Stereocontrolled construction of the trans tetrahydrofuran units in Annonaceous acetogenins

Article abstract of DOI:10.1016/S0957-4166(99)00259-1

An efficient synthetic method for the construction of trans- tetrahydrofuran (THF) unit from trans-1,5,9-decatriene was successfully developed by means of Sharpless AD reactions and oxidative cyclizations catalyzed by Co(modp)₂ under an oxygen

Full text of DOI:10.1016/S0957-4166(99)00259-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2551–2562
Stereocontrolled construction of the trans-tetrahydrofuran units in
Annonaceous acetogenins
Shi-Kai Tian, Zhi-Min Wang,∗ Jian-Kang Jiang and Min Shi ∗
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received 6 May 1999; accepted 17 June 1999
Abstract
An efficient synthetic method for the construction of trans-tetrahydrofuran (THF) unit from trans-1,5,9-
decatriene was successfully developed by means of Sharpless AD reactions and oxidative cyclizations catalyzed by
Co(modp)2 under an oxygen atmosphere. Based on this new synthetic strategy, the trans-mono-THF unit, trans-bis-
THF unit and trans-tris-THF unit in Annonaceous acetogenins were smoothly obtained. © 1999 Elsevier Science
Ltd. All rights reserved.
1. Introduction
The Annonaceous acetogenins, polyketide-derived fatty acids isolated from the Annonaceae family
of tropical and subtropical trees, are a growing class of fascinating natural compounds which show
interesting cytotoxic, antitumor, antimicrobial, antimalarial, antifeedant, pesticidal and immunosuppres-
sive effects.1 They are characterized by the presence of one to three THF rings in the center of a long
hydrocarbon chain with a butenolide moiety at the end. Both due to their potent biological activities and
their unique and diverse structures, Annonaceous acetogenins are attractive targets for synthetic chemists.
For example, gigantetrocin A was isolated by McLaughlin’s group from Goniothalamus giganteus Hook.
f. and Thomas (Annonaceae)2 and significantly and selectively was demonstrated to be cytotoxic to
human tumor cells in culture.2,3 Its absolute configuration has been determined by spectroscopic analysis.
The striking characteristics are the existence of four hydroxyl groups, an α,β-unsaturated γ-lactone
and a mono trans-tetrahydrofuran (THF) ring unit (Fig. 1). Asimilobin, a relatively rare bulladecin type
acetogenin,1 was isolated by McLaughlin’s group both from the seeds of Asimina triloba4 and the bark of
Goniothalamus giganteus (Annonaceae),5 and showed cytotoxicity values comparable with adriamycin
∗
Corresponding authors. E-mail: mshi@pub.sioc.ac.cn
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00259-1

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S.-K. Tian et al. / Tetrahedron: Asymmetry 10 (1999) 2551–2562
Figure 1.
against six human solid tumor cell lines. Its absolute configuration had been first determined by spec-
troscopic analysis and was then corrected by the first total synthesis of this natural product (Fig. 1).6
The remarkable features are the adjacent threo/trans/threo/trans bis-THF ring and one flanking hydroxyl
group at the α-position of the THF core. Goniocin, a novel cytotoxic acetogenin, was isolated from
Goniothalamus giganteus.7 The structure of goniocin has been determined by spectroscopic analysis
which was recently further verified by Sinha et al. in the first total synthesis of this compound.8 It
possesses a tris-THF moiety and represents the first, and so far the only, example of a new subgroup
of this family (Fig. 1).
Since the γ-lactone unit could be very easily synthesized according to the literature,9 obviously
stereocontrolled construction of THF units played a central role in the total syntheses of Annonaceous
acetogenins10 and several recent reports majoring in dealing with this task exhibited more convenient
approaches to mono- and bis-THF units.11–15 Likewise, it is the most challenging research field in
the total synthesis of Annonaceous acetogenins. Herein we wish to report the full details of our
synthetic route to those trans- and threo-THF units utilizing the Sharpless AD reaction and Mukaiyama’s
oxidative cyclization catalyzed by Co(modp)2 [bis(1-morpholinocarbamoyl-4,4-dimethyl-1,3-pentane-
dionato) cobalt(II)] from achiral triene 1.
2. Results and discussion
Regioselective oxidation of trans-1,5,9-decatriene 1 by Sharpless AD reaction16 installed the two
prime stereogenic centers, with greater than 94% ee,17 in the mono-THF ring backbone. The obtained
diol 2 was subsequently mono-protected by MOMCl and then oxidatively cyclized to form a mono trans-
19
THF ring compound 4 with greater than 95% de18 in 74% yield using Co(modp)2 as a catalyst under
an oxygen atmosphere (Scheme 1). This compound was then monoprotected by a benzyl group to give
the benzyl ether 5 which has been successfully used in the first total synthesis of gigantetrocin A.20
Using this new synthetic strategy we can also synthesize the adjacent trans-bis-THF and tris-THF unit
(Scheme 2). The resulting diendiol 6, which is the enantiomer of 2, was oxidized and cyclized under

S.-K. Tian et al. / Tetrahedron: Asymmetry 10 (1999) 2551–2562
2553
Scheme 1. Conditions: (a) K3Fe(CN)6, K2CO3, NaHCO3, MeSO2NH2, (DHQ)2PHAL, K2OsO2(OH)4, t-BuOH: H2O (1:1),
0°C; 57%. (b) NaH, MOMCl, THF; 67%. (c) Co(modp)2, TBHP, O2, i-PrOH; 74%. (d) NaH, BnBr, THF; 98%
the catalysis of Co(modp)2 to form a trans/threo/trans bis-THF ring building block 7 with greater than
95% de. Compound 7 was mono-protected with a benzyl group to afford the benzyl ether 821 which
has been successfully used in the first total synthesis of asimilobin.6 The compound 8 was subjected to
Swern oxidation to give the aldehyde 9 which was subsequently coupled with (3-buten-1-yl)magnesium
bromide22 and followed by another Swern oxidation to afford the ketone 10. The compounds 9 and 10
were directly used for the next reaction without purification or characterization. Compound 10 was then
reduced by L-Selectride23 to give the enol 11 with 90% de.24 By forming a new THF ring via another
step of oxidative cyclization catalyzed by Co(modp)2, compound 11 was smoothly transformed to the
tris-THF unit 12, with high diastereoselectivity (greater than 95% de), which constitutes the central core
of THF unit in goniocin. To the best of our knowledge, this is the most convenient and efficient synthetic
method to construct the adjacent trans-bis-THF ring and tris-THF ring building block in high yield and
high stereoselectivity. In particular, the adjacent trans-bis-THF ring can be readily synthesized in only
two steps (Scheme 2). Moreover, the enantiomers 7–12 could be readily obtained simply by changing
the chiral ligand in the Sharpless AD reaction.16 Thus, based on catalytic asymmetric reaction, this new
synthetic method has a great advantage in the synthesis of THF units in Annonaceous acetogenins.
Scheme 2. Conditions: (a) K3Fe(CN)6, K2CO3, MeSO2NH2, (DHQD)2PHAL, K2OsO2(OH)4, t-BuOH:H2O (1:1), 0°C. (b)
Co(modp)2, TBHP, O2, i-PrOH. (c) NaH, BnBr, THF. (d) Swern oxidation. (e) CH2_CHCH2CH2MgBr, THF, −20°C. (f)
L-Selectride, THF, −78°C

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On the other hand, since the number and stereochemistry of the substituted THF rings strikingly affect
the activity of acetogenins and only one to three THF rings were found in these polyketide-derived fatty
acids, it will be very interesting to observe the bioactivity of the nonnatural acetogenins containing more
than three THF rings. Moreover, non-natural oligo-THFs are suitable for ion binding and 2,5-trans-linked
oligo-THFs represent potential building blocks for a membrane-bound artificial ion channel.25 Thus, we
started to synthesize the tetrakis-trans-THF unit using our synthetic method. Regioselective oxidation of
trans-1,5,9-decatriene 1 by Sharpless AD reaction and cyclization catalyzed by Co(modp)2 under oxygen
atmosphere to form a trans/threo/trans bis-THF ring building block 13, which is the enantiomer of 7,
with more than 95% de (Scheme 3). This C2-symmetric compound was subjected to Swern oxidation
and the resulting dial 14 was coupled with two molar (3-buten-1-yl)magnesium bromide and followed
by another Swern oxidation to afford dione 15. The compounds 14 and 15 were directly used for the next
reaction without purification and characterization. Reduction of compound 15 with L-Selectride gave the
diendiol 16a with diastereoselectivity of 16a:16b=2.6:1.26 By forming two new THF rings via another
oxidative cyclization reaction catalyzed by Co(modp)2, compound 16a was smoothly transformed to a
C2-symmetric tetrakis-THF unit 17a27 which was protected as the benzyl ether to give 18a. Repeating
these procedures on compound 17a will certainly produce some other interesting C2-symmetric building
blocks with more trans-2,5-linked THF rings.
Scheme 3. Conditions: (a) Co(modp)2, TBHP, O2, i-PrOH; 78%. (b) Swern oxidation. (c) (3-Buten-1-yl)magnesium bromide,
THF, de 45%. (d) L-Selectride, THF, −78°C; 40% (four steps). (e) NaH, BnBr, THF; 40% (two steps)
Due to its intrinsic property of C2 symmetry, compound 16a was mono-protected as a TBS ether 19a
(Scheme 4) then catalytically oxidized under an oxygen atmosphere to give a tris-THF compound 20a,
which could be used to construct the THF unit of cyclogoniodenin T (Fig. 2).5
In conclusion, the key building blocks for the total synthesis of gigantetrocin A, asimilobin, goniocin
and cyclogoniodenin T have been successfully synthesized by using Sharpless AD and Co(modp)2
catalyzed cyclization reaction. Especially by expanding a new trans-THF ring from a trans-2,5-linked
bis-THF unit, the construction of the THF unit in goniocin was successfully achieved in eight steps. In
the meantime, expansion of two trans-THF rings from a trans-2,5-linked THF unit both bidirectionally
and simultaneously was achieved by taking advantage of its intrinsic property of C2 symmetry, although
the de was not so high. This new synthetic strategy has great applicable potency in the synthesis of trans-

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2555
Scheme 4. Conditions: (a) TBSCl, imidazole, THF; 75%. (b) Co(modp)2, TBHP, O2, i-PrOH; 76%
Figure 2.
2,5-linked THF units with more than four THF rings toward a polyether helix with ion channel activity,28
and this work is in progress.
3. Experimental
Optical rotations were determined in a solution of CHCl3 and methanol at room temperature by using a
Perkin–Elmer 241 MC digital polarimeter; [α]D values are given in units of 10−1 deg cm2 g−1. 1H NMR
spectra were determined for solutions in CDCl3 with tetramethylsilane (TMS) as internal standard on
a Bruker AMX-300 spectrometer; J values are in hertz. IR spectra were determined by a Perkin–Elmer
983 spectrometer. Mass spectra were recorded with an HP-5989 instrument. High resolution mass spectra
were recorded on a Finnigan MA+ instrument. Microanalyses were carried out using an Italian Carlo-
Erba 1106 analyzer.
3.1. (5S,6S)-1,9-Decadiene-5,6-diol 2
To a well-stirred solution of (DHQ)2PHAL (1.09 g, 1.40 mmol), K2OsO2(OH)4 (309 mg, 0.840 mmol),
K3Fe(CN)6 (139 g, 421 mmol), K2CO3 (58.1 g, 421 mmol) and MeSO2NH2 (13.3 g, 140 mmol) in t-
BuOH:H2O (1:1) (1400 mL) at 0°C was added triene 1 (19.1 g, 140 mmol). After being stirred vigorously
for 12 h, the reaction mixture was quenched with Na2SO3 (140 g) and extracted with EtOAc. The organic
layers were dried over MgSO4 and then concentrated under reduced pressure. The residue was purified
20
by flash chromatography (EtOAc:petroleum ether, 1:10) to give 2 (13.6 g, 57%) as a colorless oil. [α]D
−21.3 (c 3.30, CHCl3); IR (neat) ν 3402, 1639 cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.48–1.68 (4H, m),
2.10–2.39 (4H, m), 2.37 (2H, br, s), 3.42–3.53 (2H, m), 4.98 (2H, dm, J=10.0), 5.04 (2H, dm, J=17.3),
5.83 (2H, ddt, J=17.3, 10.0, 6.6); 13C NMR (CDCl3, 75 MHz) δ 29.87, 32.56, 73.82, 114.91, 138.23;
MS (EI) m/z (%) 171 (MH+, 14.5), 153 (100), 135 (50.0), 85 (14.3); [HRMS found: 170.1309 (M+);
C10H18O2 requires: 170.1307].

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3.2. (5S,6S)-6-Methoxymethoxy-1,9-decadiene-5-ol 3
To a solution of 2 (3.85 g, 22.6 mmol) in 50 mL anhydrous THF was added 75% NaH (724 mg, 22.6
mmol) and the reaction mixture was stirred for 1 h at room temperature. Then, a 5 mL THF solution of
methoxymethyl chloride (1.82 g, 1.72 mL, 22.6 mmol) was added into the mixture and further stirred
for 24 h at room temperature. The reaction was quenched by adding water and extracted with ether and
washed with brine. The organic layer was dried over anhydrous MgSO4. The solvent was removed under
reduced pressure and the residue was purified by flash chromatography (eluent: EtOAc:petroleum ether,
20
1:5) to give 3 (3.23 g, 67%) as a colorless oil. [α]D +21.4 (c 3.08, CHCl3); IR (neat) ν 3446, 3075,
1640, 1103, 916 cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.46–1.75 (4H, m), 2.09–2.33 (4H, m), 2.78 (1H,
d, J=4.8), 3.36–3.45 (1H, m), 3.41 (3H, s), 3.49–3.57 (1H, m), 4.69 (1H, d, J=6.7), 4.72 (1H, d, J=6.7),
4.98 (2H, dm, J=10.2), 5.04 (2H, dm, J=17.1), 5.82 (2H, ddt, J=17.1, 10.2, 6.7); 13C NMR (CDCl3,
75 MHz) δ 29.48, 29.93, 30.31, 32.57, 55.91, 72.22, 82.74, 97.28, 114.83, 114.97, 138.24, 138.53; MS
(EI) m/z (%) 215 (MH+, 2.0), 183 (2.0), 169 (2.6), 153 (1.5), 135 (2.0), 129 (1.0); [found: C, 67.33; H,
10.18%; C12H22O3 requires: C, 67.26; H, 10.35%].
3.3. (2S,5S,6S)-2,5-Epoxy-6-methoxymethoxy-9-decanene-1-ol 4
To a solution of 3 (3.0 g, 14.0 mmol) in 200 mL 2-propanol was added Co(modp)2 (755 mg, 1.40 mmol,
10 mol%) and tert-butyl hydroperoxide (1.26 g, 14.0 mmol) and the reaction mixture was stirred at 60°C
under an oxygen atmosphere for 4 h. After cooling to room temperature, the reaction was quenched
by adding saturated aqueous sodium thiosulfate (Na2S2O3) solution and stirred for 30 min. 2-Propanol
was removed under reduced pressure and extracted with ethyl acetate. The organic layer was washed
with brine and dried over Mg2SO4. The solvent was removed under reduced pressure and the residue
was purified by flash chromatography (eluent: EtOAc:petroleum ether, 1:4) to give 4 (2.38 g, 74%) as a
colorless oil. [α]D −24.1 (c 1.58, CHCl3); IR (neat) ν 3426, 1639 cm−1; 1H NMR (CDCl3, 300 MHz)
20
δ 1.50–1.76 (4H, m), 1.89–2.03 (2H, m), 2.08–2.27 (2H, m), 3.41 (3H, s), 3.46–3.55 (2H, m), 3.62–3.68
(1H, m), 3.99–4.13 (2H, m), 4.70 (1H, d, J=6.8), 4.81 (1H, d, J=6.8), 4.98 (1H, dm, J=10.2), 5.04 (1H,
dm, J=17.1), 5.82 (1H, ddt, J=17.1, 10.2, 6.6); 13C NMR (CDCl3, 75 MHz) δ 27.56, 28.49, 29.62, 30.54,
55.83, 64.79, 79.42, 79.61, 81.37, 96.92, 114.84, 138.45; [HRMS (EI) found: 230.1521 (M+); C12H22O4
requires: 230.1518].
3.4. (5S,6S,9S)-5-Methoxymethoxy-6,9-epoxy-10-benzyloxy-1-decanene 5
To a solution of 4 (2.24 g, 9.74 mmol) in THF (30 mL) was added 75% NaH (375 mg, 11.7 mmol) and
the reaction mixture was stirred at room temperature for 1 h. Then benzyl bromide (2.0 g, 1.39 mL, 11.7
mmol) was added into the mixture and further stirred for 12 h. The solvent was removed under reduced
pressure and the residue was extracted with ether (3×50 mL). The organic layer was washed with brine
and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified
by flash chromatography (eluent: EtOAc:petroleum ether, 1:20) to give 5 (3.05 g, 98%) as a colorless
oil. [α]D20 −35.6 (c 1.92, CHCl3); IR (neat) ν 3063, 3026, 1639, 1496, 1453, 1099, 920 cm−1; 1H NMR
(CDCl3, 300 MHz) δ 1.50–1.76 (4H, m), 1.89–2.03 (2H, m), 2.10–2.26 (2H, m), 3.39 (3H, s), 3.45–3.50
(2H, m), 3.50–3.55 (1H, m), 4.04–4.10 (1H, m), 4.15–4.24 (1H, m), 4.55 (1H, d, J=12.1), 4.60 (1H, d,
J=12.1), 4.69 (1H, d, J=6.7), 4.81 (1H, d, J=6.7), 4.98 (1H, dm, J=10.2), 5.04 (1H, dm, J=17.1), 5.82
(1H, ddt, J=17.1, 10.2, 6.6), 7.27–7.39 (5H, m); 13C NMR (CDCl3, 75 MHz) δ 27.99, 28.85, 29.84,

S.-K. Tian et al. / Tetrahedron: Asymmetry 10 (1999) 2551–2562
2557
30.45, 55.85, 72.91, 73.37, 78.29, 79.35, 81.31, 96.97, 114.77, 127.58, 127.68, 128.39, 138.56, 138.61;
[HRMS (EI) found: 320.2000 (M+); C19H28O4 requires: 320.1988].
3.5. (5R,6R)-1,9-Decadiene-5,6-diol 6
The reaction procedure was the same as that of 2 except adding chiral ligand (DHQD)2PHAL instead
20
of (DHQ)2PHAL. [α]D +22.0 (c 4.00, CHCl3).
3.6. (2R,5R,6R,9R)-2,5;6,9-Diepoxydeca-1,10-diol 7
To a solution of 6 (1.70 g, 10.0 mmol) in i-PrOH (250 mL) were added Co(modp)2 (2.16 g, 4.00 mmol)
and t-BuOOH (1.80 g, 20.0 mmol). After being heated at 60°C under oxygen for 3 h, the reaction mixture
was cooled to room temperature, then saturated aqueous Na2S2O3 (10 mL) was added and the mixture
was stirred for a further 10 min. i-PrOH was evaporated under reduced pressure. The resulting mixture
was extracted with EtOAc. The organic extracts were dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography (EtOAc:petroleum ether, 1:1) to give 7 (1.57
g, 78%) as a colorless oil. [α]D18 −18.5 (c 0.80, CHCl3); {lit.28 80% de. [α]D20 +12.5 (c 0.80, CHCl3)};
1H NMR (CDCl3, 300 MHz) δ 1.52–1.68 (2H, m), 1.70–1.85 (2H, m), 1.91–2.05 (4H, m), 2.49 (2H, br,
s), 3.50 (2H, dd, J=11.8, 5.3), 3.71 (2H, dd, J=11.8, 2.6), 3.85–3.95 (2H, m), 4.10–4.21 (2H, m); MS
(EI) m/z 171 (M+−2H2O), 153, 101.
3.7. (2R,5R,6R,9R)-10-Benzyloxy-2,5;6,9-diepoxy-1-decanol 8
To a solution of diol 7 (1.01 g, 5.0 mmol) in dry THF (50 mL) at 0°C was added NaH (120 mg, 5.0
mmol). After being stirred for 1 h, a solution of benzyl bromide (855 mg, 0.60 mL, 5.0 mmol) in THF (2
mL) was added dropwise over 10 min. After being stirred for 8 h, the solvent was removed under reduced
pressure. To the mixture was added water and EtOAc. After separation, the aqueous layer was extracted
with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography (EtOAc:petroleum ether, 2:3) to give 8 (1.03
g, 71%) as a colorless oil. [α]D +6.3 (c 1.00, CHCl3); IR (neat) ν 3426, 1601, 1495 cm−1; H NMR
(CDCl3, 300 MHz) δ 1.55–1.81 (4H, m), 1.91–2.10 (4H, m), 3.46–3.57 (3H, m), 3.70 (1H, dd, J=11.7,
3.2), 3.86–3.96 (2H, m), 4.09–4.17 (1H, m), 4.18–4.26 (1H, m), 4.56 (2H, s), 7.25–7.39 (5H, m); 13C
NMR (CDCl3, 75 MHz) δ 27.47, 28.44, 28.79, 64.64, 72.79, 73.39, 78.48, 79.95, 82.21, 127.68, 128.36,
138.45; MS (EI) m/z (%) 293 (MH+, 11.0), 261 (3.21), 201 (26.6); [HRMS (EI) found: 292.1678 (M+);
C17H24O4 requires: 292.1675].
20
1
3.8. (2R,5R,6R,9R)-10-Benzyloxy-2,5;6,9-diepoxy-1-decanal 9, ketone 10 and alcohol 11
To a solution of oxalyl chloride (522 mg, 0.36 mL, 4.1 mmol) in dry CH2Cl2 (10 mL) at −78°C under
nitrogen was added DMSO (641 mg, 0.58 mL, 8.22 mmol) as a solution in CH2Cl2 (10 mL). After
being stirred for 10 min, a solution of 8 (425 mg, 1.46 mmol) in CH2Cl2 (2 mL) was added and the
reaction mixture was allowed to stir for 2 h at −78°C. Then triethylamine (1.5 mL) was added and the
mixture was warmed naturally to room temperature. After 1 h the reaction was quenched with water and
extracted with CH2Cl2. The organic extracts were washed with saturated brine and dried over MgSO4.
After concentration, the crude aldehyde 9 was obtained.

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To freshly prepared CH2_CHCH2CH2MgCl (0.50 M, 6 mL, 3.0 mmol) in THF was added a solution
of 9 (ca. 1.2 mmol) in THF (10 mL) under nitrogen at −20°C. After being stirred for 30 min, the mixture
was warmed to room temperature naturally. The reaction mixture was stirred for 1 h. Saturated aqueous
ammonium chloride was added into the reaction solution and the mixture was extracted with ether. The
organic layer was washed with saturated brine and dried over MgSO4. After concentration, the residue
was purified by flash chromatography (EtOAc:petroleum ether, 1:1) to give the crude product (ca. 1.0
mmol) which was subjected to the Swern oxidation mentioned above again to afford the crude ketone 10.
To a solution of 10 (ca. 1.0 mmol) in anhydrous THF (3 mL) was added slowly L-Selectride (1.0 M in
THF) (2.0 mL, 2.0 mmol) at −78°C under argon and the reaction mixture was stirred for 1 h. The reaction
was quenched by adding methanol (1.0 mL). The solvent was removed under reduced pressure and the
residue was purified by flash chromatography (EtOAc:petroleum ether, 1:2) to give 11 (231 mg, 4 steps
46%) as a colorless oil. [α]D22 +11.9 (c 2.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.41–1.58 (2H, m),
1.58–1.80 (4H, m), 1.90–2.11 (4H, m), 2.11–2.21 (1H, m), 2.21–2.35 (1H, m), 2.29 (1H, br, s), 3.38–3.43
(1H, m), 3.47 (1H, dd, J=10.0, 5.0), 3.53 (1H, dd, J=10.0, 5.3), 3.80–3.99 (3H, m), 4.15–4.24 (1H, m),
4.57 (2H, s), 4.97 (1H, dm, J=10.2), 5.04 (1H, dm, J=17.1), 5.84 (1H, ddt, J=17.1, 10.2, 6.6), 7.22–7.39
(5H, m); 13C NMR (CDCl3, 75 MHz) δ 28.37, 28.48, 28.77, 28.89, 29.87, 32.68, 72.36, 72.78, 78.55,
81.94, 82.01, 82.98, 114.73, 127.57, 127.69, 128.36, 138.59; MS (EI) m/z (%) 346 (M+, 1.3), 329 (9.9),
310 (1.2), 287 (2.0), 261 (8.7); [HRMS (EI) found: 346.2157 (M+); C21H30O4 requires: 346.2144].
3.9. (2R,5R,6R,9R,10R,13R)-10-Benzyloxy-2,5;6,9;10,13-triepoxy-1-decanol 12
Treatment of 11 (231 mg, 0.67 mmol), in the same manner as that described in the preparation of 4
20
1
from 3, afforded 12 (236 mg, 98%) as a colorless oil. [α]D +3.9 (c 1.35, CHCl3); H NMR (CDCl3,
300 MHz) δ 1.57–1.80 (6H, m), 1.89–2.10 (6H, m), 3.42–3.54 (3H, m), 3.67 (1H, dd, J=11.6, 3.2),
3.87–4.01 (4H, m), 4.08–4.15 (1H, m), 4.15–4.24 (1H, m), 4.54 (1H, d, J=12.2), 4.59 (1H, d, J=12.2),
7.22–7.39 (10H, m); 13C NMR (CDCl3, 75 MHz) δ 27.47, 28.09, 28.22, 28.45, 28.64, 28.85, 64.77,
72.93, 73.32, 78.39, 79.85, 81.67, 81.89, 81.98, 82.09, 127.50, 127.65, 128.32, 138.50; MS (EI) m/z
(%) 362 (M+, 0.41), 345 (2.4), 331 (0.8), 271 (3.9), 261 (5.8); [HRMS (FAB) found: 363.2182 (MH+);
C21H31O5 requires: 363.2172].
3.10. (2S,5S,6S,9S)-2,5;6,9-Diepoxydeca-1,10-diol 13
To a solution of 2 (1.70 g, 10.0 mmol) in i-PrOH (250 mL) was added Co(modp)2 (2.16 g, 4.0 mmol)
and t-BuOOH (1.80 g, 20.0 mmol). After being heated at 60°C under oxygen for 3 h, the reaction
mixture was cooled to room temperature and stirred for a further 10 min after adding saturated aqueous
Na2S2O3 (10 mL). i-PrOH was evaporated under reduced pressure. The resulting mixture was extracted
with EtOAc. The organic extracts were dried over MgSO4 and concentrated under reduced pressure. The
residue was purified by flash chromatography (EtOAc:petroleum ether, 1:1) to give 13 (1.57 g, 78%) as
18
20
a colorless oil. [α]D +18.5 (c 0.80, CHCl3); {lit.28 80% de. [α]D +12.5 (c 0.80, CHCl3)}; 1H NMR
(CDCl3, 300 MHz) δ 1.52–1.68 (2H, m), 1.70–1.85 (2H, m), 1.91–2.05 (4H, m), 2.49 (2H, br, s), 3.50
(2H, dd, J=11.8, 5.3), 3.71 (2H, dd, J=11.8, 2.6), 3.85–3.95 (2H, m), 4.10–4.21 (2H, m); MS (EI) m/z
171 (M+−2H2O), 153, 101.

S.-K. Tian et al. / Tetrahedron: Asymmetry 10 (1999) 2551–2562
2559
3.11. (2S,5S,6S,9S)-2,5;6,9-Diepoxydecadial 14, diketone 15 and diol 16
To a solution of oxalyl chloride (3.18 g, 2.18 mL, 25.0 mmol) in dry CH2Cl2 (150 mL) at −78°C under
a nitrogen atmosphere was added DMSO (4.29 g, 3.90 mL, 55.0 mmol) as a solution in CH2Cl2 (10 mL).
After being stirred for 10 min, a solution of 13 (1.68 g, 8.32 mmol) in CH2Cl2 (20 mL) was added and
the reaction mixture was allowed to stir for a further 2 h. Then triethylamine (10 mL) was added and the
mixture was warmed naturally to room temperature. After 1 h the reaction was quenched with water and
extracted with CH2Cl2. The organic extracts were washed with saturated brine and dried over MgSO4.
After concentration, the crude aldehyde 14 was obtained which was used for the next reaction without
further purification.
To freshly prepared CH2_CHCH2CH2MgCl (0.40 M, 40 mL, 16.6 mmol) in THF was added a solution
of 14 (ca. 8.3 mmol) in THF (10 mL) under a nitrogen atmosphere at −78°C. After being stirred for
15 min, the mixture was warmed to room temperature naturally. The reaction mixture was stirred for
1 h. Saturated aqueous ammonium chloride was added and the mixture was extracted with ether. The
organic layer was washed with saturated brine and dried over MgSO4. After concentration, the residue
was purified by flash chromatography (EtOAc:petroleum ether, 1:1) to give the product (2.5 g, 80%)
which was subjected to the Swern oxidation mentioned above again to afford the crude diketone 15.
To a solution of 15 (ca. 2.64 mmol) in anhydrous THF (10 mL) was added slowly L-Selectride (1.0 M
in THF) (6.5 mL, 6.5 mmol) at −78°C under an argon atmosphere and the reaction mixture was stirred
for 40 min. The reaction was quenched by adding methanol (1.0 mL). The solvent was removed under
reduced pressure and the residue was purified by flash chromatography (EtOAc:petroleum ether, 1:2) to
20
give the mixture 16a and 16b (500 mg, 61%) as a colorless oil. 16a: [α]D −12.4 (c 2.50, CHCl3); IR
1
(neat) ν 3426, 3073, 1636, 1065 cm−1; H NMR (CDCl3, 300 MHz) δ 1.41–1.58 (4H, m), 1.58–1.74
(4H, m), 1.90–2.04 (4H, m), 2.08–2.23 (2H, m), 2.23–2.37 (2H, m), 2.29 (2H, br, s), 3.39–3.46 (2H, m),
3.81–3.97 (4H, m), 4.97 (2H, dm, J=10.2), 5.04 (2H, dm, J=17.1), 5.84 (2H, ddt, J=17.1, 10.2, 6.6);
13C NMR (CDCl3, 75 MHz) δ 28.41, 29.07, 29.90, 32.70, 73.39, 81.95, 83.16, 114.81, 138.59; MS (EI)
m/z (%) 310 (M+, 0.11), 293 (1.1), 275 (0.6), 251 (5.9); [HRMS (EI) found: 310.2154 (M+); C18H30O3
1
requires: 310.2144]. 16b: IR (neat) ν 3428, 3072, 1634, 1062 cm−1; H NMR (CDCl3, 300 MHz) δ
1.40–1.54 (4H, m), 1.58–1.74 (4H, m), 1.90–2.04 (4H, m), 2.08–2.23 (2H, m), 2.23–2.37 (2H, m), 2.29
(2H, br, s), 3.39–3.46 (2H, m), 3.81–3.97 (4H, m), 4.97 (2H, dm, J=10.2), 5.04 (2H, dm, J=17.1), 5.84
(2H, ddt, J=17.1, 10.2, 6.6); 13C NMR (CDCl3, 75 MHz) δ 24.68, 30.32, 31.63, 32.55, 70.87, 73.46,
82.37, 82.61, 82.82, 83.24, 114.90, 138.42; MS (EI) m/z (%) 310 (M+, 0.14), 293 (3.1), 275 (1.2), 251
(6.4); [HRMS (EI) found: 310.2150 (M+); C18H30O3 requires: 310.2144].
3.12. (2S,5S,6S,9S,10S,13S,14S,17S)-2,5;6,9;10,13;14,17-Tetraepoxyoctadeca-1,18-diol 17a
This compound was prepared from 16a (96 mg, 0.31 mmol) in the same manner as that described in
the preparation of 3 and it was used for the next reaction without further purification.
3.13. (2S,5S,6S,9S,10S,13S,14S,17S)-1,18-Dibenzyloxy-2,5;6,9;10,13;14,17-tetraepoxyoctadecane 18
To a solution of 17a (106 mg, 0.31 mmol) in anhydrous THF (2 mL) was added NaH (75%, 30 mg,
0.94 mmol) and the reaction mixture was stirred for 1 h at room temperature. Benzyl bromide (137 mg,
0.095 mL, 0.80 mmol) was added into the reaction solution and the mixture was further stirred for 24 h.
After usual workup, the residue was purified by flash chromatography (EtOAc:petroleum ether, 1:3) to
22
1
give 18 (70 mg, 43%) as a colorless oil. [α]D −9.2 (c 1.90, CHCl3); H NMR (CDCl3, 300 MHz) δ

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S.-K. Tian et al. / Tetrahedron: Asymmetry 10 (1999) 2551–2562
1.61–1.84 (8H, m), 1.86–2.10 (8H, m), 3.45 (2H, dd, J=10.0, 5.0), 3.52 (2H, dd, J=10.0, 5.3), 3.88–4.01
(6H, m), 4.15–4.24 (2H, m), 4.54 (2H, d, J=12.2), 4.59 (2H, d, J=12.2), 7.22–7.39 (10H, m); 13C NMR
(CDCl3, 75 MHz) δ 28.10, 28.17, 28.43, 28.85, 72.91, 73.32, 78.37, 81.57, 81.77, 81.89, 127.52, 127.69,
128.34, 138.52; MS (EI) m/z (%) 522 (M+, 0.35), 431 (0.83); [HRMS (FAB) found: 523.3046 (MH+);
C32H43O6 requires: 523.3060].
3.14. (5S,6S,9S,10S,13S,14S)-5-tert-Butyldimethylsiloxy-14-hydroxy-6,9;10,13-diepoxy-1,18-octa-
decadiene 19a
To a solution of 16a (155 mg, 0.50 mmol) and imidazole (84 mg, 1.24 mmol) in THF (5 mL) was
added TBDMSCl (75 mg, 0.50 mmol) and the reaction mixture was stirred for 24 h at room temperature.
After usual workup, the residue was purified by flash chromatography (EtOAc:petroleum ether, 1:10)
22
to give 19a (159 mg, 75%) as a colorless oil. [α]D −15.6 (c 2.50, CHCl3); IR (neat) ν 3426, 3074,
1
1635, 1101 cm−1; H NMR (CDCl3, 300 MHz) δ 0.05 (3H, s, SiMe), 0.08 (3H, s, SiMe), 0.88 (9H, s,
Me3C), 1.39–1.77 (8H, m), 1.79–2.0 (4H, m), 2.0–2.37 (4H, m), 3.39–3.46 (1H, m), 3.60–3.68 (1H, m),
3.80–3.91 (3H, m), 3.91–3.99 (1H, m), 4.90–5.08 (4H, m), 5.73–5.90 (2H, m); MS (EI) m/z (%) 425
(MH+), 366 (4.6), 348 (7.1), 321 (3.8); [HRMS (FAB) found: 425.3076 (MH+); C24H45O4Si requires:
425.3087].
3.15. (5S,6S,9S,10S,13S,14S,17S)-5-tert-Butyldimethylsiloxy-18-hydroxy-6,9;10,13;14,17-triepoxy-
1-octadecene 20a
This compound was prepared in the same manner as that described in the preparation of 7 or 12 as
22
1
a colorless oil. [α]D −11.9 (c 2.00, CHCl3); H NMR (CDCl3, 300 MHz) δ 0.06 (3H, s), 0.07 (3H,
s), 0.89 (9H, s), 1.35–1.50 (1H, m), 1.51–1.84 (7H, m), 1.85–2.10 (7H, m), 2.10–2.32 (1H, m), 3.48
(1H, dd, J=11.6, 5.6), 3.60–3.68 (1H, m), 3.68 (1H, dd, J=11.6, 3.2), 3.87–4.01 (5H, m), 4.10–4.16 (1H,
m), 4.90–5.05 (2H, m), 5.78–5.88 (1H, m); 13C NMR (CDCl3, 75 MHz) δ 18.28, 26.03, 27.43, 27.50,
28.27, 28.39, 28.49, 28.72, 30.07, 31.97, 74.37, 79.91, 81.65, 81.78, 81.98, 82.14, 82.19, 114.33, 139.08;
MS (EI) m/z (%) 441 (MH+), 382 (3.4), 365 (6.6), 347 (1.8), 321 (1.7); [HRMS (FAB) found: 441.3052
(MH+); C24H45O4Si requires: 441.3036].
Acknowledgements
We thank the National Natural Sciences Foundation of China for financial support.
References
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1996, 13, 275.
2. Fang, X.-L.; Rupprecht, J.-K.; Alkofahi, A.; Hui, Y.-H.; Liu, Y.-M.; Smith, D. L.; Wood, K. V.; McLaughlin, J. L.
Heterocycles 1991, 32, 11.
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2433, and references cited therein.
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5. Zhang, Y.; Zeng, L.; Woo, M.-H.; Cu, Z.-M.; Ye, Q.; Wu, F.-E.; McLaughlin, J. L. Heterocycles 1995, 41, 1743.
6. Wang, Z.-M.; Tian, S.-K.; Shi, M. Tetrahedron Lett. 1999, 40, 977.

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7. Gu, Z.-M.; Fang, X.-P.; Zeng, L.; McLaughlin, J. L. Tetrahedron Lett. 1994, 35, 5367.
8. Sinha, S. C.; Sinha, A.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1998, 120, 4017.
9. Yao, Z.-J.; Wu. Y.-L. J. Org. Chem. 1995, 60, 1170.
10. For a recent review on synthesis, see: Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G.; Appendino, G. ChemTracts 1998,
11, 803.
11. Keinan, E.; Sinha, A.; Yazbak, A.; Sinha, S. C.; Sinha, S. C. Pure & Appl. Chem. 1997, 69, 423, and citations therein.
12. Li, K.; Vig, S.; Uchum, F. M. Tetrahedron Lett. 1998, 39, 2063.
13. Zhang, H.; Seepersaud, M.; Seepersaud, S.; Mootoo, D. R. J. Org. Chem. 1998, 63, 2049.
14. Figadère, B.; Peyrat, J.-F.; Cavé, A. J. Org. Chem. 1997, 62, 3428.
15. Towne, T. B.; McDonald, F. E. J. Am. Chem. Soc. 1997, 119, 6022.
16. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
20
17. The absolute configuration and ee value of compound 2 {[α]D −21.3 (c 3.30, CHCl3)} were confirmed by comparing
the specific optical rotation with that prepared from (2S,3S)-1,4-dichlorobutan-2,3-diol which has been reported in the
literature: Vanhessche, K. P. M.; Wang, Z.-M.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 3469.
18. No cis-THF ring was observed by 1H NMR (CDCl3, 300 MHz) and 13C NMR (CDCl3, 75 MHz) spectral analysis.
19. Inoki, S.; Mukaiyama, T. Chem. Lett. 1990, 67.
20. Wang, Z.-M.; Tian, S.-K.; Shi, M. Tetrahedron: Asymmetry 1999, 10, 667.
21. The 1H and 13C NMR spectra of compound 8, the mono-benzyl ether of diol 7, were compared with those of all its possible
diastereomers 8b, 8c and 8d (for 8d see also: Koert, U.; Stein, M.; Wagner, H. Liebigs Ann. 1995, 1415), and no other
diastereomer was detected.
8b: 1H NMR (CDCl3, 300 MHz) δ 1.69–1.85 (3H, m), 1.85–1.97 (3H, m), 1.97–2.10 (2H, m), 3.46–3.57 (3H, m), 3.77 (1H,
dd, J=11.7, 2.8), 3.86–3.94 (1H, m), 3.95–4.03 (1H, m), 4.08–4.16 (1H, m), 4.19–4.28 (1H, m), 4.56 (2H, s), 7.25–7.39
(5H, m); 13C NMR (CDCl3, 75 MHz) δ 27.35, 28.79, 65.68, 72.57, 73.38, 78.76, 80.16, 81.67, 81.98, 82.23, 127.67,
128.39, 138.42. 8c: 1H NMR (CDCl3, 300 MHz) δ 1.55–1.77 (3H, m), 1.77–1.90 (2H, m), 1.90–2.04 (3H, m), 3.42–3.57
(3H, m), 3.68 (1H, dd, J=11.7, 3.1), 3.78–3.87 (1H, m), 3.88–3.98 (1H, m), 4.06–4.22 (2H, m), 4.56 (2H, s), 7.25–7.39
(5H, m); 13C NMR (CDCl3, 75 MHz) δ 27.50, 27.69, 28.33, 28.89, 64.66, 72.81, 73.39, 78.60, 80.05, 82.13, 82.66, 127.71,
128.39, 138.47. 8d: 1H NMR (CDCl3, 300 MHz) δ 1.73–1.84 (3H, m), 1.84–2.02 (5H, m), 3.41–3.56 (3H, m), 3.74 (1H,
dd, J=11.7, 2.8), 3.84–3.96 (2H, m), 4.05–4.18 (2H, m), 4.56 (2H, s), 7.25–7.39 (5H, m); 13C NMR (CDCl3, 75 MHz) δ
27.32, 27.97, 28.18, 28.70, 65.43, 72.50, 73.36, 78.48, 80.06, 81.59, 81.89, 127.60, 127.77, 128.38, 138.24.
22. No satisfactory diastereoselectivity (de 32%) was obtained by direct coupling of these two reagents in the presence of
CuBr·SMe2 (Mead, K.; Macdonald, T. L. J. Org. Chem. 1985, 50, 422).

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S.-K. Tian et al. / Tetrahedron: Asymmetry 10 (1999) 2551–2562
23. Hanessian, S.; Grillo, T. A. J. Org. Chem. 1998, 63, 1049.
1
24. The de value is calculated according to the H NMR (CDCl3, 300 MHz) spectrum of 11 and its diastereomer 110. The
integration of the signal located at δ 3.38–3.59 [11: 3H (Ha, Hf) and 110: 2H (Hf0)] is 0.609 and that located at δ 3.80–3.99
[11: 3H (Hb–Hd) and 110: 4H (Ha0–Hd0)] is 0.629. From the equation (3×11+2×110):(3×11+4×110)=0.609:0.629 we
obtained 11:110=20:1.
25. Koert, U. Synthesis 1995, 1, 115.
26. Ignoring 16c, the diastereoselectivity value is calculated according to the H NMR (CDCl3, 300 MHz) spectrum of the
1
mixtures. The integration of the signal located at δ 3.39–3.46 (threo, 16a: 2H, 16b: 1H) is 0.899 and that located at δ
3.81–3.97 (erythro,1b 16a: 4H, 16b: 5H) is 2.239. From the equation (16a×2+16b×1):(16a×4+16b×5)=0.899:2.239 we
obtained 16a:16b=2.6:1.
27. No diastereoisomer with cis-THF ring was detected from the 1H NMR (CDCl3, 300 MHz) spectrum of 18a.
28. Koert, U.; Stein, M.; Harms, K. Angew. Chem., Int. Ed. Engl. 1994, 33, 1180.