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

Article abstract of DOI:10.1080/10426500307862

5-(7-Hydroxyheptyl)-1,2-dithiolan-3-one 1-oxide was designed and synthesized in our laboratories that contain the heterocycle of 1,2-dithiolan-3-one 1-oxide, a reactive core of antibiotic leinamycin. In addition, the activated ester of 5-(7-hydroxyheptyl)-1,2-dithiolan-3-one 1-oxide was prepared, which presumably is useful for coupling this DNA-cleaving functionality to certain DNA-binding agents.

Full text of DOI:10.1080/10426500307862

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of 5-(7-Hydroxyheptyl)-1,2-dithiolan-3-one 1-
Oxide, a Core Functionality of Antibiotic Leinamycin
Alex H. F. Lee a , Jian Chen a , Albert S. C. Chan a & Tianhu Li a
a Hong Kong Polytechnic University , Hung Hom, Kowloon, Hong Kong
Published online: 27 Oct 2010.
To cite this article: Alex H. F. Lee , Jian Chen , Albert S. C. Chan & Tianhu Li (2003) Synthesis of 5-(7-Hydroxyheptyl)-1,2-
dithiolan-3-one 1-Oxide, a Core Functionality of Antibiotic Leinamycin, Phosphorus, Sulfur, and Silicon and the Related
Elements, 178:5, 1163-1174, DOI: 10.1080/10426500307862
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:1163–1174
C
Copyright 2003 Taylor & Francis
1042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390208992
SYNTHESIS OF 5-(7-HYDROXYHEPTYL)-
1,2-DITHIOLAN-3-ONE 1-OXIDE, A CORE
FUNCTIONALITY OF ANTIBIOTIC LEINAMYCIN
Alex H. F. Lee, Jian Chen, Albert S. C. Chan, and Tianhu Li
Hong Kong Polytechnic University, Hung Hom, Kowloon,
Hong Kong
(Received October 1, 2002; accepted November 19, 2002)
5-(7-Hydroxyheptyl)-1,2-dithiolan-3-one 1-oxide was designed and syn-
thesized in our laboratories that contain the heterocycle of 1,2-
dithiolan-3-one 1-oxide, a reactive core of antibiotic leinamycin. In ad-
dition, the activated ester of 5-(7-hydroxyheptyl)-1,2-dithiolan-3-one 1-
oxide was prepared, which presumably is useful for coupling this DNA-
cleaving functionality to certain DNA-binding agents.
Keywords: Antibiotic; antitumor agents; heterocycle; leinamycin
Since the discovery of structural elucidation1 and total synthesis2 of
the antibiotic leinamycin in 1990s, it has been demonstrated that
this antibiotic exhibited potent activity against murine experimen-
tal tumor leukemia P388 and saccoma 180 as well as against Gram-
positive bacteria.3 Subsequent examination indicated that the latent
DNA-cleaving activity of leinamycin is accountable for its cytotoxic
properties.4,5 Unlike any previously discovered natural products in
molecular structure, on the other hand, leinamycin possesses the
unique 1,2-dithiolan-3-one 1-oxide heterocycle as its reactive core.6
In addition, certain mechanistic investigations revealed that the het-
erocycle of 1,2-dithiolan-3-one 1-oxide plays a crucial role in the
thiol-activated DNA-cleaving processes in which free radicals are
6
involved.4 With the intention of further exploring the chemical and
We thank the University Grants Committee of Hong Kong (Areas of Excellence
Scheme, AoEP/10-01), the Hong Kong Polytechnic University ASD Fund, and The Hong
Kong Research Grant Council (B-Q534) for the financial support; we also thank Dr. Jinyou
Xu for helpful discussions.
Address correspondence to Tianhu Li, Department of Applied Biology, Hong Kong
Polytechnic University, Hung Hom, Kowloon, Hong Kong. E-mail: bctli@polyu.edu.hk
1163

1164
A. H. F. Lee et al.
biological properties of leinamycin, we recently have designed and syn-
thesized 5-(7-hydroxyheptyl)-1,2-dithiolan-3-one 1-oxide 1 in our lab-
oratories that contains the heterocycle of 1,2-dithiolan-3-one 1-oxide
in its structure, the reactive core of leinamycin.6 In addition, the ac-
tivated ester of 5-(7-hydroxyheptyl)-1,2-dithiolan-3-one 1-oxide 2 was
prepared which presumably is useful for coupling this DNA-cleaving
functionality to certain DNA-binding agents.7,8 The synthesis of 5-(7-
hydroxyheptyl)-1,2-dithiolan-3-one 1-oxide 1 as well as 2 is discussed
in this article.
RESULTS AND DISCUSSION
Scheme 1 depicts our synthetic route toward 5-(7-hydroxyheptyl)-
1,2-dithiolan-3-one 1-oxide starting with a monosilylation reaction of
octane-1,8-diol by using stoichiometric equivalent sodium hydride as
base. The aldehyde 5 was obtained through an oxidation reaction of the
alcohol 4 with PDC.9 Olefination of 5 was carried out via an Horner-
Emmons type reaction involving phosphonate anions.10 Hydrolysis of
6 posed a challenge in our synthesis because this ester is exceptionally
stable toward many commonly used hydrolytic reagents such as sodium
hydroxide and potassium hydroxide/aqueous-ethanol. After several at-
tempts, our hydrolysis of 6 was accomplished successfully by stirring
this ester in KOtBu/tBuOH. The yield of this reaction in our studies can
even be optimized to 87% when LiOH/EtOH is used. Benzyl thioether 8
was obtained through a reaction of prop-2-enoic acid 7 with toluene- -
thiol in piperidine.11 Since the mercapto acid 9 is too unstable to survive
in many purification processes, Li/liquid ammonia12 was employed to
carry out this debenzylation reaction. Cyclization reaction of 9 in the
solution of isobutyl chloroformate and triethylamine gave rise to the
corresponding thiolactone 10. The ring-opening reaction of thiolactone
10 afforded the corresponding mercapto thioic acid 11, a process cat-
alyzed by hydrogen sulfide.11 Oxidative reaction of 11 with sodium io-
date supported on neutral alumina in biphases circumstance and gave
rise to the ring-closure product 12.13 Desilylation of 12 in hydrochloric
acid/ethanol was used to produce the corresponding alcohol 13. Finally,
mCPBA was applied to accomplish the S-oxidation of 1,2-dithiolan-3-
one moiety to afford the 1,2-dithiolan-3-one 1-oxide 1a and 1b, a pair
of diastereomers separable through flash column chromatography.
In order to covalently linking the core functionality of leinamycin to
certain DNA-binding agents for the future use, the activated ester 2
also was synthesized.7,8 The linker 15 was prepared first through the

Core Functionality of Antibiotic Leinamycin
1165
SCHEME 1 Synthesis of 1a and 1b: (a) TBDMSCl, NaH, THF, rt, 67%;
(b) PDC, CH2Cl2, rt, 65%; (c) triethyl phosphonacetate, NaH, THF, 70 C to rt,
64%; (d) LiOH, EtOH, rt, 87%; (e) toluene- -thiol, piperidine, reflux, overnight,
66%; (f) Li, NH3(l), 78 to 60 C, then NH4Cl(s) 98%; (g) isobutylchlorofor-
mate, Et3N, CH2Cl2, 10 to 0 C, 56%; (h) H2S(g), Et3N, 40 to 30 C, then HCl
(aq), rt; (i) NaIO3-Al2O3, CHCl3-hexane, rt, 40 min, 87%; (j) HCl (aq)-EtOH, rt,
30 min, 92%; (k) mCPBA, CH2Cl2, 50 to 40 C, 80%.
reaction of adipic acid and N-hydroxysuccinimide catalyzed by DMAP
followed by the condensation14 between 1,2-dithiolan-3-ones 13 and 15.
Subsequent oxidation of 16 by mCPBA afforded the desired product 1,2-
dithiolan-3-one 1-oxides 2 comprising two inseparable diastereomers in
1:1 ratio (deduced from 1H NMR and 1H-1H COSY NMR) with the chiral
centers at 10 and 3 positions (see Figure 1).

1166
A. H. F. Lee et al.
SCHEME 2 Synthesis of 2: (a) NHS, DCC, cat. DMAP, THF, 0 C, 49%; (b) DCC,
cat. DMAP, CH2Cl2, 0 C, 44%; (c) mCPBA, CH2Cl2, 50 to 40 C, 45%.
EXPERIMENTAL
All 1H NMR and 13C NMR spectra were obtained on a Bruker Ad-
vance DPX 400 FT-NMR Spectrometer or Varian Unity INOVA 500
FT-NMR Spectrometer. Low resolution mass spectra were obtained on
Fisons VG Platform Mass Spectrometer, or Hewelett Packard G1800C
GCD Series II GCMS. High resolution mass spectra (HRMS) were mea-
sured by Finnigan MAT95 Mass Spectrometer. All reactions were moni-
tored by thin layer chromatography (TLC) performed on Merck precoat-
ed silica gel 60 F254 plates. Flash column chromatography was carried
out on columns of NA or Merck Keisel silica gel 60 (230–400 mesh).
FIGURE 1 Structures of leinamycin and the newly designed core functional-
ities of the antibiotic.

Core Functionality of Antibiotic Leinamycin
1167
THF and dichloromethane were distilled from Na/benzophenone and
CaH2, respectively, prior to use. Unless otherwise noted, materials and
solvents were obtained from commercial suppliers and used without
further purification.
8-tert-Butyldimethylsiloxy-n-octan-1-ol (4)
60% w/w sodium hydride (9.0 g, 0.226 mmol) was suspended in distilled
THF (400 mL) followed by the addition of octane-1,8-diol 3 (29.70 g,
0.204 mmol) in THF (150 mL). The mixture was stirred at room temper-
ature for 2 h at which time a large amount of opaque white precipitates
were formed. After the addition of tert-butyldimethylsilyl chloride (34.0
g, 0.226 mmol) in THF (50 mL), the mixture was stirred vigorously at
room temperature overnight. The reaction was quenched by the addi-
tion of ca 300 mL of saturated aqueous K2CO3 and extracted with di-
ethyl ether (2 250 mL). The combined organic extracts were washed
with brine (150 mL), dried over Na2SO4, and concentrated in vacuo to
1
afford 4 (35.60 g, 67%) as colorless syrup: H NMR (CDCl3) 0.04 (s,
6H), 0.89 (s, 9H), 1.34 (m, 6H), 1.54 (m, 6H), 3.59 (t, 2H, J = 6.5 Hz),
3.64 (t, 2H, J = 6.5 Hz); 13C NMR (CDCl3) 5.27, 18.37, 25.63, 25.66,
25.72, 25.97, 29.38, 32.76, 32.83, 63.06, 63.29; ESIMS m/z (%) 261 [(M
+ 1)+, 8], 257 (12), 169 (6), 147 (100).
8-tert-Butyldimethylsiloxy-n-octan-l-al (5)
To a slurry mixture of PDC (61.0 g, 0.161 mmol) and activated molecu-
lar sieves (type 5A powder, 20 g) in distilled CH2Cl2 (150 mL) was added
a solution of 4 (28.5 g, 0.108 mmol) in distilled CH2Cl2 (100 mL). The
mixture was stirred vigorously at room temperature for 4 h. After the
addition of diethyl ether (100 mL), the ethereal mixture was suction-
filtered, and the filter-cake was washed with diethyl ether and EtOAc.
After evaporation under vacuum, the residue was purified by flash col-
umn chromatography with hexane:EtOAc (15:1, v/v) as eluent to afford
5 (18.16 g, 65%) as a colorless syrup: 1H NMR (CDCl3) 0.04 (s, 6H), 0.89
(s, 9H), 1.31 (bs, 6H), 1.50 (bt, 2H, J = 6.5 Hz), 1.63 (bt, 2H, J = 7.0 Hz),
2.42 (td, 2H, J = 7.5, 2.0 Hz), 3.59 (t, 2H, J = 6.5 Hz), 9.76 (t, 1H,
J = 2.0 Hz); 13C NMR (CDCl3) 5.34, 18.29, 21.96, 25.56, 25.91, 29.09,
32.70, 43.82, 63.10, 202.68; ESIMS m/z (%) 259 [(M + 1)+ 100], 257 (31);
HRESIMS found 259.2225, calculated for C14H31O2Si 259.2257.
10-tert-Butyldimethylsiloxy-dec-2-enoic
Acid Ethyl Ester (6)
Triethyl phosphonoacetate (13.0 mL, 65.8 mmol) was added dropwise
to 60% w/w NaH (5.26 g, 65.8 mmol) in distilled THF (250 mL) at room

1168
A. H. F. Lee et al.
temperature. The mixture was stirred at room temperature for 2 h at
which time certain heat evolutions were observable. After the addi-
tion of 5 (17.0 g, 65.8 mmol) in distilled THF (150 mL), the mixture
was heated at reflux for 1.5 h. After cooling the mixture to room tem-
perature, solvent was removed under reduced pressure to yield a yel-
low syrup. The residue was dissolved in CH2Cl2, washed with water
(30 mL), brine (40 mL), and dried over Na2SO4. After evaporation under
vacuum, the crude product was purified by flash column chromatogra-
phy with hexane:EtOAc (30:1, v/v) as eluent to afford 6 (13.8 g, 64%)
1
as a slightly yellow oil: H NMR (CDCl3) 0.04 (s, 6H), 0.89 (s, 9H),
1.28 (t, 3H, J = 7.0 Hz), 1.30 (bs, 4H), 1.47 (m, 6H), 2.18 (m, 2H), 3.58
(t, 2H, J = 7.0 Hz), 4.17 (q, 2H, J = 7.5 Hz), 5.80 (dt, 1H, J = 15.5,
1.5 Hz), 6.95 (m, 1H); 13C NMR (CDCl3) 5.25, 14.30, 18.39, 25.71,
26.00, 27.98, 29.14, 29.20, 32.19, 32.83, 60.14, 63.26, 121.25, 149.46,
166.82; ESIMS m/z (%) 329 [(M + 1)+, 100]; HRESIMS found 329.2418,
calculated for C18H37O3Si 329.2384.
10-tert-Butyldimethylsiloxy-dec-2-enoic Acid (7)
To a solution of 6 (12.67 g, 38.56 mmol) in ethanol (70 mL) and wa-
ter (2 mL) was added 56% w/w LiOH (9.70 g, 231.0 mmol) at room
temperature. The mixture was stirred vigorously at the same temper-
ature for 20 h followed by filtration of the mixture through a filter pa-
per. The filter-cake was washed with an appropriate volume of EtOAc.
After evaporation under vacuum, the residue was dissolved in water
(30 mL) which was acidified to pH 4-5 by adding 10% aqueous HCl.
The aqueous mixture was extracted with CH2Cl2 (3 90 mL). The or-
ganic phase was washed with brine (30 mL) and dried over Na2SO4.
After evaporation under vacuum, the crude product was purified by
flash column chromatography using hexane: EtOAc (10:1 → 5:1, v/v)
as eluent to afford 7 (10.08 g, 87%) as a colorless oil which was readily
1
formed a white crystal at room temperature: H NMR (CDCl3) 0.05
(s, 6H), 0.89 (s, 9H), 1.31 (bs, 5H), 1.48 (m, 5H), 2.22 (q, 2H, J = 7.0
Hz), 3.60 (t, 2H, J = 7.0 Hz), 5.83 (d, 1H, J = 15.5 Hz), 7.08 (quintet,
1H, J = 7.0 Hz); 13C NMR (CDCl3) 5.28, 18.36, 25.66, 25.97, 27.81,
29.10, 29.14, 32.28, 32.77, 63.23, 120.55, 152.40, 171.81; ESIMS m/z (%)
301 [(M + 1)+, 100], 275 (5), 187 (7), 169 (7); HRESIMS found 300.2122,
calculated for C16H32O3Si 300.2124.
3-Benzylsulfanyl-10-(tert-butyldimethysiloxy)decanoic
Acid (8)
A mixture of 7 (8.15 g, 27.1 mmol), toluene- -thiol (3.20 mL, 27.3 mmol)
and piperidine (15 mL) was heated at reflux overnight. After cooling

Core Functionality of Antibiotic Leinamycin
1169
the mixture in ice bath, 10% aqueous HCl was added to allow the pH of
the solution to reach 2-3. The resultant white suspension was extracted
with diethyl ether (3 100 mL) and the combined extracts were washed
with brine (3 40 mL) and dried over Na2SO4. After evaporation under
vacuum, the crude product was purified by flash column chromatogra-
phy with hexane: EtOAc (10:1 → 3:1, v/v) as eluent to afford pure 8
1
(7.57 g, 66%) as a colorless oil: H NMR (CDCl3) 0.05 (s, 6H), 0.90
(s, 9H), 1.26 (m, 7H), 1.38 (m, 1H), 1.51 (m, 4H), 2.60 (m, 2H), 2.96
(quintet, 1H, J = 6.0 Hz), 3.59 (t, 2H J = 6.5 Hz), 3.76 (s, 2H), 7.23 (dt,
1H, J = 7.0 Hz), 7.32 (m, 4H); 13C NMR (CDCl3) 5.26, 18.37, 25.28,
25.61, 25.69, 25.97, 26.53, 29.03, 29.22, 29.24, 29.68, 32.54, 32.79, 34.62,
34.79, 35.54, 40.61, 41.13, 63.31, 127.01, 128.46,128.90, 138.21, 176.91;
ESIMS m/z (%) 424 [(M + 1)+, 31], 394 (16), 379 (11), 378 (68), 327
(28), 311 (28), 256 (12), 228 (19), 227 (100); HRESIMS found 424.2430,
calculated for C23H40O3SSi 424.2457.
10-(tert-Butyldimethysiloxy)-3-mercaptodecanoic
Acid (9)
A flask was equipped with a stirrer, calcium chloride drying tube, ni-
trogen inlet, dry ice condenser, and ammonia inlet. After the flask was
flushed thoroughly with a stream of nitrogen, the ammonia was passed
through and condensed into the flask followed by the addition of 8
(6.80 g, 16.0 mmol) in distilled THF (50 mL) at 78 C. Finely divided
metal lithium was added to allow the deep blue color of the solution to
persist. The mixture was stirred at 60 to 78 C for 1.5 h followed by
the addition of adequate amount of solid NH4Cl to quench the reaction.
After passing N2 through the white slurry mixture to remove the re-
maining ammonia at room temperature, the solid residue was dissolved
in water (50 mL) which was acidified with 15% v/v aqueous HCl to allow
its pH to reach 2-3. The aqueous mixture was extracted with CH2Cl2
(3 100 mL). The combined organics was washed with water (30 mL),
brine (3 25 mL), and dried over Na2SO4. Evaporation of solvent under
vacuum afforded 9 (5.26 g, 98%) as a white turbid syrup with foul smell.
This compound was subjected to the next step reaction without purifi-
cation (this mercaptan is readily oxidized by oxygen in air): 1H NMR
(CDCl3) 0.05 (s, 6H), 0.89 (s, 9H), 1.31 (bs, 6H), 1.51 (m, 5H), 1.66 (m,
1H), 1.72 (d, 1H, J = 7.5 Hz), 2.57 (dd, 1H, J = 16.0, 8.5 Hz), 2.74 (dd,
1H, J = 16.0, 5.0 Hz), 3.19 (m, 1H), 3.60 (t, 2H, J = 6.5 Hz); 13C NMR
(CDCl3); 5.27, 18.37, 25.60, 25.69, 25.97, 26.96, 29.01, 29.10, 29.23,
32.76, 36.13, 38.09, 44.05, 63.28, 176.82; ESIMS m/z (%) 333 (M+, 19),
327 (18), 311 (21), 275 (22), 256 (61), 228 (49), 227 (32), 211 (31), 183
(52), 143 (63), 136 (100).

1170
A. H. F. Lee et al.
4-(7-tert-Butyldimethysiloxyheptyl)thietan-2-one (10)
To a solution of 9 (5.26 g, 15.7 mmol) and freshly distilled Et3N (2.20 mL,
20.4 mmol) in CH2Cl2 (40 mL) was added isobutyl chloroformate (2.30
mL, 17.3 mmol) at 10 C. The mixture was stirred for 30 min at which
time its temperature was allowed to warm up to reach 0 C. It was di-
luted with CH2Cl2 (25 mL) and washed successively with cold 15%
aqueous HCl (3 15 mL), diluted Na2CO3 aqueous solution (20 mL)
and brine (20 mL). The combined organics were dried over Na2SO4. Af-
ter evaporation under vacuum the residue was purified by flash column
chromatography with hexane: EtOAc (20:1, v/v) as eluent to yield 10
(2.74 g, 56%) as a colorless syrup: 1H NMR (C6D6) 0.07 (s, 6H), 0.98 (s,
9H), 1.03 (m, 2H), 1.05 (m, 2H), 1.12 (m, 2H), 1.28 (m, 4H), 1.49 (quin-
tet, 2H, J = 6.5 Hz), 2.77 (m, 1H), 2.87 (dd, 1H, J = 17.5, 3.5 Hz), 3.31
(dd, 1H, J = 17.0, 7.0 Hz), 3.56 (t, 2H, J = 6.0 Hz); 13C NMR (C6D6)
4.44, 19.20, 26.85, 29.49, 29.99, 30.19, 33.67, 33.88, 38.53, 61.61,
63.89, 189.58; ESIMS m/z (%) 318 [(M + 1)+, 16], 317 (M+, 100), 301
(8); HRESIMS found 316.1756, calculated for C16H32O2SSi 316.1742.
10-(tert-Butyldimethysiloxyheptyl)-3-
mercaptodecanethioic Acid (11)
A solution of 10 (2.08 g, 6.58 mmol) in CCl4 (12 mL) chilled at 30
to 40 C was saturated with hydrogen sulfide gas. The mixture was
stirred at the same temperature for 20 min followed by the addition
of freshly distilled Et3N (1.07 mL, 9.87 mmol). The resultant solution
was saturated with H2S gas for 7 h followed by the introduction of
N2 to expel the remaining H2S gas at 0 C. The mixture was diluted
with CHCl3 (20 mL) and washed with water (2 10 mL). The aqueous
mixture was acidified with 10% aqueous HCl to allow its pH to reach
1-2. The organic phase was washed with brine (2 10 mL) and dried
over Na2SO4. Evaporation of solvent under reduced pressure to afford
11 as a yellow oil with foul odor which was subjected to the oxidative
coupling reaction in the next step without further purification (this
thioic acid is not stable enough for further characterization): 1H NMR
(CDCl3) 0.05 (s, 6H), 0.91 (s, 9H), 0.98 (bs, 2H), 1.40 (m, 4H), 1.43 (m,
6H), 2.67 (dd, 1H, J = 16.0, 9.0 Hz), 3.00 (dd, 1H, J = 16.0, 5.5 Hz),
3.60 (t, 2H, J = 14.5 Hz), 3.65 (m, 1H), 3.70 (m, 1H).
5-(7-tert-Butyldimethysiloxyheptyl)-
1,2-dithiolan-3-one (12)
To a solution of 11 (2.33 g, 6.58 mmol) in the mixture of hexane: CHCl3
(24 mL: 2 mL) was added NaIO3/Al2O3-NaIO3 (14.2 g). The mixture

Core Functionality of Antibiotic Leinamycin
1171
was stirred at room temperature for 40 min followed by filtration. The
filter-cake was washed with appropriate volume of CH2Cl2. The filtrate
was concentrated in vacuo. The resultant residue was purified by flash
column chromatography with hexane: EtOAc (15:1, v/v) as eluent to
afford 12 (2.01 g, 87%) as a slightly yellow oil: 1H NMR (CDCl3) 0.04
(s, 6H), 0.89 (s, 9H), 1.32 (bs, 6H), 1.49 (m, 4H), 1.78 (m, 2H), 2.67
(dd, 1H, J = 16.0, 8.5 Hz), 3.00 (dd, 1H, J = 16.5, 5.5 Hz), 3.60 (t, 2H,
J = 7.0 Hz), 3.70 (m, 1H); 13C NMR (CDCl3) 5.29, 18.34, 25.65, 25.95,
27.77, 29.12, 32.73, 32.86, 49.20, 49.25, 63.15, 206.47; ESIMS m/z (%)
349 [(M + 1)+, 19], 317 (33), 301 (7), 256 (11), 236 (11), 235 (100), 217
(22); HRESIMS found 348.1588, calculated for C16H32O2S2Si 348.1605.
5-(7-Hydroxyheptyl)-1,2-dithiolan-3-one (13)
To a solution of 12 (1.462 g, 4.201 mmol) in EtOH (20 mL) was added
aqueous HCl (15%, 0.9 mL). The mixture was stirred at room tempera-
ture for 40 min followed by the addition of Et3N (0.5 mL). The organic
phase was concentrated in vacuo. The residue was dissolved in CH2Cl2
(30 mL), washed with water (20 mL), brine (20 mL), and dried over
Na2SO4. After evaporation under vacuum, the crude product was puri-
fied by flash column chromatography with hexane: EtOAc (5:1, v/v) to
1
yield 13 (0.906 g, 92%) as a yellow syrup: H NMR (C6D6) 0.92 (m,
3H), 1.01 (m, 4H), 1.18 (m, 3H), 1.35 (quintet, 2H, J = 7.5 Hz), 1.97 (dd,
2H, J = 16.5, 8.5 Hz), 2.25 (dd, 1H, J = 16.5, 5.5 Hz), 2.83 (m, 1H), 3.35
(t, 2H, J = 7.0 Hz); 13C NMR (C6D6) 25.98, 27.83, 29.29, 29.40, 32.72,
33.01, 48.80, 49.02, 62.56, 205.44; ESIMS m/z (%) 234. (M+, 100), 217
(24); HRESIMS found 234.0747, calculated for C10H18O2S2 234.0746.
5-(7-Hydroxyheptyl)-1,2-dithiolan-3-one 1-Oxide (1)
To a solution of 13 (0.521 g, 2.22 mmol) in distilled CH2Cl2 (15 mL) was
added a solution of 70–75% mCPBA (1.410 g, 5.55 mmol) in distilled
CH2Cl2 (10 mL). The mixture was stirred at 40 to 50 C for 30 min.
After warming up the mixture to 0 C, saturated sodium sulfite solution
was added followed by the extraction of the aqueous suspension with
CH2Cl2 (3 20 mL). The combined organic extracts were washed with
saturated sodium sulfite aqueous solution (20 mL), water (20 mL), brine
(20 mL), and dried over Na2SO4. After evaporation under vacuum, the
crude product was purified by flash column chromatography with hex-
ane: EtOAc (5:1 → 1:2, v/v) as eluent to afford two diastereomers la
1
and lb, la (0.220 g, 39%, a colorless oil): H NMR (C6D6) 0.827 (m,
1H), 1.01 (m, 2H), 1.11 (m, 4H), 1.21 (quintet, 2H, J = 7.0 Hz), 1.43 (m,
3H), 2.18 (dd, 1H, J = 20.0, 5.0 Hz), 2.24 (m, 1H), 2.72 (dd, 1H, J = 16.5,

1172
A. H. F. Lee et al.
12.0 Hz), 3.40 (t, 2H, J = 6.2 Hz); 13C NMR (C6D6) 25.89, 26.62, 28.03,
29.19, 29.37, 32.89, 41.82, 62.52, 64.37, 200.25; ESIMS m/z (%) 251 [(M
+ 1)+, 100], 233 (38), 65 (35); HRESIMS found 251.0959, calculated
1
for C10H19O3S2 251.0944. 1b (0.231 g, 41%, a colorless oil): H NMR
(C6D6) 0.64 (m, 1H), 0.77 (m, 4H), 0.98 (m, 3H), 1.17 (m, 2H), 1.39
(quintet, 2H, J = 5.0 Hz), 2.19 (dd, 1H, J = 17.0, 1.0 Hz), 2.69 (q, 1H,
J = 6.0 Hz), 3.20 (dd, 1H, J = 17.5, 6.5 Hz), 3.40 (t, 2H, J = 6.0 Hz);
13C NMR (C6D6) 25.90, 27.16, 28.81, 29.18, 32.87, 42.27, 62.50, 66.82,
201.44; ESIMS m/z (%) 251 [(M + 1)+, 100], 233 (41), 65 (55);HRESIMS
found 251.0986, calculated for C10H19O3S2 251.0944.
Hexanedioic Acid Mono-(2,5-dioxo-
pyrrolidin-1-yl)Ester (15)
To a solution of adipic acid 14 (5.02 g, 34.1 mmol) and N-
hydroxysuccinimide (4.05 g, 40.9 mmol) in distilled THF (60 mL) was
added N,N0-dicyclohexylcarbodiimide (7.22 g, 34.9 mmol) in distilled
THF (20 mL) at 0 C. The mixture was stirred at the same tempera-
ture for 15 min followed by the addition of a catalytic amount of DMAP
( 30 mg) in one portion. The mixture was stirred overnight at which
time it was allowed to warm up to room temperature. After filtration
of the resultant DHU, the filtrate was concentrated by rotavaporation.
The residue was redissolved in CH2Cl2 (50 mL), washed with water
(2 20 mL), brine (20 mL) and dried over Na2SO4. After evaporation
under vacuum, the residue was purified by flash column chromatogra-
phy with hexane: EtOAc: CH2Cl2 (10:10:1, v/v/v) as eluent to afford 15
1
(3.83 g, 49%) as a white crystal: H NMR (CDCl3) 1.79 (m, 4H), 2.42
(t, 2H, J = 7.0 Hz), 2.65 (t, 2H, J = 7.0 Hz), 2.84 (bd, 4H, J = 4.5 Hz),
13C NMR (CDCl3) 23.88, 24.09, 25.80, 30.81, 33.58, 168.50, 169.53,
179.23; ESIMS m/z (%) 244 [(M + 1)+, 38], 226 (11), 225 (100), 111 (9),
91 (14); HRESIMS found 243.1318, calculated for C10H13NO6 243.1294.
Hexanedioic Acid 2,5-dioxo-pyrrolidin-1-yl Ester
7-heptyl-[5-(1,2-dithiolan-3-one)] Ester (16)
To a solution of 15 (0.301 g, 1.239 mmol) and 13 (0.264 g, 1.130 mmol)
in distilled CH2Cl2 (6 mL) was added N,N0-dicyclohexylcarbodiimide
(0.260 g, 1.241 mmol) in distilled CH2Cl2 (2 mL) at 0 C. The mixture
was stirred at the same temperature for 10 min followed by the addition
of a catalytic amount of DMAP ( 15 mg). After 3 h at room tempera-
ture, the resultant DHU was filtered off. The filter-cake was washed
with CH2Cl2. The filtrate was concentrated in vacuo. The residue was
purified by flash column chromatography with hexane: EtOAc (5:1, v/v)

Core Functionality of Antibiotic Leinamycin
1173
1
as eluent to afford 16 (0.223 g, 44%) as a white semi solid: H NMR
(C6D6) 0.91 (m, 3H), 1.03 (m, 2H), 1.13 (m, 2H), 1.24 (m, 1H), 1.43
(m, 6H), 1.56 (bs, 2H), 1.71 (bs, 2H), 2.00 (t, 2H, J = 8.5 Hz), 2.04 (dd,
1H, J = 16.0, 6.5 Hz), 2.08 (t, 2H, J = 7.0 Hz), 2.31 (dd, 1H, J = 16.0,
5.5 Hz), 2.89 (m, 1H), 4.00 (t, 2H, J = 7.0 Hz); 13C NMR (C6D6) 24.01,
24.08, 25.16, 25.92, 27.69, 28.84, 29.05, 30.46, 32.59, 33.55, 48.68, 48.89,
64.11, 168.68, 169.78, 172.40, 205.21; ESIMS m/z (%) 460 [(M + 1)+,
24], 449 (44), 349 (9), 345 (21), 225 (100); HRESIMS found 459.1861,
calculated for C20H29NO7S2 459.1857.
Hexanedioic Acid 2,5-dioxo-pyrrolidin-l-yl Ester
7-heptyl-[5-(1,2-dithiolan-3-one 1-oxo)] Ester (2)
To a solution of 16 (0.188 g, 0.409 mmol) in distilled CH2Cl2 (20 mL)
was added 70 to 75% mCPBA (0.250 g, 1.024 mmol) in distilled CH2Cl2
(4 mL). The mixture was stirred at 40 to 50 C for 45 min. Upon
raising temperature to 0 C, saturated sodium sulfite aqueous solution
was added followed by the extraction of the aqueous suspension with
CH2Cl2 (3 15 mL). The combined organic extracts were washed with
saturated sodium, sulfite aqueous solution (3 10 mL), water (20 mL),
brine (20 mL), and dried over Na2SO4. After evaporation under vacuum,
the crude product was purified by flash column chromatography with
hexane: EtOAc (5:1→1:1, v/v) as eluent to afford 2 (two inseparable
1
diastereomers* in 1:1 ratio, 0.090 g, 45%) as a colorless oil: H NMR
(C6D6) 0.83 (m, 2H), 0.96 (m, 2H), 1.04 (m, 3H), 1.15 (m, 3H), 1.44
(m, 6H), 1.55 (bs, 2H), 1.69 (bs, 2H), 2.01 (t, 2H, J = 7.0), 2.07 (t, 2H,
J = 7.0 Hz), 2.22 (dd, 1H, J = 19.5, 2.5 Hz), 2.31 (m, 0.5 H) , 2.75 (dd,
1H, J = 16.5, 12.5 Hz), 3.20 (m, 0.5 H) , 4.01 (t, 2H, J = 7.0 Hz); 13C
NMR (C6D6) 24.12, 24.20, 25.27, 25.99, 26.65, 27.16, 28.05, 28.81,
28.94, 28.99, 29.10, 29.29, 30.56, 33.68, 41.88, 42.31, 64.15, 64.33, 66.89,
168.79, 168.88, 172.50, 200.27; ESIMS m/z (%) 476 (M+, 29), 450 (9), 449
(35), 361 (21), 226 (12), 225 (100), 65 (21); HRESIMS found 476.1444,
calculated for C20H29NO8S2 476.1475.
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