First total synthesis of grahamimycin A

Full text of DOI:10.1021/jo000762c

J . Org. Chem. 2000, 65, 7221-7224
7221
F ir st Tota l Syn th esis of Gr a h a m im ycin A
Sch em e 1. Retr osyn th esis of Gr a h a m im ycin A
Yuichi Kobayashi* and Michitaka Matsuumi
Department of Biomolecular Engineering, Tokyo Institute of
Technology, Midori-ku, Yokohama 226-8501, J apan
ykobayas@bio.titech.ac.jp
Received May 18, 2000
In tr od u ction
1
Grahamimycin A and grahamimycin A are 14-mem-
bered bislactones isolated from medium used for the
aerobic fermentation of cultures of Cytospora sp. ATCC
1
2
0502. Although their structures are similar, the former
exhibits stronger antibacterial and antifungal activity
toward pathogenic microorganisms. Interestingly, gra-
Sch em e 2. Syn th esis of Alcoh ol 7
2
hamimycin A was shown to be identical to colletoketol,
which had been isolated3 from the pathogenic plant
fungus Colletotrichum capsici along with other similar
bislactones such as colletodiol, colletoallol, and colletol.
1
Among these natural products, grahamimycin A and
colletodiol are the only ones that have been target
molecules for synthesis.4 The synthetic strategies ex-
ploited for these compounds, however, seem to be only
marginally applicable to construction of grahamimycin
A. Recently we reported an oxidative conversion of
,5
-alkylfurans into trans 4-oxo-2-alkenoic acids (eq 1).6
Resu lts a n d Discu ssion
2
First, we examined a route shown in Scheme 2 to
synthesize the intermediate 7. Enantiomerically enriched
7
alcohol 8 (>98% ee) was converted into aldehyde 11 by
a conventional sequence of reactions through 9 in good
yield. Reaction of 11 with 2-furyllithium (12) afforded a
ca. 1:1 mixture of the diastereomers 13, which appeared
as a single spot on a TLC. To remove the unwanted
diastereomer, the reaction shown in eq 2 was applied,
The conversion is convenient and compatible with the
major functional groups commonly used in organic syn-
thesis. Keeping the furan-ring oxidation in mind, graha-
mimycin A (1) was retrosynthesized through the seco acid
4
into the furan 5 and further into acid 6 and alcohol 7
as depicted in Scheme 1. Herein we report the first total
synthesis of 1 based on this idea.
(
1) Gurusiddaiah, S.; Ronald, R. C. Antimicrob. Agents Chemother.
981, 19, 153-165.
2) (a) O’Neill, J . A.; Simpson, T. J .; Willis, C. L. J . Chem. Soc.,
1
(
which was originally developed for the kinetic resolution
Chem. Commun. 1993, 738-740. (b) Keck, G. E.; Boden, E. P.; Wiley:
8
of racemic furfuryl alcohols by using the Sharpless
M. R. J . Org. Chem. 1989, 54, 896-906.
9
(3) MacMillan, J .; Simpson, T. J . J . Chem. Soc., Perkin Trans. 1
reagent (t-BuO
2
H, Ti(OPr)
4
, L-(+)- or D-(-)-DIPT). Reac-
1
973, 1487-1493.
tion of 13 with L-(+)-DIPT proceeded without being
(
4) Synthesis of Grahamimycin A : (a) Seidel, W.; Seebach, D.
1
Tetrahedron Lett. 1982, 23, 159-162. (b) Ghiringhelli, D. Tetrahedron
Lett. 1983, 24, 287-290. (c) Hillis, L. R.; Ronald, R. C. J . Org. Chem.
(7) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J . Am. Chem. Soc. 1987, 109, 5856-
5858.
(8) Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J . Org. Chem.
1989, 54, 2085-2091.
(9) (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J . Am. Chem. Soc. 1981, 103, 6237-6240. (b) Finn,
M. G.; Sharpless, K. B. In Asymmetric Synthesis; Morrison, J . D., Ed.,
Academic Press: New York, 1985; Vol. 5, Chapter 8, p 247. (c) Rossiter,
B. E. In Asymmetric Synthesis; Morrison, J . D., Ed., Academic Press:
New York, 1985; Vol. 5, Chapter 7, p 193.
1
1
985, 50, 470-473. (d) Bestmann, H.-J .; Schobert, R. Tetrahedron Lett.
987, 28, 6587-6590. (e) Ohta, K.; Miyagawa, O.; Tsutsui, H.;
Mitsunobu, O. Bull. Chem. Soc. J pn. 1993, 66, 523-535.
(5) Synthesis of Colletodiol: (a) Tsutsui, H.; Mitsunobu, O. Tetra-
hedron Lett. 1984, 25, 2159-2162. (b) Tsutsui, H.; Mitsunobu, O.
Tetrahedron Lett. 1984, 25, 2163-2166. (c) Schnurrenberger, P.;
Hungerb u¨ hler, E.; Seebach, D. Liebigs Ann. Chem. 1987, 733-744.
(
d) See ref 2b.
(6) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J . Org.
Chem. 1998, 63, 7505-7515.
1
0.1021/jo000762c CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/21/2000

7
222 J . Org. Chem., Vol. 65, No. 21, 2000
Notes
Sch em e 3. Syn th esis of Gr a h a m im ycin A (1)
affected by the chiral center at the C(8) position (graha-
mimycin A numbering) and a mixture of 10R-alcohol 14,
pyranone 16, and DIPT was successfully obtained. Sub-
2
sequently, the mixture in Et O was stirred vigorously
with aqueous NaOH to accomplish decomposition of 16
and hydrolysis of DIPT, thus facilitating chromatographic
isolation of 14 (41% yield). The high diastereomeric purity
1
of >95% at the C(10) position was determined by H NMR
spectroscopy of the crude diol 17 derived from 14 (PPTS,
MeOH).10 In addition, the relative stereochemistry of 14
1
3
was independently confirmed by C NMR spectroscopy
of the acetonide 18 prepared from diol 17 (Me C(OMe)
). Finally, protection of 14 as the MOM
2
2
,
1
1a
2 2
PPTS, CH Cl
ether followed by selective hydrolysis of the THP group
afforded 7 in 82% yield.
CO
DBU, LiCl, MeCN) afforded ester 21, which was not
Et under the conditions developed by Masamune13
2
(
contaminated with the cis isomer (geometric isomer
1
purity >95% by H NMR spectroscopy), and hydrolysis
1
4
then gave 6 in 62% yield (Scheme 3). Condensation of
acid 6 and alcohol 7 afforded 22, and deprotection of the
THP group with p-TsOH in MeOH produced the key
intermediate 5 in good yield. The furan ring of 5 was
transformed into the 4-oxo-2-enoic acid moiety by the
protocol of eq 1, and the resulting seco acid 4, without
purification, was subjected to Yamaguchi macrocycliza-
Because enantiomerically enriched furfuryl alcohols of
>
95% ee are conveniently prepared by the reaction of eq
, reduction of ketone 19 seems to be a better way to
prepare the alcohol 7 (eq 3). However, chromatographic
2
tion15 (Cl
which upon deprotection of the MOM group with CF
3
6 2
C H COCl, 60 °C) to afford the MOM ether 23,
3
-
2
5
CO
2
H furnished (-)-grahamimycin A (1) ([R]
D
) -34.2
,3
(c 0.052, CHCl
3
); lit.1 -33 to -34) in 30% overall yield
1
13
from 5. The H NMR (300 MHz) and C NMR (75 MHz)
spectra of synthetic 1 were in agreement with those
separation of diastereomeric alcohols 7 and 20 (1:1),
1,3
previously reported.
prepared by reduction with NaBH
successful as a result of the close R
4
in 79% yield, was not
f
values. Consequently,
In addition, we reinvestigated the reduction of 1 with
4
NaBH to produce colletodiol (3). This was reported by
further investigation to find a reagent suitable for
stereoselective reduction of 19 was not continued.
Another fragment 6 proposed in Scheme 1 was pre-
pared from aldehyde 11, the intermediate used in Scheme
both Simpson2 and Ronald, but neither gave detailed
information about the procedure. Reduction was carried
out at -15 °C in MeOH to furnish 3 in 81% yield with a
a
1
2
7
high stereoselectivity of >95%: [R]
) (lit.16 [R]
CHCl ) +36 (c 1.0, CHCl )). The H NMR,
3
D
) +35.8 (c 0.118,
1
2
2
, according to a modification of Simpson’s procedure.
1
3
D
2 2
Thus, the Wittig reaction of 11 with (EtO) P(dO)CH -
1
3
C NMR, and IR spectra of 3 thus synthesized were in
accord with the reported data.2
b,3
1
(
10) Diagnostic signals in the H NMR spectra of the syn alcohol 17
In conclusion, we have succeeded, for the first time, in
the synthesis of grahamimycin A (1) () colletoketol). We
also confirmed high stereoselectivity in the reduction of
1 to colletodiol (2). We believe that the synthesis provides
a good tool for investigation of the biochemical aspects
and the anti alcohol are 4.94 (dd, J ) 9, 4 Hz, 1 H) and 5.03 (dd, J )
1
8
3
, 3.5 Hz, 1 H), respectively. Data for 17: H NMR (300 MHz, CDCl )
δ 1.23 (d, J ) 6 Hz, 1 H), 1.82-2.06 (m, 2 H), 3.09 (br s, 1 H), 3.46 (br
s, 1 H), 4.02-4.15 (m, 1 H), 4.94 (dd, J ) 9, 4 Hz, 1 H), 6.23 (dm, J )
1
3
3
Hz, 1 H), 6.32 (dd, J ) 3, 1 Hz, 1 H), 7.36 (dd, J ) 2, 1 Hz, 1 H);
C
NMR δ 156.2, 141.9, 110.2, 105.7, 68.4, 68.3, 43.3, 24.2.
11) (a) Resonances for the acetonide methyl groups of 18 are
observed at δ 30.4 and 19.9 ppm, which are the characteristic values
(
1
1b,c
1
for the syn acetonide.
CDCl ) δ 1.24 (d, J ) 6 Hz, 3 H), 1.46 (s, 3 H), 1.56 (s, 3 H), 1.69-1.77
m, 2 H), 4.04-4.19 (m, 1 H), 4.89-5.02 (m, 1 H), 6.28 (d, J ) 3 Hz, 1
Spectral data of 18: H NMR (300 MHz,
(13) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183-2186.
3
(
1
3
H), 6.33 (dd, J ) 3, 2 Hz, 1 H), 7.38 (d, J ) 2 Hz, 1 H); C NMR δ
(14) (a) Boden, E. P.; Keck, G. E. J . Org. Chem. 1985, 50, 2394-
2395. (b) Sunazuka, T.; Hirose, T.; Harigaya, Y.; Takamatsu, S.;
Hayashi, M.; Komiyama, K.; Omura, S. J . Am. Chem. Soc. 1997, 119,
10247-10248.
1
54.3, 142.2, 110.1, 106.7, 99.1, 65.3, 65.1, 36.7, 30.4, 22.3, 19.9. (b)
Rychnovsky, S. D.; Skalitzky, D. J . Tetrahedron Lett. 1990, 31, 945-
9
3
48. (c) Evans, D. A.; Rieger, D. L.; Gage, J . R. Tetrahedron Lett. 1990,
1, 7099-7100.
(15) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(16) Powell, J . W.; Whalley, W. B. J . Chem. Soc. C 1969, 911-912.
(
12) O’Neill, J . A.; Lindell, S. D.; Simpson, T. J .; Willis, C. L. J .
Chem. Soc., Perkin Trans. 1 1996, 637-644.

Notes
J . Org. Chem., Vol. 65, No. 21, 2000 7223
of grahamimycin A as well as colletodiol by using
analogues thereof.
(1R,3R)-1-(2-F u r yl)-3-t et r a h yd r op yr a n yloxy-1-b u t a n ol
(
14). To a solution of Ti(O-i-Pr)
Cl (3 mL) was added L-(+)-DIPT (0.25 mL, 1.2 mmol) at -20
C. After 10 min of stirring, alcohol 13 (239 mg, 0.993 mmol)
dissolved in CH Cl (2 mL) and a solution of t-BuOOH in CH
Cl (0.24 mL, 2.5 M, 0.60 mmol) were added, and the resulting
solution was kept in a freezer (-20 °C) for 30 h. To the solution
were added Me S (0.044 mL, 0.60 mmol) and, after 30 min at
4 2
(0.29 mL, 0.99 mmol) in CH -
2
°
Exp er im en ta l Section
2
2
2
-
Gen er a l Meth od s. Infrared (IR) spectra are reported in
2
-
1
1
wavenumbers (cm ). Unless otherwise noted, H NMR (300
1
3
MHz) and C NMR (75 MHz) spectra were measured in CDCl
using SiMe (δ ) 0 ppm) and the center line of CDCl triplet (δ
77.1 ppm) as internal standards, respectively. Methyl (R)-3-
3
2
-
5
20 °C, 10% tartaric acid solution (0.20 mL) and NaF (0.25 g,
.95 mmol). The mixture was stirred vigorously at room tem-
perature for 60 min and filtered through a pad of Celite with
Et O. The filtrate was concentrated, and the residue was diluted
in Et O (16 mL). The solution was cooled to 0 °C, and 3 N NaOH
8 mL, 24 mmol) was added to it. The resulting mixture was
stirred at room temperature for 1 h vigorously, and the product
was extracted with Et O three times. The combined extracts
4
3
)
hydroxybutanoate (8) (98% ee) was kindly offered by Takasago
International Corporation, J apan. Routinely, organic extracts
were dried over MgSO and concentrated using a rotary evapo-
4
rator to afford residues, which were purified by chromatography
on silica gel.
Meth yl (R)-3-Tetr a h yd r op yr a n yloxybu ta n oa te (9). A
2
2
(
2
were dried and concentrated to afford an oil, which was purified
by chromatography (hexane/EtOAc) to afford 14 (98 mg, 41%).
The diastereomeric purity at the C(10) position of 14 was
solution of 8 (7.50 g, 63.5 mmol, >98% ee), DHP (7.5 mL, 83
mmol), and p-TsOH‚H
2
O (120 mg, 0.63 mmol) in CH
mL) was stirred at 0 °C for 2 h, and saturated NaHCO
2
Cl
2
(130
was
3
1
determined to be >95% ds by H NMR specroscopy of the diol
added into the solution. After 10 min of vigorous stirring, the
resulting mixture was extracted with EtOAc twice, and the
combined extracts were washed with brine, dried, and concen-
trated to give an oil, which was purified by chromatography
1
0
1
7
prepared by deprotection of the THP group (PPTS (0.1
-
1
equiv), MeOH, rt, 12 h). Data for 14: IR (neat) 3421, 1023 cm
;
1
H NMR δ 1.20 and 1.32 (2d, J ) 6 and 6 Hz, total 3 H), 1.46-
2
.19 (m, 8 H), 3.06-4.26 (m, 4 H), 4.63-5.05 (m, 2 H), 6.22-
(
1
6
hexane/EtOAc) to afford THP ether 9 (12.35 g, 96%): IR (neat)
741, 1199, 1022 cm- ; H NMR δ 1.18 and 1.28 (2d, J ) 6 and
1 1
6.26 (m, 1 H), 6.31-6.35 (m, 1 H), 7.35-7.38 (m, 1 H). Anal.
Calcd for C13
H
20
O
4
: C, 64.98; H, 8.39. Found: C, 65.00; H, 8.48.
1R,3R)-1-(2-F u r yl)-1-m eth oxym eth yloxy-3-tetr a h yd r o-
p yr a n yloxybu ta n e (15). A solution of 14 (2.05 g, 8.53 mmol),
MOMCl (1.48 mL, 19.1 mmol), and i-Pr NEt (4.5 mL, 25.7 mmol)
in CH Cl (20 mL) was stirred at room temperature overnight
and diluted with EtOAc and saturated NaHCO . The resulting
Hz, 3 H), 1.41-1.86 (m, 6 H), 2.33-2.74 (m, 2 H), 3.42-3.53
(
(
m, 1 H), 3.66 and 3.67 (2s, 3 H), 3.77-3.94 (m, 1 H), 4.10-4.31
(m, 1 H), 4.62-4.78 (m, 1 H). Anal. Calcd for C10 : C, 59.39;
18 4
H O
H 8.97. Found: C, 59.47; H, 8.98.
R)-3-Tetr a h yd r op yr a n yloxy-1-bu ta n ol (10). To an ice-
cold suspension of LiAlH (2.32 g, 61.1 mmol) in THF (90 mL)
was added a solution of 9 (12.35 g, 61.1 mmol) dissolved in THF
10 mL × 3), and the mixture was stirred at 0 °C for 30 min
and at room temperature for 60 min. The mixture was cooled to
°C again, and EtOAc (27 mL, 0.31 mol), H O (22 mL, 1.22 mol)
2
(
2
2
3
4
mixture was stirred vigorously at room temperature for 1 h. The
phases were separated, and the aqueous phase was extracted
with EtOAc twice. The combined extracts were dried and
concentrated to give an oil, which was purified by chromatog-
raphy (hexane/EtOAc) to furnish MOM ether 15 (2.19 g, 90%):
(
0
2
in THF (44 mL), and NaF (25.7 g, 0.612 mol) were added to the
mixture. The resulting mixture was stirred vigorously at room
temperature for 1 h and filtered through a pad of Celite with
EtOAc. The filtrate was concentrated, and the residue was
purified by chromatography (hexane/EtOAc) to afford alcohol 10
-
1
1
IR (neat) 1029, 921 cm ; H NMR δ 1.15 and 1.27 (2d, J ) 6
and 6 Hz, total 3 H), 1.42-2.08 (m, 7 H), 2.15-2.33 (m, 1 H),
3
(
.347 and 3.353 (2s, total 3 H), 3.33-3.97 (m, 3 H), 4.45-4.90
m, 4 H), 6.26-6.38 (m, 2 H), 7.37-7.43 (m, 1 H). Anal. Calcd
for C15 O : C, 63.36; H, 8.51. Found: C, 63.41; H, 8.55.
(2R,4R)-4-(2-F u r yl)-4-m eth oxym eth yloxy-2-bu ta n ol (7).
A solution of 15 (2.24 g, 7.88 mmol) and p-TsOH‚H O (74 mg,
0.39 mmol) in MeOH (80 mL) was stirred at room temperature
for 4 h and diluted with saturated NaHCO . Most of the MeOH
1
H
24
(
9.61 g, 90%). The H NMR spectrum of 10 was identical with
5
1
7
that reported.
(
1R,3R)- a n d (1S,3R)-1-(2-F u r yl)-3-t et r a h yd r op yr a n yl-
oxy-1-bu ta n ol (13). To a solution of (COCl) (3.8 mL, 43.6
mmol) in CH Cl (90 mL) was injected DMSO (6.14 mL, 86.5
2
2
2
2
3
mmol) at -60 °C. The solution was stirred at the same temper-
was removed by evaporation, and the resulting mixture was
extracted with EtOAc twice. The combined extracts were dried
and concentrated. Chromatography (hexane/EtOAc) of the crude
ature for 15 min, and a solution of alcohol 10 (5.05 g, 29.0 mmol)
dissolved in CH
at -60 °C, Et
2
Cl
2
(10 mL × 3) was added. After 1 h of stirring
2
8
N (28.3 mL, 204 mmol) was added, and the
resulting mixture was warmed gradually to 0 °C over 2 h. Brine
was added to the mixture, and the product was extracted with
product afforded alcohol 7 (1.43 g, 91%): [R]
D
) +177 (c 1.07,
3
-
1 1
CHCl ); IR (neat) 3432, 1025, 922 cm ; H NMR δ 1.22 (d, J )
3
6 Hz, 3 H), 1.89 (ddd, J ) 14, 5, 3 Hz, 1 H), 2.15 (dt, J ) 14, 9
Hz, 1 H), 2.87 (s, 1 H), 3.39 (s, 3 H), 3.38-4.00 (m, 1 H), 4.52 (d,
J ) 7 Hz, 1 H), 4.62 (d, J ) 7 Hz, 1 H), 4.87 (dd, J ) 9, 5 Hz, 1
H), 6.29-6.35 (m, 2 H), 7.39 (s, 1 H); 13C NMR δ 152.9, 142.6,
110.1, 108.6, 93.8, 70.5, 66.9, 55.9, 42.9, 23.7. Anal. Calcd for
2
Et O three times. The combined ethereal solutions were washed
with brine, dried, and concentrated to give aldehyde 11, which
was used for the next reaction without further purification.
To an ice-cold solution of furan (7.5 mL, 104 mmol) and
bipyridine (ca. 10 mg) in THF (110 mL) was added n-BuLi (34
mL, 2.53 M in hexane, 86 mmol), and the solution was stirred
at 0 °C for 80 min to prepare 2-furyllithium (12). The solution
was cooled to -70 °C, and the above crude aldehyde 11 dissolved
in THF (10 mL × 3) was added slowly. Stirring was continued
at -70 °C for 2 h, and the solution was poured into a mixture of
C
10
H
16
O
4
: C, 59.98; H 8.05. Found: C, 59.59; H, 8.04.
Eth yl (5R,2E)-5-Tetr ah ydr opyr an yloxy-2-h exen oate (21).
According to the procedure described above, alcohol 10 (8.72 g,
50.0 mmol) dissolved in CH Cl (30 mL) was converted into
aldehyde 11 by using (COCl) (5.64 mL, 64.7 mmol), DMSO (9.10
mL, 129 mmol), Et N (42 mL, 302 mmol), and CH Cl (120 mL).
2
2
2
3
2
2
Et
layer was separated and the aqueous layer was extracted with
Et O twice. The combined ethereal solutions were dried and
2
O and saturated NH
4
Cl with vigorous stirring. The organic
Crude 11 was used for the next reaction without further
purification.
To an ice-cold suspension of LiCl (2.65 g, 62.5 mmol) in MeCN
2
concentrated to leave an oil, which was purified by chromatog-
raphy (hexane/EtOAc) to afford alcohol 13 as a mixture of the
diastereoisomers (5.69 g, 82% from alcohol 10): IR (neat) 3418,
2 2 2
(120 mL) were added sequentially (EtO) P(dO)CH CO Et (12.5
mL, 62.4 mmol), DBU (11.6 mL, 77.9 mmol), and crude aldehyde
11 dissolved in MeCN (10 mL × 3). The mixture was stirred at
0 °C for 30 min and then at room temperature for 60 min.
-
1 1
1
023 cm ; H NMR δ 1.20, 1.22, 1.32, and 1.33 (4d, J ) 6, 6, 6,
and 6 Hz, total 3 H), 1.46-2.19 (m, 8 H), 3.11-3.17 (m, 1 H),
Saturated NH
MeCN was removed by evaporation. The product was extracted
with Et O three times, and the combined extracts were dried
4
Cl was added to the mixture, and most of the
3
6
.44-3.59 (m, 1 H), 3.84-4.24 (m, 2 H), 4.51-5.10 (m, 2 H),
.22-6.26 (m, 1 H), 6.31-6.35 (m, 1 H), 7.35-7.38 (m, 1 H).
2
Anal. Calcd for C13
H, 8.45.
H
20
O
4
: C, 64.98; H, 8.39. Found: C, 65.19;
and concentrated. The residual oil was purified by chromatog-
1
raphy (hexane/EtOAc) to afford ester 21 (9.16 g, 76%). The H
NMR spectrum of 21 was in good agreement with that re-
ported.12
(17) Quinkert, G.; D o¨ ller, U.; Eichhorn, M.; K u¨ ber, F.; Nestler, H.
P.; Becker, H.; Bats, J . W.; Zimmermann, G.; D u¨ rner, G. Helv. Chim.
Acta 1990, 73, 1999-2047.
(5R,2E)-5-Tetr a h yd r op yr a n yloxy-2-h exen oic Acid (6). To
an ice-cold solution of ester 21 (9.16 g, 37.8 mmol) in THF (175

7
224 J . Org. Chem., Vol. 65, No. 21, 2000
Notes
mL) were added H O (120 mL) and 2 N LiOH (57 mL). The
2
mixture was stirred at room temperature for 3 h and slightly
acidified by addition of 1 N HCl (pH ca. 4). Most of the t-BuOH
was removed by using a vacuum pump. After addition of brine,
the mixture was extracted with EtOAc three times. The com-
bined extracts were dried and concentrated to leave crude 4,
which was used for the next reaction without further purifica-
tion. Analytically pure sample was obtained by chromatogra-
mixture was stirred vigorously at room temperature for 20 h,
and most of the THF was removed by evaporation. The residue
was diluted with EtOAc and slightly acidified (pH ) ca. 4) with
1
N HCl. The phases were separated, and the aqueous layer was
extracted with EtOAc. The combined EtOAc phases were dried
and concentrated to give an oil, which was purified by chroma-
1
-1 1
tography (hexane/EtOAc) to afford acid 6 (5.87 g, 81%). The H
phy: IR (neat) 3161, 1712, 1178 cm ; H NMR δ 1.25 (d, J ) 6
Hz, 3 H), 1.28 (d, J ) 6 Hz, 3 H), 2.03 (ddd, J ) 15, 6, 4 Hz, 1
H), 2.21 (ddd, J ) 15, 9, 5 Hz, 1 H), 2.28-2.46 (m, 2 H), 3.36 (s,
3 H), 3.90-4.08 (m, 1 H), 4.29 (dd, J ) 6, 5 Hz, 1 H), 4.63 (d, J
) 7 Hz, 1 H), 4.70 (d, J ) 7 Hz, 1 H), 5.07-5.26 (m, 1 H), 5.75
(d, J ) 16 Hz, 1 H), 5.58-6.07 (m, 2 H), 6.75 (d, J ) 16 Hz, 1
NMR spectrum of 6 was in good agreement with that reported.12
(
1′R,3′R)-3′-(2-F u r yl)-3′-m et h oxym et h yloxy-1′-m et h yl-
p r op yl (5R,2E)-5-Tetr a h yd r op yr a n yloxy-2-h exen oa te (22).
To an ice-cold solution of alcohol 7 (1.42 g, 7.09 mmol), acid 6
(
1.97 g, 9.19 mmol), DMAP (171 mg, 1.40 mmol), and CSA (165
mg, 0.71 mmol) in CH Cl (50 mL) was added DCC (2.20 g, 10.7
mmol) in CH Cl (20 mL). The resulting solution was stirred at
room temperature for 20 h and filtered through a pad of Celite
with Et O. The filtrate was concentrated and the residual oil
was purified by chromatography (hexane/EtOAc) to afford ester
1
3
H), 6.80-7.02 (m, 1 H), 7.41 (d, J ) 16 Hz, 1 H); C NMR δ
199.1, 168.3, 165.4, 145.8, 136.5, 130.8, 123.7, 96.5, 78.9, 67.1,
56.5, 41.9, 38.5, 23.3, 20.2.
2
2
2
2
3
To a solution of the above acid 4 and NEt (0.72 mL, 5.18
mmol) in THF (10 mL) was added 2,4,6-trichlorobenzoyl chloride
(0.25 mL, 1.55 mmol). The solution was stirred at room tem-
2
-
1 1
2
1
2
(
4
1
2 (2.16 g, 77%): IR (neat) 1717, 1655, 1023 cm ; H NMR δ
.12-1.30 (m, 6 H), 1.41-1.89 (m, 6 H), 1.98-2.16 (m, 1 H),
.20-2.58 (m, 3 H), 3.36 (s, 3 H), 3.42-3.54 (m, 1 H), 3.79-4.00
perature for 4 h, and the resulting white precipitate (Et N‚HCl)
3
was removed by dilution with toluene (ca. 20 mL) followed by
filtration through a pad of Celite with additional toluene (20
mL). The filtrate, after further dilution with toluene (100 mL),
was divided into two equal portions, while two solutions of
DMAP (each 85 mg, 0.70 mmol) in toluene (each 25 mL) were
prepared. Each toluene solution containing the mixed anhydride
was added to each solution of DMAP in toluene at 60 °C over 7
h. After the addition, the solutions were stirred further for 1 h
and cooled to room temperature. The combined solutions were
concentrated to afford a residue, which was purified by chro-
matography (hexane/EtOAc) to afford lactone 23 (128 mg, 37%)
m, 2 H), 4.50 (d, J ) 7 Hz, 1 H), 4.58 (d, J ) 7 Hz, 1 H), 4.63-
.76 (m, 2 H), 4.80-4.94 (m, 1 H), 5.83 and 5.85 (2d, J ) 16 and
6 Hz, total 1 H), 6.24-6.34 (m, 2 H), 6.83-7.06 (m, 1 H), 7.38
(
32 7
s, 1 H). Anal. Calcd for C21H O : C, 63.62; H, 8.14. Found: C,
6
3.44; H, 8.09.
1′R,3′R)-3′-(2-F u r yl)-3′-m et h oxym et h yloxy-1′-m et h yl-
p r op yl (5R,2E)-5-Hyd r oxy-2-h exen oa te (5). A solution of
THP ether 22 (2.16 g, 5.45 mmol) and p-TsOH‚H O (52 mg, 0.27
mmol) in MeOH (55 mL) was stirred at room temperature for 3
h and diluted with saturated NaHCO . Most of the MeOH was
(
2
3
2
9
from furan 5: [R]
D
3
) -11.3 (c 0.558, CHCl ); IR (neat) 1728,
removed by evaporation, and the resulting mixture was ex-
tracted with EtOAc three times. The combined extracts were
dried and concentrated to leave a residue, which was purified
by chromatography (hexane/EtOAc) to afford alcohol 5 (1.40 g,
-
1 1
1
701, 1173, 1054 cm ; H NMR δ 1.23 (d, J ) 6 Hz, 3 H), 1.40
(
(
d, J ) 6 Hz, 3 H), 2.06-2.25 (m, 3 H), 2.41-2.50 (m, 1 H), 3.37
s, 3 H), 4.25 (t, J ) 4 Hz, 1 H), 4.66 (d, J ) 7 Hz, 1 H), 4.72 (d,
3
1
J ) 7 Hz, 1 H), 5.20-5.35 (m, 2 H), 5.58 (d, J ) 16 Hz, 1 H),
6.70 (ddd, J ) 16, 11, 6 Hz, 1 H), 6.79 (d, J ) 16 Hz, 1 H), 7.21
8
2%): [R]
D
) +55.9 (c 1.02, CHCl
3
); IR (neat) 3448, 1716, 1032
-
1 1
cm ; H NMR δ 1.24 (d, J ) 6 Hz, 3 H), 1.27 (d, J ) 6 Hz, 3 H),
(
1
d, J ) 16 Hz, 1 H); 13C NMR δ 200.1, 166.9, 165.2, 143.1, 134.0,
1
3
4
.67 (br s, 1 H), 2.09 (ddd, J ) 14, 8, 5 Hz, 1 H), 2.23-2.40 (m,
H), 3.36 (s, 1 H), 3.89-4.01 (m, 1 H), 4.51 (d, J ) 7 Hz, 1 H),
.58 (d, J ) 7 Hz, 1 H), 4.69 (dd, J ) 8, 7 Hz, 1 H), 4.82-4.95
32.3, 127.2, 96.4, 79.1, 70.6, 66.2, 56.4, 40.9, 39.7, 20.5, 20.4.
Anal. Calcd for C16
H, 7.21.
22 7
H O : C, 58.89; H, 6.79. Found: C, 58.68;
(
6
m, 1 H), 5.87 (dt, J ) 16, 2 Hz, 1 H), 6.26 (dd, J ) 3, 1 Hz, 1 H),
Gr a h a m im ycin A (1). To an ice-cold solution of 23 (9.3 mg,
0.028 mmol) in CH Cl (0.44 mL) was added CF CO H (0.44 mL,
.7 mmol). The solution was allowed to stand in a refrigerator
at ca. 3 °C) for 17 h and concentrated to leave an oil, which
was purified by chromatography (hexane/EtOAc) to afford 1 (7.0
.31 (dd, J ) 3, 2 Hz, 1 H), 6.93 (dt, J ) 16, 8 Hz, 1 H), 7.38 (d,
1
3
2
2
3
2
J ) 2 Hz, 1 H); C NMR δ 165.5, 152.7, 144.9, 142.6, 124.1,
10.1, 108.9, 93.9, 68.2, 68.1, 66.8, 55.7, 42.0, 40.3, 23.4, 20.2.
Anal. Calcd for C16 : C, 61.52; H, 7.74. Found: C, 61.21;H,
5
(
1
24 6
H O
7
.61.
3E,6R,8R,11E,14R)-8,14-Dim eth yl-6-m eth oxym eth yloxy-
,9-d ioxa cyclotetr a d eca -3,11-d ien e-2,5,10-tr ion e (23). To a
(188 mg, 2.24
O (10:1, 6 mL) was added NBS (240 mg,
.35 mmol) dissolved in acetone/H O (10:1, 2 mL) at -15 °C.
2
5
3
21
mg, 87%): [R]
.48, CHCl ), lit. [R]
recrystallized from hexane/CH
D
) -34.2 (c 0.052, CHCl
3
) [lit. [R]
3
D
) -33 (c
(
1
22
1
(
3
D
) -34 (c 1.47, CHCl )]; mp 138-140 °C
1
3
1
2
Cl
2
) [lit. mp 138-139 °C; lit.
) 1725,
mixture of 5 (350 mg, 1.12 mmol) and NaHCO
mmol) in acetone/H
1
3
mp 147.5-150 °C]. Spectral data of 1 updated: IR (CHCl
3
2
-
1 1
1
1
706, 1655, 1362, 1175 cm ; H NMR δ 1.39 (d, J ) 7 Hz, 3 H),
2
.43 (d, J ) 6 Hz, 3 H), 1.80 (ddd, J ) 16, 5, 4 Hz, 1 H), 2.13
The mixture was stirred for 2.5 h, and furan (0.16 mL, 2.2 mmol)
was added to destroy excess NBS. After 60 min at -15 °C,
pyridine (0.09 mL, 1.1 mmol) was added, and the mixture was
stirred at room temperature for 21 h. Brine and EtOAc were
added, and the resulting mixture was acidified with 1 N HCl to
pH ca. 4. The phases were separated, and the aqueous phase
was extracted with EtOAc. The combined extracts were dried
and concentrated to give an oil, which was passed through a
short silica gel column with hexane/EtOAc to furnish the
(
(
ddd, J ) 16, 5, 3 Hz, 1 H), 2.37 (dt, J ) 13, 11 Hz, 1 H), 2.56
dddd, J ) 13, 5, 3, 2 Hz, 1 H), 3.14 (d, J ) 5 Hz, 1 H), 4.54 (dt,
J ) 4, 5 Hz, 1 H), 5.00-5.14 (m, 1 H), 5.30-5.42 (m, 1 H), 5.90
(
d, J ) 16 Hz, 1 H), 6.71 (d, J ) 16 Hz, 1 H), 6.75 (ddd, J ) 16,
1
1
1
1, 5 Hz, 1 H), 7.09 (d, J ) 16 Hz, 1 H); 13C NMR δ 200.7, 165.3,
65.2, 143.9, 134.3, 132.6, 126.8, 72.9, 70.8, 67.1, 40.5, 40.3, 20.7,
8.6.
Red u ction of Gr a h a m im ycin (1) to Colletod iol (3). To a
solution of 1 (16 mg, 0.057 mmol) in MeOH (0.8 mL) at -15 °C
was added NaBH (4.3 mg, 0.11 mmol) portionwise. After 30 min
at -15 °C, the solution was diluted with saturated NH Cl and
-
1
1
corresponding aldehyde: IR (neat) 3455, 1712, 1655 cm ; H
4
NMR δ 1.24 (d, J ) 6 Hz, 3 H), 1.30 (d, J ) 6 Hz, 3 H), 2.02
4
(
2
)
5
ddd, J ) 15, 6, 4.5 Hz, 1 H), 2.23 (ddd, J ) 15, 9, 5 Hz, 1 H),
EtOAc. The resulting mixture was extracted with EtOAc three
times, and the combined extracts were dried and concentrated.
The residue was purified by chromatography to furnish 3 (13
.25-2.41 (m, 3 H), 3.37 (s, 3 H), 3.89-4.01 (m, 1 H), 4.32 (t, J
6 Hz, 1 H), 4.68 (d, J ) 7 Hz, 1 H), 4.72 (d, J ) 7 Hz, 1 H),
.10-5.24 (m, 1 H), 5.75 (d, J ) 16 Hz, 1 H), 6.58-7.10 (m, 2
2
7
16
mg, 81%): [R]
D
) +35.8 (c 0.118, CHCl
3
) (lit. [R]
D
) +36 (c
13
H), 7.28 (d, J ) 16 Hz, 1 H), 9.73 (d, J ) 8 Hz, 1 H); C NMR
δ 199.5, 193.6, 165.6, 146.3, 140.8, 138.2, 123.8, 96.6, 79.0, 67.0,
6
2
1
.0, CHCl
3
)); mp 163-165 °C (recrystallized from hexane/Et
2
O)
1
6
2b
18
1
(
lit. 164-167 °C; lit. 165 °C; lit. 159-161 °C). The H NMR,
6.7, 56.4, 41.8, 38.3, 23.3, 20.0.
To a solution of the aldehyde obtained above and 2-methyl-
-butene (1.2 mL, 11 mmol) in t-BuOH (15 mL) and the
1
3
C NMR, and IR spectra of 3 thus synthesized were in accord
2b,3
with the reported data.
phosphate buffer (pH 3.6, 7 mL) was added NaClO
2
(151 mg,
Ack n ow led gm en t. We gratefully acknowledge the
generous supply of methyl (R)-3-hydroxybutanoate from
Takasago International Corporation.
purity 80%, 1.33 mmol) dissolved in H O (7 mL). The resulting
2
(18) Fujimoto, H.; Nagano, J .; Yamaguchi, K.; Yamazaki, M. Chem.
Pharm. Bull. 1998, 46, 423-429.
J O000762C