Synthesis of the oxa-bridged octalin system of two anti-anaerobe antibiotics, luminamicin and lustromycin

Article abstract of DOI:10.1016/j.tetlet.2007.05.104

An efficient, stereocontrolled entry to the 11-oxatricyclo[5.3.1.^1,70^3,8]undecane nucleus of luminamicin and lustromycin was afforded via intramolecular hetero-Michael addition of enone 7 followed by intramolecular aldol condensation of aldehyde 5 by way of the epimerization at the stereocenter attached by the aldehyde group.

Full text of DOI:10.1016/j.tetlet.2007.05.104

Tetrahedron Letters 48 (2007) 5297–5300
Synthesis of the oxa-bridged octalin system of two
anti-anaerobe antibiotics, luminamicin and lustromycin
Toshiaki Sunazuka, Masaki Handa, Tomoyasu Hirose, Takanori Matsumaru,
ꢀ
Yuko Togashi, Kaoru Nakamura, Yuzuru Iwai and Satoshi Omura*
Kitasato Institute for Life Sciences, and Graduate School of Infection Control Sciences, Kitasato University,
and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
Received 13 April 2007; revised 15 May 2007; accepted 18 May 2007
Available online 24 May 2007
Abstract—An efficient, stereocontrolled entry to the 11-oxatricyclo[5.3.1.1,703,8]undecane nucleus of luminamicin and lustromycin
was afforded via intramolecular hetero-Michael addition of enone 7 followed by intramolecular aldol condensation of aldehyde
5 by way of the epimerization at the stereocenter attached by the aldehyde group.
Ó 2007 Elsevier Ltd. All rights reserved.
14-membered
lactone
The emergence of resistance against commonly-used
antibiotics will be a long-lasting and serious clinical
problem. We therefore need to continue the develop-
ment of new medicines that have unique mechanisms
of action. During the course of screening for biologically
active compounds, we have found several novel anti-
anaerobe antibiotics from actinomycetes origin, namely
thiotetromycin,1 clostomicin,2 luminamicin (1),3 and
lustromycin (2).4,5 The structure of luminamicin is iden-
tical to that of coloradocin, later isolated by McAlpin,6
and is very similar to that of 2. As shown in Figure 1,
these structures consist of a cis-decalin ring system asso-
ciated with a 10-membered macrolactone and a 14-
membered macrolactone moiety having an enol ether
conjugated with a maleic anhydride functionality. Lumi-
namicin and lustromycin showed selective activity
against anaerobic and micro-aerophilic bacteria, includ-
ing pathogenic species of Clostridium, Neisseria, and
Haemophilus, but were not active against most aerobic
bacteria.3,6 1 and 2 might thus be new leads for medi-
cines to compare with vancomycin, which is clinically
used in pseudomembranous colitis therapy.
O
O
O
O
O
O
O
O
H
OH
O
OH
H
10-membered
lactone
O
O
O
1
O
O
H
O
OMe
O
OMe
OMe
HO
HO
H13
H
H
4
O
O
cis-decalin
9
H
H
Luminamicin (1)
Lustromycin (2)
Figure 1. Structures of luminamicin (1) and lustromycin (2).
only modest yield. Go¨ssinger et al.8 have also reported
the synthesis of the decalin subunit of coloradocin.
Recently, our group has determined the absolute and
relative stereochemistry of 1 using conformational ana-
lysis via high temperature molecular dynamics, NMR
spectroscopy, and the modified Mosher method.9 In
conjunction with our continuing program directed
toward the structure elucidation and syntheses of impor-
tant antimicrobial natural products, we describe here
studies of the synthesis of the oxa-bridged octalin system
4 of luminamicin and lustromycin.
Kallmerten and Evans7 have reported the construction
of the C13–O linkage of the 11-oxatricyclo[5.3.1.1,703,8]-
undecane skeleton by intramolecular addition of a C9
alcohol to an olefin using phenylselenenyl chloride in
We would set up compound 3 as a target compound
for the southern moiety of 1. Our retrosynthetic strategy
of the southern moiety 3 was shown in Scheme 1. The
*
Corresponding author. Tel.: +81 3 5791 6101; fax: +81 3 3444
8360; e-mail: omura-s@kitasato.or.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.104

5298
T. Sunazuka et al. / Tetrahedron Letters 48 (2007) 5297–5300
HO2C
OH
O
EtO
OMe
O
H
O
OH
O
OMe
H
H
O
H
H
O
O
H
H
O
HO
H
4
3
3
Intramolecular
aldol condensation
EtO
O
EtO
O
OEt
O
O
CO2Et
Construction
of pyran ring
O
CO2Et
O
OH
O
CHO
OR
OR
7
6
5
Scheme 1. Synthetic strategy of the 11-oxatricyclo[5.3.1.1,703,8]undecane nucleus 4.
oxa-bridged octalin system 4 removed from 3 could be
obtained via intramolecular hetero-Michael addition of
enone 7 to form the 2-oxabicyclo[2.2.2]octene nucleus
6 first, followed by intramolecular aldol condensation
of aldehyde 5 with the epimerization event at the stereo-
center attached by the aldehyde group. The selective
conversion of diester 6 into 5 would not be a matter
due to the necessity to form the methyl ketone moiety
at the further stage and the intramolecular discrimina-
tion in the intramolecular aldol condensation step.
methyl)-2-cyclohexenone 14 in 85% yield for 2 steps.
Protection of 14 with benzyloxymethyl chloride or pival-
olyl chloride gave 15a or 15b in 94% and 98% yields,
respectively. Finally, diastereoselective aldol reaction12
of 15a/b with diethyl ketomalonate at À78 °C rendered
the tertiary alcohol ( )-7a/b in 89% and 79% yields,
respectively.
The first key reaction, intramolecular hetero-Michael
addition was investigated to obtain the oxa-bicyclic
compound 17 by using 7a protected with BOM ether.
Firstly, treatment of 7a with any base did not produce
desired 17. Retro-Michael addition should occur due
to one of the a-methylene protons being placed anti-
periplanar against the bridged oxygen bond. Therefore,
we attempted to use the Lewis acid conditions, not only
because of the activation of the carbonyl group but also
to capture the enolate formed after hetero-Michael
addition (Table 1). Using TMSOTf in the presence of
Enone 7 is conveniently available from 3,5-dimethoxy-
benzoic acid 8 as a starting material, as a minor modifi-
cation of the van Tamelen10 and Smith11 protocol
(Scheme 2). Here, Birch reduction of 8, followed by
LiAlH4 reduction (9), acid hydrolysis (10), and esterifi-
cation of vinylogous acid group (11), then afforded enol
ether 12 in 53% yield for 4 steps. 1,2-Reduction of 12
followed by acid hydrolysis of 13 produced 5-(hydroxy-
HCl
THF:H2O
= 10 : 1
MeO
OMe
MeO
OMe
MeO
OMe
LiAlH4
THF
Na, NH3
r.t.
–78 ºC
40 ºC
CO2H
CO2H
OH
10
8
9
HO
O
EtO
O
EtO
OH
LiAlH4
THF
TsOH, EtOH
benzene
reflux
53% (4 steps)
60 ºC
OH
11
OH
OH
13
12
CO2Et
O
O
CO2Et
O
O
CO2Et
BOMCl, i-Pr2NEt
CH2Cl2, r.t.
or
80% AcOH
LDA, THF
CO2Et
OH
r.t., 85% (2 steps)
PivCl, pyridine
r.t.
–78 ºC
OR
OR
OH
7a; R = BOM (89%)
7b; R = Piv (79%)
15a; R = BOM (94%)
15b; R = Piv (98%)
14
Scheme 2. Synthesis of the tertiary alcohol 7a/b.

T. Sunazuka et al. / Tetrahedron Letters 48 (2007) 5297–5300
5299
Table 1. Intramolecular hetro-Michael addition of the tertiary alcohol 7a using Lewis acid
EtO
EtO
OEt
OEt
O
CO2Et
O
CO2Et
Conditions
CH2Cl2
O
O
O
RO
O
O
CO2Et
CO2Et
+
+
O
O
OH
OTMS
OBOM
OBOM
OBOM
OBOM
7a
16
17
18; R = TBS
19; R = TIPS
Entry
Reagent
Temperaturea
Productsb (%)
17
7a
16
18/19
1
2
3
4
5
TMSOTf (4 equiv)
2,6-Lutidine (6 equiv)
À78 °C
rt
40
23
40
56
—
—
28
39
—
—
—
—
TMSOTf (2 equiv)
2,6-Lutidine (3 equiv)
8
—
TMSOTf (2 equiv)
2,6-Lutidine (3 equiv)
40 °C
rt
—
—
—
—
TBSOTf (6 equiv)
2,6-Lutidine (9 equiv)
18: 87
19: 87
TIPSOTf (4 equiv)
2,6-Lutidine (6 equiv)
40 °C
a Reagents were added at the indicated temperature and the reaction was performed at the temperature.
b Isolation yields after column chromatography.
2,6-lutidine at À78 °C afforded desired 17 (28%) with
TMS ether 16 (23%), and recovered enone 7a (40%) (en-
try 1). Ketone 17 was generated from the corresponding
enol silyl ether during the column chromatography.
Warming to room temperature to consume the starting
material 7a obtained 17 in 39% yield (entry 2). Heating
to 40 °C did not obtain 17 but produced 16 in 56% yield
(entry 3). Furthermore, treatment of 7a with TBSOTf or
TIPSOTf gave the oxa-bicyclic TBS enol ether 18 or
TIPS enol ether 19, both in 87% yields (entries 4 and
5). Efforts to convert from 18 and 19 into ketone 17 fol-
lowed by methylation or olefination were unfruitful
because of the retro-Micheal reaction. We therefore
needed to construct the synthetic pathway without for-
mation of ketone 17.
Based on these results, we attempted the conversion into
olefin via the enol triflate in the hetero-Michael reaction
(Scheme 3). Treatment of 7a/b with Tf2O in the presence
of 2,6-di-t-butyl-4-methylpyridine (DTBMP)13 at room
temperature, followed by reduction of the formed enol
triflate 20a/b with HCO2H and a catalytic amount of
EtO
O
OEt
O
EtO
O
OEt
O
O
CO2Et
Tf2O, DTBMP
CH2Cl2
PdCl2(PPh3)2
HCO2H, Et3N, DMF
CO2Et
O
O
OH
TfO
r.t.
60 ºC (2 steps)
OR
OR
OR
6a; R = BOM (49%)
6b; R = Piv (50%)
7a; R = BOM
7b; R = Piv
20a; R = BOM
20b; R = Piv
SO2Ph
O
n-BuLi
MeSO2Ph
THF
EtO
EtO
O
EtO
O
(COCl)2, DMSO
Al(Hg)
Et3N, CH2Cl2
THF-H2O
O
O
O
H
O
O
O
r.t., 94%
–78 ºC ~ 0 ºC, 99%
–78 ºC, 76%
CHO
OH
OH
21
22
5
EtO
O
EtO
O
O
EtO
O
O
DBU
CH2Cl2
MsCl, Et3N
r.t., 88%
O
CHO
H
H
H
H
O
O
O
r.t.
OH
H
23
24
4
Scheme 3. Synthesis of the 11-oxatricyclo[5.3.1.1,703,8]undecane nucleus 4.

5300
T. Sunazuka et al. / Tetrahedron Letters 48 (2007) 5297–5300
14
10. van Tamelen, E.; Hildahl, G. T. J. Am. Chem. Soc. 1956,
78, 4405.
11. Smith, A. B., III; Richmond, R. E. J. Am. Chem. Soc.
1983, 105, 575.
12. Armstrong, A.; Critchley, T. J.; Gourdel-Martin, M.-E.;
Kelsey, R. D.; Mortlock, A. A. J. Chem. Soc., Perkin
Trans. 1 2002, 1344.
13. (a) Stang, P. J.; Hanack, M.; Subramanian, L. R.
Synthesis 1982, 85; (b) Stang, P. J.; Treptow, W. Synthesis
1980, 283.
14. (a) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett.
1984, 25, 4821; (b) Yang, M.-S.; Chang, S.-Y.; Lu, S.-S.;
Rao, P. D.; Liao, C.-C. Synlett 1999, 225.
15. Chun, J.; Li, G.; Byun, H.-S.; Bittman, R. J. Org. Chem.
2002, 67, 2600.
PdCl2(PPh3)2 to afford the desired oxa-bicyclic olefin
6a/b in 49% and 50% yields for 2 steps, respectively.
Substrate 6b, having a pivaloyl ester, was then used
due to its efficient convertibility. Diastereoselective
alkylation and deprotection of the pivaloyl ester of 6b
with an excess amount of (phenylsulfonyl)methyl-
lithium15 at À78 °C followed by reductive elimination of
phenylsulfone group of 21 with Al(Hg)16 afforded meth-
ylketone 22 in 70% yield for 2 steps. In the alkylation
step,17 we observed the useful diastereoselectivity
(10:1) due to the decreased reactivity of the left-hand
ester by the interaction with the adjacent olefin. Swern
oxidation of 22 then gave ketoaldehyde 5 quantitatively.
The second key reaction, the intramolecular aldol con-
densation of 5 through epimerization toward the more
hindered isomer 23 of the aldehyde group, was investi-
gated to afford the tricyclic compound 4. First, treat-
ment of 5 with DBU18 in CH2Cl2 at room temperature
gave the aldol product 24 (16%) and the desired enone
4 (73%). Aldol compound 24 was converted to 4 quan-
titatively via in the treatment with MsCl and Et3N at
room temperature. Then, the one-pot reaction was
carried out. Treatment with DBU followed by addition
of MsCl and Et3N after the consumption of 5, afforded
desired 4 in 88% yield.19
16. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87,
1345.
17. To a solution of methyl phenyl sulfone (5.77 g, 36.9 mmol)
in THF (246 mL) was added 1.54 M n-BuLi (24.0 mL,
36.9 mmol) in hexane at À15 °C. The mixture was stirred
for 30 min at the temperature, and then cooled to À78 °C.
To the mixture was added 6b (1.36 g, 3.69 mmol) in THF
(38.0 mL) over 15 min. After the addition, the resultant
mixture was stirred for 10 min at À78 °C, and saturated
aqueous NH4Cl was added. The organic layer was
extracted with EtOAc. The combined organic layers were
dried and concentrated. The crude product was purified by
flash chromatography (CHCl3/MeOH = 200:1) to give a
1
sulfone 21 (1.11 g, 2.82 mmol, 76%) as a colorless oil: H
In summary, we have developed a concise, stereo-
controlled entry to the novel 11-oxatricyclo[5.3.1.1,703,8]-
undecane nucleus of luminamicin and lustromycin.
Further studies toward the total syntheses of these
compounds are now in progress.
NMR (300 MHz, CDCl3) d 0.82 (1H, ddd, J = 13.5, 4.5,
1.5 Hz), 1.16 (3H, t, J = 7.0 Hz), 1.82 (1H, m), 2.13 (1H,
ddd, J = 13.5, 9.0, 4.0 Hz), 3.17 (1H, dd, J = 11.0, 9.0 Hz),
3.31 (1H, dd, J = 11.0, 6.0 Hz), 3.75 (1H, dt, J = 6.5,
2.0 Hz), 4.02 (1H, dq, J = 11.0, 7.0 Hz), 4.10 (1H, dq,
J = 11.0, 7.0 Hz), 4.45 (1H, d, J = 16.0 Hz), 4.68 (1H, d,
J = 16.0 Hz), 4.73 (1H, m), 6.32 (1H, m), 6.49 (1H, ddd,
J = 8.0, 5.0, 1.5 Hz), 7.57 (2H, m), 7.67 (1H, m), 7.96
(2H, m); 13C NMR (75 MHz, CDCl3) d 13.9, 29.4, 31.6,
36.8, 61.5, 62.4, 65.9, 68.5, 87.9, 128.6 (2C), 129.1 (2C),
130.8, 134.1, 134.2, 139.4, 168.0, 195.8; IR (KBr) 3388,
1738, 1319, 1228, 1159, 1026 cmÀ1; HRMS (FAB, NBA,
PEG200 + 400 + NaI matrix) m/z for C19H22O7NaS
[M+Na]+ calcd 417.0984, found 417.0980.
Acknowledgments
This work was supported in part by the Ministry of
Education, Culture, Sports, Science and Technology
(MEXT), Japan and the Japan Keirin Association,
and a Grant of the 21st Century COE Program and
by the Uehara Memorial Foundation. We also thank
Ms. A. Nakagawa, Ms. C. Sakabe, Ms. N. Sato, and
Ms. Y. Kawauchi for the various instrumental analyses.
18. (a) Hecker, S. J.; Heathcock, C. H. J. Am. Chem. Soc.
1986, 108, 4586; (b) Farr, R. A.; Peet, N. P.; Kang, M. S.
Tetrahedron Lett. 1990, 31, 7109.
19. To a solution of aldehyde 5 (75.8 mg, 300 lmol) in CH2Cl2
(15.0 mL) was added DBU (21 lL, 150 lmol) at room
temperature. The resultant mixture was stirred for 18 h at
the same temperature until the starting material was
consumed. Then Et3N (377 lL, 2.70 mmol) and MsCl
(70 lL, 902 lmol) were added at room temperature, the
mixture was stirred for 15 min, and H2O was added. The
organic layer was extracted with CHCl3. The combined
organic layers were washed with 0.2 N HCl, dried over,
and concentrated. The crude product was purified by flash
chromatography (hexane/EtOAc = 3:1) to give a tricyclic
compound 4 (61.8 mg, 264 lmol, 88%) as a colorless solid:
References and notes
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1. Omura, S.; Iwai, Y.; Nakagawa, A.; Iwata, R.; Takahashi,
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1
mp 58–60 °C; H NMR (300 MHz, CDCl3) d 1.25 (3H, t,
ꢀ
Omura, S. J. Antibiot. 1986, 39, 1205.
J = 7.0 Hz), 1.56 (1H, m), 1.99 (1H, ddd, J = 13.0, 4.5,
3.0 Hz), 2.35 (1H, m), 3.72 (1H, ddd, J = 6.5, 3.5, 1.5 Hz),
4.16–4.27 (2H, m), 4.88 (1H, m), 5.89 (1H, d, J = 10.0 Hz),
6.47 (1H, m), 6.68 (1H, ddd, J = 8.0, 5.5, 1.5 Hz), 7.36
(1H, dd, J = 10.0, 7.0 Hz); 13C NMR (75 MHz, CDCl3) d
14.2, 26.1, 31.1, 39.4, 61.4, 69.5, 79.4, 122.7, 131.6, 136.4,
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156.2, 170.2, 193.0; IR (KBr) 1750, 1685, 1263, 1074 cmÀ1
;
HRMS (FAB, NBA, PEG200 + 400 + NaI matrix) m/z
for C13H14O4Na [M+Na]+ calcd 257.0790, found
257.0784.
9. Gouda, H.; Sunazuka, T.; Ui, H.; Handa, M.; Sakoh, Y.;
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