3, 134.3 ppm. HRMS (EI): calcd. for C16H13O2Cl [M +
Na]+ 295.0502; found 295.0511.
Methyl 2-(But-1-enyl)benzoate (6g): 84% yield, (E:Z = 1:1); Rf =
Methyl 2-[2-(Furan-2-yl)vinyl]benzoate (6c): 79% yield, (E:Z = 4:1);
Rf = 0.65 (ethyl acetate/hexanes, 2:8); brownish oil. IR (CH2Cl2):
˜
0.5, (ethyl acetate/hexanes, 1:9); colourless oil. IR (CH Cl ): ν =
˜
2
2
1074, 1284, 1435, 1721 cm–1. 1H NMR (400 MHz, CDCl3): δ =
ν = 1076, 1167, 1245, 1433, 1715 cm–1. 1H NMR (400 MHz,
3,3
1.15 (t, 3JH,H = 7.2 Hz, 3 H, CH2CH3), 2.23–2.31 (qd,
J
H,H
= 1.6,
CDCl3): δ = 3.84 (s, 3 H, COOCH3), 6.39–6.43 (m, 2 H, 3Ј, 4Ј-H),
6.84 (d, 3JH,H = 16.0 Hz, 1 H, ArCHCHfuryl), 7.28–7.32 (td, 4JH,H
7.6 Hz, 2 H, CH2CH3), 3.89 (s, 3 H, COOCH3), 6.14–6.21 (dt,
3,3
3
3
3
J
H,H
= 6.4, 16.0 Hz, 1 H, ArCHCHEt), 7.13 (d, JH,H = 7.2 Hz,
= 1.2 Hz, JH,H = 7.8 Hz, 1 H, 3-H), 7.42 (d, JH,H = 1.2 Hz, 1 H,
5Ј-H), 7.46–7.51 (m, 1 H, 4-H), 7.66 (d, 3JH,H = 7.6 Hz, 1 H, 3-H),
7.87 (d, 3JH,H = 16.4 Hz, 1 H ArCHCHfuryl), 7.90–7.92 (dd, 4JH,H
3
1 H, 3-H), 7.23–7.31 (m, 3 H, 2-ArH, olefin), 7.54 (d, JH,H
=
7.2 Hz, 1 H, 6-H), 7.91–7.94 (m, 1 H, 4-H) ppm. Non-overlapped
3
3
peaks of Z-isomer: δ = 1.00 (t, JH,H = 7.2 Hz, 3 H, CH2CH3),
= 1.2 Hz, JH,H = 8.0 Hz, 1 H, 6-H) ppm. Non-overlapped peaks
3,3
3
2.09–2.17 (qd,
J
H,H
= 0.8, 7.2 Hz, 2 H, CH2CH3), 3.87 (s, 3 H,
of Z-isomer: δ = 3.86 (s, 3 H, COOCH3), 5.93 (d, JH,H = 4.0 Hz,
1 H, 3Ј-H), 6.22–6.24 (m, 1 H, 4Ј, 5Ј-H), 6.91 (d, JH,H = 12.0 Hz,
3,3
3
COOCH3), 5.68–5.74 (dt,
6.83 (d, JH,H = 11.6 Hz, 1 H, ArCHCHEt), 7.43–7.46 (m, 2 H,
ArH), 7.82–7.84 (dd, JH,H = 1.2 Hz, JH,H = 8.0 Hz, 1 H, ArH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 13.5, 14.3, 21.7, 26.2, 51.8,
51.9, 126.4, 126.5, 127.2, 127.5, 128.0, 128.2, 130.3, 130.7, 131.4,
131.8, 133.8, 135.5, 139.1, 139.7, 167.8, 168.1 ppm.
J
H,H
= 7.6, 11.2 Hz, 1 H, ArCHCHEt),
3
1 H, ArCHCHfuryl), 7.20 (d, 3JH,H = 1.2 Hz, 1 H, 3-H), 7.35–7.40
(m, 1 H, ArH), 8.02 (d, 3JH,H = 8.0 Hz, 1 H, 6-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 52.2, 109.2, 111.6, 119.1, 125.5, 126.4,
127.1, 128.6, 130.7, 132.1, 138.6, 142.5, 153.3, 167.9 ppm. Non-
overlapped peaks of Z-isomer: δ = 51.9, 109.6, 111.1, 117.6, 127.3,
128.1, 130.4, 130.8, 131.8, 141.5 ppm. HRMS (EI): calcd. for
C14H12O3 [M + Na]+ 251.0684; found 251.0681.
4
3
(E)-Methyl 2-{2-[5-(tert-Butoxycarbonylamino)-2,2-dimethyl-1,3-di-
oxan 5-yl]vinyl}benzoate (6h): 80% yield, (E only); Rf = 0.51 (ethyl
acetate/hexanes, 2:8); viscous oil. IR (CH Cl ): ν = 1076, 1166,
˜
2
2
(E)-Methyl 2-(2-nitrostyryl)benzoate (6d): 80% yield, (E only); Rf =
1246, 1367, 1481, 1716 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.37 (s, 9 H, tBu), 1.39 (s, 3 H, CH3), 1.42 (s, 3 H, CH3), 3.81 (s,
3 H, COOCH3), 3.87–3.96 (m, 4 H, 2 CH2), 5.24 (s, 1 H, NH),
0.51 (ethyl acetate/hexanes, 1:9); yellow solid; m.p. 107–109 °C. IR
1
(CH Cl ): ν = 1078, 1250, 1342, 1514, 1572, 1712 cm–1. H NMR
˜
2
2
(400 MHz, CDCl3): δ = 3.93 (s, 3 H, COOCH3), 7.36–7.44 (m, 2
3
6.09 (d, JH,H = 16.4 Hz, 1 H, ArCHCHC), 7.19–7.23 (m, 1 H, 5-
H, Ar-H, olefin), 7.47 (d, 3JH,H = 16.0 Hz, 1 H, ArCHCHArNO2),
H), 7.29 (d, 3JH,H = 16.4 Hz, 1 H, ArCHCHC), 7.36–7.40 (m, 1 H,
3
3
7.56 (t, JH,H = 7.2 Hz, 1 H, 5-H), 7.62 (d, JH,H = 7.6 Hz, 1 H, 3-
3
4
4-H), 7.47 (d, JH,H = 7.6 Hz, 1 H, 3-H), 7.80–7.83 (dd, JH,H
=
3
3
H), 7.76 (d, JH,H = 8.0 Hz, 1 H, 4-H), 7.87 (d, JH,H = 7.6 Hz, 1
H, 3Ј-H), 7.97–8.01 (m, 2 H, NO2ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 52.2, 124.7, 126.3, 127.8, 128.0, 128.1, 128.5, 128.9,
130.7, 132.6, 132.8, 133.2, 133.3, 138.8, 147.9, 167.6 ppm. HRMS
(EI): calcd. for C16H13NO4 [M + Na]+ 306.0742; found 306.0748.
1.2 Hz, JH,H = 7.6 Hz, 1 H, 6-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 12.8, 18.0, 26.6, 27.1, 28.4, 30.6, 50.7, 51.7, 64.9, 78.3,
97.0, 126.0, 126.3, 126.9, 128.2, 129.2, 130.0, 130.9, 137.6, 153.6,
166.3 ppm. HRMS (EI): calcd. for C21H29NO6 [M + Na]+
414.1893; found 414.1894.
3
Methyl 2-(2,4,6-Trimethoxystyryl)benzoate (6e): 75% yield, (E:Z =
4:1); Rf = 0.5 (ethyl acetate/hexanes, 2:8); colourless sticky gum.
(S)-Methyl 2-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)vinyl]benzoate (6i):
65% yield, (E:Z = 4.8:1); Rf = 0.51 (ethyl acetate/hexanes, 2:8);
IR (CH Cl ): ν = 1120, 1191, 1492, 1603, 1718 cm–1. 1H NMR
˜
2
2
viscous oil. [α]3D7 = +2.625 (c = 3.5, CHCl ). IR (CH Cl ): ν = 1059,
˜
3
2
2
(400 MHz, CDCl3): δ = 3.73 (s, 3 H, COOCH3), 3.79 (s, 6 H, 2
OCH3), 3.81 (s, 3 H, OCH3), 6.07 (s, 2 H, 3Ј, 5Ј-H), 7.12–7.16 (m,
1262, 1370, 1720 cm–1. H NMR (400 MHz, CDCl3): δ = 1.43 (s,
1
3
3 H, CCH3), 1.48 (s, 3 H, CCH3), 3.71 (t, JH,H = 8.0 Hz, 1 H, 5Ј-
3
1 H, 3-H), 7.24 (d, JH,H = 16.4 Hz, 1 H, ArCHCHArOMe), 7.37
3,3
Ha), 3.89 (s, 3 H, COOCH3), 4.17–4.21 (dd,
J
= 6.0, 8.0 Hz,
H,H
3
3
(t, JH,H = 8.4 Hz, 1 H, 4-H), 7.67 (d, JH,H = 8.0 Hz, 1 H, 3-H),
3
1 H, 5Ј-Hb), 4.73 (q, JH,H = 7.2 Hz, 1 H, 4Ј-H), 6.03–6.09 (dd,
= 7.6, 16.0 Hz, 1 H, ArCHCHR), 7.30–7.34 (td, JH,H
1.2 Hz, JH,H = 7.6 Hz, 1 H, 5-H), 7.45–7.51 (m, 2 H, 4-H,
4
3
7.73–7.75 (dd, JH,H = 1.2 Hz, JH,H = 8.0 Hz, 1 H, 6-H), 8.13
(d, 3JH,H = 16.8 Hz, 1 H, ArCHCHArOMe) ppm. Non-overlapped
peaks of Z-isomer: 3.38 (s, 6 H, 2 OCH3), 3.67 (s, 3 H, OCH3),
5.89 (s, 2 H, 3Ј, 5Ј-H), 6.42 (d, J = 12.0 Hz, 1 H, ArCHCHAr-
OMe), 6.96–7.00 (m, 1 H, 4-H), 7.05–7.09 (m, 2 H, ArH), 7.78–
7.82 (m, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 51.8,
55.3, 55.8, 90.7, 108.3, 122.6, 126.0, 126.5, 128.2, 130.2, 131.7,
141.1, 159.6, 160.4, 168.4 ppm. Non-overlapped peaks of Z-isomer:
δ = 55.1, 90.4, 121.1, 126.1, 128.6, 129.1, 129.8, 130.8, 131.1, 141.6,
158.2, 160.7, 167.9 ppm. HRMS (EI): calcd. for C19H20O5 [M +
Na]+ 351.1208; found 351.1212.
3,3
4
J
H,H
=
3
3
ArCHCHR), 7.58 (d, JH,H = 7.6 Hz, 1 H, 3-H), 7.87–7.89 (dd,
4JH,H = 1.2 Hz, JH,H = 8.0 Hz, 1 H, 6-H) ppm. Non-overlapped
3
peaks of Z-isomer: 1.39 (s, 3 H, CCH3), 1.46 (s, 3 H, CCH3), 3.65
3
(t, JH,H = 8.0 Hz, 1 H, 5Ј-Ha), 3.87 (s, 3 H, COOCH3), 4.59–
3,3
4.65 (m, 1 H, 5Ј-Hb), 5.71–5.76 (dd,
J
H,H
= 8.0, 12.0 Hz, 1 H,
ArCHCHR), 7.19 (d, 3JH,H = 12.0 Hz, 1 H, ArCHCHR), 7.35–7.39
(m, 1 H, 3-H), 7.97–7.99 (m, 1 H, 6-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 25.8, 26.5, 52.1, 69.5, 77.2, 109.6, 128.3, 130.8, 31.9,
137.7, 167.6 ppm. Non-overlapped peaks of Z-isomer: δ = 25.3,
Methyl 2-(3-Chlorostyryl)benzoate (6f): 86% yield, (E:Z = 24:1); Rf 25.9, 52.0, 69.7, 76.4, 109.5, 128.3, 130.8, 131.9, 137.7, 167.2 ppm.
= 0.7 (ethyl acetate/hexanes, 2:8); colourless oil. IR (CH Cl ): ν =
HRMS (EI): calcd. for C15H18O4 [M + Na]+ 285.1103; found
1077, 1246, 1262, 1432, 1593, 1718 cm–1. 1H NMR (400 MHz, 285.1107.
˜
2
2
Eur. J. Org. Chem. 2010, 555–564
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
561

A. Senthilmurugan, I. S. Aidhen
2-{2-[(4S,4ЈR,5R)-2,2,2Ј,2Ј-Tetramethyl-4,4Ј-bi(1,3-diox- CCH3), 1.54 (s, 3 H, 2Ј CCH3), 3.40 (s, 3 H, OCH3), 3.92 (s, 3 H,
FULL PAPER
Methyl
3
3
olan)-5-yl]vinyl}benzoate (6j): 64% yield, (E:Z = 15.7:1); Rf = 0.25
COOCH3), 4.69 (d, JH,H = 6.0 Hz, 1 H, 4Ј-H), 4.76 (d, JH,H =
5.6 Hz, 1 H, 3Ј-H), 4.89 (d, JH,H = 5.6 Hz, 1 H, 2Ј-H), 5.05 (s, 1
3
(ethyl acetate/hexanes, 2:8); viscous oil. [α]3D7 = +15.495 (c = 7.0,
1
3,3
CHCl ). IR (CH Cl ): ν = 1077, 1263, 1434, 1719 cm–1. H NMR H, 5Ј-H), 6.11–6.17 (dd,
J
= 8.4, 16.0 Hz, 1 H, ArCHCHR),
˜
3
2
2
H,H
3
(400 MHz, CDCl3): δ = 1.35 (s, 3 H, 2Ј CCH3), 1.40 (s, 3 H, 2Ј
7.31–7.35 (m, 1 H, 5-H), 7.40 (d, JH,H = 16.0 Hz, 1 H,
ArCHCHR), 7.45–7.50 (td, JH,H = 1.2 Hz, JH,H = 7.2 Hz, 1 H,
4-H), 7.53 (d, JH,H = 6.8 Hz, 1 H, 3-H), 7.88–7.90 (dd, JH,H =
CCH3), 1.45 (s, 3 H, 2 CCH3), 1.47 (s, 3 H, 2 CCH3), 3.84 (t, 3JH,H
4
3
3,3
3
4
= 7.6 Hz, 1 H, 5Ј-H), 3.89 (s, 3 H, COOCH3), 3.97–4.01 (dd,
J
H,H
3,3
3
= 5.2, 8.4 Hz, 1 H, 5Ј-H), 4.10–4.14 (dd,
J
= 6.0, 8.4 Hz, 1
= 0.8,
= 6.8, 16.0 Hz, 1 H,
0.8 Hz, JH,H = 7.6 Hz, 1 H, 6-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 25.0, 26.5, 52.0, 54.6, 84.7, 85.6, 88.0, 109.3, 112.4,
127.3, 127.4, 128.8, 130.4, 131.3, 131.5, 132.0, 138.1, 167.6 ppm.
HRMS (EI): calcd. for C18H22O6 [M + Na]+ 357.1314; found
357.1319.
H,H
3,3
H, 4Ј-H), 4.18–4.23 (m, 1 H, 4-H), 4.54–4.58 (td,
J
H,H
3,3
7.2 Hz, 1 H, 5-H), 6.08–6.14 (dd,
J
H,H
4
3
ArCHCHR), 7.29–7.33 (td, JH,H = 0.8 Hz, JH,H = 7.6 Hz, 1 H,
4
5-H), 7.44–7.55 (m, 3 H, ArH, ArCHCHR), 7.86–7.88 (dd, JH,H
= 1.2 Hz, JH,H = 7.6 Hz, 1 H, 6-H) ppm. 13C NMR (100 MHz,
3
Methyl 2-[(E)-2-{(3αS,4R,6αR)-2,2-Dimethyltetrahydrofuro[3,4-d]-
[1,3]dioxol-4-yl}vinyl]benzoate (6n): 75% yield, (E only); Rf = 0.25,
CDCl3): δ = 25.3, 26.7, 26.9, 27.0, 52.0, 66.9, 76.6, 80.2, 81.2, 109.6,
127.4, 127.5, 128.8, 129.8, 130.4, 131.4, 132.0, 138.4, 167.7 ppm.
HRMS (EI): calcd. for C20H26O6 [M + Na]+ 385.1627; found
385.1629.
(ethyl acetate/hexanes, 2:8); viscous oil. [α]3D5 = –5.268 (c = 4.0,
1
CHCl ). IR (CH Cl ): ν = 1076, 1095, 1258, 1371, 1718 cm–1. H
˜
3
2
2
NMR (400 MHz, CDCl3): δ = 1.26 (s, 3 H, CCH3), 1.45 (s, 3 H,
3,3
CCH3), 3.47–3.51 (dd,
J
= 4.0, 10.8 Hz, 1 H, 4Ј-H), 3.81 (s,
H,H
Methyl 2-{2-[(3αS,4R,6S,6αS)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[3,4-d][1,3]dioxol-4-yl]vinyl}benzoate (6k): 65% yield, (E:Z =
3,3
3 H, OCH3), 4.00–4.05 (m, 2 H, 5Ј-H), 4.62–4.65 (dd,
J
=
H,H
3,3
4.0, 6.0 Hz, 1 H, 3Ј-H), 4.75–4.77 (dd,
J
H,H
= 3.6, 6.0 Hz, 1 H,
5.6:1); Rf
= 0.5, (ethyl acetate/hexanes, 2:8); viscous oil.
3,3
2Ј-H), 6.18–6.24 (dd,
J
= 8.0, 16.0 Hz, 1 H, ArCHCHR),
[α]3D6 = –3.157 (c = 6.2, CHCl ). IR (CH Cl ): ν = 1011, 1208, 1262,
H,H
˜
3
2
2
4
3
7.21–7.25 (td, JH,H = 0.8 Hz, JH,H = 8.0 Hz, 1 H, 5-H), 7.40 (t,
1722 cm–1. H NMR (400 MHz, CDCl3): δ = 1.23 (s, 3 H, CCH3),
1
3JH,H = 7.6 Hz, 1 H, 4-H), 7.48 (d, JH,H = 16.0 Hz, 1 H,
3
3
1.42 (s, 3 H, CCH3), 3.81 (s, 3 H, COOCH3), 4.44 (d, JH,H
=
3
ArCHCHR), 7.58 (d, JH,H = 7.6 Hz, 1 H, 3-H), 7.79–7.81 (m, 1
12.0 Hz, 1 H, PhCHH), 4.59–4.70 (m, 5 H, PhCHH, 3Ј, 4Ј, 5Ј-H),
H, 6-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.8, 26.1, 52.0,
72.8, 81.4, 82.5, 83.5, 112.2, 126.4, 127.4, 127.7, 128.5, 130.3, 132.0,
132.9, 138.4, 167.7 ppm. HRMS (EI): calcd. for C17H20O5 [M +
Na]+ 327.1208; found 327.1215.
3,3
5.06 (s, 1 H, 2Ј-H), 6.18–6.24 (dd,
J
H,H
= 8.0, 16.0 Hz, 1 H,
4
ArCHCHR), 7.16–7.28 (m, 6 H, Bn, 5-H), 7.37–7.41 (td, JH,H
0.8 Hz, JH,H = 9.6 Hz, 1 H, 4-H), 7.49 (d, JH,H = 15.6 Hz, 1 H,
=
3
3
3
ArCHCHR), 7.58 (d, JH,H = 7.6 Hz, 1 H, 3-H), 7.79–7.81 (dd,
4JH,H = 0.8 Hz, JH,H = 7.6 Hz, 1 H, 6-H) ppm. Non-overlapped
3
2-Methoxy-6-methylbenzaldehyde and 3-Bromo-6-methoxy-2-meth-
ylbenzaldehyde (11 and 13): 30% yield; Rf = 0.25, (ethyl acetate/
peaks of Z-isomer: δ = 1.17 (s, 3 H, CCH3), 1.44 (s, 3 H, CCH3),
2
hexanes, 0.4:9.6); crystalline solid. IR (CH Cl ): ν = 1080, 1256,
˜
2
2
3.81 (s, 3 H, COOCH3), 4.35 (d, JH,H = 12.0 Hz, 1 H), 5.02 (s, 1
1284, 1433, 1462, 1576, 1728 cm–1. 1H NMR (400 MHz, CDCl3):
3,3
H), 5.92–5.97 (dd,
J
H,H
= 9.2, 12.0 Hz, 1 H, ArCHCHR), 7.11–
δ = 2.56 (s, 3 H, OCH3), 2.63 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3),
7.13 (m, 1 H, PhCHH), 7.33–7.35 (m, 3 H, ArH), 7.89–7.91 (m, 1
H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.9, 26.2, 52.0,
68.9, 81.8, 85.5, 105.4, 112.5, 126.3, 127.5, 127.7, 127.8, 128.04,
128.07, 128.2, 128.5, 128.6, 130.4, 132.1, 132.9, 137.4, 138.3,
167.7 ppm. Non-overlapped peaks of Z-isomer: δ = 68.9, 75.9, 81.6,
85.6, 124.4, 125.8, 127.0, 127.6, 128.0, 128.4, 129.3, 130.6, 131.7,
134.9, 137.2, 138.0, 167.3 ppm. HRMS (EI): calcd. for C24H26O6
[M + Na]+ 433.1627; found 433.1632.
3
3.89 (s, 3 H, OCH3), 6.74 (d, JH,H = 8.8 Hz, 1 H, 3-H), 6.80 (d,
3JH,H = 8.0 Hz, 1 H, 5Ј-H), 6.83 (d, 3JH,H = 8.4 Hz, 1 H, 5-H), 7.37
3
3
(t, JH,H = 8.0 Hz, 1 H, 4-H), 7.66 (d, JH,H = 8.8 Hz, 1 H, 4Ј-H),
10.53 (s, 1 H, CHO), 10.63 (s, 1 H, CHO) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.9, 21.3, 55.8, 55.9, 109.0, 110.5, 118.3,
123.3, 124.1, 125.1, 126.5, 134.3, 137.8, 140.4, 141.9, 162.0, 163.1,
191.8, 192.2 ppm.
Methyl 2-(2-{(3αS,4R,6S,6αS)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[3,4-d][1,3]dioxol-4-yl}vinyl)-6-methoxybenzoate (20): 70%
yield, (E:Z = 4:1); Rf = 0.4, (ethyl acetate/hexanes, 2:8), colourless
(E)-Methyl
2-{2-[3,4,5-Tris(benzyloxy)-6-methoxytetrahydro-2H-
pyran-2-yl]vinyl}benzoate (6l): 50% yield, (E only); Rf = 0.5 (ethyl
acetate/hexanes, 2:8); viscous oil. [α]3D5 = +1.855 (c = 3.5, CHCl3).
oil. [α]3D6 = –8.160 (c = 4.0, CHCl ). IR (CH Cl ): ν = 1008, 1070,
˜
3
2
2
IR (CH2Cl2):
ν
˜
=
1074, 1261, 1453, 1721 cm–1. 1H NMR
1265, 1468, 1576, 1729 cm–1. 1H NMR (400 MHz, CDCl3): δ =
3
(400 MHz, CDCl3): δ = 3.28 (t, JH,H = 9.6 Hz, 1 H, 4Ј-H), 3.34
(s, 3 H, OCH3), 3.48–3.51 (dd,
1.30 (s, 3 H, CCH3), 1.48 (s, 3 H, CCH3), 3.82 (s, 3 H, OCH3),
3,3
J
H,H
= 3.6, 9.6 Hz, 1 H, 3Ј-H),
3.92 (s, 3 H, COOCH3), 4.52 (d, 3JH,H = 11.6 Hz, 1 H, 3Ј-H), 4.55–
3
3.75 (s, 3 H, OCH3), 3.96 (t, JH,H = 9.2 Hz, 1 H, 5Ј-H), 4.19–4.23
3,3
4.58 (dd,
J
H,H
= 4.0, 8.0 Hz, 1 H, 4Ј-H), 4.61–4.66 (m, 1 H, 2Ј-
3,3
(dd,
J
H,H
= 7.2, 9.6 Hz, 1 H, 2Ј-H), 4.55–4.74 (m, 6 H, OBn, 6Ј-
3,3
H), 4.67–4.76 (m, 3.5 H), 5.12 (s, 1 H, 5Ј-H), 6.32–6.37 (dd,
J
H,H
2
2
H), 4.77 (d, JH,H = 10.8 Hz, 1 H, OBn), 4.89 (d, JH,H = 10.8 Hz,
3
= 7.6, 16.0 Hz, 1 H, ArCHCHR), 6.66 (d, JH,H = 16.0 Hz, 1 H,
ArCHCHR), 6.79–6.88 (m, 2 H, ArH), 7.21–7.35 (m, 10 H, ArH,
Bn) ppm. Non-overlapped peaks of Z-isomer: δ = 1.31 (s, 3 H,
CCH3), 1.50 (s, 3 H, CCH3), 3.84 (s, 3 H, OCH3), 3.88 (s, 3 H,
COOCH3), 4.43 (d, JH,H = 12.0 Hz, 1 H, 3Ј-H), 5.09 (s, 1 H, 5Ј-
H), 6.00–6.05 (dd,
3,3
1 H, OBn), 5.96–6.01 (dd,
J
H,H
= 6.8, 16.0 Hz, 1 H, ArCHCHR),
7.12–7.36 (m, 19 H, ArH, Bn), 7.42–7.46 (dd, 4JH,H = 0.8 Hz, 3JH,H
3
= 16.0 Hz, 1 H, ArCHCHR), 7.79 (d, JH,H = 7.6 Hz, 1 H, 6-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 52.0, 55.3, 71.2, 73.4, 75.1,
75.8, 79.9, 81.8, 82.3, 98.2, 127.3, 127.4, 127.5, 127.6, 127.9, 128.0,
128.1, 128.3, 128.4, 128.5, 129.2, 130.5, 131.8, 132.0, 138.2, 138.3,
167.6 ppm. HRMS (EI): calcd. for C37H38O7 [M + Na]+ 617.2515;
found 617.2527.
3
3,3
J
H,H
= 8.0, 12.0 Hz, 1 H, ArCHCHR), 6.97
(d, 3JH,H = 8.0 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 25.0, 26.1, 52.3, 56.0, 69.0, 80.9, 81.7, 85.5, 105.4, 110.2, 112.6,
118.4, 122.9, 126.9, 127.6, 127.8, 128.0, 128.1, 128.4, 128.5, 130.4,
135.3, 137.4, 156.5, 168.3 ppm. Non-overlapped peaks of Z-isomer:
δ = 24.9, 68.8, 75.9, 85.6, 105.3, 110.4, 130.3 ppm. HRMS (EI):
calcd. for C25H28O7 [M + Na]+ 463.1733; found 463.1731.
Methyl 2-[(E)-2-{(3αR,4R,6R,6αR)-6-Methoxy-2,2-dimethyltetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl}vinyl]benzoate (6m): 56% yield, (E
only); Rf = 0.5, (ethyl acetate/hexanes, 2:8); viscous oil. [α]3D5
=
–4.648 (c = 3.5, CHCl ). IR (CH Cl ): ν = 1076, 1102, 1255, 1372, Methyl 2-Methoxy-6-(2-{(3αR,4R,6R,6αR)-6-methoxy-2,2-dimeth-
˜
3
2
2
1720 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.35 (s, 3 H, 2Ј
yltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}vinyl)benzoate (21): 77%
562
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 555–564

Synthesis of (+)-Varitriol Analogues via Julia Olefination
3,3
yield, (E:Z = 8.5:1.5); Rf = 0.4, (ethyl acetate/hexanes, 2:8), colour-
1 H, 4Ј-H), 3.32 (s, 3 H, OCH3), 3.47–3.50 (dd,
J
= 3.6,
H,H
less oil. [α]3D6 = –1.598 (c = 3.0, CHCl ). IR (CH Cl ): ν = 1065,
9.6 Hz, 1 H, 3Ј-H), 3.70 (s, 3 H, OCH3), 3.74 (s, 3 H, COOCH3),
˜
3
2
2
3
3,3
1263, 1468, 1576, 1729 cm–1. 1H NMR (400 MHz, CDCl3): δ =
3.94 (t, JH,H = 9.6 Hz, 1 H, 5Ј-H), 4.12–4.16 (dd,
J
= 6.4,
H,H
1.33 (s, 3 H, CCH3), 1.51 (s, 3 H, CCH3), 3.36 (s, 3 H, OCH3), 9.6 Hz, 1 H), 4.56–4.62 (m, 3 H, OCH2Ph), 4.67 (m, 3 H,
3.83 (s, 3 H, OCH3), 3.92 (s, 3 H, COOCH3), 4.65–4.70 (m, 2 H, OCH2Ph), 4.88 (d, 2JH,H = 10.8 Hz, 1 H, OCH2Ph), 5.88–5.94 (dd,
3
3,3
3
3Ј, 4Ј-H), 4.77 (d, JH,H = 8.4 Hz, 1 H, 2Ј-H), 5.02 (s, 1 H, 5Ј-H),
J
H,H
= 6.0, 16.0 Hz, 1 H, ArCHCHR), 6.66 (d, JH,H = 8.8 Hz,
3,3
6.18–6.24 (dd,
J
= 8.0, 16.0 Hz, 1 H, ArCHCHR), 6.53 (d,
1 H, 5-H), 6.67–6.72 (m, 1 H, ArCHCHR), 7.13–7.31 (m, 17 H, 5-
H,H
3,3
3
3
J
H,H
= 16.0 Hz, 1 H, ArCHCHR), 6.83 (d, JH,H = 8.0 Hz, 1 H, H, OBn), 7.45 (d, JH,H = 8.8 Hz, 1 H, 4-H) ppm. 13C NMR
5-H), 7.09 (d, 3JH,H = 8.0 Hz, 1 H, 3-H), 7.31 (t, JH,H = 8.0 Hz, 1 (100 MHz, CDCl3): δ = 52.4, 55.1, 56.2, 70.5, 73.4, 75.1, 75.9, 79.8,
3
H, 4-H) ppm. Non-overlapped peaks of Z-isomer: δ = 1.30 (s, 3 H,
81.8, 82.2, 98.0, 111.5, 114.4, 125.0, 127.6, 127.9, 128.01, 128.05,
128.1, 128.2, 128.3, 128.4, 128.5, 129.7, 133.2, 133.9, 136.0, 138.1,
CCH3), 1.45 (s, 3 H, CCH3), 3.34 (s, 3 H, OCH3), 3.84 (s, 3 H,
3
OCH3), 3.89 (s, 3 H, COOCH3), 4.89 (d, JH,H = 8.0 Hz, 1 H, 2Ј- 138.2, 138.7, 155.7, 167.4 ppm. HRMS (EI): calcd. for C38H39BrO8
3,3
H), 5.01 (s, 1 H, 5Ј-H), 5.76–5.71 (dd,
J
H,H
= 8.0, 12.0 Hz, 1 H,
[M + Na]+ 725.1726; found 725.1728.
3
3
ArCHCHR), 6.88 (d, JH,H = 8.0 Hz, 1 H, 5-H), 7.38 (t, JH,H
=
Methyl
3-Bromo-2-[(E)-2-{(3αS,4R,6αR)-2,2-dimethyltetrahydro-
8.0 Hz, 1 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.0,
26.4, 52.4, 54.7, 56.0, 84.6, 85.5, 87.9, 109.4, 110.2, 112.4, 117.9,
122.8, 128.9, 130.4, 131.9, 135.1, 156.4, 168.2 ppm. Non-over-
lapped peaks of Z-isomer: δ = 24.6, 54.4, 82.8, 84.8, 85.8, 108.9,
110.3, 122.0, 132.3 ppm. HRMS (EI): calcd. for C19H24O7 [M +
Na]+ 387.1420; found 387.1420.
furo[3,4-d][1,3]dioxol-4-yl}vinyl]-6-methoxybenzoate (28): 54%
yield, (E only); Rf = 0.4, (ethyl acetate/hexanes, 2:8), colourless oil.
IR (CH Cl ): ν = 1066, 1264, 1471, 1577, 1727 cm–1. 1H NMR
˜
2
2
(400 MHz, CDCl3): δ = 1.32 (s, 3 H, CCH3), 1.50 (s, 3 H, CCH3),
3,3
3.52–3.55 (dd,
OCH3), 3.87 (s, 1 H, COOCH3), 3.99–4.02 (dd,
6.8 Hz, 1 H, 4Ј-H), 4.07 (d, 3JH,H = 10.8 Hz, 1 H, 2Ј-H), 4.66–4.68
J
= 3.6, 10.8 Hz, 1 H, 3Ј-H), 3.82 (s, 3 H,
H,H
3,3
J
H,H
= 3.6,
Methyl 2-[(E)-2-{(3αS,4R,6αR)-2,2-Dimethyltetrahydrofuro[3,4-d]-
[1,3]-dioxol-4-yl}vinyl]-6-methoxybenzoate (22): 67% yield, (E only);
Rf = 0.3, (ethyl acetate/hexanes, 2:8, 2ϫ elusion), colourless crys-
3,3
3,3
(dd,
J
H,H
= 4.0, 6.0 Hz, 1 H, 5Ј-H), 4.80–4.83 (dd,
6.0 Hz, 1 H, 5Ј-H), 6.05–6.11 (dd,
ArCHCHR), 6.73 (d, JH,H = 8.8 Hz, 1 H, 5-H), 6.77 (d, JH,H
J
= 4.0,
H,H
3,3
J
H,H
= 7.2, 16.0 Hz, 1 H,
3
3
tals; m.p. 105–110 °C. [α]3D5 = –46.291 (c = 4.0, CHCl3). IR
=
16.0 Hz, 1 H, ArCHCHR), 7.51 (d, 3JH,H = 8.8 Hz, 1 H, 4-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 24.2, 25.2, 51.6, 55.2, 71.9, 80.3,
81.2, 82.1, 110.6, 111.4, 113.6, 123.6, 129.3, 129.9, 132.8, 134.8,
154.7, 166.4 ppm. HRMS (EI): calcd. for C18H21BrO6 [M + H]+
413.0600; found 413.0591.
1
(CH Cl ): ν = 1066, 1092, 1264, 1471, 1577, 1727 cm–1. H NMR
˜
2
2
(400 MHz, CDCl3): δ = 1.31 (s, 3 H, CCH3), 1.50 (s, 3 H, CCH3),
3,3
3.50–3.54 (dd,
J
H,H
= 3.6, 10.8 Hz, 1 H, 3Ј-H), 3.80 (s, 3 H,
3,3
OCH3), 3.89 (s, 3 H, COOCH3), 3.98–4.01 (dd,
7.6 Hz, 1 H, 4Ј-H), 4.05 (d,
4.81 (m, 2 H, 5Ј-H), 6.31–6.37 (dd,
J
= 3.6,
H,H
3,3
J
H,H
= 10.8 Hz, 1 H, 2Ј-H), 4.63–
3,3
J
H,H
= 7.2, 16.0 Hz, 1 H,
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectra of 2, 3, 6i–6n, 20–23, 26, 27
and 28.
3,3
ArCHCHR), 6.65 (d,
J
H,H
= 16.0 Hz, 1 H, ArCHCHR), 6.81 (d,
3JH,H = 8.4 Hz, 1 H, 5-H), 7.20 (d, 3JH,H = 8.0 Hz, 1 H, 3-H), 7.29
(t, JH,H = 8.0 Hz, 1 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3):
3
δ = 24.9, 26.1, 52.3, 55.9, 72.8, 81.3, 82.3, 83.3, 110.2, 112.3, 118.3,
122.8, 127.0, 130.2, 130.3, 135.3, 156.4, 168.4 ppm. HRMS (EI): Acknowledgments
calcd for C18H22O6 [M + H]+ 335.1495; found 335.1493.
The authors thank DST New Delhi for the funding towards the
(2R,3R,4R)-2-[2-(Hydroxymethyl)-3-methoxystyryl]tetrahydrofuran-
3,4-diol (23): 62% yield (2 steps); Rf = 0.3, (MeOH/CH2Cl2,
400 MHz NMR spectrometer to the Department of Chemistry,
IIT-Madras under the IRPHA scheme and ESI-MS facility under
the FIST program. BNRS (DAE) is acknowledged for funding of
project 2008/37/21/BRNS. A. S. M. is thankful to IIT-Madras for
HTRA. The authors also thank Mr. Ramkumar for X-ray crystal-
lographic studies.
0.2:9.8); colourless needles, m.p. 137–140 °C. IR (CH Cl ): ν =
˜
2
2
1000, 1123, 1263, 1469, 1579, 3373 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 3.77–3.84 (m, 4 H, OCH3, 5Ј-H), 3.87–3.91 (m, 1 H,
5Ј-H), 4.08–4.12 (m, 1 H, 4Ј-H), 4.23–4.28 (m, 1 H, 3Ј-H), 4.42 (t,
3JH,H = 4.4 Hz, 1 H, 2Ј-H), 4.76 (s, 2 H, ArCH2O), 6.13–6.18 (dd,
3,3
3
J
H,H
= 6.4, 16.0 Hz, 1 H, ArCHCHR), 6.78 (d, JH,H = 8.0 Hz,
3,3
[1] D. Faulkner, J. Nat. Prod. Rep. 2000, 17, 7–55.
1 H, 4-H), 6.94 (d,
J
H,H
= 16.0 Hz, 1 H, ArCHCHR), 7.07 (d,
3JH,H = 7.6 Hz, 1 H, 6-H), 7.21 (t, JH,H = 8.0 Hz, 1 H, 5-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 55.7, 55.8, 72.0, 72.1, 73.1, 81.5,
109.7, 119.4, 125.9, 129.0, 129.2, 129.9, 138.0, 157.8 ppm. HRMS
(EI): calcd. for C14H18O5 [M + Na]+ 289.1052; found 289.1053.
3
[2] a) J. Malmstrøm, C. Christophersen, A. F. Barrero, J. E. Oltra,
J. Justicia, A. Rosales, J. Nat. Prod. 2002, 65, 364; b) A. M. S.
Mayer, K. R. Gustafson, Eur. J. Cancer 2004, 40, 2676–2704.
[3] R. T. Clemens, M. P. Jennings, Chem. Commun. 2006, 2720.
[4] G. D. McAllister, J. E. Robinson, R. J. K. Taylor, Tetrahedron
2007, 63, 12123.
Methyl 3-Bromo-6-methoxy-2-methylbenzoate (14): 50% yield; Rf =
[5] V. Kumar, A. K. Shaw, J. Org. Chem. 2008, 73, 7526–7531.
[6] L. Nagarapu, V. Paparaju, A. Satyender, Bioorg. Med. Chem.
Lett. 2008, 18, 2351.
[7] For reviews on Julia olefination, see: a) C. Aissa, Eur. J. Org.
Chem. 2009, 1831–1844; b) R. Dumeunier, I. Marko in Modern
Carbonyl Olefination: Methods and Applications (Ed.: T.
Takeda), Wiley-VCH, Weinheim, 2004, pp. 104–150; c) P. R.
Blakemore, J. Chem. Soc. Perkin Trans. 1 2002, 2563.
[8] M. Palik, O. Karlubikova, A. Lasikova, J. Kozisek, T. Gracza,
Eur. J. Org. Chem. 2009, 5, 709–715.
[9] H. J. Lee, S. J. Lim, S. Jun Oh, D. H. Moon, D. J. Kim, J. Tae,
K. H. Yoo, Bioorg. Med. Chem. Lett. 2008, 18, 1628.
[10] For the synthesis of aldehydes 5i–n, refer to a) 5i: C. R. Schmid,
J. D. Bryant, Org. Synth. 1993, 72, 6; b) 5j: J. M. Richter, B. W.
0.4, (CH Cl /hexanes, 1:1), colourless oil. IR (CH Cl ): ν = 1263,
˜
2
2
2
2
1435, 1462, 1731 cm–1. H NMR (400 MHz, CDCl3): δ = 2.30 (s,
1
3 H, ArCH3), 3.79 (s, 3 H, OCH3), 3.91 (s, 3 H, COOCH3), 6.65
3
3
(d, JH,H = 8.8 Hz, 1 H, 5-H), 7.50 (d, JH,H = 8.8 Hz, 1 H, 4-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 20.1, 52.5, 56.1, 110.2,
116.1, 125.5, 133.8, 135.5, 155.4, 167.9 ppm. HRMS (EI): calcd.
for C10H11BrO3 [M + Na]+ 280.9789; found 280.9782.
Methyl 3-Bromo-6-methoxy-2-{(E)-2-[(2R,3R,4S,5R,6S)-3,4,5-tris-
(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl]vinyl}benzoate (27):
77% yield, (E only); Rf = 0.4, (ethyl acetate/hexanes, 2:8), colour-
less oil. IR (CH Cl ): ν = 1045, 1068, 1260, 1286, 1431, 1454, 1569,
˜
2
2
1731 cm–1. H NMR (400 MHz, CDCl3): δ = 3.22 (t, J = 9.2 Hz,
1
Eur. J. Org. Chem. 2010, 555–564
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
563

A. Senthilmurugan, I. S. Aidhen
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Received: September 5, 2009
Published Online: December 8, 2009
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