Total synthesis of 14,21-diepi-squamocin-K

Article abstract of DOI:10.1016/j.tet.2013.02.015

A new method to prepare annonaceous acetogenins is described in the synthesis of the 14,21-diepimer (14) of squamocin-K. The synthesis utilized the controlled sequence of ring-closing metathesis (RCM) and cross metathesis (CM) reactions to incorporate the stereocenters and skeleton from (3R,4R)-1,5-hexadiene-3,4-diol and 10-chloro-1-decene. The lactone moiety was attached through nucleophilic substitution and achieved the desymmetrization. Inhibitory activities of 14 against human hormone-refractory prostate cancer cell line (PC-3) were also evaluated.

Full text of DOI:10.1016/j.tet.2013.02.015

Tetrahedron 69 (2013) 2971e2976
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of 14,21-diepi-squamocin-K
Chun-Wei Liu a, Tze-Chiun Yeh a, Chia-Hsiu Chen a, Chia-Chun Yu b, Cheng-Sheng Chen a,
,
b
Duen-Ren Hou a , Jih-Hwa Guh
*
a Department of Chemistry, National Central University, No. 300 Jhong-Da Rd., Jhongli City, Taoyuan, Taiwan
b School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd., Taipei, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method to prepare annonaceous acetogenins is described in the synthesis of the 14,21-diepimer
(14) of squamocin-K. The synthesis utilized the controlled sequence of ring-closing metathesis (RCM) and
cross metathesis (CM) reactions to incorporate the stereocenters and skeleton from (3R,4R)-1,5-
hexadiene-3,4-diol and 10-chloro-1-decene. The lactone moiety was attached through nucleophilic
substitution and achieved the desymmetrization. Inhibitory activities of 14 against human hormone-
refractory prostate cancer cell line (PC-3) were also evaluated.
Received 5 November 2012
Received in revised form 31 January 2013
Accepted 2 February 2013
Available online 8 February 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Annonaceous acetogenin
Ring-closing metathesis
Cross metathesis
Asymmetric synthesis
C2 Symmetry
1. Introduction
acetogenins, and the formal synthesis of asimicin.9 Here, we report
our progress in applying this strategy, which is exemplified in the
Annonaceous acetogenins are a large family of natural products,
widely found in the tropical plant family of Annonaceae.1 These
compounds are potent inhibitors of mitochondrial complex I and
have profound biological effects, such as cytotoxic, antitumor, an-
tiparasitic, pesticidal, antimicrobial, and immunosuppressive ac-
tivities.2 Recent research also showed that they are toxic to cortical
neurons and linked to some neurodegenerative disorders.3
total synthesis of 14,21-diepi-squamocin-K (Fig. 1).
The structure of annonaceous acetogenins is characterized by
the long-chain (C32 or C34) fatty acids ending with an unsaturated
g-lactone and a hydrophilic central core constituted of cyclic ethers
and hydroxyl groups. Based on the structure of their central core,
these acetogenins are classified as mono-tetrahydrofuran (THF),
adjacent bis-THF, and others.2b Most of the known annonaceous
acetogenins belong to the subgroup of the adjacent bis-
tetrahydrofurans, which in general, are also more potent in bi-
ological studies than the other two types.4 The stereochemistry of
the bis-THF core was reported to affect the anticancer activity of
these compounds.4h Thus, many synthetic efforts for preparing or
mimicking such acetogenins have been developed.5e7
Fig. 1. Representative annonaceous acetogenins.
2. Results and discussion
The retrosynthetic analysis is shown in Scheme 1. We planned to
assemble the molecular skeleton by controlled ring-closing me-
tathesis (RCM) and cross metathesis (CM),10 which extended the C2
symmetry of diene-diol 1. Desymmetrization and the incorporation
of the lactone moiety were to be achieved by an SN2 reaction.
Diene-diol 1 was converted to bis-methoxymethyl ether 2, which
wastreatedwithborontrichloridefollowedbydiisopropylethylamine
(DIPEA) and two additional units of 1 to give diol 3 (Scheme 2). The
remaining hydroxyl groups of 3 were protected by benzyl (Bn) or
Recently, we reported that the C2 symmetrical (3R,4R)-1,5-
hexadiene-3,4-diol (1)8 could be the sole source for the key skel-
eton and stereocenters of the adjacent bis-THF core of annonaceous
* Corresponding author. E-mail addresses: drhou@ncu.edu.tw, lab123@gmail.com
(D.-R. Hou).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.015

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C.-W. Liu et al. / Tetrahedron 69 (2013) 2971e2976
Table 1
Reaction conditions for the metathesis reactions of 3e5
Entry
Reactant
Product
Solvent
Temp (ꢀC)
Time (h)
Yield (%)
1a
2a
3a
4b
5b
6b
7b
8b
3
5c
5a
5b
6b
6c
6a
6a
6a
Toluene
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
70
75
70
40
40
40
70
84
3
3
3
16
16
16
16
16
0
67
70
87
56
0
4a
4b
5b
5c
5a
5a
5a
Toluene
(CH2Cl)2
43
70
a
Ring-closing metathesis.
Cross metathesis with 10-chloro-1-decene (10 equiv).
b
Scheme 1. Retrosynthetic analysis of 14,21-diepi-squamocin-K.
8 generated bis-THF derivative 9 with the stereochemistry erythro/
cis/threo/cis/erythro. This was converted to the more reactive diio-
dide 10 for the subsequent nucleophilic substitution reaction. Al-
though the reaction using lactone 11 as the nucleophile has been
widely applied in related syntheses,6 we found that nucleophilic
substitution involving 10 and 11 was challenging as previously
reported by Brown’s and Tanaka’s groups.6j,15 After screening many
reaction conditions, we found that the use of N,N-dimethylforma-
mide (DMF) as the solvent and potassium hydride as the base
yielded the mono-alkylation product 12 in a satisfactory yield
(51%).16 The remaining iodo group in 12 was reduced to give 13, and
the unsaturated lactone 14 was produced after the oxidation of
phenyl sulfide and elimination of the corresponding sulfoxide. The
14,21-diepi-squamocin-K (14) was produced after removal of the
benzyl groups by reaction with 2,3-dichloro-5,6-dicyano-p-
Scheme 2. Synthesis of 14,21-diepi-squamocin-K.
methoxymethyl (MOM) groups (4a and 4b, respectively). Although
the attempted RCM reaction of 3 with the second generation Grubbs
catalyst gave the complicated mixture due to the competitive path-
ways between RCM and CM (Table 1, entry 1),11 the RCM reactions of
the protected 4a and 4b were successful to provide bis-4,7-dihydro-
1,3-dioxepines 5a and 5b (Table 1, entries 2 and 3). Hydrolysis of 5b
afforded5c. BothMOM-protected5band diol 5csmoothlyunderwent
intermolecular CM reactions with excess 10-chloro-1-decene to give
6b and 6c, respectively (entries 4, 5). In contrast, the CM reaction of
Bn-protected 5a was sluggish (entries 6 and 7). Fortunately, a satis-
factory yield (70%) for the CM process of 5a to 6a was obtained in
refluxing 1,2-dichloroethane (entry 8). The observed reactivity dif-
ferences between 5aec in CM are explained by the differing affinities
of the allylic substituents for the ruthenium catalyst
(OHzOMOM>OBn).12 The development of practical RCM and CM
conditions for the benzyl-protected substrates 4a and 5a was useful
because the OBn group was stable to the strongly acidic conditions
needed for the later hydrolysis of the methylene acetals (vide infra).13
Consequently, compound 6a was adopted for the synthesis of 14.
Tetraene 6a was hydrogenated to 714 and subsequent removal of
the methylene acetal and formation of the acetonide gave diol 8, in
which the hydroxyl groups along the C2 symmetrical axis are dif-
ferentiated (Scheme 3). Mesylation, deprotection, and cyclization of
Scheme 3. Synthesis of 14,21-diepi-squamocin-K (continued).

C.-W. Liu et al. / Tetrahedron 69 (2013) 2971e2976
2973
benzoquinone (DDQ).17 Preliminary assay of 14 against the cell
proliferation of human hormone-refractory prostate cancer cell line
(PC-3) showed moderate activity (IC50 19.9 mM).
(30 mLꢁ3). The combined organic layers were washed with satd
NaCl(aq) (30 mL), dried (Na2SO4), filtered, and concentrated. The
crude product was purified by column chromatography (SiO2,
EtOAc/hexanes, 1:3; Rf 0.39) to give 3 (2.02 g, 5.5 mmol, 66%; two
3. Conclusion
steps) as a colorless oil. [
a
]
20 ꢂ200.1 (c 1.76, CHCl3); 1H NMR (CDCl3,
D
300 MHz)
d
3.32 (d, J¼3.6 Hz, 2H), 4.05e4.07 (m, 4H), 4.21e4.23 (m,
In summary, we have developed a total synthesis to prepare
annonaceous acetogenins having an adjacent bis-THF core. Our
approach uses the C2 diene-diol 1 as the only source of stereo-
centers, which circumvents formation of the chiral centers by
stereoselective oxidations of olefins as is often seen in other syn-
theses of such acetogenins.6 The sequence of the controlled RCM
and CM on compounds 4 and 5 built the molecular skeleton and
2H), 4.65e4.72 (m, 4H), 5.15e5.38 (m, 12H), 5.63e5.81 (m, 6H); 13C
NMR (CDCl3, 75 MHz) d 74.7, 79.1, 82.1, 89.4, 116.7,119.7,119.9,133.8,
134.3, 136.6; HRMS (ESI) calcd for [MþNa]þ (C20H30O6Na) 389.1940,
found 389.1936; IR (neat) 3475, 3081, 2983, 2896, 1743, 1645, 1425,
1024, 927, 702 cmꢂ1
.
4.1.3. (3R,4R,8R,9R,13R,14R)-1,16-Diphenyl-3,4,8,9,13,14-hexavinyl-
2,5,7,10,12,15-hexaoxahexadecane (4a). Compound (443 mg,
negated the use of protecting groups on the terminal olefins.9
A
3
new reaction condition was developed for the nucleophilic sub-
stitution of 11 to diiodide 10. The desymmetrization by SN2 reaction
avoided the low efficiency in applying CM for this purpose.6m,18 For
further applications, the diol 8 could be used to prepare other di-
astereomers because its hydroxyls groups are differentiated, and
the remaining iodo group after the reaction of 10 and 11 could allow
further conjugation.
1.21 mmol) in N,N-dimethylformamide (DMF, 2.5 mL) was added
to a slurry of sodium hydride (290 mg, 7.24 mmol) in DMF (4 mL)
at 0 ꢀC, and the mixture was stirred for 1 h at 0 ꢀC. Benzyl bromide
(1.24 g, 7.24 mmol) was added, and this mixture was stirred for
another 2 h. It was then concentrated, quenched with satd
NH4Cl(aq) (10 mL), and extracted with ethyl acetate (10 mLꢁ3). The
combined organic layers were washed with water (5 mLꢁ3), satd
NaCl(aq) (10 mL), dried (Na2SO4), filtered, and concentrated. The
crude product was purified by column chromatography (SiO2,
EtOAc/hexanes, 1:5; Rf 0.34) to give 4a (376.1 mg, 0.69 mmol, 60%)
4. Experimental section
4.1. General method
as a colorless oil. 1H NMR (CDCl3, 300 MHz)
d 3.82e3.86 (m, 2H),
4.16e4.24 (m, 4H), 4.40 (d, J¼12.0 Hz, 2H), 4.62 (d, J¼12.0 Hz, 2H),
All purchased chemicals were used without further purification.
Anhydrous solvents were distilled prior to use: THF and diethyl
ether from sodium benzophenone ketyl; CH2Cl2 and DMF from
calcium hydride. 1H and 13C NMR spectra were obtained on 300 or
500 MHz spectrometers and referenced to TMS or residual CHCl3.
Column chromatography was conducted using silica gel
(230e400 mesh). TOF analyzer type was used for the HRMS (ESI)
measurement. Double focusing mass spectrometer was used for the
HRMS (EI) and HRMS (FAB) measurement.
4.69 (m, 4H), 5.17e5.31 (m, 12H), 5.75e5.88 (m, 6H), 7.24e7.30 (m,
10H); 13C NMR (CDCl3, 75 MHz)
d 70.5, 78.1, 78.3, 82.0, 88.9, 118.7,
119.3, 127.4, 127.6, 128.2, 134.2, 134.6, 135.1, 138.5; HRMS (ESI)
calcd for [MþNa]þ (C34H42O6Na) 569.2879, found 569.2870; IR
(neat) 3079, 3027, 2952, 2892, 1643, 1496, 1454, 1423, 1027, 927,
736 cmꢂ1
.
4.1.4. (5R,6R,10R,11R,15R,16R)-5,6,10,11,15,16-Hexavinyl-2,4,7,9,12,14,
17,19-octaoxaicosane (4b). Chloromethyl methyl ether (MOMCl,
2.35 g, 29.2 mmol) was added to a solution of 3 (1.1 g, 9.7 mmol),
diisopropylethylamine (6.3 g, 48.6 mmol), and dichloromethane
(25 mL) at 0 ꢀC. The reaction mixture was refluxed for 16 h,
quenched with satd NH4Cl(aq) (30 mL), and extracted with ether
(50 mLꢁ3). The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated. The crude product was purified by column
chromatography (SiO2, EtOAc/hexanes, 1:5; Rf 0.55) to give 4b
(4.33 g, 9.53 mmol, 98%) as a colorless oil. 1H NMR (CDCl3,
4.1.1. (5R,6R)-5,6-Divinyl-2,4,7,9-tetraoxadecane (2). Chloromethyl
methyl ether (MOMCl, 2.35 g, 29.2 mmol) was added to a solution
of 1 (1.1 g, 9.7 mmol), diisopropylethylamine (6.3 g, 48.6 mmol),
and dichloromethane (25 mL) at 0 ꢀC. The reaction mixture was
refluxed for 16 h, quenched with satd NH4Cl(aq) (30 mL), and
extracted with ether (50 mLꢁ3). The combined organic layers were
dried (Na2SO4), filtered, and concentrated. The crude product was
purified by column chromatography (SiO2, EtOAc/hexanes, 1:5; Rf
300 MHz)
d
3.32 (d, J¼3.6 Hz, 2H), 4.05e4.07 (m, 4H), 4.21e4.23 (m,
20
0.55) to give 2 (1.93 g, 9.53 mmol, 98%) as a light yellow oil. [a]
2H), 4.65e4.72 (m, 4H), 5.15e5.38 (m, 12H), 5.63e5.81 (m, 6H); 13C
D
ꢂ167.9 (c 2.96, CHCl3) 1H NMR (CDCl3, 300 MHz)
d
3.35 (s, 6H),
NMR (CDCl3, 75 MHz) d 74.7, 79.1, 82.1, 89.4, 116.7,119.7,119.9,133.8,
4.08e4.10 (m, 2H), 4.59 (d, J¼6.8 Hz, 2H), 4.69 (d, J¼6.8 Hz, 2H),
134.3, 136.6; HRMS (ESI) calcd for [MþNa]þ (C24H38O8Na) 477.2464,
5.25e5.32 (m, 4H), 5.74e5.82 (m, 2H); 13C NMR (CDCl3, 75 MHz)
found 477.2462.
d
55.6, 79.1, 94.2, 118.7, 134.8; HRMS (EI) calcd for [M]þ (C10H18O4)
202.1205, found 202.1205; IR (neat) 3081, 2950, 2890, 1745, 1425,
1236, 1150, 1101, 1033, 922 cmꢂ1
4.1.5. (4R,40R,7R,70R)-7,70-Bis((R)-1-(benzyloxy)allyl)-4,40,7,70-tetra-
hydro-4,40-bi(1,3-dioxepine) (5a). A reaction mixture comprising 4a
(81.7 mg, 0.149 mmol), Grubbs second generation catalyst (12.6 mg,
0.015 mmol), and toluene (7.5 mL) was stirred at 75 ꢀC under an
atmosphere of nitrogen for 3 h and then concentrated. The crude
product was purified by column chromatography (SiO2, EtOAc/
hexanes, 1:5; Rf 0.45) to give 5a (49.0 mg, 0.10 mmol, 67%) as
.
4.1.2. (3R,4R,8R,9R,13R,14R)-4,8,9,13-Tetravinyl-5,7,10,12-tetraoxahe-
xadeca-1,15-diene-3,14-diol (3). Boron trichloride (6.6 mL,
6.7 mmol) was added to a solution of 2 (1.68 g, 8.3 mmol) and
dichloromethane (12 mL) at 0 ꢀC under nitrogen. The reaction
mixture was stirred for 0.5 h at 0 ꢀC, at rt for another 2 h, and then
concentrated to give (3R,4R)-3,4-bis(chloromethoxy)hexa-1,5-
a colorless oil. 1H NMR (CDCl3, 300 MHz)
d 3.85e3.89 (m, 2H), 4.40
(d, J¼12.3 Hz, 4H), 4.49 (s, 2H), 4.66 (d, J¼12.0 Hz, 2H), 4.90e4.94
diene. 1H NMR (CDCl3, 300 MHz)
d 4.25e4.29 (m, 2H), 5.38e5.45
(m, 4H), 5.28e5.36 (m, 4H), 5.75e5.86 (m, 6H), 7.25e7.32 (m, 10H);
(m, 6H), 5.55e5.59 (m, 2H), 5.68e5.77 (m, 2H).
13C NMR (CDCl3, 75 MHz)
d 70.3, 76.8, 80.8, 95.2, 119.6, 127.6, 127.8,
The crude (3R,4R)-3,4-bis(chloromethoxy)hexa-1,5-diene was
diluted with dichloromethane (40 mL), and the solution was added
dropwise to a solution of 1 (2.84 g, 24.9 mmol), diisopropylethyl-
amine (5.36 g, 41.5 mmol), and dichloromethane (100 mL) at 0 ꢀC.
The reaction mixture was heated at reflux for 16 h, quenched with
NaHCO3(aq) (2%, 100 mL), and extracted with dichloromethane
128.3, 131.7, 132.4, 134.7, 138.1; HRMS (ESI) calcd for [MþNa]þ
(C30H34O6Na) 513.2253, found 513.2258; IR (neat) 3031, 2787, 1496,
1454, 1126, 1066, 933, 738 cmꢂ1
.
4.1.6. (4R,40R,7R,70R)-7,70-Bis((R)-1-(methoxymethoxy)allyl)-4,40,7,70-
tetrahydro-4,40-bi(1,3-dioxepine) (5b). The
reaction mixture

2974
C.-W. Liu et al. / Tetrahedron 69 (2013) 2971e2976
comprising 4b (183.2 mg, 0.404 mmol), Grubbs second generation
catalyst (34 mg, 0.04 mmol), and toluene (20 mL) was stirred at
70 ꢀC under an atmosphere of nitrogen for 3 h and then concen-
trated. The crude product was purified by column chromatography
(SiO2, EtOAc/hexanes, 1:3; Rf 0.55) to give 5b (111.4 mg, 0.283 mmol,
132.6, 136.9; HRMS (ESI) calcd for [MþNa]þ (C36H60Cl2O8Na)
713.3563, found 713.3561.
4.1.10. (1R,10R,2E,20E)-1,10-((4R,40R,7R,70R)-4,40,7,70-Tetrahydro-[4,40-
bi(1,3-dioxepine)]-7,70-diyl)bis(11-chloroundec-2-en-1-ol)
(6c). Grubbs second generation catalyst, (32.9 mg, 0.037 mmol) was
added to the solution of 10-chloro-1-decene (641.2 mg, 3.67 mmol)
and dichloromethane (3 mL). The reaction mixture was warmed to
40 ꢀC and stirred for 20 min under an atmosphere of nitrogen.
Compound 5c (120.1 mg, 0.367 mmol) in dichloromethane (3 mL)
was then added dropwise. The reaction mixturewas heated at reflux
for 16 h and concentrated. The crude product was purified by col-
umn chromatography to give 6c (124.0 mg, 0.205 mmol, 56%) as
70%) as a colorless oil. 1H NMR (CDCl3, 300 MHz)
d 3.36 (s, 6H),
4.13e4.17 (m, 4H), 4.42 (s, 2H), 4.52 (s, 2H), 4.57 (d, J¼3.5 Hz, 2H),
4.70 (d, J¼3.3 Hz, 2H), 4.92 (m, 4H), 5.27e5.35 (m, 4H), 5.75e5.85
(m, 6H); 13C NMR (CDCl3, 75 MHz)
d 55.6, 76.6, 76.7, 78.3, 94.0, 95.2,
119.5, 132.0, 132.4, 134.3; HRMS (ESI) calcd for [MþNa]þ
(C20H30O8Na) 421.1838, found 421.1837.
4.1.7. (1R,10R)-1,10-((4R,40R,7R,70R)-4,40,7,70-Tetrahydro-[4,40-bi(1,3-
dioxepine)]-7,70-diyl)bis(prop-2-en-1-ol) (5c). A solution of 5b
(75.8 mg, 0.19 mmol), hydrochloric acid (6 N, 2 mL), THF (4 mL),
and water (4 mL) was stirred at rt for 24 h. The reaction mixture
was concentrated, satd NaHCO3(aq) (5 mL) was added, and the
mixture was extracted with ethyl acetate (5 mLꢁ3). The combined
organic layers were dried (Na2SO4), filtered, and concentrated. The
crude product was purified by column chromatography (SiO2,
EtOAc/hexanes, 1:1; Rf 0.20) to give 5c (64.3 mg, 0.19 mmol, 99%)
a colorless oil. [
a
]
20 þ42.0 (c 0.23, CHCl3); 1H NMR (CDCl3, 300 MHz)
D
d
1.20e1.45 (m, 20H), 1.68e1.80 (m, 4H), 1.90e2.15 (m, 4H),
3.49e3.53 (t, J¼6.6 Hz, 4H), 4.00 (m, 2H), 4.20e4.21 (m, 2H), 4.51 (m,
2H), 4.97e5.00 (m, 4H), 5.43e5.47 (m, 2H), 5.74e5.83 (m, 6H); 13C
NMR (CDCl3, 75 MHz)
d 26.8, 28.7, 28.8, 28.9, 29.2, 32.3, 32.5, 45.1,
74.5, 76.7, 79.1, 95.1, 127.7, 131.5, 132.0, 136.2; HRMS (ESI) calcd for
[MþNa]þ (C32H52Cl2O6Na) 625.3039, found 625.3038.
as a colorless oil. 1H NMR (CDCl3, 300 MHz)
d
2.66 (br, 2H), 4.08 (t,
4.1.11. (4R,40R,7R,70R)-7,70-Bis((R)-1-(benzyloxy)-11-chloroundecyl)-
4,40-bi(1,3-dioxepane) (7). A suspension of 6a (47.2 mg,
0.060 mmol), triethylamine (3.3 mg, 0.03 mmol), and palladium
(10% on activated carbon, 3.4 mg, 0.003 mmol) was stirred at rt for
3 h under a hydrogen atmosphere (1 atm). The suspension was
filtered and concentrated. The crude product was purified by col-
umn chromatography (SiO2, EtOAc/hexanes, 1:5; Rf 0.45) to give 7
J¼6.5 Hz, 2H), 4.24e4.27 (m, 2H), 4.51 (t, J¼1.5 Hz, 2H), 4.96 (s,
4H), 5.27e5.43 (m, 4H), 5.77 (s, 4H), 5.80e5.92 (m, 2H); 13C NMR
(CDCl3, 75 MHz)
d 74.5, 76.7, 78.5, 95.0, 118.5, 131.4, 132.2, 136.1;
HRMS (ESI) calcd for [MþNaþ] (C16H22O6Na) 333.1314, found
333.1321.
4.1.8. (4R,40R,7R,70R)-7,70-Bis((R,E)-1-(benzyloxy)-11-chloroundec-2-
(39.5 mg, 0.05 mmol, 83%) as a light yellow oil. [
a
]
20 þ28.7 (c 0.87,
D
en-1-yl)-4,40,7,70-tetrahydro-4,40-bi(1,3-dioxepine)
(6a). Grubbs
CHCl3); 1H NMR (CDCl3, 300 MHz)
d
1.23e1.39 (m, 32H), 1.70e1.76
second generation catalyst, (8.5 mg, 0.01 mmol) was added to
a solution of 10-chloro-1-decene (174.7 mg, 1.0 mmol) and 1,2-
dichloroethane (1 mL). The reaction mixture was warmed to
40 ꢀC and stirred for 20 min under an atmosphere of nitrogen.
Compound 5a (49.1 mg, 0.1 mmol) in 1,2-dichloroethane (2 mL)
was then added dropwise. The reaction mixture was heated to
reflux for 16 h and concentrated. The crude product was purified by
(m, 12H), 3.31e3.35 (m, 2H), 3.51 (t, J¼13.5 Hz, 4H), 3.64e3.65 (m,
2H), 3.78e3.81 (m, 2H), 4.55 (s, 4H), 4.79e4.84 (m, 4H), 7.26e7.31
(m, 10H); 13C NMR (CDCl3, 75 MHz)
d 25.9, 26.8, 28.8, 29.4, 29.5,
29.7, 30.0, 32.3, 32.6, 45.1, 72.5, 76.6, 78.7, 81.4, 93.3, 127.5, 127.7,
127.9, 128.2, 138.7; HRMS (ESI) calcd for [MþNa]þ (C46H72Cl2O6Na)
813.4604, found 813.4601; IR (neat) 3029, 2925, 2856, 1455, 1361,
1120, 1055, 734 cmꢂ1
.
column chromatography (SiO2, EtOAc/hexanes, 1:5; Rf 0.45) to give
20
6a (54.9 mg, 0.07 mmol, 70%) as a light yellow oil. [
a
]
þ67.4 (c
4.1.12. (3R,30R,4R,40R)-1,10-((4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-
diyl)bis(4-(benzyloxy)-14-chlorotetradecan-3-ol) (8). A solution of 7
(544.9 mg, 0.688 mmol), methanol (25 mL), and concd hydrochloric
acid (3.2 mL) was heated at reflux for 5 h. The reaction mixture was
concentrated, satd NaHCO3(aq) (20 mL) was added, and the mixture
was extracted with ethyl acetate (10 mLꢁ3). The combined organic
layers were dried (Na2SO4), filtered, and concentrated. The crude
product was purified by column chromatography (SiO2, EtOAc/hex-
D
0.63, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
1.28e1.40 (m, 20H),
1.70e1.76 (m, 4H), 2.02e2.09 (m, 4H), 3.51 (t, J¼6.6 Hz, 4H),
3.77e3.81 (m, 2H), 4.37e4.41 (m, 4H), 4.51 (m, 2H), 4.63 (d,
J¼12.3 Hz, 2H), 4.90e4.94 (m, 4H), 5.40e5.48 (m, 2H), 5.65e5.80
(m, 6H) 7.26e7.31 (m, 10H); 13C NMR (CDCl3, 75 MHz)
d 27.0, 28.8,
29.0, 29.1, 29.2, 32.5, 32.8, 45.3, 70.1, 76.8, 78.1, 80.1, 95.3, 126.6,
127.6, 128.0, 128.4, 131.7, 132.8, 137.0, 138.7; HRMS (ESI) calcd for
[MþNaþ] (C46H64 O6Cl2Na) 805.3978, found 805.3981; IR (neat)
anes, 1:1; Rf 0.39) to give the tetraol (375.1 mg, 0.488 mmol, 71%) as
20
3031, 2927, 2856, 1455, 1124, 1086, 735 cmꢂ1
.
a light yellow gel. [
a
]
D
þ1.1 (c 0.64, CHCl3); 1H NMR (CDCl3,
300 MHz)
d
1.25e1.37 (m, 28H),1.46e1.76 (m, 8H),1.69e1.76 (m, 8H),
4.1.9. (4R,40R,7R,70R)-7,70-Bis((R,E)-11-chloro-1-(methoxymethoxy)
undec-2-en-1-yl)-4,40,7,70-tetrahydro-4,40-bi(1,3-dioxepine)
(6b). Grubbs second generation catalyst (17.6 mg, 0.02 mmol) was
added to the solution of 10-chloro-1-decene (364 mg, 2.08 mmol)
and dichloromethane (2 mL). The reaction mixture was warmed to
40 ꢀC and stirred for 20 min under an atmosphere of nitrogen.
Compound 5b (64.6 mg, 0.208 mmol) in dichloromethane (2 mL)
was then added dropwise. The reaction mixture was heated at
reflux for 16 h and concentrated. The crude product was purified by
3.24e3.28 (m, 2H), 3.38 (m, 2H), 3.49 (t, J¼16.8 Hz, 4H), 3.53e3.58
(m, 2H), 4.45e4.49 (m, 2H), 4.60e4.67 (m, 2H), 7.31 (m, 10H); 13C
NMR (CDCl3, 75 MHz)
d 20.9, 21.3, 25.3, 25.8, 27.1, 29.0, 29.6, 30.1,
30.4, 32.8, 45.3, 72.7, 73.1, 74.9, 82.7, 128.1, 128.5, 128.7, 138.5; HRMS
(FAB) calcd for [MþNa]þ (C44H73O6Cl2) 767.4783, found 767.4787.
p-Toluenesulfonic acid monohydrate (8.1 mg, 0.043 mmol) was
added to
a solution of the intermediate tetraol (667.1 mg,
0.85 mmol), 2,2-dimethoxypropane (266.3 mg, 2.56 mmol), and
dichloromethane (5.1 mL). After being stirred at rt for 16 h, the
reaction mixture was diluted with dichloromethane (10 mL),
washed with NaOH(aq) (1 N, 5 mLꢁ3), dried (Na2SO4), filtered, and
concentrated. The crude product was purified by column chroma-
column chromatography (SiO2, EtOAc/hexanes, 1:3; Rf 0.32) to give
20
6b (124.5 mg, 0.18 mmol, 87%) as a light yellow oil. [
a
]
D
þ58.7 (c
0.73, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
1.20e1.45 (m, 20H),
1.61e1.89 (m, 4H), 1.95e2.10 (m, 4H), 3.49 (t, J¼6.8 Hz, 4H),
4.01e4.13 (m, 2H), 4.30e4.40 (m, 2H), 4.47e4.55 (m, 4H), 4.68e4.70
(d, J¼6.9 Hz, 2H), 4.92 (dd, J¼8.7 Hz, J¼4.5 Hz, 4H), 5.28e5.47 (m,
tography (SiO2, EtOAc/hexanes, 1:3; Rf 0.36) to give 8 (626.5 mg,
20
0.775 mmol, 91%) as a light yellow oil. [
a
]
þ14.2 (c 0.72, CHCl3);
D
1H NMR (CDCl3, 300 MHz)
d
1.26e1.38 (m, 34H), 1.61e1.63 (m, 8H),
2H), 5.62e5.89 (m, 6H); 13C NMR (CDCl3, 75 MHz)
d
26.8, 28.6, 28.8,
1.96 (m, 8H), 3.24e3.31 (m, 2H), 3.51 (t, J¼16.5 Hz, 4H), 3.58e3.60
28.9, 29.2, 32.2, 32.6, 45.0, 55.4, 76.7, 78.0, 93.5, 95.2, 125.9, 131.7,
(m, 4H), 4.46e4.50 (m, 2H), 4.60e4.66 (m, 2H), 7.26e7.36 (m, 10H);

C.-W. Liu et al. / Tetrahedron 69 (2013) 2971e2976
2975
13C NMR (CDCl3, 75 MHz)
d
22.8, 25.4, 27.0, 27.5, 29.0, 29.6, 29.7,
rt, quenched with satd NH4Cl(aq) (1 mL) and water (2 mL), and
extracted with ether (10 mL). The organic layer was washed with
water (2 mL), dried (Na2SO4), filtered, and concentrated. The
crude product was purified by column chromatography (SiO2,
EtOAc/hexanes, 1:5; Rf 0.32) to give the iodo-lactone (38.8 mg,
0.039 mmol, 51%) as a light yellow oil. 1H NMR (CDCl3, 300 MHz)
30.1, 30.2, 32.8, 45.3, 72.5, 80.9, 82.5, 83.5, 108.2, 127.9, 128.0, 128.6,
138.6; HRMS (FAB) calcd for [MþNa]þ (C47H76Cl2O6Na) 829.4917,
found 829.4908; IR (neat) 3467, 3029, 2927, 2856, 1720, 1496, 1259,
1070, 736 cmꢂ1
.
4.1.13. (2R,20R,5S,50S)-5,50-Bis((R)-1-(benzyloxy)-11-chloroundecyl)
octahydro-2,20-bifuran (9). Methanesulfonyl chloride (67.3 mg,
0.588 mmol) was added to the solution of 8 (158.4 mg, 0.196 mmol),
triethylamine (118.7 mg, 1.175 mmol), and dichloromethane
(0.5 mL) at 0 ꢀC. The reaction mixture was stirred at rt for 5 h,
quenched with satd NaHCO3(aq) (1 mL), and extracted with
dichloromethane (2 mLꢁ3). The combined organic layers were
dried (Na2SO4), filtered, and concentrated. The residue was purified
by column chromatography (SiO2, EtOAc/hexanes, 1:3; Rf0.49) to
d 1.15e1.43 (m, 31H), 1.49e1.59 (m, 8H), 1.69e1.81 (m, 6H),
1.82e1.97 (m, 3H), 2.35e2.53 (m, 1H), 3.16 (t, J¼14.1 Hz, 2H),
3.60e3.61 (m, 2H), 3.75 (m, 2H), 3.92e3.96 (m, 2H), 4.43e4.70
(m, 3H), 4.74 (d, J¼9.3 Hz, 2H), 7.30e7.32 (m, 13H), 7.49e7.55 (m,
2H).
A suspension of the iodo-lactone (38.8 mg, 0.039 mmol), trie-
thylamine (7.9 mg, 0.078 mmol), and palladium (10% on activated
carbon, 8.3 mg, 0.008 mmol) was stirred at 40 ꢀC for 2 h under
a hydrogen atmosphere (1 atm). The suspension was filtered and
concentrated to give 12 (29.8 mg, 0.034 mmol, 88%) as a light
give the dimesylate (175.8 mg, 0.182 mmol, 93%) as a colorless oil.
20
[
a]
þ16.0 (c 1.81, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
1.25e1.38
yellow oil. 1H NMR (CDCl3, 300 MHz)
d 0.80e0.90 (m, 3H),
D
(m, 34H), 1.55e1.66 (m, 8H), 1.72e1.84 (m, 8H), 2.9 (s, 6H), 3.51 (t,
J¼11.7 Hz, 4H), 3.58 (m, 4H), 4.55e4.59 (m, 4H), 4.72 (m, 2H),
1.15e1.43 (m, 33H), 1.43e1.54 (m, 8H), 1.72e1.81 (m, 4H), 1.84e1.97
(m, 3H), 2.26e2.52 (m, 1H), 3.59e3.61 (m, 2H), 3.75e3.77 (m, 2H),
3.91e3.96 (m, 2H), 4.45e4.58 (m, 3H), 4.72 (d, J¼11.7 Hz, 2H),
7.30e7.32 (m, 13H), 7.52e7.54 (m, 2H); 13C NMR (CDCl3, 75 MHz)
7.27e7.33 (m, 10H); 13C NMR (CDCl3, 75 MHz)
d 14.1, 22.7, 24.9, 25.4,
26.9, 27.3, 28.9, 29.5, 29.7, 31.5, 31.6, 32.7, 38.5, 45.2, 60.4, 72.5, 79.4,
79.9, 108.3, 127.5, 128.0, 128.5, 138.0.
d
23.7, 24.3, 24.6, 25.6, 25.9, 27.3, 27.9, 28.2, 28.6, 29.5, 32.6, 34.6,
A solution of the above dimesylate (140.1 mg, 0.145 mmol), p-
toluenesulfonic acid monohydrate (47.5 mg, 0.250 mmol), methanol
(14.4 mL), and water (1.6 mL) was stirred at 60 ꢀC for 5 h. The re-
action mixture was concentrated, satd NaHCO3(aq) (15 mL) was
added, and the mixture was extracted with ethyl acetate (15 mLꢁ3).
The combined organic layers were dried (Na2SO4), filtered, and
concentrated. The residue was redissolved in DMF (1 mL), and the
solution was transferred into a flask containing a suspension of
sodium hydride (14 mg, 0.58 mmol) and DMF (3 mL) at 0 ꢀC. The
mixture was stirred at rt for 16 h, quenched with satd NH4Cl(aq)
(5 mL), diluted with water (10 mL), and extracted with ether
(50 mL). The organic layer was washed with water (10 mL), dried
(Na2SO4), filtered, and concentrated. The crude product was purified
by column chromatography (SiO2, EtOAc/hexanes, 1:3; Rf 0.48) to
36.4, 40.1, 42.4, 56.0, 56.2, 73.2, 73.6, 80.3, 80.8, 82.3, 127.2, 127.6,
128.2, 128.3, 129.0, 129.7, 129.9, 130.4, 136.8, 137.1, 177.1;
HRMS (ESI) calcd for [MþNa]þ (C55H80O6SNa) 891.5573, found
891.5565.
4.1.15. (S)-3-((R)-11-(Benzyloxy)-11-((2R,20R,5S,50S)-50-((R)-1-(ben-
zyloxy)undecyl)octahydro-[2,20-bifuran]-5-yl)undecyl)-5-
methylfuran-2(5H)-one (13). 3-Chloroperoxybenzoic acid (mCPBA,
0.7 mg, 0.0041 mmol) was added to a solution of 12 (3.4 mg,
0.0039 mmol) and dichloromethane (1 mL) at 0 ꢀC. After being
stirred for 20 min at 0 ꢀC, satd sodium thiosulfate(aq) (0.5 mL) and
satd NaHCO3(aq) (0.5 mL) were added, and the mixture was
extracted with ethyl acetate (1 mLꢁ3). The combined organic layers
were dried (Na2SO4), filtered, and concentrated. The residue was
redissolved in toluene (1 mL), and the solution was heated in at
100 ꢀC for 3 h and then concentrated. The crude product was pu-
rified by column chromatography (SiO2, EtOAc/hexanes, 1:5; Rf
0.41) to give 13 (2.1 mg, 0.0028 mmol, 71%) as a light yellow oil.
give 9 (66.9 mg, 0.091 mmol, 63%) as a light yellow oil. [
a
]
20 þ3.9 (c
D
1.02, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
1.23 (m, 28H), 1.39e1.42
(m, 8H), 1.72e1.94 (m, 8H), 3.51 (t, J¼12.3 Hz, 4H), 3.61 (m, 2H), 3.76
(m, 2H), 3.93e3.95 (m, 2H), 4.57 (d, J¼11.4 Hz, 2H), 4.75 (d,
J¼11.4 Hz, 2H), 7.25e7.32 (m, 10H); 13C NMR (CDCl3, 75 MHz)
d
14.1,
[
a
]
20 þ3.28 (c 0.83, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 0.80e0.90
D
22.7, 24.8, 25.7, 26.9, 28.2, 28.9, 29.5, 31.6, 32.2, 32.7, 45.2, 73.4, 80.3,
82.3, 82.6, 127.3, 127.7, 128.2, 139.4; HRMS (ESI) calcd for [MþNa]þ
(C44H68Cl2O4Na) 753.4392, found 753.4394; IR (neat) 3029, 2925,
(m, 3H), 1.23e1.44 (m, 33H), 1.50 (m, 8H), 1.74e1.98 (m, 6H), 2.24 (t,
J¼7.4 Hz, 2H), 3.62 (m, 2H), 3.75 (m, 2H), 3.90e3.96 (m, 2H), 4.56 (d,
J¼11.55 Hz, 2H), 4.74 (d, J¼11.6 Hz, 2H), 4.96e4.98 (m, 1H), 6.95 (s,
2854, 1733, 1458, 1261, 1068, 734 cmꢂ1
.
1H), 7.25e7.32 (m,10H); 13C NMR (CDCl3,125 MHz)
d 14.1,15.3,19.2,
22.7, 25.2, 25.6, 26.9, 27.4, 28.2, 29.2, 29.3, 29.5, 29.6, 29.7, 31.9, 32.2,
73.3, 77.4, 80.3, 82.3, 82.6, 127.3, 127.6, 127.7, 128.0, 128.2, 129.2,
134.3, 139.4, 148.8, 173.9; HRMS (ESI) calcd for [MþNa]þ
(C49H74O6Na) 781.5383, found 781.5378.
4.1.14. (2R,20R,5S,50S)-5,50-Bis((R)-1-(benzyloxy)-11-iodoundecyl)oc-
tahydro-2,20-bifuran (10). A solution of 9 (497.7 mg, 0.68 mmol),
sodium iodide (2.04 g, 13.63 mmol), and acetone (23 mL) was
heated at reflux for 16 h. The reaction mixture was concentrated,
water (10 mL) and ether (10 mL) were added, and the mixture was
extracted with ethyl acetate (10 mLꢁ3). The combined organic
layers were dried (Na2SO4), filtered, and concentrated. The crude
product was purified by column chromatography (SiO2, EtOAc/
4.1.16. 14,21-Diepi-squamocin-K (14). 2,3-Dichloro-5,6-dicyanobe-
nzoquinone (DDQ, 5.0 mg, 0.022 mmol) was added to the mix-
ture of 13 (2.1 mg, 0.0028 mmol), 1,2-dichloromethane (0.5 mL),
and buffer solution (pH 7.0, 50 mM, sodium phosphate, 0.02 mL).
The reaction mixture was heated in a 50 ꢀC oil bath for 3 h, satd
NaCl(aq) (0.5 mL) was added, and the mixture was extracted with
ether (1 mLꢁ3). The combined organic layers were dried (Na2SO4),
filtered, and concentrated. The crude product was purified by col-
umn chromatography (SiO2, EtOAc/hexanes, 1:1; Rf 0.60) to give 14
hexanes, 1:3; Rf 0.45) to give 10 (553.6 mg, 0.61 mmol, 89%) as
20
a light yellow oil. [
300 MHz)
a]
þ2.35 (c 0.74, CHCl3); 1H NMR (CDCl3,
D
d
1.24 (m, 32H), 1.50e1.54 (m, 4H), 1.78e1.81 (m, 8H),
3.16 (t, J¼13.8 Hz, 4H), 3.6 (m, 2H), 3.76 (m, 2H), 3.94e3.95 (m, 2H),
4.57 (d, J¼11.4 Hz, 2H), 4.74 (d, J¼11.4 Hz, 2H), 7.26e7.34 (m, 10H);
13C NMR (CDCl3, 75 MHz)
d
7.34, 14.1, 22.7, 25.7, 28.2, 28.5, 29.4,
(1.3 mg, 0.0022 mmol, 80%) as a light yellow oil. [
a
]
20 ꢂ4.4 (c 0.34,
D
29.5, 29.7, 30.5, 32.1, 33.6, 73.3, 80.4, 82.3, 82.6, 127.3, 127.7, 128.3,
139.4.
Compound 12. A solution of diiodide 10 (70.0 mg, 0.076 mmol)
and lactone 11 (12.7 mg, 0.061 mmol) in DMF (0.5 mL) was added
to a suspension of potassium hydride (4.2 mg, 0.1039 mmol) in
DMF (0.5 mL) at 0 ꢀC. The reaction mixture was stirred for 16 h at
CHCl3); 1H NMR (CDCl3, 500 MHz)
d
0.80e0.90 (m, 3H), 1.23e1.44
(m, 33H), 1.50 (m, 8H), 1.74e1.98 (m, 8H), 2.28 (t, J¼7.8 Hz, 2H),
3.91e3.97 (m, 6H), 4.99e5.05 (m, 1H), 7.00e7.01 (d, J¼1.5 Hz, 1H);
13C NMR (CDCl3, 125 MHz)
d 14.1, 19.2, 22.7, 23.7, 25.1, 26.0, 29.0,
29.1, 29.3, 29.49, 29.53, 29.6, 29.7, 32.7, 72.2, 77.3, 80.8, 83.2, 134.3,
148.8,173.9; HRMS (ESI) calcd for [MþNa]þ (C35H62O6Na) 601.4444,

2976
C.-W. Liu et al. / Tetrahedron 69 (2013) 2971e2976
Depienne, C.; Respondek, G.; Yamada, E. S.; Lannuzel, A.; Yagi, T.; Hirsch, E. C.;
Oertel, W. H.; Jacob, R.; Michel, P. P.; Ruberg, M.; Hoglinger, G. U. J. Neurosci.
2007, 27, 7827e7837 and references cited therein.
found 601.4440; IR (neat) 3440, 2925, 2854, 1755, 1261, 1080,
800 cmꢂ1
The sulforhodamine B assay for measurement of cell pro-
liferation was performed in human hormone-refractory prostate
cancer cell line PC-3.
€
.
4. Recent examples: (a) Wu, T.-Y.; Yang, I.-H.; Tsai, Y.-T.; Wang, J.-Y.; Shiurba, R.;
Hsieh, T.-J.; Chang, F.-R.; Chang, W. C. J. Nat. Prod. 2012, 75, 572e576; (b) Chen, Y.;
Chen, J.-w.; Xu, S.-s.; Wang, Y.; Li, X.; Cai, B.-c.; Fan, N.-b Bioorg. Med. Chem. Lett.
2012, 22, 2717e2719; (c) Dai, Y.; Harinantenaina, L.; Brodie, P. J.; Callmander, M.
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4.2. Sulforhodamine B (SRB) assay
Cells were seeded in 96-well plates in medium with 5% FBS.
After 24 h, cells were fixed with 10% trichloroacetic acid (TCA) to
represent cell population at the time of compound addition (T0).
After additional incubation of DMSO or test compound for 48 h,
cells were fixed with 10% TCA and SRB at 0.4% (w/v) in 1% acetic acid
was added to stain cells. Unbound SRB was washed out by 1% acetic
acid and SRB bound cells were solubilized with 10 mM Trizma base.
The absorbance was read at a wavelength of 515 nm. Using the
following absorbance measurements, such as time zero (T0), con-
trol growth (C), and cell growth in the presence of the compound
(Tx), the percentage growth was calculated at each of the com-
pound concentrations levels. Percentage growth inhibition was
calculated as: [1ꢂ(TxꢂT0)/(CꢂT0)]ꢁ100%. Growth inhibition of
50% (IC50) is determined at the compound concentration, which
results in 50% reduction of total protein increase in control cells
during the compound incubation.
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Acknowledgements
This research was supported by the National Science Council
(NSC 98-2119-M-008-001), Taiwan. The authors thank Prof. John C.
Gilbert, Santa Clara University, for helpful comments. We are
grateful to Ms. Ping-YuLin at the Institute of Chemistry, Academia
Sinica, and Valuable Instrument Center in National Central Uni-
versity for obtaining mass analysis.
Supplementary data
1H and 13C NMR spectra of all new compounds are available.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.02.015. These data include MOL files
and InChIKeys of the most important compounds described in this
article.
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