Toward the total synthesis of Luminamicin: Construction of 14-membered lactone framework possessing versatile enol ether moiety

Article abstract of DOI:10.1016/j.tetlet.2012.03.098

Luminamicin (1) was found to exhibit selective antibacterial activity against anaerobic bacteria by our group in 1985. The concise structure of 14-membered lactone of 1 was synthesized. Construction of a versatile enol ether moiety was achieved by Stille cross coupling via hydrostanylation of the ethynyl ether, and a maleic anhydride moiety was derived from the furan constitution by the oxidation after the macrolactonization at a late-stage.

Full text of DOI:10.1016/j.tetlet.2012.03.098

Tetrahedron Letters 53 (2012) 2813–2816
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Toward the total synthesis of Luminamicin: construction of 14-membered
lactone framework possessing versatile enol ether moiety
Aoi Kimishima, Tomoyasu Hirose, Akihiro Sugawara, Takanori Matsumaru, Kaoru Nakamura,
Ken Katsuyama, Masaki Toda, Hirokazu Takada, Rokuro Masuma, Satoshi Omura , Toshiaki Sunazuka
⇑
⇑
¯
Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Luminamicin (1) was found to exhibit selective antibacterial activity against anaerobic bacteria by our
group in 1985. The concise structure of 14-membered lactone of 1 was synthesized. Construction of a ver-
satile enol ether moiety was achieved by Stille cross coupling via hydrostanylation of the ethynyl ether,
and a maleic anhydride moiety was derived from the furan constitution by the oxidation after the mac-
rolactonization at a late-stage.
Received 20 February 2012
Revised 21 March 2012
Accepted 26 March 2012
Available online 29 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Luminamicin
Coloradocin
Antianaerobic activity
14-Membered macrolactone
Conjugated enol ether
In 1985, Luminamicin (1, Fig. 1) was isolated from the fermen-
tation broth of Streptomyces sp. OMR-59 by our group. It was found
to exhibit selective antibacterial activity against anaerobic bacte-
ria, particularly Clostridium sp., with a minimum inhibitory concen-
framework with an enol ether, and maleic anhydride functionality
has, as yet, been reported.
Importantly, 1 and the related macrolide, Lustromycin (2),8 ex-
hibit antibacterial activity against anaerobic bacteria, but do not
show antibacterial activity against aerobic bacteria.8,9 In contrast,
Nodusmicin (3)10,11 and Nargenicin (4),12,13 which possess a simi-
lar C(1–9–16) framework, are the reverse, showing antibacterial
activity against aerobic bacteria but not against anaerobic bacte-
ria.14 We thus became interested in which functional groups of 1
play a key role in determining the type of bioactivity shown by
the compound.
tration (MIC) value of 3–12 l
/mL.1 Two years after its discovery,
McAlpine and co-workers reported the isolation of Coloradocin,
an antianaerobic bactericide from the fermentation broth of
Actinoplanes coloradoensis,2 and showed it to be identical to 1.3
Luminamicin contains a highly functionalized oxa-bridged cis-
decalin ring system, namely 11-oxatricyclo[5.3.1.1,703,8]undecane,
associated with a 10-membered macrolactone moiety possessing
trisubstituted E-olefin and a 14-membered macrolactone with an
enol ether conjugated with a maleic anhydride functionality. In
2005, the absolute configuration of 1 was determined, as shown
in Figure 1, by our group using conformational analysis via high
temperature molecular dynamics, NMR spectroscopy, and the
modified Mosher method.4
Due to its intriguing architectural structure and interesting
biological activity, synthetic studies of the oxa-bridged cis-decaline
core of 1, 11-oxatricyclo[5.3.1.1,703,8]undecane, have been reported
by Kallmerten,5 Gössinger,6 and our group.7 However, no synthetic
study of the 14-membered macrolactone, the C(16–21–29)
One of the most difficult tasks in the synthesis of the 14-mem-
bered macrolactone framework of 1 is construction of enol ether
directly connecting the maleic anhydride unit. Therefore we cre-
ated a simplified 14-membered skeleton compound (5), with a
C(16–21–29) component, including maleic anhydride conjugated
with vinyl ether as a model compound, in order to establish a con-
venient reliable procedure to access the framework as well as
investigate structure–activity relationships. Herein we describe a
concise 14-membered lactone assembly, which allows investiga-
tion of key antibacterial properties of 1, together with antibacterial
assay of 5 and its analogues.
From the retrosynthetic strategy (Scheme 1), we envisioned 5 to
be constructed via oxidation of the furan (6) at the final stage,
accomplished through macrolactonization of the seco acid (7). A
Stille coupling between the iodofuran ester (8) and the stannyl
alkyl ether (11) would be expected to produce the enol ether
carbon–carbon bond of 7. The required ether (11) could be formed
⇑
¯
Corresponding authors. Tel.: +81 3 5791 6101; fax: +81 3 3444 8360 (S.O.); tel./
fax: +81 3 5791 6340 (T.S.).
¯
E-mail addresses: omuras@insti.kitasato-u.ac.jp (S. Omura), sunazuka@lisci.
kitasato-u.ac.jp (T. Sunazuka).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.098

2814
A. Kimishima et al. / Tetrahedron Letters 53 (2012) 2813–2816
O
O
O
O
26
24
O
O
O
O
21
27
OH
O
OH
O
OH
O
OH
29
28
18
O
O
O
O
O
16
O
O
1
O
O
HO
HO
HO
HO
14
13
2
H
O
O
H
11
OMe
OMe
OMe
OMe
H
N
4
OMe
O
12
H
10
9
H
O
7O
6
O
HO
H
H
Nodusmicin (3)
Nargenicin (4)
Luminamicin (1)
Lustromycin (2)
antianaerobic bacterial activity
antiaerobic bacterial activity
(Clostridium)
(Staphylococcus)
Figure 1. Structures of Luminamicin (1), Lustromycin (2), Nodusmicin (3), and Nargenicin (4).
O
O
O
O
O
Oxidation
Macrolactonization
O
O
O
OPMB
OPMB
OPMB
HO2C
O
O
O
O
HO
7
6
5
O
O
O
I
I
I
Stille
coupling
EtO2C
CO2Et
OH
EtO2C
8
9
10
OH
Bu3Sn
O
O
Hydrostannylation
OPMB
OPMB
OPMB
TBSO
TBSO
TBSO
13
11
12
Scheme 1. Retrosynthetic analysis of model compound 5.
by regioselective hydrostanylation of the ethynyl ether (12), which
can be converted from the alcohol (13).15,16 The necessary 8 can be
converted from commercially available 10.
Substitution of the bromide functionality of 10, which is pre-
pared by modified Keay protocol,17 with PPh3 and CBr4 resulted
in the formation of bromomethylfuran (14)18 in quantitative yield,
followed by a diethylmalonate substitution reaction to produce 9
in 99% yield. Krapcho decarboxylation19 (NaCl and DMAP in H2O
and DMSO) of 9 provided the coupling precursor 8 in 88% yield
(Scheme 2).
yield over two steps from 12 [67% as a theoretical yield given the
ratio of the hydrostannylation (Table 1; run 1)] (Scheme 3). Inci-
dentally, a Stille coupling using Z-b-vinyl stannane (1100) provided
the corresponding furan vinyl ether in 29% yield (not shown), sug-
gesting that the yield of a Stille coupling was found to be signifi-
cantly low, despite the high selectivity of the hydrostannylation
(Table 1; run 3). With 15 in hand, deprotection of the TBS group
with TBAF afforded ethyl ester (16), which was hydrolyzed under
basic condition to produce the seco acid (7), which upon Shiina
macrolactonization22 yielded the desired macrolide compound
(6) in good yield. Toward construction of the oxidative stage of
the model compound 5, we investigated the two-step oxidation
of 6 to the corresponding maleic anhydride. To obtain lactol 17, a
single oxygen protocol23–25 with hv, O2, DBU, and Rose Bengal at
ꢀ78 °C, resulted in decomposed products. Likewise, CO(N-
H2)2ꢁH2O2, ReMeO3 oxidation protocol26 provided the same
result . Pleasingly, NaClO2ꢁNaH2PO4 oxidation protocol, reported
by Clive,27,28 afforded the desired lactol 17 in 64% yield as a single
regioisomer, which upon the second oxidation of 17 with
Dess–Martin periodinane29 afforded a desired maleic anhydride
functionality of 5 in 60% yield.
Construction of the macrolactone (6), including enol ether with
furan began with introduction of the ethynyl group to 13,20 fol-
lowed by hydrostannylation of 12 to yield both b-O-vinyltin (11)
and
a
-O-vinyltin (110) (11/110/1100 = 5/4/0), using PdCl2(PPh3)2,
Bu3SnH condition (run 1, Table 1), which are determined by 1H
NMR of the crude product. Although the use of Pd(PPh3)4,21 led
to a similar result (11/110/1100 = 1/1/0; run 2), the use of AIBN
and Bu3SnH predominantly provided the Z selective product (11/
110/1100 = 0/1/20; run 3). However, the desired 11 appeared in
low regioselectivity accompanying the formation of 110 under most
conditions.
Due to instability of 11 and 110, the resulting crude product was
immediately subjected to Stille coupling with 8 in the presence of
PdCl2(PPh3)2 and Et4NCl to yield the coupling product 15 in 37%
We then turned our attention to antibacterial activity of
compounds 5, 6, 8, 12, and 17 against Clostridium perfringens using
a paper disc agar diffusion protocol.1 Although Luminamicin (1)

A. Kimishima et al. / Tetrahedron Letters 53 (2012) 2813–2816
2815
Scheme 2. Synthesis of iodofuran ester 8. Reagents and conditions: (a) PPh3, CBr4, CH2Cl2, 0 °C, 15 min, quant.; (b) diethyl malonate, DMF, THF, rt, 2 h, 99%; (c) NaCl, DMAP,
H2O, DMSO, 180 °C, 19 h, 88%.
Table 1
Results of hydrostannylation of ethynyl ether (12), prepared from 13
Runa
Reagents
Solvents
Temp.; Time
Products (ratio)b 11:110:1100
1
2
3
PdCl2(PPh3)2 (0.05 equiv), Bu3SnH
Pd(PPh3)4 (0.05 equiv), Bu3SnH
AIBN (0.2 equiv), Bu3SnH
CH2Cl2
CH2Cl2
Toluene
rt; 0.5 h
rt; 1.5 h
80 °C; 40 min
5:4:0
1:1:0
0:1:20
a
All the runs were carried out by using 1.05 equiv of Bu3SnH.
Products ratio was calculated by 1H NMR.
b
Scheme 3. Synthesis of the model compound 5. Reagents and conditions: (a) Iodofuran (8), PdCl2(PPh3)2, Et4NCl, DMF, 80 °C, 1 h, 37% from 12 (67% theoretical yield from 11);
(b) TBAF, THF, rt, 2 h, 86%; (c) 0.2 M NaOH, MeOH, THF, H2O, rt, 1 h; (d) MNBA, DMAP, CH2Cl2, 0 °C, slow addition of 7 over 20 min to a reagents solution, 89% from 16; (e)
NaClO2, NaH2PO4, 2-methyl-2-butene, 2-PrOH, H2O, rt, 8 h, 64%; (f) DMP[O], CH2Cl2, rt, 5 h, 60%.
exhibited antibacterial activity against Clostridium perfringens as a
positive control, none of the compounds demonstrated any activity
at all. Based on these results, the C(16–21–29) framework was
deemed not to be responsible for creating bioactivity against
anaerobic bacteria, thereby suggesting the whole framework of 1
and 2 is necessary for bioactivity against anaerobic bacteria.
In conclusion, we have achieved the synthesis of the simplified
model compound 5, possessing vinyl enol ether conjugated with
maleic anhydride functionality, utilizing Stille coupling to con-
struct the furan moiety conjugated with vinyl ether, together with
Shiina macrolactonization to form the 14-membered macrolac-
tone. Additionally, we found that the simplified molecules (5, 6,
8, 12, and 17) do not exhibit antibacterial activity against anaero-
bic bacteria. Further studies toward the total syntheses of 1 and 2
are now in progress.
Acknowledgements
This work was supported by a Grant for the 21st Century COE Pro-
gram, Ministry of Education Culture, Sports, Science and Technology
(MEXT) (Grant No. 18790022), a Grant-in-Aid for Scientific Research
(Grant No. 16590012), Grant-in-Aid for Research Activity Start-up
(Grant No. 22890175), the JSPS Research Fellowships for Young
Scientists (T.M.), the Uehara Memorial Foundation (T.H.), and the

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