An Efficient Synthesis of Antibiotic (-)-A26771B

Full text of DOI:10.1021/jo991282s

612
J . Org. Chem. 2000, 65, 612-615
An Efficien t Syn th esis of An tibiotic
(-)-A26771B
Yuichi Kobayashi* and Hiroki Okui
Department of Biomolecular Engineering,
Tokyo Institute of Technology, 4259 Nagatsuta-cho,
Midori-ku, Yokohama 226-8501, J apan
Received August 11, 1999
F igu r e 1. Two intermediates for the synthesis of 1.
In tr od u ction
by two groups.12,14 However, preparation of the unneces-
sary hydroxyl group at C(4) and its differentiation from
the hydroxyl group(s) at the C(5) and/or C(15) positions
make their syntheses rather lengthy.
Recently, we published the efficient protocol for con-
version of 2-substituted furans into γ-oxo-R,â-unsatur-
ated carboxylic acids (eq 1).15 The synthetic advantage
The γ-oxygenated R,â-unsaturated carboxylic acid unit
is a common structure found in some macrocyclic lactones
such as cytochalasins, aspicilin, brefeldins, patulolides,
pyrenophorin, and A26771B, and their biological proper-
ties as well as their structures have attracted much
interest from organic chemists.1 So far, methods for the
preparation of this unit have been elaborated and used
for the total syntheses. Regarding antibiotic (-)-A26771B
(1),2 the total syntheses, the macrocyclization, and the
of this oxidative conversion is that the stability of the
furan ring permits a variety of reactions to be utilized
for elaboration of the substituent R at C(2) of the furan
ring. In addition, the high chemoselectivity of the re-
agents used for the furan oxidation allows common
functional groups and protecting groups such as hydroxyl,
carbonyl, acetal, and silyloxy groups to be involved in the
substituent R. Herein we report an asymmetric synthesis
of 1 that is accomplished highly efficiently utilizing the
synthetic advantages mentioned above.
assembly of the C(1)-C(5) unit have been published.3-14
It is surprising, however, that the construction of the
chiral centers at C(5) and C(15), the most important
synthetic point, has been investigated only by the Tat-
suta-Kinoshita group with success of installing a suc-
cinic moiety onto the key diol intermediate 2 regioselec-
tively (Figure 1).4,5 Later, the synthesis of 2 was reported
Resu lts a n d Discu ssion
We envisioned a new seco acid of type 3 (Figure 1) in
which the necessary C(1)-C(5) functionality is incorpo-
rated with the correct oxidation levels. Thus, installation
of the succinic moiety at C(5) is a step which should be
done after the macrocyclization.16 Consequently, this
would be more efficient than the previous methods if a
synthesis of 1 through 3 is accomplished without epimer-
ization at the C(5) carbon and without protection of the
C(4) oxo group. We examined the route shown in Scheme
1, where the chiral center of the C(5) is secured by the
kinetic resolution of racemic furfuryl alcohol rac-6 with
t-BuOOH/Ti(O-i-Pr)4 and DIPT,17 while the C(15) chiral
center is derived from (S)-(+)-epichlorohydrin (9).
(1) (a) Boeckman, R. K., J r.; Goldstein, S. W. In The Total Synthesis
of Natural Products; ApSimon, J ., Ed.; Wiley: New York, 1988; Vol.
7, Chapter 1. (b) Asaoka, M.; Takei, H. J . Synth. Org. Chem. J pn. 1986,
44, 819-828.
(2) (a) Michel, K. H.; Demarco, P. V.; Nagarajan, R. J . Antibiot. 1977,
30, 571-575. (b) Arai, K.; Rawlings, B. J .; Yoshizawa, Y.; Vederas, J .
C. J . Am. Chem. Soc. 1989, 111, 3391-3399.
(3) Hase, T. A.; Nylund, E.-L. Tetrahedron Lett. 1979, 2633-2636.
(4) (a) Tatsuta, K.; Nakagawa, A.; Maniwa, S.; Kinoshita, M.
Tetrahedron Lett. 1980, 21, 1479-1482. (b) Tatsuta, K.; Nakagawa,
A.; Maniwa, S.; Amemiya, Y.; Kinoshita, M. Nippon Kagaku Kaishi
1981, 762-768.
(5) Tatsuta, K.; Amemiya, Y.; Kanemura, Y.; Kinoshita, M. Bull.
Chem. Soc. J pn. 1982, 55, 3248-3253.
(6) Asaoka, M.; Yanagida, N.; Takei, H. Tetrahedron Lett. 1980, 21,
4611-4614.
Swern oxidation of the commercially available bromo
alcohol 4 afforded the aldehyde 5,18 which upon reaction
with 2-furyllithium gave racemic furfuryl alcohol rac-6
in high yield. Kinetic resolution of rac-6 by using t-
(7) Asaoka, M.; Abe, M.; Mukuta, T.; Takei, H. Chem. Lett. 1982,
215-218.
(8) Trost, B. M.; Brickner, S. J . J . Am. Chem. Soc. 1983, 105, 568-
575.
(9) Fujisawa, T.; Okada, N.; Takeuchi, M.; Sato, T. Chem. Lett. 1983,
1271-1272.
(10) Bestmann, H. J .; Schobert, R. Angew. Chem., Int. Ed. Engl.
1985, 24, 791-792.
(15) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J . Org.
Chem. 1998, 63, 7505-7515.
(11) Ichimoto, I.; Sato, M.; Tsuji, H.; Kirihata, M.; Ueda, H. Chem.
Express 1988, 3, 499-502.
(16) Previously, the Hase group reported the methyl ester of
A26771B through 3 (R ) C(dO)(CH2)2CO2Me).3 The synthesis, how-
ever, suffers from low yields in some steps involved. Moreover, selective
hydrolysis of the methyl succinate part to obtain acid 1 is not described.
(17) Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J . Org. Chem.
1989, 54, 2085-2091.
(12) Quinkert, G.; Ku¨ber, F.; Knauf, W.; Wacker, M.; Koch. U.;
Becker, H.; Nestler, H. P.; Du¨rner, G.; Zimmermann, G.; Bats, J . W.;
Egert, E. Helv. Chim. Acta 1991, 74, 1853-1923.
(13) Baldwin, J . E.; Adlington, R. M.; Ramcharitar, S. H. Tetrahe-
dron 1992, 48, 2957-2976.
(18) Aldehyde 5 was also prepared in 88% yield from inexpensive
9-decen-1-ol by bromination (CBr4, PPh3) followed by ozonolysis. See
the Experimental Section for details.
(14) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J . Org. Chem. 1993,
58, 7789-7796.
10.1021/jo991282s CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/29/1999

Notes
J . Org. Chem., Vol. 65, No. 2, 2000 613
Sch em e 1a
a
Reagents and conditions: (a) (COCl)2, DMSO, and then NEt3 (94%); (b) 2-furyllithium, THF (91%); (c) t-BuOOH (0.6 equiv), Ti(OPr)4
(0.2 equiv), D-(-)-DIPT (0.24 equiv), -15 °C, 15 h (36% based on rac-6); (d) MOMCl, i-Pr2NEt, CH2Cl2 (88%); (e) Mg (3.3 equiv), Br(CH2)2Br
(0.07 equiv), THF, 45-80 °C; (f) 9, CuCN (0.05 equiv), THF, -50 to -30 °C, 4.5 h (83%); (g) LiAlH4 (96%); (h) NBS (1.2 equiv), NaHCO3
(2 equiv), acetone/H2O (10:1), -15 °C, 2.5 h; furan (3 equiv), -15 °C, 1 h; C5H5N (2 equiv), rt, 5 h (70%); (i) NaClO2 (3 equiv), Me2CdCHMe
(10 equiv), phosphate buffer (pH 3.6); (j) 2,4,6-Cl3C6H2COCl, NEt3, and then DMAP, toluene, 65-70 °C, 5 h (66% from 12); (k) TFA,
CH2Cl2, rt, 4 h; (l) succinic anhydride (2 equiv), DMAP (1 equiv) (63% from 14).
BuOOH (0.6 equiv), Ti(O-i-Pr)4 (0.2 equiv), and D-(-)-
DIPT (0.24 equiv) at -15 °C for 15 h gave a mixture of
pyran 16, optically active alcohol (S)-6, and D-(-)-DIPT
method20 at 65-70 °C and proceeded successfully to
afford lactone 14 in 66% yield from 12. Comparison of
the H NMR spectrum (300 MHz) of 14 with that of a
1
mixture21 of 14 and its C(5) epimer22 confirmed that <5%
epimerization at the C(5) carbon took place during the
macrocyclization. Finally, deprotection of MOM group
with CF3CO2H followed by esterification with succinic
anhydride furnished 1 in 63% yield without epimeriza-
1
tion. The H and 13C NMR spectra and [R]D value of 1
thus synthesized were identical with those previously
reported ([R]26D -13.7 (c 0.19, MeOH); lit. [R]D -13 to -14
(MeOH)).2,4,12
In summary, the efficient and short-step synthesis of
antibiotic A26771B was achieved through the new seco
acid 3 (R ) MOM).23
after the usual workup. Since 16 is not useful in the
synthesis any more, the mixture was treated with aque-
ous NaOH to convert both 16 and DIPT into water-
soluble compounds according to the literature,17 and thus
purification of (S)-6 (>95% ee)19 by chromatography was
carried out quite easily in 36% yield. Although the yield
of (S)-6 does not exceed the theoretical yield of 50% based
on rac-6, the present method is efficient enough for
practical use due to the operational simplicity of the steps
and the adaptability to large-scale production of (S)-6.
Protection of (S)-6 with MOMCl unexpectedly afforded
a mixture of bromide and chloride 7 (X ) Br, Cl) in a
ratio of 2:3-7 which was determined by 1H NMR
spectroscopy. Without separation, both halides were
converted into Grignard reagent 8 under forcing condi-
tions, keeping the higher temperature of 45-80 °C (bath
temperature). Reaction of epoxide 9 (98.9% ee) with 8 (1.5
equiv) proceeded well in the presence of CuCN (0.05
equiv) to afford 10, which upon reduction with LiAlH4
furnished the alcohol 11 in good yield.
Exp er im en ta l Section
Gen er a l Meth od s. Infrared (IR) spectra are reported in
wavenumbers (cm-1). Unless otherwise noted, 1H NMR (300
MHz) and 13C NMR (75 MHz) spectra were measured in CDCl3
using SiMe4 (δ ) 0 ppm) and the center line of the CDCl3 triplet
(δ ) 77.1 ppm) as internal standards, respectively. The following
solvents were distilled before use: THF (from Na/benzophenone),
Et2O (from Na/benzophenone), and CH2Cl2 (from CaH2). (S)-
Epichlorohydrin (9) (98.9% ee) was kindly offered by Daiso,
J apan. The phosphate buffer of pH 3.6 was prepared by mixing
Na2HPO4‚12H2O (2.31 g), citric acid (1.31 g), and H2O (98.6 g).
Routinely, organic extracts were concentrated using a rotary
evaporator, and residues were purified by chromatography on
silica gel.
9-Br om on on a n a l (5) fr om 9-Br om o-1-n on a n ol (4). To a
solution of (COCl)2 (1.41 mL, 16.2 mmol) in CH2Cl2 (35 mL) was
Oxidation of furan 11 with NBS under the reported
conditions15 proceeded efficiently with 70% yield, and
further oxidation of aldehyde 12 with NaClO2 furnished
crude seco acid 13 ()3 (R ) MOM) in Figure 1).
Macrocyclization of 13 was carried out by the Yamaguchi
(20) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(21) A mixture of 14 and the epimer at C(5) was synthesized by the
method of Scheme 1 using racemic alcohol rac-6 as the C(1)-C(13)
part.
(22) Diagnostic peaks in the 1H NMR spectrum of the epimer:
4.36 (t, J ) 6 Hz, 1 H), 6.75 (d, J ) 16 Hz, 1 H), 7.24 (d, J ) 16 Hz, 1
δ
(19) Determined by comparing the 1H NMR spectrum of the MTPA
H).
ester of (S)-6 with that of rac-6.
(23) The synthesis was achieved with 12 steps in 6.3% overall yield.

614 J . Org. Chem., Vol. 65, No. 2, 2000
Notes
added a solution of DMSO (2.55 mL, 36.0 mmol) in CH2Cl2 (7.6
mL) at -55 °C. After 5 min, 4 (1.67 g, 17.5 mmol) dissolved in
CH2Cl2 (7.5 mL) was added over 5 min. The mixture was stirred
at the same temperature for 15 min, and then NEt3 (5.2 mL, 37
mmol) was added. The mixture was allowed to warm to 0 °C
over 40 min with vigorous stirring and poured into brine.
Product was extracted with Et2O two times, and the combined
extracts were dried over MgSO4 and concentrated. The residue
was purified by chromatography (hexane/Et2O) to afford 5 (1.55
thus obtained was >95% by 1H NMR spectroscopy of the MTPA
ester: [R]28 -8.49 (c 0.47, CHCl3).
D
(S)-2-[(9-Ha lo-1-m eth oxym eth oxy)n on a n yl]fu r a n (7, X )
Br , Cl). A solution of (S)-6 (7.83 g, 27.1 mmol), i-Pr2NEt (19
mL, 109 mmol), and MOMCl (4.1 mL, 54 mmol) in CH2Cl2 (90
mL) was stirred at room temperature overnight and poured into
a mixture of EtOAc and saturated NaHCO3. The resulting
mixture was stirred for 30 min vigorously, the layers were
separated, and the aqueous layer was extracted with EtOAc.
The combined extracts were dried over MgSO4 and concentrated
to furnish an oil, which was purified by chromatography (hexane/
g) in 94% yield: IR (neat) 1724, 1269 cm-1 1H NMR δ 1.26-
;
1.48 (m, 8 H), 1.58-1.68 (m, 2 H), 1.85 (quintet, J ) 7 Hz, 2 H),
2.42 (dt, J ) 2, 7 Hz, 2 H), 3.40 (t, J ) 7 Hz, 2 H), 9.77 (t, J )
2 Hz, 1 H).
1
EtOAc) to give 7 (7.31 g). The H NMR spectrum of the product
showed it to be a mixture of 7 (X ) Br) and 7 (X ) Cl) in a ratio
of 2:3, and hence the yield was calculated to be 88%. Compound
7 (X ) Br, Cl) thus obtained was distilled for the next reaction
without separation: bp 140 °C (1 Torr); IR (neat) 3120, 1504,
1032, 738 cm-1; 1H NMR δ 1.20-1.46 (m, 10 H), 1.70-1.93 (m,
4 H), 3.36 (s, 3 H), 3.40 (t, J ) 7 Hz, 0.8 H), 3.52 (t, J ) 7 Hz,
1.2 H), 4.53 (d, J ) 7 Hz, 1 H), 4.58 (t, J ) 7 Hz, 1 H), 4.61 (d,
J ) 7 Hz, 1 H), 6.26 (dd, J ) 3, 1 Hz, 1 H), 6.32 (dd, J ) 3, 2 Hz,
1 H), 7.38 (dd, J ) 2, 1 Hz, 1 H).
(2R,12S)-1-Ch lor o-12-(2-fu r yl)-12-m eth oxym eth oxyd od e-
ca n -2-ol (10). To a mixture of Mg (0.95 g, 0.040 mol) and THF
(5 mL) was added 1,2-dibromoethane (0.07 mL, 0.81 mmol) to
activate Mg. Exothermic reaction occurred immediately, and
then halide 7 (X ) Br and Cl in a mole ratio of 2:7) (3.57 g, 12.0
mmol) dissolved in THF (6 mL) was added to it. After the
addition, the mixture was heated to 45 °C (bath temperature)
for 3.5 h and then to 80 °C for 2.5 h, and cooled to room
temperature. The Grignard reagent 8 thus prepared was used
for the next reaction without titration.
9-Br om on on a n a l (5) fr om 9-Decen -1-ol. To an ice cold
solution of 9-decen-1-ol (9.92 mL, 55.6 mmol) and CBr4 (20.8 g,
62.7 mmol) in CH2Cl2 (84 mL) was added PPh3 (9.60 g, 74.7
mmol) portionwise. The mixture was stirred at 0 °C for 2 h and
then at room temperature overnight. Most of the volatile
material was removed by using a rotary evaporator, and the
residue was diluted with hexane. The resulting mixture was
filtered through a pad of Celite with hexane, and the filtrate
was concentrated to give crude 1-bromo-9-decene, which was
used for the next reaction without further purification: 1H NMR
δ 1.24-1.48 (m, 10 H), 1.85 (quintet, J ) 7 Hz, 2 H), 2.03 (q, J
) 7 Hz, 2 H), 3.40 (t, J ) 7 Hz, 2 H), 4.93 (ddt, J ) 10, 2, 1 Hz,
1 H), 4.99 (ddt, J ) 17, 2, 2 Hz, 1 H), 5.81 (ddt, J ) 17, 10, 7 Hz,
1 H).
To a solution of the above bromide and NEt3 (2.5 mL, 17.9
mmol) in EtOH (80 mL) was gently bubbled ozone gas at -70
°C for 2 h. To remove excess ozone, argon gas was bubbled for
1 h, during which time the solution was allowed to warm to room
temperature, and then SMe2 (16 mL, 218 mmol) was added to
it. The solution was stirred overnight and concentrated to give
an oil, which was purified by chromatography (hexane/Et2O) to
afford 5 (10.84 g) in 88% yield.
(1R)- a n d (1S)-9-Br om o-1-(2-fu r yl)n on a n -1-ol (r a c-6). To
an ice cold solution of furan (10 mL, 137 mmol) and bipyridine
(ca 10 mg) in THF (50 mL) was added n-BuLi (50 mL, 2.46 M in
hexane, 123 mmol) dropwise. After being stirred for 3 h at 0 °C,
the solution was cooled to -70 °C, and 5 (10.84 g, 49.0 mmol)
dissolved in THF (30 mL) was added slowly. The solution was
stirred between -70 and -60 °C for 4 h and poured into a
mixture of Et2O and saturated NH4Cl with vigorous stirring.
The phases were separated, and the aqueous phase was ex-
tracted with Et2O. The combined extracts were dried over MgSO4
and concentrated to give an oil, which was purified by chroma-
tography (hexane/EtOAc) to afford rac-6 (12.93 g) in 91% yield:
IR (neat) 3369, 1504, 1149, 737 cm-1; 1H NMR δ 1.28-1.48 (m,
10 H), 1.79-1.89 (m, 5 H), 3.40 (t, J ) 7 Hz, 2 H), 4.66 (t, J )
7 Hz, 1 H), 6.23 (d, J ) 3 Hz, 1 H), 6.33 (dd, J ) 3, 2 Hz, 1 H),
7.37 (dd, J ) 2, 1 Hz, 1 H); 13C NMR δ 157.1, 142.1, 110.3, 105.9,
67.9, 35.5, 34.0, 32.8, 29.28, 29.25, 28.6, 28.1, 25.4. Anal. Calcd
for C13H21BrO2: C, 53.99; H, 7.32. Found: C, 53.78; H, 7.31.
(1S)-9-Br om o-1-(2-fu r yl)n on a n -1-ol ((S)-6). To a mixture
of 4 Å molecular sieves (5 g) and Ti(O-i-Pr)4 (2.44 mL, 8.27 mmol)
in CH2Cl2 (34 mL) was added D-(-)-DIPT (2.11 mL, 9.94 mmol)
at -20 °C. The mixture was stirred at -20 °C for 10 min, and
then rac-6 (11.97 g, 41.4 mmol) in CH2Cl2 (7 mL) and, after 30
min, t-BuOOH in CH2Cl2 (5.3 mL, 4.72 M, 25 mmol) were added
at -20 °C. The mixture was stirred at -15 °C for 15 h, and the
reaction was quenched by addition of SMe2 (1.8 mL, 24.5 mmol).
After 30 min of stirring at -20 °C, the cooling bath was removed,
and aqueous tartaric acid (1.7 mL, 10% solution), Et2O (34 mL),
NaF (10 g, 240 mmol), and Celite (10 g) were added successively.
The resulting mixture was stirred at room temperature for 2 h
and filtered through a pad of Celite with Et2O. The filtrate was
concentrated to afford a mixture of (S)-6, pyran 16, and D-(-)-
DIPT.
To a flask containing CuCN (36 mg, 0.402 mmol) at -50 °C
were added the above Grignard reagent 8 and epoxide 9 (98.9%
ee, 0.63 mL, 8.05 mmol) dissolved in THF (5 mL). After the
addition, the mixture was warmed to -30 °C over 4.5 h and
poured into a mixture of Et2O and saturated NH4Cl with
vigorous stirring. The organic layer was separated, and the
aqueous layer was extracted with Et2O two times. The combined
extracts were dried over MgSO4 and concentrated to give an oil,
which was purified by chromatography (hexane/EtOAc) to
furnish 10 (2.30 g) in 83% yield: IR (neat) 3446, 1504, 1034,
1
741 cm-1; H NMR δ 1.20-1.55 (m, 16 H), 1.75-1.98 (m, 2 H),
2.12 (d, J ) 5 Hz, 1 H), 3.36 (s, 3 H), 3.47 (dd, J ) 11, 7 Hz, 1
H), 3.63 (dd, J ) 11, 3 Hz, 1 H), 3.74-3.84 (m, 1 H), 4.53 (d, J
) 7 Hz, 1 H), 4.58 (t, J ) 7 Hz, 1 H), 4.61 (d, J ) 7 Hz, 1 H),
6.26 (dd, J ) 3, 1 Hz, 1 H), 6.32 (dd, J ) 3, 2 Hz, 1 H), 7.38 (dd,
J ) 2, 1 Hz, 1 H); 13C NMR δ 154.4, 142.4, 110.1, 108.1, 94.1,
71.5, 71.0, 55.6, 50.6, 34.2, 34.0, 29.4, 29.3, 25.7, 25.5.
(2R,12S)-12-(2-F u r yl)-12-m et h oxym et h oxyd od eca n -2-
ol (11). To an ice cold solution of 10 (1.97 g, 5.67 mmol) dissolved
in THF (11 mL) was added LiAlH4 (215 mg, 5.67 mmol) slowly.
The resulting mixture was stirred at room temperature over-
night and cooled to 0 °C. Excess hydride was destroyed by
addition of EtOAc (6 mL, 61 mmol) and H2O (0.51 mL, 28 mmol).
After the mixture was stirred for 10 min at room temperature,
NaF (1.18 g, 28 mmol) and EtOAc (4 mL) were added, and the
resulting mixture was stirred at room temperature for 2 h and
filtered through a pad of Celite with EtOAc. The filtrate was
concentrated to give an oil, which was purified by chromatog-
raphy (hexane/EtOAc) to furnish 11 (1.71 g) in 96% yield: [R]27
D
-111 (c 0.506, CHCl3); IR (neat) 3417, 1504, 1034, 739 cm-1; 1H
NMR δ 1.18 (d, J ) 6 Hz, 3 H), 1.20-1.46 (m, 17 H), 1.74-1.98
(m, 2 H), 3.36 (s, 3 H), 3.72-3.83 (m, 1 H), 4.53 (d, J ) 7 Hz, 1
H), 4.57 (t, J ) 7 Hz, 1 H), 4.61 (d, J ) 7 Hz, 1 H), 6.26 (dd, J
) 3, 1 Hz, 1 H), 6.31 (dd, J ) 3, 2 Hz, 1 H), 7.38 (dd, J ) 2, 1
Hz, 1 H); 13C NMR δ 154.5, 142.4, 110.0, 108.1, 94.1, 71.0, 68.2,
55.5, 39.4, 34.0, 29.55, 29.60, 29.5, 29.3, 25.74, 25.66, 23.5. Anal.
Calcd for C18H32O4: C, 69.19; H, 10.32. Found: C, 69.06; H,
10.55.
To the above mixture dissolved in Et2O (70 mL) was added 3
N NaOH (30 mL, 90 mmol) at 0 °C. The mixture was stirred
vigorously for 30 min and diluted with Et2O and brine. The
resulting mixture was filtered through a pad of Celite with Et2O.
The filtrates were separated, and the aqueous layer was
extracted with Et2O two times. The combined ethereal solutions
were dried over MgSO4 and concentrated to give an oil, which
was purified by chromatography (hexane/Et2O) to afford (S)-6
(4.29 g, 36% based on rac-6). The enantiomeric excess of (S)-6
(2E,5S,15R)-15-Hydr oxy-5-m eth oxym eth oxy-4-oxo-2-h exa-
d ecen a l (12). To a mixture of 11 (726 mg, 2.32 mmol) and
NaHCO3 (390 mg, 4.64 mmol) in acetone/H2O (10:1, 10 mL) was
added NBS (496 mg, 2.79 mmol) dissolved in acetone/H2O (10:
1, 5.5 mL) at -15 °C. The mixture was stirred for 2.5 h, and
furan (0.50 mL, 6.9 mmol) was added to destroy excess NBS.
After 1 h at -15 °C, pyridine (0.37 mL, 4.6 mmol) was added,
and the cooling bath was removed. The mixture was stirred at

Notes
J . Org. Chem., Vol. 65, No. 2, 2000 615
room temperature for 5 h and poured into the phosphate buffer
(pH 3.6) with EtOAc. The phases were separated, and the
aqueous phase was extracted with EtOAc. The combined organic
phases were dried over MgSO4 and concentrated to give the
residue, which was purified by chromatography (hexane/EtOAc)
to afford 12 (530 mg) in 70% yield: IR (neat) 3448, 1715, 1695,
The layers were separated, and the aqueous layer was washed
with Et2O. The toluene and ether extracts were combined, dried
over MgSO4, and concentrated to afford a residue, which was
purified by chromatography (hexane/EtOAc) to afford lactone
14 (130 mg) in 66% yield from 12: [R]27 -49 (c 0.282, CHCl3);
D
1
IR (neat) 1725, 1715, 1630, 920 cm-1; H NMR δ 1.30 (d, J ) 6
1
1039, 920 cm-1; H NMR δ 1.18 (d, J ) 6 Hz, 3 H), 1.22-1.50
Hz, 1 H), 1.06-1.66 (m, 16 H), 3.35 (s, 3 H), 4.23 (dd, J ) 7, 5
Hz, 1 H), 4.65 (d, J ) 7 Hz, 1 H), 4.68 (d, J ) 7 Hz, 1 H), 5.04-
5.15 (m, 1 H), 6.77 (d, J ) 16 Hz, 1 H), 7.32 (d, J ) 16 Hz, 1 H);
13C NMR δ 199.3, 165.2, 135.1, 132.1, 96.3, 81.9, 72.6, 56.1, 34.8,
30.5, 27.7, 27.64, 27.56, 26.7, 26.4, 23.6, 21.9, 20.1. Anal. Calcd
for C18H30O5: C, 66.23; H, 9.26. Found: C, 66.04; H, 9.40.
(m, 16 H), 1.60-1.81 (m, 3 H), 3.35 (s, 3 H), 3.73-3.84 (m, 1 H),
4.18 (dd, J ) 8, 6 Hz, 1 H), 4.68 (br s, 2 H), 6.94 (dd, J ) 16, 8
Hz, 1 H), 7.28 (d, J ) 16 Hz, 1 H), 9.8 (d, J ) 8 Hz, 1 H); 13C
NMR δ 200.1, 193.3, 140.8, 138.3, 96.8, 82.4, 68.0, 56.2, 39.2,
31.9, 29.5, 29.4, 29.3, 29.23, 29.19, 25.6, 24.9, 23.4.
(2E,5S,15R)-5-Meth oxym eth oxyh exadec-2-en -15-olide (14).
To a solution of 12 (197 mg, 0.60 mmol) and 2-methyl-2-butene
(0.64 mL, 6.04 mmol) in t-BuOH (3 mL) and the phosphate buffer
(pH 3.6, 1.5 mL) was added NaClO2 (204 mg, purity 80%, 1.80
mmol) dissolved in H2O (1.5 mL), and the resulting mixture was
stirred for 3 h at room temperature. Most of the solvents were
removed by using a vacuum pump, and the residue was diluted
with EtOAc and the phosphate buffer (pH 3.6). The organic layer
was separated, and the aqueous layer was extracted with EtOAc.
The combined organic layers were dried over MgSO4 and
concentrated to leave crude 13, which was used for the next
reaction without further purification: IR (neat) 3421, 1720, 1701,
1036 cm-1; 1H NMR δ 1.19 (d, J ) 6 Hz, 3 H), 1.20-1.50 (m, 17
H), 1.58-1.78 (m, 2 H), 3.35 (s, 3 H), 3.76-3.87 (m, 1 H), 4.15
(dd, J ) 7, 6 Hz, 1 H), 4.64 (d, J ) 7 Hz, 1 H), 4.67 (d, J ) 7 Hz,
1 H), 5.4 (br peak, 1 H), 6.80 (d, J ) 16 Hz, 1 H), 7.45 (d, J ) 16
Hz, 1 H).
A solution of the above acid 13 and NEt3 (0.42 mL, 3.01 mmol)
in THF (3 mL) was stirred at room temperature for 20 min, and
2,4,6-trichlorobenzoyl chloride (0.14 mL, 0.896 mmol) in THF
(3 mL) was added. The solution was stirred at room temperature
for a further 2 h. The resulting white precipitate (triethylamine
hydrochloride) was removed by dilution with toluene (100 mL)
followed by filtration through a pad of Celite with additional
toluene. The filtrate, after further dilution with toluene (total
300 mL), was divided into three equal portions, while three
solutions of DMAP (each 98 mg, 0.802 mmol) in toluene (each
30 mL) were prepared. Each toluene solution of the mixed
anhydride was added to each solution of DMAP at 65-70 °C
over 5 h. After the addition, the solutions were stirred for a
further 30 min and cooled to room temperature. The combined
solutions were washed with saturated NaHCO3 and with brine.
(-)-A26771B (1). To an ice cold solution of 14 (64 mg, 0.196
mmol) in CH2Cl2 (10 mL) was added CF3CO2H (0.65 mL). The
cooling bath was removed, and the solution was stirred at room
temperature for 4 h. The volatile compounds were removed by
using a vacuum pump, and the residue was filtered through a
short column of silica gel with EtOAc to afford 15, which was
used for the next reaction without further purification: 1H NMR
(selected peaks) δ 1.30 (d, J ) 7 Hz, 3 H), 4.50-4.57 (m, 1 H),
5.12-5.23 (m, 1 H), 6.80 (d, J ) 16 Hz, 1 H), 7.26 (d, J ) 16 Hz,
1 H).
A solution of the above 15, succinic anhydride (39 mg, 0.39
mmol), and DMAP (24 mg, 0.20 mmol) in CH2Cl2 (3 mL) was
stirred at room temperature for 6 h and poured into a mixture
of EtOAc and the phosphate buffer (pH 3.6) with vigorous
stirring. The layers were separated, and the aqueous layer was
extracted with EtOAc two times. The combined extracts were
dried over MgSO4 and concentrated to leave an oil, which was
purified by chromatography (benzene/acetone) to afford 1 (47
mg, 63% from 14): [R]26D -13.7 (c 0.188, MeOH); lit.2,4,12 -13 to
-14 (MeOH). The 1H NMR and 13C NMR spectra of 1 were
identical with those reported in the literature.2,4,12
Ack n ow led gm en t. We thank Daiso Chemical for a
generous supply of (S)-(+)-epichlorohydrin.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra for 5, 7, 10, 12, 13, 14, and a mixture of 14 and the
epimer of 14. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O991282S