Synthesis of acetomycin bislactone analogues

Article abstract of DOI:10.1055/s-2004-822388

Bislactones 5 and 6 have been designed as esterase-resistant acetomycin analogues and prepared in 10 steps from methyl 2-methylacetoacetate. Consecutive quaternary and tertiary carbon centers at the C-3 and C-4 positions on the γ-lactone ring are constructed by Pd-catalyzed allylic alkylation in one step. The relative stereochemistry for 6 has been determined by X-ray crystallographic analysis.

Full text of DOI:10.1055/s-2004-822388

PAPER
1343
Synthesis of Acetomycin Bislactone Analogues
Synthesis
u
of
A
cetomyc
n
inBislactone
’
A
nalog
i
ues chi Uenishi,* Hironobu Muraoka, Masatake Nameki, Naoko Hata
Kyoto Pharmaceutical University, Misasagi-Shichounocho, Yamashina, Kyoto 607-8412, Japan
Fax +81(75)5954763; E-mail: juenishi@mb.kyoto-phu.ac.jp
Received 15 April 2004
Dedicated to Prof. Mukaiyama on the occasion of his 77th birthday
Synthesis of Bislactones
Abstract: Bislactones 5 and 6 have been designed as esterase-resis-
tant acetomycin analogues and prepared in 10 steps from methyl 2-
methylacetoacetate. Consecutive quaternary and tertiary carbon
centers at the C-3 and C-4 positions on the g-lactone ring are con-
structed by Pd-catalyzed allylic alkylation in one step. The relative lyzed allylic alkylation can be a powerful C-C bond-form-
stereochemistry for 6 has been determined by X-ray crystallograph-
The retro-synthetic analysis for 5 and 6 is shown in
Figure 1. Recently, we have demonstrated that Pd-cata-
ing reaction to construct consecutive quaternary and
ic analysis.
tertiary carbons stereoselectively, and this reaction served
the shortest synthesis of (–)-acetomycin.10 Based on this
Key word: bioorganic chemistry, palladium, esterase, stereoselec-
tive synthesis, g-lactone
method, we plan to connect the C-3 and C-4 carbons. Ozo-
nolysis of an alkenyl bond gives aldehyde that corre-
sponds to the C-5 carbon. Branched carbons at the C-4
position will lead to g-lactone function.
Introduction
H
H
H
Me
Acetomycin (1) was isolated from Streptomyces ramulo-
sus sp. in 1958 by Prelog et al.1 The three-dimensional
structures of the brominated derivative,2 as well as that of
acetomycin itself,3 were determined by X-ray crystallo-
graphic analysis. Initially, only a weak antibacterial activ-
ity was known,4 but Mamber et al. showed in 1987 that
acetomycin possessed unique anti-cancer activity against
L-1210 murine leukemia cells and HCT-8 human colon
adenocarcinoma cells.5 Although acetomycin has potent
anti-cancer activity, it is not a useful medicine due to the
rapid hydrolysis by esterase present in tissues.6 We have
been making efforts to design esterase-resistant analogues
of acetomycin.7 We reported the synthesis of 5-carbo and
5-ethoxy analogues, 3 and 4,8,9 which exhibited inactivity
against esterase but unfortunately also insufficient anti-
cancer activity. Since a g-lactone ring was found to be sta-
ble to esterase, we have designed new acetomycin bislac-
tone analogues, 5 and 6 (Figure 1). In their structures, C-
5 acetoxy groups of 1 and 4,5-diepi-acetomycin (2) are
connected to C-4 carbon to form an additional g-lactone
ring. Endo-bislactone (5) is structurally similar to 1, and
exo-bislactone (6) is structurally similar to 2. Since the
acetoxy group, which is prone to esterase attacks, is re-
placed with a g-lactone ring in their specific structures,
they are expected to be resistant to hydrolysis by esterase.
Hopefully, they will indicate inhibition of the growth of
cancer cells.
4
Me
O
H
OAc
H
5
Me
O
Me
O
Me
Me
3
Me
Me
H
Me
O
1
OAc
O
O
2
X
O
O
O
1
2
3 ; X = CH2I
4 ; X = OEt
acetomycin
4,5-diepi-acetomycin
O
H
4
H
Me
Me
5
O
4
Me
3
O
5
O
Me
3
H
O
O
O
H
O
O
O
5
6
endo-bislactone
exo-bislactone
Oxidation
OR
COOH
Pd-catalyzed
allylic alkylation
4
Me
O
OR
5
Me
Ozonolysis
3
OMe
CHO
O
Figure 1 Structures of acetomycin and its analogues, and retrosyn-
thetic analysis of bislactones.
The coupling fragment 9 was prepared in three steps as
shown in Scheme 1. The reaction of lithium salt of 4-
benzyloxybutyne11 with 3-benzyloxypropanal12 gave pro-
pargyl alcohol 7 in 78% yield. Partial reduction of the tri-
ple bond by LiAlH4 followed by carbonate formation with
methyl chloroformate in the presence of DMAP gave 9 in
87% yield in two steps.
SYNTHESIS 2004, No. 9, pp 1343–1348
x
x
.
x
x
.2
0
0
4
Advanced online publication: 26.05.2004
DOI: 10.1055/s-2004-822388; Art ID: C02704SS
© Georg Thieme Verlag Stuttgart · New York
The key coupling reaction is shown in Scheme 2. The
coupling of sodium salt of methyl 2-methylacetoacetate

1344
J. Uenishi et al.
PAPER
with 9 was conducted in THF at room temperature in the The synthesis of the other isomer 6 was also accomplished
presence of a Pd catalyst prepared in situ by Pd(OAc)2 and from 11¢ in exactly the same reaction sequences as those
PPh3. A 6:5 mixture of diastereoisomers 10 and 10¢ was shown in Scheme 3. The total yield was 27% in 8 steps.
obtained in 90% yield. Protection of ketone as a 1,3-diox- Each yield is indicated in the experimental section.
olane with ethylene glycol in the presence of p-TsOH
gave 11 and 11¢ in 92% yield, which were separable by
chromatography. At a later stage, it was found that the po-
lar isomer 11 leads to 5 and that the less polar isomer 11¢
leads to 6.
OH
a
OBn
BnO
BnO
OHC
OBn
7
OX
b, c
BnO
OBn
8
9
X = H
X = COOMe
Scheme 1 Reagents and conditions: a) LDA, THF, –78 °C; b)
LiAlH4, THF, 0 °C; c) ClCOOMe, DMAP, CH2Cl2, r.t.
OBn
Me
Me
O
a
Me
OBn
COOMe
Me
COOMe
9
O
10 and 10'
R
R
H
H
Me
Me
b
R
R
Me
Me
COOMe
COOMe
11'
O
O
O
O
11
Scheme 3 Reagents and conditions: a) C12H25SLi, HMPA, r.t.; b)
Ozone, CH2Cl2, –78 °C, then Me2S; c) TBDMSOTf, 2,6-lutidine,
CH2Cl2, 0 °C; d) 10% Pd on charcoal, H2, CH2Cl2:EtOH (1:1); e) Jo-
nes reagent, acetone, r.t.; f) HF/pyridine, THF–pyridine (4:1), r.t.; g)
CSA, CHCl3, r.t.; h) BCl3, CH2Cl2, r.t.
R = (CH2)2OBn
Scheme 2 Reagents and conditions: a) NaH, THF, r.t., then
Pd(OAc)2, PPh3, 60 °C; b) (CH2OH)2, p-TsOH, benzene, reflux.
The synthesis of 5 was achieved in 8 steps from the polar
isomer 11 as shown in Scheme 3. First, we examined a ba-
sic hydrolysis of the methyl ester of 11, but it totally failed
because of steric hindrance of neopentyl carboxylate.
However, a nucleophilic attack of lithium thiolate13 on
methyl carbon of the ester was successful in giving car-
boxylic acid 12 quantitatively. Ozonolysis of the alkenyl
bond gave an aldehyde, which immediately cyclized to
form 5-hydroxy-g-lactone 13 as anomeric mixtures in
86% yield. The resulting hydroxy group at C-5 was then
protected as a silyl ether in 94% yield. Deprotection of
Figure 2 Crystal structure of 6
benzyl ether followed by oxidation with Jones reagent Fortunately, a nice single crystal was obtained for 6. X-
gave carboxylic acid 16 via 15 in 83% yield in two steps. ray crystallographic analysis of 6 confirmed the relative
Removal of the silyl group and successive acid treatment structure of the quaternary carbon center and bislactone
afforded bislactone 17 in 68% yield. Finally, deprotection rings. An ortep view of the exo-bislactone structure is
of the 1,3-dioxolane function with BCl3 gave the desired shown in Figure 2. It can be clearly seen that one of the
acetomycin bislactone analogue 5 in 73% yield.
Synthesis 2004, No. 9, 1343–1348 © Thieme Stuttgart · New York

PAPER
Synthesis of Acetomycin Bislactone Analogues
IR (neat): 3434 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.83 (td, J = 5.9, 5.5 Hz, 1 H), 2.36
(q, J = 6.6 Hz, 2 H), 2.76 (br s, 1 H), 3.51 (t, J = 6.6 Hz, 2 H), 3.62
(dt, J = 9.2, 6.1 Hz, 2 H), 3.69 (dt, J = 9.2, 5.5 Hz, 1 H), 4.30 (dt,
J = 6.2, 5.9 Hz, 2 H), 4.51 (s, 4 H), 5.57 (dd, J = 15.4, 6.2 Hz, 1 H),
7.26–7.38 (m, 10 H).
1345
lactone rings is located on the opposite side of the C-3
acetyl group.
No hydrolysis was observed when 5 or 6 was incubated
with PLE (pig liver esterase) in buffer solution at room
temperature even for two days. Since acetomycin was hy-
drolyzed with 2–3 hours under the same conditions, these
bislactones were found to be resistant to esterase. Cyto-
toxicity against tumor cells will be reported elsewhere in
due course.
13C NMR (75 MHz, CDCl3): d = 32.6, 36.6, 68.3, 69.7, 71.6, 72.9,
73.2, 127.5, 127.6, 127.6 (2 ×), 127.7 (2 ×), 128.3 (2 ×), 128.4 (2 ×),
134.3 (2 ×), 138.0, 138.4.
MS (FAB): m/z = 327 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C21H27O3: 327.1960; found:
327.1965.
Conclusion
(E)-1,7-Dibenzyloxy-3-methoxycarbonyloxy-4-heptene (9);
Typical Procedure
Acetomycin bislactone analogues 5 and 6 were prepared
in 10 steps from methyl 2-methylacetoacetate. The stereo-
chemistry was determined by X-ray crystallographic anal-
ysis. They are completely resistant to esterase.
To a stirred solution of 8 (4.6 g, 14.2 mmol) and DMAP (2.76 g,
22.6 mmol) in CH2Cl2 (180 mL) was added methyl chloroformate
(8.0 g, 85 mmol) dropwise, and the mixture was stirred overnight at
r.t. The mixture was diluted with EtOAc and washed with water and
brine and dried over MgSO4. The crude product was purified by
flash column chromatography on silica gel with 10% EtOAc in hex-
ane as eluent to give carbonate 9 (5.1 g) in 93% yield as a colorless
oil.
1H NMR (300 MHz and 400 MHz) and 13C NMR (75 MHz and 100
MHz) were recorded on JEOL LA-300 and Varian Unity spectro-
meters in CDCl3 with TMS as an internal standard. Mass spectra
were obtained on JMS-SX 102A QQ instruments. IR spectra were
obtained on JASCO FT/IR-410 instruments. All air- or moisture-
sensitive reactions were carried out in flame-dried glassware under
a N2 atmosphere. CH2Cl2 was distilled fleshly over P2O5 under a N2
atmosphere. THF was dried over benzophenone ketyl and was dis-
tilled before use. TLC was performed with Merck 60F254 precoated
silica gel plates. Flash column chromatography was carried out
using Merck silica gel 60 (230–410 mesh).
IR (neat): 1721 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.89 (ddd, J = 12.8, 6.6, 6.2 Hz, 1
H), 2.02 (ddt, J = 7.7, 6.2, 5.9 Hz, 1 H), 2.63 (td, J = 7.0, 6.6 Hz, 2
H), 3.47–3.54 (m, 4 H), 3.75 (s, 3 H), 4.47 (s, 2 H), 4.50 (s, 2 H),
5.24 (dt, J = 7.3, 6.2 Hz, 1 H), 5.52 (ddt, J = 15.4, 7.7, 1.5 Hz, 1 H),
5.80 (dt, J = 15.4, 6.6 Hz, 1 H), 7.22–7.46 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 32.7, 34.6, 54.5, 66.0, 69.3, 72.9,
73.0, 76.4, 127.5 (2 ×), 127.6 (2 ×), 127.6 (2 ×), 128.3 (2 ×), 129.3
(2 ×), 131.5 (2 ×), 138.3 (2 ×), 155.0.
1,7-Dibenzyloxy-4-heptyn-3-ol (7); Typical Procedure
To a cooled solution of lithium diisopropylamide (23.5 mmol) in
THF (25 mL) and hexane (15 mL) at –78 °C was added 4-benzyl-
oxybutyne (3.6 g, 22.5 mmol) and the mixture was stirred for 10
min at the same temperature. Then a THF solution (20 mL) of alde-
hyde (3.6 g, 22.5 mmol) was dropped to the mixture at the same
temperature and the mixture was stirred for 10 min at r.t. Saturated
NH4Cl was added at –78 °C and the mixture was extracted with
EtOAc. The extract was washed with water and brine and dried over
MgSO4. The crude product was purified by flash chromatography
on silica gel eluted with 20% EtOAc in hexane as eluent. The oily
alcohol 7 (5.3 g) was obtained in 78% yield.
MS (FAB): m/z = 407 [M+ + Na].
HRMS (FAB): m/z [M + H]+ calcd for C23H28O5Na: 407.1834;
found: 407.1825.
Pd-Catalyzed Coupling Reaction of 9 and Methyl 2-Methylace-
toacetate; Typical Procedure
To a solution of sodium salt of methyl 2-methylacetoacetate in THF
(40 mL) prepared by NaH (239 mg, 9.96 mol) and methyl 2-meth-
ylacetoacetate (1.33 g, 10.3 mmol) was added a THF solution (40
mL) of 9 (3.18 g, 8.27 mmol), Pd(OAc)2 (149 mg, 0.662 mmol) and
PPh3 (382 mg, 1.46 mmol). The mixture was heated at 60 °C for 30
min. After cooling, 10% aq HCl was added and the mixture was ex-
tracted with 20% EtOAc in hexane. The extract was washed with
water and brine, and dried over MgSO4. The crude oily product was
purified by column chromatography on silica gel with 20% EtOAc
in hexane as eluent to give 10 (3.28 g) in 90% yield as a 5:6 diaste-
reomeric mixture.
IR (neat): 3419 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.93 (dtd, J = 14.3, 6.2, 4.4 Hz, 1
H), 2.05 (dtd, J = 9.5, 8.1, 4.4 Hz, 2 H), 2.53 (td, J = 7.0, 1.8 Hz, 2
H), 3.01 (br s, 1 H), 3.57 (t, J = 7.0 Hz, 2 H), 3.66 (ddd, J = 9.5, 6.2,
4.7 Hz, 1 H), 3.83 (ddd, J = 14.3, 8.1, 4.7 Hz, 1 H), 4.52 (s, 2 H),
4.54 (s, 2 H), 4.59 (br s, 1 H), 7.26–7.38 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 20.1, 36.9, 61.5, 67.7, 68.4, 72.9,
73.3, 81.6, 82.1, 127.7, 128.4, 137.9, 138.0.
IR (neat): 1738, 1714 cm–1.
1H NMR (400 MHz, CDCl3, 5:6 mixture of diastereomers): d = 1.30
(s, 5/11 × 3 H), 1.40 (s, 6/11 × 3 H), 1.41–1.56 (m, 2 H), 1.68 (m, 6/
11 × 1 H), 1.82 (m, 5/11 × 1 H), 2.11 (s, 6/11 × 3 H), 2.17 (s, 5/11
× 3 H), 2.24–2.53 (m, 2 H), 3.37–3.57 (m, 4 H), 3.62 (s, 5/11 × 3 H),
3.70 (s, 6/11 × 3 H), 4.39–4.51 (m, 4 H), 5.16 (ddt, J = 15.2, 9.9, 1.3
Hz, 6/11 × 1 H), 5.31 (ddt, J = 15.0, 9.7, 1.2 Hz, 5/11 × 1 H), 4.48
(dt, J = 15.1, 6.9 Hz, 1 H), 7.24–7.36 (m, 10 H).
13C NMR (100 MHz, CDCl3, 5:6 mixture of diastereomers): d =
12.9, 15.4, 16.4, 21.3, 26.6, 26.9, 29.9, 30.6, 33.0, 33.0, 43.9, 44.0,
47.8, 51.8, 52.2, 52.3, 63.6, 63.9, 64.8, 64.9, 68.0, 68.7, 69.9, 70.0,
72.7, 72.8, 72.8, 127.4 (2 ×), 127.5 (2 ×), 127.6 (4 ×), 127.6 (2 ×),
128.3 (4 ×), 128.3 (4 ×), 129.5 (2 ×), 130.2 (2 ×), 131.1 (2 ×), 131.4
(2 ×), 138.5, 138.6, 172.0, 172.5, 205.0, 205.2.
MS (FAB): m/z = 325 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C21H25O3: 325.1804; found:
325.1807.
(E)-1,7-Dibenzyloxy-4-hepten-3-ol (8); Typical Procedure
To a suspension of LiAlH4 (1.75 g, 15.4 mmol) in THF (100 mL)
was dropped a THF solution of 7 (5.0 g, 15.4 mmol) at 0 °C, and the
mixture was stirred for 2 h at r.t. The reaction mixture was quenched
with sat. NH4Cl and extracted with EtOAc. The extract was washed
with brine and dried over MgSO4. The crude product was purified
by flash chromatography on silica gel with 20% EtOAc in hexane
as eluent to give 8 (4.72 g) in 94% yield as a colorless oil.
Synthesis 2004, No. 9, 1343–1348 © Thieme Stuttgart · New York

1346
J. Uenishi et al.
PAPER
MS (FAB): m/z = 439 [M+ + H].
(ABq, J = 12.1 Hz, 2 H), 4.48 (s, 2 H), 5.28–5.40 (m, 2 H), 7.23–
7.36 (m, 10 H).
HRMS (FAB): m/z [M + H]+ calcd for C27H35O5: 439.2484; found:
439.2479.
13C NMR (100 MHz, CDCl3): d = 14.5, 20.7, 30.5, 33.1, 42.5, 58.0,
64.1, 64.8, 67.8, 70.1, 72.6, 72.9, 112.1, 127.4, 127.6, 127.7 (2 ×),
127.7 (2 ×), 128.3 (2 ×), 128.4 (2 ×), 129.1, 131.0, 138.4, 138.6,
176.3.
MS (FAB): m/z = 469 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C28H37O6: 469.2590; found:
Preparation of 11 and 11¢; Typical Procedure
A mixture of 10 (1.94 g, 4.42 mmol) and ethylene glycol (0.55 g,
8.85 mmol) and p-toluenesulfonic acid (0.17 g, 0.88 mmol) was re-
fluxed in benzene (50 mL) for 16 h and the resulting water was re-
moved by Dean–Stark apparatus. After cooling, the mixture was
diluted with EtOAc and washed with sat. aq NaHCO3, water and
brine. The organic layer was dried over MgSO4 and condensed. The
residue was purified by flash chromatography on silica gel with 10–
30% EtOAc in hexane as eluent to give polar isomer 11 (0.99 g) in
46% yield and less polar isomer 11¢ (0.98 g) in 46% yield.
469.2586.
12¢
Amorphous solid; Rf = 0.35 (50% EtOAc in hexane).
IR (neat): 1697 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.17 (s, 3 H), 1.30 (m, 1 H), 1.48
(s, 3 H), 2.23 (m, 1 H), 2.27 (qd, J = 6.9, 1.2 Hz, 2 H), 2.78 (td, J =
9.6, 1.8 Hz, 1 H), 3.31–3.47 (m, 4 H), 3.83–4.03 (m, 4 H), 4.43
(ABq, J = 12.1 Hz, 2 H), 4.47 (s, 2 H), 5.24 (ddt, J = 14.1, 9.5, 1.3
Hz, 1 H), 5.45 (td, J = 7.0, 15.1 Hz, 1 H), 7.24–7.36 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 12.5, 21.2, 29.2, 33.0, 42.4, 58.7,
64.1, 65.5, 68.2, 70.1, 72.8, 72.9, 112.1, 127.4, 127.5 (3 ×), 127.7
(2 ×), 128.3 (2 ×), 128.4 (2 ×), 130.6, 130.7, 138.5, 138.8, 176.6.
11
Colorless oil; Rf = 0.42 (30% EtOAc in hexane).
IR (neat): 1721 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.18 (s, 3 H), 1.35 (s, 3 H), 1.41–
1.47 (m, 2 H), 2.33 (dt, J = 6.8, 5.7 Hz, 2 H), 2.88 (dt, J = 8.9, 4.2
Hz, 1 H), 3.34–3.49 (m, 4 H), 3.69 (s, 3 H), 3.78–3.93 (m, 4 H), 4.41
(ABq, J = 12.0 Hz, 2 H), 4.49 (s, 2 H), 5.30–5.42 (m, 2 H), 7.24–
7.36 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 13.0, 21.2, 30.9, 33.1, 42.4, 51.9,
58.7, 64.0, 65.3, 68.3, 70.2, 72.6, 72.9, 111.8, 127.4, 127.5, 127.6 (4
×), 128.3 (2 ×), 128.3 (2 ×), 128.5, 131.4, 138.5, 138.7, 174.9.
MS (FAB): m/z = 469 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C28H37O6: 469.2590; found:
469.2583.
MS (FAB): m/z = 483 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C29H39O6: 483.2747; found:
Ozonolysis of Alkenes 12 and 12¢; Typical Procedure
Through a CH2Cl2 solution (35 mL) of alkenyl substrate (12 or 12¢,
3 mmol) ozone was bubbled at –78 °C until the substrate disap-
peared as indicated by TLC. After the excess of ozone gas was re-
placed with nitrogen gas, ozonide was decomposed with an excess
of dimethyl sulfide. The mixture was diluted with EtOAc and
washed with water, brine and dried over MgSO4. The crude product
was purified by flash column chromatography on silica gel with
50% EtOAc in hexane as eluent to give lactone. Compound 13 was
obtained as crystals in 86% yield and 13¢ was obtained as an oil in
86% yield.
483.2754.
11¢
Colorless oil; Rf = 0.49 (30% EtOAc in hexane).
IR (neat): 1737 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.12 (s, 3 H), 1.28–1.34 (m, 2 H),
1.53 (s, 3 H), 2.14–2.36 (m, 2 H), 2.81–2.86 (m, 1 H), 3.31–3.49 (m,
4 H), 3.57 (s, 3 H), 3.81–4.03 (m, 4 H), 4.44 (ABq, J = 12.1 Hz, 2
H), 4.47 (s, 2 H), 5.20 (dd, J = 9.5, 15.2 Hz, 1 H), 5.36–5.41 (m, 1
H), 7.22–7.36 (m, 10 H).
13
Colorless crystals; mp 96–98 °C (hexane); Rf = 0.40 (50% EtOAc
in hexane).
IR (KBr): 3388, 1768 cm–1.
13C NMR (100 MHz, CDCl3): d = 11.3, 21.2, 28.9, 33.0, 42.9, 47.8,
51.4, 64.0, 65.7, 68.3, 70.1, 72.8, 72.8, 112.0, 127.3, 127.4 (2 ×),
127.5, 127.6 (2 ×), 128.2 (2 ×), 128.3 (2 ×), 130.2, 131.2, 138.4,
138.8, 174.3.
MS (FAB): m/z = 483 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C29H39O6: 483.2747; found:
1H NMR (400 MHz, CDCl3, 4:1 mixture of diastereomers): d = 1.32
(s, 1/5 × 3 H), 1.37 (s, 1/5 × 3 H), 1.41 (s, 4/5 × 3 H), 1.43 (s, 4/5 ×
3 H), 1.76 (m, 4/5 × 1 H), 1.86 (m, 1/5 × 1 H), 2.07 (m, 1 H), 2.57
(ddd, J = 10.3, 5.5, 4.6 Hz, 4/5 × 1 H), 2.70 (td, J = 6.0, 1.8 Hz, 1/5
× 1 H), 3.47–3.63 (m, 2 H), 3.93–4.15 (m, 4 H), 4.51 (ABq, J = 12.1
Hz, 4/5 × 2 H), 4.53 (ABq, J = 12.1 Hz, 1/5 × 2 H), 5.49 (d, J = 5.7
Hz, 4/5 × 1 H), 5.60 (s, 4/5 × 1 H), 5.66 (s, 1/5 × 1 H), 5.67 (d, J =
7.1 Hz, 1/5 × 1 H), 7.27–7.38 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 14.2, 20.2, 20.3 20.8 21.0, 22.4,
25.3, 26.5, 43.8, 47.9, 50.7, 52.8, 55.2, 60.4, 62.9, 63.2, 63.8, 64.0,
64.2, 67.6, 68.9, 73.1, 73.2, 97.3, 101.5, 110.6, 111.3, 127.7 (2 ×),
127.8, 127.8, 128.5 (2 ×), 138.1, 171.2, 177.4.
483.2752.
Demethylation of Methyl Esters 11 and 11¢; Typical Procedure
The mixture of methyl ester (11 or 11¢, 3 mmol) and lithium salt of
dodecanethiol prepared by dodecanethiol (3.3 equiv) and BuLi (3
equiv) in HMPA (7 mL) was stirred for 3 h at r.t. To this mixture
10% HCl was added at 0 °C and the mixture was extracted with
EtOAc. The extract was washed with brine and dried over MgSO4.
The crude product was purified by flash chromatography on silica
gel with 30–100% EtOAc in hexane as eluent to give carboxylic
acids 12 quantitatively and 12¢ in 96% yield.
MS (FAB): m/z = 337 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C18H25O6: 337.1651; found:
337.1647.
12
Amorphous solid; Rf = 0.26 (50% EtOAc in hexane).
IR (KBr): 1699 cm–1.
Anal. Calcd for C18H25O6: C, 64.27; H, 7.19. Found: C, 64.06, H,
7.20.
1H NMR (400 MHz, CDCl3): d = 1.22 (s, 3 H), 1.35 (s, 3 H), 1.43
(m, 1 H), 1.77 (m, 1 H), 2.32 (q, J = 6.6 Hz, 2 H), 2.79 (ddd, J =
11.2, 8.8, 2.0 Hz, 1 H), 3.35–3.50 (m, 4 H), 3.86–3.99 (m, 4 H), 4.41
13¢
Colorless oil; Rf = 0.52 (50% EtOAc in hexane).
IR (neat): 3411, 1770 cm–1.
Synthesis 2004, No. 9, 1343–1348 © Thieme Stuttgart · New York

PAPER
Synthesis of Acetomycin Bislactone Analogues
1347
1H NMR (400 MHz, CDCl3, 1:1 mixture of diastereomers): d = 1.26
(s, 1/2 × 3 H), 1.38 (s, 1/2 × 3 H), 1.44 (s, 1/2 × 3 H), 1.46 (s, 1/2 ×
3 H), 1.61 (m, 1/2 × 1 H), 1.94 (m, 1 H), 2.25 (m, 1/2 × 1 H), 2.49
(dt, J = 11.5, 3.3 Hz, 1/2 × 1 H), 2.78 (ddd, J = 11.5, 5.7, 3.3 Hz,
1/2 × 1 H), 3.52–3.66 (m, 4 H), 3.85–4.06 (m, 4 H), 4.52 (ABq, J =
11.9 Hz, 1/2 × 2 H), 4.53 (s, 1/2 × 2 H), 4.95 (br s, 1 H), 5.39 (d,
J = 3.1 Hz, 1/2 × 1 H), 5.72 (d, J = 5.7 Hz, 1/2 × 1 H), 7.26–7.37 (m,
5 H).
13C NMR (100 MHz, CDCl3): d = 16.0, 16.6, 19.5, 19.8, 25.2, 28.9,
41.7, 45.5, 51.4, 53.9, 64.7, 65.0, 65.1, 65.2, 68.0, 68.6, 73.1, 73.2,
96.6, 101.2, 111.8, 112.1, 127.6 (2 ×), 127.6 (2 ×), 127.7 (2 ×),
128.4 (2 ×), 128.5 (2 ×), 137.9, 138.0, 176.8, 178.8.
15
Colorless oil; Rf = 0.38 (50% EtOAc in hexane).
IR (neat): 3502, 1770 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.18 (s, 3 H), 0.20 (s, 3 H), 0.92
(s, 9 H), 1.33 (s, 3 H), 1.40 (s, 3 H), 1.77 (m, 1 H), 2.00–2.14 (m, 2
H), 3.74 (ddd, J = 12.5, 6.0, 1.6 Hz, 2 H), 3.94–4.04 (m, 4 H), 5.67
(d, J = 7.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = –5.1, –4.2, 17.7, 20.3, 20.8, 25.6
(3 ×), 29.3, 53.7, 54.8, 61.5, 63.2, 64.2, 101.7, 111.4, 176.1.
MS (FAB): m/z = 361 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C17H33O6Si: 361.2046;
found: 361.2050.
MS (FAB): m/z = 337 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C18H25O6: 337.1651; found:
337.1647.
15¢
Amorphous solid; Rf = 0.33 (50% EtOAc in hexane).
IR (neat): 3504, 1777 cm–1.
Silylation of 13 and 13¢; Typical Procedure
To a solution of 13 or 13¢’ (2.5 mmol) and 2,6-lutidine (5 equiv) in
CH2Cl2 (20 mL) was added TBDMSOTf (2.5 equiv) at 0 °C. The
mixture was stirred at r.t. for 2 h, diluted with Et2O and washed with
water and brine. The ethereal solution was dried over MgSO4 and
residual oil was purified by flash chromatography on silica gel with
15–20% EtOAc in hexane as eluent. Silyl ether 14 was obtained in
94% yield and 14¢ was obtained in 93% yield.
1H NMR (400 MHz, CDCl3): d = 0.15 (s, 3 H), 0.16 (s, 3 H), 0.90
(s, 9 H), 1.36 (s, 3 H), 1.47 (s, 3 H), 1.64 (br s, 1 H), 2.80 (ddd, J =
10.6, 5.3, 3.7 Hz, 1 H), 1.82–1.97 (m, 2 H), 3.60–3.76 (m, 2 H),
3.90–4.10 (m, 4 H), 5.75 (d, J = 5.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = –5.7, –4.4, 16.3, 17.7, 19.6, 25.5
(3 ×), 28.2, 41.3, 51.4, 60.9, 65.0, 65.1, 97.1, 112.2, 178.7.
MS (FAB): m/z = 361 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C17H33O6Si: 361.2046;
14
Colorless oil; Rf = 0.58 (30% EtOAc in hexane).
IR (neat): 1774 cm–1.
found: 361.2050.
1H NMR (400 MHz, CDCl3): d = 0.10 (s, 6 H), 0.92 (s, 9 H), 1.32
(s, 3 H), 1.38 (s, 3 H), 1.77–1.87 (m, 1 H), 2.04–2.23 (m, 2 H), 3.49–
3.63 (m, 2 H), 3.92–4.02 (m, 4 H), 4.51 (ABq, J = 11.9 Hz, 2 H),
5.62 (d, J = 6.8 Hz, 1 H), 7.26–7.37 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = –3.58 (2 ×), 17.8, 20.8, 20.9, 25.6
(3 ×), 26.8, 53.0, 54.8, 63.3, 64.3, 69.1, 73.0, 102.0, 111.4, 127.6,
127.7 (2 ×), 128.4 (2 ×), 138.3, 176.4.
Preparation of Carboxylic Acids 16 and 16¢; Typical Procedure
To a stirred solution of alcohol (16 or 16¢, 1 mmol) in acetone (18
mL) was added Jones reagent (2 M in H2O, 1 mL) and the mixture
was stirred for 2 h at r.t. After an excess of reagent was decomposed
with i-PrOH, water and EtOAc were added. Organic layer was
washed with water and brine, and dried over MgSO4. The crude
product was purified by flash chromatography on silica gel with 50–
100% EtOAc in hexane as eluent. Crystalline 16 was obtained in
83% yield and 16¢ was obtained in 81% yield as an amorphous solid.
MS (FAB): m/z = 451 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C24H39O6Si: 451.2516;
16
found: 451.2511.
Colorless crystals; mp 149–151 °C (Et2O); Rf = 0.40 (EtOAc).
IR (KBr): 3020, 1768, 1714 cm–1.
14¢
Colorless oil; Rf = 0.47 (30% EtOAc in hexane).
1H NMR (400 MHz, CDCl3): d = 0.14 (s, 3 H), 0.17 (s, 3 H), 0.90
(s, 9 H), 1.34 (s, 3 H), 1.50 (s, 3 H), 2.50 (dd, J = 15.2, 5.5 Hz, 1 H),
2.57–2.62 (m, 1 H), 2.67 (dd, J = 15.2, 8.8 Hz, 1 H), 3.93–4.11 (m,
4 H), 5.53 (d, J = 6.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = –5.3, –4.4, 17.8, 19.5, 21.7, 25.5
(3 ×), 31.9, 51.6, 53.9, 62.5, 63.9, 100.9, 111.3, 175.9, 177.6.
IR (neat): 1780 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.03 (s, 3 H), 0.09 (s, 3 H), 0.86
(s, 9 H), 1.35 (s, 3 H), 1.47 (s, 3 H), 1.87–2.00 (m, 2 H), 2.80 (ddd,
J = 11.0, 5.3, 3.8 Hz, 1 H), 3.39–3.52 (m, 2 H), 3.87–4.06 (m, 4 H),
4.49 (ABq, J = 12.0 Hz, 2 H), 5.59 (d, J = 5.3 Hz, 1 H), 7.26–7.37
(m, 5 H).
13C NMR (100 MHz, CDCl3): d = –5.8, –4.5, 16.3, 17.7, 19.7, 25.5,
25.5 (3 ×), 41.3, 51.4, 65.0, 65.2, 67.9, 73.0, 97.0, 112.2 (3 ×), 127.7
(2 ×), 128.4, 138.4, 178.7.
MS (FAB): m/z = 375 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C17H31O7Si: 375.1839;
found: 375.1843.
Anal. Calcd for C17H30O7Si: C, 54.52; H, 8.07. Found: C, 54.29, H,
7.82.
MS (FAB): m/z = 451 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C24H39O6Si: 451.2516;
found: 451.2511.
16¢
Amorphous solid; Rf = 0.35 (EtOAc).
IR (neat): 2955, 1782, 1711 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.10 (s, 3 H), 0.15 (s, 3 H), 0.89
(s, 9 H), 1.36 (s, 3 H), 1.49 (s, 3 H), 2.71–2.78 (m, 2 H), 3.06 (td,
J = 8.8, 5.3 Hz, 1 H), 3.83–4.07 (m, 4 H), 5.85 (d, J = 5.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = –5.8, –4.7, 16.7, 17.7, 19.1, 25.5
(3 ×), 30.4, 40.2, 51.0, 64.9, 65.1, 96.6, 112.0, 177.7, 178.5.
Deprotection of Benzyl Ethers 15 and 15¢; Typical Procedure
A solution of 14 or 14¢ (2 mmol) in a 1:1 mixture of CH2Cl2 and
EtOH (40 mL) was stirred in the presence of 10% Pd on charcoal
under a hydrogen atmosphere. After the hydrogenation was com-
pleted, the reaction mixture was filtered and condensed. The pure
product was obtained in quantitative yield.
MS (FAB): m/z = 375 [M+ + H].
Synthesis 2004, No. 9, 1343–1348 © Thieme Stuttgart · New York

1348
J. Uenishi et al.
PAPER
HRMS (FAB): m/z [M + H]+ calcd for C17H31O7Si: 375.1839;
IR (KBr): 1801, 1715 cm–1.
found: 375.1835.
1H NMR (400 MHz, CDCl3): d = 1.65 (s, 3 H), 2.30 (dd, J = 18.9,
8.4 Hz, 1 H), 2.48 (s, 3 H), 2.99 (dd, J = 18.9, 9.7 Hz, 1 H), 3.21
(ddd, J = 9.7, 8.4, 5.3 Hz, 1 H), 6.26 (d, J = 5.3 Hz, 1 H).
Formation of Bislactone; Typical Procedure
A mixture of silyl ether (16 or 16¢, 0.5 mmol), pyridinium poly(hy-
drogen fluoride) (250 mg) in a 4:1 mixture of THF and pyridine (6.5
mL) was stirred for 5 h at r.t. After the reaction completed, KCl–
HCl buffer solution (pH 2.2) was added and extracted with EtOAc
for several times. The combined organic extracts were dried over
MgSO4 and condensed. The resulting crude hydroxycarboxylic acid
was dissolved in CHCl3 (10 mL) and stirred for 3.5 h in the presence
of CSA (0.25 mmol). The reaction mixture was diluted with EtOAc
and washed with water and brine. The organic layer was dried over
MgSO4 and the crude product was purified by flash chromatogra-
phy on silica gel with 40–50% EtOAc in hexane as eluent to give
bislactone in 68% yield for 17 and in 55% for 17¢.
13C NMR (100 MHz, CDCl3): d = 23.3, 27.6, 30.4, 45.0, 60.6, 100.1,
172.2, 173.0, 203.7.
MS (FAB): m/z = 199 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C9H11O5: 199.0607; found:
199.0609.
Anal. Calcd for C9H10O5: C, 54.55; H, 5.09. Found: C, 54.28, H,
5.21.
6
Colorless crystals; mp 127–128.5 °C (MeOH); Rf = 0.31 (50%
EtOAc in hexane).
17
IR (neat): 1791, 1712 cm–1.
Colorless oil; Rf = 0.32 (50% EtOAc in hexane).
IR (neat): 1793 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.36 (s, 3 H), 1.51 (s, 3 H), 2.61
(dd, J = 18.7, 10.0 Hz, 1 H), 3.06 (ddd, J = 10.0, 8.8, 5.5 Hz, 1 H),
3.47 (dd, J = 18.7, 8.8 Hz, 1 H), 3.95–4.21 (m, 4 H), 6.21 (d, J = 5.5
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.2, 21.6, 28.5, 45.9, 54.1, 64.2,
64.5, 100.1, 109.8, 173.1, 174.5.
MS (FAB) m/z = 243 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C11H15O6: 243.0868; found:
1H NMR (400 MHz, CDCl3): d = 1.57 (s, 3 H), 2.37 (s, 3 H), 2.48
(dd, J = 8.1, 18.5 Hz, 1 H), 2.74 (dd, J = 18.5, 10.3 Hz, 1 H), 3.90
(ddd, J = 10.3, 8.1, 5.7 Hz, 1 H), 6.21 (d, J = 5.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 17.1, 25.5, 28.0, 40.9, 61.3, 101.7,
171.9, 172.8, 201.4.
MS (FAB): m/z = 199 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C9H11O5: 199.0607; found:
199.0612.
Anal. Calcd for C9H10O5: C, 54.55; H, 5.09. Found: C, 54.35, H,
5.27.
243.0874.
17¢
References
Colorless oil; Rf = 0.34 (50% EtOAc in hexane).
(1) Ettlinger, L.; Gaumann, E.; Hutter, R.; Schierlein, W. K.;
Kradolfer, F.; Neipp, L.; Prelog, V.; Zahner, H. Helv. Chim.
Acta 1958, 41, 216.
(2) Uhr, H.; Zeeck, A. J. Antibiot. 1985, 38, 1684.
(3) Cano, F. H.; Foces, C. Acta Crystallogr. 1988, C44, 919.
(4) (a) Alarcon, B.; Lacal, J. C.; Sousa, J. M. F.; Carrasco, L.
Antiviral Res. 1984, 4, 231. (b) Chen, Y.; Zeeck, A.; Chen,
Z.; Zahner, H. Kangsnengsu 1984, 9, 16.
(5) Mamber, S. W.; Mitulski, J. D.; Hamelehle, K. L.; French, J.
C.; Hokanson, G. C.; Shillis, J. L.; Leopold, W. R.; Von
Hoff, D. D.; Tunac, J. B. J. Antibiot. 1987, 40, 73.
(6) Mamber, S. W.; Mitulski, J. D.; Borondy, P. E.; Tunac, J. B.
J. Antibiot. 1987, 40, 77.
IR (neat): 1789 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.36 (s, 3 H), 1.41 (s, 3 H), 2.55
(dd, J = 18.5, 7.7 Hz, 1 H), 2.71 (dd, J = 18.5, 10.3 Hz, 1 H), 3.38
(ddd, J = 10.3, 7.7, 5.9 Hz, 1 H), 4.01–4.05 (m, 4 H), 6.23 (d, J =
5.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 16.5, 19.3, 28.7, 41.4, 54.7, 64.9,
65.2, 102.1, 111.4, 173.6, 174.9.
MS (FAB): m/z = 243 [M+ + H].
HRMS (FAB): m/z [M + H]+ calcd for C11H15O6: 243.0869; found:
243.0874.
(7) Uenishi, J.; Kobayashi, N.; Komine, S.; Okadai, T.;
Yonemitsu, O.; Sasaki, T.; Yamada, Y. Chem. Pharm. Bull.
1999, 47, 517.
(8) Uenishi, J.; Kobayashi, N.; Yonemitsu, O.; Sasaki, T.;
Yamada, Y. Heterocycles 1997, 44, 277.
(9) Uenishi, J. Adv. Pharm. Sci. 1999, 15, 1.
(10) Uenishi, J.; Kawatsura, M.; Ikeda, D.; Muraoka, N. Eur. J.
Org. Chem. 2003, 20, 3909.
(11) Qin, D.-G.; Zha, H.-Y.; Yao, Z.-J. J. Org. Chem. 2002, 67,
1038.
Deprotection of Cyclic Acetals 17 and 17¢; Typical Procedure
To an ice cooled solution of 17 or 17¢ (0.4 mmol) in CH2Cl2 (5.5
mL) was added BCl3 (1.0 M in CH2Cl2 solution, 0.8 mL) and the
mixture was stirred for 1 h at r.t. After the reaction completed, the
mixture was diluted with CH2Cl2 and washed with aq NaHCO3 and
brine. The CH2Cl2 layer was dried over MgSO4 and the crude prod-
uct was purified by flash chromatography on silica gel with 40%
EtOAc in hexane as eluent to give the desired product. Crystalline
5 and 6 were obtained in 73% and 78% yields, respectively.
(12) Kozikowski, A. P. J. Org. Chem. 1984, 49, 2301.
(13) Node, M.; Kumar, K.; Nishide, K.; Ohsugi, S.; Miyamoto, T.
Tetrahedron Lett. 2001, 42, 9207.
5
Colorless crystals; mp 135–136 °C (MeOH); Rf = 0.24 (50% EtOAc
in hexane).
Synthesis 2004, No. 9, 1343–1348 © Thieme Stuttgart · New York