Novel malyngamide structural analogs: Synthesis and biological evaluation

Article abstract of DOI:10.1007/s00044-013-0466-y

In the course of our search for new anticancer agents, a series of novel malyngamide derivatives were synthesized by sharpless asymmetric epoxidation, followed by Julia-Kocinski olefination reactions as key reaction sequence. Anticancer activities of all these derivatives were screened against IMR-32, SF-295, SKNSH, HeLa, Colon-502713, SW-620, and Hop-62 cell lines for the first time.

Full text of DOI:10.1007/s00044-013-0466-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:4581–4591
DOI 10.1007/s00044-013-0466-y
ORIGINAL RESEARCH
Novel malyngamide structural analogs: synthesis and biological
evaluation
•
G. Venkateswar Reddy T. Vijaya Kumar B. Siva
•
•
•
K. Suresh Babu P. V. Srinivas Irum Sehar
•
•
•
A. K. Saxena J. Madhusudana Rao
Received: 13 July 2012 / Accepted: 1 January 2013 / Published online: 13 January 2013
Ó Springer Science+Business Media New York 2013
Abstract In the course of our search for new anticancer
agents, a series of novel malyngamide derivatives were
synthesized by sharpless asymmetric epoxidation, followed
by Julia-Kocinski olefination reactions as key reaction
sequence. Anticancer activities of all these derivatives were
screened against IMR-32, SF-295, SKNSH, HeLa, Colon-
502713, SW-620, and Hop-62 cell lines for the first time.
indispensable tools in biochemical research and played vital
roles in the recent advancements of life sciences. Malynga-
mides (Suntornchaswej et al., 2007; Li et al., 2007): are a
class of fatty acid amides, are the secondary metabolites
isolated from the marine cyanobacterium Lyngbya majus-
cule, and constitute an interesting group of marine natural
products, for which a wide variety of biological activities
have been described, including anti-inflammatory, anti-fee-
dant activity, cytotoxicity to marine animals, anti-leukemic,
and anti-tumor activity, antifungal, anti-HIV, and most often
antineoplastic activities (Wylie and Paul, 1988). Most of
these malyngamides possessing a fatty acid side chain con-
taining a 4E double bond and a 7S stereogenic center which is
connected via an amide linkage to a heavily oxygenated six
membered ring or a heterocycle and/or with a functional unit
of a vinylic chloride. A close observation at the structures of
all these amides (or) in most of the malyngamides clearly
suggests that acid portion (left hand part of malyngamides)
of the molecule always remains the same; however, the
amines keep changing (Fig. 1).
Keywords Malyngamides ꢀ Plants of Piperaceae family ꢀ
Anticancer activity ꢀ Hybrid amides ꢀ
Sharpless asymmetric epoxidation ꢀ Julia olefination
Introduction
Marine organisms have been proven to be valuable resources
for discovery of structurally unique and biologically
important natural products. Apart from human medicines,
the research involving marine natural products in the last
three decades has also generated significant discoveries that
are now utilized routinely as pharmacological tools with
unique cellular targets. Some of them have become
In a similar fashion, plants of the Piperaceae family are a
well-known source of structurally diverse amides having a
broad range of biological activities such as cytotoxic,
stomach aches, insect repellents, anti-inflammatory,
insecticidal, and anti-feedant activities (Parmar et al.,
1997). In a recent study conducted in our laboratory was
found that these piper amides also exhibited a good degree
of a-glucosidase inhibition (Srinivas et al., 2006). The
structural analysis of these piper amides shows that these
piperamides are made up of different acids but the amine
portion in a majority of them being either pyrrole or
piperidine or isobutyl amine (Fig. 1).
G. V. Reddy ꢀ T. V. Kumar ꢀ B. Siva ꢀ K. S. Babu (&) ꢀ
P. V. Srinivas ꢀ J. M. Rao
Natural Products Chemistry Division, CSIR-Indian Institute
of Chemical Technology, Hyderabad 500607, India
e-mail: suresh@iict.res.in
I. Sehar ꢀ A. K. Saxena
Pharmacology Division, CSIR-Indian Institute of Integrative
Medicine (IIM), Canal Road, Jammu 180001, India
Present Address:
P. V. Srinivas
Process, Research and Development Center, Biocon Limited,
Bangalore 560100, India
Based on the above interesting observations, we have
conceived an idea for the synthesis of some hybrid amides
by taking the acid portion from malyngamides (marine
123

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Med Chem Res (2013) 22:4581–4591
O
O
O
O
O
O
O
O
O
O
N
H
O
O
N
N
N
H
Piperine (1)
Trichostachine (2)
Retrofractamide A (3)
4,5-Dihydropiperlongumine (4)
OH
OMe
OMe
MeO
O
O
OMe
HO
H
OMe
O
O
N
O
N
HN
N
O
N
O
N
OMe
N
HO
Cl
OMe
Cl
OMe
Cl
Cl
Malyngamide M (5)
Malyngamide A (6)
Malyngamide R (8)
Malyngamide O (7)
Malyngamide U (9)
Fig. 1 Representative structures of piper amides, malyngamides, and their comparison
source) and the amines chosen from the terrestrial amides
(Piperaceae) which may be interesting from the biological
point of view. Hence, the present study deals with the
synthesis of hybrid amides wherein both the portions of the
molecules are of natural origin. In this paper, we report
synthesis and in vitro anticancer activity of these mal-
yngamide structural analogs against cancer cell lines (IMR-
32, SF-295, SKNSH, HeLa, colon-502713, SW-620, and
Hop-62). All the compounds displayed weak cytotoxic
activity.
Julia–Kocinski olefination for the formation of 4E double
bond, and a crucial element of stereochemistry at C-7 was
introduced using sharpless asymmetric epoxidation which
directs the stereochemistry embedded in the required
sterocenter at C-7.
Synthesis of sulfone (12)
Sulfone (12) can be easily accessed from readily available
1,4-butane diol (15) as shown in Scheme 2. Mono pro-
tection of diol 15 with DHP in DCM/THF using cat p-TSA
affords compound 17 in 80 % yield. Mitsunobu reaction
(Mitsunobu and Yamada, 1967) of compound 17 with
PTSH in the presence of TPP/DIAD was performed to give
sulfide as thioether which upon oxidation with ammonium
molybdate in ethanol furnished the sulfone 12 in 80 %
yield.
Results and discussion
As outlined retrosynthetically in Scheme 1, malyngamide
analogs were divided into two parts (i) lyngbic acid con-
taining 4E double bond and (ii) 7S stereocenter and an
amine portion. According to our earlier reports (Shailesh
et al., 2011), lyngbic acid (10) could be obtained by Julia–
Kocinski olefination reaction of two fragments 12 and 13.
Fragment 13, containing one stereogenic center, could be
derived from allylic alcohol 16 via sharpless asymmetric
epoxidation, which can be obtained through two step
sequence starting from the inexpensive octanaldehyde. The
present synthesis will be highlighted by the utilization of
Synthesis of lyngabic acid (10)
Thus, based on the above plan, the synthesis of lyngbic
acid 10 began with octanaldhyde 15, which is condensed
with (EtO)2POCH2CO2Et using Horner–Wadsworth–
Emmons (HWE) reaction (Ireland and Norbeck, 1985;
Blanchette et al., 1984), gave the expected (E)-a, b-
Scheme 1 Retrosynthetic
analysis of malyngamide
analogs
Julia-Kocinski olefination
O
Sharpless epoxidation
OMe
O
OMe
R
OH
Lyngbic acid (10)
Malyngamides
O
S
OMe
OMe
Ph
N
OTHP
O
OTHP
N
O
N
N
13
11
12
O
n-Octanal
OH
14
15
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Med Chem Res (2013) 22:4581–4591
4583
unsaturated ester and subsequent reduction of the unsatu-
rated ester with diisobutylaluminum hydride (DIBAL-H) to
give the allylic alcohol 18 with 90 % yield over two steps.
Sharpless asymmetric epoxidation (Gao et al., 1987) of
allylic alcohol 18 using (?)-DET resulted in pure epoxide
14 (98 % yield) with 98 % ee. Regioselective opening of
epoxide 14 using Red-Al provided the corresponding 1,3-
diol 19 (Finan and Kishi, 1982; Viti et al.1982), in 90 %
yield, in which primary hydroxyl group was protected with
TBDMSCl using imidazole in DCM to give its corre-
sponding tert-butyldimethylsilyl (TBS) ether in quantita-
tive yield. Resultant secondary alcohol was converted to its
methyl ether using MeI/NaH in THF to give compound 20
in 90 % yield. Desilylation of compound 20 was performed
under standard conditions TBAF (Corey and Ven-
kateswarlu, 1972) in THF to afford primary alcohol 21 in
92 % yield which was further converted to aldehyde by
oxidation with IBX to give compound 13 in quantitative
yield (Frigerio and Santagostino, 1994).
The conjunction of precursors 12 and 13 was then
investigated via Julia–Kocinski olefination reaction. The
sulfone 12 was further subjected to Kocienski-modified
(Blakemore et al., 1998; Kocienski et al., 2000), Julia
olefination (Baudin et al., 1991) reaction with the aldehyde
13 in the presence of LiHDMS in dry THF at -78 °C to rt
to give the key fragment 11 with the desired E-olefin
exclusively in moderate yield, 70 %. Thus, removal of the
THP group under acidic conditions (Corey et al., 1978)
using p-TSA in MeOH delivered primary alcohol 22 in
89 % yield. After oxidation of alcohol 22 using Jone’s
reagent (CrO3, H2O, H2SO4, acetone, 0 °C to room tem-
perature) smoothly furnished acid 10 with 82 % yield was
obtained (Smith and Kim, 2004) (Scheme 2).
Synthesis of malyngamide analogs (23–34)
Once lyngabic acid 10 is in our hand, we focused on the
construction of amides (Wohlrab et al., 2007) using
Scheme 2 Synthesis of
lyngabic acid (10)
O
S
Ph
i) PT-SH, DIAD, PPh3,
THF
DHP, PTSA
DCM, 80%
N
OTHP
OTHP
OH
N
O
HO
HO
N
N
ii) (NH4)6 Mo7 O24 4H2O
16
17
12
H2O2, EtOH, 80%,
2 steps
i) nBuLi, (EtO)2POCH2CO2Et, THF, -78 oC
ii) DIBAL-H, DCM 0 oC to rt
O
OH
15
18
i) Ti(OiPr)4, (+)-DET, t-BuOOH, DCM, -20 o
C
O
i) Red Al, THF, 0 oC to rt, 3 h
OH
14
OMe
OH
i) TBSCl, Imidazole, DCM, 0 oC to rt
ii) MeI, NaH, THF, 0 oC to rt
OTBS
OH
20
19
OMe
IBX, DMSO, THF, rt, 3 h
TBAF, THF, 0 oC to rt, 2 h
OH
21
OMe
OMe
LiHMDS, sulfone 12, THF, -78 oC to rt
O
OTHP
13
11
OMe
Jones reagent, Acetone, 0 oC to rt
PTSA, MeOH, 0 oC to rt
OH
22
OMe
O
OH
10
123

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Med Chem Res (2013) 22:4581–4591
different amines by EDCI and HOBt in DCM as depicted
in Scheme 3.
After getting the homoallyalcohol 35, cross metathesis
(Bouz et al., 2004) reaction was performed between homo
allylalcohol 35 and 4-pentenoic acid in DCM at 45 °C
which afforded 36 that was used further to prepare the
various amides using different amines as depicted in
Scheme 5. Purity and identity were verified for all com-
pounds by MS and NMR spectroscopic techniques.
Synthesis of malyngamide analogs (23a–27a)
To fully explore the potentiality of the hybrids, we also
envisioned to change the stereochemistry at C-7 carbon of
parent, lyngbic acid, and then check out the activity of
analogs. For this, we followed the same synthetic approach
as mentioned in Scheme 2, except the usage of (-)-DET in
sharpless asymmetric epoxidation of allylic alcohol 18 to
install the beta center (Scheme 4). Once acid 10a is in our
hand, we constricted the amides using different amines.
The synthesized new amide derivatives (23–34, 23a–
27a, and 37–41) were tested for their anticancer activities
for the first time against the IMR-32, SF-295, SKNSH,
HeLa, colon-502713, SW-620, and Hop-62 cancer cell
lines using the MTT method. The results indicated that all
the compounds displayed moderate activity with an IC
50
from 29.8 to 174 (Table 1).
Biological evaluation
Synthesis of malyngamide analogs (37–41)
Similarly, we also synthesized the lyngbic acid analogs
replacing the methoxy group by hydroxyl functional group.
Thus the acid 36 was obtained by the cross metathesis
reaction which was performed between homo allylic
alcohol 35 and 4-pentenoic acid. The journey for the syn-
thesis of acid 36 began with octanaldhyde 15, which was
subjected to an enantioselective Maruoka allylation (Ha-
nawa et al., 2003; Reddy et al., 2009), using titanium
complex (R,R)-I and allyltri-n-butyltin to furnish the
homoallylic alcohol 35 in 86 % yield with excellent
enantioselectivity of 98 % ee.
In vitro cytotoxicity of extracts against human
cancer cell lines
The human cancer cell lines were procured from National
Cancer Institute, Frederick, USA. Cells were grown in
tissue culture flasks in complete growth medium (RPMI-
1640 medium with 2 mM glutamine, pH 7.4, supplemented
with 10 % fetal calf serum, 100 lg/mL streptomycin, and
100 units/mL penicillin) in a carbon dioxide incubator
(37 °C, 5 % CO2, 90 % RH). The cell at subconfluent stage
Scheme 3 Synthesis of
malyngamide analogs (23–34)
OMe
O
OMe
O
EDCI, HOBt
R
DCM, 0 oC, 10 h, 85-90%
OH
10
23: R = isobutyl
29: R = p-Chloro phenyl amino
30: R = p-Flouro benzyl amino
31: R = p-Methoxy benzyl amino
32: R = 4-Chloro-2,5-dimethoxy phenyl amino
33: R = p-triflouromethyl benzyl amino
34: R = p-bromo phenyl amino
24: R = Piperidyl
25: R = Pyrrolidinyl
26: R = phenylethyl amino
27: R = 3-ethyl indolyl amino
28: R = benzylamino
i) nBuLi, (EtO)2POCH2CO2Et, THF, -78 oC
ii) DIBAL-H, DCM 0 oC to rt
Scheme 4 Synthesis of
malyngamide analogs
(23a–27a)
O
OH
15
18a
i) Ti(OiPr)4, (+)-DET, t-BuOOH, DCM, -20 oC
O
OH
14a
OMe
O
OMe
O
EDCI, HOBt
DCM, 0 oC, 10 h, 85-90%.
OH
R
10a
23a: R = Isobutyl amino
24a: R = Piperidinyl
25a: R = pyrrolidinyl
26a: R = phenylethyl amino
27a: R = 3-ethyl indolyl amino
123

Med Chem Res (2013) 22:4581–4591
4585
Scheme 5 Synthesis of
malyngamide analogs (37–41)
OH
(R,R)-I (10 mol %), Bu3SnCH2CH=CH2
O
CH2Cl2, -15 oC to 0 o
C
15
35
OH
O
4-penteneoic acid (3 equiv), 5 mol%
OH
Grubbs second generation catalyst, CH2Cl2, reflux
36
37: R = isobutyl amino
38: R = Piperdinyl
39: R = pyrrolidinyl
40: R = Phenylethyl amino
41: R = 3-ethyl indolyl amino
OH
O
EDCI, HOBt
R
DCM, 0 oC to rt, 10 h, 85-90%
OiPr
O
Ti
N
N
O
O
O
O
Cl
Ti
Ru
PriO
Cl
Ph
P(Cy)3
Grubb's II catalyst
(R,R)-I
Table 1 Cytotoxic activities of the malyngamide derivatives
Compound
Tissue
Neuroblastoma
CNS
Cervix
HeLa
Prostate
Colon
Lung
IMR-32
IC50 (lM)
SF-295
SKNSH
PC-3
Colon-502713
SW-620
Hop-62
23
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
59.6
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
>100
[100
72.9
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
64.1
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
174
24
25
26
27
28
29
30
[100
[100
[100
62.9
31
32
33
29.8
34
65.7
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
23a
24a
25a
26a
27a
37
[100
118
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
95.8
89.8
[100
[100
[100
[100
[100
[100
100
38
39
120
40
164
41
89.8
were harvested from the flask by treatment with trypsin
[0.05 % in PBS (pH 7.4) containing 0.02 % EDTA]. Cells
with viability of more than 98 % as determined by trypan
blue exclusion were used for determination of cytotoxicity;
the cell suspension of 1 9 105 cells/mL was prepared in
complete growth medium.
123

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Med Chem Res (2013) 22:4581–4591
Stock solutions (2 9 10-2 M) of compounds were pre-
Technical grade ethyl acetate and hexanes used for column
chromatography were distilled prior to use. Column chro-
matography was carried out using silica gel (60–120 mesh)
packed in glass columns. All the reactions were performed
under an atmosphere of nitrogen inflame-dried or oven-dried
glassware with magnetic stirring. The progress of the reac-
tions was monitored by analytical thin layer chromatography
(TLC) performed on Merck Silica Gel 60F254 plates.
1H NMR and 13C NMR spectra were recorded in CDCl3
solvent on 300 MHz or 75 MHz Bruker spectrometers, with
tetramethylsilane as an internal standard. The chemical shifts
are expressed as d values in parts per million (ppm) and the
coupling constants (J) are given in hertz (Hz). FTIR spectra
were recorded as KBr thin films or neat. For EIMS, ESIMS,
m/z ratios are reported as values in atomic mass units. Optical
rotations were determined for solutions in chloroform or
methanol with JASCODIP 300 digital polarimeter at 25 °C.
pared in DMSO. The stock solutions were serially diluted
with complete growth medium containing 50 lg/mL of
gentamycin to obtain working test solutions of required
concentrations.
Invitrocytotoxicityagainst six humancancercelllineswas
determined (Monks et al., 1991) using 96-well tissue culture
plates. The 100 lL of cell suspension was added to each well
of the 96-well tissue culture plate. The cells were allowed to
growincarbondioxideincubator(37 °C, 5 %CO2, 90 % RH)
for 24 h. Test materials in complete growth medium (100 lL)
were added after 24 h of incubation to the wells containing
cell suspension. The plates were further incubated for 48 h in
carbon dioxide incubator. The cell growth was stopped by
gently layering trichloroacetic acid (50 %, 50 lL) on top of
the medium in all the wells. The plates were incubated at 4 °C
for one hour to fix the cells attached to the bottom of the wells.
The liquid of all the wells was gently pipetted out and dis-
carded. The plates were washed five times with distilled water
to remove trichloroacetic acid, growth medium low molecular
weight metabolites, serum proteins, etc. and air-dried. The
plants were stained with sulforhodamine B dye (0.4 % in 1 %
acetic acid, 100 lL) for 30 min. The plates were washed five
times with 1 % acetic acid and then air-dried. (Skehan et al.,
1990). The adsorbed dye was dissolved in Tris–HCL Buffer
(100 lL, 0.01 M, pH 10.4) and plates were gently stirred for
10 min on a mechanical stirrer. The optical density (OD) was
recorded on ELISA reader at 540 nm.
General procedure for synthesis of the compounds
(E)-dec-2-en-1-ol (16)
To a solution of ethyl 2-(diethoxyphosphoryl)acetate
(8.3 g, 37.5 mmol) in THF (100 mL) at -78 °C, nBuLi
(1.6 M in hexanes, 23.4 mL, 37.5 mmol) was added
dropwise. The reaction was stirred for 15 min and then a
solution of aldehyde 15 (4.0 g, 31.2 mmol) in THF
(20 mL) was added dropwise. The dark yellow solution
was stirred at -78 °C for 30 min, and then a saturated
NH4Cl solution (20 mL) was added. The mixture was
warmed to rt and diluted with H2O (20 mL). The layers
were separated, and the aqueous was extracted 2XEtOAc
(30 mL). The organics were dried, filtered, and concen-
trated in vacuo. The resulting oil was purified by flash
column chromatography (5 % EtOAc/Hexanes) to afford
5.5 g (90 %) of ester as a colorless oil.
The cell growth was determined by subtracting mean OD
value of respective blank from the mean OD value of exper-
imentalset.Percentgrowthinthe presenceoftestmaterialwas
calculated considering the growth in the absence of any test
material as 100 % and in turn percent growth inhibition in the
presence of test material was calculated.
Conclusion
To a stirred solution of above ester (5.5 g, 28.1 mmol) in
dry DCM, 1 M DIBAL-H solution in toluene (56.2 mL
56.2 mmol) was added dropwise at -78 °C and the reaction
mixture was stirred for 15 min at same temperature. Then the
reaction mixture was quenched with a saturated aqueous
solution of sodium potassium tartarate (30 mL) and CH2Cl2
(50 mL) was added successively. After stirring for 0.5 h at
0 °C the organic layer was separated. The aqueous layer was
extracted which was CH2Cl2. The combined organic layers
were dried over Na2SO4 and concentrated in vacuo. Purifi-
cation was accomplished by flash column (10 % EtOAc/
Hexanes) which afforded 16 (3.9 g, 90 %) as a clear oil: 1H
NMR (300 MHz, CDCl3): d 5.72–5.50 (m, 2H), 4.06–4.00
(m, 2H), 2.05–1.96 (m, 2H), 1.85 (brs, 1H), 1.40–1.19 (m,
10H), 0.86 (t, 3H, J = 6.8 Hz); 13C NMR (75 MHz, CDCl3):
d 133.36, 128.75, 63.63, 32.15, 31.76, 29.09, 22.59, 14.01;
EIMS m/z [M ? Na]?: 179.
In conclusion, the present report describes the first stereo-
selective synthesis of the malyngamide hybrids in very
good yields. Sharpless epoxidation, Julia–Kocinski olefin-
ation, Marouka asymmetric allylation, and cross metathesis
reactions are key steps for the synthesis of Malyngamide
analogs. Thus the synthesized compounds are new and
screened for their in vitro anticancer activity against the
cancer cell lines for the first time.
Experimental section
General
All the reagents and solvents were reagent grade and used
without further purification unless specified otherwise.
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Med Chem Res (2013) 22:4581–4591
4587
((2S,3S)-3-heptyloxiran-2-yl)methanol (14)
mixture was stirred at rt for 10 h. After completion of
reaction H2O was added and extracted with DCM. The
organic layers were washed with brine, dried over anhy-
drous Na2SO4, and concentrated and purified by flash
chromatography (20 % EtOAc–hexane) to give TBS ether
(2.97 g, 90 %) as a colorless oil.
˚
To a stirred suspension of activated 4 A molecular sieves
(1.0 g) in dry CH2Cl2 (70 mL) was cooled to -40 °C then
treated, sequentially, with diethyl D-(?)-tartrate (0.46 mL,
2.70 mmol), Ti(OPri)4 (0.66 mL, 2.26 mmol), and t-butyl
hydroperoxide (8.6 mL of a 5.2 M solution in isooctane).
The resulting mixture was stirred at -40 °C for 0.5 h then
a solution of compound 16 (3.5 g, 22.4 mmol) in CH2Cl2
(20 mL) was added, via cannula, at such a rate as to
maintain the reaction temperature below -20 °C. After an
additional 3 h at -20 °C the reaction mixture was warmed
to 0 °C then treated with water (13 mL). The reaction
mixture was then warmed to rt and after a further 1 h
treated with NaOH (3.0 mL of a 30 % aqueous solution
saturated with sodium chloride) and stirred vigorously.
After 30 min of stirring, the mixture was filtered through a
small pad of Celite and then the separated aqueous layer
was extracted with DCM (3 9 70 mL). The combined
organic layers were dried (Na2SO4), filtered, and concen-
trated under reduced pressure to give a light-yellow oil.
Subjection to flash chromatography (30 % ethyl acetate/
hexane elution) afforded the title compound 14 (3.4 g,
90 %) as a white soli: mp 52 °C; [a]2D5 -35.5 (c 1, CHCl3);
TBS ether compound (2.5 g, 8.6 mmol) was added to
suspension of NaH (416 mg, 17.3 mmol as a 60 % in
mineral oil) in dry THF (30 mL) at 0 °C. After stirred for
30 min at same temperature, MeI (1.07 mL, 17.2 mmol)
was added and stirred for 10 h at rt. The reaction was
quenched with saturated NH4Cl (10 mL), extracted with
EtOAc and dried over anhydrous Na2SO4, and concen-
trated and purified by flash chromatography (10 % EtOAc–
hexane) to afford 18 (2.3 g, 90 %) as a colorless oil: [a]D25
?3.2 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): d
3.74–3.59 (m, 2H), 3.30 (s, 3H), 3.28–3.22(m, 1H),
1.66–1.58 (m, 2H), 1.48–1.38 (m, 2H), 1.33–1.25 (m,
10H), 0.95–0.85 (m, 12H), 0.08 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 77.81, 59.74, 56.51, 36.99, 33.61,
31.48, 29.80, 29.30, 25.92, 25.13, 22.65, 14.08, -5.58;
ESIMS m/z [M ? Na]?: 325.
(S)-3-methoxydecan-1-ol (19)
IR (KBr): 3421, 3119, 2951, 2918, 2848, 876, 760 cm-1
;
1H NMR (300 MHz, CDCl3): d 3.92–3.81 (m, 1H),
3.65–3.53 (m, 1H), 2.94–2.87 (m, 1H), 2.86–2.82 (m, 1H),
1.60–1.50 (m, 2H), 1.49–1.40 (m, 2H), 1.37–1.23 (m, 8H),
0.86 (t, 3H, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): d
61.58, 58.59, 55.78, 31.82, 31.61, 29.43, 29.26, 26.03,
22.68, 14.18; ESIMS: m/z [M ? Na]?: 195.
To a stirred solution of TBS ether 18 (2.0 g, 6.6 mmol) in
THF (20 mL) under an atmosphere of N2, at room tem-
perature, a 1.0 M solution of tetrabutylammonium fluoride
(13.2 mL, 1.0 M in THF, 13.2 mmol) in THF was added
dropwise via syringe. The reaction was allowed for 10 h at
room temperature; after complete consumption of starting
material the reaction mixture was then concentrated in
vacuo. Purification by flash column chromatography (20 %
EtOAc/Hexanes) afforded 19 (1.1 g, 91 %) as a clear oil:
(S)-decane-1,3-diol (17)
[a]D25 ?12.8 (c 1, CHCl3); IR (KBr): 3425, 980 cm-1; H
1
Red-Al (65 % in toluene, 20 mL, 66.6 mmol) was added
dropwise to a solution of 14 (3.2 g, 18.6 mmol) in dry THF
(50 mL) at 0 °C for 4 h, then quenched with H2O (7 mL),
stirred for additional 20 min at room temperature, and fil-
tered over Celite using ethyl acetate. The organic solution
was washed with brine, dried over anhydrous Na2SO4, and
concentrated and purified by flash chromatography (40 %
EtOAc–hexane) to afford 17 (2.9 g, 90 %) as colorless oil:
NMR (300 MHz, CDCl3): d 3.78–3.61 (m, 2H), 3.42–3.36
(m, 1H), 3.34 (s, 3H), 2.79–2.65 (brs, 1H), 1.78–1.62 (m,
2H), 1.60–1.38 (m, 2H), 1.36–1.22 (m, 10H), 0.89 (t, 3H,
J = 6.0 Hz), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3): d
80.95, 60.85, 56.36, 35.56, 33.00, 31.82, 29.80, 29.28,
25.07, 22.65, 14.05; ESIMS m/z [M ? Na]?: 211.
1
[a]2D5 -3.2 (c 1, CHCl3); H NMR (300 MHz, CDCl3): d
2-((S,E)-7-methoxytetradec-4-enyloxy)tetrahydro-2H-
3.90–3.72 (m, 3H), 1.73–1.57 (m, 2H), 1.51–1.36 (m, 2H),
1.32–1.23 (m, 10H), 0.88 (t, 3H, J = 5.92 Hz); 13C NMR
(75 MHz, CDCl3): d 71.63, 61.20, 38.37, 37.81, 31.91,
27.73, 25.68, 22.72, 14.19; EIMS m/z [M ? Na]?: 197.
pyran (11)
To a solution of iodoxybenzoic acid (2.4 g, 8.7 mmol) in
DMSO (10 mL), alcohol 19 (1.1 g, 8.7 mmol) in THF
(20 mL) was added and allowed to stir for 1 h at room
temperature. After completion of the reaction, the reaction
mixture was filtered through a pad of Celite and washed
with ether (40 mL). The filtrate was washed with water
(10 mL) and brine (10 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo. The crude product was purified
(S)-tert-butyl(3-methoxydecyloxy)dimethylsilane (18)
TBDMSCl (2.01 g, 13.4 mmol) was added to a solution of
17 (2.0 g, 11.4 mmol), imidazole (1.5 g, 22.9 mmol), and
DMAP (139 mg) in dry DCM (X mL), at 0 °C and the
123

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Med Chem Res (2013) 22:4581–4591
by column chromatography (10 % hexanes–EtOAc) which
afforded aldehyde 13 (1.0 g, 92 %) of the title compound
as colorless oil.
(3 9 15 mL), and dried (Na2SO4) and concentrated in
vacuo. The residue was purified by column chromatogra-
phy (40 % EtOAc–hexane) to afford the acid 10 (727 mg,
86 %) as colorless oil: [a]2D5 -9.2 (c 1, CHCl3); IR (KBr):
A solution of sulfone (1.8 g, 4.16 mmol) in dry THF
(20 mL) at -78 °C was treated with lithium bis(tri-
methyl)amide (4.98 mL, 1.0 M in THF, 4.98 mmol). The
resultant red color solution was stirred at -78 °C for
30 min, after which a solution of aldehyde 13 (1.0 g,
5.37 mmol) in dry THF (10 mL) was added slowly. The
reaction mixture was stirred at -78 °C for 2 h and allowed
to warm to ambient temperature overnight. The cloudy
reaction mixture was quenched with water (2 mL) and
poured into brine (30 mL). The layers were separated and
extracted with EtOAc. The combined extracts were dried
over anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography (10 % EtOAc–hexane) provided 11
(1.4 g, 80 %) as a pale yellow oil: [a]2D5 -10.2 (c 1,
CHCl3); IR (KBr): 2933, 2857, 1454, 1351, 1102,
3128, 2976, 2859, 1446, 1090, 971 cm-1 1H NMR
;
(300 MHz, CDCl3): d 11.23 (br s, 1H), 5.56–5.36 (m, 2H),
3,32 (s, 3H), 3.20–3.09 (m, 1H), 2.53–2.28 (m, 6H),
1.49–1.38 (m, 2H), 1.35–1.22 (m, 10H), 0.88 (t, 3H,
J = 6.42 Hz); 13C NMR (75 MHz, CDCl3): d 179.32,
130.14, 80.88, 56.45, 36.36, 33.92, 33.22, 31.84, 29.62,
29.3, 27.61, 25.23, 22.62, 14.10; ESIMS m/z [M ? Na]?
:
279.
(S)-undec-1-en-4-ol (33)
To a stirred solution of 1 M TiCl4 in CH2Cl2 (0.64 mL,
6.4 mmol) in DCM (20 mL) dried Ti(OPri)4 (0.55 mL,
1.92 mmol) was added at 0 °C under nitrogen condition.
The solution was allowed to warm up to room temperature.
After 1 h, silver (I) oxide (297 mg, 1.2 mmol) was added
at room temperature, and the whole mixture was stirred for
5 h under exclusion of direct light. The mixture was diluted
with CH2Cl2 (10 mL), and treated with (R)-binaphthol
(733 mg, 2.5 mmol) at room temperature for 2 h to furnish
chiral bis-Ti(IV) oxide (R,R)-I. The in situ generated (R,R)-
I was cooled to -15 °C, and treated sequentially with
aldehyde 15 (1.6 g, 12.8 mmol) and allyltributyltin
(4.4 mL, 14 mmol) at -15 °C. The whole mixture was
allowed to warm to 0 °C and stirred for 4 h. The reaction
mixture was quenched with saturated NaHCO3 and
extracted with CH2Cl2. The organic extracts were dried
over Na2SO4 and concentrated under reduced pressure.
Purification by column chromatography (silica gel, 95/5
hexanes–EtOAc) afforded 33 (1.8 g, 86 %, 98 % ee) of the
title compound as pale yellow color oil: [a]2D5 -9.5 (c 1,
CHCl3); IR (KBr): 3350, 2925, 2856, 1641, 1462, 998,
1
1035 cm-1; H NMR (300 MHz, CDCl3): d 5.45–5.26(m,
2H), 4.72 (t, 1H, J = 3.58 Hz), 3.80–3.68 (m, 1H),
3.66–3.58 (m, 1H), 3.46–3.3.34 (m, 2H), 3.23 (s, 3H)
3.08–2.97 (m, 1H) 2.17–1.92 (m, 4H), 1.82–1.69 (m, 2H)
1.66–1.42 (m, 8H), 1.36–1.22 (m, 10H), 0.89 (t, 3H,
J = 6.4 Hz); 13C NMR (75 MHz, CDCl3): d 132.02,
126.49, 98.76, 80.98, 66.94, 62.20, 56.43, 36.30, 33.29,
31.79, 30.71, 29.71, 29.48, 29.26, 25.45, 25.22, 22.61,
19.58, 14.04; ESIMS m/z [M ? Na]?: 349.
(S,E)-7-methoxytetradec-4-en-1-ol (20)
To a stirred solution of compound 11 (1.3 g, 3.98 mmol) in
methanol (20 mL) PTSA (cat.) was added and then the
reaction was stirred at rt for 10 h. The solvent was then
concentrated in vacuo. Flash chromatography of the resi-
due over silica gel (20 % EtOAc–hexane) afforded the
primary alcohol 20 (0.88 g, 92 % yield) as a colorless oil:
[a]2D5 -13.2 (c 1, CHCl3); IR (KBr): 3420, 1200,
1
915 cm-1; H NMR (300 MHz, CDCl3): d 5.78–5.66 (m,
1
981 cm-1; H NMR (300 MHz, CDCl3): d 5.52–5.34(m,
1H), 5.13–5.00 (m, 2H), 3.63–3.48 (m, 1H), 2.30–2.16 (m,
1H), 2.12–1.98 (m, 1H), 1.49–1.32 (m, 2H), 1.29–1.12 (m,
10H) 0.81 (t, 3H, J = 6.6 Hz); 13C NMR (75 MHz,
CDCl3): d 134.8, 117.8, 70.6, 41.8, 36.7, 31.7, 29.5, 29.2,
25.6, 22.5, 14.0; EIMS m/z [M ? Na]?: 193.
2H), 3.62 (t, 2H, J = 6.23 Hz), 3.30 (s, 3H) 3.18–3.06 (m,
1H) 2.20–2.13 (m, 2H), 2.12–2.02 (m, 2H) 1.69–1.52 (m,
4H), 1.33–1.20 (m, 10H), 0.89 (t, 3H, J = 5.4 Hz); 13C
NMR (75 MHz, CDCl3): d 132.09, 126.84, 80.80, 62.55,
56.43, 36.37, 33.35, 33.31, 32.34, 31.82, 29.74, 29.68,
29.28, 29.19, 22.64, 14.06; ESIMS m/z [M ? Na]?: 265.
(S,E)-7-hydroxytetradec-4-enoic acid (34)
(S,E)-7-methoxytetradec-4-enoic acid (10)
To a solution of 33 (364 mg, 2 mmol), and 4-pentenoic
acid (600 mg, 6 mmol), in CH2Cl2(4 mL) 5 mol % of
Grubbs second generation catalyst (84.8 mg, 0.1 mmol)
was added and it was warmed to reflux for 6 h. After the
completion of reaction, the reaction mixture was concen-
trated on to silica gel and flash chromatography (40 %
EtOAc/hexane) to give brown color oil 34 (405 mg, 80 %)
To a solution of 20 (800 mg, 2.45 mmol) in acetone
(30 mL) Jones reagent 3.4 mL at 0 °C was added and the
mixture was stirred at the same temperature for 2 h. Iso-
propyl alcohol was added and the resulting mixture was
filtered and concentrated in vacuo, the residue was dis-
solved in 50 mL of EtOAc, washed with brine
1
of the title compound. [a]2D5 -3.2 (c 1, CHCl3); H NMR
123

Med Chem Res (2013) 22:4581–4591
4589
(300 MHz, CDCl3): d 5.58–5.45 (m, 2H), 3.71–3.50 (m,
1H), 2.50–2.31 (m, 4H), 2.28–2.16 (m, 1H), 2.14–1.97 (m,
1H), 1.51–1.36 (m, 2H), 1.33–1.16 (m, 10H), 0.87 (t, 3H,
J = 7.5 Hz); 13C NMR (75 MHz, CDCl3): d 177.8, 131.5,
127.3, 71.0, 40.1, 36.3, 31.6, 29.4, 29.1, 27.6, 25.4, 22.4,
13.9; ESIMS m/z [M ? Na]?: 265.
152.7, 132.3, 130.6, 128.8, 124.6, 65.4, 61.2, 55.0, 29.8,
27.3, 24.6, 18.7, 18.6; ESIMS m/z [M ? Na]?: 389.
Typical experimental procedure for synthesis of amides:
To a solution of Acid (1 mmol) and amine (1.2 mmol) in
5 mL of CH2Cl2 (0.4 mmol) of HOBt (1-hydroxybenzo-
triazole), (4.0 mmol) of EDCI (N-(3-dimethylaminopro-
pyl)-N0-ethylcarbodiimide) at 0 °C were added. After
stirring 10 h at 23 °C, the reaction was quenched with 1 N
HCl, extracted with ether, washed with brine, dried over
Na2SO4, and concentrated. Purification by column chro-
matography (silica gel, 90/10–85/15 hexanes–EtOAc)
afforded amide with the 85–90 % yield.
4-(tetrahydro-2H-pyran-2-yloxy)butan-1-ol (36)
To a mixture of 1,4-butanediol 35 (2.7 g, 30 mmol) and
dihydropyran (2.5 g, 30 mmol) in THF (5 mL)/CH2C12
(50 mL), a catalytic amount of p-toluenesulfonic acid
(0.57 g, 3 mmol) was added at 0 °C and the mixture was
stirred for 1 h. The mixture was dissolved in diethyl ether
(70 mL). The ethereal solution was washed with water
(20 mL 9 3) and saturated NaCl solution (20 mL), and
then dried over Na2SO4. Evaporation of the solvent fol-
lowed by Purification by column chromatography (silica
gel, 60/40 hexanes–EtOAc) afforded 36 as title compound
as colorless oil: IR (KBr): 3401, 2939, 1440, 1352, 1200,
Spectral data for new amide derivatives:
Compound 21: pale yellow oil: [a]2D5 ?5.2 (c 1, CHCl3);
1H NMR (300 MHz, CDCl3): d 5.52–5.43 (m, 2H), 3.31
(s, 3H), 3.12–3.07 (m, 3H), 2.42–2.31 (m, 2H),
2.28–2.14 (m, 5H), 1.38–1.22 (m, 12H), 0.97–0.8 5
(m,9H); 13C NMR (75 MHz, CDCl3): d 172.48, 130.85,
127.39, 80.60, 56.31, 46.71, 36.45, 36.20, 33.21, 31.70,
29.62, 29.17, 28.70, 28.36, 25.18, 22.52, 19.97, 13.96;
ESIMS m/z [M ? Na]?: 334.
Compound 21a: pale yellow oil: [a]2D5 -6.1(c 1, CHCl3);
Compound 22: colorless oil, [a]2D5 -3.2 (c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d 5.50–5.42 (m, 2H), 3.54 (t,
2H, J = 5.28 Hz), 3.39 (t, 2H, J = 5.28 Hz), 3.31 (s,
3H), 3.15–3.08 (m, 1H), 2.41–2.31 (m, 4H), 2.17 (t, 2H,
J = 5.85 Hz), 1.69–1.60 (m, 2H), 1.59–1.48 (m, 4H),
1.31–1.23 (m, 12H), 0.88 (t, 3H, J = 6.23 Hz); 13C
NMR (75 MHz, CDCl3): d 170.82, 131.48, 127.07,
80.86, 56.58, 46.75, 42.73, 36.45, 33.42, 33.36, 31.91,
29.83, 29.38, 28.61, 26.64, 25.36, 24.66, 22.74, 14.18;
ESIMS m/z [M ? H]?: 324.
Compound 22a: colorless oil, [a]2D5 ?2.8 (c 1, CHCl3);
Compound 23: colorless oil, [a]2D5 -2.7 (c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d 5.53–5.40 (m, 2H), 3.43 (t,
2H, J = 4.48 Hz), 3.43 (t, 2H, J = 4.48 Hz), 3.30 (s,
3H), 3.13–3.28 (m, 1H), 2.32–2.28 (m, 4H), 2.21 (t, 2H,
J = 6.23 Hz), 1.69–1.60 (m, 2H), 1.56–1.48 (m, 2H),
1.30–1.23 (m, 12H), 0.88 (t, 3H, J = 6.02 Hz); 13C
NMR (75 MHz, CDCl3): d 171.14, 131.42, 127.02,
80.82, 56.52, 46.62, 45.62, 36.40, 34.71, 33.37, 31.85,
29.70, 29.31, 26.12, 24.41, 22.66, 14.10; ESIMS m/z
[M ? H]?: 310.
Compound 23a: colorless oil, [a]2D5 ?3.2 (c 1, CHCl3);
Compound 24: colorless oil, [a]2D5 -9.7 (c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.28–7.12 (m, 5H), 5.82 (br
s, 1H), 5.40 (m, 2H), 3.45 (q, 2H, J = 6.86 Hz), 3.26 (s,
3H), 3.19–3.09 (m, 1H), 2.80 (t, 2H, J = 7.1 Hz),
2.29–2.25 (m, 2H), 2.17–2.11 (m, 4H), 1.40–1.20 (m,
12H), 0.83 (t, 3H, J = 6.21 Hz); 13C NMR (75 MHz,
1020, 810 cm-1
; d
1H NMR (300 MHz, CDCl3):
4.61–4.59 (m, 1H), 3.91–3.78 (m, 2H), 3.70–3.66 (m,
2H), 3.55–3.41 (m, 2H), 1.90 (s, 1H), 1.85–1.65 (m, 6H),
1.62–1.47 (m, 4H); 13C NMR (75 MHz, CDCl3): d 98.9,
98.8, 67.6, 62.9, 67.4, 62.9, 62.8, 62.4, 62.3, 30.8, 30.6,
30.2, 29.9, 26.6, 26.5, 25.5, 25.4, 19.6, 19.5; EIMS m/z
[M ? Na]?: 197.
1-phenyl-5-(4-(tetrahydro-2H-pyran-2-
yloxy)butylsulfonyl)-1H-tetrazole (12)
Triphenylphosphine (3.9 g, 15.2 mmol), 1-phenyl-1H-tet-
razole-5-thiol (PT-SH, 2.8 g, 15.2 mmol), and 36 (2.0 g,
10.1 mmol) were dissolved in 40 mL of anhydrous THF, to
which DIAD (3.06 g, 15.2 mmol) was added at room
temperature. After being stirred for 0.5 h, the reaction
mixture was diluted with 50 mL of EtOH and cooled to
0 °C. In a separate flask 30 % aqueous H2O2 (23.4 g,
206 mmol) and ammonium molybdate (2.56 g, 2.06 mmol)
were mixed, producing a bright yellow solution that was
added to the reaction via pipet. After being stirred over-
night at room temperature, the reaction mixture was diluted
by the addition of water and CH2Cl2. The layers were
separated, and the aqueous layer was extracted three times
with CH2Cl2. The combined organic layers were washed
with water and brine, dried over Na2SO4, and filtered, and
concentrated in vacuo. Purification on silica gel (10 %
EtOAc in PE) provided 3.3 g (80 % yield) of 12 as yellow
color oil: IR (KBr): 2956, 2927, 2859, 1730, 1591, 1499,
1460, 820 cm-1; 1H NMR (300 MHz, CDCl3): d 7.75–7.67
(m, 2H), 7.65–7.56 (m, 3H), 4.60–4.54 (m, 1H), 3.90–3.77
(m, 4H), 3.57–3.39 (m, 2H), 2.17–2.03 (m, 2H), 1.89–1.73
(m, 4H), 1.64–1.46 (4H); 13C NMR (75 MHz, CDCl3): d
123

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Med Chem Res (2013) 22:4581–4591
CDCl3): d 170.32, 137.34, 129.46, 127.39, 127.34,
NMR (75 MHz, CDCl3): d172.18, 158.78, 136.92,
130.42, 128.95, 127.45, 113.87, 80.53, 56.26, 55.10,
24.81, 36.29, 36.18, 35.61, 33.18, 31.68, 29.61, 29.16,
28.57, 25.13, 22.51, 13.95; ESIMS m/z [M ? Na]?: 398.
Compound 30: colorless oil, [a]2D5 -2.1 (c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d 8.26 (s, 1H), 6.85 (s, 1H),
5.55–5.46 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.29 (s,
3H), 3.20–3.06 (m, 1H), 2.51–2.41 (m, 4H), 2.25–2.14
(m, 2H), 1.36–1.18 (m, 12H), 0.88 (t, 3H, J = 6.42 Hz);
13C NMR (75 MHz, CDCl3): d 170.90, 149.36, 141.88,
130.57, 128.19, 127.82, 127.27, 112.38, 105.10, 80.92,
56.91, 56.72, 56.57, 38.02, 36.58, 33.57, 32.05,
29.98, 29.52, 28.55, 25.51, 22.87, 14.3; ESIMS m/z
[M ? Na]?: 449.
126.18, 125.19, 80.47, 56.65, 41.24, 37.24, 37.09,
36.52, 34.12, 32.67, 30.73, 30.22, 29.66, 26.32, 23.72,
14.05; ESIMS m/z [M ? Na]?: 382.
Compound 24a: colorless oil, [a]2D5 ?9.0 (c 1, CHCl3);
Compound 25: colorless oil, [a]2D5 -2.7 (c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d 8.89 (br s, 1H), 7.58 (d, 1H,
J = 7.81 Hz), 7.35 (d, 1H, J = 8.12 Hz), 7.17 (t, 1H,
J = 8.1 Hz), 7.12 (t, 1H, J = 7.9 Hz), 6.98 (s, 1H),
5.80–5.72 (br s, 1H), 5.42–5.32 (m, 2H), 3.54 (q, 2H,
J = 6.6 Hz), 3.32 (s, 3H), 3.19–3.07 (m, 1H), 2.95 (t,
2H, J = 6.8 Hz), 2.33–2.28 (m, 2H), 2.18–2.14 (m, 4H),
1.46–1.22 (m, 12H), 0.89 (t, 3H J = 6.81 Hz); 13C NMR
(75 MHz, CDCl3): d 170.41, 135.10, 129.54, 126.20,
126.13, 121.11, 120.83, 118.15, 117.45, 111.63, 110.54,
80.49, 56.71, 40.54, 37.22, 37.14, 34.17, 32.69, 30.74,
30.20, 29.61, 26.33, 26.24, 23.79, 15.02; ESIMS m/z
[M ? Na]?: 421.
Compound 25: colorless oil, [a]2D5 ?3.8 (c 1, CHCl3);
Compound 26: colorless oil, [a]2D5 ?2.7 (c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.38–7.19 (m, 5H),
5.50–5.41 (m, 2H), 4.41 (d, 2H, J = 5.66 Hz), 3.28 (s,
3H), 3.18–3.01 (m, 1H), 2.46–2.11 (m, 6H), 1.36–1.21
(m, 12H), 0.88 (t, 3H, J = 6.23 Hz); 13C NMR
(75 MHz, CDCl3): d 172.36, 138.32, 130.76, 128.58,
127.68, 127.36, 80.61, 56.36, 43.50, 36.40, 36.23, 33.25,
31.75, 29.68, 29.23, 28.63, 25.22, 22.58, 14.03; ESIMS
m/z [M ? Na]?: 368.
Compound 31: colorless oil, [a]2D5 -2.1 (c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.56 (d, 2H, J = 7.93 Hz),
7.36 (d, 2H, J = 7.74 Hz), 5.50–5.43 (m, 2H), 4.50–4.42
(br s, 2H), 3.28 (s, 3H), 3.17–3.04 (m, 1H), 2.42–2.26
(m, 4H), 2.21–2.12 (m, 2H), 1.32–1.21 (m, 12H), 0.88 (t,
3H, J = 5.47 Hz); 13C NMR (75 MHz, CDCl3): d
172.71, 142.59, 136.78, 130.69, 127.71, 125.42,
115.64, 80.55, 56.26, 42.85, 36.15, 33.22, 31.74, 29.66,
29.21, 28.56, 25.24, 22.56, 13.98; HRESIMS m/z
[M ? Na]?: 436.
Compound 32: paleyellow oil, [a]2D5 -1.9 (c 1, CHCl3);
1H NMR (300 MHz, CDCl3):
d 7.41 (d, 2H,,
J = 8.58 Hz), 7.23 (d, 2H, J = 8.77 Hz), 5.56–5.47
(m, 2H), 3.29 (s, 3H), 3.20–3.08 (m, 1H), 2.48–2.36 (m,
4H), 2.26–2.13 (m, 2H), 1.38–1.17 (m, 12H), 0.88 (t, 3H,
J = 6.23 Hz); 13C NMR (75 MHz, CDCl3): d 170.92,
136.98, 131.83, 130.47, 128.10, 121.41, 80.59, 56.34,
37.38, 36.24, 33.23, 31.78, 29.68, 29.26, 28.37, 25.27,
22.60, 14.05; ESIMS m/z [M ? H]?: 410.
Compound 27: colorless oil, [a]2D5 -3.8 (c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.46 (d, 2H,, J = 8.68 Hz),
7.24 (d, 2H, J = 8.87 Hz), 5.55–5.49 (m, 2H), 3.28 (s,
3H), 3.1–3.09 (m,1H), 2.44–2.20 (m, 4H), 2.24–2.15 (m,
2H), 1.32–1.20 (m, 12H), 0.88 (t, 3H, J = 6.42 Hz); 13
C
NMR (75 MHz, CDCl3): d 171.08, 136.71, 130.72,
129.12, 128.37, 121.30, 80.83, 56.60, 37.62, 36.49,
33.49, 32.02, 29.93, 29.50, 28.63, 25.51, 22.85, 1429;
ESIMS m/z [M ? H]?: 366.
Compound 35: colorless oil, [a]2D5 ?4.7(c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d 5.59–5.40 (m, 2H),
3.59–3.47 (br s, 1H), 3.12–2.98 (m, 3H), 2.40–2.28 (m,
2H), 2.26–2.13 (m, 4H), 2.07–1.94 (m, 1H), 1.49–1.37
(m, 2H), 1.34–1.23(m, 10H), 0.96–0.83 (m, 9H); 13C
NMR (75 MHz, CDCl3): d 172.40, 132.24, 127.64,
70.85, 46.79, 40.54, 36.75, 36.49, 31.78, 29.60, 29.24,
28.83, 28.44, 25.68, 22.61, 20.03, 14.04; ESIMS m/z
[M ? Na]?: 320.
Compound 28: colorless oil, [a]2D5 -1.4 (c 1, CHCl3); 1H
NMR (300 MHz, CDCl3):
d
7.25–7.16 (m,2H),
7.04–6.93 (m, 2H), 5.48–5.40 (m, 2H), 4.36 (d, 2H,
J = 5.66 Hz), 3.28 (s, 3H), 3.16–3.00 (m, 1H),
2.42–2.23 (m, 4H), 2.19–2.11 (m, 2H), 1.30–1.22 (m,
12H), 0.88 (t, 3H, J = 6.42 Hz); 13C NMR (75 MHz,
CDCl3): d 172.43, 160.33, 134.22, 130.69, 129.29,
129.18, 127.58, 115.48, 115.15, 80.51, 56.27, 42.59,
36.25, 36.14, 33.17, 31.71, 29.63, 29.18, 28.56, 25.18,
22.53, 13.98; ESIMS m/z [M ? Na]?: 386.
1
Compound 36: oil, [a]2D5 ?2.8(c 1, CHCl3); H NMR
(300 MHz, CDCl3): d 5.52–5.31 (m, 2H), 3.58–3.49 (m,
1H), 3.47–3.35 (m, 4H), 3.38–2.24 (m, 4H), 2.25–2.14
(m, 2H), 2.02–1.79 (m,6H), 1.46–1.36 (m, 2H),
1.35–1.19 (m, 10H), 0.88 (t, 3H, 6.04); 13C NMR
(75 MHz, CDCl3): d 170.60, 132.72, 127.19, 70.74,
46.48, 42.61, 40.55, 36.71, 33.16, 31.77, 29.59, 29.22,
28.45, 26.52, 25.57, 25.40, 24.48, 22.59, 14.03; ESIMS
m/z [M ? Na]?: 332.
Compound 29: colorles oil, [a]2D5 -3.6 (c 1, CHCl3); H
1
NMR (300 MHz, CDCl3): d 7.18 (d, 2H, J = 8.49 Hz),
6.82 (d, 2H, J = 8.49 Hz), 5.49–5.41 (m, 2H), 4.33 (d,
2H, J = 5.47 Hz), 3.78 (s, 3H), 3.29 (s, 3H),
3.15–3.00(m, 1H), 2.42–2.20 (m, 4H), 2.18–2.11 (m,
Compound 37: colorless oil, [a]2D5 ?3.6(c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d 5.59–5.36 (m, 2H),
2H), 1.34–1.21 (m, 12H), 0.88 (t, 3H, J = 6.42 Hz); 13
C
123

Med Chem Res (2013) 22:4581–4591
4591
Corey EJ, Niwa H, Knolle J (1978) Total synthesis of (S)-12-hydroxy-
5,8,14-cis-10-trans-eicosatetraenoic acid (Samuelsson’s HETE).
J Am Chem Soc 100:1942
Finan JM, Kishi Y (1982) Reductive ring openings of allyl-alcohol
epoxides. Tetrahedron Lett 23:2719
Frigerio M, Santagostino M (1994) A mild oxidizing reagent for
alcohols and 1,2-diols: o-iodoxybenzoic acid (IBX) in DMSO.
Tetrahedron Lett 35:8019
Gao Y, Hanson RM, Klunder JM, Ko SY, Masamune H, Sharpless
KB (1987) J Am Chem Soc 109:5765
3.60–3.49 (br s, 1H), 3.47–3.36 (m, 4H), 2.39–2.25 (m,
4H), 2.24–2.10 (m, 2H),2.06–1.83 (m, 2H), 1.49–1.35
(m, 2H), 1.32–1.17 (m, 12H), 0.88 (t, 3H, J = 6.04 Hz);
13C NMR (75 MHz, CDCl3): d 171.19, 132.67, 127.22,
70.81, 46.62, 45.66, 40.54, 36.67, 34.44, 31.76, 29.59,
29.21, 27.40, 26.01, 25.65, 24.31, 22.58, 14.02; ESIMS
m/z [M ? Na]?: 318.
Compound 38: colorless oil, [a]2D5 ?3.9(c 1, CHCl3); 1H
Hanawa H, Hashimoto T, Maruoka K (2003) Bis((s)-binapthoxy)(iso-
propoxy)titanium) oxide a l-oxo-type chiral Lewis acid: appli-
cation to catalytic asymmetric allylation of aldehydes. J Am
Chem Soc 125:1708
Ireland RE, Norbeck DW (1985) Application of the Swern oxidaion
to the manipulation of higly reactive carbonyl compounds. J Org
Chem 50:2198
Kocienski PJ, Bell, PR, Blakemore PR (2000) 1-tert-Butyl-1H-
tetrazol-5-yl sulfones in the modified Julia olefination. Synlett
365
NMR (300 MHz, CDCl3):
d
7.37–7.07 (m,5H),
5.94–5.75 (br s, 1H), 5.5–5.34 (m,2H), 3.56–3.38 (m
3H), 2.78 (t, 2H, 6.61 Hz), 2.36–2.09 (m, 4H), 2.06–1.88
(m, 2H), 1.47–1.18 (m, 12H), 0.88 (t, 3H, J = 6.62 Hz);
13C NMR (75 MHz, CDCl3): d 172.32, 138.89, 132.16,
128.71, 128.57, 127.68, 126.44, 70.79, 40.48, 36.79,
36.37, 35.63, 31.78, 29.60, 29.24, 28.67, 25.68, 22.61,
14.05; ESIMS m/z [M ? Na]?: 368.
Compound 39: colorless oil, [a]2D5 ?5.8(c 1, CHCl3); 1H
NMR (300 MHz, CDCl3): d 8.78 (br s, 1H), 7.48 (d, 1H,
J = 7.34 Hz), 7.34 (d, 1H, J = 7.85 Hz), 7.21 (t, 1H,
J = 8.03 Hz), 7.12 (t, 1H, J = 7.89 Hz), 6.86 (s, 1H),
5.80–5.72 (br s, 1H), 5.40–5.31 (m, 2H), 3.54 (m 2H),
3.20–3.09 (m, 1H), 2.98 (t, 2H, J = 6.72 Hz), 2.33–2.28
(m, 2H), 2.18–2.10 (m, 4H), 1.45–1.22 (m, 12H), 0.88 (t,
3H J = 6.03 Hz); 13C NMR (75 MHz, CDCl3): d
171.41, 134.45, 129.53, 126.22, 126.23, 121.21,
120.85, 118.15, 117.45, 111.63, 110.54, 70.71, 40.54,
37.22, 37.14, 34.17, 32.69, 30.74, 30.20, 29.61, 26.33,
26.25, 23.79, 14.12; HRESIMS m/z [M ? H]? found
385.2846; calculated for C24H37N2O2: 385.2850.
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Hose C, Langley J, Cronise P, Vaigro-Wolff A, Gray-Goodrich
M, Campbell H, Mayo J, Boyd M (1991) Feasibility of a high-
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Acknowledgments The authors gratefully acknowledge the keen
interest of Dr. J. S. Yadav, Director, IICT, Hyderabad, India in the
present work. GV thanks UGC for financial support.
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