Syntheses and cytotoxicities of four stereoisomers of muricatacin from D-glucose

Article abstract of DOI:10.1016/S0968-0896(98)00062-5

Four stereoisomers of muricatacin 1a-d were prepared by the reaction of corresponding aldehydes 4a-d, which in turn were prepared from d-glucose, with the anion of triethylphosphonoacetate followed by reduction and cyclization under acidic conditions. Cytotoxicities of four stereoisomers were tested against in vitro A-549 cell line as well as MCF-7 cell line. Stereochemistry at C₄ and C₅ position of muricatacin did not affect the cytotoxicities significantly. Copyright (C) 1998 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(98)00062-5

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 1043±1049
Syntheses and Cytotoxicities of Four Stereoisomers of
Muricatacin from D-Glucose
Sung-Hwa Yoon,a,* Ho-Sang Moon,a Sung-Kwan Hwang,a
SeungRyong Choia and Suk-Ku Kangb
aDepartment of Applied Chemistry, Ajou University, Suwon, 442-749 Korea
bDepartment of Chemistry, SungKyunKwan University, Suwon, 441-380 Korea
Received 28 January 1998; accepted 17 March 1998
AbstractÐFour stereoisomers of muricatacin 1a±d were prepared by the reaction of corresponding aldehydes 4a±d,
which in turn were prepared from d-glucose, with the anion of triethylphosphonoacetate followed by reduction and
cyclization under acidic conditions. Cytotoxicities of four stereoisomers were tested against in vitro A-549 cell line
as well as MCF-7 cell line. Stereochemistry at C4 and C5 position of muricatacin did not a€ect the cytotoxicities
signi®cantly. # 1998 Elsevier Science Ltd. All rights reserved.
Introduction
to prepare four stereoisomers of muricatacin to under-
stand the e€ect of stereochemistry at C4 and C5 position
of muricatacin on cytotoxicity. Here, we report a
stereocontrolled synthesis of four enantiomerically pure
stereoisomers of muricatacin, ( )-(4R,5R), (+)-(4S,5R),
( )-(4R,5S), and (+)-(4S,5S)-enantiomers from d-glu-
cose, as well as their cytotoxicities.
Muricatacin (1), an acetogenin derivative, which is iso-
lated from the seeds of the tropical fruit Annona muri-
cata L., has received a great deal of attention because it
shows some cytotoxicities against human tumor cell
lines and its congeners show a wide range of biological
activities.1 The natural muricatacin is comprised of
( )-(4R,5R)-5-hydroxyheptadeca-4-nolide and its (+)-
(4S,5S) enantiomer, with the former predominating.
(+)-Muricatacin and/or ( )-muricatacin was recently
synthesized from various starting materials.2
Results and Discussion
Synthesis
According to Scheme 1, the synthesis of ( )-(4R,5R)-
muricatacin (1a) started from 5,6-dideoxy-1,2-iso-
propylidene-5-C-(n-undecanyl)-a-d-glucofuranose
(2)
which was available from d-glucose in four steps.3±6
Monoprotection of 2 with benzyl chloride in tetra-
hydrofuran (THF) using NaH as a base, followed by
removal of the isopropylidene group with 9.6 N HCl,
a€orded 1,2-diol compound 3. Oxidative cleavage of 3
with sodium periodate gave (2S,3R)-O-protected 2,3-
dihydroxy aldehyde 4a. Horner±Emmons ole®nation of
the aldehyde 4a with the anion of triethylphosphono-
acetate gave (E)-unsaturated ester 5a in 73% yield.
Hydrogenation of 5a in the presence of 10% Pd-C
under 1 atm of hydrogen followed by treatment of
In connection with our projects to explore the structure-
activity relationship of acetogenin derivatives, we needed
Key words: Muricatacin; stereoisomer; g-lactone; cytotoxicity.
*Corresponding author: Tel: 331-219-2515; Fax: 331-214-8918;
E-mail: shyoon@madang.ajou.ac.kr
0968-0896/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00062-5

1044
S.-H. Yoon et al./Bioorg. Med. Chem. 6 (1998) 1043±1049
Scheme 1. Preparation of muricatacin 1a±d. (a) See reference7; (b) NaH, BnCl, THF, rt, 5h; (c) 9,6 N HCl/TFA, DME, rt, 48h; (d)
NaIO4, MeOH, rt, 1h; (e) NaH, (EtO)2POCH2CO2Et, THF, rt 3h; (f) H2, Pd-C, EtOAc, rt, 24h; (g) TFA-H2O (4:1), rt, 3h; (h)
DMSO, (COCl)2, Et3N, CH2Cl2, 60 ꢀC!rt, 2h; (i) NaBH4, MeOH, rt; (j) Tf2O, pyridine, CH2Cl2, 10 ꢀC; (k) DBU, ether, rt; (l)
Sia2BH, THF, 0 ꢀC!rt, then H2O2, aq. NaOH.
tri¯uoroacetic acid a€orded ( )-(4R,5R)-muricatacin
(1a) in 45% overall yield from 4a.7 Therefore, in order
to synthesize the remained three stereoisomers of ( )-
(4R,SR)-murcatacin, we ®rst needed to prepare the
appropriately stereocontrolled 0-protected 2,3-dihy-
droxy aldehydes 4b-4d.
provide the hemiacetal, which was subjected to the oxi-
dative cleavage with sodium periodate to give the
(2R,3R)-2-benzyloxy-3-formyloxy-1-pentadecanal 4b.
The synthesis of (2S,3S)-O-protected 2,3-dihydroxy
aldehyde 4c was ®rst undertaken by changing the C4 b-
oriented dodecyl group in 2 into a-oriented one. For
this purpose, dodeca-3-enofuranose 8 was prepared
by the elimination reaction of the tri¯ate derived
from the O-tri¯ation of the C3 hydroxyfuranose 2
with tri¯uoromethanesulfonic anhydride in pyridine.10
Hydroboration11 of 8 with disiamylborane followed by
oxidation with H2O2/NaOH a€orded the 3-hydroxyl-b-
l-xylofuranose 9 exclusively with 60% yield after
separation by silica gel column (230±400 mesh) chro-
matography. After preparation of 9, the same reaction
conditions for the synthesis of 4a from 2 were used to
convert 9 into 4c.
The corresponding (2R,3R)-O-protected 2,3-dihydroxy
aldehyde 4b required for the synthesis of (4S,5R)-mur-
icatacin 1b was prepared from the C-3 unprotected
furanose 2. In order to introduce S con®guration at C3
position, the C3 b-hydroxyl group in 2 was oxidized to
the ketone 6 under Swern oxidation condition,8 and 6
was subsequently reduced with NaBH4 in MeOH at
room temperature9 to a€ord the C3 a-hydroxyl com-
pound 7 as the sole isolated product. After protection of
the hydroxy group in 7 with benzyl group, the iso-
propylidene group was removed with 9.6 N HCl/TFA to

S.-H. Yoon et al./Bioorg. Med. Chem. 6 (1998) 1043±1049
1045
Table 1. In vitro inhibition of A-549 and MCF-7 cell lines
50 MHz. Chemical shifts were given in relative tetra-
methylsilane. Infrared spectra were recorded on a
Nicolet FT-IR 550 spectrometer. GC-Mass spectro-
scopy was carried out on a Hewlett Packard (5972 ser-
ies) instrument. Elemental analyses were performed by
Fisons Eager 200 instrument, Italy. Flash column
chromatography was done by using Merck silica gel 60
(15±40 mm). Following abbreviations are used for
reagent and solvents: DBU (1,8-diazabicyclo[5,4,0]
undec-7-ene), DME (1,2-dimethoxyethane), DMSO
(dimethyl sulfoxide), THF (tetrahydrofuran).
Compd
IC50 (mg/mL)
MCF-7
A-549
1a
1b
1c
1d
18.5
29.8
23.7
24.3
17.6
16.7
22.2
15.9
Similar approaches were used to prepare the (2R,3S)-O-
protected 2,3-dihydroxy aldehyde 4d. Thus, after the C3
a-oriented compound 10 was prepared from 9 posses-
sing the C3 b-hydroxyl group by the use of the methods
applied in the synthesis of 7 from 2, it was subsequently
converted into 4d by the same reaction sequences
described for the synthesis of 4b from 7. Finally, the
three remaining (+)-(4S,5R), ( )-(4R,5S) and (+)-
(4S,5S)-enantiomers 1b±d were synthesized from 4b, 4c,
and 4d, respectively, by the methods for the synthesis of
( )-(4R,5R) muricatacin (1a) from 4a.
5,6-Dideoxy-1,2-isopropylidene-5-C-(n-undecanyl)-ꢀ-D-
glucofuranose (2). This was prepared from d-glucose
according to the procedure reported by S-K Kang et al.7
White solid; mp 76±77 ꢀC; [a]20d= 24.8ꢀ (c=10.0,
CHCl3); 1H NMR (CDCl3) d 0.87 (t, 3H, J=6.7 Hz,
CH3), 1.02±1.45 (m, 22H, (CH2)11 ), 1.32 (s, 3H
acetonide), 1.63 (s, 3H, acetonide), 2.02 (d, 1H J=6.2 Hz,
OH), 4.01±4.12 (m, 2H, C3-H and C4-H), 4.52 (d, 1H,
J=3.8 Hz, C2-H), 5.86 (d, 1H, J=3.8 Hz, C1-H); 13C
NMR (CDCl3) d 4.1, 22.7, 26.1, 26.6, 29.3, 30.7, 31.9,
75.4 (C4), 80.3 (C2), 85.3 (C3), 104.2 (C1), 111.4 (C7).
Cytotoxicities
3-O-Benzyl-5,6-dideoxy-1,2-O-dihydroxy-5-C-(n-undec-
anyl)-ꢀ-D-glucofuranose (3). To a suspension of NaH
(610 mg of 95% powder, 25.4 mmol) in anhydrous
DMSO (30 mL) was added 2 (5.1 g, 19.6 mmol) in anhy-
drous THF (150 mL) under a nitrogen atmosphere. After
the mixture was stirred for 30 min at room temperature,
benzyl chloride (3.2 g, 25.4 mmol) was added. The reac-
tion mixture was stirred for 5 h at room temperature
and then quenched with saturated aqueous NH4Cl
solution (50 mL). The organic solvent was removed and
the aqueous solution was extracted with CH2Cl2
(50 mLÂ3). The organic layer was dried (Na2SO4), ®l-
tered, and concentrated. The crude product was chro-
matographed on a silica gel column (hexane:ethyl
acetate=1:1) to give a 3-O-benzyl-1,2,5,6-diisopropyl-
The cytotoxicities of 1a±d were tested against in vitro A-
549 cell line as well as MCF-7 cell line by measuring the
inhibition of cell growth.12 As shown in Table 1, the
four stereoisomers generally exhibited weak and similar
inhibition in both cell lines. Although (4R,5R)-com-
pound 1a showed a slightly higher cell growth inhibition
in A-549 cell line compared to the rest of the stereo-
isomers, the di€erence was minimal. This indicates that
the stereochemistry at C4 and C5 position of muri-
catacin might not a€ect the cytotoxicities signi®cantly.
Conclusion
In conclusion, we have established ecient methods for
the syntheses of four stereoisomers 1a-1d of muricatacin
(1) from d-glucose and found that the stereochemistry
at C4 and C5 position of muricatacin did not a€ect the
cytotoxicities signi®cantly.
idene-a-d-glucofuranose (7.3 g, 96%) as slightly yellow
oil: IR (neat) 3060, 3040, 2980, 2890 cm
1
;
1H NMR
(CDCl3) d 0.88 (t, 3H, J=6.6 Hz, CH3), 1.12±1.48 (m
22H, ±(CH2)11±), 1.31 (s, 3H, acetonide), 1.63 (s, 3H,
acetonide), 3.75 (d, 1H, J=3.0 Hz, C3-H), 4.05±4.18 (m,
1H, C4-H), 4.43±4.72 (m, 3H, OCH2 and C2-H), 5.90
(d, 1H, J=3.9 Hz, C1-H), 7.32 (m, 5H, phenyl). To a
solution of 3-O-benzylated compound (6.3 g, 15.1 mmol)
in DME (20 mL) was slowly added dropwise 9.6N HCl
(10 mL). The reaction mixture was stirred for 48 h at
room temperature and then neutralized with saturated
aqueous NaHCO3 solution. After the evaporation of
DME, the aqueous layer was extracted with CH2Cl2
(30 mLÂ3). The organic layer was dried (Na2SO4), ®ltered,
and concentrated. The residue was chromatographed on
a silica gel column (hexane:ethyl acetate=1:2) to give 3
(3.8 g, 67%) as a white solid mp 52±53 ꢀC; IR (neat)
Experimental
Chemistry
Melting points were determined on a Fisher±Johns
melting point apparatus and are uncorrected. Optical
rotations were determined at a sodium D line using a
JasCo 370-DIP polarimeter and measured in chloro-
form. 1H NMR and 13C NMR spectra were recorded on
a Varian Gemini 200 spectrometer at 200 MHz and

1046
S.-H. Yoon et al./Bioorg. Med. Chem. 6 (1998) 1043±1049
1
3550, 2990, 2850, 1100 cm 1; H NMR (CDCl3) d 0.86
(t, 3H, J=6.6 Hz, CH3), 1.14±1.58 (m, 22H, (CH2)11-),
1.63 (m, 1H, OH), 3.8 (m, 1H, C3-H), 4.23 (m, 2H, C2-H
& C4-H) 4.53±4.75 (dd, 2H, J=11.9, 49.9 Hz, OCH2),
5.45 (d, 1H, J=4.1 Hz, C1-H), 7.32 (s, 5H, -phenyl).
under an atmosphere of hydrogen for 24 h at room
temperature. The catalyst was ®ltered and the ®ltrate
was concentrated to give the corresponding saturated
ester as a white solid. The ester was dissolved in H2O-
tri¯uoroacetic acid (4:1) (100 mL) and the resulting
solution was stirred for 3 h at room temperature. After
the solution was neutralized with saturated aqueous
NaHCO3 solution, the neutralized aqueous layer was
extracted with chloroform (30 mLÂ3). The organic layer
was dried (Na2SO4), ®ltered, and concentrated. The
residue was chromatographed on a silica gel column
(hexane:ethyl acetate=1:2) to give the product, which
was recrystallized from hexane-ethyl acetate (10:1) to
give 1a (500 mg, 61%) as a white solid: mp 71±72 ꢀC,
lit.2c 73±74 ꢀC, lit.1 50 ꢀC, lit.2f 72 ꢀC, [a]20d= 11.62ꢀ
(c=11.7, CHCl3), lit.2c 23.14ꢀ (c=2.36, CHCl3), lit.2a
22.9ꢀ (c=1.1, CHCl3); IR (KBr) 3400 (-OH), 2960,
(2S,3R)-2-Benzyloxy-3-formyloxy-1-pentadecanal (4a).
To a solution of 3 (3.7 g, 9.8 mmol) in MeOH (200 mL)
was added 0.6N NaIO4 solution (250 mL). The reaction
mixture was stirred for 1 h at room temperature and
then concentrated. After the reaction mixture was diluted
with H2O (50 mL), it was extracted with CH2Cl2
(30 mLÂ3). The organic layer was dried (Na2SO4), ®ltered,
and concentrated. The residue was chromatographed on
a silica gel column (hexane:ethyl acetate=1:2) to give 4a
(2.7 g, 73%) as a white solid: mp 30±31 ꢀC, [a]20
d
=11.62ꢀ (c=11.7, CHCl3); IR (neat) 3050, 2935, 2850,
1737, 1713, 1173 cm 1; 1H NMR (CDCl3) d 0.90 (t, 3H,
J=6.6 Hz, ±CH3), 1.32 (s, 20H, ±(CH2)10±), 1.69 (m, 2H,
±CH2), 3.88 (dd, 1H, J=0.9, 3.1 Hz, C2-H), 4.55±4.86
(dd, 2H, J=11.9, 49.7 Hz, ±OCH2), 5.28 (m, 1H, C3-H),
7.34 (s, 5H,-phenyl), 8.05 (s, 1H, ±OCHO), 9.66 (d, 1H,
J=1.0 Hz, ±CHO); 13C NMR (CDCl3) d 15.5, 24.0,
26.5, 30.5, 31.3, 33.3, 73.8 (C3), 74.8 (±OCH2), 84.1 (C2),
129.4, 129.5, 129.9, 137.9, 161.6 (±OCHO), 202.4 (±CHO).
1
2920, 1753 (C=O) cm 1; H NMR (CDCl3) d 0.91 (t,
3H, J=6.8 Hz, ±CH3), 1.25±1.56 (s, 22H, ±(CH2)11±),
2.08 (s, 1H, ±OH), 2.12±2.48 (m, 2H, C3-H), 2.61 (m,
2H, C2-H), 3.56 (m, 1H, C5-H), 4.43 (ddd, 1H, J=3.2,
7.3, 10.6 Hz, C4-H); 13C NMR (CDCl3) d 13.9, 22.5,
23.9, 25.3, 28.5, 29.2, 29.3, 31.7, 73.5 (C5), 82.78 (C4),
177.05 (C1); Mass (m/e) 285 (MH+), 267, 199, 180, 97,
86 (base peak); Anal. calcd for C17H32O3: C, 71.79; H,
11.34. Found: C, 71.84; H, 11.48.
Ethyl (4R,5R)-4-benzyloxy-5-hydroxy-(2E)-heptadecan-
oate (5a). To a suspension of NaH (250 mg of 95%
powder, 10.4 mmol) in anhydrous THF (10 mL) was
slowly added a solution of triethyl phosphonoacetate
(1.9 g, 8.5 mmol) in anhydrous THF (5 mL). The reaction
mixture was stirred for 30 min at 0 ꢀC, and compound
4a (2.5 g, 6.6 mmol) in THF (10 mL) was slowly added
to this mixture. The reaction mixture was stirred for 3 h
at room temperature under a nitrogen atmosphere and
then quenched with NH4Cl solution (30 mL). After the
organic solvent was removed, the aqueous layer was
extracted with CH2Cl2 (50 mLÂ3). The combined
organic layer was dried (Na2SO4), ®ltered, and con-
centrated. The residue was chromatographed on a silica
gel column (hexane:ethyl acetate=1:1) to give 5a (2.0 g,
73%) as a slightly yellow oil: IR (neat) 3480 (±OH),
3040, 2930, 2860, 1730 (C=O) cm 1; 1H NMR (CDCl3)
d 0.91 (t, 3H, J=6.8 Hz, ±CH3), 1.25±1.58 (m, 25H,
±(CH2)11± and ±CH3), 2.62 (d, 1H, J=3.1 Hz, ±OH),
3.68 (m, 1H, C5-H), 3.83 (m, 1H, C4-H), 4.23 (q, 2H,
J=4.6 Hz, ±CO2CH2±), 4.32±4.69 (dd, 2H, J=11.8,
50.1 Hz, ±OCH2), 6.13 (d, 1H, J=14.6 Hz, C2-H), 6.87
(dd, 1H, J=14.6, 6.7 Hz, C3-H), 7.33 (s, 5H, ±phenyl);
13C NMR (CDCl3) d 14.1, 22.6, 25.5, 29.3, 29.5, 31.8,
32.6, 51.7, 71.4 (C5), 73.3 (±OCH2), 81.9 (C4), 124.0
(C2), 127.9, 128.0, 128.5, 137.4, 144.8 (C3), 166.3.
5,6-Dideoxy-1,2-isopropylidene-3-carbonyl-5-C-(n-undec-
anyl)-ꢀ-D-allofuranose (6). A solution of oxaloyl chlor-
ide (0.26 mL, 3.1 mmol) and DMSO (3 mL) in CH2Cl2
(25 mL) was stirred for 15 min at 60 ꢀC under a nitro-
gen atmosphere. To this solution was added 2 (640 mg,
2.0 mmol) in CH2Cl2 (15 mL). After the reaction mixture
was stirred for 50 min at 60 ꢀC, Et3N (5 mL) was added
and the resulting mixture was stirred for 2 h at room
temperature. The reaction mixture was diluted with
H2O (20 mL) and then extracted with CH2Cl2 (30 mLÂ3).
The organic layer was dried (Na2SO4), ®ltered, and
concentrated. The residue was chromatographed on a
silica gel column (hexane:ethyl acetate=1:1) to give 6
(530 mg, 82%) as a white solid: mp 66±67 ꢀC; IR (KBr)
2960, 2890, 1820 (C=O) cm 1; 1H NMR (CDCl3) d 0.86
(t, 3H, J=6.6 Hz, ±CH3), 1.02±1.45 (s, 22H, (CH2)11±),
1.38 (s, 3H, acetonide), 1.50 (s, 3H, acetonide), 4.32 (m,
2H, C2-H and C4-H), 5.86 (d, 1H, J=4.1 Hz, C1-H).
5,6-Dideoxy-1,2-isopropylidene-5-C-(n-undecanyl)-ꢀ-D-
allofuranose (7). To a solution of 6 (430 mg, 1.3 mmol)
in MeOH (150 mL) was added NaBH4 (250 mg,
6.7 mmol) at 0 ꢀC. The reaction mixture was stirred for
12 h at room temperature. After the evaporation of
methanol, the reaction mixture was diluted with water
(50 mL) and then extracted with CH2Cl2 (30 mLÂ3).
The organic layer was dried (Na2SO4), ®ltered, and
concentrated. The residue was chromatographed on a
silica gel column (hexane:ethyl acetate=1:1) to give 7
( )-(4R,5R)-5-Hydroxyheptadeca-4-nolide (1a). In the
presence of 10% Pd-C (500 mg), a solution of 5a (1.2 g,
2.9 mmol) in ethyl acetate (100 mL) was hydrogenated

S.-H. Yoon et al./Bioorg. Med. Chem. 6 (1998) 1043±1049
1047
(410 mg, 96%) as
a
white solid: mp 81±82 ꢀC,
1H, C5-H), 4.55 (ddd, 1H, J=3.2, 7.3, 10.6 Hz, C4-H);
13C NMR (CDCl3) d 13.9, 21.8, 23.1, 25.9, 28.5, 29.2,
29.5, 31.9, 71.9 (C5), 82.5 (C4), 177.1 (C1); Mass (m/e)
285 (MH+), 266, 199, 111, 86 (base peak); Anal. Calcd
for C17H32O3: C, 71.79; H, 11.34. Found: C, 71.53; H,
11.58.
[a]20d=+46.4ꢀ (c=10.0, CHCl3); IR (KBr) 3480 ( OH),
1
2960, 2880 cm
;
1H NMR (CDCl3) d 0.91 (t, 3H,
J=6.9 Hz, ±CH3), 1.21±1.52 (m, 22H, ±(CH2)11±), 1.31
(s, 3H, acetonide), 1.62 (s, 3H, acetonide), 2.32 (d, 1H,
J=7.9 Hz, ±OH), 3.52±3.82 (m, 2H, C3-H and C4-H),
4.5 (t, 1H, J=4.1 Hz, C2-H), 5.79 (d, 1H, J=4.0 Hz, C1-
H); 13C NMR (CDCl3) d 14.1, 22.7, 25.7, 29.3, 29.7,
31.9, 75.4 (C4), 80.3 (C2), 85.3 (C3), 104.2 (C1), 111.4
(C7).
3,5,6-Trideoxy-1,2-O-isopropylidene-ꢀ-D-erythro-dode-3-
cenofuranose (8). To a solution of 2 (3.5 g, 7.0 mmol) in
CH2Cl2 (100 mL) was added pyridine (2 mL). After the
solution was stirred for 30 min at
10 ꢀC, tri-
(2R,3R)-2-Benzyloxy-3-formyloxy-1-pentadecanal (4b). 7
(400 mg, 1.2 mmol) was subjected to the same sequence
of the reactions as described for the synthesis of 4a from
2. Benzylation of 7 (480 mg, 96%), followed by the
cleavage of the isopropylidene group, gave the 1,2-diol
compound (280 mg, 65%): IR (neat) 3500, 2950, 2850,
¯uoromethanesulfonic anhydride (3.9 g, 13.9 mmol) was
carefully added. The reaction mixture was stirred for 1 h
at 10 ꢀC under a nitrogen atmosphere and then diluted
with ether (100 mL) to give a white precipitate. After
®ltration of the precipitate, the ®ltrate was successively
washed with H2O, 5% HCl, saturated aqueous
NaHCO3 solution, and saturated aqueous NH4Cl solu-
tion. The organic layer was dried (Na2SO4), ®ltered, and
concentrated. The residue was chromatographed on a
silica gel column (hexane:ethyl acetate=1:2) to give the
tri¯ated compound (5.1 g, 94%) as a slightly yellow oil.
1
1100 cm 1; H NMR (CDCl3) d 0.86 (t, 3H, J=6.6 Hz,
±CH3), 1.13±1.58 (m, 22H, ±(CH2)11±), 1.72 (m, 1H,
±OH), 3.56 (m, 1H, C3-H), 3.95±4.20 (m, 2H, C2-H and
C4-H), 4.65 (s, 2H, ±OCH2), 5.25 (m, 1H, C1-H), 7.34 (s,
5H, -phenyl). Oxidative cleavage reaction of the 1,2-O-
diol compound gave 4b (250 mg, 55%) as a slightly yel-
low oil: [a]20d=+29.9ꢀ (c=11.9, CHCl3); IR (neat)
3050, 2960, 2850, 1760, 1480 cm 1; 1H NMR (CDCl3) d
0.92 (t, 3H, J=6.9 Hz, ±CH3), 1.32 (s, 20H, ±(CH2)10±),
1.65 (m, 2H, ±CH2), 3.87 (dd, 1H, J=1.9, 3.4 Hz, C2-H),
4.68 (s, 2H, ±OCH2), 5.38 (m, 1H, C3-H), 7.33 (s, 5H,
±phenyl), 8.07 (s, 1H, ±OCHO), 9.65 (d, 1H, J=2.0 Hz,
±CHO); 13C NMR (CDCl3) d 15.4, 24,0, 26.6, 30.7, 31.0,
33.2 (C3), 74.3 (±OCH2), 84.9 (C2), 129.3, 129.5, 129.9,
138.0, 161.6 (±OCHO), 202.3 (±CHO).
To
a solution of the tri¯ated compound (5.1 g,
10.2 mmol) in ether (100 mL) was added DBU (6.8 g,
45.3 mmol). After the reaction mixture was stirred for
24 h at room temperature under a nitrogen atmosphere,
it was washed with H2O and brine. The organic layer
was dried (Na2SO4), ®ltered, and concentrated. The
residue was chromatographed on a silica gel column
(hexane:ethyl acetate=2:3) to give 7 (2.6 g, 76%) as a
slightly yellow oil: IR (neat) 2960, 2930, 2852, 1667,
1
1382 cm 1; H NMR (CDCl3) d 0.91 (t, 3H, J=6.7 Hz,
±CH3), 1.22±1.54 (s, 20H, ±(CH2)10±), 1.37 (s, 3H, acet-
onide), 1.55 (s, 3H, acetonide), 2.12 (t, 2H, J=7.5 Hz,
±CH2), 4.89 (t, 1H, J=2.3 Hz, C2-H), 5.25 (m, 1H, C3-
H), 6.01 (d, 1H, J=5.3 Hz, C1-H).
Ethyl (4S,5R)-4-benzyloxy-5-hydroxy-(2E)-heptadecan-
oate (5b). 4b (250 mg, 0.66 mmol) was subjected to the
same reaction described for the synthesis of 5a. 5b
(186 mg, 68%) was obtained as a slightly yellow oil: IR
1
(neat) 3420 (±OH), 3050, 2920, 2860, 1730 (C=O) cm
;
5,6-Dideoxy-1,2-isopropylidene-5-C-(n-undecanyl)-ꢀ-D-
galactofuranose (9). To a solution of 2-methyl-2-butene
(5.5 mL, 5.02 mmol) in anhydrous THF (5 mL) was
added dropwise borane-disul®de complex (1.25 mL of
2.0 M solution in THF, 2.5 mmol) with a syringe under
a nitrogen atmosphere at 0 ꢀC. After the mixture was
stirred for 2 h at 0 ꢀC, the solution of 8 (390 mg,
1.3 mmol) in THF (20 mL) was added dropwise to the
mixture. The reaction mixture was stirred for 24 h at
room temperature and then H2O2 (0.42 mL, 4.0 mmol)
was carefully added at 0 ꢀC. The reaction mixture was
stirred for 24 h again at room temperature and then
quenched with sodium sul®te. The reaction mixture was
®ltered and the organic solvent was removed. The aqu-
eous layer was extracted with ether (3Â20 mL). The
etherate was dried (Na2SO4), ®ltered, and concentrated.
The residue was chromatographed on a silica gel col-
umn (hexane:ethyl acetate=1:2) to give 8 (210 mg, 50%)
as a white solid: mp 52±53 ꢀC; [a]20d= 22.3ꢀ (c=6.9,
1H NMR (CDCl3) d 0.91 (t, 3H, J=6.8 Hz, ±CH3),
1.21±1.52 (m, 25H, ±(CH2)11± and ±CH3), 2.28 (m, 1H, ±
OH), 3.88 (m, 1H, C5-H), 3.95 (m, 1H, C4-H), 4.21 (q,
2H, J=4.5 Hz, ±CO2CH2±), 4.37±4.72 (dd, 2H, J=11.5,
49.7 Hz, ±OCH2), 6.11 (d, 1H, J=14.5 Hz, C2-H), 6.96
(dd, 1H, J=14.5, 6.8 Hz, C3-H), 7.35 (s, 5H, -phenyl);
13C NMR (CDCl3) d 15.5, 24.0, 27.1, 30.7, 30.9, 33.5,
55.0, 72.6 (C5), 74.5 (±OCH2), 82.7 (C4), 126.0 (C2),
129.0, 129.1, 129.8, 138.9, 145.3 (C3), 167.1.
(+)-(4S,5R)-5-Hydroxyheptadeca-4-nolide (1b). 5b (120 mg,
0.29 mmol) was subjected to the same reaction described
for the synthesis of 1a. 1b (48 mg, 59%) was obtained
as a white solid: mp 71.5 ꢀC; [a]20d=+14.3ꢀ (c=7.4,
CHCl3); IR (KBr) 3430 (±OH), 2960, 2920, 1780 (C=O)
1
cm
;
1H NMR (CDCl3) d 0.91 (t, 3H, J=6.8 Hz, ±
CH3), 1.23±1.55 (s, 22H, ±(CH2)11±), 1.92 (s, 1H, ±OH),
2.12±2.47 (m, 2H, C3-H), 2.59 (m, 2H, C2-H), 3.95 (m,

1048
S.-H. Yoon et al./Bioorg. Med. Chem. 6 (1998) 1043±1049
CHCl3); IR (KBr) 3430 (±OH), 2930, 2850 1464,
1
178.9 (C1); Anal. Calcd for C17H32O3: C, 71.79; H,
11.34. Found: C, 71.61; H, 11.43.
1379 cm 1; H NMR (CDCl3) d 0.91 (t, 3H, J=6.9 Hz,
±CH3), 1.22±1.51 (m, 22H, (CH2)11±), 1.33 (s, 3H, aceto-
nide), 1.62 (s, 3H, acetonide), 1.81 (d, 1H, J=4.4 Hz,
±OH), 3.92 (m, 1H, C4-H), 4.11 (dd, 1H, J=3.9, 7.9 Hz,
C3-H), 4.52 (d, 1H, J=3.9 Hz, C2-H), 5.91 (d, 1H,
J=3.9 Hz, C1-H); 13C NMR (CDCl3) d 14.3, 22.9, 26,2,
26.4, 27.1, 29.5, 29.6, 32.1, 33.9, 79.1 (C4), 87.6 (C2),
87.9 (C3), 105.5 (C1), 112.7 (C7).
5,6-Dideoxy-1,2-isopropylidene-5-C-(n-undecanyl)-ꢀ-D-
gulofuranose (10). 9 (400 mg 1.2 mmol) was subjected to
the same reaction described for the synthesis of 7. 10
(300 mg, 76%) was obtained as a white solid: mp 52 ꢀC;
[a]20d= 2.5ꢀ (c=0.65, CHCl3); IR (KBr) 3472 (±OH),
1
2930, 2850 1464, 1379 cm 1; H NMR (CDCl3) d 0.90
(t, 3H, J=6.8 Hz, ±CH3), 1.24±1.49 (m, 22H, ±(CH2)11±),
1.41 (s, 3H, acetonide), 1.62 (s, 3H, acetonide), 2.57 (d,
1H, J=7.4 Hz, ±OH), 3.86 (m, 1H, C4-H), 4.18 (dd, 1H,
J=5.7, 11.8 Hz, C3-H), 4.62 (dd, 1H, J=4.2, 5.9 Hz, C2-
H), 5.66 (d, 1H, J=4.2 Hz, C1-H); 13C NMR (CDCl3) d
14.1, 22.6, 26.1, 26.9, 29.1, 29.6, 32.9, 70.2 (C4), 80.2
(C2), 82.5 (C3), 101.5 (C1), 111.5 (C7).
(2S,3S)-2-Benzyloxy-3-formyloxy-1-pentadecanal (4c).
The same sequence of the reactions described for the
synthesis of 4b was applied. Benzylation of 9 (200 mg,
0.61 mmol) followed by the removal of the iso-
propylidene group gave the 1,2-O-diol compound
(130 mg, 62%) as a white solid: mp 53±54 ꢀC; IR (KBr)
1
3370, 3030, 29200, 2850, 1100 cm 1; H NMR (CDCl3)
d 0.88 (t, 3H, J=6.8 Hz, ±CH3), 1.12±1.57 (m, 22H,
±(CH2)11±), 1.62 (m, 1H, ±OH), 3.81 (m, 1H, C3-H), 4.21
(m, 2H, C4-H), 4.61±4.81 (m, 3H, ±OCH2 and C2-H),
5.31 (m, 1H, C1-H), 7.33 (s, 5H, phenyl). Oxidative
cleavage reaction of the 1,2-O-diol compound a€orded
4c (100 mg, 58%) as a slightly yellow oil: [a]20d= 24.3ꢀ
(2R,3S)-2-Benzyloxy-3-formyloxy-1-pentadecanal (4d).
The same sequence of the reactions described for the
synthesis of 4b was applied. Benzylation of 10 (300 mg,
0.91 mmol) followed by the removal of the iso-
propylidene group gave 1,2-O-diol compound (130 mg,
56%) as a white solid: IR (neat) 3350, 3060, 2920, 2850,
1
(c=39.1, CHCl3); IR (neat) 3050, 2960, 2830, 1780
1
1100 cm 1; H NMR (CDCl3) d 0.90 (t, 3H, J=6.8 Hz,
(C=O) cm
;
1H NMR (CDCl3) d 0.91 (t, 3H,
±CH3), 1.14±1.60 (m, 22H, ±(CH2)11±), 1.65 (m, 1H, ±OH),
3.91 (m, 1H, C3-H), 4.15 (m, 2H, C4-H), 4.61±4.83 (m,
3H, ±OCH2 and C2-H), 5.08 (m, 1H, C1-H), 7.33 (s, 5H,
-phenyl). Oxidative cleavage reaction of the 1,2-O-diol
compound a€orded 4d (160 mg, 47%) as a slightly yel-
low oil: [a]20d=+20.2ꢀ (c=10.0, CHCl3); IR (neat)
3050, 2920, 2846, 1739 (C=O) cm 1; 1H NMR (CDCl3)
d 0.92 (t, 3H, J=6.9 Hz, ±CH3), 1.25 (s, 20H, ±(CH2)10±),
1.75 (m, 2H, ±CH2), 3.88 (dd, 1H, J=1.6, 3.6 Hz, C2-H),
4.53±4.82 (dd, 2H, J=11.8, 49.6 Hz, ±OCH2), 5.28 (m,
1H, C3-H), 7.35 (s, 5H, -phenyl), 8.05 (s, 1H, ±OCHO),
9.66 (d, 1H, J=1.4 Hz, ±CHO); 13C NMR (CDCl3) d
20.9, 25.4, 29.5, 29.7, 30.3, 32.1, 72.7 (C3), 76.1 (±OCH2),
84.0 (C2), 128.5, 128.8, 129.0, 129.9, 160.3 (±OCHO),
201.2 (±CHO).
J=6.9 Hz, ±CH3), 1.26 (s, 20H, ±(CH2)10±), 1.68 (m,
2H, ±CH2), 3.88 (d, 1H, J=3.1 Hz, C2-H), 4,65 (s, 2H,
±OCH2), 5.39 (m, 1H, C3-H), 7.35 (s, 5H, -phenyl), 8.05
(s, 1H, ±OCHO), 9.66 (d, 1H, J=1.8 Hz, ±CHO); 13C
NMR (CDCl3) d 15.5, 24.1, 26.5, 30.7, 31.4, 33.3, 73.8
(C3), 74.8 (±OCH2), 84.1 (C2), 129.5, 129.7, 130.0, 13
7.9, 162.1 (±OCHO), 202.4 (±CHO).
Ethyl (4R,5S)-4-benzyloxy-5-hydroxy-(2E)-heptadecan-
oate (5c). 4c (300 mg, 0.91 mmol) was subjected to the
same reaction described for the synthesis of 5a. 5c
(240 mg, 63%) was obtained as a slightly yellow oil: IR
1
3470 ( OH), 3030, 2920, 2860, 1721 (C=O) cm 1; H
NMR (CDCl3) 0.89 (t, 3H, J=6.8 Hz, ±CH3), 1.21±1.52
(m, 25H, ±(CH2)11± and ±CH3), 2.11 (d, 1H, J=3.1 Hz,
±OH), 3.81 (m, 1H, C5-H), 3.93 (m, 1H, C4-H), 4.21 (q,
2H, J=4.6 Hz, ±CO2CH2±), 4.37±4.72 (dd, 2H, J=11.7,
50.3 Hz, ±OCH2), 6.08 (d, 1H, J=14.8 Hz, C2-H), 6.96
(dd, 1H, J=14.8, 6.9 Hz, C3-H), 7.36 (s, 5H, -phenyl).
Ethyl (4S,5S)-4-benzyloxy-5-hydroxy-(2E)-heptadecan-
oate (5d). 4d (200 mg, 0.53 mmol) was subjected to the
same reaction described for the synthesis of 5b. 5d
(140 mg, 62%) was obtained as a slightly yellow oil. IR
1
(neat) 3460 (±OH), 3070, 2920, 2860, 1721 (C=O) cm
;
( )-(4R,5S)-5-Hydroxyheptadeca-4-nolide (1c). 5c (240 mg,
0.57 mmol) was subjected to the same reaction described
for the synthesis of 1a from 5a. 1c (130 mg, 50%) was
obtained as a white solid: mp 70.5 ꢀC; [a]20d= 13.6ꢀ
1H NMR (CDCl3) d 0.89 (t, 3H, J=6.8 Hz, ±CH3),
1.21±1.52 (m, 25H, ±(CH2)11± and ±CH3), 2.52 (m,
1H, ±OH), 3.58 (m, 1H, C5-H), 3.81 (m, 1H, C4-H),
4.23 (q, 2H, J=4.6 Hz, ±CO2CH2±), 433±4.72 (dd, 2H,
J=11.9, 49.9 Hz, ±OCH2), 6.10 (d, 1H, J=14.8 Hz,
C2-H), 6.96 (dd, 1H, J=14.8, 6.8 Hz, C3-H), 7.36 (s, 5H,
-phenyl).
(c=5.0, CHCl3); IR (KBr) 3430 (±OH), 2960, 2920,
1
1780 (C=O) cm
;
1H NMR (CDCl3) d 0.90 (t,
3H, J=6.9 Hz, ±CH3), 1.22±1.51 (s, 22H, ±(CH2)11±),
2.08 (s, 1H, ±OH), 2.10 2.45 (m, 2H, C3-H), 2.61 (m,
2H, C2-H), 3.94 (m, 1H, C5-H), 4.43 (ddd, 1H, J=3.0,
7.1, 10.1 Hz, C4-H); 13C NMR (CDCl3) d 15.5, 22.4,
24.0, 24.8, 26.6, 30.0, 30.7, 30.9, 72.7 (C5), 84.2 (C4),
(+)-(4S,5S)-5-Hydroxyheptadeca-4-nolide (1d). 5d (140 mg,
0.34 mmol) was subjected to the reaction described for
the synthesis of 1a. 1d (50 mg, 52%) was obtained as a

S.-H. Yoon et al./Bioorg. Med. Chem. 6 (1998) 1043±1049
1049
white solid: mp 72.0 ꢀC, lit.2c 73±74 ꢀC, lit.2a 65 ꢀC;
From succinic aldehyde derivative; Marshall, J. A.; Welmaker,
G. S. J. Org. Chem., 1994, 59, 4122. (c) From allyl alcohol
derivative; Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B.; Sinha,
S. C.; Sinha-Bagchi, A.; Keinan, E. Tetrahedron Lett., 1992, 32,
6407. (d) From 2,3-epoxyalcohol derivative; Bonini, C.; Feder-
rici, C.; Rossi, L.; Righi, G. J. Org. Chem., 1995, 60, 4803. (e)
From d-isoascorbic acid; Gravier-Pelletier, C.; Saniere, M.;
Charvet, I; Merrer, Y. L.; Depezay, J.-C. Tetrahedron Lett.,
1994, 35, 115. (f) From cyclooctyne and furan; Scholz, G.;
Tochtermann, W. Tetrahedron Lett., 1991, 32, 5535. (g) From
cyclooctyne and furan, Tochtermann, W.; Scholz, G.; Bunte,
G.; Wol€, C.; Peters, E.-V. Peters, K.; Schnering, H. G. Liebig.
Ann. Chem., 1992, 1069. (h) From 5-acyl-heptadecabutanolide;
Tam, V. T.; Chaboche, C.; Figadere, B.; Chappe, B.; Hieu, B.
C.; Cave, A. Tetrahedron Lett., 1994, 35, 883.
[a]20d=+16.9ꢀ (c=6.5, CHCl3), lit.2c+23.02ꢀ (c=1.26,
CHCl3), lit.2a +25ꢀ (c=1.7, MeOH); IR (KBr) 3390
1
(±OH), 2917, 2910, 1745 (C=O) cm
;
1H NMR
(CDCl3) d 0.90 (t, 3H, J=6.9 Hz, ±CH3), 1.20±1.51 (s,
22H, ±(CH2)11±), 1.82 (s, 1H, ±OH), 2.22 (m, 2H, C3-H),
2.51 (ddd, 2H, J=5.6, 10.1, 12.7 Hz, C2-H), 3.51 (m,
1H, C5-H), 4.44 (ddd, 1H, J=3.0, 7.0, 10.1 Hz, C4-H);
13C NMR (CDCl3) d 14.1, 22.7, 24.1, 25.5, 28.7, 29.4,
31.9, 33.0, 73.7 (C5), 82.9 (C4), 177.0 (C1); Anal. Calcd
for C17H32O3: C, 71.79; H, 11.34. Found: C, 71.57; H,
11.64.
Cytotoxicity assay
3. Nakata, T.; Fukui, M.; Oishi, T. Tetrahedron Lett., 1988, 29,
2219.
Cytotoxicities (SRB assay) against in vitro A-549 and
MCF-7 cell lines were determined at the Choong-Wae
Pharmaceutical Company, LTD., Korea, according to
the procedure described by Skehan et al.12
4. Rowell, R. M.; Whislter, R. L. J. Org. Chem., 1966, 31,
1541.
5. Price, G. C.; Knell, M. J. Am. Chem. Soc., 1942, 64, 552.
6. Tulishim, D.; Ronald, J. D. J. Org. Chem., 1991, 50, 6819.
7. Kang, S.-K.; Cho, H.-S.; Sim, H.-S.; Kim, B.-K. J. Carbo-
hydr. Chem., 1992, 11, 807.
Acknowledgements
We gratefully acknowledge Dr. D. Pack for performing
the in vitro cytotoxicity assay.
8. Hirst, G. C.; Johnson Jr., T. O.; Overman, L. E. J. Am.
Chem. Soc., 1993, 115, 2992.
9. Wig®eld, D. C.; Phelips, D. J. J. Org. Chem., 1976, 41, 2396.
10. Achab, S.; Das, B. C. J. Chem. Soc. Chem. Commun., 1983,
391.
References and Notes
1. Rieser, M. J.; Kozlowski, J. F.; Wood, K. V.; McLaughlin,
J. L. Tetrahedron Lett., 1991, 32, 1137.
11. Zweifel, G.; Brown, H. C. Org. Synth., 1972, 52, 59.
12. Skehan, P; Storeng, R.; Scudiero, D.; Monks, A; McMa-
hon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.;
Boyd, M. R. J. Natl Cancer Inst., 1990, 82, 1107.
2. (a) From l-glutamic acid; Figadre, B.; Harmange, A. L.;
Laurens, A.; Cave, A. Tetrahedron Lett., 1991, 32, 7539. (b)