Stereochemistry of enacyloxins. Part 5: Synthesis of a C9′-C15′ fragment of enacyloxins, a series of antibiotics from Frateuria sp. W-315

Article abstract of DOI:10.1515/HC.2011.007

The C9′-C15′ fragment of enacyloxins, a series of antibiotics isolated from Frateuria sp. W-315, was synthesized from diethyl D-tartrate. Copyright by Walter de Gruyter Berlin Boston.

Full text of DOI:10.1515/HC.2011.007

Heterocycl. Commun., Vol. 17(1-2), pp. 3–5, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.007
Preliminary Communication
Stereochemistry of enacyloxins. Part 5: Synthesis of a C9′-C15′
fragment of enacyloxins, a series of antibiotics from Frateuria
sp.W-315
and B could make use of naturally occurring methyl (S)-β-
hydroxyisobutyrate (HIBA-Me) or diethyl d-tartrate.
Hiroyuki Furukawa, Hiroaki Hoshikawa, Wataru
Igarashi, Manabu Yaosaka, Teiko Yamada, Shigefumi
Kuwahara and Hiromasa Kiyota*
We first chose (S)-HIBA-Me as a starting material as its
(S)-configuration was to be applied to the C12′-position of the
C9′-C15′ fragment (Scheme 2). (S)-HIBA-Me was converted
to the known dibromide 5 according to the literature (Ley et
al., 2009). A lithium acetylide formed by basic treatment of
5 was trapped with formaldehyde to afford a propargyl alco-
hol 6 in 88% yield. Hydroalumination followed by adding
N-chlorosuccimide (NCS) (Heathcock et al., 1984) gave a
vinyl chloride 7. The hydroxy group of 7 was protected as
p-methoxyphenylmethyl ether (8). Acidic removal of the THP
group proceeded in 82%, however, sometimes suffered from
concomitant dechlorination. TEMPO oxidation and Wittig
reaction of 9 gave an enone 10; however, the next Sharpless
asymmetric dihydroxylation resulted in a complex mixture.
In addition, it was found that partial epimerization occurred
during the oxidation of 3. To confirm this and to elucidate
optimized conditions, various oxidants were tested as shown
in Table 1. The optical purity of aldehyde 4 was determined
by derivatization to 12. Optical rotation value was compared
with that of the known ent-12 (Nagaoka and Kishi, 1981). The
optical purity of 12 was further confirmed by 1H NMR analy-
sis of the corresponding (S)-MTPA ester (13). As a result, all
Graduate School of Agricultural Science, Tohoku
University, 1-1 Tsutsumidori-Amamiya, Aoba-ku,
Sendai 981-8555, Japan
*Corresponding author
e-mail: kiyota@biochem.tohoku.ac.jp
Abstract
The C9′-C15′ fragment of enacyloxins, a series of antibiot-
ics isolated from Frateuria sp. W-315, was synthesized from
diethyl d-tartrate.
Keywords: antibiotics; diethyl d-tartrate; enacyloxins;
Frateuria sp. W-315; synthesis.
Enacyloxins (ENXs) are unique polyhydroxy-polyenic and
yellow-colored antibiotics produced by Frateuria sp. W-315
in a Czapek-Dox medium spent by Neurospora crassa
(Scheme 1) (Watanabe et al., 1990). ENXs show antibiotic
activity against Gram-positive and Gram-negative bacte-
ria, but inactive for yeast and fungi (Watanabe et al., 1990;
Oyama et al., 1994). Its mode of action was considered to be
an inhibition of peptide biosynthesis by hindering the release
of EF-Tu GDP from the ribosome (Parmeggiani et al., 2006).
Furthermore, ENXs have attracted considerable attention
because of the inhibitory activity toward organelle protein
synthesis in Plasmodium falciparum (Clough et al., 1999).
The whole stereochemistry of ENXs [ENX IVa (1)] was elu-
cidated by our synthetic (Fujimori et al., 2001; Takeuchi et
al., 2001; Watanabe et al., 2001) and spectroscopic studies
(Furukawa et al., 2007), and Parmeggiani’s X-ray crystal-
lographic analysis of the Escherichia coli EF-Tu/guanylyl
iminodiphosphate-ENX IIa (2) complex (Parmeggiani et al.,
2006). Continuing our chemical work of ENXs, we began the
synthetic studies of the polyol fragment. Here, we describe an
efficient synthesis of C9′-C15′ fragment.
24'
Cl
OH
20'
10'
8'
19'
17'
15'
13'
11'
1'
O
18'
16'
14'
12'
23'
21'
9'
H2N
O
OH
R
OH
Cl
HO2C
O
3
4
1
ENX IVa (1) R=β-OH, α-H
ENX IIa (2) R=O
O
OH
8'
CO2R
Ph3P
C
OP
X
OP
10'
15'
O
16'
9'
23'
OP
A
OP
O
OP
Cl
B
OH
OH
OH
OH
OH
HO
CO2Et
O
Scheme 1 shows our retrosynthetic plan. Disconnection
of the whole molecule (1 or 2) leads to three fragments A,
B, and C. The C8′-C9′ double bond could be formed by
Wittig reaction and nucleophilic addition is suitable for the
C15′-C16′ connection. The stereochemistry of fragments A
or
EtO2C
CO2Me
OH
diethyl D-tartrate
D-arabinose
(S)-HIBA-Me
Scheme 1 Enacyloxins and their retrosynthetic analysis.

4
H. Furukawa et al.
a
b
c
O
OH
OH
O
O
CO2Me
a
b
CO2Et
OH
OTHP
3
OTHP
4
EtO2C
(S)-HIBA-Me
OH
TBSO
O
TBSO
O
OH
diethyl D-tartrate
14
15
Br
d
e
Br
O
Br
O
OTHP
5
OTHP
6
THPO
Cl OH
c
d
Br
OH
7
OH
TBSO
O
O
TBSO
O
16
17
f
g
h
THPO
O
Cl OMPM
OH Cl OMPM
O
e
f
8
9
15'
OH
OEE
OEE
i
OH
O
O
O
9'
15'
EtO
EtO
9'
18
C9'-C15' fragment (19)
Cl OMPM
O
OH Cl OMPM
11
10
Scheme 3 Synthesis of C9′-C15′ fragment 2.
(a, b) Araki et al., 2002. (c) i. Swern oxidation (87%). ii. CBr4, PPh3,
Et3N, CH2Cl2 (43%). (d) BuLi, (CH2O)n, THF (43%). (e) i. ethyl
vinyl ether, PPTS, CH2Cl2 (quant.). ii. TBAF, THF (76%). (f) Dess-
Martin periodinane (68%).
Scheme 2 Synthetic studies of C9′-C15′ fragment-1. (a) i. DHP,
PPTS, CHCl3. ii. LiAlH4, THF. (b) Swern oxidation. (c) CBr4, PPh3,
Et3N, MeCN (69% from 3). (d) BuLi, (CH2O)n, THF (88%). (e)
Red-Al®, PhMe, then NCS (50%). (f) NaH, p-methoxyphenylmethyl
chloride, NaI, THF (quant.). (g) PPTS, MeOH (82%). (h) i. TEMPO,
KBr, aq. NaOCl, CH2Cl2. ii. Ph3P=CHCO2Et, PhMe (77% from 9).
(i) AD-mix β, MeSO2NH2, t-BuOH-H2O.
reported the conversion of diethyl d-tartrate to alcohol 15,
which had all the asymmetric center of the target fragment.
Introduction of the asymmetric methyl group was performed
by hydroboration-oxidation of 14 with 9-BBN. The hydroxy
group of 15 was converted to a dibromide 16 and then to a
propargyl alcohol 17. Epimerization of the methyl group
was not detected. The TBS group was removed (18) and the
resulting hydroxy group was oxidized to give C9′-C15′ frag-
ment aldehyde 19. The overall yield was 8.3% in six steps
from 14.
the moderate conditions caused the epimerization. Thus, we
thought HIBA-Me was insufficient as a starting material and
formation of the vinylic chloride moiety should be introduced
at a later step of synthesis.
Next, we planned to use a dihydroxy moiety of d-tartrate
for the C13′-C14′ position (Scheme 3). Araki et al. (2002)
In conclusion, the C9′-C15′ fragment for the total synthe-
sis of enacyloxin antibiotics was prepared from the known
alcohol derived from diethyl d-tartrate. Preparation of a C16′-
C23′ is described by Igarashi et al. (2011).
Table 1 Oxidation conditions for 3 and optical purity of
derivative 13.
Table
a
O
OH
OH
OH
OTHP
3
OTHP
4
OTHP
3'
Acknowledgments
b
c
OBn
OBn
The authors thank Dr. Toshihiko Watanabe for useful discussion and
Kaneka Corporation for the gift of (S)-HIBA-Me. Financial supports
by grant-in-aid from the Japan Society for the Promotion of Science
(No. 17580092), the Naito Foundation, the Intelligent Cosmos
Foundation and the Kuribayashi Ikuei Foundation are gratefully
acknowledged.
O-(S)-MTPA
12
13
(a) LiAlH4, THF. (b) i. NaH, BnCl, NaI, THF. ii. TsOH, MeOH
(ca. 55% from 3). (c) (R)-MTPACl, Py, CH2Cl2 (quant.).
Entry
1
Conditions
[α]d
Optical
of 12a
purity (%)b
References
DMSO, (COCl)2, Et3N,
-70°C to 0°C
–14.0°
81
Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D. Total synthesis of
attenols A and B. Tetrahedron 2002, 58, 1983–1995.
Clough, B.; Rangachari, K.; Strath, M.; Preiser, P. R.; Wilson, R.
J. M. Antibiotic inhibitors of organellar protein synthesis in
Plasmodium falciparum. Protist 1999, 150, 189–195.
Fujimori, T.; Nakayama, O.; Kiyota, H.; Kamijima, Y.; Watanabe, T.;
Oritani, T. Absolute configuration of the cyclohexane ring part
of enacyloxins, a series of antibiotics from Frateuria sp. W-315.
Heterocycl. Commun. 2001, 7, 327–330.
2
3
DMSO, SO3·Py, Et3N, 0°C
Dess-Martin periodinane,
CH2 Cl2, 0°C
–12.0°
–14.6°
69
85
4
PCC, MS4Å, CH2Cl2, 0°C
–6.9°
40
a[α]D (c=4.00, CHCl3). bOptical purity was calculated based on
ent-12 {>98% ee, [α]D=+17.2° (c=3.24, CHCl3)} reported by
Nagaoka and Kishi (1981).

Synthesis of a C9′-C15′ fragment of enacyloxins
5
Furukawa, H.; Kiyota, H.; Yamada, T.; Yaosaka, M.; Takeuchi, R.;
Watanabe, T.; Kuwahara, S. Complete structural and configu-
rational assignment of the enacyloxin family, a series of anti-
biotics from Frateuria sp. W-315. Chem. Biodivers. 2007, 4,
1601–1604.
Heathcock, C. H.; Mahaim, C.; Schlecht, M. F.; Utawanit, T. A
synthetic approach to the quassinoids. J. Org. Chem. 1984, 49,
3264–3274.
Igarashi, W.; Hoshikawa, H.; Furukawa, H.; Yamada, T.; Kuwahara,
S.; Kiyota, H. Stereochemistry of enacyloxins. Part 6: synthesis of
a C16′-C23′ fragments of enacyloxins, a series of antibiotics from
Frateuria sp. W-315. Heterocycl. Commun. 2011, 17, 7–9.
Ley, S. V.; Tackett, M. N.; Maddess, M. L.; Anderson, J. C.; Brennan,
P. E.; Cappi, M. W.; Heer, J. P.; Helgen, C.; Kori, M.; Kouklovsky,
C.; et al. Total synthesis of rapamycin. Chem. Eur. J. 2009, 15,
2874–2914.
enacyloxin IVa to enaxyloxin IIa. Biosci. Biotechnol. Biochem.
1994, 58, 1914–1917 and references cited therein.
Parmeggiani, A.; Krab, I. M.; Watanabe, T.; Nielsen, R. C.; Dahlberg,
C.; Nyborg, J.; Nissen, P. Enacyloxin IIa pinpoints a binding pocket
of elongation factor Tu for development of novel antibiotics. J.
Biol. Chem. 2006, 281, 2893–2900 and references cited therein.
Takeuchi, R.; Kiyota, H.; Yaosaka, M.; Watanabe, T.; Enari, K.;
Sugiyama, T.; Oritani, T. (12′S,17′R,18′S,19′R)-Absolute con-
figuration of enacyloxins, a series of antibiotics from Frateuria
sp. W-315. J. Chem. Soc., Perkin Trans 1 2001, 2676–2681.
Watanabe, T.; Sugiyama, T.; Takahashi, M.; Shima, J.; Yamashita,
K.; Izaki, K.; Furihata, K.; Seto, H. New polyenic antibiotics
active against Gram-positive and Gram-negative bacteria. Agric.
Biol. Chem. 1990, 54, 259–261.
Watanabe, T.; Kiyota, H.;Takeuchi, R.; Enari, K.; Oritani, T. Structure
elucidation of decarbamoyl enacyloxin IIa and IVa, new members
of enacyloxin antibiotics from Frateuria sp. W-315. Heterocycl.
Commun. 2001, 7, 313–316.
Nagaoka, H.; Kishi, Y. Further synthetic studies of rifamycin S.
Tetrahedron 1981, 37, 3873–3888.
Oyama, R.; Watanabe, T.; Hanzawa, H.; Sano, T.; Sugiyama, T. An
extracellular quinoprotein oxidase that catalyzes conversion of
Received April 19, 2011; accepted April 26, 2011

Copyright of Heterocyclic Communications is the property of De Gruyter and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.