Stereochemistry of enacyloxins. Part 6: Synthesis of C16′-C23′ fragments of enacyloxins, a series of antibiotics from Frateuria sp. W-315

Article abstract of DOI:10.1515/HC.2011.008

The C16′-C23′ fragments of enacyloxins, a series of antibiotics isolated from Frateuria sp. W-315, were synthesized from D-arabinose. Copyright by Walter de Gruyter Berlin Boston.

Full text of DOI:10.1515/HC.2011.008

Heterocycl. Commun., Vol. 17(1-2), pp. 7–9, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.008
Preliminary Communication
Stereochemistry of enacyloxins. Part 6: Synthesis of C16′-C23′
fragments of enacyloxins, a series of antibiotics from Frateuria
sp.W-315
oxidized with iodine (4a) (Stewart et al., 2002), the remaining
2-hydroxy group was protected as TBDPS and MOM ether to
give 4e and 4f, respectively. The lactonic carbonyl group of
4e was again reduced by DIBAL to give 2e.
The representative results of Wittig and the related reactions
of hemiacetals 2a– 2e are listed in Table 1. Usual conditions for
Wittig reaction gave no olefin product (entry 1), and thus we
Wataru Igarashi, Hiroaki Hoshikawa, Hiroyuki
Furukawa, Teiko Yamada, Shigefumi Kuwahara
and Hiromasa Kiyota*
Graduate School of Agricultural Science, Tohoku
University, 1-1 Tsutsumidori-Amamiya, Aoba-ku, Sendai
981-8555, Japan
applied Fitjer’s harsh conditions (Fitjer and Quabeck, 1985).
Unprotected and TBDPS protected hemiacetals 2a and 2e
afforded olefin 6a and 6e, respectively, in 70% yield; however,
these products (E/Z=1:1) were an inseparable mixture (entries 2
and 10). Ohira reagents (Ohira, 1989) gave an alkyne 9 in mod-
erate yield (entry 4). The low reactivity of the carbamate 2b was
due to its high polarity (entries 5–7). Other reactions such as
Julia olefination and Wittig-Schlosser reactions gave a complex
mixture or recovered a starting material (data not shown).
*Corresponding author
e-mail: kiyota@biochem.tohoku.ac.jp
Abstract
The C16′-C23′ fragments of enacyloxins, a series of antibiot-
ics isolated from Frateuria sp. W-315, were synthesized from
d-arabinose.
Keywords: antibiotics; d-arabinose; enacyloxins; Frateuria
sp. W-315; synthesis; Wittig-Horner reaction.
OH
O
20'
OH
15'
O
19'
18'
OEE
17'
16'
O
O
OH
9'
In the preceding paper, we described our synthesis of a C9′-
C15′ fragment 1 of enacyloxins (ENXs) (Furukawa et al.,
2011). As a continuation, we began to prepare a C16′-C23′
fragment A, a nucleophilic counterpart of 1, from d-arabinose
to construct a C9′-C23′ polyol fragment (Scheme 1). The ste-
reochemistry of 17′,18′,19′-positions could be derived from
2,3,4-positions of d-arabinose.
C9'-C15' fragment
(1)
OH
OP
20'
O
OH
19'
17'
16'
18'
X
23'
OH
OP OP
OH OH
D-arabinose
C16'-C23' fragment (A)
First, we chose a route via an alkyne (Scheme 2). 3,4-cis-
Dihydroxy group of d-arabinose was selectively protected as
an acetonide (2a) (Ballou, 1957; Kiso and Hasegawa, 1976).
Oxidative fragmentation of 2a was accomplished by León’s
procedure (León et al., 2006) to give erythrose derivative
3. In our case, the intermediary formate was not isolated.
Nucleophilic addition of 1-butynyllithium gave a diastereo-
meric mixture (4RS)-5 (R/S=2.5:1). The undesired S-isomer
could be removed after reduction of the triple bond [(E)-6a].
Although (E)-6a has the same stereochemistry with A, the
elimination of the asymmetry of 2-position of 2a and the sepa-
ration of R/S-isomers are problems.
Scheme 1 Retrosynthetic analysis of the C16′-C23′ fragment.
OH
O
OH
OH
a
O
b
c
2
D-arabinose
O
O
O
O
2a
3
O
O
d
OH
OH
Thus, direct elongation of the anomeric 1-position of 2a
was examined. Several 2a derivatives with a protection of the
2-hydroxy group were prepared (Scheme 3). Carbamoyl (2b),
p-methoxyphenylmethyl (MPM, 2c), and TBS (2d) (Enholm
and Trivellas, 1989) ethers were prepared via a benzyl ether 7
(Ballou, 1957). Whereas the 1-position of 2a was selectively
OH
(4RS)-5
O
OH
(E)-6a
O
Scheme 2 Alkyne route. (a) Kiso and Hasegawa, 1976. (b) NaIO4,
NaHCO3, CH2Cl2-EtOH-H2O (57%). (c) EtC≡CH, BuLi, THF, -78°C,
(R/S=2.5:1, 76%). (d) i. LiAlH4, ether, reflux. ii. separation (66%).

8
W. Igarashi et al.
OBn
OH
O
O
OH
O
OR
OR
O
O
b, c, d
a
O
OH
O
O
R
D-arabinose
a
b
2b CONH2
2c MPM
O
O
OH
O
O
7
2d TBS
O
Ph2
P
c
OR
O
2e TBDPS
h
4e R=TBDPS
4f R=MOM
12e R=TBDPS
12f R=MOM
O
OH
O
OR
O
f, g
e
O
O
2a
O
OSEM
d
R
4e TBDPS
4f MOM
O
O
OH
Br
4a
O
OR
O
MOMO
(E)-6a R=H
13
Scheme 3 Preparation of various substrates for chain elonga-
tion. (a) i. BnOH, AcCl. ii. 2,2-DMP, PPTS (97%, two steps). (b)
i. NaOCN, TFA, CH2Cl2 (97%). ii. H2, 10% Pd-C, EtOH. (c) i.
NaH, MPMCl, DMSO (71%). ii. Raney Ni (W2), EtOH (26%). (d)
i. TBSCl, imidazole, DMF. ii. H2, Pd(OH)2, NaHCO3, EtOH (95%
from 7). (e) i. I2, NaHCO3, acetone-H2O (60%). (f) i. TBDPSCl, imi-
dazole, DMF (78%). (g) MOMCl, (i-Pr)2NEt, CH2Cl2 (quant.). (h)
DIBAL, CH2Cl2 (quant.).
(E)-6f R=MOM
OSEM
OSEM
16'
e, f
R
23'
MOMO
OH
MOMO
OH
C16'-C23' fragments
15 R=PPh3+Br_
16 R=SO2Ph
14
Because the separation or isomerization of the E/Z-isomers
(6a, 6d, and 6e), chain elongation of alkenes (8e and 11), and
alkyne 9 failed, Wittig-Horner reaction (Buss and Warren,
1985) with lactones 4e and 4f was examined (Scheme 4).
Nucleophilic attack of the anion derived from diphenylpro-
pylphosphine oxide to 4e followed by reduction with NaBH4
Scheme 4 Synthesis of C9′-C15′ fragment. (a) i. PrP(O)Ph2, BuLi,
THF. ii. NaBH4, EtOH-H2O. (b) NaH, DMF [10% for (E)-6a and
54% for (E)-6f]. (c) i. TsCl, Et3N, CH2Cl2. ii. AcOH-H2O. iii. NaH,
THF. iv. SEMCl, (i-Pr)2NEt, CH2Cl2 [41%, four steps from (E)-
6f]. (d) MgBr2, CH2Cl2 (quant.). (e) PPh3, THF (15%). (f) PhSSPh,
NaBH4, EtOH. ii. Mo7O24(NH3)6·4H2O, H2O2, EtOH (40%).
Table 1 Wittig and related reactions of the hemiacetals.
OH
O
O
OR
O
OH
OH
OR
O
OR O
O
8a R=H
6a R=H
O
8c R=MPM
6d R=TBS
8e R=TBDPS
6e R=TBDPS
R
2a H
2b CONH2
2c MPM
O
O
RO2C
2d TBS
OH
Br
OH
2e TBDPS
OH
O
H2NOCO
O
9
10 R=Et
Br
10' R=Me
O
OH
11
TBDPSO
O
Entry
Hemiacetal
Conditions
Product
(E/Z)
Yield
(%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2b
2b
2b
2c
2d
2e
2e
2e
Ph3PPrI, NaH, CH2Cl2, 0°C–20°C
Ph3PPrBr, KOt-Bu, toluene, reflux
Ph3PMeBr, KOt-Bu, toluene, reflux
Ohira reagent, K2CO3, MeOH
Ph3P=CHCO2Et, toluene, 50°C
Ph3P=CHCO2Me, CH2Cl2, 50°C
(EtO)2P(O)CH2CO2Et, NaH, DMF
Ph3PMeBr, KOt-Bu, toluene, reflux
Ph3PPrI, BuLi, toluene
–
–
6a (50:50)
70
78
40
5
21
–
70
32
70
10
15
8a
9
10 (43:57)
10′ (10:90)
–
8c
9
6d (0:100)
6e (50:50)
8e
10
11
12
Ph3PPrBr, KOt-Bu, toluene, reflux
Ph3PMeBr, KOt-Bu, toluene, reflux
(Ph3PCHBr2)Br, Zn, 1,4-dioxane
11

Synthesis of C16′−C23′ fragment of enacyloxins
9
afforded 12e. As 1H NMR was very complex, crude 12e was
treated with NaH. Only E-isomer without TBDPS group
(E)-6a was isolated in 10% yield. The same reaction sequence
was performed using alkaline tolerable MOM protect-
ing group, giving (E)-6f in 40% yield. The corresponding
(Z)-isomer was not detected. (E)-6f was converted to a
3-SEM-oxy 1,2-epoxide 13 to discriminate 2,3-oxygen func-
tions, and the epoxy ring was cleaved with MgBr2 in CH2Cl2
to give a bromohydrin 14. Finally, the C16′-C23′ fragments,
Wittig salt 15, and Julia sulfone 16 were prepared.
In conclusion, the C16′-C23′ fragments, Wittig salt 15,
and Julia sulfone 16 were prepared in diastereomerically pure
forms from d-arabinose using Wittig-Horner reaction as the
key step. Coupling reactions of the C16′-C23′ fragments with
the C9′-C15′ aldehyde are under investigation.
Buss, A. D.; Warren, S. The stereocontrolled Horner-Wittig reaction:
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Furukawa, H.; Hoshikawa, H.; Igarashi, W.; Yaosaka, M.; Yamada,
T.; Kuwahara, S.; Kiyota, H. Stereochemistry of enacyloxins.
Part 5: Synthesis of a C9′-C15′ fragment of enacyloxins, a series
of antibiotics from Frateuria sp. W-315. Heterocycl. Commun.
2011, 17, 3–5.
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Acknowledgments
The authors thank Dr. Toshihiko Watanabe for useful discus-
sion. Financial support 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.
References
Ballou, C. E. A new synthesis of d-erythrose derivatives from d-ara-
binose. J. Am. Chem. Soc. 1957, 79, 165–166.
Received April 19, 2011; accepted April 26, 2011

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