Synthesis of 5-(7-hydroxyhept-3-enyl)-1,2-dithiolan-3-one 1-oxide, a core functionality of antibiotic leinamycin

Article abstract of DOI:10.1016/S0040-4020(02)01600-9

5-(7-Hydroxyhept-3-enyl)-1,2-dithiolan-3-one 1-oxide 1 possessing both the 1,2-dithiolan-3-one 1-oxide five-membered ring and the double bond at the gamma position of the heterocycle, characteristic of the antibiotic leinamycin, was synthesized. In addition, the activated ester form of 1 was prepared that may be useful for coupling 1 to certain DNA-binding agents.

Full text of DOI:10.1016/S0040-4020(02)01600-9

Tetrahedron 59 (2003) 833–839
Synthesis of 5-(7-hydroxyhept-3-enyl)-1,2-dithiolan-3-one 1-oxide,
a core functionality of antibiotic leinamycin
Alex H. F. Lee,a,b Albert S. C. Chana,b and Tianhu Lia,b
,
*
aOpen Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis,† The Hong Kong
Polytechnic University, Hung Hom, Kowloon, Hong Kong, People’s Republic of China
bDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong,
People’s Republic of China
Received 7 October 2002; revised 19 November 2002; accepted 5 December 2002
Abstract—5-(7-Hydroxyhept-3-enyl)-1,2-dithiolan-3-one 1-oxide 1 possessing both the 1,2-dithiolan-3-one 1-oxide five-membered ring
and the double bond at the gamma position of the heterocycle, characteristic of the antibiotic leinamycin, was synthesized. In addition, the
activated ester form of 1 was prepared that may be useful for coupling 1 to certain DNA-binding agents. q 2003 Elsevier Science Ltd. All
rights reserved.
1. Introduction
certain pharmaceutical companies have expressed their
interest in pursuing leinamycin as an anticancer drug
candidate.14
The antibiotic leinamycin was isolated from Streptomyces
sp. by Hara et al. at Kyowa Hakko Kogyo Ltd in 1989.
Subsequent spectroscopic analysis and X-ray crystal-
lography1–4 resolved its exact molecular structure as that
shown in Figure 1. Further bioassays demonstrated that this
natural product exhibited potent activity against murine
experimental tumor leukemia P388 and sarcoma 180 as well
as against Gram-positive bacteria.5 In addition, leinamycin
is capable of causing single stranded DNA cleavage in vitro
in the presence of thiols as activating reagents, a mechanism
that may underlie the cytotoxic properties of this anti-
biotic.6–13 Based on these promising biological properties,
From the viewpoint of chemistry, one of the distinctive
characteristics of leinamycin in structure is its possession of
an unusual 1,3-dioxo-1,2-dithiolane moiety connected to an
18-membered lactam ring.15,16 In addition, certain mecha-
nistic investigations demonstrate that the double bond at the
gamma position of the heterocycle plays a significant role in
the DNA-cleaving process induced by leinamycin.5,7–9,17
With the aim of further exploring the chemical and
biological properties of this antibiotic, we have recently
designed and synthesized 5-(7-hydroxyhept-3-enyl)-1,2-
Figure 1.
Keywords: antibiotic leinamycin; heterocycle; DNA-cleaving agent; activated ester; antisense oligonucleotide; 1,2-dithiolan-3-one 1-oxide.
*
Corresponding author. Address: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon,
Hong Kong, China. Tel.: þ852-2766-7778; fax: þ852-2364-9932; e-mail: bctli@polyu.edu.hk
†
A University Grants Committee Area of Excellence Scheme in Hong Kong.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01600-9

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A. H. F. Lee et al. / Tetrahedron 59 (2003) 833–839
dithiolan-3-one 1-oxide 1 as well as its corresponding
activated ester 2 that possess both the 1,3-dioxo-1,2-
dithiolane heterocycle and a double bond at the gamma
position of the heterocycle. It is anticipated that 2 could be
readily linked to a DNA binding reagent such as antisense
oligonucleotide or peptides.18 – 20 We now report the
synthesis of 5-(7-hydroxyhept-3-enyl)-1,2-dithiolan-3-one
1-oxide 1 and its corresponding activated ester 2 in detail.
vinylmagnesium bromide with 5 gave rise to allylic alcohol
6. The ethyl ester 7 was obtained through the reaction of 6
with triethyl orthoacetate in the presence of a catalytic
amount of propanoic acid. Compound 8 was produced
through the reduction reaction of 7 with LiAlH4 in THF,
which was re-oxidized using PDC in CH2Cl2 to afford
aldehyde 9. The synthesis of 10 was carried out by means of
the Horner–Emmons reaction21 of 9 with phosphonate
carbanions in an aprotic polar solvent. Hydrolysis of 10 was
achieved by utilizing lithium hydroxide/ethanol. Production
of benzyl thioether 12 was accomplished by the reaction of
prop-2-enoic acid 11 with toluene-a-thiol in piperidine.22
Li/liquid ammonia was employed to carry out this
debenzylation reaction because the mercapto acid 13 is
too unstable to survive in many purification processes.
2. Results and discussion
Our synthesis of 1 began with the monosilylation of 1,4-
butanediol followed by an oxidation reaction using PDC to
afford the corresponding aldehyde 5. The reaction of
Scheme 1.

A. H. F. Lee et al. / Tetrahedron 59 (2003) 833–839
835
Scheme 2.
Cyclization of 13 in a solution of isobutyl chloroformate and
triethylamine gave rise to the corresponding thiolactone 14.
The mercapto thioic acid 15 was obtained through a ring
opening reaction17 of 14. Oxidative ring closure of
mercapto-thiolic acid 15 generated dithiolane 16 through
exposure of the reaction mixture to sodium iodate supported
on neutral alumina.23 Desilylation of 16 in hydrochloric
acid/ethanol was utilized to produce the corresponding
alcohol 17. Finally, m-CPBA was used to accomplish the
S-oxidation of 1,2-dithiolan-3-one moiety to produce the
1,2-dithiolan-3-one 1-oxide 1 (Scheme 1).
on Merck precoated silica gel 60 F254 plates. Flash
chromatography was carried out on columns of NA or
Merck silica gel 60 (230–400 mesh). THF was distilled
from Na/benzophenone and dichloromethane was distilled
from CaH2 respectively prior to use. Unless otherwise
noted, materials and solvents were obtained from com-
mercial suppliers and used without further purification.
3.1.1. 4-tert-Butyldimethylsiloxy-n-butan-1-ol (4). A sol-
ution of 3 (23.0 mL, 0.25 mol) in THF (40 mL) was added
to a suspension of sodium hydride (11.20 g, 0.28 mol) in
THF (600 mL), and the mixture was stirred at room
temperature for 2.5 h. tert-Butyldimethylsilyl chloride
(42.2 g, 0.28 mol) in THF (60 mL) was added and the
mixture was stirred at room temperature overnight followed
by the addition of saturated aqueous K2CO3 (300 mL). The
mixture was extracted with diethyl ether (3£250 mL) and
the combined organic extracts were washed with brine
(150 mL), dried (Na2SO4) and concentrated in vacuo to
yield the known compound,24 4 (57.42 g, 99%) as a
colorless syrup: IR (film) 3682, 3611, 3339, 3017, 2930,
With the intention of covalently linking the core function-
ality of leinamycin to certain DNA-binding agents for the
future use, 2 was also synthesized. Compound 18 was
prepared from the reaction of adipic acid and N-hydroxy-
succinimide, and this was condensed with compound 17 to
afford 19. Subsequently oxidation of 19 by m-CPBA
provided the activated ester 2 (Scheme 2).
1
2858, 1424, 1265, 1219, 1091, 1025, 784, 666 cm21; H
3. Experimental
3.1. General
NMR (CDCl3, 500 MHz) d 3.65 (m, 4H), 1.64 (m, 4H), 0.90
(s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3, 100 MHz) d 63.3,
62.8, 30.2, 29.9, 25.9, 18.3, 25.5; ESIMS m/z (%): 205
([Mþ1]þ, 100).
1H and 13C NMR spectra were obtained on a Bruker
Advance DPX 400 FT-NMR Spectrometer or Varian Unity
INOVA 500 FT-NMR Spectrometer as solutions in CDCl3
unless otherwise indicated, and the chemical shifts are
reported in parts per million (ppm, d). Coupling constants
are reported in hertz (Hz). Low resolution mass spectra were
obtained on Fisons VG Platform Mass Spectrometer, or
Hewlett Packard G1800C GCD Series II GCMS. High
resolution mass spectra (HRMS) were measured by
Finnigan MAT95 and Thermo Finnigan MAT95XL Mass
Spectrometers. IR spectra were recorded on Nicolet Avatar
360 FT-IR Spectrometer as a thin film on the polished NaCl
plates and the characteristic bands were reported in
reciprocal centimeters (cm21). All reactions were
monitored by thin layer chromatography (TLC) performed
3.1.2. 4-tert-Butyldimethylsiloxy-1-butyraldehyde (5). A
solution of 4 (31.5 g, 0.15 mol) in distilled CH2Cl2 (80 mL)
was added to a mixture of PDC (84.6 g, 0.23 mol) and
activated molecular sieves (type 5A powder, 25 g) in
distilled CH2Cl2 (200 mL), and the mixture was stirred for
8 h. Diethyl ether (50 mL) was added, and the ethereal
mixture was suction-filtered and the filter-cake was washed
with diethyl ether and EtOAc. The organics were concen-
trated in vacuo and the residue was purified by flash
chromatography (hexane/EtOAc 20:1) to afford 525 (29.6 g,
77%) as a colorless oil: IR (film) 3058, 2991, 2955, 2924,
1
2853, 1716, 1424, 1271, 1096, 892, 840, 743 cm21; H
NMR (CDCl3, 500 MHz) d 9.79 (s, 1H), 3.65 (t, 2H,

836
A. H. F. Lee et al. / Tetrahedron 59 (2003) 833–839
J¼6.0 Hz), 2.50 (td, 2H, J¼7.0, 1.5 Hz), 1.86 (quintet, 2H,
J¼6.5 Hz), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3,
100 MHz) d 202.6, 62.0, 40.7, 25.8, 25.4, 18.2, 25.5;
ESIMS m/z (%): 203 ([Mþ1]þ, 8), 187 (100); HREIMS
calcd for C10H21O2Si [M2H]þ 201.1305; found: 201.1305.
The residue was purified by flash column chromatography
(hexane/EtOAc 4:1) to give 8 (13.41 g, 97%) as a colorless
oil: IR (film) 3621, 3452, 3350, 3017, 2935, 2848, 1255,
;
1209, 1091, 835, 739, 661 cm21 1H NMR (CDCl3,
500 MHz) d 5.44 (m, 2H), 3.65 (t, 2H, J¼6.5 Hz), 3.60 (t,
2H, J¼6.5 Hz), 2.05 (m, 4H), 1.63 (quintet, 2H, J¼6.5 Hz),
1.55 (quintet, 2H, J¼6.5 Hz), 0.89 (s, 9H), 0.04 (s, 6H); 13C
NMR (CDCl3, 100 MHz) d 130.6, 129.8, 62.6, 32.6, 32.4,
28.9, 28.8, 25.9, 18.3, 25.3; ESIMS m/z (%): 258 (Mþ, 18),
209 (14), 187 (29), 177 (11), 145 (59), 127 (100);
HRFABMS calcd for C14H31O2Si [MþH]þ 259.2088;
found: 259.2086.
3.1.3. 6-tert-Butyldimethylsiloxy-hex-1-en-3-ol (6). A few
drops of iodomethane were added to a mixture of
magnesium turnings (2.8 g, 0.106 mol) and distilled THF
(10 mL) followed by the addition of 1 M of vinyl bromide in
THF (92.0 mL). After reflux for 1 h, the resultant Grignard
reagent was cooled to room temperature, filtered and
transferred to a different flask by cannula. A solution of 5
(15.6 g, 76.7 mmol) in distilled THF (35.0 mL) at 2708C
was added to this filtered Grignard reagent, and the mixture
was stirred at the same temperature for 1 h. The mixture was
further stirred overnight while the solution was allowed to
warm up to room temperature. Saturated aqueous NH4Cl
(50 mL) was added into the white turbid solution chilled in
an ice bath. The aqueous phase was extracted with EtOAc
(3£100 mL) and the combined organic extracts were
washed with water (50 mL) and brine (2£50 mL), dried
(Na2SO4) and concentrated in vacuo to give a yellow syrup.
Purification with flash column chromatography (hexane/
EtOAc 15:1) to afford 6 (15.3 g, 86%) as a slightly yellow
oil: IR (film) 3442, 3345, 3017, 2960, 2925, 2847, 1465,
3.1.6. 8-tert-Butyldimethysiloxy-oct-4-en-1-al (9). A sol-
ution of 8 (8.99 g, 34.80 mmol) in distilled CH2Cl2
(120 mL) was added to a mixture of PDC (19.64 g,
52.20 mmol) and activated molecular sieves (type 5A
powder, 7.2 g) in distilled CH2Cl2 (250 mL) at room
temperature, and the mixture was stirred at the same
temperature for 3 h. Diethyl ether (90 mL) was added, and
the ethereal phase was suction-filtered. The combined
organics were concentrated in vacuo and the residue was
purified by flash column chromatography (hexane/EtOAc
20:1) to yield 9 (6.25 g, 70%) as a colorless oil: IR (film)
3360, 3022, 2929, 2853, 1726, 1470, 1260, 1209, 1096, 835,
758, 666 cm21; 1H NMR (CDCl3, 500 MHz) d 9.76 (s, 1H),
5.44 (m, 2H), 3.58 (t, 2H, J¼6.5 Hz), 2.49 (td, 2H, J¼7.0,
1.5 Hz), 2.32 (q, 2H, J¼7.0 Hz), 2.03 (q, 2H, J¼7.5 Hz),
1.55 (quintet, 2H, J¼7.5 Hz), 0.88 (s, 9H), 0.04 (s, 6H); 13C
NMR (CDCl3, 100 MHz) d 202.4, 131.4, 127.9, 62.5, 43.5,
43.4, 32.4, 28.7, 25.9, 25.2, 18.3, 25.3; ESIMS m/z (%):
257 ([Mþ1]þ, 100), 228 (20), 125 (12); HRESIMS calcd for
C14H29O2Si [MþH]þ 257.1929; found: 257.1917.
1255, 1209, 1096, 927, 835, 753, 661 cm21 1H NMR
;
(CDCl3, 500 MHz) d 5.87 (m, 1H), 5.23 (d, 1H, J¼17.5 Hz),
5.09 (d, 1H, J¼10.5 Hz), 4.12 (m, 1H), 3.66 (t, 2H,
J¼6.0 Hz), 1.63 (m, 4H), 0.90 (s, 9H), 0.06 (s, 6H); 13C
NMR (CDCl3, 100 MHz) d 141.2, 114.3, 72.6, 63.4, 34.4,
28.7, 25.9, 18.3, 25.4; ESIMS m/z (%): 231 ([Mþ1]þ, 100),
213 (24), 205 (31), 195 (20), 187 (12); HRESIMS calcd for
C12H27O2Si [MþH]þ 231.1773; found: 231.1775.
3.1.7. Ethyl (E)-10-tert-butyldimethylsiloxy-dec-2-enoate
(10). Triethyl phosphonoacetate (7.2 mL, 36.32 mmol) was
added to NaH (2.61 g, 32.40 mmol) in THF (100 mL), and
the solution was stirred at room temperature for 1 h
followed by the addition of 9 (7.76 g, 30.27 mmol) in
THF (60 mL). The mixture was heated at reflux for 1 h and
allowed to cool down to room temperature. After the
removal of the solvents, the residue was dissolved in
CH2Cl2, and the mixture was washed with water (30 mL)
and brine (40 mL), dried (Na2SO4) and concentrated in
vacuo. The residue was purified by flash column chroma-
tography (hexane/EtOAc 60:1) to afford 10 (7.41 g, 75%) as
a slightly yellow syrup: IR (film) 3017, 2930, 2853, 1711,
1655, 1470, 1368, 1250, 1209, 1096, 1035, 840, 743,
661 cm21; 1H NMR (CDCl3, 500 MHz) d 6.95 (s, 1H), 5.81
(dd, 1H, J¼15.5, 1.5 Hz), 5.42 (m, 2H), 4.18 (q, 2H,
J¼7.0 Hz), 3.59 (t, 2H, J¼7.0 Hz), 2.25 (q, 2H, J¼7.0 Hz),
2.14 (q, 2H, J¼6.0 Hz), 2.03 (q, 2H, J¼6.5 Hz), 1.56
(quintet, 2H, J¼7.0 Hz), 1.28 (t, 3H, J¼6.5 Hz), 0.89 (s,
9H), 0.04 (s, 6H); 13C NMR (CDCl3, 100 MHz) d 166.7,
148.6, 131.1, 128.7, 121.5, 62.5, 60.1, 32.5, 32.2, 32.2, 30.9,
28.7, 25.9, 18.3, 18.3, 14.3, 25.3; ESIMS m/z (%): 327
([Mþ1]þ, 13), 277 (10), 255 (12), 235 (13), 214 (9), 213
(100), 167 (22); HRCIMS calcd for C18H33O3Si [M2H]2
325.2204; found: 325.2204.
3.1.4. 8-tert-Butyldimethylsiloxy-oct-4-enoic acid ethyl
ester (7). A mixture of 6 (12.7 g, 55.1 mmol), triethyl
orthoacetate (80 mL, 0.496 mol) and catalytic amount of
propanoic acid (0.41 mL, 5.50 mmol) was refluxed for 4 h
followed by the removal of triethyl orthoacetate. The
residues were dissolved in EtOAc (80 mL), and the mixture
was extracted with brine (2£30 mL), dried (Na2SO4) and
concentrated in vacuo. The residue was purified by flash
column chromatography (hexane/EtOAc 25:1) to afford 7
(15.9 g, 96%) as a yellow syrup: IR (film) 3012, 2955, 2925,
2848, 1721, 1521, 1470, 1255, 1214, 1086, 1040, 835, 748,
1
661 cm21; H NMR (CDCl3, 500 MHz) d 5.43 (m, 2H),
4.12 (q, 2H, J¼7.0 Hz), 3.58 (t, 2H, J¼6.4 Hz), 2.32 (m,
4H), 2.02 (q, 2H, J¼6.3 Hz), 1.55 (quintet, 2H, J¼6.6 Hz),
1.26 (t, 3H, J¼11.0 Hz), 0.88 (s, 9H), 0.03 (s, 6H); 13C
NMR (CDCl3, 100 MHz) d 173.3, 131.1, 128.3, 62.5, 60.2,
34.4, 32.5, 28.7, 27.9, 25.9, 18.3, 14.2, 25.3; ESIMS m/z
(%): 301 ([Mþ1]þ, 100), 169 (25); HRCIMS calcd for
C16H31O3Si [M2H]2 299.2034; found: 299.2048.
3.1.5.
8-tert-Butyldimethylsiloxy-oct-4-en-1-ol
(8).
LiAlH4 (2.34 g, 58.8 mmol) was added to a solution of 7
(16.08 g, 53.5 mmol) in distilled THF (150 mL) at 08C, and
the solution was stirred at room temperature for 1.5 h.
EtOAc (20 mL) and 10% aqueous HCl were added and the
mixture was extracted with EtOAc (3£90 mL). The
combined extracts were washed with water (40 mL) and
brine (40 mL), dried (Na2SO4) and concentrated in vacuo.
3.1.8. (E)-10-tert-Butyldimethylsiloxy-dec-2-enoic acid
(11). LiOH (25.52 g, 0.340 mol) was added to a solution
of 10 (18.64 g, 56.74 mmol) in ethanol (120 mL) and water

A. H. F. Lee et al. / Tetrahedron 59 (2003) 833–839
837
(5 mL), and the mixture was stirred at room temperature for
22 h. The mixture was filtered and the filter-cake was
washed with EtOAc. The combined organics were concen-
trated in vacuo and the residue was dissolved in water
(30 mL). The aqueous solution was acidified to pH 4–5 by
adding 10% aqueous HCl. The mixture was extracted with
CH2Cl2 (3£90 mL) and brine (30 mL), dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by
flash column chromatography (hexane/EtOAc 10:1) to
afford 11 (14.83 g, 87%) as a white solid: mp 35.0–
36.88C; IR (film) 3611, 3442, 3349, 3017, 2925, 2848, 1695,
extracted with CH2Cl2 (3£50 mL) and brine (25 mL), dried
(Na2SO4) and concentrated in vacuo to afford 13 (0.596 g,
96%) as a colorless syrup: IR (film) 3395, 3012, 2924, 2585,
1711, 1516, 1465, 1409, 1209, 1045, 840, 758, 666 cm21
;
1H NMR (CDCl3, 500 MHz) d 5.42 (m, 2H), 3.60 (t, 2H,
J¼6.5 Hz), 3.18 (m, 1H), 2.73 (dd, 1H, J¼16.5, 5.5 Hz),
2.57 (dd, 1H, J¼16, 8.5 Hz), 2.11 (m, 4H), 1.70 (d, 1H,
J¼8.0 Hz), 1.57 (m, 4H), 0.89 (s, 9H), 0.06 (s, 6H); 13C
NMR (CDCl3, 100 MHz) d 176.8, 131.2, 128.7, 62.6, 44.0,
37.9, 35.5, 32.5, 29.9, 28.8, 25.9, 25.6, 18.3, 25.3; ESIMS
m/z (%): 332 (Mþ, 12), 330 (22), 286 (8), 285 (14), 284 (78),
227 (100), 217 (41), 146 (20), 139 (18), 129 (8); HRESIMS
calcd for C16H34O3SSi [Mþ2]þ 334.1989; found: 334.2010.
1
1655, 1429, 1214, 1096, 1045, 835, 753, 656 cm21; H
NMR (CDCl3, 500 MHz) d 7.06 (m, 1H), 5.83 (dt, 1H,
J¼15.5, 2.0 Hz), 5.43 (m, 2H), 3.60 (t, 2H, J¼6.5 Hz), 2.28
(q, 2H, J¼6.5 Hz), 2.16 (q, 2H, J¼7.0 Hz), 2.04 (q, 2H,
J¼7.0 Hz), 1.56 (quintet, 2H, J¼6.5 Hz), 0.85 (s, 9H), 0.04
(s, 6H); 13C NMR (CDCl3, 100 MHz) d 171.7, 151.6, 131.3,
128.5, 120.9, 62.6, 32.5, 32.3, 30.8, 28.7, 25.9, 18.3, 25.3;
ESIMS m/z (%): 298 ([Mþ1]þ, 24), 227 (11), 213 (31), 186
(8), 185 (100), 167 (40); HRESIMS calcd for C16H30O3Si
[MþH]þ 298.1956; found: 298.1951.
3.1.11. 4-(7-tert-Butyldimethysiloxyhept-3-enyl)thietan-
2-one (14). Freshly distilled isobutyl chloroformate
(1.40 mL, 10.76 mmol) was added to a solution of 13
(3.23 g, 9.786 mmol) and Et3N (1.27 mL, 11.74 mmol) in
CH2Cl2 (25 mL) at 2108C. The mixture was stirred for
15 min while its temperature was allowed to warm up to
08C. The mixture was diluted with CH2Cl2 (25 mL) and
washed with cold 15% aqueous HCl (3£15 mL), water
(20 mL) and brine (20 mL). The organic phase was dried
(Na2SO4) and concentrated in vacuo. The resultant residue
was purified by flash column chromatography (hexane/
EtOAc 15:1) to yield 14 (1.378 g, 56%) as a slightly yellow
oil: IR (film) 3053, 2980, 2925, 2853, 1747, 1655, 1419,
1265, 1096, 979, 886, 840, 753, 702 cm21; 1H NMR (C6D6,
500 MHz) d 5.28 (m, 1H), 5.17 (m, 1H), 3.54 (t, 2H,
J¼6.5 Hz), 3.24 (q, 1H, J¼7.0 Hz), 2.81 (q, 1H, J¼4 Hz),
2.77 (m, 1H), 2.06 (q, 2H, J¼7.0 Hz), 1.70 (m, 2H), 1.56
(quintet, 2H, J¼6.5 Hz), 1.32 (q, 2H, J¼8.0 Hz), 0.99 (s,
3.1.9. 3-Benzylsulfanyl-10-tert-butyldimethylsiloxy-dec-
6-enoic acid (12). A mixture of 11 (12.12 g, 40.33 mmol),
toluene-a-thiol (5.51 mL, 44.36 mmol) and freshly distilled
piperidine (30 mL) was refluxed under nitrogen overnight.
The mixture was chilled in an ice bath followed by the
addition of 10% aqueous HCl to allow the pH of the aqueous
solution to reach 2–3. The suspension was extracted with
diethyl ether (3£100 mL) and the combined extracts were
washed with brine (3£40 mL), dried (Na2SO4) and
concentrated in vacuo. The residue was purified by column
chromatography (hexane/EtOAc 10:1 initially and 3:1
subsequently) to afford 12 (12.21 g, 72%) as a yellow oil:
IR (film) 3683, 3339, 3017, 2935, 2848, 1706, 1521, 1419,
1
9H), 0.07 (s, 6H); H NMR (CDCl3, 500 MHz) d 5.46 (m,
1H), 5.39 (m, 1H), 4.01 (q, 1H, J¼10 Hz), 3.60 (t, 2H,
J¼6.5 Hz), 3.52 (m, 2H), 2.06 (m, 5H), 1.90 (m, 1H), 1.57
(quintet, 2H, J¼6.5 Hz), 0.89 (s, 9H), 0.04 (s, 6H); 13C
NMR (CDCl3, 100 MHz) d 190.9, 131.8, 128.1, 62.5, 60.6,
37.6, 32.7, 32.6, 32.5, 31.7, 28.8, 25.9, 18.3, 25.3; ESIMS
m/z (%): 315 ([Mþ1]þ, 100), 273 (71), 257 (89), 183 (46),
149 (14), 141 (39); HRCIMS calcd for C16H29O2SSi
[M2H]2 313.1663; found: 313.1657.
1
1209, 1096, 968, 922, 748, 661 cm21; H NMR (CDCl3,
500 MHz) d 7.31 (m, 4H), 7.22 (m, 1H), 5.33 (m, 2H), 3.75
(s, 2H), 3.59 (t, 2H, J¼6.5 Hz), 2.97 (quintet, 1H,
J¼6.0 Hz), 2.60 (dd, 2H, J¼7.0, 2.5 Hz), 2.05 (m, 4H),
1.60 (m, 4H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR (CDCl3,
100 MHz) d 176.7, 138.5, 130.8, 130.5, 129.6, 129.1, 128.9,
128.5, 127.0, 62.6, 40.6, 35.5, 34.6, 32.5, 29.6, 28.8, 25.9,
25.6, 18.3, 25.3; ESIMS m/z (%): 423 ([Mþ1]þ,29), 422
(Mþ, 29), 377 (12), 376 (80), 310 (14), 309 (100), 252 (83),
227 (30), 219 (40), 213 (39), 190 (44), 167 (14); HRCIMS
calcd for C23H37O3SSi [M2H]2 421.2238; found:
421.2246.
3.1.12. 10-tert-Butyldimethylsiloxy-3-mercapto-dec-6-
enethioic acid (15). A stirred solution of the thiolactone
14 (1.021 g, 3.247 mmol) in CCl4 (20 mL) at ca 2358C was
saturated with hydrogen sulfide gas, and the mixture was
stirred at the same temperature for 20 min. Freshly distilled
Et3N (0.55 mL, 4.871 mmol) was added to the reaction
mixture through a hypodermic syringe. The solution was
further saturated with H2S gas for 8 h at the same
temperature. The resultant mixture was diluted with
CHCl3 (20 mL) and washed with 10% aqueous HCl
(2£10 mL), water (10 mL) and brine (10 mL), dried
(Na2SO4) and concentrated in vacuo to give 15 (0.996 g,
88%) as a yellow oil which was subjected to the oxidative
reaction in the next step without further purification.
3.1.10. 10-tert-Butyldimethylsiloxy-3-mercapto-dec-6-
enoic acid (13). A flask equipped with a stirrer, calcium
chloride drying tube, nitrogen inlet, dry ice condenser and
ammonia inlet was flushed thoroughly with a stream of
nitrogen. A solution of 12 (0.791 g, 1.878 mmol) in distilled
THF (8 mL) was added to the flask chilled at 2788C.
Gaseous ammonia (ca. 25 mL) was passed through and
condensed into the flask at the same temperature. Finely
divided metal lithium was added and a deep blue color of the
solution persisted. The mixture was stirred at 2788C for
30 min followed by the addition of solid NH4Cl. After
removal of remaining ammonia by a stream of nitrogen, the
residue was dissolved in water (20 mL) and the mixture was
acidified by the addition of 15% aqueous HCl to allow the
pH of the aqueous solution to reach 2–3. The mixture was
3.2. Preparation of sodium iodate supported on neutral
alumina
Sodium iodate (0.4 g, 2 mmol) was added to 5 mL of
distilled water in a 50 mL round-bottom flask, and the
mixture was warmed up to allow the solution to become

838
A. H. F. Lee et al. / Tetrahedron 59 (2003) 833–839
transparent. 1.0 g of alumina was added to the mixture, and
the mixture was shaken for 30 min followed by the removal
of solvents in vacuo.
661 cm21; 1H NMR (C6D6, 500 MHz) d 5.25 (m, 1H), 5.06
(m, 1H), 3.32 (t, 2H, J¼6.5 Hz), 2.69 (dd, 1H, J¼17.0,
12.5 Hz), 2.33 (m, 1H), 2.16 (dd, 1H, J¼17.0, 5.5 Hz), 1.95
(q, 2H, J¼7.0 Hz), 1.69 (m, 2H), 1.53 (m, 1H), 1.42 (q, 2H,
J¼6.5 Hz), 1.21 (m, 1H); 13C NMR (C6D6, 100 MHz) d
200.1, 132.2, 63.6, 61.8, 41.7, 32.4, 29.6, 29.1, 27.7; ESIMS
m/z (%): 249 ([Mþ1]þ,100), 217 (10); HRCIMS calcd for
C10H16O3S2 [M]2 248.0546; found 248.0539.
3.2.1. 5-(7-tert-Butyldimethysiloxyhept-3-enyl)-1,2-
dithiolan-3-one (16). Excess NaIO3/Al2O3–NaIO3 (8.1 g)
was added to 15 (0.996 g, 2.854 mmol) in a mixture of
hexane and CHCl3 (16 mL: 2 mL), and the mixture was
stirred at room temperature for 40 min followed by suction
filtration. The filter-cake was washed with CH2Cl2 (50 mL).
The combined organics were concentrated in vacuo, and the
residue was purified by flash column chromatography
(hexane/EtOAc 15:1) to afford 16 (0.791 g, 80%) as a
slightly yellow oil: IR (film) 3012, 2935, 2858, 1705, 1470,
1429, 1388, 1255, 1214, 1096, 968, 840, 763, 661,
3.2.4. Hexanedioic acid mono-(2,5-dioxo-pyrrolidin-1-
yl)ester (18). To a solution of adipic acid (5.02 g,
34.1 mmol)
and
N-hydroxysuccinimide
(4.05 g,
40.9 mmol) in distilled THF (60 mL) at 08C was added
N,N0-dicyclohexylcarbodiimide (7.22 g, 34.9 mmol) in dis-
tilled THF (20 mL). The mixture was stirred at the same
temperature for 15 min followed by the addition of catalytic
amount of DMAP (,30 mg) and further stirred overnight
during which time period the mixture was allowed to warm
up to room temperature. The resultant DCU was filtered off
and the filtrate was concentrated in vacuo. The resultant
residue was redissolved in CH2Cl2 (50 mL). The organics
were washed with water (2£20 mL) and brine (20 mL),
dried (Na2SO4) and concentrated in vacuo. The resultant
residue was purified by flash column chromatography
(hexane/ EtOAc/CH2Cl2 10:1:1) to afford 18 (3.83 g,
49%) as white crystals: IR (film) 3017, 1742, 1521, 1424,
1214, 1060, 758, 677 cm21; 1H NMR (CDCl3, 500 MHz) d
2.84 (brd, 4H, J¼4.5 Hz), 2.65 (t, 2H, J¼7.0 Hz), 2.42 (t,
2H, J¼7.0 Hz), 1.79 (m, 4H); 13C NMR (CDCl3, 100 MHz)
d 179.2, 169.5, 168.5, 33.6, 30.8, 25.8, 24.1, 23.9; ESIMS
m/z (%): 244 ([Mþ1]þ, 38), 226 (11), 225 (100), 111 (9), 91
(14); HRESIMS calcd for C10H13NO6 [M]þ 243.1029;
found: 243.1018.
1
615 cm21; H NMR (CDCl3, 500 MHz) d 5.50 (m, 1H),
5.39 (m, 1H), 3.70 (quintet d, 1H, J¼7.3, 2.5 Hz), 3.60 (t,
2H, J¼6.5 Hz), 3.00 (dd, 1H, J¼16, 5.5 Hz), 2.67 (dd, 1H,
J¼16.5, 8.5 Hz), 2.17 (quintet, 2H, J¼6.5 Hz), 2.03 (q, 2H,
J¼6.5 Hz), 1.82 (m, 2H), 1.57 (quintet, 2H, J¼7.0 Hz), 0.89
(s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3, 100 MHz) d 206.5,
132.1, 127.9, 62.5, 49.2, 48.3, 32.5, 32.4, 30.6, 28.8, 25.9,
19.1, 18.3, 25.3; ESIMS m/z (%): 350 (20), 347 ([Mþ1]þ,
14), 339 (38), 307 (68), 275 (84), 257 (100), 233 (54), 199
(63), 193 (40), 161 (49); HRCIMS calcd for C16H30O2S2Si
[M]2 346.1462; found: 346.1460.
3.2.2. 5-(7-Hydroxyhept-3-enyl)-1,2-dithiolan-3-one (17).
15% Aqueous HCl was added to a solution of 16 (0.439 g,
1.267 mmol) in absolute EtOH (15 mL), and the mixture
was stirred at room temperature for 30 min followed by the
addition of Et3N (0.5 mL). The neutralized solution was
extracted with CH2Cl2 (20 mL) and washed with water
(10 mL) and brine (10 mL). The extracts were dried
(Na2SO4) and concentrated in vacuo. The residue was
purified by flash chromatography (hexane/EtOAc 5:1) to
afford 17 (0.207 g, 71%) as a yellow syrup: IR (film) 3688,
3606, 3447, 3345, 3022, 2919, 2858, 1721, 1404, 1214, 1091,
1045, 835, 758, 677 cm21; 1H NMR (C6D6, 500 MHz) d 5.26
(m, 1H), 5.10 (m, 1H), 3.38 (t, 2H, J¼6.0 Hz), 2.92 (m, 1H),
2.28 (dd, 1H, J¼15.5, 5.0 Hz), 1.97 (m, 3H), 1.73 (m, 2H),
1.44 (quintet, 2H, J¼7.0 Hz), 1.33 (m, 1H), 1.12 (m, 1H); 13C
NMR (C6D6, 100 MHz) d 204.5, 131.6, 128.5, 61.9, 48.6,
48.2, 32.6, 32.3, 30.6, 29.1; ESIMS m/z (%): 234 ([Mþ2]þ,
31), 232 (Mþ, 43), 223 (23), 217 (12), 203 (25), 201 (43), 199
(100), 185 (22), 171 (47); HRESIMS calcd for C10H16O2S2
[M]þ 232.0683; found: 232.0687.
3.2.5. Hexanedioic acid 2,5-dioxo-pyrrolidin-1-yl ester
7-hept-3-enyl-[5-(1,2-dithiolan-3-one)] ester (19). N,N0-
dicyclohexylcarbodiimide (0.110 g, 0.506 mmol) in dis-
tilled CH2Cl2 (2 mL) was added to a solution of 17 (0.108 g,
0.456 mmol) and 18 (0.125 g, 0.506 mmol) in CH2Cl2
(4 mL) at 08C, and the mixture was stirred at the same
temperature for 5 min. A catalytic amount of DMAP
(,10 mg) was added, and the mixture was stirred at room
temperature for 3 h. The resultant DCU was filtered off and
the filter-cake was washed with CH2Cl2. The combined
organics were concentrated in vacuo and the resultant
residue was purified by flash column chromatography
(hexane/EtOAc 5:1) to afford 19 (0.104 g, 50%) as a
white semi solid: IR (film) 3048, 2981, 1819, 1783, 1741,
1
3.2.3. 5-(7-Hydroxyhept-3-enyl)-1,2-dithiolan-3-one 1-
oxide (1). A solution of 70–75% m-CPBA (0.480 g,
1.902 mmol) in distilled CH2Cl2 (6 mL) was added to a
solution of 1,2-dithiolan-3-one 17 (0.178 g, 0.761 mmol) in
distilled CH2Cl2 (10 mL), and the mixture was stirred at
240 to 2508C for 30 min and warmed up to 08C. Saturated
sodium sulfite solution was added, and the aqueous
suspension was extracted with CH2Cl2 (3£20 mL). The
combined organic extracts were washed with saturated
sodium sulfite solution (20 mL), water (20 mL) and brine
(20 mL), dried (Na2SO4) and concentrated in vacuo. The
resultant residue was purified by flash column chromato-
graphy (hexane/EtOAc 3:1 initially and 2:1 subsequently) to
afford 1 (0.087 g, 46%) as a slightly yellow oil: IR (film)
3339, 3012, 2925, 2853, 1721, 1440, 1209, 1040, 758,
1419, 1363, 1260, 1204, 1060, 892, 733, 702 cm21; H
NMR (C6D6, 500 MHz) d 5.19 (m, 1H), 5.09 (m, 1H), 3.99
(t, 2H, J¼6.5 Hz), 2.95 (m, 1H), 2.30 (dd, 1H, J¼13.5,
8.0 Hz), 2.07 (t, 2H, J¼6.5 Hz), 1.99 (dd overlap with t, 3H,
J¼17.0, 7.0 Hz), 1.89 (q, 2H, J¼7.5 Hz), 1.78 (m, 1H), 1.70
(m, 3H), 1.50 (m, 4H), 1.42 (m, 5H), 1.16 (m, 1H); 13C
NMR (C6D6, 100 MHz) d 205.0, 172.3, 168.7, 168.7, 13.1,
129.1, 63.4, 48.6, 48.1, 33.5, 32.2, 30.6, 30.5, 28.9, 28.5,
25.1, 24.1, 24.0; ESIMS m/z (%): 457 (Mþ, 33), 344 (13),
343 (100), 317 (49), 225 (21), 217 (30), 215 (38), 212 (24),
149 (21), 135 (35), 91 (52); HRCIMS calcd for
C20H27NO7S2 [M]2 457.1234; found: 457.1225.
3.2.6. Hexanedioic acid 2,5-dioxo-pyrrolidin-1-yl ester 7-
hept-3-enyl-[5-(1,2-dithiolan-3-one 1-oxo)] ester (2). A

A. H. F. Lee et al. / Tetrahedron 59 (2003) 833–839
839
3. Hirayama, N.; Matsuzawa, E. S. Chem. Lett. 1993, 11,
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solution of 70–75% m-CPBA (0.110 g, 0.434 mmol) in
CH2Cl2 (3 mL) was added to a solution of 1,2-dithiolan-3-
one 19 (0.080 g, 0.170 mmol) in CH2Cl2 (10 mL), and the
mixture was stirred at 240 to 2508C for 30 min. After
warming the mixture up to 08C, saturated sodium sulfite
aqueous solution was added, followed by the extraction of
the aqueous suspension with CH2Cl2 (2£15 mL). The
combined organic extracts were washed with saturated
sodium sulfite aqueous solution (3£10 mL), water (20 mL)
and brine (20 mL), dried (Na2SO4) and concentrated in
vacuo. The residue was purified by flash column chroma-
tography (hexane/EtOAc 8:1 initially and 3:1 subsequently)
to afford 2 (0.058 g, 71%) as a colorless oil consisting of two
inseparable diastereomersp due to the chiral centers at 1’ and
3 positions of the molecule: IR (film) 3017, 2955, 1818,
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1782, 1736, 1516, 1419, 1214, 1060, 922, 748, 666 cm21
;
1H NMR (C6D6, 500 MHz) d 5.13 (m, 1H), 4.96 (m, 1H),
3.98 (m, 2H), 3.24 (dd, 0.5H, J¼17.0, 6.0 Hz)p, 2.84 (q,
0.5H, J¼6.5 Hz)p, 2.74 (dd, 0.5H, J¼17.0, 13.0)p, 2.44 (m,
0.5H)p, 2.25 (m, 1H), 2.08 (t, 2H, J¼7.0 Hz), 1.99 (m, 2H),
1.88 (quintet, 2H, J¼7.0 Hz), 1.69 (m, 3H), 1.49 (m, 9H),
1.30 (m, 1H), 1.12 (m, 1H); 13C NMR (C6D6, 100 MHz) d
172.4, 168.8, 168.7, 131.4, 131.15, 128.9, 128.4, 65.9, 63.6,
63.3, 42.2, 41.7, 33.5, 30.5, 29.8, 29.5, 28.9, 28.9, 28.5,
28.4, 28.2, 27.7, 25.2, 24.1, 24.0; ESIMS m/z (%): 474
([Mþ1]þ, 22), 360 (8), 359 (51), 317 (23), 231 (16), 225
(100), 213 (23), 135 (21), 91 (26); HRCIMS calcd for
C20H27NO8S2[M]2 473.1184; found: 473.1191.
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Acknowledgements
We thank the Hong Kong Polytechnic University Area of
Strategic Development Fund, the University Grants Com-
mittee of Hong Kong (Areas of Excellence Scheme,
AoEP/10-01) and The Hong Kong Research Grant Council
research grant (B-Q534) for the financial support and to Dr
Jinyou Xu for helpful discussions.
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