Synthesis of long-chain fatty acid derivatives as a novel anti-Alzheimer's agent

Article abstract of DOI:10.1016/j.bmcl.2013.12.008

In order to develop new drugs for Alzheimer's disease, we prepared 17 fatty acid derivatives with different chain lengths and different numbers and positions of double bonds by using Wittig reaction and stereospecific hydrogenation of triple bonds as key reactions. Among them, (4Z,15Z)- octadecadienoic acid (10) and (23Z,34Z)-heptatriacontadienoic acid (16) showed the most potent neurite outgrowth activities on Aβ(25-35)-treated rat cortical neurons, which activities were comparable to that of a positive control, NGF. Both fatty acids 10 and 16 possess two (Z)-double bonds at the n-3 and n-14 positions, which might be important for the neurite outgrowth activity.

Full text of DOI:10.1016/j.bmcl.2013.12.008

Bioorganic & Medicinal Chemistry Letters 24 (2014) 604–608
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of long-chain fatty acid derivatives as a novel
anti-Alzheimer’s agent
e
Hong-Yan Zhang a, Yu-ichiro Yamakawa b, Yuji Matsuya b, Naoki Toyooka c,d, , Chihiro Tohda ,
⇑
Suresh Awale f, Feng Li g, Shigetoshi Kadota a, Yasuhiro Tezuka a,
⇑
a Division of Natural Products Chemistry, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
b Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
c Graduate School of Science and Technology for Research, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
d Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
e Division of Division of Neuromedical Science, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
f Frontier Research Core for Life Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
g Research Promotion Office, Joint Usage/Research Center for Science-Based Natural Medicine, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama
930-0194, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to develop new drugs for Alzheimer’s disease, we prepared 17 fatty acid derivatives with
different chain lengths and different numbers and positions of double bonds by using Wittig reaction
and stereospecific hydrogenation of triple bonds as key reactions. Among them, (4Z,15Z)-octadecadienoic
acid (10) and (23Z,34Z)-heptatriacontadienoic acid (16) showed the most potent neurite outgrowth
activities on Ab(25–35)-treated rat cortical neurons, which activities were comparable to that of a
positive control, NGF. Both fatty acids 10 and 16 possess two (Z)-double bonds at the n-3 and n-14
positions, which might be important for the neurite outgrowth activity.
Received 9 October 2013
Revised 20 November 2013
Accepted 2 December 2013
Available online 9 December 2013
Keywords:
Long-chain fatty acid
Neurite outgrowth activity
Anti-Alzheimer’s agent
Synthesis
Ó 2013 Elsevier Ltd. All rights reserved.
Fatty acids play a very important role in human health, growth,
and development as an energy source, signaling molecules, and a
structural component of membranes. In particular, long-chain
polyunsaturated fatty acids (LCPUFA) including the n-6 fatty acids
(e.g., arachidonic acid, AA) and the n-3 fatty acids (e.g., docosahex-
aenoic acid, DHA; eicosapentaenoic acid, EPA) are known to be
nutritionally important fatty acids; they are essential for neurocog-
nitive development and normal brain functions.1 In addition, sup-
plementation of LCPUFA are important for the development of
childhood intelligence,2 cognitive function,3 prevention of demen-
tia in later life.4 Whereas several studies reported that LCPUFA
such as AA, DHA, and EPA are of significant benefit in the preven-
tion and treatment of Alzheimer’s disease and other dementias by
promoting neurite outgrowth.5
elderly and the continuing expansion of life expectancy lead to a
fast increase in the number of patients suffering from Alzheimer’s
disease. It was reported that the numbers of people with dementia
were about 36.5 million worldwide in 2010.7 Despite the great
number of ongoing investigations, effective treatment is lacking.
Donepezil hydrochloride, a cholinesterase inhibitor, is clinically
used in the treatment of Alzheimer’s disease,8 but it plays a role
just slowing the progression of the disease, rather than to cure
it.9 Therefore, the development of alternative approaches and no-
vel agents are urgently needed for the treatment of Alzheimer’s
disease. Alzheimer’s disease is caused by the irreversible neuronal
degeneration and atrophy in the central nervous system, involving
neuronal death, neuritic atrophy, and synaptic loss.10 Actually,
reinforce the neuronal networks in the damage brain might be pos-
sible by reformation of synapses and regeneration of neurite
through the activation of remaining healthy neurons.11
In a course of our study on anti-Alzheimer’s desease, we found
that a CHCl3 extract of Rosa damasene (Rosaceae) from Iran and its
active constituent displayed pronounced neurite outgrowth activ-
ity under neuritic atrophy condition and the active constituent (A)
displayed potent neurite outgrowth activity comparable to a posi-
tive control, nerve growth factor (NGF) (Fig. 1). Chemical analysis
of the active constituent suggested it to be a very long-chain
Alzheimer’s disease, the most common form of dementia, is a
progressive and fatal neurodegenerative disease affecting the el-
derly population with a prevalence rising from 1% at the age of
60 to at least 35% at the age of 90 years.6 The growing number of
⇑
Corresponding authors. Tel.: +81 76 434 7627 (Y.T.); tel.: +81 76 445 6859
(N.T.).
E-mail addresses: toyooka@eng.u-toyama.ac.jp (N. Toyooka), tezuka@inm.
u-toyama.ac.jp (Y. Tezuka).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.008

H.-Y. Zhang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 604–608
605
HOOC
HO
(
)
n
1.
Br
, n-BuLi,
HMPA / THF (87%)
1.
(
)
9
, n-BuLi,
(
)
m
CH3
HMPA / THF (62%)
HO
( A )
Br
m + n = 22
( )9
( )8
18
2. Lindlar Hydrogenation
HOOC
∗
2. KH, APA (80%)
100
50
Jones oxidation
(45% in 2 steps)
( )9
( )9
HO
∗
4
( )10
( )9
1. H2. 10% Pd/C / EtOAc
2. Jones oxidation
19
HOOC
( )20
1
(43% in 3 steps)
Scheme 1. Synthesis of fatty acids 1 and 4.
NaN(SiMe3)2 under the salt-free conditions14 furnished a TBDPS-
protected alcohol which has a desired double bond of cis-configu-
0
Cont
Veh
F -4
DHA
NGF
(A)
Aβ(25–35)
ration at the position
D1. The TBDPS protecting group was
removed with TBAF to form the corresponding alcohol 5. Finally,
the same reactions were effected as the preparation of 4 and 1,
mono-unsaturated C28 fatty acid 6 and corresponding saturated
fatty acid 2 were obtained.
Figure 1. Dendrite extension activities of compound (A) in Ab(25–35)-treated rat
cortical neurons. Ab(25–35), 10 M; compound (A), 1 M; subfraction F-4, from
g/mL; DHA, 1 M; NGF, 100 ng/mL; Veh, 0.1%
l
l
which compound (A) was isolated, 5
l
l
DMSO.
According to the procedure of Weber et al.,15 1,18-octadecan-
edicarboxylic acid was converted to its methyl ester and subse-
quent reduction by LAH reagent to afford the diol, which was
mono-protected by TBDPS.16 A key common aldehyde 22 was syn-
thesized from the TBDPS mono-protected alcohol in 4 steps: (1)
iodination,17 (2) reaction with propargylic alcohol,18 (3) catalytic
hydrogenation, and (4) PCC oxidation.
(C37) polyunsaturated fatty acid although its total structure could
not be determined due to a minor amount obtained. Thus, we
presumed the active constituent to be a n-3 fatty acid by the anal-
ogy with EPA and DHA, and started to synthesize a series of fatty
acids to find out anti-Alzheimer’s reagent. In this letter, we would
like to report the results on fatty acids with one and two double
bonds (1–17, Fig. 2).
Wittig reaction between the aldehyde 22 and the ylide of C18
-
phosphonium salt 23 was effected as described in Scheme 3. After
deprotection and oxidation of the product, (Z)-hentetracont-23-
enoic acid (9) having one double bond of cis-configuration at the
First, we synthesized four mono-unsaturated fatty acids with
C22, C28, C37, and C41 chain length (4, 6, 8, and 9, respectively)
and three saturated fatty acids with C22, C28, and C37 chain length
(1, 2, and 3, respectively).
position D1 and C41 chain length was obtained. In a similar way,
(Z)-heptatriacont-23-enoic acid (8) and heptatriacontanoic acid
(3) were synthesized by using the ylide of C14-phosphonium salt
24 in place of the ylide of C18-phosphonium salt in Wittig reaction
(Scheme 3).
As depicted in Scheme 4, C37 fatty acids 13–16 with two
cis-double bonds were prepared by Wittig reactions of the key
aldehyde 22 with C14-phosphonium salts 25–28, respectively,
and subsequent deprotection and oxidation.
Phosphonium salt 25 required for the synthesis of fatty acid 13
was obtained from 3-butyn-1-ol after protection of the hydroxy
group as its THP ether, alkylation by 1-bromodecane, hydrogena-
tion over Lindlar’s catalyst, deprotection by PPTS, iodination, and
heating with PPh3.19 Whereas preparation of phosphonium salt
26 was started by heating 6-bromo-1-hexanol with PPh3 to furnish
a phosphonium salt. Wittig reaction of the phosphonium salt with
octanal and subsequent iodination afforded an iodide. Finally, the
iodide was heated with PPh3 to give the phosphonium salt 26.
On the other hand, oxidation of 8-bromo-1-octanol with PCC to
an aldehyde, which was subjected to Wittig reaction with
As shown in Scheme 1, (Z)-docos-11-enoic acid (4) and its sat-
urated fatty acid, docosanoic acid (1), were synthesized by using
1-bromononane as a starting material, which was reacted with
propargylic alcohol in the presence of n-BuLi and HMPA to afford
a homologated alcohol. This alcohol was subjected to prototropic
migration of triple bond with KH and 1,3-diaminopropane (APA)
to form the desired terminal acetylenic alcohol 18.12 Alcohol 19
was obtained by the alkylation of 18, followed by the Lindlar
hydrogenation.13,14 Finally, Jones oxidation of 19 gave fatty acid
4 with C22 chain length and one double bond of cis-configuration
at the position
D2. The corresponding saturated C22 fatty acid 1
was also prepared by catalytic hydrogenation of 19 over 10% Pd/
C and subsequent Jones oxidation of the resulting saturated
alcohol.
The synthesis of (Z)-octacos-14-enoic acid (6) and octacosanoic
acid (2) was started with the preparation of aldehyde 20 as shown
in Scheme 2. Thus, Z-selective Wittig reaction between aldehyde
20 and the ylide of C14-phosphonium salt 21 in the presence of
Comp.
R
m
n
Comp.
R
m
n
Δ1 Δ2 Δ3 Δ4 Δ5
Δ1 Δ2 Δ3 Δ4 Δ5
COOH
COOH
2
7
1
1
1
1
1
1
1
1
1
2
3
4
5
6
7
8
9
COOH
COOH 12
COOH 21
6
1
1
1
1
1
1
1
1
5
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
10
11
12
13
14
15
16
17
×
×
×
×
×
×
×
×
×
×
×
×
COOH 10
COOH 21
COOH 21
COOH 21
COOH 21
COOH 29
COOH
6
×
×
×
CH2OH 12
COOH 12
CH2OH 21
COOH 21
COOH 21
×
×
×
×
×
×
×
×
×
×
×
×
×
×
Figure 2. List of synthesized fatty acids. : double bond; : single bond.

606
H.-Y. Zhang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 604–608
1. TBDPSCl, Et3N / CH2Cl2 (95%)
HO
2.
BrPh3P
1.
, n-BuLi,
(
)
(21),
13
HMPA / THF (70%)
NaN(SiMe3)2 / THF (95%)
OH
CHO
Br
TBDPSO
( )11
( )13
3. H2. 10% Pd/C / EtOAc
4. PCC, CH2Cl2 (70% in 2 steps)
2. TBAF / THF (50%)
20
Jones oxidation (70%)
HOOC
( )12
( )12
HO
6
( )13
( )12
1. H2. 10% Pd/C / EtOAc
2. Jones oxidation
5
HOOC
( )26
2
(53% in 2 steps)
Scheme 2. Synthesis of fatty acids 2 and 6.
1. I2, PPh3, imidazole
/ toluene (80%)
1. H2SO4 / MeOH
2. LiAlH4 / THF
(78% in 2 steps)
HO
2.
, n-BuLi,
OH
TBDPSO
COOH
HOOC
HMPA / THF (70%)
( )20
( )18
3. TBDPSCl, imidazole
/ DMF (57%)
3. H2, Pd/C / EtOAc
4. PCC / CH2Cl2
(87% in 2 steps)
IPh3P
HOOC
( )21
1.
(23), NaN(SiMe3)2 / THF (90%)
(
)
17
( )16
9
2. TBAF / THF (54%)
3. Jones oxidation (20%)
CHO
TBDPSO
( )22
22
BrPh3P
1.
(
)
(24),
13
NaN(SiMe3)2 / THF (42%)
HO
( )22
( )12
2. TBAF / THF (54%)
7
1. H2. 10% Pd/C / EtOAc
Jones oxidation (31%)
2. Jones oxidation (12% in 2 steps)
HOOC
( )21
( )12
HOOC
( )35
8
3
Scheme 3. Synthesis of fatty acids 3, 8, and 9.
1. DHP, PPTS / CH2Cl2 (89%)
Br
1. (60%)
2. (87%)
3. (43%)
2.
(
)
9
, n-BuLi, HMPA / THF (90%)
IPh3P
3. Lindlar Hydrogenation (94%)
HOOC
HO
( )2
( )9
( )21
( )9
4. PPTS / EtOH (82%)
5. I2, PPh3 / toluene (92%)
6. PPh3 / CH3CN
25
13
1. PPh3 / CH3CN
OHC
1. (85%)
2. (69%)
3. (70%)
2.
(
)
6
, NaN(SiMe3)2 / THF (50%)
OH
Br
HOOC
IPh3P
( )21
( )6
( )4
( )6
( )5
( )6
3. I2, PPh3 / toluene (75%)
4. PPh3 / CH3CN
1. 22, NaN(SiMe3)2 / THF
2. TBAF / THF
14
26
3. Jones oxidation
1. PCC / CH2Cl2 (83%)
1. (75%)
2. (78%)
3. (76%)
2.
BrPh3P
, NaN(SiMe3)2 / THF (91%)
(
)
5
OH
OH
HOOC
HOOC
Br
Br
BrPh3P
( )21
( )8
( )7
( )6
( )4
( )4
3. PPh3 / CH3CN
15
27
28
1. PCC / CH2Cl2 (93%)
2.
1. (88%)
2. (75%)
3. (71%)
BrPh3P
, NaN(SiMe3)2 / THF (79%)
(
)
2
BrPh3P
( )21
( )9
( )11
( )10
3. PPh3 / CH3CN
16
Scheme 4. Synthesis of fatty acids 13–16.

H.-Y. Zhang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 604–608
607
C6-phoshonium salt, subsequently heated with PPh3, to furnish the
phosphonium salt 27. Finally, the same reactions were effected as
the preparation of the phosphonium salt 27; 11-bromo-1-undeca-
nol and C3-phosphonium salt were used to generate the phospho-
nium salt 28. These four phosphonium salts are all having C14 chain
and one double bond of cis-configuration. Among them, the phos-
phonium salt 28 was considered as a key Wittig reagent in our
experiment.
Among the four fatty acids 13–16, fatty acid 16 showed the
most potent neurite outgrowth activity (Fig. 2). Therefore, in the
subsequent synthesis, we focused on a series of fatty acids (10–
12 and 17) with two double bonds of cis-configuration at the posi-
tions
D1 and D5 and different carbon chain length.
The synthesis of fatty acids 10–12 and 17 was carried out fol-
lowing the sequence shown in Scheme 5. These fatty acids were
synthesized by means of the Wittig reactions of the key Wittig
reagent 28 with the corresponding aldehydes and subsequent
deprotection and oxidation. Monoprotection of commercial 1,4-
butanediol, 1,9-nonanediol, and 1,12-dodecanediol with TBDPSCl
and oxidation with PCC gave the corresponding aldehydes with
4-, 9-, and 12-carbon atoms, respectively, required for the synthe-
sis of 10–12. Whereas the TBDPS-mono-protected alcohol used for
the key common aldehyde 22 was subjected to PCC oxidation, Wit-
tig reaction with BrPh3P(CH2)11OH, hydrogenation over 10% Pd/C,
and PCC oxidation to produce the aldehyde with 31-carbon atoms
required for the synthesis of 17.
Figure 3. Dendrite extension activities of synthetic fatty acids 1–17 in Ab(25–35)-
All the 17 fatty acid derivatives with different chain lengths and
different numbers and positions of double bonds were tested for
their neurite outgrowth activity.
treated rat cortical neurons. Ab(25–35), 10
100 ng/mL (hashed column). n = 8–18.
lM; 1–17, 1 lM (black columns); NGF,
Amyloid b (Ab), a proteolytic product of amyloid-b precursor
protein (APP), is the major amyloid component of amyloid deposits
known as extracellular senile plaques and is thought to induce
slow neuronal degeneration in the brains of Alzheimer’s disease
patients.20 Though Ab in extracellular senile plaques is Ab(1–40)
and Ab(1–42), Ab(25–35) is usualy used as a model of the naturally
occurring Ab.21 This fragment similarly forms a b-sheet structure22
and induces neuronal cell death, neuritic atrophy, and synaptic
loss.23 Moreover, a single intracerebroventricular (i.c.v.) injection
of Ab(25–35) could induce major neuropathological signs related
to early stages of Alzheimer’s disease in rats.24 Thus, we used
Ab(25–35) to induce neuritic atrophy for preparing in vitro models
of Alzheimer’s disease.25,26 Results are shown in Fig. 3.
acid27 (10) and (23Z,34Z)-heptatriacontadienoic acid27 (16)
showed the most potent neurite outgrowth activities, which is
comparable to that of a positive control, NGF. Activities of the other
synthetic compounds were observed in the following order: 1, 8,
14, 17 > 2, 11 > 5, 6 > 3, 4, 7 > 9, 12, 13, 15. Structurally, compounds
10 and 16 both have two Z-double bonds at the positions
D
D1 and
5 in C18 and C37 chain, respectively.27 Thus, the possession of
two (Z)-double bonds at the positions
D1 and D5 may relate to
their activity.
In conclusion, we prepared 17 fatty acid derivatives 1–17 with
different chain lengths and different numbers and positions of dou-
ble bonds by using Wittig reaction and stereospecific hydrogena-
tion of triple bonds as key reactions. They were tested for their
dendrite extension activities in Ab(25–35)-treated rat cortical neu-
rons. Among them, fatty acids 10 and 16 showed the most potent
NGF, which is important for the growth, maintenance, and sur-
vival of certain target neurons, was used as the positive control.
Among the synthetic compounds 1–17, (4Z,15Z)-octadecadienoic
1. (78%)
2. (70%)
3. (60%)
1. TBDPSCl, imidazole / DMF (50%)
2. PCC / CH2Cl2 (80%)
HOOC
HOOC
OH
OH
HO
HO
( )2
( )9
CHO
CHO
TBDPSO
TBDPSO
( )4
( )3
10
1. TBDPSCl, imidazole / DMF (50%)
2. PCC / CH2Cl2 (80%)
1. (82%)
2. (90%)
3. (33%)
( )7
( )9
( )9
( )8
1. 28, NaN(SiMe3)2 / THF
2. TBAF / THF
3. Jones oxidation
11
1. (77%)
2. (62%)
3. (45%)
1. TBDPSCl, imidazole / DMF (50%)
2. PCC / CH2Cl2 (80%)
OH
( )12
HO
HOOC
HOOC
CHO
CHO
TBDPSO
TBDPSO
( )10
( )9
( )11
12
1. PCC / CH2Cl2 (100%)
1. (63%)
2. (42%)
3. (52%)
OH
2.
BrPh3P
, NaN(SiMe3)2 / THF (71%)
(
)
11
OH
TBDPSO
( )29
( )9
( )20
( )30
3. H2, 10% Pd/C / EtOAc
17
4. PPh3 / CH3CN (75% in 2 steps)
Scheme 5. Synthesis of fatty acids 10–12 and 17.

608
H.-Y. Zhang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 604–608
20. (a) Kaminsky, Y. G.; Marlatt, M. W.; Smith, M. A.; Kosenko, E. A. Exp. Neurol.
2010, 221, 26; (b) Hamley, I. W. Chem. Rev. 2012, 112, 5147.
21. Hughes, E.; Burke, R. M.; Doig, A. J. J. Biol. Chem. 2000, 275, 25109.
22. (a) Martinez-Senac, M. D. M.; Villalain, J.; Gomez-Fernandez, J. C. Eur. J.
Biochem. 1999, 265, 744; (b) Terzi, E.; Holzemann, G.; Seelig, J. Biochemistry
1994, 33, 1345.
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J. 1995, 311, 1; (b) Pike, C. J.; Walencewicz-Wasserman, A. J.; Kosmoski, J.;
Cribbs, D. H.; Glabe, C. G.; Cotman, C. W. J. Neurochem. 1995, 64, 253; (c)
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activities, which were comparable to the positive control, NGF.
Compound 10 possesses two (Z)-double bonds at the n-3 and
n-14 positions in the C18 chain and 16 possesses them in the C37
chain. These might be important for the neurite outgrowth activity.
This result should suggest that these might be good candidates to
develop drugs for Alzheimer’s disease.
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Lindhoudt, J. C.; van Mourik, G. L.; Pabon, H. J. J. Tetrahedron Lett. 1976, 17,
2565.
25. (a) Sugimoto, K.; Tamura, K.; Tohda, C.; Toyooka, N.; Nemoto, H.; Matsuya, Y.
Bioorg. Med. Chem. 2013, 21, 4459; (b) Bai, Y.; Tohda, C.; Zhu, S.; Hattori, M.;
Komatsu, K. J. Nat. Med. 2011, 65, 417; (c) Tohda, C.; Naito, R.; Joyashiki, E. BMC
Complement. Altern. Med. 2008, 8, 49. http://dx.doi.org/10.1186/1472-6882-8-
49; (d) Tohda, C.; Tamura, T.; Komatsu, K. Brain Res. 2003, 990, 141.
26. Experiments were performed by the procedures described in Ref. 24a in
accordance with the Guidelines for the Care and Use of Laboratory Animals of
Sugitani Campus of the University of Toyama and NIH Guidelines on the Care
and Use of Laboratory Animals. All protocols were approved by the Committee
for Animal Care and Use of Sugitani Campus of the University of Toyama. Rat
cortical neurons were cultured in 8-well chamber slides at a density of 1.45–
2.6 Â 105 cells/cm2. The cells were treated with 10
l
M Ab(25–35) for 3 days,
followed by the addition of compounds (1 lM), mouse b-NGF (100 lg/mL), or
vehicle (0.1% DMSO). 4 days later, the cells were fixed with 4%
paraformaldehyde and then immunostained with monoclonal antibody
a
against MAP2 (1:1000) as a dendritic marker. Alexa Fluor 488-conjugated goat
anti-mouse IgG (1:200) was used as a second antibody. Eight to eighteen
fluorescent images per treatment were captured by a fluorescent microscope
AX-80 with DP70 digital camera system (Olympus, Tokyo, Japan) at
320
lm  425 lm. The total length of dendrites was divided by neuron
numbers to be calculated the average length. Statistical comparisons were
perfomed with One-way analysis of variance (ANOVA), followed by the Holm-
Sidak post hoc test using SigmaStat 3.5 (SYSTAT, CA, USA). Values of p <0.05
were considered significant. The data are presented as means SE.
27. The spectral data of 10 and 16 are as follows: 10: IR (neat) 3006, 2925, 2854,
1712, 1458 (br s), 1283 cmÀ1 1H NMR (300 MHz, CDCl3): dH 0.95 (3H, t, J = 7.4
;
Hz), 1.27 (14H, br s), 2.02 (8H, br s), 2.39 (2H, br s), 5.35 (4H, m); 13C NMR (100
MHz, CDCl3) dC 4.1, 20.5, 24.7, 27.2, 29.1–29.8, 32.6, 34.1, 126.9, 129.4, 131.5,
131.9, 179.1; MS (EI) m/z: 280 (M+); HRMS calcd for C18H32O2 280.2402, found
13. Miyaoka, H.; Tamura, M.; Yamada, Y. Tetrahedron 2000, 56, 8083.
14. (a) Müller, S.; Schmidt, R. R. Helv. Chim. Acta 1993, 76, 616; (b) Bestmann, H. J.;
Strannsky, W.; Vostrosky, O. Chem. Ber. 1976, 109, 1694.
15. Weber, M. E.; Schlesinger, P. H.; Gokel, G. W. J. Am. Chem. Soc. 2005, 127, 636.
16. Harcken, C.; Brückner, R. New J. Chem. 2001, 25, 40.
280.2409; 16: mp: 61–62 °C; IR (KBr) 3004, 2917, 2850, 1695, 1472 cmÀ1 1H
;
NMR (300 MHz, CDCl3): dH 0.96 (3H, t, J = 7.4 Hz), 1.25 (50H, br s), 1.63 (2H,
quint, J = 7.4 Hz), 2.02 (8H, m), 2.35 (2H, t, J = 7.4 Hz), 5.35 (4H, m); 13C NMR
(100 MHz, CDCl3) dC 14.1, 20.5, 24.7, 27.2, 29.1–29.8, 32.6, 34.0, 129.3, 129.8,
130.4, 179.8; MS (EI) m/z: 546 (M+); HRMS calcd for C37H70O2 546.5376, found
546.5378.
17. Ren, G.-B.; Wu, Y. Tetrahedron 2008, 64, 4408.
18. Cossy, J.; Pete, J. P. Tetrahedron Lett. 1986, 27, 573.
19. Morikawa, T.; Nishiwaki, T.; Nakamura, K.; Kobayashi, Y. Chem. Pharm. Bull.
1989, 37, 813.