482
Y.-G. Wang et al.
LETTER
1) Br2
PdCl2(PhCN)2
1) Br2, CCl4
O
HO2C
O
2) KOH (aq)
80%
HO2C
Et3N, MeCN
85%
2) Et3N (cat.)
MeOH
6
7
8
71%
O
HN
Br
N3
NaReO4, TfOH
NaN3
RO2C
MeO2C
MeO2C
DMF
98%
Ac2O, CCl4
63%
O
O
O
9
4
5a, R = Me
1, R = H
LiOH
88%
Scheme 1 Synthesis of alaremycin (1)
To an ice-cold solution of lactone 8 (850 mg, 7.58 mmol) in CCl4
(10 mL) was added Br2 (0.39 mL, 7.57 mmol) in CCl4 (2 mL) drop-
wise. After 30 min at 0 °C, the solution was concentrated to give a
residue, which was dissolved in MeOH (10 mL) containing a few
drops of Et3N. After 1 h at r.t., the solution was concentrated, and
the crude product was purified by chromatography (hexane–
EtOAc) to furnish a-bromo ketone 9 (1.20 g, 71%). 1H NMR (300
MHz, CDCl3): d = 1.77 (d, J = 7.0 Hz, 3 H), 2.49–2.78 (m, 2 H),
2.91 (ddd, J = 18.0, 7.5, 6.0 Hz, 1 H), 3.14 (ddd, J = 18.0, 6.5, 6.0
Hz, 1 H), 3.69 (s, 3 H), 4.49 (q, J = 7 Hz, 1 H). 13C NMR (75 MHz,
CDCl3): d = 20.2, 28.4, 33.6, 47.5, 52.0, 172.8, 202.9.
mass. Unidentified products were also obtained when sub-
mitted to RONa in ROH (R = Me, Et), the conditions pre-
viously applied by us to an a-azido-g-lactone (R = Et).6
On the other hand, reaction of 4 with Ac2O at 120 °C in
AcOH for 6 hours afforded 5a directly, but only in 25%
yield with unreacted 4 and other by-products, while long-
er reaction resulted in formation of the by-products in
larger quantity. We then examined NaReO4-catalyzed re-
action in Ac2O under acidic conditions.8 Thus, reaction of
4 in Ac2O in the presence of NaReO4 (1 mol%) and
CF3SO3H (1 mol%) at 50 °C afforded 1 in 46% yield. To
improve the yield, the reaction was repeated in Ac2O and
a co-solvent such as Et2O, CH2Cl2, THF, MeCN, CCl4 in
a 1:1 proportion at 50 °C for 8 hours. Among the co-sol-
vents, CCl4 was found to be most effective to afford 5a in
63%.
A mixture of a-bromo ketone 9 (1.20 g, 5.38 mmol) and NaN3 (699
mg, 10.8 mmol) in DMF (5 mL) was stirred at r.t. for 1 h, and dilut-
ed with H2O. The resulting mixture was extracted with Et2O three
times to give a residue, which was purified by chromatography
(hexane–EtOAc) to furnish azide 4 (976 mg, 98%). 1H NMR (300
MHz, CDCl3): d = 1.41 (d, J = 7.0 Hz, 3 H), 2.56–2.62 (m, 2 H),
2.77–2.83 (m, 2 H), 3.63 (s, 3 H), 3.97 (q, J = 7.0 Hz, 1 H). 13C
NMR (75 MHz, CDCl3): d = 15.8, 27.6, 33.7, 51.9, 63.2, 172.6,
205.8.
Finally, hydrolysis of methyl ester 5a with LiOH in aque-
ous MeOH produced 1 in 88% yield. The 1H NMR and 13C
NMR spectra in DMSO-d6 and in MeOH-d4, respectively,
were identical with those reported.2
To a solution of NaReO4 (1 mg, 0.0037 mmol) and CF3SO3H (1 mL,
0.011 mmol) in Ac2O (0.5 mL) and CCl4 (0.5 mL) was added azide
4 (50 mg, 0.27 mmol). The mixture was heated to 50 °C for 8 h and
concentrated to produce a residue, which was purified by chroma-
In summary, we have established synthesis of alaremycin
(1) starting with 5-hexenoic acid (6) in 26% total yield in
8 steps. The quantity of 1 synthesized is enough for bio-
logical study, and the following procedure will be helpful
to repeat the synthesis for further study.
1
tography (hexane–EtOAc) to afford amide 5a (34 mg, 63%). H
NMR (300 MHz, CDCl3): d = 2.12 (s, 3 H), 2.68 (t, J = 6.5 Hz, 2
H), 3.11 (t, J = 6.5 Hz, 2 H), 3.70 (s, 3 H), 5.84 (t, J = 1 Hz, 1 H),
6.93 (d, J = 1 Hz, 1 H), 7.99 (br s, 1 H). 13C NMR (75 MHz, CDCl3):
d = 24.8, 28.1, 30.8, 52.0, 109.5, 137.7, 169.0, 172.7, 194.9.
To a solution of amide 5a (180 mg, 0.904 mmol) in MeOH (1.1 mL)
and H2O (1.1 mL) was added 1 N LiOH (1.2 mL, 1.2 mmol). The
mixture was stirred at 0 °C for 30 min, acidified to pH 3–4 with 10%
tartaric acid, and extracted with EtOAc three times. The crude acid
1 thus obtained was purified by chromatography (hexane–EtOAc)
to afford acid 1 (148 mg, 88%); mp 132–135 °C (recrystallized
from MeOH–EtOAc–hexane).
Brief Procedure Leading to Compound 1
To a solution of acid 6 (3.70 g, 32.4 mmol) in CH2Cl2 (15 mL) at
–60 °C was added Br2 (1.67 mL, 32.4 mmol) in CH2Cl2 (5 mL)
dropwise. After 1.5 h at –60 °C to –50 °C, the solution was poured
into sat. Na2S2O3 with vigorous stirring. The mixture was extracted
with CH2Cl2 to afford crude bromine adduct (8.53 g), which was
used for the next reaction without further purification.
References and Notes
A mixture of the above compound and KOH (17.47 g, 311.4 mmol)
in H2O (30 mL) was refluxed for 10 h, diluted with H2O (30 mL),
and acidified to pH 2 by addition of 12 N HCl. The mixture was ex-
tracted with Et2O three times to afford crude 7, which was purified
by distillation (3.02 g, 83%); bp 130 °C (10 Torr).
(1) Wachi, M.; Iwai, N.; Kunihisa, A.; Nagai, K. Biochimie
1999, 81, 909.
(2) Awa, A.; Iwai, N.; Ueda, T.; Suzuki, K.; Asano, S.;
Yamagishi, J.; Nagai, K.; Wachi, M. Biosci. Biotechnol.
Biochem. 2005, 69, 1721.
A solution of acid 7 (1.60 g, 14.3 mmol), PdCl2(PhCN)2 (54 mg,
0.14 mmol), and Et3N (60 mL, 0.43 mmol) in MeCN (25 mL) was
refluxed for 5 h and concentrated. The residue was purified by chro-
matography (hexane–EtOAc) to afford enol lactone 8 (1.36 g,
85%).
(3) Isono, K.; Suzuki, S. J. Antibiot. Ser. A 1962, 15, 77.
Synlett 2006, No. 3, 481–483 © Thieme Stuttgart · New York