Potent antitumor mimetics of annonaceous acetogenins embedded with an aromatic moiety in the left hydrocarbon chain part

Article abstract of DOI:10.1021/jm101053k

Annonaceous acetogenins are a large family of naturally occurring polyketides exhibiting remarkable anticancer activities. The first generation of annonaceous acetogenin mimetic (1, AA005) exhibits comparable activity as that of natural products and presents much higher selectivity between cancer and normal cells. In this work, we report the design, synthesis, and evaluation of a new series of compound 1 analogues in which a variety of conformation- constrained fragments were embedded in the left hydrocarbon chain part. Compound 7 bearing a biphenyl moiety was identified to exhibit more potent antiproliferative activity and preferentially target cancer cells over normal cells and thus represents a new lead for further optimization.

Full text of DOI:10.1021/jm101053k

J. Med. Chem. 2011, 54, 525–533 525
DOI: 10.1021/jm101053k
Potent Antitumor Mimetics of Annonaceous Acetogenins Embedded with an Aromatic
Moiety in the Left Hydrocarbon Chain Part
Qicai Xiao,†,^ Yongqiang Liu,‡,^ Yatao Qiu,† Guangbiao Zhou,† Chan Mao,§ Zheng Li, Zhu-Jun Yao,*,§ and Sheng Jiang*,†
†Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China,
‡Laboratory of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane
Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China, §School of Chemistry and Chemical Engineering,
Nanjing National Laboratory of Microstructures, Nanjing University, 22 Hankou Road, Nanjing 210093, China, and Department of Radiology,
The Methodist Hospital Research Institute, Houston Texas 77030, United States . ^ These authors contributed equally to the work.
Received August 16, 2010
Annonaceous acetogenins are a large family of naturally occurring polyketides exhibiting remarkable
anticancer activities. The first generation of annonaceous acetogenin mimetic (1, AA005) exhibits
comparable activity as that of natural products and presents much higher selectivity between cancer and
normal cells. In this work, we report the design, synthesis, and evaluation of a new series of compound 1
analogues in which a variety of conformation-constrained fragments were embedded in the left
hydrocarbon chain part. Compound 7 bearing a biphenyl moiety was identified to exhibit more potent
antiproliferative activity and preferentially target cancer cells over normal cells and thus represents a
new lead for further optimization.
Introduction
assembly strategy was thus developed in a systematic
fashion.16 Subsequently, introduction of appropriate con-
formational constraints into the middle part can increase the
potency up to 30 times against MDA-MB-468 cells. However,
little has been known about the conformational contribu-
tions of the left hydrocarbon chains of 1 to the bioactivity.
We assumed that the hydrophobic tail of compound 1 inter-
acts with the hydrophobic pocket of complex I. In the
present study, we decided to keep the middle and right parts
intact and pay our attention to the left hydrophobic tail of
compound 1 by replacement with more constrained parts
(Figure 1).
To fully explore the potential of compound 1 analogues as
selective anticancer agents and to further understand SAR of
compound 1, a synthetic approach that enables the early stage
replacement of hydrophobic tail from a common precursor
has also been developed. By use of this strategy, a small library
was efficiently set up and applied in the corresponding bio-
logical assessment. Herein, we report the above-mentioned
strategy for generation of new 1-like compounds with the
modified left part and their cytotoxicities against a number of
cancer cells.
During the past century, many useful drugs have been deve-
loped from natural sources1 and more than 60% of currently
available anticancer drugs are either natural compounds or
their analogues.2,3 To date, natural products and their core
structures are still the focus in the search for new pharmaceu-
tically useful compounds.4,5 Annonaceous acetogenins, a
well-established family of natural products, have been attract-
ing worldwide attention for several decades because of their
significant bioactivities, especially as growth inhibitors of
certain tumor cells.6,7 They have been shown to function by
blocking oxidative pathways in complex I of mitochondria,6,8
and there is evidence that some members of the family induce
apoptosis in cancer cells.9 These features make the annonac-
eous acetogenins excellent leads for development of new
antitumor agents. We have been engaged in modifying the
annonaceous acetogenins into the corresponding mimetics
with simpler structures for several years.10-19 In our pre-
vious studies, we invented annonaceous acetogenin mimetic
(1, AA005) by replacement of both THF rings of natural
bullatacin with an ethylene glycol ether unit.10-12 Compound
1 not only shows potent antitumor activities against a variety
of human cancer cells with IC50 values ranging from 50 to
100 nM but also exhibits significant selectivity between a
number of human normal and cancerous cells. A further
investigation showed that introduction of a (4R)-hydroxy
group into compound 1 raises the potency by up to 15 times.13
However, introduction of (10R)- or (10S)-hydroxy group into
the skeleton of compound 1 little affects the activity.12,17 To
generate further improved analogues of 1, a parallel fragment-
Results and Discussion
Retrosynthetic Analysis. Retrosynthetic analysis of the
compounds 2-8 is illustrated in Figure 2. We chose a syn-
thetic approach that allowed for generation of a variety of
analogues from a common precursor 14. By variation of the
combination of different fragments 15-21, seven precursors
of compound 1 were obtained by parallel assembly of pre-
functionalized subunits. Trimethylsilylacetylene 52 plays as
a two-directional C-alkylation reagent to link epoxide inter-
mediates 11 and 29-35, constructing the whole molecular
skeleton of compounds 2-8. All the starting materials 13 and
51 are readily available or easy to prepare.
*To whom correspondence should be addressed. For Z.-J.Y.: phone, þ86
25 8359 3732; fax, þ86 25 8359 3732; e-mail, yaoz@nju.edu.cn. For S.J.:
phone, þ86 186 8888 8237; fax, þ86 20 3201 5299; e-mail, jiang_sheng@
gibh.ac.cn.
r
2010 American Chemical Society
Published on Web 12/20/2010
pubs.acs.org/jmc

526 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2
Xiao et al.
Figure 1. Design of new compound 1-like molecules with conformation-constrained left chain.
Figure 2. Retrosynthetic analysis of compounds 2-8.
Chemistry. To synthesize compounds 2-8, we built the
suitably convergent synthetic routes. The right part of 11
was synthesized as shown in Scheme 1. Introduction of the
butenolide unit to 9 involved a three-step sequence: (i) aldol
reaction of 9 with (S)-O-tetrahydropyranyl lactal, (ii) acid-
catalyzed THP cleavage and in situ lactonization, and (iii)
R-elimination of hydroxyl in the presence of (CF3CO)2O
and Et3N.13,16,20,21 Regioselective epoxidation of 10 was
achieved by treatment with MCPBAa to give 11 in 83%
yield.
13. The remaining hydroxyl group of 13 was reacted with
(-)-(R)-epichlorohydrin to afford the building block 14 in
83% yield. Regioselective opening of epoxide 14 by treat-
ment with the monolithium salt of various substituted
acetylenes 15-21 followed by protection with MOM
afforded the “left-hand” segments 22-28 (in parallel). Reduc-
tions of the triple bonds and deprotection of benzyl protec-
tive groups were carried out by hydrogenation. O-Alkylation
of the newly exposed primary hydroxyl functionality with
(R)-epichlorohydrin gave the desired intermediates 29-35.
Regioselective opening of epoxides 29-35 by the lithium
As shown in Scheme 2, protection of one hydroxyl group
of ethylene glycol afforded the corresponding benzyl ether
salt of trimethylsilyl acetylene in the presence of BF3 Et2O
3
followed by treatment with MOMCl and removal of TMS
with TBAF afforded compounds 36-42. Deprotonation
of the terminal alkynes 36-42 with n-BuLi followed by
a Abbreviations: MCPBA, 3-chloroperbenzoic acid; TMS, trimethyl-
silyl; DCM, dichloromethane; DIPEA, N,N0-diisopropylethylamine;
TBAF, tetrabutylammonium fluoride; MOMCl, chloromethyl methyl
ether; BTEAC, benzyltriethylammonium chloride; THP, tetrahydro-
pyran.
treatment with epoxide 11 in the presence of BF3 Et2O
3
at -78 ꢀC gave the whole skeleton precursors 43-49.

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 527
The triple bond of 43-49 was selectively reduced with in situ
generated diimide. Global deprotection of the MOM ethers
with a catalytic amount of concentrated HCl in MeOH
provided the final products 2-8.
Biological Results. Compounds 1-8 were evaluated with
MTT assays for their activity in inhibition of cell growth
against several human solid tumor cell lines, such as
SGC7901, A549, MCF7, HCT-116, and HT-29, and human
normal cell lines, such as HLF and Beas-2B. The results
are summarized in Table 1 and showed interesting cell
line selectivity. In our cell assay, compound 1 displayed
suggests that a longer hydrophobic tail (decane) is needed for
more potent inhibition of cancer cells growth of 1. On the basis
of this result, we thus designed and synthesized compound 3
with an n-butylcyclohexane side chain. Compound 3 exhibits a
GI50 value of 0.75, 4.5 1.8, 1.6, and 5.4 μM against SGC7901,
A549, MCF7, HCT-116, and HT-29 cell lines, respectively.
Compound 3 is 6-18 times less potent than compound 1 in
cancer cell lines and has decreased selectivity toward human
cancer cells over normal cells more than 50-fold by comparison
with compound 1, further confirming the importance of the
long hydrophobic tail in the mimicry.
We assumed that the long hydrophobic tail in compound 1
may interact with the hydrophobic pocket in complex I.
Therefore, introducing a more aromatic residue in the left
part of compound 1 would be able to improve van der Waals
good selectivity for the cancer cell lines (SGC7901, GI50
=
0.065 μM; A549, GI50=0.305 μM; MCF7, GI50 = 0.276 μM;
HCT-116, GI50 = 0.113 μM; HT-29, GI50 = 0.291 μM)
over the normal cell lines (HLF, GI50=20.9 μM; Beas-2B,
GI50 = 120 μM). Compound 2, in which the C10H21 tail was
replaced by a much shorter hexane group, was designed to
test the importance of the long linear hydrophobic tail of 1.
Our assay showed that compound 2 loses 20-66 times
potency (by comparison of 1) with a GI50 of 2.0, 10.8, 5.8,
4.2, and 19.4 μM against SGC7901, A549, MCF7, HCT-116,
and HT-29 cell lines, respectively. The selectivity for cancer
cells over normal cells of compound 2 slightly decreased. This
Table 1. Antiproliferative Activity of Compounds 1-8a
GI50 (μM)
compd SGC7901 A549 MCF7 HCT116 HT29 HLF Beas-2B
1
2
3
4
5
6
7
8
0.065
2.0
0.305 0.276
0.113
4.2
1.6
0.291 20.9
19.4 11.1
120
10.8
4.5
5.8
1.8
>100
61
>100
0.75
0.275
1.0
5.4
1.1
69
5.5
7.4
0.773 0.84
0.394
2.8
2.3
6.0
4.5
24.5
23.3
>100 >100
11.3 >100
Scheme 1. Synthesis of the right part of 11a
0.198
0.02
0.082
4.3
0.177 0.154
3.7 12.6
0.134
1.1
0.355 >100 >100
1.1 10 >100
a Compound 1 was used as a positive control. SGC7901, human
gastric cancer cell line; A549, human lung cancer cell line; MCF7, human
breast cancer cell line; HCT116, colorectal carcinoma cell line; HT29,
human colon cancer cell line; HLF, human lung fibroblasts; Beas-2B,
human bronchial epithelial cell. Inhibition of cell growth by the listed
compounds in cells was determined by using a MTT assay. Standard
error of the GI50 was generally less than 10%.
a Reagents and conditions: (a) (i) LDA, THF-HMPA, (S)-O-tetra-
hydropyranyl lactal, -78 ꢀC; (ii) 10% H2SO4, THF, room temp; (iii)
(CF3CO)2O, Et3N, CH2Cl2, 67%. (b) m-CPBA, CH2Cl2, 0 ꢀC, 83%.
Scheme 2. Synthesis of Compounds 2-8a
a Reagents and conditions: (a) NaH, THF, benzyl bromide, room temp to reflux, 81%; (b) (R)-epichlorohydrin 51, BTEAC, 50% aq NaOH, room
temp, 80%; (c) (i) BuLi, BF3 Et2O, 15-21 (in parallel), THF, -78 ꢀC; (ii) MOMCl, DIPEA, DCM, 0 ꢀC to room temp, 69-84% in two steps; (d) (i) 10%
3
Pd/C, H2, EtOH, HOAc, room temp; (ii) (R)-epichlorohydrin, BTEAC, 50% NaOH, room temp, 69-84% in two steps; (e) (i) trimethylsilylacetylene 52,
n-BuLi, BF3 Et2O, THF, -78 ꢀC; (ii) MOMCl, DIPEA, DCM, 0 ꢀC to room temp; (iii) TBAF, THF, 0 ꢀC, 57-84% in three steps; (f) n-BuLi, BF3 Et2O,
3
3
11, THF, -78 ꢀC, 43-78%; (g) (i) TsNHNH2, NaOAc, DME/H2O, reflux; (ii) HCl, THF, CH3OH, room temp, 54-94% in two steps.

528 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2
Xiao et al.
interactions.22 Considering these characteristic interactions,
we thus designed and synthesized a series of new analogues
by replacement of a cyclohexane subunit of compound 3
with aromatic ones, including phenyl ring, biphenyl ring,
and naphthalene ring to increase the van der Waals interac-
tions. As shown in Table 1, the potency of the modified
compound 4 increases approximately 2- to 6-fold when
replacing the cyclohexane moiety with phenyl ring. Com-
pared to cyclohexane, the phenyl ring may result in favorable
and well-defined van der Waals interactions. To verify this, a
hydroxyl group in the meta-position on the phenyl ring was
then introduced in compound 4, aiming to decrease van der
Waals interactions. Compared to compound 4, the resulting
compound 5 has almost lost the inhibitory activities against
MCF7 and HT-29 cell lines and shows much less potency
against other cell lines. This means that the meta-position on
the phenyl ring in compound 4 is very important to achieve
better anticancer activities. Compound 6, in which a meth-
oxyl group was introduced in the para-position on the phenyl
ring of compound 4, is 1.5 times more potent than 4 against
SGC7901 cell lines, although it almost lost the activities
against MCF7 cell lines. With such information, we then
introduce an additional phenyl group in the para position of
the phenyl ring of 4, which is much more hydrophilic than the
previous compounds. To our delight, compound 7 exhibited
potent growth inhibitory activities against a variety of
indicate that the introduction of appropriate aromatic groups
into the linear compound 1 skeleton is a useful optimizing tool
for this unique class of anticancer agents. Furthermore, the
developed methodology will be potentially applicable to the
synthesis of further analogues of this family, as well as other
complex focused libraries, and may accelerate discovery of
clinically useful antitumor agents.
Experimental Section
All NMR spectra were recorded at 400 MHz for 1H NMR and
100 or 125 MHz for 13C NMR in CDCl3 solution with TMS as an
internal standard, and the chemical shifts are given in δ values.
Mass spectra were performed on Kompact Axima-CFR MALDI
mass spectrometers. Optical rotations were recorded on a Perkin-
Elmer 341 polarimeter. Anhydrous solvents were obtained as
follows: THF was distilled from sodium and benzophenone, and
dichloromethanewas distilled fromCaH2. All othersolventswere
reagent grade. All moisture sensitive reactions were carried out in
a flame-dried flask under nitrogen or argon atmosphere. Analy-
tical HPLC conditions were as follows: Agilent C18 column
(250 mm ꢀ 4.6 mm, 5 μm); solvent A 0.05% TFA in water;
solvent B methanol. The composition of the solvents is shown in
Supporting Information. Additional chromatographic param-
eters were as follows: flow rate, 1.0 mL/min; injection volume,
10 μL; column temperature, 30 ꢀC; UV wavelength, 215 nm. The
purity of all tested compounds was >95% using the analytical
method described above unless stated otherwise.
(5S)-5-Methyl-3-(7-(oxiran-2-yl)heptyl)furan-2(5H)-one (11).
Compound 11 was synthesized as the reference (see Supporting
Information).16 1H NMR (400 MHz, CDCl3): δ 6.96 (d, J = 2.8
Hz, 1H), 4.95 (dq, J = 6.8, 1.7 Hz, 1H), 2.85 (m, 1H), 2.71-2.68
(m, 1H), 2.41 (dd, J = 5.0, 2.7 Hz, 1H), 2.21 (t, J = 7.7 Hz, 2H),
1.51-1.29 (m, 12H), 1.36 (d, J = 6.8 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3): δ 173.7, 148.9, 134.2, 77.3, 52.2, 46.9, 32.4,
29.2, 29.1, 29.0, 27.3, 25.8, 25.1, 19.1 ppm. MS (ESI, m/z): 239
(Mþ þ 1).
cancer cell lines (SGC7901, GI50=0.02 μM; A549, GI50
0.177 μM; MCF7, GI50 = 0.154 μM; HCT-116:, GI50
=
=
0.134 μM; HT-29, GI50 = 0.355 μM). It is 14 times more
potent than 4 and 3.5 times more potent than 1 against
SGC7901 cell lines. Furthermore, the biphenyl compound 7
offers a much improved selectivity between cancerous and
normal cell lines (HLF, GI50 > 100 μM; Beas-2B, GI50 >100
μM) over that of 1. The improved therapeutic index indicates
that the newly introduced biphenyl moiety of compound 7
could be a structural factor for higher selectivity against
cancer cells over normal cells. Obviously, introduction of an
appropriate aromatic group in the left region of compound 1
is a useful strategy for the improvement of anticancer activity
of these acetogenin mimetics. However, such protocol has to
be controlled in a proper range. Overweight of the intro-
duced hydrophobic moiety will lead to a decrease of potency
under some circumstances. For instance, compound 8, in
which the decane tail of compound 1 was replaced with a
naphthalene group, showed moderate potency and selec-
tivity.
(S)-2-((2-(Benzyloxy)ethoxy)methyl)oxirane (14). To a solu-
tion of 13 (10.7 g, 0.07 mol) was added BTEAC (1.60 g, 15%,
w/w) and (R)-(-)-epichlorohydrin (6.6 mL, 0.084 mol). After
the mixture was stirred for 3 min, a solution of 50% NaOH
(55 mL) was added over 0.5 h. The reaction mixture was
vigorously stirred at room temperature for additional 3.5 h until
it was quenched by water (40 mL). The resulting solution was
extracted by ether (40 mL ꢀ 3). The combined organic layers
were washed successfully with saturated aqueous NH4Cl and
brine, dried over Na2SO4 (anhydrous), filtered, and concen-
trated. The residue was purified by silica gel chromatography to
give 14 (11.7 g, 80%) as a colorless oil. [R]25D: 6.1 (c 2.6, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.35-7.27 (m, 5H), 4.58 (s, 2H),
3.80 (dd, J = 11.6, 3.0 Hz, 1H), 3.75-3.63 (m, 4H), 3.45 (dd, J =
11.6, 5.8 Hz, 1H), 3.18-3.16 (m, 1H), 2.80-2.78 (m, 1H), 2.62
(dd, J = 5.0, 2.7 Hz, 1H) ppm. HRMS (ESI): C12H16O3 calcul-
ated [M þ H]þ 209.1172, found 209.1175, [M þ Na]þ 231.0992,
found 231.0988.
Conclusion
A series of new analogues 2-8 of anticancer annonaceous
acetogenin mimetic 1 have been designed, synthesized, and
evaluated in this work. Introduction of more hydrophobic
aromatic moieties to the left part of 1 has been investigated for
the first time. A flexible parallel fragment-assembly strategy
has been successfully applied to the enantioselective syntheses
ofthese analoguesusingacetylene-epoxidecouplings asa key
methodology. Biological results demonstrate that fragment
variations in the left chain of 1 have various effects to the
cytotoxicity and selectivity toward cancer cells over normal
cells. Compound 7 bearing a biphenyl moiety was identified to
show more potent inhibitory activity against a wide range of
cancer cells at low to moderate nanomolar range and exhib-
ited higher action selectivity against cancer cells than normal
cells by comparison with compound 1. These results clearly
(S)-5-(Hex-2-ynyl)-11-phenyl-2,4,7,10-tetraoxaundecane (22).
To a solution of 15 (0.885 g, 13.0 mmol) in anhydrous THF
(20 mL) was added slowly n-BuLi (13.0 mmol, 2.5 M in hexane)
at -78 ꢀC. The reaction mixture was stirred for 45 min at -78 ꢀC
under argon atmosphere, and BF3 Et2O (13.0 mmol) was then
3
added. After the mixture was stirred for an additional 30 min, a
solution of 14 (1.353 g, 6.5 mmol) in anhydrous THF (5 mL) was
added. The resulting reaction mixture was stirred for 3 h until it
was quenched by saturated aqueous NH4Cl (5 mL). The whole
mixture was concentrated under reduced pressure. The residue
was extracted with ether (15 mL ꢀ 3). The combined organic
layers were washed with saturated aqueous NaHCO3 and brine,
dried over Na2SO4 (anhydrous), filtered, and concentrated. The
resulting residue was used in the next step without further
purification.

Article
To the above crude product in dry DCM (20 mL) under
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 529
74.8, 73.3, 72.9, 71.1, 69.6, 55.5, 23.0 ppm. MS (ESI, m/z): 431
[M þ 1]þ, 453 [M þ 23]þ.
nitrogen atmosphere was added DIPEA (9.1 mL, 52 mmol) at
0 ꢀC. Then MOMCl (2.5 mL, 32.5 mmol) was added slowly, and
the reaction mixture was stirred at ambient temperature for 20 h.
The reaction was quenched with saturated aqueous NH4Cl
(5 mL), and DCM was then evaporated under reduced pressure.
The residue was extracted with ethyl acetate (15 mL ꢀ 3). The
combined organic layers were washed with saturated aqueous
NH4Cl and brine, dried over Na2SO4 (anhydrous), filtered, and
concentrated. Purification by silica gel chromatography af-
(S)-5-(3-(6-Methoxynaphthalen-2-yl)prop-2-ynyl)-11-phenyl-
2,4,7,10-tetraoxaundecane (28). The procedure was the same as
described above for the synthesis of 22. Compound 28 was
obtained as a buff oil (0.72 g, 79% for two steps). [R]25D: 5.1
(c 2.6, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.64
(t, J = 8.6 Hz, 2H), 7.41 (dd, J = 8.4, 1.6 Hz, 1H), 7.36-7.26
(m, 5H), 7.14 (dd, J = 8.9, 2.5 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H),
4.81 (s, 2H), 4.58 (s, 2H), 4.04-4.00 (m, 1H), 3.92 (s, 3H), 3.77-
3.64 (m, 6H), 3.43 (s, 3H), 2.82-2.71 (m, 2H) ppm. 13C NMR
(100 MHz, CDCl3): δ 158.2, 138.4, 133.9, 131.0, 129.2, 129.1,
128.6, 128.3, 127.7, 127.5, 126.6, 119.2, 118.7, 105.9, 96.1, 85.9,
82.5, 74.8, 73.3, 72.9, 71.1, 69.6, 55.5, 55.3, 23.0 ppm. MS (ESI,
m/z): 435 [M þ 1]þ.
forded 22 as a yellow oil (1.50 g, 72% for two steps). [R]25
:
D
10.6 (c 0.69, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.33-7.26
(m, 5H), 4.73 (s, 2H), 4.56 (s, 2H), 3.87-3.84 (m, 1H), 3.69-3.59
(m, 6H), 3.38 (s, 3H), 2.45 (br, 2H), 2.10 (t, J = 6.8 Hz, 2H),
1.51-1.46 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H) ppm. 13C NMR (100
MHz, CDCl3): δ 138.3, 128.3, 127.7, 127.6, 95.9, 81.9, 76.2, 74.8,
73.2, 72.9, 70.9, 69.5, 55.4, 22.4, 22.1, 20.8, 13.5 ppm. MS (ESI,
m/z): 343 [M þ 23]þ.
(S)-2-((S)-5-Hexyl-2,4,7,10-tetraoxaundecan-11-yl)oxirane (29).
A mixture of 22 (1.36 g, 4.26 mmol), 10% palladium on charcoal
(0.10 g), and EtOH (20 mL, containing 2 mL HOAc) was stirred at
room temperature for 16 h under hydrogen atmosphere. After
filtration, the organic phase was concentrated. The residue was
used in the next step without further purification.
To the above intermediate was added BTEAC (0.17 g, 15%,
w/w) and (R)-(-)-epichlorohydrin (0.40 mL, 5.11 mmol). After
3 min, a solution of 50% NaOH (3.5 mL) was added over 15 min.
The reaction mixture was vigorously stirred at room temperature
for 22 h until it was diluted with water (3 mL). The resulting
solution was extracted by ether (15 mL ꢀ 3). The combined
organic phases were washed successively with saturated aqueous
NH4Cl and brine, dried over Na2SO4 (anhydrous), filtered, and
concentrated. The residue was purified by silica gel chromatog-
(S)-5-(4-Cyclohexylbut-2-ynyl)-11-phenyl-2,4,7,10-tetraox-
aundecane (23). The procedure was the same as described above
for the synthesis of 22. Compound 23 was obtained as a buff oil
(0.82 g, 69% for two steps). [R]25D: 9.6 (c 0.48, CHCl3). 1H NMR
(400 MHz, CDCl3): δ 7.34-7.26 (m, 5H), 4.74 (s, 2H), 4.57 (s,
2H), 3.87-3.85 (m, 1H), 3.70-3.61 (m, 6H), 3.38 (s, 3H), 2.48-
2.45 (m, 2H), 2.03 (dt, J = 6.6, 2.4 Hz, 2H), 1.79-1.68 (m, 4H),
1.45-1.36 (m, 1H), 1.28-0.91 (m, 6H) ppm. 13C NMR (100
MHz, CDCl3): δ 138.4, 128.3, 127.6, 127.5, 96.0, 80.8, 76.7, 75.1,
73.2, 73.0, 71.0, 69.5, 55.4, 37.5, 32.7, 26.6, 26.3, 26.1, 22.2 ppm.
MS (ESI, m/z): 375 [M þ 1]þ, 397 [M þ 23]þ.
(S)-11-Phenyl-5-(3-phenylprop-2-ynyl)-2,4,7,10-tetraoxaun-
decane (24). The procedure was the same as described above
for the synthesis of 22. Compound 24 was obtained as a buff oil
raphy toafford29 as abuffoil(1.033 g, 84%for two steps). [R]25
:
D
-3.6 (c 2.72, CHCl3). 1H NMR (400 MHz, CDCl3): δ 4.71 (d, J =
6.8 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 3.74 (dd, J = 11.6, 3.0 Hz,
1H), 3.68-3.35 (m, 8H), 3.33 (s, 3H), 3.11-3.09 (m, 1H),
2.75-2.72 (m, 1H), 2.56 (dd, J = 5.0, 2.7 Hz, 1H), 1.48-1.23
(m, 10H), 0.83 (t, J = 6.4 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3): δ 96.0, 76.2, 74.1, 71.9, 70.7, 55.3, 50.7, 44.1, 32.0, 31.7,
29.3, 25.3, 22.5, 13.9 ppm. MS (ESI, m/z): 308 [M þ 18]þ, 31þ3
[M þ 23]þ. HRMS (ESI): C15H30O5 calculated [M þ Na]
313.1985, found 313.1989.
1
(1.51 g, 76% for two steps). [R]25D: 11.9 (c 0.55, CHCl3). H
NMR (400 MHz, CDCl3): δ 7.41-7.26 (m, 10H), 4.80 (s, 2H),
4.58 (s, 2H), 4.01-3.99 (m, 1H), 3.74-3.65 (m, 6H), 3.43 (s,
3H), 2.76-2.72 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ
138.4, 131.6, 128.3, 128.2, 127.7, 127.6, 127.5, 123.8, 96.1, 86.4,
82.1, 74.8, 73.3, 72.9, 71.0, 69.6, 55.5, 22.9 ppm. MS (ESI, m/z):
355 [M þ 1]þ.
(S)-5-(3-(3-(Methoxymethoxy)phenyl)prop-2-ynyl)-11-phenyl-
2,4,7,10-tetraoxaundecane (25). The procedure was the same as
described above for the synthesis of 22. Compound 25 was
obtained as a buff oil (0.81 g, 74% for two steps). [R]25D: 2.8
(S)-2-((S)-5-(4-Cyclohexylbutyl)-2,4,7,10-tetraoxaundecan-11-
yl)oxirane (30). The procedure was the same as described above
for the synthesis of 29. Compound 30 was obtained as pale yellow
1
oil (0.40 g, 74% for two steps). [R]25D: 2.6 (c 1.57, CHCl3). H
1
(c 1.5, CHCl3). H NMR (400 MHz, CDCl3): δ 7.35-7.33 (m,
NMR (400 MHz, CDCl3): δ 4.74 (d, J = 6.8 Hz, 1H), 4.63 (d, J =
6.8 Hz, 1H), 3.76 (dd, J = 11.6, 3.0 Hz, 1H), 3.70-3.39 (m, 8H),
3.36 (s, 3H), 3.14-3.11 (m, 1H), 2.77-2.75 (m, 1H), 2.58 (dd, J =
5.0, 2.3 Hz, 1H), 1.67-1.11 (m, 17H), 0.86-0.80 (m, 2H) ppm.
13C NMR (100 MHz, CDCl3): δ 96.1, 76.3, 74.2, 71.9, 70.8, 55.4,
50.7, 44.1, 37.6, 37.4, 33.4, 32.1, 26.9, 26.7, 26.4, 25.7 ppm. MS
(ESI, m/z): 345 [M þ 1]þ. HRMS (ESI): C19H36O5 calculated
[M þ Na] þ 367.2455, found 367.2459.
5H), 7.21-7.16 (m, 1H), 7.08-6.95 (m, 3H), 5.15 (s, 2H), 4.78 (s,
2H), 4.57 (s, 2H), 3.97-3.95 (m, 1H), 3.73-3.64 (m, 6H), 3.46 (s,
3H), 3.42 (s, 3H), 2.74-2.70 (m, 2H) ppm. 13C NMR (125 MHz,
CDCl3): δ 157.0, 138.3, 129.3, 128.3, 127.7, 127.6, 125.3, 124.7,
119.2, 116.2, 96.0, 94.4, 86.4, 81.8, 74.6, 73.2, 72.8, 71.0, 69.4,
56.0, 55.5, 22.8 ppm. MS (ESI, m/z): 415 [M þ 1]þ.
(S)-5-(3-(4-Methoxyphenyl)prop-2-ynyl)-11-phenyl-2,4,7,10-
tetraoxaundecane (26). The procedure was the same as described
above for the synthesis of 22. Compound 26 was obtained as a
buff oil (0.92 g, 84% for two steps). [R]25D: 6.1 (c 2.7, CHCl3). 1H
NMR (400 MHz, CDCl3): δ 7.35-7.26 (m, 7H), 6.82-6.79 (m,
2H), 4.78 (s, 2H), 4.57 (s, 2H), 4.00-3.97 (m, 1H), 3.79 (s, 3H),
3.73-3.64 (m, 6H), 3.42 (s, 3H), 2.77-2.67 (m, 2H) ppm. 13C
NMR (100 MHz, CDCl3): δ 159.3, 138.4, 132.9, 128.3, 127.6,
127.5, 116.0, 113.9, 96.1, 84.7, 81.9, 74.9, 73.3, 72.9, 71.0, 69.6,
55.5, 55.2, 22.9 ppm. MS (ESI, m/z): 385 [M þ 1]þ.
(S)-2-((S)-5-(3-Phenylpropyl)-2,4,7,10-tetraoxaundecan-11-yl)-
oxirane (31). The procedure was the same as described above for
the synthesis of 29. Compound 31 was obtained as a buff oil (0.99
g, 72% for two steps). [R]25D: -1.8 (c 1.12, CHCl3). 1H NMR(400
MHz, CDCl3): δ 7.28-7.15 (m, 5H), 4.76 (d, J = 6.8 Hz, 1H),
4.64 (d, J = 6.8 Hz, 1H), 3.77 (dd, J = 11.7, 2.8 Hz, 1H),
3.74-3.38 (m, 8H), 3.36 (s, 3H), 3.14-3.12 (m, 1H), 2.77 (t, J =
4.4 Hz, 1H), 2.63 (t, J = 7.4 Hz, 2H), 2.60-2.57 (m, 1H),
1.77-1.55 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ
142.3, 128.4, 128.3, 125.7, 96.1, 76.1, 74.1, 71.9, 70.8, 55.4, 50.8,
44.1, 35.9, 31.7, 27.1 ppm. MS (ESI, m/z): 325 [M þ 1]þ. HRMS
(ESI): C18H28O5 calculated [MþNa] þ 347.1829, found 347.1829.
(S)-2-((S)-5-(3-(3-(Methoxymethoxy)phenyl)propyl)-2,4,7,
10-tetraoxaundecan-11-yl)oxirane (32). The procedure was
the same as described above for the synthesis of 29. Com-
pound 32 was obtained as a buff oil (0.54 g, 74% for two
steps). [R]25D: 3.7 (c 1.21, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.20-7.16 (m, 1H), 6.86-6.82 (m, 3H), 5.16 (s, 2H),
(S)-5-(3-(Biphenyl-4-yl)prop-2-ynyl)-11-phenyl-2,4,7,10-tet-
raoxaundecane (27). The procedure was the same as described
above for the synthesis of 22. Compound 27 was obtained as a
yellow oil (0.63 g, 70% for two steps). [R]25D: 8.3 (c 0.64,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.58 (dd, J = 7.9, 1.4
Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.47-7.43 (m, 4H), 7.37-
7.32 (m, 5H), 7.30-7.28 (m, 1H), 4.81 (s, 2H), 4.59 (s, 2H),
4.03-4.01 (m, 1H), 3.75-3.66 (m, 6H), 3.44 (s, 3H), 2.78-2.75
(m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 140.5, 132.0,
128.8, 128.3, 127.7, 127.5, 127.0, 126.9, 122.7, 96.1, 87.1, 82.0,

530 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2
Xiao et al.
4.76 (d, J = 7.0 Hz, 1H), 4.65 (d, J = 7.0 Hz, 1H), 3.80-3.50 (m,
9H), 3.48 (s, 3H), 3.37 (s, 3H), 3.16-3.14 (m, 1H), 2.79-2.77 (m,
1H), 2.60 (t, J =2.50 Hz, 2H), 1.61-1.56 (m, 4H) ppm. 13C NMR
(100 MHz, CDCl3): δ 157.4, 144.1, 129.2, 122.0, 116.5, 113.6, 96.1,
94.6, 76.1, 74.1, 71.9, 70.8, 55.9, 55.5, 50.7, 44.1, 35.9, 31.7, 26.9,
ppm. MS (ESI, m/z): 407 [M þ 23]þ. HRMS (ESI): C20H32O7
calculated [M þ Na] þ 407.2040, found 407.2038.
NH4Cl (5 mL) . The volatiles were evaporated under reduced
pressure. The residue was extracted with ethyl acetate (15 mL ꢀ
3). The combined organic layers were washed with saturated
aqueous NH4Cl and brine, dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was used directly in the
subsequent step.
The above intermediate in THF (15 mL) was treated with
TBAF (3.6 mmol, 1.0 M in THF) for 1 h at -10 ꢀC. The mixture
was quenched by saturated aqueous NH4Cl (3 mL). The vola-
tiles were evaporated under reduced pressure. The residue was
extracted with ether (10 mL ꢀ 3). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated. Purification by silica gel chromatography
afforded 36 as a buff oil (0.62 g, 57% for three steps). [R]25D: 3.3
(c 0.85, CHCl3). 1H NMR (400 MHz, CDCl3): δ 4.73 (d, J = 6.8
Hz, 1H), 4.71 (s, 2H), 4.63 (d, J = 6.8 Hz, 1H), 3.87-3.84 (m,
1H), 3.69-3.66 (m, 1H), 3.65-3.47 (m, 8H), 3.37 (s, 3H), 3.36 (s,
3H), 2.51-2.46 (m, 2H), 1.97 (t, J = 2.6 Hz, 1H), 1.50-1.26 (m,
10H), 0.86 (t, J = 6.3 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3): δ 96.1, 80.7, 76.3, 74.4, 74.2, 72.5, 70.9, 70.7, 69.8, 55.5,
55.4, 32.1, 31.8, 29.3, 25.4, 22.5, 21.9, 14.0 ppm. MS (ESI, m/z):
383 [M þ 23]þ. HRMS (ESI): C19H36O6 calculated [M þ Na] þ
383.2404, found 383.2407.
(5S,12S)-5-(4-Cyclohexylbutyl)-12-(prop-2-ynyl)-2,4,7,10,13,
15-hexaoxahexadecane (37). The procedure was the same as
described above for the synthesis of 36. Compound 37 (0.29 g,
61% for three steps) was obtained as a buff oil. [R]25D: 1.7
(c 0.88, CHCl3). 1H NMR (400 MHz, CDCl3): δ 4.75 (d, J = 6.8
Hz, 1H), 4.74 (s, 2H), 4.65 (d, J = 6.8 Hz, 1H), 3.90-3.85 (m,
1H), 3.72-3.68 (m, 1H), 3.66-3.47 (m, 8H), 3.39 (s, 3H), 3.38 (s,
3H), 2.57-2.44 (m, 2H), 1.99 (t, J = 2.6 Hz, 1H), 1.69-1.11 (m,
17H), 0.89-0.81 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ
96.0, 80.7, 76.2, 74.2, 74.1, 72.4, 70.9, 70.7, 70.0, 55.5, 55.4, 37.6,
37.5, 33.4, 32.1, 29.2, 27.4, 27.0, 26.7, 26.4, 25.9, 25.8, 21.9 ppm.
MS (ESI, m/z): 437 [M þ 23]þ. HRMS (ESI): C23H42O6
calculated [M þ Na] þ 437.2874, found 437.2874.
(S)-2-((S)-5-(3-(4-Methoxyphenyl)propyl)-2,4,7,10-tetraox-
aundecan-11-yl)oxirane (33). The procedure was the same as
described above for the synthesis of 29. Compound 33 was
obtained as a buff oil (0.58 g, 69% for two steps). [R]25D: -2.6
(c 1.15, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.09 (dd, J =
6.7, 1.9 Hz, 2H), 6.82 (dd, J = 6.6, 2.0 Hz, 2H), 4.75 (d, J = 6. 8
Hz, 1H), 4.64 (d, J = 6.8 Hz, 1H), 3.78 (s, 3H), 3.76-3.72 (m,
1H), 3.70-3.39 (m, 8H), 3.37 (s, 3H), 3.16-3.13 (m, 1H), 2.78 (t,
J = 4.6 Hz, 1H), 2.60 (t, J = 5.6 Hz, 1H), 2.57 (t, J = 8.0 Hz,
2H), 1.76-1.53 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ
157.8, 134.4, 129.2, 113.8, 96.1, 76.1, 74.1, 71.9, 71.0, 70.8, 55.4,
55.2, 50.8, 44.1, 35.0, 31.6, 27.3 ppm. MS (ESI, m/z): 355 [M þ
1]þ. HRMS (ESI): C19H30O6 calculated [M þ Na] þ 377.1935,
found 377.1934.
(S)-2-((S)-5-(3-(Biphenyl-4-yl)propyl)-2,4,7,10-tetraoxaunde-
can-11-yl)oxirane (34). The procedure was the same as described
above for the synthesis of 29. Compound 34 was obtained as
pale yellow oil (0.44 g, 75% for two steps). [R]25D: 3.2 (c 1.84,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.61 (dd, J = 8.1, 1.3
Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.45 (dd, J = 7.8, 1.8 Hz, 2H),
7.37-7.33 (m, 1H), 7.28 (dd, J = 4.1, 3.8 Hz, 2H), 4.80 (d, J =
6.8 Hz, 1H), 4.69 (d, J = 6.8 Hz, 1H), 3.81 (dd, J = 11.7, 2.9 Hz,
1H), 3.78-3.43 (m, 8H), 3.41 (s, 3H), 3.18-3.16 (m, 1H),
2.81-2.79 (m, 1H), 2.70 (t, J = 7.5 Hz, 2H), 2.62 (dd, J =5.0,
2.7 Hz, 1H), 1.83-1.63 (m, 4H) ppm. 13C NMR (100 MHz,
CDCl3): δ 141.5, 141.2, 138.8, 128.8, 128.7, 127.0, 126.9, 96.2,
76.2, 74.1, 71.9, 70.8, 55.5, 50.8, 44.1, 35.5, 31.7, 27.1 ppm. MS
(ESI, m/z): 418 [M þ 18]þ, 423 [M þ 23]þ. HRMS (ESI):
C24H32O5 calculated [M þ Na] þ 423.2142, found 423.2140.
(S)-2-((S)-5-(3-(6-Methoxynaphthalen-2-yl)propyl)-2,4,7,10-
tetraoxaundecan-11-yl)oxirane (35). The procedure was the
same as described above for the synthesis of 29. Compound
(5S,12S)-5-(3-Phenylpropyl)-12-(prop-2-ynyl)-2,4,7,10,13,15-
hexaoxahexadecane (38). The procedure was the same as de-
scribed above for the synthesis of 36. Compound 38 was
obtained as a buff oil (0.84 g, 70% for three steps). [R]25D: 3.2
(c 2.30, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.30-7.16 (m,
5H), 4.76 (d, J = 6.8 Hz, 1H), 4.74 (s, 2H), 4.65 (d, J = 6.8 Hz,
1H), 3.91-3.85 (m, 1H), 3.76-3.71 (m, 1H), 3.66-3.47 (m, 8H),
3.40 (s, 3H), 3.37 (s, 3H), 2.64 (t, J = 3.5 Hz, 2H), 2.58-2.44 (m,
2H), 2.00 (t, J = 2.0 Hz, 1H), 1.81-1.56 (m, 4H) ppm. 13C NMR
(100 MHz, CDCl3): δ 142.3, 128.4, 128.2, 125.7, 96.1, 80.7, 76.2,
74.4, 74.1, 72.5, 70.9, 70.7, 69.9, 55.5, 55.4, 35.9, 31.7, 27.1, 21.9
ppm. MS (ESI, m/z): 417 [M þ 23]þ. HRMS (ESI): C22H34O6
calculated [M þ Na] þ 417.2248, found 417.2253.
35 was obtained as a buff oil (0.50 g, 75% for two steps). [R]25
:
D
2.3 (c 2.57, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.66-7.65
(m, 2H), 7.54 (s, 1H), 7.29 (dd, J = 8.4, 1.6 Hz, 1H), 7.13-7.10
(m, 2H), 4.76 (d, J = 6.8 Hz, 1H), 4.65 (d, J = 6.8 Hz, 1H), 3.91
(s, 3H), 3.78-3.39 (m, 9H), 3.37 (s, 3H), 3.14-3.11 (m, 1H),
2.78-2.74 (m, 3H), 2.59 (dd, J = 5.0, 2.6 Hz, 1H), 1.84-1.58
(m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ 157.2, 137.5,
133.0, 129.2, 128.9, 127.8, 126.7, 126.2, 118.6, 105.8, 96.1, 76.1,
74.1, 71.9, 70.8, 55.4, 55.3, 50.8, 44.1, 35.8, 31.8, 27.1 ppm. MS
(ESI, m/z): 427 [M þ 23]þ. HRMS (ESI): C23H32O6 calculated
[M þ Na] þ 427.2091, found 427.2089.
(5S,12S)-5-(3-(3-(Methoxymethoxy)phenyl)propyl)-12-(prop-
2-ynyl)-2,4,7,10,13,15-hexaoxahexadecane (39). The procedure
was the same as described above for the synthesis of 36.
Compound 39 (0.51 g, 80% for three steps) was obtained as a
buff oil. [R]25D: 4.6 (c 0.79, CHCl3). 1H NMR (400 MHz, CDCl3):
δ 7.20-7.16 (m, 1H), 6.87-6.82 (m, 3H), 5.16 (s, 2H), 4.76-4.70
(m, 3H), 4.64 (d, J = 6.8 Hz, 1H), 3.91-3.86 (m, 1H), 3.74-3.71
(m, 1H), 3.66-3.49 (m, 8H), 3.48 (s, 3H), 3.39 (s, 3H), 3.36 (s, 3H),
2.60 (t, J = 7.6 Hz, 2H), 2.53-2.46 (m, 2H), 1.99 (t, J = 2.0 Hz,
1H), 1.76-1.55 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ
157.4, 144.0, 129.2, 122.0, 116.5, 113.6, 96.1, 96.0, 94.6, 80.7, 76.1,
74.4, 74.0, 72.5, 70.9, 70.7, 69.9, 55.8, 55.4, 35.9, 31.7, 26.9, 21.9
ppm. MS (ESI, m/z): 477 [M þ 23]þ. HRMS (ESI): C24H38O8
calculated [M þ Na] þ 477.2459, found 477.2457.
(5S,12S)-5-Hexyl-12-(prop-2-ynyl)-2,4,7,10,13,15-hexaoxa-
hexadecane (36). To a solution of trimethylsilylacetylene 52
(0.90 mL, 6.1 mmol) in dried THF (12 mL) was added slowly
n-BuLi (6.1 mmol, 2.5 M in hexane) at -78 ꢀC. The reaction
mixture was stirred for 45 min at -78 ꢀC under argon atmo-
sphere, and BF3 Et2O (6.1 mmol) was added. After the mixture
3
was stirred for an additional 30 min, a solution of 29 (0.871 g,
3.0 mmol) in dried THF (4 mL) was added. The reaction
mixture was stirred for 3 h until it was quenched by saturated
aqueous NH4Cl (3 mL). The volatiles were evaporated under
reduced pressure. The residue was extracted with ether (15 mL
ꢀ 3). The combined organic layers were washed with saturated
aqueous NaHCO3 and brine, dried over anhydrous Na2SO4,
filtered, and concentrated. The resulting oil was used in the
next step without further purification.
(5S,12S)-5-(3-(4-Methoxyphenyl)propyl)-12-(prop-2-ynyl)-2,
4,7,10,13,15-hexaoxahexadecane (40). The procedure was the
same as described above for the synthesis of 36. Compound 40
To the above crude product in dry DCM (12 mL) under
nitrogen atmosphere was added DIPEA (4.2 mL, 24 mmol). The
reaction mixture was cooled to 0 ꢀC, and MOMCl (1.2 mL,
15 mmol) was added slowly. The mixture was stirred at ambient
temperature for 20 h until it was quenched by saturated aqueous
was obtained as a buff oil (0.48 g, 84% for three steps). [R]25
:
D
1.3 (c 0.69, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.08 (dd,
J = 6.6, 1.9 Hz, 2H), 6.82 (dd, J = 6.6, 2.0 Hz, 2H), 4.75 (d, J =
6.8 Hz, 1H), 4.73 (s, 2H), 4.64 (d, J = 6.8 Hz, 1H), 3.88-3.86

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 531
(m, 1H), 3.78 (s, 3H), 3.73-3.70 (m, 1H), 3.65-3.47 (m, 8H),
3.39 (s, 3H), 3.37 (s, 3H), 2.57 (t, J = 7.4 Hz, 2H), 2.53-2.43 (m,
2H), 2.00 (t, J = 2.7 Hz, 1H), 1.76-1.53 (m, 4H) ppm. 13C
NMR (100 MHz, CDCl3): δ 157.8, 134.5, 129.2, 113.8, 96.1,
80.7, 76.1, 74.3, 74.1, 72.5, 70.9, 70.7, 69.9, 55.5, 55.4, 55.2, 35.0,
31.6, 27.4, 21.9 ppm. MS (ESI, m/z):447 [M þ 23]þ. HRMS(ESI):
C23H36O7 calculated [M þ Na]þ 447.2353, found 447.2356.
(5S,12S)-5-(3-(Biphenyl-4-yl)propyl)-12-(prop-2-ynyl)-2,4,7,
10,13,15-hexaoxahexadecane (41). The procedure was the same
as described above for the synthesis of 36. Compound 41 was
obtained as a pale yellow oil (0.44 g, 83% for three steps).
[R]25D: 1.8 (c 0.79, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.58
(d, J = 7.8 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.42 (dd, J = 7.6,
7.5 Hz, 2H), 7.34-7.30 (m, 1H), 7.26 (dd, J = 4.0, 2.9 Hz, 2H),
4.77 (d, J = 6.8 Hz, 1H), 4.73 (s, 2H), 4.66 (d, J = 6.8 Hz, 1H),
3.89-3.86 (m, 1H), 3.76-3.70 (m, 1H), 3.66-3.49 (m, 8H), 3.39
(s, 3H), 3.38 (s, 3H), 2.68 (t, J = 7.5 Hz, 2H), 2.53-2.48 (m,
2H), 1.99 (t, J = 2.4 Hz, 1H), 1.81-1.58 (m, 4H) ppm. 13C
NMR (100 MHz, CDCl3): δ 141.5, 141.2, 138.8, 128.8, 128.7,
127.0, 96.2, 96.1, 80.7, 76.2, 74.4, 74.1, 72.5, 71.0, 70.8, 69.9,
CDCl3): δ 6.97 (d, J = 1.2 Hz, 1H), 4.97 (dq, J = 6.8, 1.5 Hz, 1H),
4.74 (d, J = 6.8 Hz, 1H), 4.71 (s, 2H), 4.63 (d, J = 6.8 Hz, 1H),
3.84-3.81 (m, 1H), 3.69-3.66 (m, 1H), 3.68-3.46 (m, 9H), 3.36 (s,
3H), 3.35 (s, 3H), 2.47-2.27 (m, 4H), 2.24 (t, J = 7.2 Hz, 2H),
1.67-1.08 (m, 29H), 1.38 (d, J = 6.8 Hz, 3H), 0.83-0.80 (m, 2H)
ppm. 13C NMR (125 MHz, CDCl3):δ173.8, 148.9, 134.2, 96.0, 95.9,
79.1, 78.2, 76.8, 76.2, 74.7, 74.1, 72.7, 70.9, 70.6, 70.0, 55.4, 37.6, 37.4,
36.2, 33.4, 32.0, 29.4, 29.2, 29.1, 27.8, 27.3, 26.9, 26.7, 26.4, 25.7, 25.6,
25.1, 22.1, 19.2ppm. MS (ESI, m/z):675 [M þ 23]þ. HRMS(ESI):
C37H64O9 calculated [M þ Na] þ 675.4443, found 675.4442.
(S)-3-((5S,12S)-17-Hydroxy-12-(methoxymethoxy)-5-(3-phen-
ylpropyl)-2,4,7,10-tetraoxatetracos-14-yn-24-yl)-5-methylfuran-
2(5H)-one (45). The procedure was the same as described above
for the synthesis of 43. Compound 45 was obtained as a buff oil
(0.20 g, 63%). [R]25D: 12.9 (c 0.36, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.29-7.17 (m, 5H), 6.98 (d, J = 1.3 Hz, 1H), 4.99 (dq,
J = 6.8, 1.6 Hz, 1H), 4.76 (d, J = 6.8 Hz, 1H), 4.73 (s, 2H), 4.64
(d, J = 6.8 Hz, 1H), 3.86-3.83 (m, 1H), 3.84-3.47 (m, 10H),
3.39 (s, 3H), 3.37 (s, 3H), 2.63 (t, J = 7.5 Hz, 2H), 2.50-2.30 (m,
4H), 2.22 (t, J = 7.3 Hz, 2H), 1.77-1.32 (m, 16H), 1.40 (d, J =
6.8 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 173.6, 148.7,
142.3, 134.3, 128.3, 128.2, 125.7, 96.1, 96.0, 79.2, 78.2, 76.7, 76.2,
74.9, 74.1, 72.8, 70.9, 70.7, 70.1, 55.4, 36.3, 35.9, 31.7, 29.4, 29.2,
29.0, 27.9, 27.4, 27.1, 25.6, 25.1, 22.2, 19.2 ppm. MS (ESI, m/z):
655 [M þ 23]þ. HRMS (ESI): C36H56O9 calculated [M þ Na] þ
655.3817, found 655.3817.
55.5, 35.6, 31.8, 27.1, 21.9 ppm. MS (ESI, m/z): 493 [M þ 23]þ.
þ
HRMS (ESI): C18H38O6 calculated [M þ Na]
493.2561,
found 493.2560.
(5S,12S)-5-(3-(6-Methoxynaphthalen-2-yl)propyl)-12-(prop-
2-ynyl)-2,4,7,10,13,15-hexaoxahexadecane (42). The proce-
dure was the same as described above for the synthesis of 36.
Compound 42 was obtained as a buff oil (0.57 g, 84% for three
steps). [R]25D: 1.7 (c 0.88, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.65-7.28 (m, 2H), 7.54 (s, 1H), 7.29 (dd, J = 8.4,
1.7 Hz, 1H), 7.13-7.10 (m, 2H), 4.76 (d, J = 6.8 Hz, 1H), 4.73
(s, 2H), 4.65 (d, J = 6.8 Hz, 1H), 3.91 (s, 3H), 3.88-3.85 (m,
1H), 3.77-3.73 (m, 1H), 3.64-3.49 (m, 8H), 3.39 (s, 3H), 3.37
(s, 3H), 2.76 (t, J = 7.6 Hz, 2H), 2.52-2.47 (m, 2H), 1.98 (t, J =
2.6 Hz, 1H), 1.85-1.59 (m, 4H) ppm. 13C NMR (100 MHz,
CDCl3): δ 157.2, 137.5, 133.0, 129.2, 128.9, 127.8, 126.7, 126.2,
118.6, 105.8, 96.1, 80.7, 76.2, 74.4, 74.1, 72.5, 70.9, 70.7, 69.9,
55.5, 55.4, 55.3, 35.9, 31.7, 27.1, 21.9 ppm. MS (ESI, m/z): 49þ7
[M þ 23]þ. HRMS (ESI): C27H38O7 calculated [M þ Na]
497.2510, found 497.2506.
(S)-3-((5S,12S)-17-Hydroxy-12-(methoxymethoxy)-5-(3-(3-
(methoxymethoxy)phenyl)propyl)-2,4,7,10-tetraoxatetracos-14-
yn-24-yl)-5-methylfuran-2(5H)-one (46). The procedure was the
same as described above for the synthesis of 43. Compound 46
was obtained as a buff oil (78.2 mg, 74%). [R]25D: 7.0 (c 0.95,
1
CHCl3). H NMR (400 MHz, CDCl3): δ 7.18-7.16 (m, 1H),
6.98 (d, J = 1.6 Hz, 1H), 6.86-6.82 (m, 3H), 5.16 (s, 2H), 4.99
(dq, J = 6.8, 1.6 Hz, 1H), 4.77-4.70 (m, 3H), 4.64 (d, J = 6.8
Hz, 1H), 3.86-3.84 (m, 1H), 3.68-3.58 (m, 10H), 3.48 (s, 3H),
3.38 (s, 3H), 3.36 (s, 3H), 2.60 (t, J = 7.4 Hz, 2H), 2.50-2.36 (m,
4H), 2.27-2.22 (m, 2H), 1.59-1.24 (m, 16H), 1.39 (d, J = 6.8
Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 173.6, 157.4,
148.7, 144.0, 134.4, 129.2, 122.0, 116.5, 113.6, 96.1, 96.0, 94.6,
79.2, 78.2, 76.1, 74.9, 74.1, 72.8, 70.9, 70.7, 70.1, 55.9, 55.4, 36.3,
35.9, 31.7, 29.4, 29.2, 29.1, 27.9, 27.4, 27.0, 25.6, 25.1, 22.2, 19.2
ppm. MS (ESI, m/z): 715 [M þ 23]þ. HRMS (ESI): C38H60O11
calculated [M þ Na]þ 715.4028, found 715.4028.
(S)-3-((5S,12S)-5-Hexyl-17-hydroxy-12-(methoxymethoxy)-
2,4,7,10-tetraoxatetracos-14-yn-24-yl)-5-methylfuran-2(5H)-
one (43). To a solution of 36 (0.37 g, 1.02 mmol) in dry THF
(6 mL) was added slowly n-BuLi (1.02 mmol, 1.6 M in hexane)
at -78 ꢀC. The reaction mixture was stirred for 45 min at -78 ꢀC
(S)-3-((5S,12S)-17-Hydroxy-12-(methoxymethoxy)-5-(3-(4-
methoxyphenyl)propyl)-2,4,7,10-tetraoxatetracos-14-yn-24-yl)-
5-methylfuran-2(5H)-one (47). The procedure was the same as
described above for the synthesis of 43. Compound 47 was
obtained as a buff oil (0.14 g, 78%). [R]25D: 10.1 (c 1.1, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.09 (d, J = 8.6 Hz, 2H), 6.98
(d, J = 1.5 Hz, 1H), 6.82 (dd, J = 6.6, 2.0 Hz, 2H), 4.99 (dq, J =
6.8, 1.7 Hz, 1H), 4.75 (d, J = 6.8 Hz, 1H), 4.73 (s, 2H), 4.64 (d,
J = 6.8 Hz, 1H), 3.87-3.82 (m, 1H), 3.78 (s, 3H), 3.73-3.71 (m,
1H), 3.63-3.41 (m, 9H), 3.39 (s, 3H), 3.37 (s, 3H), 2.57 (t, J =
7.5 Hz, 2H), 2.54-2.34 (m, 4H), 2.26 (t, J = 8.2 Hz, 2H),
1.58-1.24 (m, 16H), 1.40 (d, J = 6.8 Hz, 3H) ppm. 13C NMR
(125 MHz, CDCl3): δ 173.8, 157.7, 148.9, 134.4, 134.2, 129.2,
113.7, 96.0, 95.9, 79.1, 78.2, 76.7, 76.0, 74.7, 74.0, 72.7, 70.9,
70.7, 70.1, 55.5, 55.2, 36.3, 35.0, 31.6, 29.4, 29.2, 29.1, 27.8,
27.4, 27.3, 25.6, 25.1, 22.1, 19.2 ppm. MS (ESI, m/z): 685 [M þ
23]þ. HRMS (ESI): C37H58O10 calculated [M þ Na] þ 685.3922,
found 685.3918.
(S)-3-((5S,12S)-5-(3-(Biphenyl-4-yl)propyl)-17-hydroxy-12-
(methoxymethoxy)-2,4,7,10-tetraoxatetracos-14-yn-24-yl)-5-
methylfuran-2(5H)-one (48). The procedure was the same as
described above for the synthesis of 43. Compound 48 was
obtained as a buff oil (97 mg, 43%). [R]25D: 13.5 (c 0.41,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 7.2 Hz,
2H), 7.50 (d, J = 8.2 Hz, 2H), 7.42 (dd, J = 7.6, 7.0 Hz, 2H),
7.33-7.29 (m, 1H), 7.25 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 1.6
Hz, 1H), 4.97 (dq, J = 6.8, 1.6 Hz, 1H), 4.77 (d, J = 6.8 Hz,
under argon atmosphere until BF3 Et2O (1.02 mmol) was
3
added. After the mixture was stirred for 30 min, a solution of
11 (0.122 g, 0.51 mmol) in dry THF (3 mL) was added. The
mixture continued to stir for 3 h, until it was quenched by
saturated aqueous NH4Cl (3 mL). The volatiles were evapo-
rated under reduced pressure. The residue was extracted with
ether (15 mL ꢀ 3). The combined organic layers were washed
with saturated aqueous NaHCO3 and brine, dried over
anhydrous Na2SO4, filtered, and concentrated. Purification
by silica gel chromatography afforded 43 (0.22 g, 62%) as a
colorless oil. [R]25D: 9.4 (c 0.55, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 6.97 (s, 1H), 4.98 (dq, J = 6.7, 1.2 Hz, 1H), 4.75 (d,
J = 6.8 Hz, 1H), 4.72 (s, 2H), 4.64 (d, J = 6.8 Hz, 1H),
3.85-3.82 (m, 1H), 3.70-3.48 (m, 10H), 3.38 (s, 3H), 3.37 (s,
3H), 2.49-2.27 (m, 4H), 2.25 (t, J = 7.4 Hz, 2H), 1.55-1.27
(m, 22H), 1.39 (t, J = 6.8 Hz, 3H), 0.87 (t, J = 6.2 Hz, 3H)
ppm. 13C NMR (125 MHz, CDCl3): δ 173.2, 148.3, 134.5, 96.2,
96.1, 79.2, 78.1, 76.5, 75.1, 74.3, 73.0, 71.0, 70.8, 70.1, 55.3, 55.2,
36.4, 32.1, 31.7, 29.3, 29.1, 29.0, 27.9, 27.4, 25.5, 25.3, 25.1, 22.4,
22.3, 19.0, 13.7 ppm. MS (ESI, m/z):621 [M þ 23]þ. HRMS(ESI):
C33H58O9 calculated [M þ Na] þ 621.3973, found 621.3974.
(S)-3-((5S,12S)-5-(4-Cyclohexylbutyl)-17-hydroxy-12-(methoxy-
methoxy)-2,4,7,10-tetraoxatetracos-14-yn-24-yl)-5-methylfuran-
2(5H)-one (44). The procedure was the same as described above
for the synthesis of 43. Compound 44 was obtained as a buff oil
(95.8 mg, 56%). [R]25D: 9.9 (c 0.58, CHCl3). 1H NMR (400 MHz,

532 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2
Xiao et al.
1H), 4.72 (s, 2H), 4.65 (d, J = 6.8 Hz, 1H), 3.85-3.83 (m, 1H),
3.76-3.73 (m, 1H), 3.67-3.50 (m, 9H), 3.38 (s, 3H), 3.37 (s,
3H), 2.67 (t, J = 7.6 Hz, 2H), 2.50-2.27 (m, 4H), 2.25 (t, J =
8.5 Hz, 2H), 1.78-1.25 (m, 16H), 1.39 (d, J = 6.8 Hz, 3H)
ppm. 13C NMR (125 MHz, CDCl3): δ 173.6, 148.7, 141.5,
141.2, 138.7, 134.4, 128.8, 128.6, 127.0, 126.9, 96.2, 96.0,
79.2, 78.2, 76.7, 76.2, 74.9, 74.1, 72.8, 70.9, 70.7, 70.1, 55.4,
36.3, 35.5, 31.8, 29.4, 29.2, 29.1, 27.9, 27.4, 27.1, 25.6, 25.1,
22.2, 19.2 ppm. MS (ESI, m/z): 731 [M þ 23]þ. HRMS (ESI):
25.5, 25.4, 25.1, 19.2 ppm. MS (EI, m/z): 569 [M þ 1]þ, 591 [M þ
23]þ. HRMS (ESI): C33H60O7 calculated [M þ H]þ 569.4412,
found 569.4416, [M þ Na] þ 591.4231, found 591.4234.
(S)-3-((13S)-8,13-Dihydroxy-14-(2-((S)-2-hydroxy-5-pheny-
lpentyloxy)ethoxy)tetradecyl)-5-methylfuran-2(5H)-one (4). The
procedure was the same as described above for the synthesis of 2.
Compound 4 was obtained as a white oil (94.7 mg, 54% for two
steps). [R]25D: 6.6 (c 0.44, CHCl3). 1H NMR (400 MHz, CDCl3):
δ 7.29-7.15 (m, 5H), 6.99 (d, J = 1.4 Hz, 1H), 4.99 (dq, J = 7.5,
1.6 Hz, 1H), 3.80 (m, 2H), 3.70-3.59 (m, 5H), 3.57 (brs, 1H,
OH), 3.52 (d, J = 2.8 Hz, 1H), 3.51 (d, J = 2.8 Hz, 1H), 3.31 (dq,
J = 9.2, 2.4 Hz, 2H), 2.96 (br, 2H, OH), 2.63 (t, J = 7.7 Hz, 2H),
2.26 (dt, J = 11.2, 7.3 Hz, 2H), 1.84-1.25 (m, 24H), 1.40 (d, J =
6.8 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 173.9, 148.9,
142.2, 134.2, 128.4, 128.2, 125.7, 77.4, 75.8, 71.7, 71.6, 70.4, 70.1,
70.0, 37.4, 37.3, 35.8, 32.9, 32.5, 29.5, 29.2, 29.1, 27.3, 25.6, 25.5,
25.4, 25.1, 19.2 ppm. MS (EI, m/z): 549 [M þ 1]þ, 571 [M þ 23]þ.
HRMS (ESI): C32H52O7 calculated [M þ H] þ 549.3786, found
549.3784.
(S)-3-((13S)-8,13-Dihydroxy-14-(2-((S)-2-hydroxy-5-(3-hydro-
xyphenyl)pentyloxy)ethoxy)tetradecyl)-5-methylfuran-2(5H)-one
(5). The procedure was the same as described above for the
synthesis of 2. Compound 5 was obtained as a white wax (64.7
mg, 80% fortwo steps). [R]25D: 7.0 (c 0.17, CHCl3). 1H NMR (400
MHz, CDCl3): δ 7.34 (brs, 1H, OH), 7.10-7.06 (m, 1H), 6.98 (d,
J = 1.5 Hz, 1H), 6.67-6.63 (m, 3H), 4.98 (dq, J = 6.8, 1.6 Hz,
1H), 3.78 (br, 2H), 3.66-3.30 (m, 12H), 2.55 (t, J = 7.5 Hz, 2H),
2.24 (t, J = 7.9 Hz, 2H), 1.77-1.23 (m, 24H), 1.39 (d, J = 6.8 Hz,
3H) ppm. 13C NMR (100 MHz, CDCl3): δ 173.9, 156.3, 148.9,
143.9, 134.3, 129.3, 120.3, 115.4, 112.9, 76.7, 75.7, 71.8, 70.5, 70.4,
70.2, 37.4, 37.2, 35.5, 32.9, 32.5, 29.5, 29.2, 29.0, 27.4, 27.2, 26.8,
25.5, 25.4, 25.1, 19.1 ppm. MS (EI, m/z): 565 [M þ 1]þ, 587 [M þ
23]þ. HRMS (ESI): C32H52O8 calculated [M þ Na] þ 587.3554,
found 587.3555.
C
42H60O9 calculated [M þ Na] þ 731.4130, found 731.4127.
(S)-3-((5S,12S)-17-Hydroxy-12-(methoxymethoxy)-5-(3-(6-
methoxynaphthalen-2-yl)propyl)-2,4,7,10-tetraoxatetracos-14-yn-
24-yl)-5-methylfuran-2(5H)-one(49). The procedurewas the same
as described above for the synthesis of 43. Compound 49 was
obtained as a buff oil (60.4 mg, 54%). [R]25D: 8.6 (c 0.55, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.67-7.64 (m, 2H), 7.53 (s, 1H),
7.29 (dd, 1H, J = 8.4, 1.7 Hz, 1H), 7.12-7.10 (m, 2H), 6.96 (d,
J = 1.6 Hz, 1H), 4.97 (dq, J = 6.8, 1.7 Hz, 1H), 4.76 (d, J = 6.8
Hz, 1H), 4.71 (s, 2H), 4.64 (d, J = 6.8 Hz, 1H), 3.90 (s, 3H),
3.84-3.82 (m, 1H), 3.76-3.73 (m, 1H), 3.67-3.40 (m, 9H), 3.38
(s, 3H), 3.36 (s, 3H), 2.75 (t, J = 7.6 Hz, 2H), 2.49-2.34 (m, 4H),
2.27-2.22 (m, 2H), 1.58-1.28 (m, 16H), 1.39 (d, J = 6.8 Hz, 3H)
ppm. 13C NMR (125 MHz, CDCl3): δ 173.8, 157.1, 148.9, 137.4,
134.2, 132.9, 129.1, 128.8, 127.8, 126.7, 126.2, 118.6, 105.6, 96.0,
95.9, 79.1, 78.3, 76.0, 74.7, 74.0, 72.6, 70.9, 70.6, 70.0, 55.5, 55.2,
36.3, 35.8, 31.6, 29.4, 29.2, 29.1, 27.8, 27.3, 27.1, 26.5, 25.6, 25.1,
22.1, 19.2 ppm. MS (ESI, m/z): 735 [M þ 23]þ. HRMS (ESI):
C41H60O10 calculated [M þ Na] þ 735.4079, found 735.4077.
(S)-3-((13S)-8,13-Dihydroxy-14-(2-((S)-2-hydroxyoctyloxy)-
ethoxy)tetradecyl)-5-methylfuran-2(5H)-one (2). To a stirred
solution of 43 (0.192 g, 0.32 mmol) and p-toluenesulfonylhy-
drazone (3.04 g, 16 mmol) in dimethoxylethane (20 mL) was
added NaOAc (2.65 g, 32 mmol) in H2O (15 mL) dropwise
within 4 h under reflux. After being stirred for an additional
10 h, the reaction mixture was then cooled to room temperature
and poured into water (5 mL). The mixture was extracted with
ethyl acetate (20 mL ꢀ 3), and the extracts were washed with
brine, dried, and concentrated to give a crude product.
(S)-3-((13S)-8,13-Dihydroxy-14-(2-((S)-2-hydroxy-5-(4-meth-
oxyphenyl)pentyloxy)ethoxy)tetradecyl)-5-methylfuran-2(5H)-
one (6). The procedure was the same as described above for the
synthesis of 4. Compound 6 was obtained as a wax solid (98.5
mg, 71% for two steps). [R]25D: 11.3 (c 0.90, CHCl3). 1H NMR
(400 MHz, CDCl3): δ 7.08 (d, J = 4.6 Hz, 2H), 6.98 (d, J = 1.5
Hz, 1H), 6.80 (dd, J = 6.6, 2.0 Hz, 2H), 4.98 (dq, J = 6.8, 1.6
Hz, 1H), 3.77 (s, 3H), 3.69-3.48 (m, 9H), 3.56 (br, 1H, OH),
3.33-3.28 (m, 2H), 2.97 (brs, 2H, OH), 2.56 (t, J = 7.6 Hz, 2H),
2.24 (dt, J = 7.7, 1.5 Hz, 2H), 1.64-1.24 (m, 24H), 1.39 (d, J =
6.8 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 173.7, 157.8,
148.7, 134.4, 129.2, 113.8, 75.8, 71.8, 71.7, 70.6, 70.2, 55.2, 37.5,
37.3, 34.9, 33.0, 32.6, 29.5, 29.2, 29.0, 27.4, 25.6, 25.5, 25.1, 19.1
ppm. MS (EI, m/z): 579 [M þ 1]þ, 601 [M þ 23]þ. HRMS (ESI):
C33H54O8 calculated [M þ H] þ 601.3711, found 601.3712.
(S)-3-((13S)-14-(2-((S)-5-(Biphenyl-4-yl)-2-hydroxypentyloxy)-
ethoxy)-8,13-dihydroxytetradecyl)-5-methylfuran-2(5H)-one (7).
The procedure was the same as described above for the synthesis
of 2. Compound 7 was obtained as a white wax solid (44.8 mg,
To the crude product obtained above in THF and CH3OH
(2.4 mL, v/v, 1:2) was added 6 N HCl (1.5 mL). The mixture was
stirred for 1.5 h at room temperature until it was quenched by
saturated aqueous NaHCO3 (3 mL). The mixture was extracted
with ethyl acetate (10 mL ꢀ 3). The combined organic layers
were washed with saturated aqueous NaHCO3 and brine, dried
over anhydrous Na2SO4, filtered, and concentrated. Purification
by silica gel chromatography afforded 2 as white wax (0.16 g, 94%
for two steps). [R]25D: 13.4 (c 1.1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 6.99 (d, J = 1.2 Hz, 1H), 5.00 (dq, J = 6.8, 1.5 Hz, 1H),
3.79 (br, 2H), 3.71-3.62 (m, 5H), 3.58 (brs, 1H, OH), 3.55 (d, J =
2.7 Hz, 1H), 3.52 (d, J = 2.7 Hz, 1H), 3.32 (dq, J = 9.5, 2.8 Hz,
2H), 2.88 (brs, 2H, OH), 2.26 (t, J = 7.6 Hz, 2H), 1.56-1.24 (m,
30H), 1.40 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H) ppm. 13
C
NMR (100 MHz, CDCl3): δ 173.7, 148.7, 134.4, 77.1, 75.9, 75.8,
71.8, 71.7, 70.6, 70.3, 37.5, 37.4, 33.1, 33.0, 31.7, 29.5, 29.3, 29.2,
29.1, 27.4, 25.6, 25.5, 25.4, 25.1, 22.5, 19.2, 13.9 ppm. MS (EI,
m/z): 515 [M þ 1]þ, 537 [M þ 23]þ. HRMS (ESI): C29H54O7
calculated [M þ H] þ 515.3942, found 515.3939.
1
51% for two steps). [R]25D: 8.6 (c 0.29, CHCl3). H NMR (400
MHz, CDCl3): δ 7.58 (dd, J = 7.1, 1.7 Hz, 2H), 7.51 (d, J = 8.2
Hz, 2H), 7.42 (dd, J = 7.8, 7.6 Hz, 2H), 7.34-7.32 (m, 1H), 7.25
(dd, J = 8.2, 1.6 Hz, 2H), 6.97 (d, J = 1.5 Hz, 1H), 4.98 (dq, J =
6.8, 1.7 Hz, 1H), 3.82 (m, 2H), 3.70-3.61 (m, 5H), 3.57 (brs, 1H,
OH), 3.54 (d, J = 2.6 Hz, 1H), 3.51 (d, J = 2.6 Hz, 1H), 3.33 (dq,
J = 8.8, 2.6 Hz, 2H), 2.97 (br, 2H, OH), 2.68 (t, J = 7.6 Hz, 2H),
2.25 (t, J = 7.2 Hz, 2H), 1.55-1.26 (m, 24H), 1.39 (d, J = 6.8 Hz,
3H) ppm. 13C NMR (100 MHz, CDCl3): δ 173.6, 148.7, 141.4,
141.2, 138.8, 134.4, 128.8, 128.6, 127.0, 126.9, 75.8, 71.8, 71.7, 70.6,
70.2, 37.5, 37.3, 35.4, 33.0, 32.7, 29.5, 29.2, 29.0, 27.4, 27.2, 25.6,
25.5, 25.1, 19.1 ppm. MS (EI, m/z): 625 [M þ 1þ]þ, 647 [M þ 23]þ.
HRMS (ESI): C38H56O7 calculated [M þ H] 625.4099, found
625.4102, [M þ Na] þ 647.3918, found 647.3915.
(S)-3-((13S)-14-(2-((S)-6-Cyclohexyl-2-hydroxyhexyloxy)-
ethoxy)-8,13-dihydroxytetradecyl)-5-methylfuran-2(5H)-one (3).
The procedure was the same as described above for the synthesis
of 2. Compound 3 was obtained as white wax (51 mg, 67% for
1
two steps). [R]25D: 18.9 (c 0.27, CHCl3). H NMR (400 MHz,
CDCl3): δ 6.98 (d, J = 1.4 Hz, 1H), 4.98 (dq, J = 6.8, 1.6 Hz,
1H), 3.78 (br, 2H), 3.68-3.60 (m, 5H), 3.56 (brs, 1H, OH), 3.52
(d, J = 2.4 Hz, 1H), 3.50 (d, J = 2.4 Hz, 1H), 3.31 (dq, J = 8.9,
3.6 Hz, 2H), 2.99 (brs, 2H, OH), 2.24 (t, J = 7.3 Hz, 2H),
1.67-1.09 (m, 37H), 1.39 (d, J = 6.5 Hz, 3H), 0.87-0.79 (m, 2H)
ppm. 13C NMR (125 MHz, CDCl3): δ 173.9, 148.9, 134.2, 77.4,
75.9, 75.8, 71.7, 70.5, 70.4, 70.2, 70.0, 37.6, 37.4, 37.3, 33.4, 33.0,
32.8, 31.6, 29.6, 29.5, 29.2, 29.1, 27.3, 26.9, 26.7, 26.4, 25.8, 25.6,
(S)-3-((13S)-8,13-Dihydroxy-14-(2-((S)-2-hydroxy-5-(6-meth-
oxynaphthalen-2-yl)pentyloxy)ethoxy)tetradecyl)-5-methylfuran-
2(5H)-one (8). The procedure was the same as described above

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 533
for the synthesis of 2. Compound 8 was obtained as a white wax
solid (36.4 mg, 62% for twosteps). [R]25D: 4.2 (c 0.33, CHCl3). 1H
NMR (400 MHz, CDCl3): δ 7.67-7.64 (m, 2H), 7.53 (s, 1H),
7.28 (dd, J = 8.4, 1.6 Hz, 1H), 7.12-7.10 (m, 2H), 6.97 (d, J =
1.4 Hz, 1H), 4.98 (dq, J = 6.8, 1.3 Hz, 1H), 3.90 (s, 3H), 3.80 (m,
2H), 3.68-3.59 (m, 5H), 3.57 (br, 1H, OH), 3.52 (d, J = 2.7 Hz,
1H), 3.50 (d, J = 2.7 Hz, 1H), 3.31 (dt, J = 9 Hz, 2H), 2.95 (br,
2H, OH), 2.76 (t, J = 7.6 Hz, 2H), 2.25 (dt, J = 7.3, 7.2 Hz, 2H),
1.78-1.25 (m, 24H), 1.39 (d, J = 6.8 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3): δ 173.6, 157.2, 148.7, 137.4, 134.4, 133.0,
129.2, 128.8, 127.8, 126.7, 126.2, 118.5, 105.9, 77.2, 75.8, 71.8,
71.7, 70.6, 70.2, 55.3, 37.5, 37.3, 35.8, 33.0, 32.6, 29.5, 29.2, 29.0,
27.4, 27.2, 25.6, 25.5, 25.1, 19.1 ppm. MS (EI, m/z): 629 [M þ 1]þ,
651 [M þ 23]þ. HRMS (ESI): C37H56O8 calculated [M þ H] þ
651.3867, found 651.3865.
Biological Assays. Cell Culture Conditions. Human cancer
cells (SGC7901, A549, MCF7) and human normal cells (HLF
and Beas-2B) were cultured in Dulbecco’s modified Eagle’s
medium (DMEM), supplemented with penicillin-streptomy-
cin, L-glutamine, and 10% FBS. Human cancer cells (HCT-116
and HT-29) were cultured in F12/DMEM, supplemented
with penicillin-streptomycin, L-glutamine, and 10% FBS. All
cell lines were maintained in a humidified atmosphere of 5% CO2
at 37 ꢀC.
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Acknowledgment. We thank the National Major Scientific
and Technological Program for Drug Discovery (Grants
2009ZX09103-101, 2009ZX09501), NSFC (Grants 20802078,
20972160, 20921091), MOST (Grants 2009CB940900,
2010CB529201, 2010CB833200), Chinese Academy of Sciences
(Grant KSCX2-YW-R-215), the Guangdong Natural Science
Foundation (Grant 8151066302000008), and the NN-CAS
Research Foundation (Grant NNCAS-2008-8) for financial
support.
Supporting Information Available: Experimental procedures
for synthesis of compound 11, RP-HPLC data for compounds
2-8, and NMR spectra for all listed compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
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