Facile synthesis of the cyclohexane fragment of enacloxins, a series of antibiotics isolated from Frateuria sp. W-315

Article abstract of DOI:10.1080/09168451.2014.905192

An efficient and good yield synthesis of the cyclohexane moiety of enacyloxins, a series of antibiotics isolated from Frateuria sp. W-315, was achieved from D-quinic acid using a successive Barton - McCombie deoxygenation.

Full text of DOI:10.1080/09168451.2014.905192

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Facile synthesis of the cyclohexane fragment of
enacloxins, a series of antibiotics isolated from
Frateuria sp. W-315
a
a
a
a
a
Aki Saito , Wataru Igarashi , Hiroyuki Furukawa , Teiko Yamada , Shigefumi Kuwahara &
b
Hiromasa Kiyota
a
Graduate School of Agricultural Science, Tohoku University, Aoba-ku, Japan
b
Graduate School of Environmental & Life Science, Okayama University, Kita-ku, Japan
Published online: 30 May 2014.
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To cite this article: Aki Saito, Wataru Igarashi, Hiroyuki Furukawa, Teiko Yamada, Shigefumi Kuwahara & Hiromasa Kiyota
2014) Facile synthesis of the cyclohexane fragment of enacloxins, a series of antibiotics isolated from Frateuria sp.
(
W-315, Bioscience, Biotechnology, and Biochemistry, 78:5, 766-769, DOI: 10.1080/09168451.2014.905192
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Bioscience, Biotechnology, and Biochemistry, 2014
Vol. 78, No. 5, 766–769
Note
Facile synthesis of the cyclohexane fragment of enacloxins, a series of
antibiotics isolated from Frateuria sp. W-315
1
1
1
1
1
Aki Saito , Wataru Igarashi , Hiroyuki Furukawa , Teiko Yamada , Shigefumi Kuwahara and
2,
Hiromasa Kiyota *
1
2
Graduate School of Agricultural Science, Tohoku University, Aoba-ku, Japan; Graduate School of Environmental
&
Life Science, Okayama University, Kita-ku, Japan
Received January 7, 2014; accepted January 30, 2014
http://dx.doi.org/10.1080/09168451.2014.905192
An efficient and good yield synthesis of the cyclo-
hexane moiety of enacyloxins, a series of antibiotics
isolated from Frateuria sp. W-315, was achieved
from D-quinic acid using a successive Barton–
McCombie deoxygenation.
form lactone ring as well as isopropylidene acetal in
high yield (5). Then radical-mediated deoxygenation
1
2)
of the tertiary hydroxy group was achieved via imidaz-
1
3)
ole-type thiocarbamate with retention of the C1 con-
1
4)
figuration to give the known lactone 6 in 72% yield.
Ring-opening of the lactone ring of 6 was performed
using sodium methoxide to give methyl ester 7 in 86%.
The second two-step reductive deoxygenation of 7
afforded 8 in 93% yield. Then hydrolysis of the acetal
group in 8 with aqueous trifluoroacetic acid gave the
target cyclohexane moiety 3 of ENXs in 87% yield.
The overall yield was 55% in 7 steps from D-quinic
acid (4). To confirm the stereochemistry, 3 was con-
Key words: enacyloxin; antibiotics; Barton–McCombie
deoxygenation; D-quinic acid
Enacyloxins (ENXs) are unique polyhydroxy-poly-
enic and yellow-colored antibiotics produced by Frate-
uria sp. W-315 in a Czapek-Dox medium spent by
1
)
5)
Neurospora crassa. ENXs show antibiotic activity
verted to the corresponding dibenzoate 9. The physi-
against Gram-positive and Gram-negative bacteria, but
cochemical and spectroscopic data of 9 are identical
with those reported by us.
1
,2)
5)
inactive for yeast and fungi.
Its mode of action was
considered to be an inhibition of peptide biosynthesis
by hindering the release of EF-Tu GDP from the ribo-
In summary, the short, efficient, and facile synthesis
of the cyclohexane moiety of enacycloxins, a series of
polyhydroxy-polyenic antibiotics produced by Frateuria
sp. W-315, was achieved using Barton–McCombie
deoxygenation as the key steps from D-quinic acid (see
Scheme 2).
3
)
some. Furthermore, ENXs have attracted considerable
attention because of the inhibitory activity toward orga-
4
)
nelle protein synthesis in Plasmodium falciparum.
The whole stereochemistry of ENXs [ENX IVa (1)]
5
–7)
was elucidated by our synthetic
and spectroscopic
8
)
studies, and Parmeggiani’s X-ray crystallographic
analysis of the Escherichia coli EF-Tu/guanylyl imin-
odiphosphate-ENX IIa (2) complex. In spite of these
unique properties, synthetic study other than by our
group has not been reported yet. On the continuation
Experimental
3
)
Optical rotation values were measured by a Horiba
Sepa-300 polarimeter. FT-IR spectra were recorded as
1
films by a Jasco 4100 spectrometer (ATR, Zn-Se). H
5
–7,9,10)
1
3
of our chemical works on ENXs,
we attempted
and C NMR spectra were recorded with Agilent
1
to improve the synthesis of the cyclohexane moiety 3.
Although our previous synthesis had led us to deter-
mine its (1S,3R,4S) stereochemistry, it suffered from
the long synthetic sequence from tri-O-acetyl-D-glucal
NMR System 600 (600 MHz for H) and 400-MR
1
13
(
400 MHz for H and 100 MHz for C) spectrometers
in CDCl with tetramethylsilane (δ 0 ppm) and CHCl
3
3
H
(δC 77 ppm) as internal standards. Mass spectra (FAB)
5
)
and non-stereoselective intramolecular alkylation.
were recorded with a Jeol JMS-700 spectrometer.
Merck silica gel 60 (70–230 mesh) was used for col-
umn chromatography.
Synthetic trial via cis-dihydroxylation of 3-cyclohexen-
ecarboxylate derivatives resulted in formation of diaste-
reomeric mixtures (Furukawa
H and Kiyota H,
unpublished results) (see Scheme 1).
Our new synthesis of the cyclohexane moiety 3
started with D-quinic acid (4) because of its stereo-
(1S,3R,4R,5R)-3,4-O-Isopropylidenedioxycyclohexane-
1,5-carbolactone (6). To a suspension of 5 (500 mg,
2.3 mmol) in dry 1,2-dichloroethane (6.7 mL) was added
thiocarbonyldiimidazole (530 mg, 2.9 mmol, 1.3 eq) and
11)
chemical similarity.
According to published proce-
dures, acid-catalyzed reaction of 4 in acetone led to
*Corresponding author. Email: kiyota@okayama-u.ac.jp
©
2014 Japan Society for Bioscience, Biotechnology, and Agrochemistry

Synthesis of the cyclohexane fragment of enacloxins
767
Cl
OH
O
10'
19'
15'
R
1' O
3
4
1
OH
H N
2
O
OH
OH Cl
O
HO
O
ENX IVa (1) R = -OH, -H
ENX IIa (2) R =
O
O
HO
HO
HO
HO
HO
deoxygenation
OMe
OH
OH
D-quinic acid (4)
cyclohexane fragment 3
Scheme 1. Enacyloxin IIa (1), IVa (2), and retrosynthesis of the cyclohexane fragment 3 from D-quinic acid (4).
O
HO
OH
HO
HO
O
O
OH
a
O
O
OH
D-quinic acid (4)
5
b
N
N
O
O
O
O
S
O
O
O
O
O
6
c
O
O
N
O
O
O
OMe
OMe
d
O
N
OH
7
O
S
O
O
e
HO
O
O
OMe
OMe
HO
3
8
f
O
BzO
BzO
OMe
9
12)
Scheme 2. Synthesis of 3. Reagents and conditions: (a) Sanchez-Abella’s procedure; (b) (i) Im
Bu SnH, AIBN, xylene, reflux (72%); (c) NaOMe, MeOH, 20 °C (86%); (d) (i) Im C = S, imidazole, ClCH
xylene, reflux (93%); (e) TFA, H
2
C = S, imidazole, ClCH
2
CH
2
Cl, reflux; (ii)
3
2
2
2 3
CH Cl, reflux; (ii) Bu SnH, AIBN,
5)
2
O, 0 °C (87%); (f) see lit. (37%).

768
A. Saito et al.
imidazole (240 mg, 3.5 mmol, 1.5 eq) at 20 °C and the
reaction mixture was stirred under reflux for 3 h after
being cooled to 20 °C, the reaction mixture was concen-
trated and diluted by 50% of 2-butanone in acetonitrile.
The dilute was concentrated to give crude thiocarbamate
as an orange amorphous solid.
N gas was passed through a dry toluene (31 mL)
2
solution of the crude thiocarbamate and AIBN (5.5 mg,
0.033 mmol, 0.02 eq) for 5 min. To this was added tri-
butyltin hydride (0.49 mL, 1.8 mmol, 1.1 eq) and the
mixture was stirred under reflux for 1.5 h, and then
cooled to 20 °C. The solvent was evaporated under
reduced pressure, and the residue was purified by silica
gel column chromatography (hexane-diethyl ether,
10:1) to give 8 (320 mg, 1.5 mmol, 93%) as a colorless
N2 gas was passed through a dry xylene (86 mL)
solution of the crude thiocarbamate and AIBN (16 mg,
0
.092 mmol, 0.04 eq) for 5 min. To this was added tri-
2
D
3
−1
butyltin hydride (1.3 mL, 5.0 mmol, 2.2 eq) and the
mixture was stirred under reflux for 1.5 h, and then
cooled to 20 °C. The solvent was evaporated under
reduced pressure, and the residue was purified by silica
gel column chromatography (hexane-diethyl ether,
oil; ½aꢀ −10.3° (c 2.0, CHCl ). IR ν
cm : 2953
3
max
(m), 1730 (s, C=O), 1217 (m, C–O), 1040 (m, C–O).
NMR (400 MHz): δH 0.92 (2 H, t, J = 7.3 Hz, H-6),
1.34 (6 H, s, gem-CH ), 1.45 (1 H, m, H-5), 1,65 (1 H,
3
m, H-5), 1.85 (1 H, ddd, J = 15.3, 11.3, 4.1 Hz, H-2),
2.19 (1 H, ddd, J = 15.3, 4.1, 3.5 Hz, H-2), 2.68 (1 H,
1
5:1–6:1) and recrystallization (hexane-diethyl ether) to
give 6 (323 mg, 1.7 mmol, 72%) as a white amorphous
m, H-1), 3.68 (3 H, s, OCH ), 4.11 (1 H, dd, J = 11.8,
5.0 Hz, H-4), 4.30 (1 H, ddd, J = 5.0, 3.5, 4.1 Hz, H-3).
3
1
4)
solid; mp 95–96 °C [Lit.:
ether), ½aꢀ −36.3° (c 2.2, CHCl ) [Lit.:
96–98 °C (hexane-diethyl
2
2
14)
−36.2°
NMR (100 MHz): δ 23.51, 25.88, 27.80, 28.04, 29.13,
D
3
C
(
c 2.2, CHCl )].
36.37, 51.69 (OMe), 72.40, 73.02, 107.93 (Me C),
3
2
The spectroscopic data were in good agreement with
those reported.
175.94 (C-1). MS m/z: 175, 177, 179, 185 [M + H –
1
4)
+
+
+
OMe] , 199 [M + H – Me] , 216 [M + H] . HRMS m/z
+
(
[M + H] ): Calcd. for C H O : 215.1283; Found:
11 19 4
2
15.1285.
Methyl (1S,3R,4S,5R)-5-Hydroxy-3,4-O-isopropyli-
dendioxycyclohexanecarboxylate (7). To a solution of
lactone 6 (380 mg, 1.9 mmol) in anhydrous methanol
Methyl (1S,3R,4S)-3,4-Dihydroxycyclohexanecarbox-
ylate (3). Cooled TFA/H O (1:1) solution (2.0 mL)
(
4.6 mL) was added dropwise a solution of sodium
methoxide (57 mg, 2.5 mmol) in anhydrous methanol
8.5 mL) over 30 min at 0 °C, and the mixture was neu-
2
was added to 8 (130 mg, 0.57 mmol) at 0 °C and the mix-
ture was stirred for 1 h at 0 °C. Then the reaction mixture
was allowed to warm to 20 °C and concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography (hexane-ethyl acetate, 1:1) to
(
tralized with AcOH. Then, to this was added an aque-
ous saturated solution of NaHCO and the mixture was
3
extracted with CH Cl . The combined organic fraction
2
2
2
D
3
was dried over Na SO , and concentrated under
give 3 (86 mg, 0.49 mmol, 87%) as a colorless oil; ½aꢀ
2
4
−
1
reduced pressure. The residue was purified by silica gel
column chromatography (hexane-ethyl acetate, 5:1) to
give 7 (380 mg, 1.6 mmol, 86%) as a colorless
–1.8° (c 1.0, CHCl ). IR ν
cm : 3419 (s, O–H), 2950
3
max
(m), 2361 (s), 1725 (s, C=O), 1212 (m, C–O), 1065 (m,
C–O). NMR (600 MHz): δH 1.49 (1 H, ddd, J = 16.8,
13.3, 11.2 Hz, H-6), 1.68 (1 H, ddd, J = 13.0, 11.4, 2.4
Hz, H-2), 1.73 (1 H, m, H-5), 1.98 (1 H, ddd, J = 16.8,
4.0, 2.4 Hz, H-6), 2.14 (1 H, ddd, 13.3, 13.0, 4.1 Hz, H-
5), 2.18 (1 H, m, H-2), 2.72 (1 H, dddd, J = 15.1, 11.4,
11.2, 4.0 Hz, H-1), 3.65 (1 H, m, H-4), 3.67 (3 H, s,
OCH ), 4.01 (1 H, m, H-3). NMR (100 MHz): δ 26.04,
27.61, 32.95, 36.38, 51.72 (OMe), 68.56, 70.73, 176.18
(C=O). MS m/z: 97, 125, 137, 154, 175 [M + H] .
HRMS m/z ([M + H] ): Calcd. for C H O : 175.0970;
Found: 175.0971.
2
D
4
−1
oil; ½aꢀ −71.7° (c 1.0, CHCl ). IR ν
cm : 3466
3
max
(
s, O–H), 2952 (m), 1730 (s, C=O), 1240 (m, C–O),
055 (m, C–O). NMR (400 MHz): δH 1.37 (6 H, s,
gem-CH ), 1.49 (1 H, dd, J = 13.4, 8.0 Hz, H-6), 1.88
1
3
(
1 H, ddd, J = 15.3, 12.0, 3.8 Hz, H-2), 2.12 (1 H, dd,
J = 13.4, 4.0 Hz, H-6), 2.35 (1 H, ddd, J = 15.3, 6.0,
.9 Hz, H-2), 2.74 (1 H, dddd, J = 12.0, 8.0, 4.0, 3.0
Hz, H-1), 3.70 (3 H, s, OCH ), 3.75 (1 H, m, H-5),
3
C
1
+
3
+
3
3
3
1
.84 (1 H, dd, J = 12.4, 6.0 Hz, H-4), 4.37 (1 H, m, H-
). NMR (100 MHz): δC 25.99, 28.17, 28.78, 32.60,
8
15 4
6.03, 51.91 (OMe), 71.44, 72.98, 107.89 (Me C),
2
75.20 (C-1). MS: m/z: 95, 155, 173 [M + H –
Methyl (1S,3R,4S)-3,4-Dibenzoyloxycyclohexanecarb
+
+
+
CO Me] , 215 [M + H – OH] , 231 [M + H] . HRMS
m/z ([M + H] ): Calcd. for C H O : 231.1233; Found:
2
oxylate (9). 9 was obtained as a colorless oil in 37%
+
22
D
1
1 19 5
from 3 according to our reported procedure; ½aꢀ
2
31.1232.
5)
−
30.2° (c 0.54, CHCl ). [Lit.: −36.8° (c 0.54,
3
CHCl )].
3
Methyl (1S,3R,4S)-3,4-O-Isopropylidenedioxycyclo-
hexanecarboxylate (8). To a suspension of 7 (380
mg, 1.6 mmol) in dry 1,2-dichloroethane (7.8 mL) was
added thiocarbonyldiimidazole (380 g, 2.1 mmol, 1.3
eq) and imidazole (220 mg, 3.2 mmol, 2 eq) at 20 °C
and the reaction mixture was stirred under reflux for 3
h. After being cooled to 20 °C, the reaction mixture
was concentrated under reduced pressure and diluted
by 50% of 2-butanone in acetonitrile. The dilute was
concentrated under reduced pressure to give crude thio-
carbamate as an orange amorphous solid.
Funding
Financial supports by grant-in-aid from Japan Society for
the Promotion of Science [grant number 17580092], [grant
number 19580120], [grant number 22580112], and [grant
number 25450144], Tokyo Ohka Foundation for the
Promotion of Science and Technology, The Naito Foundation,
Intelligent Cosmos Foundation and Kuribayashi Ikuei
Foundation are gratefully acknowledged.

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