Mimicry of annonaceous acetogenins: enantioselective synthesis of a (4R)-hydroxy analogue having potent antitumor activity.

Article abstract of DOI:10.1021/jo016396u

The (4R)-hydroxylated analogues of annonaceous acetogenin mimicking compound 2 were designed and synthesized structurally on the basis of the naturally occurring annonaceous acetogenin bullatacin, which was discovered as a typical member of the novel fami

Full text of DOI:10.1021/jo016396u

3
404
J . Org. Chem. 2002, 67, 3404-3408
Mim icr y of An n on a ceou s Acetogen in s: En a n tioselective Syn th esis
of a (4R)-Hyd r oxy An a logu e Ha vin g P oten t An titu m or Activity
†
‡
†
†
‡
Sheng J iang, Zhong-Hai Liu, Gang Sheng, Bu-Bing Zeng, Xiao-Guang Cheng,
†
,†
Yu-Lin Wu, and Zhu-J un Yao*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, 354 Fenglin Road, Shanghai 200032, China, and Institute of Materia Medica, Chinese
Academy of Medical Sciences, 1 Xiannongtan Street, Beijing 100050, China
yaoz@pub.sioc.ac.cn
Received December 21, 2001
The (4R)-hydroxylated analogues of annonaceous acetogenin mimicking compound 2 were designed
and synthesized structurally on the basis of the naturally occurring annonaceous acetogenin
bullatacin, which was discovered as a typical member of the novel family of polyketides with potent
cytotoxicity, antitumoral, and other biological activities. The preliminary screenings show that the
-
3
-2
IC50 values of 2 were 1.6 × 10 and 8 × 10 µg/mL against HT-29 and HCT-8, respectively. A
remarkable enhancement effect was observed by the activity comparison of 1c and its (4R)-
hydroxylated analogue 2.
In tr od u ction
Annonaceous acetogenins, isolated from the Annon-
aceae plants, have been attracting worldwide attention
in recent years due to their biological activities, especially
1
as growth inhibitors of certain tumor cells. They have
been shown to function by blocking complex I in mito-
2
chondria as well as ubiquinone-linked NADPH oxidase
in the cells of specific tumor cell lines, including some
multidrug-resistant ones.3 These features make these
acetogenins excellent leads for the new antitumor agents.
In a previous work by us, the compounds 1a -1d (Figure
1
), which rely on structure simplification while maintain-
ing all essential functionalities of the acetogenins, were
in vitro tested against several human solid tumor cell
lines and showed interesting cell line selectivity. All four
analogues show remarkable activity against the HCT-8
and HT-29 cell lines, while compound 1c was found to
be the best. To investigate the effect of the 4-hydroxyl
group, which was commonly observed in many of these
naturally occurring acetogenins, we designed compound
F igu r e 1.
Ch em ica l Syn th esis
4
The retrosynthetic strategy of 2 is illustrated in Figure
. A two-directional C-alkylation of 1,7-octadiyne 4 with
2
epoxides 3 and 5 was designed as the key step to
construct the molecule skeleton.
The synthesis of the key intermediate 3 is shown in
Scheme 1. It starts from the readily available chiral
aldehyde 9, which was easily prepared from D-mannitol
2
as the target for investigation (Figure 1). Structurally,
it combines both the advantages of bullatacin, one of the
most potent naturally occurring acetogenins, and our
4
previous results on the study of annonaceous acetogenin
mimicry.
5
on a large scale. The extension of the hydrocarbon chain
was achieved by Witting reaction of 9 to give 16 in 90%
6
*
To whom correspondence should be addressed. Fax: +8621 6416
yield, which was further hydrogenated over 10% Pd-C
6
128.
and afforded 17 in 95% yield. Acid-catalyzed deprotection
of 17 was achieved in 93% yield with 10% HCl. The
resultant diol 8 was regioselectively O-alkylated with
†
Shanghai Institute of Organic Chemistry.
Chinese Academy of Medical Sciences.
‡
(1) Reviews: (a) Ruppreht, J . K.; Hui, Y. H.; Mclaughlin, J . L. J .
Nat. Prod. 1990, 53, 237. (b) Fang, X. P.; Rieser, M. J .; Gu, Z. M.;
Mclaughlin, J . L. Phytochem. Anal. 1993, 4, 27. (c) Zeng, L.; Ye, Q.;
Oberlies, N. H.; Shi, G. E.; Gu, Z. M.; He, K.; Mclanghlin, J . L. Nat.
Prod. Rep. 1996, 275. (d) Cave, A.; Figadere, B.; Laurens, Cortes, A.
D. Prog. Chem. Org. 1997, 70, 81.
2
-benzyloxyethyl iodide through a cyclic stannate and
7
gave 18 in 81% yield. The remaining hydroxyl group was
masked as the MOM ether 19 (96% yield) first, and then
the terminal benzyl protecting group was removed by
(
2) Gonzalez, M. C.; Tormo, J . R.; Bermejo, A.; Zafra-Polo, M. C.;
Estornell, E.; Cortes, D. Bioorg. Med. Chem. Lett. 1997, 7, 1113.
3) Oberlies, N. H.; Croy, V. L.; Harrison, M. L.; Mclaughlin, J . L.
Cancer Lett. 1997, 115, 73.
4) Zeng, B. B.; Wu, Y. K.; Yu, Q.; Wu, Y. L.; Li, Y.; Chen, X.. G.
Angew. Chem., Int. Ed. 2000, 39, 1934-1937.
(
(5) Schmid, C. R.; Bryant, J . D.; Dowlatzedah, M.; Phillips, J . L.;
Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J . Org. Chem.
1991, 56, 6, 4056-4058.
(
(6) Wang, Y.-F.; Wu, Y.-L. Hecheng Huaxue 1993, 1, 215.
1
0.1021/jo016396u CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/20/2002

Mimicry of Annonaceous Acetogenins
J . Org. Chem., Vol. 67, No. 10, 2002 3405
Sch em e 1a
a
Reagents and conditions: (a) C8H17CHdPPh3, 90%; (b)10% Pd-C, H2, CH3OH, 95%; (c) 10% HCl, CH3OH, 93%; (d) (i) Bu2SnO, CH3OH/
CHCl3 (1:10); (ii) CsF, DMF, ICH2CH2OBn, 25 °C, two steps, 81%; (e) i-Pr2NEt, MOMCl, CH2Cl2, 96%; (f) Na, NH3(l), 92%; (g) NaOH,
H2O, Bu4NHSO4, (R)-epichlorohydrin, 88%.
Sch em e 2a
a
Reagents and conditions: (a) (i) LDA, THF-HMPA, (S)-O-
tetrahydropyranyl lactal, -78 °C; (ii) 10% H2SO4, THF, rt; (iii)
CF3CO)2O, Et3N, CH2Cl2, 60%; (b) m-CPBA, CH2Cl2, 0 °C, 86%
(
yield based on 31% recovery of 11; (c) (S,S)-Salen-Co(OAc), H2O,
3%.
4
applied. The reaction was performed in the presence of
S,S)-Salen-Co(OAc) complex (0.5 mol %) and H O (0.55
equiv) to yield 5 (43%) and diol 22 (50%, 70% de) at 4
(
2
°
C. The de value (>99%) of 5 was measured by HPLC
F igu r e 2.
using 21 as the reference.
With both intermediates in hand, a stepwise two-
directional C-alkylation of 1,7-octadiyne was performed
to construct the skeleton of 2. At first, the mono-lithiated
derivative of 1,7-octadiyne was reacted with epoxide 3
reductive cleavage to afford 6 in 92% yield. The coupling
reaction of the alcohol 6 with (R)-(-)-epichlorohydrin 7
furnished the key intermediate 3 in 88% yield in the
presence of a phase-transfer catalyst.8
in the presence of BF
3
2
‚Et O to afford 23 in 80% yield,
The other key intermediate (5) was synthesized as in
Scheme 2. Compound 13 can be easily prepared from
malonate and allyl bromide. Subsequent introduction of
and then the produced hydroxyl was protected as the
MOM ether 24 in 96% yield. 24 was treated with n-BuLi
again and then reacted with epoxide 5 as above to give
25 in 69% yield.12 The triple C-C bonds of 25 were
reduced by diimide. Deprotection of the MOM ethers in
9
the butenolide unit to 11 involved a three-step se-
quence: (i) aldol reaction of 13 with (S)-O-tetrahydro-
pyranyl lactal, (ii) acid-catalyzed THP cleavage and in
situ lactonization, and (iii) â-elimination of hydroxyl in
25 with BF
3
2 2
‚Et O in Me S afforded the target 2 in 72%
yield.13 (Scheme 3).
1
0
3 2 3
the presence of (CF CO) O and Et N. Regioselective
epoxidation of 11 was achieved by treatment with
MCPBA to give 21 in 86% yield. To resolve the terminal
epoxides, J acobsen’s hydrolytic kinetic resolution was
Biologica l Eva lu a tion
1
1
The preliminary testing (Table 1) of the compound 2
in vitro against the HT-29 cell line shows that it exhibits
better activity than adriamycin and 1c. It is also found
that the activities greatly increase (up to 15 times more
potent) by the introduction of the (4R)-hydroxyl in 1c.
(7) (a) Nagashima, N.; Ohno, M. Chem. Lett. 1987, 141. (b) Byun,
H.-S.; Kumar, E. R.; Bittman, R. J . Org. Chem. 1994, 59, 2630. (c)
Martinez, R.; Bernhardt, P.; Castro, P.; Godjoian, G.; Gutierrez, C. G.
Tetrahedron 1998, 54, 8919.
(
8) Huerou, Y. L.; Doyon, J .; Gree, R. L. J . Org. Chem. 1999, 64,
782-6790.
9) (a) Brillon, D. Synth. Commun. 1986, 16, 291-298. (b) Ho, T.-L.
Synth. Commun. 1979, 9, 609-611.
10) (a) Yao, Z.-J .; Wu, Y.-L. Tetrahedron Lett. 1994, 35, 157. (b)
6
(11) (a) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N.
Science 1997, 277, 936-938. (b) Yu, Q.; Wu, Y.-K.; Xia, L. J .; Tang, M.
H.; Wu, Y.-L. Chem. Commun. 1999, 129-130.
(12) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391-394.
(13) (a) Hu, T.-S.; Yu, Q.; Wu, Y.-L.; Wu, Y. K. J . Org. Chem. 2001,
66, 853-861. (b) Marshall, J . A.; Chen, M. Z. J . Org. Chem. 1997, 62,
5996-6000.
(
(
Yao, Z.-J .; Wu, Y.-L. J . Org. Chem. 1995, 60, 1170-1176. (c) Yu, Q.;
Wu, Y.; Wu, Y.-L.; Xia, L.-J .; Tang, M.-H. Chirality 2000, 12, 127-
1
29.

3
406 J . Org. Chem., Vol. 67, No. 10, 2002
J iang et al.
Sch em e 3a
a
Reagents and conditions: (a) n-BuLi, BF3‚Et2O, THF, -78 °C, 80%; (b) i-Pr2NEt, MOMCl, CH2Cl2, 96%; (c) n-BuLi, BF3‚Et2O, THF,
, -78 °C, 69%; (d) (i) TsNHNH2, NaOAc, DME, reflux; (ii) BF3‚Et2O, Me2S, 0 °C, 72%.
5
Ta ble 1. Cytotoxicity Da ta of 1c, 2, a n d Ad r ia m ycin
(30 mL) was added. The reaction mixture was warmed to rt
slowly and stirred overnight. Petroleum ether (200 mL) and
aqueous saturated NH Cl (20 mL) were added at rt, and the
4
IC50 (µg/mL)
sample
HT-29
HCT-8
KB
HELF
aqueous phase was extracted with petroleum ether. The
combined organic layers were dried over sodium sulfate and
concentrated. The residue was purified by flash chromatog-
-
2
1
2
c
2.4 × 10 (15)
-3
-2
-2
1.6 × 10 (1)
8.0 × 10
>10
7.6 × 10
>10
1.92
1
-
2
-2
raphy to give 16 as an oil (10.9 g, 90%). H NMR (300 MHz,
adriamycin 6.0 × 10 (37.5) 3.6 × 10
CDCl
3
): 5.63 (1H, m), 5.40 (1H, t, J ) 9.8 Hz), 4.84 (1H, q, J
7.8 Hz), 4.05 (2H, m), 2.06-2.17 (2H, m), 1.40 (3H, s), 1.38
3H, s), 1.40-1.27 (12H, m), 0.88 (3H, t, J ) 6.9 Hz) ppm. MS
)
(
(
This obviously indicates that (4R)-hydroxyl is an impor-
tant group that contributes activity against tumor cell
lines. Additionally, compound 2 shows better selectivity
among the various tumor cells.
+
EI, m/z): 240 (M ). Anal. Calcd for C15
1.74. Found: C, 74.96; H, 12.00.
4S)-Decyl-2,2-d im eth yl[1,3]d ioxola n e (17). A mixture
of 16 (10.9 g, 45.4 mmol), CH OH (100 mL), and Pd-C (10%,
.2 g) was stirred vigorously under a H atmosphere until
26 2
H O : C, 74.95; H,
1
(
3
Con clu sion
0
2
hydrogen could not be absorbed. The mixture was filtrated and
In summary, (4R)-hydroxylated analogue 2 structur-
ally based on annonaceous acetogenin mimic 1c was
synthesized enantioselectively. The preliminary screen-
ings show that the introduction of the (4R)-hydroxyl
group greatly enhanced the cytotoxicity against HCT-8
and HT-29 compared with those of 1c. These results open
a potential way to find more active antitumor agents with
a simplified structure based on natural annonaceous
acetogenins. The described procedure also could be
expanded to synthesize the annonaceous acetogenins
with a (4R)-hydroxylated butenolide unit in high yield
and excellent enantiomeric purity. It has the advantages
of starting from readily available chemical substrates and
inexpensive reagents as well.
concentrated. Flash chromatography of the crude product
afforded 17 as an oil (10.44 g, 95%). 1H NMR (300 MHz,
CDCl
3
): 4.04 (2H, m), 3.49 (1H, t, J ) 7.0 Hz), 1.40 (3H, s),
1.38 (3H, s), 1.20-2.20 (18H, m), 0.88(3H, t, J ) 7.1 Hz) ppm.
2
5
[R]
(2S)-Dod eca n e-1,2-d iol (8). To a stirred solution of com-
pound 17 (10.44 g, 43.1 mmol) in CH OH (100 mL) was added
0% HCl (10 mL). The reaction was stirred overnight at rt.
Methanol was removed under reduced pressure, and aqueous
saturated NaHCO was added until a pH of 7 was reached.
D
) +15.2 (c 1.18, CHCl
3
).
3
1
3
The mixture was extracted with ethyl acetate (3 × 30 mL),
dried over sodium sulfate, and concentrated. Recrytallization
of the crude product with ethyl acetate afforded 8 as a white
1
solid (8.10 g, 93%). H NMR (300 MHz, CDCl
3
): 3.69 (1H, m),
3.65 (1H, t, J ) 3.0 Hz), 3.43 (1H, m), 1.26-1.88 (18H, m),
0
.88 (3H, t, J ) 6.6 Hz) ppm (two protons of hydroxyls were
-
1
not observed). IR (neat): 3316, 2920, 2851, 1470, 1438 cm
.
Exp er im en ta l Section
+
25
MS (EI, m/z): 206 (M ). [R]
Calcd for C12
12.90.
D
) +9.36 (c 1.1, CH
3
OH). Anal.
H O : C, 71.23; H, 12.95. Found: C, 70.97; H,
26 2
Gen er a l Meth od s. Optical rotations were measured at rt.
1
IR spectra were recorded on an FT-IR instrument. H NMR
spectra were recorded at 300, 400, and 600 MHz and are
(2S)-1-(2-Ben zyloxyeth oxy)d od eca n -2-ol (18). A stirred
mixture of compound 8 (1.01 g, 5 mmol), Bu SnO (1.25 g, 5
mmol), and CHCl /CH OH (10:1, 20 mL) was refluxed until
the solution turned clear. The solvent was removed under
reduced pressure, and the residue was dried in vaccum for 6
h. To the residue were added DMF (30 mL) and CsF (0.911 g,
reported in parts per million (δ) downfield relative to TMS as
2
1
3
internal standard, and C NMR spectra were recorded at 100
and 150 MHz and are reported in parts per million (δ). Flash
column chromatography was performed on silica gel (10-40
µm) using a mixture of petroleum ether and ethyl acetate as
the eluent.
3
3
2 2
6 mmol), followed by ICH CH OBn (1.97 g, 7.50 mmol) in DMF
(
4S)-Dec-1-en yl-2,2-d im eth yl[1,3]d ioxola n e (16). The
stirred mixture of 1-bromononane (10.4 g, 50.2 mmol) and Ph
13.2 g, 50.2 mmol) was heated at 140 °C under N . After 3 h,
(7 mL). The reaction was stirred for 18 h at 50 °C. The solvent
was removed under reduced pressure, and the residue was
treated with saturated brine and stirred for 0.5 h. The mixture
was extracted with ethyl acetate (3 × 10 mL). The organic
3
P
(
2
the reaction was cooled, and dry THF (100 mL) was added to
dissolve the syrup. A solution of n-BuLi in hexanes (1.6 M,
4
phase was washed with saturated NH Cl and saturated brine,
3
1.4 mL, 50.2 mmol) was then added under a N
at 0 °C. The reaction was stirred for 15 min at 0 °C, and then
R)-glyceraldehyde acetonide (6.53 g, 50.2 mmol) in dry THF
2
atmosphere
dried over sodium sulfate, and concentrated. Flash chroma-
tography of the residue afforded 18 as an oil (1.36 g, 81%). H
NMR (300 MHz, CDCl ): 7.34 (5H, m), 4.57 (2H, s), 3.79
3
1
(

Mimicry of Annonaceous Acetogenins
J . Org. Chem., Vol. 67, No. 10, 2002 3407
(
(
(
1H,m), 3.61-3.72 (4H, m), 3.52 (1H, q, J ) 7.2,1.2 Hz), 3.31-
1H, t, J ) 8.1 Hz), 2.70 (1H, br s), 1.79 (2H, m), 1.26-1.45
16H, m,), 0.88 (3H, t, J ) 7.2 Hz) ppm. IR (neat): 3426, 3028,
rated aqueous NaHCO
rated to give a crude oil. To the mixture of the above oil and
Et N (18 mL, 0.128 mol) in CH Cl (40 mL) at 0 °C was added
(CF CO) O (9 mL, 0.064 mmol). The reaction was stirred at 0
°C for 12 h and at rt for 6 h, quenched with saturated NH Cl,
and extracted with CH Cl . After being dried (Na SO ), the
3 2 4
and brine, dried (Na SO ), and evapo-
3
2
2
-
1
+
25
1
1
100, 702 cm . MS (EI, m/z): 337 (M + 1). [R]
0.6, CHCl ).
2-(2S)-Met h oxym et h oxyd od ecyloxy)et h oxym et h yl]-
ben zen e (19). To a solution of compound 18 (3.50 g, 10.4
mmol) in CH Cl (60 mL) were added i-Pr NEt (6.68 mL, 38.3
mmol) and MOMCl (2.9 mL, 38.3 mmol) at 0 °C. The reaction
was stirred overnight at rt and quenched with aqueous NH
D
) +4.08 (c
3
2
3
4
[
2
2
2
4
extracts were filtered and concentrated under reduced pres-
sure. The crude product was purified by flash column chro-
2
2
2
1
matography on silica gel to afford pure 11 (2.80 g, 60%). H
4
-
3
NMR (300 MHz, CDCl ): 7.06 (1H, dd, J ) 3.0, 1.5 Hz), 5.89
Cl (20 mL). The mixture was extracted with ethyl acetate. The
organic phase was washed with saturated brine, dried over
sodium sulfate, and concentrated. Flash chromatography of
(1H, m), 5.19 (1H, ddt, J ) 1.4, 2.9, 8 Hz), 5.15 (1H, dd, J )
1.3 Hz), 5.02 (1H, m), 3.04 (2H, ddd, J ) 1.5, 3.1, 8.2 Hz), 1.43
(3H, dd, J ) 1.6, 6.6 Hz) ppm. IR (neat): 3084, 2983, 2935,
-
1
the crude product afforded 19 as a yellow liquid (3.80 g, yield
1755, 1643, 1321, 1199, 1118, 1072, 1027, 919, 863, 675 cm
.
1
+
25
9
6%). H NMR (300 MHz, CDCl
3
): 7.32 (5H, m), 4.70 (2H, dd,
MS (EI, m/z): 139 (M + 1). [R]
D
) +47.2 (c 3.56, CHCl
2
3
).
+
J ) 6.8 Hz), 4.55 (2H, s), 3.69 (1H,m), 3.62-3.75 (4H, m), 3.66
HRMS (EI, m/z): calcd for C
8
H
10
O
[M ] 138.0681, found
(
(
3H, s), 3.50 (2H, d, J ) 5.0 Hz), 1.22-1.52 (18H, m,), 0.87
3H, t, J ) 7.1 Hz) ppm. IR (neat): 2922, 1448, 1108, 1042
138.0689.
(5S)-Meth yl-3-oxir a n ylm eth yl-5H-fu r a n -2-on e (21). To
a 25 mL flask were added 11 (0.26 g, 1.88 mmol), dry CH Cl
(5 mL), and MCPBA (0.295 g, 1.88 mmol) in dry CH Cl (10
mL) at 0 °C under a N atmosphere. The reaction mixture was
-1
+
25
cm . MS (EI, m/z): 350 (MH - OCH
CHCl ).
-[(2S)-Meth oxym eth oxydodecyloxy]eth a n ol (6). To liq-
3
). [R]
D
) -13.7 (c 6.06,
2
2
3
2
2
2
2
uid ammonia (100 mL) was added Na (0.60 g, 26.1 mmol)
slowly at -78 °C. The mixture was stirred until the disap-
pearance of Na metal. Compound 19 (1.57 g, 4.13 mmol) in
THF (40 mL) was then added, and the reaction was stirred
for 3 h. The reaction was quenched by slow addition of aqueous
stirred at rt for 12 h. Excess MCPBA was removed by the
addition of aqueous sodium thiosulfate. The mixture was
transferred to a separating funnel. The organic layer was
diluted with CH
saturated NaHCO
Na SO . The solvent was removed under reduced pressure, and
2
Cl
2
(20 mL), washed successively with
3
and saturated brine, and then dried over
NH
extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with brine and dried (Na SO ). After
4
Cl (20 mL) and warmed to rt. The aqueous layer was
2
4
the residue was chromatographed on silica gel to give a yellow
1
2
4
liquid (21) (0.18 g, 86%) along with recovered 11 (0.08 g). H
concentration and flash chromatography, compound 6 was
obtained as a yellow liquid (1.10 g, 92%). H NMR (300 MHz,
3
NMR (300 MHz, CDCl ): 7.26 (1H, dd, J ) 1.5, 3 Hz), 5.05
1
(1H, dq, J ) 1.3, 5.6 Hz), 3.15 (1H, m), 2.82 (1H, dd, J ) 4.4
Hz), 2.66 (1H, m), 2.56 (1H, dd, J ) 2.6, 4.8 Hz), 2.41 (1H, m),
1.43 (3H, dd, J ) 1.7, 6.8 Hz) ppm. IR (neat): 2950, 2861, 1718,
CDCl
J ) 5.0, 3.5 Hz), 3.51(2H, d, J ) 4.9 Hz), 3.39 (3H, s), 2.21
1H, br s), 1.50 (2H, t, J ) 6.6 Hz), 1.25 (16H, m,), 0.87 (3H,
t, J ) 6.6 Hz) ppm. IR (neat): 3453, 2926, 2856, 1467, 1215,
3
): 4.72 (2H, dd, J ) 6.8 Hz), 3.72 (3H, m), 3.58 (2H, q,
-
1
+
25
(
1648, 1199 cm . MS (EI, m/z): 155 (M + 1). [R]
(c 0.703, CHCl ). HRMS (EI, m/z): calcd for C
154.0630, found 154.0617.
(5S)-Meth yl-3-[(2S)-oxir an ylm eth yl]-5H-fu r an -2-on e (5)
D
) +42.6
+
3
8 10 3
H O [M ]
-
1
+
25
1
(
042, 919 cm . MS (EI, m/z): 273 (MH - H
c 6.3, CHCl ). Anal. Calcd for C16 : C, 66.04; H, 11.80.
Found: C, 66.02; H, 11.93.
2S )-[2-((2S )-Me t h oxym e t h oxyd od e cyloxy)e t h oxy-
2
O). [R]
D
) +9.8
3
34 4
H O
a n d
(5S)-3-[(2R)-2,3-Dih yd r oxyp r op yl]-5-m eth yl-5H-
(
fu r a n -2-on e (22). The mixture of compound 21 (0.182 g, 1.18
III
m eth yl]oxir a n e (3). To (R)-(-)-epichlorohydrin (0.36 g, 3.89
mmol) were added compound 6 (0.67 g, 2.31 mmol), 50% NaOH
aqueous solution (2 mL), and tetrabutylammonium hydrogen
sulfate (0.067 g) successively at rt. The resulting suspension
was stirred for 24 h at rt. The solution was diluted with 20
mL of ether, and the aqueous layer was extracted with ether
mmol) and (S,S)-Salen-Co (OAc) (3.92 mg, 0.0059 mmol, 0.5
mol %) was stirred at 4 °C, and water (11.68 µL, 0.649 mmol,
0.55 equiv) was slowly added by using a syringe over 1 h. After
addition, stirring was continued at 4 °C for 24 h. Flash
chromatography of the mixture afforded 5 as a yellow oil (78
mg, 43%) and diol 22 (100 mg, 50%). The following are the
1
(
3 × 10 mL). The combined organic layers were washed with
brine (3 × 15 mL), dried (Na SO ), and concentrated. Flash
chromatography of the residue afforded 3 as a colorless liquid
data for 5. H NMR (300 MHz, CDCl
3
): 7.26 (1H, dd, J ) 1.3,
2
4
3 Hz), 5.06 (1H, dq, J ) 1.6, 3.5 Hz), 3.17 (1H, m), 2.83 (1H,
dd, J ) 4.2 Hz), 2.66 (1H, m), 2.57 (1H, dd, J ) 2.5, 4.7 Hz),
2.42 (1H, m), 1.44 (3H, dd, J ) 1.7, 6.7 Hz) ppm. IR (neat):
1
(
0.70 g, 88%). H NMR (300 MHz, CDCl
.7 Hz), 4.67 (1H, d, J ) 6.7 Hz), 3.40-3.83 (9H, m), 3.39 (3H,
s), 3.17 (1H, m), 2.80 (1H, m), 2.62 (1H, m), 1.51 (2H, t, J )
.3 Hz), 1.26 (16H, br s), 0.88 (3H, t, J ) 6.6 Hz) ppm. IR
3
): δ 4.77 (1H, d, J )
-
1
6
2950, 2861, 1718, 1648, 1199, 1151, 737, 698 cm . MS (EI,
+
25
m/z): 155 (M + 1). [R]
D
3
) -2.1 (c 1.95, CHCl ). HPLC:
6
>99% de (a Chiracel AS column; UV detector 214 nm; eluent
i-PrOH/hexane (2:8); flow rate 0.7 mL/min). The following are
the data for 22. H NMR (300 MHz, CDCl
-1
(film): 2926, 2856, 1467, 1143, 1108, 1041, 918 cm . MS (ESI,
+
1
m/z): 364 (M + H
0.98. Found: C, 66.18; H, 10.50. [R]
P en t-4-en oic Acid Meth yl Ester (13). This compound was
2
O). Anal. Calcd for C19
H
38
O
5
: C, 65.90; H,
3
): 7.23 (1H, d, J )
2
5
1
D
) -8.1 (c 1.14, CHCl ).
3
1.1 Hz), 5.10 (1H, m), 3.93 (1H, m), 3.66 (1H, dd, J ) 11.3, 3.3
Hz), 3.52 (1H, dd, J ) 6, 11.3 Hz), 3.20 (1H, br s), 2.51 (2H,
m), 1.77(1H, br s), 1.45 (3H, d, J ) 6.9 Hz) ppm. IR (neat):
9
1
4
prepared as in the literature. H NMR (90 MHz, CCl ): 5.80
-
1
(
1H, m), 5.03 (2H, m), 3.75 (3H, s), 2.26-2.42 (4H, m) ppm.
3401, 2983, 2935, 1741, 1323, 1207, 1104, 1085, 1028 cm
.
-
1
+
IR (film): 2950, 1750, 1650, 1440, 1170 cm
.
MS (EI, m/z): 173 (M + 1). HRMS (EI, m/z): calcd for C
8
H
10
O
3
+
(
5S)-3-Allyl-5-m eth yl-5H-fu r a n -2-on e (11). To a solution
2
[M - H O] 154.0630, found 154.0613.
of diisopropylamine (7.1 mL, 0.051mol) in anhydrous THF (100
mL) was added n-BuLi (21.1 mL, 1.6 M in hexane, 0.034 mol)
at 0 °C, and the mixture was stirred for 30 min. After the
mixture was stirred for an additional 30 min at -78 °C,
anhydrous HMPA (11.3 mL, 0.065 mol) was added, and the
mixture was stirred for 30 min. A solution of 13 (3.85 g, 0.034
mol) in THF (20 mL) was injected into the above mixture. After
Com p ou n d 23. To a solution of 1,7-octadiyne 4 (1.53 g,
14.43 mmol) in THF (10 mL) was added n-butylithium in
hexane (2.0 M, 7.2 mL, 14.39 mmol) at -78 °C under a
nitrogen atmosphere. After the resulting solution was stirred
for 10 min, boron trifluoride etherate (1.824 mL, 14.39 mmol)
was added, and stirring was continued for 30 min at -78 °C.
Then a solution of 3 (1.66 g, 4.80 mmol) in THF (12 mL) was
added, and the resulting solution was stirred for 3 h at -78
3
0 min, a solution of O-THP-(S)-lactal (6.45 g, 0.041 mol) in
THF (30 mL) was introduced, and the reaction mixture was
°C. The reaction was quenched by addition of aqueous NH
Cl. The whole mixture was extracted with ethyl acetate (3 ×
15 mL). The organic layer was dried over Na SO and
4
-
stirred for 2 h at -78 °C. The mixture was quenched with
saturated aqueous NH
4
Cl and extracted with ether. The
2
4
organic layer was washed with brine and dried (Na
Removal of the solvents afforded a crude oil, which was treated
with 10% H SO (30 mL) in THF (100 mL) for 18 h at rt. The
reaction mixture was diluted with ether, washed with satu-
2
SO
4
).
concentrated. Flash chromatography of the residue afforded
23 as a yellow liquid (1.728 g, 80%). 1H NMR (300 MHz,
2
4
CDCl
3
): 4.79 (1H, d, J ) 6.9 Hz), 4.67 (1H, d, J ) 6.9 Hz),
3.89 (1H, m), 3.40-3.76 (9H, m), 3.33 (3H, s), 2.69 (1H, m),

3
408 J . Org. Chem., Vol. 67, No. 10, 2002
J iang et al.
2
.39 (2H, m), 2.21-2.19 (4H, m), 1.96 (1H, m), 1.43-1.83 (22H,
3-{(2R,13S)-2,13-Dih yd r oxy-14-[2-(2S)-h ydr oxydodecyl-
oxy]eth oxy}tetr a d ecyl}-5-m eth yl-5H-fu r a n -2-on e (2). To
a stirred solution of 25 (74 mg, 0.114 mmol) and p-toluene-
sulfonyl hydrazide (1.45 g, 7.84 mmol) in dimethoxyethane (15
mL) at reflux was added NaOAc (728 mg, 8.88 mmol) in water
m), 0.88 (3H, t, J ) 6.6 Hz) ppm. IR (neat): 3462, 3313, 2926,
2
-
1
856, 1465, 1144, 1106, 1040, 919 cm . MS (ESI, m/z): 470
+
25
(
M
+ H
Com p ou n d 24. To a solution of compound 23 (0.53 g, 1.17
mmol) and i-Pr NEt (2.35 mL, 13.5 mmol) in dry CH Cl (20
mL) was added MOMCl (1.016 mL, 13.5 mmol) slowly at 0
C. The reaction was stirred overnight at rt and quenched with
aqueous saturated NH Cl (3 mL). The mixture was extracted
2
O). [R]
D
) +6.25 (c 0.52, CHCl
3
).
2
2
2
(
12 mL) over 4 h. The mixture was then cooled to rt, poured
into water, and extracted with CH Cl
(3 × 10 mL). The
combined organic layers were dried over Na SO and concen-
trated. The residue was dissolved in dimethyl sulfide (9 mL).
To this solution at 0 °C was added BF ‚Et O (0.22 mL, 1.71
mmol). The reaction mixture was stirred at rt for 40 min and
quenched with saturated aqueous NaHCO at 0 °C. The
2
2
°
2
4
4
with ethyl acetate (3 × 30 mL). The organic layer was washed
with saturated brine, dried over sodium sulfate, and concen-
3
2
trated. Flash chromatography of the residue afforded 24 as a
yellow liquid (0.56 g, 97%). H NMR (300 MHz, CDCl
4
m), 2.45 (2H, m), 2.20 (4H, m), 1.96 (1H, m), 1.26-1.69 (22H,
m), 0.88 (3H, t, J ) 6.7 Hz) ppm. IR (film): 3316, 2927, 2857,
1
1
3
): 4.65-
3
.88 (4H, m), 3.84 (1H, m), 3.56-3.72 (10H, m), 3.50-3.54 (6H,
mixture was extracted with ethyl acetate (3 × 15 mL), and
the extracts were washed with brine, dried over Na SO , and
2
4
concentrated under reduced pressure. The residue was purified
-
1
+
466, 1151, 1107, 1041, 919 cm . MS (ESI, m/z): 519 (M +
by column chromatography to afford 2 (47 mg, 72%) as a waxy
2
5
Na). [R]
D
) -1.8 (c 1.83, CHCl
3
). Anal. Calcd for C29
H
52
O
6
:
1
solid. H NMR (400 MHz, CDCl
3
): 7.18 (1H, d, J ) 1.0 Hz),
C, 70.12; H, 10.55. Found: C, 70.08; H, 10.52.
5
.05 (1H, qd, J ) 1.3, 6.8 Hz), 3.77-3.81 (4H, m), 3.63-3.71
Com p ou n d 25. To a solution of 24 (374 mg, 0.75 mmol) in
THF (3 mL) was added n-butyllithium in hexanes (1.6 M, 0.47
mL, 0.75 mmol) at -78 °C under a nitrogen atmosphere, and
the resulting solution was stirred for 30 min. Boron trifluoride
etherate (0.095 mL, 0.75 mmol) was then added, and stirring
was continued for 15 min at -78 °C, after which a solution of
(5H, m), 3.54 (2H, dd, J ) 2.7, 9.8 Hz), 3.32 (3H, m), 2.53 (2H,
dt, J ) 1.7, 16.0 Hz), 2.40 (2H, dd, J ) 8.2, 15.2 Hz), 2.28 (2H,
m), 2.04 (1H, m), 1.42 (3H, d, J ) 5.9 Hz), 1.26-1.60 (30H,
m), 0.88 (3H, t, J ) 6.8 Hz) ppm. 13C NMR (400 MHz, CDCl
):
3
171.2, 151.9, 131.3, 78.1, 75.9, 70.6, 70.3, 70.1, 60.5, 37.5, 33.4,
33.1, 29.8, 29.6, 29.4, 25.6, 22.8, 21.1, 19.2, 14.3, 14.2 ppm. IR
5
(58 mg, 0.38 mmol) in THF (2 mL) was added. After being
stirred for 2 h at -78 °C, the reaction was quenched by
addition of aqueous NH Cl (1.0 mL). The whole mixture was
extracted with ethyl acetate (3 × 10 mL). The organic layer
was dried over Na SO and concentrated. Flash chromatog-
raphy of the residue afforded 25 as an oil (168 mg, 69%). H
NMR (600 MHz, CDCl ): 7.24 (1H, d, J ) 1.4 Hz), 5.06 (1H,
q, J ) 3.3 Hz), 4.76 (1H, d, J ) 7.2 Hz), 4.73 (2H, br s), 4.66
1H, d,J ) 6.6 Hz), 3.98 (1H, m), 3.83 (1H, m), 3.61-3.71 (7H,
m) 3.51 (2H, m), 3.36-3.39 (6H, m) 2.60 (1H, m), 2.35-2.53
5H,m), 2.18-2.20 (4H, m), 1.57-1.60 (4H, m), 1.52 (2H, m),
-
1
(film): 3500, 2919, 2850, 1751, 1470, 1156, 1028, 720 cm
.
+
+
25
4
MS (ESI, m/z): 571 (M + 1), 593 (M + Na). [R]
) +6.6 (c
[M + H]
D
+
0
.63, CHCl
3
). HRMS (ESI, m/z): calcd for C33
H
63
O
7
2
4
5
71.4562, found 571.4567.
1
3
Ack n ow led gm en t. The Major State Basic Research
and Development Program (Grant G2000077500), NSFC
Grant 29790126), the Chinese Academy of Sciences,
(
(
(
1
7
9
7
2
2
6
.43 (3H, d, J ) 6.6 Hz), 1.26-1.41 (16H, m), 0.88 (3H, t, J )
and the Shanghai Commission of Science and Technol-
ogy are appreciated for financial support.
1
3
3
.2 Hz) ppm. C NMR (600 MHz, CDCl ): 174.3, 152.0, 130.7,
6.1, 95.9, 83.2, 81.4, 80.0, 76.6, 76.3, 75.8, 74.9, 74.2, 72.9,
0.9, 70.7, 55.5, 32.1, 31.9, 29.8, 29.6, 29.3, 28.1, 28.0, 27.6,
5.5, 22.7, 22.2, 19.1, 18.3, 14.1 ppm. IR (neat): 3463, 2927,
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
-
1
856, 1757, 1320, 1151, 1104, 1040, 919 cm . MS (ESI, m/z):
13
2
, 3, 8, and 25 and C NMR spectra for 2 and 25. This material
+
+
25
68 (M + H
2
O), 673 (M + Na). [R]
D
) +0.1 (c 1.61, CHCl
3
).
is available free of charge via the Internet at http://pubs.acs.org.
Anal. Calcd for C37
H, 9.41.
62 9
H O : C, 68.28; H, 9.60. Found: C, 68.23;
J O016396U