Studies on mimicry of naturally occurring annonaceous acetogenins: Non-THF analogues leading to remarkable selective cytotoxicity against human tumor cells

Article abstract of DOI:10.1002/chem.200390021

A class of structurally simplified analogues of the naturally occurring annonaceous acetogenins were developed, amongst which some non-THF analogues showed remarkable cytotoxicities against tumor cell lines, as well as good selectivity between human tumor cells and normal cells. The synthetic routes were significantly shortened because of the removal of the chiral centers bearing the THF rings on the natural templates. This simplification also provides access to the parallel synthesis of these mimics by a combinatorial strategy. The remaining stereogenic centers at the positions α to the ethereal links were introduced by the Chiron approach from the easily accessible chiral building blocks 6a and/or 6b, made in turn from L-ascorbic acid or Dmannitol, while the one in the butenolide segment was taken from L-lactate. All four diastereomeric non-THF analogues 2a-2d showed remarkable activity against the HCT-8 cell line, and better differentiation was found when testing against the HT-29 cell line. It was also discovered that both the butenolide and ethylene glycol subunits play essential roles in the cytotoxicities against tumor cell lines, while the 10-substituted hydroxy group and the absolute configuration of methyl group at the butenolide moiety are less important for their activity.

Full text of DOI:10.1002/chem.200390021

FULL PAPER
Studies on Mimicry of Naturally Occurring Annonaceous Acetogenins:
Non-THF Analogues Leading to Remarkable Selective Cytotoxicity against
Human Tumor Cells
Bu-Bing Zeng,[a] Yikang Wu,[a] Sheng Jiang,[a] Qian Yu,[a] Zhu-Jun Yao,[a] Zhong-Hai Liu,[b]
Hong-Yan Li,[b] Yan Li,[b] Xiao-Guang Chen,[b] and Yu-Lin Wu*[a]
Abstract: A class of structurally simpli-
fied analogues of the naturally occurring
annonaceous acetogenins were devel-
oped, amongst which some non-THF
analogues showed remarkable cytotox-
icities against tumor cell lines, as well as
good selectivity between human tumor
cells and normal cells. The synthetic
routes were significantly shortened be-
cause of the removal of the chiral
centers bearing the THF rings on the
natural templates. This simplification
also provides access to the parallel syn-
thesis of these mimics by a combinato-
rial strategy. The remaining stereogenic
centers at the positions a to the ethereal
links were introduced by the Chiron
approach from the easily accessible
chiral building blocks 6a and/or 6b,
made in turn from l-ascorbic acid or d-
mannitol, while the one in the buteno-
lide segment was taken from l-lactate.
All four diastereomeric non-THF ana-
logues 2a 2d showed remarkable ac-
tivity against the HCT-8 cell line, and
better differentiation was found when
testing against the HT-29 cell line. It was
also discovered that both the butenolide
and ethylene glycol subunits play essen-
tial roles in the cytotoxicities against
tumor cell lines, while the 10-substituted
hydroxy group and the absolute config-
uration of methyl group at the buteno-
lide moiety are less important for their
activity.
Keywords: annonaceous
genins asymmetric synthesis
cytotoxicity natural products
structure activity relationships
aceto-
¥
¥
¥
¥
appeared in the literature require more than 10 steps, which
makes scaling-up very difficult. A further challenge in the
total synthesis comes from the multiple chiral centers: usually
there are at least five oxygen-linked carbon chiral centers in
the target molecules. Their derivation and the related studies
on structure activity relationships are therefore very diffi-
cult. Herein we wish to report a potential solution to the
problem, which relies on structural simplification while
retaining the activity of the acetogenins.
It has been postulated[5] that the acetogenins× antitumor
activities are associated with their ionophoric ability, although
it has also been mentioned in a brief communication that
acetogenins have no ionophoric effects in biological studies
with living cell.[6] In fact, Ca2‡ complexes of acetogenins have
been detected, and the activity of acetogenins was assumed to
be due to a role in the bioavailability of such cations in the cell
membranes.[7] Besides, it has long been known that bis-THF
annonaceous acetogenins containing more ethereal oxygen
usually are more active than mono-THF annonaceous aceto-
genins, and acetogenins containing free hydroxy groups are
more active than their ether, ester, or ketone counterparts.
Therefore, the hydroxy and ethereal oxygen atoms in the
acetogenins appear to be essential for the biological activities,
and thus the THF rings, especially their ethylene bridge, do
not seem to be necessary for the activities. As a preliminary
Introduction
Annonaceous acetogenins, a relatively newly discovered class
of natural products found in Annonaceae in the 1980s, have
been attracting worldwide attention because of their potent
biological activities, especially as growth inhibitors[1] of a wide
range of tumor cells. They have been shown[2] to function by
blocking complex I in mitochondria as well as ubiquinone-
linked NADH oxidase in the cells of specific tumor cell lines,
including some multidrug-resistant[3] ones. These features
make the acetogenins potential leads for new antitumor
agents. However, the natural resource is scarce, so the
substantial amounts of enantiomerically pure samples re-
quired for further biological and clinical studies appear to be
attainable only by means of chemical synthesis. All the total
syntheses[4] of annonaceous acetogenins that have so far
[a] Prof. Y.-L. Wu, Dr. B.-B. Zeng, Prof. Y. Wu, S. Jiang, Dr. Q. Yu,
Prof. Z.-J. Yao
State Key Laboratory of Bio-organic & Natural Products Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (China)
Fax : (‡86)21-6416-6128
E-mail: ylwu@pub.sioc.ac.cn
[b] Dr. Z.-H. Liu, H.-Y. Li, Y. Li, Prof. X.-G. Chen
Institute of Materia Medica, Chinese Academy of Medical Sciences
1 Xiannongtan St., Beijing 100050 (China)
282
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282 290
experiment, we synthesized a highly simplified analogue, in
which the THF part of annonaceous acetogenins was replaced
by a diethylene or triethylene glycol unit and all the chiral
centers of the THF region were eliminated. Testing of these
analogues showed activities comparable to those of mono-
THF natural templates.[8] These interesting results greatly
encouraged us to design more new analogues based on this
general consideration. A further means of such a structural
simplification is to remove the ethylene bridge in these THF
rings and reserve the flanking hydroxy groups (Figure 1). This
eliminates only two chiral centers for each THF ring, but still
greatly simplifies the synthesis in comparison with those of the
natural molecules.
Scheme 1. The butenolide part of the targets is induced at the last stage of
synthesis and all four precursor methyl esters can be attained from the
combination of 4a,b and 5a,b, which are derived from the corresponding
protected glyceraldehydes 6a or 6b. MOM ˆ methoxymethyl.
mediates 4 and 5, and finally finishing the building of the
chiral butenolides by a reliable sequence of aldol condensa-
tion, lactonization, and dehydration.
Figure 1. Design for simplifying bis-THF natural annonaceous acetogenins
into linear mimics.
The execution of the synthesis has three parts. Generally,
the synthesis included the independent preparations of the
segments 4 and 5, and then combination of both segments to
the target molecules. The synthesis of segment 4b started
from the chiral building block (R)-glyceraldehyde acetonide
(6b) prepared from d-mannitol (Scheme 2). After the chain
extension[12] at the aldehyde 6b by a Wittig reaction followed
by hydrogenation, the acetonide 8b was converted into diol
9b and then condensed with 2-benzyloxyethyl iodide regio-
As a natural template, the bis-THF annonaceous acetoge-
nin isodesacetyluvaricin (1a) and its isomers could be trans-
formed into the linear[9] mimics 2. Thus four chiral centers will
be removed from the lead molecule. Also, it will greatly
reduce the difficulty encountered in the synthetic endeavors
and promises easier scaling-up in future processes.[10]
Parallel syntheses of all four enantiomerically pure analogues
2: To explore the potential influence of the configurations of
hydroxy groups on biological activities, the syntheses of all
four possible isomers of the simplified analogue 2 were
planned (Scheme 1). First of all, the three-carbon unit of the
chiral butenolide was removed from the skeleton, which could
be built up by our previously reported methodology from
ethyl lactate.[11] The protected dihydroxy esters 3a d could
À
be further disconnected at the O C19 bond (numbering
according to bis-THF acetogenins) to give two segments 4
and 5, each containing one chiral center. The R isomers of
compounds 4a and 5a could be transformed to the commonly
available (S)-glyceraldehyde acetonide 6a. Correspondingly,
the S isomers of compounds 4b and 5b could be prepared
from (R)-glyceraldehyde acetonide 6b. Our synthetic proto-
col for all four targets 2a d was highly concise, starting from
a pair of enantiomeric glyceraldehyde acetonides through a
simple combination of the two pairs of enantiopure inter-
ˆ
Scheme 2. Reagents and conditions: a) C8H17CH PPh3, 90%; b) H2/
EtOH/Pd C, 96%; c) HCl/MeOH; d) 1) Bu2SnO/CHCl3/MeOH (10:1:1)/
reflux; 2) CsF/ICH2CH2OBn/DMF, 81% over two steps; e) MOMCl/
iPr2NH/CH2Cl2, 85%; f) Na/NH3 (liq), 97%; g) I2/imidazole/PPh3, 92%.
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283

Y.-L. Wu et al.
FULL PAPER
selectively via a cyclic stannate intermediate.[13] The secon-
dary hydroxy group of 10b was masked as a methoxymethyl
(MOM) ether and the terminal benzyl protective group was
then removed by Na/NH3 (liquid). The resultant primary
hydroxy group of 12b was transformed into the desired iodide
4b. Following the same reaction sequence, the segment 4a
was synthesized from the (S)-glyceraldehyde acetonide 6a,
which could be prepared from l-ascorbic acid.
The preparation of the other segment, 5, started from cis-
À
eruic acid (13, Scheme 3). At first, the C C double bond of 13
was cleaved by ozonization following a literature procedure[14]
to give the hydroxy acid, which was esterified to the
Scheme 4. Reagents and conditions: a) 1) Bu2SnO/CHCl3/MeOH (10:1)/
reflux; 2) CsF/DMF, 54% over two steps; b) MOMCl/iPr2NH/CH2Cl2,
93%; c) 1) LDA/(S)-Me(OTHP)CHCHO; 2) 9% H2SO4/THF; 3)
(F3CCO)2O/NEt3/CH2Cl2, 43%; d) HCl/MeOH, 68%.LDA ˆ lithium dii-
sopropylamide.
4a and 5b led to 2b, reaction of 4b with 5a led to 2d, and
condensation of 4a with 5a yielded 2a.
It is worthy noting that the strategy presented here to
construct the butenolide moiety[15] after the completion of the
chain extension gave much better yields than the one
previously adopted,[16] in which the butenolide unit was
introduced at the earlier stage of synthesis.
Syntheses of (36R)-analogue and (10R)-hydroxy-substituted
analogue of 2c: The successful synthesis of simplified bis-THF
annonaceous acetogenins and their remarkable selective
inhibition effects on tumor cell lines (vide infra) prompted
us to exploit a further structure modification. In this section,
we describe how two more structural modifications based on
the most active analogue 2c were synthesized and inves-
tigated.
Scheme 3. Reagents and conditions: a) 1) O3/ 0 58C/EtOH/cyclohexane
(1:5); 2) KBH4; 3) MeOH/SOCl2, 87% from 13; b) CBr4/PPh3/C6H6, 87%;
c) 1) PPh3; 2) tBuOK, then 6a or 6b; 3) H2/EtOH/Pd C, 67% over three
‡
steps; d) H /MeOH, 91%.
corresponding methyl ester 14 in methanol in the presence of
SOCl2. Smooth bromination of the hydroxy with CBr4 and
PPh3 provided the bromo ester 15 as the intermediate to the
corresponding phosphonium salt for the following Wittig
reaction in the same pot. Practically, the in situ formation of
phosphonium salt from 15 could be achieved by reaction with
PPh3 without solvents at elevated temperature. The Wittig
The bis-THF annonaceous acetogenin trilobin (19) was
isolated from Asimina triloba in 1995. It shows very potent
cytotoxicity against human tumor cells.[17] Following our
methodology, removal of the ethylene bridges of THF rings
gives a new, analogous (10R)-hydroxylated 2a. Because 2c is
the most potent compound among the series of compounds 2,
the stereochemistry of the analogue was then tuned into the
10R-hydroxylated 2c (20), whose structure is shown in Figure 2.
Reaction of compound 12b with (R)-epichlorohydrin gave
the epoxide 21 in the presence of phase transfer catalyst.
Epoxy opening with monotrimethylsilyl acetylene lithium
followed by TMS deprotection and MOM protection afforded
one segment, 22, of the target molecule. The other segment,
27, was synthesized from methyl undecylenate (23), according
to our previously reported hydrolytic kinetic resolution
method.[18] Treatment of 22 with butyllithium followed by
reaction with 27 in the presence of BF3 etherate at À788C
gave the whole skeleton 28 in 53% yield. The triple bond of 28
was selectively reduced by reaction with diimide. Deprotec-
tion of MOM ethers by boron trifluoride and dimethylsulfide
gave the final product 20 (Scheme 5).
À
olefination with 6a or 6b, hydrogenation of the C C double
bond and removal of the acetonide protective group led to 5a
or 5b, respectively.
With both segments in hand, the parallel syntheses of these
stereomeric analogues were executed straightforwardly by
combination of these intermediates. By selective etherifica-
tion with dibutyltin oxide and cesium fluoride, both segments
were successfully condensed by a selective ether bond
formation at the primary position. For example compound
3c was obtained from the intermediates 4b and 5b in good
yields (Scheme 4). The newly produced secondary hydroxy
group was then protected as a MOM ether before the chiral
unit of the methylated g-butenolide was introduced by an
aldol strategy. After removal of the THP protective group
with concurrent lactone ring-closure, the b-hydroxy was
converted into its trifluoroacetate and then eliminated quickly
into the methylated g-butenolide in the presence of triethyl-
amine. Finally, the MOM-masked hydroxy groups were
released by acidified methanol to afford the target 2c. Other
target molecules were synthesized in a similar sequence by
choosing appropriate precursors 4 and 5. In short, coupling of
The same sequence was applied to the synthesis of the
(36R)-isomer of compound 2c, starting from the same
intermediate 17c. (R)-Me(OTHP)CHCHO was used to yield
the R-methylated g-butenolide and thus finally the target
compound (15S,24S,36R)-2 (30) (Scheme 6).
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Annonaceous Acetogenin Analogues
282 290
Biological activity: The synthesized
samples were evaluated with MTT
assays (MTTˆ 3-(4,5-cimethylthiazol-
2-yl)-2,5-diphenyl tetrazolium bro-
mide) for their cytotoxicities against
several human solid tumor cell lines.
The results for all the four compounds
2a c showed potent activities (Ta-
ble 1), as well as interesting cell line
selectivity. No activities were found in
the experiments against KB and A2780
cell lines. However, impressive positive
effects were observed with HCT-8, in
Figure 2. The molecular design of 20 uses natural trilobin as the template, removing the ethylene bridge
of THF ring and inverting the configuration of the two flanking hydroxy groups.
which the EC50 values are all on the order of nanomolar. More
interesting results were obtained from the testing with HT-29
cell line: different stereochemistry combinations of the
mimics showed remarkable differences in the activities. In
comparison with the positive control adriamycin, these
analogues were cytotoxic to HCT-8 and HT-29 cells, but
somewhat less so than those of adriamycin. However, they
show selectivity among different cell lines, and no comparable
selectivity was observed in the case of adriamycin.
Table 1. Biological activity of structures 2 compared with adriamycin.
Compound
EC50 [mgmLÀ1
]
KB
A2780
HCT-8
HT-29
2a
2b
2c
2d
> 1
> 1
> 1
> 1
> 1
> 1
> 1
> 1
0.066
0.097
0.032
0.065
0.00465
0.272
1.12
0.11
7.83
0.00098
Adriamycin
0.00289
0.00102
Two series of compounds with partial structures of com-
pounds 2 were also investigated. One series of compounds is
similar to compounds 2 but for the g-methyl butenolide
subunits, such as compounds 31 (Figure 3). The other is the
Scheme 5. Reagents and conditions: a) 50% NaOH, Bu4NHSO4 (cat),
92.7%; b) 1) (CH3)3SiCCLi, BF3 ¥ Et2O, À788C; 2) Bu4NF, THF; 3)
MOMCl, (iPr)2NEt, CH2Cl2, 08C RT, 66% for three steps; c) 1) LDA/
HMPA, THF, then (S)-Me(OTHP)CHCHO; 2) 9% H2SO4, THF, 81%;
d) m-CPBA, CH2Cl2, 92%; e) (CF3CO)2O, Et3N, CH2Cl2, 08C RT, 87%;
f) 0.5 mol% (R,R)-salen-CoIII-OAc, 0.5 equiv H2O, 36% for 27; g) nBuLi/
BF3 ¥ Et2O, THF, À788C; h) 1) TsNHNH2, NaOAc, DME/H2O, reflux; 2)
BF3 ¥ Et2O, DMS, 64%. HMPA ˆ hexamethylphosphoramide, m-CPBA ˆ
m-chloroperoxybenzoic acid.
Figure 3. Two series of compounds with partial structures of 2 show almost
no cytotoxicity.
a-alkyl or hydroxylated alkyl-substituted derivative of bute-
nolides (3-substituted (5S or 5R)-methyl-2(5H)-furanone).
For example, the chiral center of compounds 32 may be S or R
(Figure 3). The corresponding EC50 values for both series
were measured and all were more than 10 mgmLÀ1. Based on
all the above information, it is clear that both the butenolide
and ethylene glycol subunits are essential structural features
for the cytotoxicity toward tumor cell lines.
The activity studies of (36R)-analogue 30 and (10R)-
hydroxy-substituted analogue 20 have similar selectivities
and cytotoxicities to their parent compound 2c (Table 2), and
Scheme 6. Reagents and conditions: a) 1) LDA; 2) 9% H2SO4/THF; 3)
(F3CCO)2O/NEt3/CH2Cl2, 60%; b) BF3 ¥ Et2O, DMS, 60%.
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Y.-L. Wu et al.
FULL PAPER
Table 2. Biological activity of selected compounds against human cell
lines.
purification. All the reactions were monitored by TLC with GF254 silica-
gel-coated plates. Flash column chromatography was carried out on silica
gel (300 400 mesh) under pressure.
Compound
EC50 [mgmLÀ1
]
Compound 7b: A mixture of n-bromononane (20.7 g, 100.0 mmol) and
triphenylphosphine (26.2 g, 100.0 mmol) was heated at 1408C under
nitrogen for 2.5 h. Dry THF (100 mL) and n-butyllithium (100.0 mmol)
were added to the resultant slurry at À208C. After the mixture had been
stirred for 0.5 h, (R)-glyceraldehyde acetonide (6b, 13.0 g, 100.0 mmol) was
added to the red solution. After being stirred at room temperature for an
additional 4 h, the reaction was quenched with saturated aqueous NH4Cl
solution. The mixture was extracted with diethyl ether (50 mL Â 3). The
combined organic layers were washed with brine, dried over Na2SO4, and
concentrated to yield the crude product, which was further purified by flash
column chromatography with 10:1 petroleum hexanes/acetate as eluent to
give pure product (S)-7b as a colorless oil in 91% yield. 1H NMR
(300 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.7 Hz, 3H), 1.27 1.40 (m, 12H), 1.40 (s,
3H), 1.425 (s, 3H), 2.10 (m, 2H), 3.51 (t, J ˆ 8.0 Hz, 1H), 4.06 (dd, J ˆ
6.0 Hz, 8.0 Hz, 1H), 4.84 (dt, J ˆ 6.3 Hz, 8.1 Hz, 1H), 5.40 (t, J ˆ 9.8 Hz,
KB
10 20
> 10
> 10
HCT-8
HT-29
20
30
2c
ꢀ 0.1
1.4
0.3
0.7
2.0
1.5
the EC50 values of (10R)-hydroxy-substituted analogue 20 are
slightly larger than those of 2c. Since similar EC50 values were
observed for 30 and 2c, the absolute configuration of the
methyl group at the butenolide subunit is not a key point.
Cytotoxicity on the human normal cell HELF has also been
studied. All of our synthetic samples gave negative results,
with an EC50 value over 10 mgmLÀ1. A preliminary antitumor
assay in mice (Lewis lung cancer) with compound 2c has been
‡
1H), 5.63 ppm (m, 1H); MS (EI): m/z (%): 240 ([M ], 6.58), 225 (4.11), 195
(1.07), 183 (1.62); elemental analysis calcd (%) for C15H26O2 (238.4): C
74.95, H 11.74; found: C 74.96, H 12.00.
carried out, too.
A
dose of 10 mgkgÀ1 Â 5 times
‡
20 mgkgÀ1 Â 4 times was administered orally and 60% inhib-
ition of tumor was observed compared with the control.
Furthermore, in vivo inhibition of colon cancer is being
studied right now.
Compound 7a: The preparation was carried out according to the procedure
of (S)-7b but with (S)-glyceraldehyde acetonide 6a as the starting material.
(R)-7a: 1H NMR (300 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.6 Hz, 3H), 1.27 1.53
(m, 12H), 1.40 (s, 3H), 1.43 (s, 3H), 2.12 (m, 2H), 3.51 (t, J ˆ 8.1 Hz, 1H),
4.06 (dd, J ˆ 6.1 Hz, 8.0 Hz, 1H), 4.84 (dt, J ˆ 6.2 Hz, 8.1 Hz, 1H), 5.40 (t,
‡
J ˆ 9.8 Hz, 1H), 5.64 (m, 1H); MS (EI): m/z (%): 240 ([M] , 0.09), 226
(8.14), 313 (2.99), 210 (1.04), 195 (2.14), 183 (8.70), 165 (10.90); elemental
analysis calcd (%) for C15H28O2 (240.4): C 74.95, H 11.74; found: C 74.95, H
11.88.
Conclusion
Compound 8b: A mixture of (S)-7b (12.0 g, 50.0 mmol), palladium on
charcoal (10%, 500 mg), and MeOH (80 mL) containing 0.5% triethyl-
amine was stirred at room temperature for 24 h under hydrogen. After
filtration and removal of the solvent, the residue was purified by column
In conclusion, a class of structurally simplified analogues of
natural annonaceous acetogenins has been developed. The
synthetic route has been significantly shortened by the
removal of the chiral centers of the THF rings in natural
templates, which opens the way for a parallel synthesis of
stereomeric mimics. The remaining stereogenic centers in
these analogues were derived from easily accessible chiral
building blocks. All four analogues 2 showed remarkable
activity against the HCT-8 cell line, while better differentia-
tion was found when testing them against the HT-29 cell line.
Further synthetic work for the study of the structure ac-
tivity relationship is also described in this report. All the
results disclose a very interesting piece of information, namely
that both the butenolide and ethylene glycol subunits play
essential roles in the cytotoxicities against tumor cell lines, in a
way that is not yet clear. Additionally, the hydroxy group
substituted at position 10 and the absolute configuration of
the methyl group at the butenolide moiety are less important
for their activity. Further studies along these general lines are
currently under way in our laboratory, and the results will be
reported in due time.
chromatography on silica gel to afford a waxy solid in 96% yield: [a]D20
ˆ
‡15.2 (c ˆ 1.18 in CHCl3); 1H NMR (300 MHz, CDCl3): d ˆ 0.88 (t, J ˆ
7.1 Hz, 3H), 1.20 2.02 (m, 18H), 1.38 (s, 3H), 1.40 (s, 3H), 3.49 (t, J ˆ
7.0 Hz, 1H), 4.04 (m, 2H).
Compound 8a: Hydrogenation of (S)-7a was carried out as for the
procedure of 8b. 8a: [a]2D0 ˆ À15.1 (c ˆ 1.11 in CHCl3); 1H NMR
(300 MHz, CDCl3): d ˆ 0.94 (t, J ˆ 6.8 Hz, 3H), 1.20 2.02 (m, 18H), 1.38
(s, 3H), 1.40 (s, 3H), 3.49 (t, J ˆ 7.2 Hz, 1H), 4.05 (m, 2H).
Compound 9b: During the work-up for preparation of compound 8b, the
filtrate was treated with 10% HCl (10 mL) and stirred overnight at room
temperature. The reaction was quenched by adding dilute aqueous NaOH
to pH 7. After removal of the solvent, the residue was extracted with ethyl
acetate. The combined organic layers were dried over MgSO4, concen-
trated and crystallized from ethyl acetate to give (S)-9b (9.5 g, 94%).
[a]2D0 ˆ ‡9.36 (c ˆ 1.1 in CH3OH); IR (film): nÄ ˆ 3316, 2920, 2851, 1470,
1438 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.6 Hz, 3H), 1.26
1.88 (m, 18H), 3.43 (m, 1H), 3.65 (t, J ˆ 3.0 Hz, 1H), 3.69 (m, 1H); MS
‡
‡
(EI): m/z (%): 202 ([M] , 3.09), 185 ([M À OH] , 1.00), 171 ([M À
‡
CH2OH] , 11.48); elemental analysis calcd (%) for C12H26O2 (202.3): C
71.23, H 12.95; found: C 70.97, H 12.90.
Compound 9a: The above procedure for 9b was employed. (R)-9a: [a]D19
ˆ
À9.6 (c ˆ 3.54 in CH3OH); IR (KBr): nÄ ˆ 3713, 3224, 1468, 1076 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.0 Hz, 3H), 1.26 1.44 (m,
‡
18H), 3.44 (m, 1H), 3.69 (m, 2H); MS (EI): m/z (%): 202 ([M] , 0.52), 186
(11.20), 171 (12.68), 153 (0.75), 111 (35.20), 97 (100.00); elemental analysis
calcd (%) for C12H26O2 (202.3): C 71.23, H, 12.95; found: C 71.17, H 12.81.
Experimental Section
Compound 10b:
Melting points are uncorrected. All NMR spectra were recorded at
300 MHz and 600 MHz (1H NMR) or 75 MHz and 150 MHz (13C NMR) in
CDCl3, respectively. Unless otherwise indicated, chemical shifts are
reported in ppm, and coupling constants (J) are reported in Hertz. Mass
spectra were recorded by EI and ESI modes on HP 59890A and Finnigan
4021 mass spectrometers, and HRMS were measured on a Finnigan MAT
or Finnigan FTMS-2000 mass spectrometer. Optical rotations were
recorded at ambient temperature. Organic solvents (such as didiethyl
ether and THF) were freshly distilled over sodium/benzophenone under
nitrogen. Commercially obtained reagents were used without further
Preparation of ethylene glycol monobenzyl ether: Sodium hydride (80%,
15.0 g) was added in portions to a mixture of DMF/MeOH (200 mL, 1:1)
and ethylene glycol (264 g, 4.0 mol). After the mixture had been stirred for
10 h, benzyl bromide (68.4 g, 0.4 mol) was added dropwise. The reaction
mixture was stirred for an additional 10 h and then quenched with 10%
HCl. The mixture was extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and concen-
trated. The residue was distilled under reduced pressure to provide
ethylene glycol monobenzyl ether (52.4 g, 86%). 1H NMR (300 MHz,
286
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Chem. Eur. J. 2003, 9, No. 1

Annonaceous Acetogenin Analogues
282 290
CDCl3): d ˆ 3.62 (t, J ˆ 6.6 Hz, 2H), 3.76 (t, J ˆ 6.8 Hz, 2H), 4.58 (s, 2H),
259 (0.60), 229 (3.61); elemental analysis calcd (%) for C16H34O4 (290.4): C
66.04, H 11.80; found: C 66.02, H 11.93.
‡
‡
7.33 (m, 5H); MS (EI): m/z (%): 202 ([M] , 3.09), 185 ([M À OH] , 1.00),
‡
171 ([M À CH2OH] , 11.48).
Compound 12a: Compound 12a was obtained from 11a using the
procedure for 12b. 12a: [a]D20 ˆ À9.3 (c ˆ 3.7 in CHCl3); IR (film): nÄ ˆ
Preparation of 2-iodoethyl benzyl ether: Iodine (43.5 g, 170 mmol) was
added in portions to a solution of ethylene glycol monobenzyl ether (15.2 g,
100.0 mmol), imidazole (20.4 g, 300 mmol) and triphenylphosphine (44.9 g,
170 mmol) in 150 mL of dry benzene over 2 h at 08C. MeOH (2.0 mL) was
added to quench the reaction when the starting material could no longer be
detected by TLC. After the reaction mixture had been stirred for 1 h, silica
gel (40 50 g) was added and stirred for an additional 20 min. The mixture
was filtered through a pad of silica gel and the filtrate was concentrated to
afford the iodide (24.2 g, 92%), which was used directly in the next step
without purification. 1H NMR (300 MHz, CDCl3): d ˆ 3.35 (t, J ˆ 6.6 Hz,
2H), 3.72 (t, J ˆ 6.8 Hz, 2H), 4.61 (s, 2H), 7.33 (m, 5H).
1
3450, 2926, 2856, 1467, 1131, 1041, 919 cmÀ1; H NMR (300 MHz, CDCl3):
d ˆ 0.86 (t, J ˆ 6.7 Hz, 3H), 1.25 (m, 16H), 1.50 (t, J ˆ 6.6 Hz, 2H), 2.38
(brs, 1H), 3.38 (s, 3H), 3.51 (d, J ˆ 4.9 Hz, 2H), 3.57 (m, 2H), 3.71 (m, 3H),
4.67 (d, J ˆ 7.0 Hz, 1H), 4.74 ppm (d, J ˆ 7.0 Hz, 1H); MS (EI): m/z (%):
‡
290 ([M] , 0.03), 273 (0.25), 2.59 (14.78), 229 (36.65).
Compound 4b: Iodine (2.18 g, 8.5 mmol) was added in small portions to a
solution of 12b (1.45 g, 5.0 mmol), imidazole (1.02 g, 15 mmol) and
triphenylphosphine (2.35 g, 9 mmol) in dry benzene at 08C over 2 h. The
reaction mixture was stirred until TLC indicated complete consumption of
the starting material. MeOH (0.5 mL) was then added into the reaction
mixture. The mixture was stirred for 30 min, silica gel (4 5 g) was added
and the mixture was stirred for a further 20 min. Filtration and concen-
tration of filtrate afforded the iodide 4b (1.68 g, 96%), which was used for
the next step without further purification. Compound 4a was prepared
from 12a according to the same procedure.
Preparation of compound 10b: A suspension of alcohol (S)-9b (2.02 g,
5.0 mmol) and dibutyltin oxide (2.5 g, 10.0 mmol) in CHCl3/MeOH (50 mL,
10:1) was refluxed for 2 h. After the solvents had been removed under
reduced pressure, the residue was dried under high vacuum for 6 h. To this
residue in dry DMF (50 mL) were added 2-iodoethyl benzyl ether (2.9 g,
11.0 mmol) and cesium fluoride (2.4 g) under nitrogen. The reaction
mixture was stirred for 18 h at 508C, and then the reaction mixture was
poured into ethyl acetate (40 mL) and brine (200 mL). The mixture was
stirred for 30 min and filtered through a pad of silica gel. The filtrate was
extracted with ethyl acetate, and the combined organic layers were washed
with saturated aqueous NH4Cl and brine, dried over Na2SO4, and
concentrated. The residue was further purified by column chromatography
on silica gel to afford compound 10b (2.73 g, 81%). [a]1D9 ˆ ‡4.08 (c ˆ 10.6
Compound 16b:
Preparation of methyl a-hydroxytridecanoate (14): A stream containing O3
was bubbled through a solution of cis-13-docosenoic acid (25 g, 74 mmol) in
the mixture of ethanol (15 mL) and cyclohexane (65 mL) for 4 h at 0 58C
till a drop of reaction solution no longer decolorized bromide/acetic acid.
The ozonide solution was then added dropwise to potassium borohydride
(8.2 g, 134 mmol) in MeOH (70 mL) at 08C, and the mixture was stirred for
8 h, acidified with 6n HCl to pH 2, and extracted with chloroform. The
combined extracts were dried over Na2SO4 and concentrated under
reduced pressure. Freshly distilled thionyl chloride (30 mL) was added
dropwise to the solution of the residue in methanol (100 mL) at 08C; the
reaction mixture was then stirred for 1 h and neutralized with saturated
aqueous NaHCO3 to pH >7.0. After removal of methanol under reduced
pressure, the residue was extracted with ethyl acetate. The combined
extracts were washed with brine, dried over anhydrous Na2SO4, and
concentrated. The crude product was further purified by column chroma-
tography on silica gel to give compound 14 (16.3 g, 90%). M.p. 47 498C;
IR (KBr): nÄ ˆ 3300, 2920, 2851, 1743, 1474, 1179 cmÀ1; 1H NMR (300 MHz,
CDCl3): d ˆ 1.24 (m, 16H), 1.56 (m, 4H), 2.28 (t, J ˆ 7.6 Hz, 2H), 3.6 (t, J ˆ
in CHCl3); IR (film): nÄ ˆ 3426, 3028, 2924, 1100, 702 cmÀ1
;
1H NMR
(600 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.9 Hz, 3H), 1.26 1.45 (m, 18H), 2.20
(brs, 1H), 3.31 (t, J ˆ 9.6 Hz, 1H), 3.52 (dd, J ˆ 9.6, 2.4 Hz, 1H), 3.61 3.72
(m, 4H), 3.79 (m, 1H), 4.57 (s, 2H), 7.34 (m, 5H); MS (EI): m/z (%): 337
‡
([M] ‡1), 149 (21.33), 91 (100.00).
Compound 10a: The procedure followed that for 10b. 10a: [a]2D0 ˆ À4.05
(c ˆ 5.83 in CHCl3); IR (film): nÄ ˆ 3422, 2922, 2854, 1450, 1102 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 7.1 Hz, 3H), 1.26 1.51 (m,
18H), 2.35 (s, 1H), 3.30 (t, J ˆ 9.0 Hz, 1H), 3.54 (dd, J ˆ 9.7, 2.6 Hz, 1H),
3.66 3.81 (m, 5H), 4.57 (s, 2H), 7.33 (m, 5H); MS (EI): m/z (%): 336
‡
([M] , 0.13), 183 (0.59), 166 (3.8), 149 (20.0); elemental analysis calcd (%)
for C21H36O3 (336.5): C 74.95, H 10.78; found: C 74.82, H 10.97.
‡
6.6 Hz, 2H), 3.64 ppm (s, 3H); MS (EI): m/z (%): 245 ([M‡H] , 3.38), 227
‡
([M À H2O] , 1.29), 214 (11.27), 195 (6.09).
Compound 11b: Chloromethyl methyl ether (1.5 mL) was added to a
solution of alcohol 10b (1.68 g, 5 mmol) and DIPEA (2.0 mL) in CH2Cl2
(5 mL) at 08C. The mixture was stirred at 48C overnight and then quenched
with saturated aqueous NH4Cl and extracted with CH2Cl2. The organic
layer was washed with water and brine, and dried over Na2SO4. Removal of
the solvent followed by column chromatography (hexane/EtOAc 10:1)
gave compound 11b (1.62 g, 85%) as a colorless oil. [a]2D0 ˆ À13.7 (c ˆ 6.06
in CHCl3); IR (film): nÄ ˆ 2922, 1448, 1108, 1042 cmÀ1; 1H NMR (300 MHz,
CDCl3): d ˆ 0.87 (t, J ˆ 6.7 Hz, 3H), 1.22 1.52 (m, 18H), 3.36 (s, 3H), 3.50
(d, J ˆ 5.1 Hz, 2H), 3.62 3.75 (m, 4H), 3.69 (m, 1H), 4.55 (s, 2H), 4.63 (d,
J ˆ 6.8 Hz, 1H), 4.76 (d, J ˆ 6.8 Hz, 1H), 7.32 ppm (m, 5H); MS (EI): m/z
Preparation of methyl w-bromotridecanoate (15): Carbon tetrabromide
(20.0 g, 60 mmol) was added to a solution of alcohol 14 (12.2 g, 50 mmol) in
dry benzene (40 mL) at room temperature. After being stirred for 20 min,
the solution was cooled to 08C, and triphenylphosphine (15.7 g, 60 mmol)
was added. The mixture was stirred for 2 h at room temperature. Petroleum
ether (200 mL) was added. The mixture was filtered through a short pad of
silica gel and the filtrates were concentrated to give the crude product,
which was further purified by column chromatography on silica gel to
provide the pure bromide 15 (14.1 g, 92%); IR (KBr): nÄ ˆ 2920, 2851, 1737,
1474, 1464, 1214, 1174 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 1.25 (m,
‡
(%): 202 ([M] , 3.09), 185 ([M À OH], 1.00), 171 ([M À CH2OH], 11.48).
14H), 1.40 (m, 2H), 1.59 (m, 2H), 1.82 (m, 2H), 2.28 (t, J ˆ 7.6 Hz, 2H),
‡
3.38 (t, J ˆ 6.9 Hz, 2H), 3.64 ppm (s, 3H); MS (EI): m/z (%): 309 ([M‡H] ,
Compound 11a: The same procedure as for 11b was employed. 11a:
[a]2D0 ˆ ‡12.9 (c ˆ 2.87 in CHCl3); IR (film): nÄ ˆ 2924, 2854, 1454, 1356,
1108, 1044, 922, 738, 700 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 0.88 (t, J ˆ
6.9 Hz, 3H), 1.260 1.528 (m, 18H), 3.38 (s, 3H), 3.52 (m, 2H), 3.63 3.66
(m, 5H), 4.57 (s, 2H), 4.66 (d, J ˆ 7 Hz, 1H), 4.76 (d, J ˆ 7 Hz, 1H),
‡
3.90), 307 ([M‡H] , 4.10), 227 (6.74), 263 (7.37), 227 (10.92), 143 (12.20).
Preparation of compound 16b: A mixture of 15 (7.68 g, 25.0 mmol) and
triphenylphosphine (6.55 g, 25.0 mmol) was heated at 808C under nitrogen
atmosphere for 5 h. The residue was cooled to 30 À 408C, and dry THF
(100 mL) was then added. The solution was cooled to À40 508C, and
potassium tert-butoxide (3.136 g, 28.0 mmol) was added and stirred for
10 min. (R)-Glyceraldehyde acetonide (6b, 4.0 g, 31.0 mmol) in dry THF
was added to the resultant red solution of ylide at À708C, and the mixture
was stirred for 2 h. The reaction was quenched with saturated aqueous
NH4Cl solution and diluted with diethyl ether. The aqueous layer was
extracted with diethyl ether (3 Â 50 mL), and the combined organic layers
were washed with brine, dried over Na2SO4, and evaporated under reduced
pressure. A solution of the above residue in methanol (20 mL) was
hydrogenated in the presence of 10% palladium on charcoal (100 mg)
overnight. After removal of the catalyst and the solvent, the residue was
purified by flash column chromatography to give the pure product (S)-16b
(54 72%): [a]1D8 ˆ ‡10.25 (c ˆ 3.8 in CHCl3); IR (KBr): nÄ ˆ 2986, 2916,
‡
7.34 ppm (m, 5H); MS (EI): m/z (%): 380 ([M] , 0.11), 350 (4.78), 320
(6.95), 227 (22.44), 91 (98.84).
Compound 12b: A solution of 11b (1.90 g) in dry THF (5 mL) was added
dropwise to a solution of lithium/naphthalene (1.0M in THF, 20 mL) at
À258C over 15 min. The reaction mixture was stirred at À258C for 2 h,
quenched by saturated aqueous NH4Cl, and extracted with ether. The
combined extracts were washed with brine, dried over Na2SO4, filtered and
concentrated. The crude product was purified by column chromatography
on silica gel to give compound 12b (1.21 g, 84% yield): [a]2D0 ˆ ‡9.8 (c ˆ 6.3
in CHCl3); IR (film): nÄ ˆ 3453, 2926, 2856, 1467, 1215, 1040, 919 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 0.87 (t, J ˆ 6.6 Hz, 3H), 1.25 (m, 16H),
1.50 (t, J ˆ 6.6 Hz, 2H), 2.21 (brs, 1H), 3.39 (s, 3H), 3.51 (d, J ˆ 4.9 Hz,
2H), 3.58 (dd, J ˆ 8.5, 3.5 Hz, 2H), 3.70 (m, 3H), 4.68 (d, J ˆ 6.8 Hz, 1H),
‡
1
4.75 ppm (d, J ˆ 6.8 Hz, 1H); MS (EI): m/z (%): 273 ([M‡1 À H2O] , 0.03),
2850, 1739, 1476, 1380, 1172 cmÀ1; H NMR (300 MHz, CDCl3): d ˆ 1.25
Chem. Eur. J. 2003, 9, No. 1
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0901-0287 $ 20.00+.50/0
287

Y.-L. Wu et al.
FULL PAPER
Compound (15S,24S)-17c: MOMCl (1.2 mL, 5.8 mmol) was added to a
mixture of (15S,24S)-3c (1.148 g, 2 mmol) and diisopropyl ethylamine
(3 mL, 17.2 mmol) in dry CH2Cl2 (5 mL) at 08C. The mixture was stirred at
room temperature for 12 h, quenched with saturated aqueous NH4Cl, and
extracted with ether. The extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel to afford 17c
(0.16 g, 90%) as a colorless oil. [a]2D0 ˆ À9.04 (c ˆ 7.9 in CHCl3); 1H NMR
(600 MHz, CDCl3): d ˆ 0.81 (t, J ˆ 7.2 Hz, 3H), 1.18 1.56 (m, 42H), 2.23 (t,
J ˆ 7.2 Hz, 2H), 3.31 (s, 6H), 3.41 3.44 (m, 4H), 3.51 3.57 (m, 4H), 3.60
(s, 3H), 3.62 (quint, J ˆ 6.0 Hz, 2H), 4.59 (d, J ˆ 6.6 Hz, 2H), 4.68 ppm (d,
J ˆ 6.6 Hz, 2H).
1.64 (m, 24H), 1.36 (s, 3H), 1.41 (s, 3H), 2.30 (t, J ˆ 7.6 Hz, 2H), 3.50 (t, J ˆ
‡
7.5 Hz, 1H), 3.67 (s, 3H), 4.04 ppm (m, 2H); MS (EI): m/z (%): 342 ([M] ),
‡
328 ([M‡1 À CH3] , 55.39), 313 (2.99), 286 (5.28), 267 (1.57), 254 (15.11);
elemental analysis calcd (%) for C20H38O4 (332.5): C 70.13, H 11.18; found:
C 70.14, H 11.26.
Compound 16a: The above protocol for 16b was adapted by starting with
(S)-glyceraldehyde acetonide 6b. 16a: [a]1D8 ˆ À9.82 (c ˆ 3.36 in CHCl3);
IR (KBr): nÄ ˆ 2986, 2917, 2851, 1739, 1476, 1198, 1172 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d ˆ 1.26 1.62 (m, 24H), 1.36 (s, 3H), 1.41 (s, 3H), 2.30
(t, J ˆ 7.6 Hz, 2H), 3.50 (t, J ˆ 7.5 Hz, 1H), 3.67 (s, 3H), 4.04 ppm (m, 2H);
‡
‡
MS (EI): m/z (%): 342 ([M] , 3.29), 328 ([M‡1 À CH3] , 57.0), 313 (2.08),
286 (5.77), 267 (1.68), 254 (15.98); elemental analysis calcd (%) for
C20H38O4 (332.5): C 70.13, H 11.18; found: C 70.15, H 11.61.
Compound 17d: Protection of compound 3d followed the same procedure
for 17c to give 17d: [a]1D9 ˆ À6.0 (c ˆ 6.6 in CHCl3); IR (film): nÄ ˆ 2922,
1
1750, 1042 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 0.81 (t, J ˆ 7.2 Hz, 3H),
Compound 5b: A solution of compound (S)-16b (3.42 g, 10 mmol) in THF
(30 mL) and 50% acetic acid (30 mL) was stirred for 5 h at 608C. The
solvent was removed in vacuum and the crude product was purified by
column chromatography on silica gel to afford diol (S)-5b (2.85 g, 94%).
[a]2D0 ˆ ‡10.6 (c ˆ 10.6 in CHCl3); IR (KBr): nÄ ˆ 3487, 2918, 2851, 1737,
1.17 1.58 (m, 42H), 2.30 (t, J ˆ 7.2 Hz, 2H), 3.31 (s, 6H), 3.41 3.44 (m,
4H), 3.51 3.56 (m, 4H), 3.60 (s, 3H), 3.60 3.64 (m, 2H), 4.59 (d, J ˆ
6.6 Hz, 2H), 4.69 ppm (d, J ˆ 6.6 Hz, 2H).
Compound 17b: Protection of compound 3b followed the same procedure
1
1472 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 1.28 (m, 22H), 1.64 (m, 2H),
for 17c to give 17b: [a]2D0 ˆ ‡5.9 (c ˆ 4.3 in CHCl3); IR (film): nÄ ˆ 2924,
1.79 (brs, 2H), 2.32 (t, J ˆ 7.2 Hz, 2H), 3.47 (m, 1H), 3.69 (m, 1H), 3.69 (s,
2854, 1736, 1466, 1110, 1042, 922 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ
3H), 3.74 ppm (m, 1H).
0.87 (t, J ˆ 7.2 Hz, 3H), 1.20 1.62 (m, 42H), 2.29 (t, J ˆ 7.2 Hz, 2H), 3.37 (s,
6H), 3.48 3.50 (m, 4H), 3.58 3.63 (m, 4H), 3.66 (s, 3H), 3.66 3.67 (m,
2H), 4.65 (d, J ˆ 6.6 Hz, 2H), 4.76 ppm (d, J ˆ 6.6 Hz, 2H); 13C NMR
(150 MHz, CDCl3): d ˆ 174.257, 96.002, 76.226, 74.115, 70.757, 55.387,
51.350, 34.081, 32.027, 31.885, 29.732, 29.590, 29.420, 29.307, 29.222, 29.123,
25.939, 24.929, 22.649, 14.064 ppm.
Compound 5a: Compound 5a was prepared from 16a by the same
procedure as 5b. 5a: [a]2D0 ˆ À9.7 (c ˆ 2.51 in CHCl3); IR (KBr) 3487, 2918,
2851, 1737, 1473, 1437 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 1.28 (m,
22H), 1.64 (m, 2H), 1.81 (brs, 2H), 2.32 (t, J ˆ 7.2 Hz, 2H), 3.47 (m, 1H),
3.69 (m, 1H), 3.70 (s, 3H), 3.73 ppm (m, 1H).
Compound 3c: A suspension of alcohol (S)-5b (1.51 g, 5.0 mmol) and
dibutyltin oxide (1.25 g, 5.0 mmol) in CHCl3/MeOH (50 mL, 10:1) was
refluxed for 2 h. After the solvents were removed under reduced pressure,
the residue was dried under high vacuum for 2 h. To the solution of above
residue in DMF (25 mL) were added iodide (S)-4b (2.1 g, 5.25 mmol) and
cesium fluoride (1.4 g, 9.2 mmol) under nitrogen. After the reaction
mixture was stirred overnight at 40 508C, the reaction was quenched by
adding ethyl acetate (40 mL) and brine (200 mL). After being stirred for
30 min, the mixture was filtered through a pad of silica gel. The aqueous
layer was extracted with ethyl acetate, and the combined organic layers
were washed with brine, dried over Na2SO4, and concentrated. The
resultant residue was purified by column chromatography on silica gel to
give (15S,24S)-3c (1.56 g, 54%). [a]2D0 ˆ ‡12.6 (c ˆ 7.7 in CHCl3); IR (film):
Compound 17a: Protection of compound 3a followed the same procedure
for 17c to give 17a: [a]1D8 ˆ ‡8.67 (c ˆ 1.3 in CHCl3); IR (film): nÄ ˆ 2924,
1
2854, 1736, 1466, 1042, 922 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 0.87 (t,
J ˆ 7.2 Hz, 3H), 1.22 1.64 (m, 42H), 2.29 (t, J ˆ 7.2 Hz, 2H), 3.37 (s, 6H),
3.46 3.52 (m, 4H), 3.57 3.63 (m, 4H), 3.66 (s, 3H), 3.66 3.70 (m, 2H),
4.65 (d, J ˆ 6.6 Hz, 2H), 4.75 ppm (d, J ˆ 6.6 Hz, 2H).
Compound (15S,24S,36S)-18c: nBuLi (1.6m in hexane, 1.25 mL, 2 mmol)
was added to a solution of diisopropylamine (0.31 mL, 2.22 mmol) in THF
(9 mL) at 08C. The reaction mixture was stirred at 08C for 30 min and
cooled to À788C. A solution of ester (15S,24S)-17c (0.55 g, 1 mmol) in dry
THF (2.0 mL) was then added. After 30 min, a solution of O-THP-(S)-
lactaldehyde (368 mg, 1.95 mmol) in dry THF (5 mL) was added. The
reaction mixture was stirred for 2 h and then quenched with saturated
aqueous NH4Cl and diluted with diethyl ether. The aqueous layer was
extracted with diethyl ether three times and the combined extracts were
washed with brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. A 9% solution of H2SO4 (3.0 mL) was added to the
resultant residue and the mixture was stirred for 48 h. The reaction was
quenched with 10% NaHCO3 and extracted with ether three times. The
extracts were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. Then (CF3CO)2O (2.0 mL) was added to the
solution of the above crude intermediate in dry CH2Cl2 (5 mL) and Et3N
(3.0 mL) at 08C. The mixture was stirred at room temperature for 8 h,
quenched with NaHCO3, and extracted with diethyl ether. The extracts
were washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification by column chromatography on silica
gel (elution with EtOAc/hexane ˆ 5:1 2:1) afforded 18c (272 mg, 43%) as
a yellow oil. IR (film): nÄ ˆ 2922, 2852, 1750, 1466, 1042, 922 cmÀ1; 1H NMR
(600 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 7.2 Hz, 3H), 1.22 1.40 (m, 34H), 1.40
(d, J ˆ 6.6 Hz, 3H), 1.48 1.58 (m, 6H) 2.26 (t, J ˆ 7.8 Hz, 2H), 3.38 (s, 6H),
3.48 3.51 (m, 4H), 3.58 3.64 (m, 4H), 3.67 3.71 (m, 2H), 4.65 (d, J ˆ
6.9 Hz, 2H), 4.76 (d, J ˆ 6.9 Hz, 2H), 4.99 (qd, J ˆ 6.6 Hz, 1.2 Hz, 1H),
6.98 ppm (d, J ˆ 1.2 Hz, 1H); 13C NMR (150 MHz, CDCl3): d ˆ 173.885,
148.11, 134.414, 96.059, 77.397, 76.280, 74.162, 71.042, 70.799, 69.225, 55.457,
55.214, 32.058, 31.929, 31.843, 29.768, 29.639, 29.553, 29.339, 29.210, 27.435,
25.489, 25.203, 22.684, 19.235, 14.111 ppm.
1
nÄ ˆ 3472, 2924, 2854, 1736, 1464, 1042 cmÀ1; H NMR (600 MHz, CDCl3):
d ˆ 0.88 (t, J ˆ 7.2 Hz, 3H), 1.25 1.48 (m, 38H), 1.52 (m, 2H), 1.67 (m, 2H),
1.94 (brs, 1H), 2.30 (t, J ˆ 7.2 Hz, 2H), 3.30 (t, J ˆ 7.8 Hz, 1H), 3.39 (s, 3H),
3.51 (m, 3H), 3.58 3.66 (m, 4H), 3.66 (s, 3H), 3.71 (m, 1H), 3.77 (m, 1H),
4.66 (d, J ˆ 6.9 Hz, 1H), 4.77 ppm (d, J ˆ 6.9 Hz, 1H); HRMS for
C33H66O7‡Na: 597.4700; found: 597.4695.
Compound 3d: The above protocol for 3c was applied to the coupling of
segments 4b and 5a to afford 3d: [a]1D8 ˆ ‡5.9 (c ˆ 0.38 in CHCl3); IR
(film): nÄ ˆ 3472, 2924, 2854, 1736, 1464, 1112, 1042, 922 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d ˆ 0.87 (t, J ˆ 6.6 Hz, 3H), 1.2 1.7 (m, 42H), 2.30 (t,
J ˆ 7.6 Hz, 2H), 2.40 (brs, 1H), 3.23 3.34 (m, 1H), 3.38 (s, 3H), 3.48 3.56
(m, 3H), 3.6 3.8 (m, 6H), 3.66 (s, 3H), 4.66 (d, J ˆ 6.9 Hz, 1H), 4.77 ppm
(d, J ˆ 6.9 Hz, 1H); HRMS for C33H66O7‡Na: 597.4700; found: 597.4707.
Compound 3b: The above protocol for 3c was applied to the coupling of
segments 4a and 5b to afford 3b: [a]2D0 ˆ À6.6 (c ˆ 4.6 in CHCl3); IR
(KBr): nÄ ˆ 2924, 2854,1734, 1364, 1148, 1044, 922, 726 cmÀ1
;
1H NMR
(600 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.9 Hz, 3H), 1.25 1.48 (m, 38H), 1.52
(m, 2H), 1.67 (m, 2H), 1.98 (brs, 1H), 2.30 (t, J ˆ 7.6 Hz, 2H), 3.30 (dd, J ˆ
12.6 Hz, 11.4 Hz, 1H), 3.38 (s, 3H), 3.48 3.56 (m, 3H), 3.60 3.8 (m, 4H),
3.66 (s, 3H), 3.71 (m, 1H), 3.78 (m, 1H), 4.66 (d, J ˆ 6.9 Hz, 2H), 4.76 ppm
‡
(d, J ˆ 6.9 Hz, 2H); MS (EI): m/z (%): 555 ([M‡1] , 0.48), 353 (5.08), 309
(20.6), 295 (100.0); HRMS for C33H66O7‡Na: 597.4700; found: 597.4693.
Compound 3a: The above protocol for 3c was applied to the coupling of
segments 4a and 5a to afford 3a: [a]2D0 ˆ À11.8 (c ˆ 3.2 in CHCl3); IR
Compound 18d: The above protocol for 18c was employed for the
transformation of 17d to 18d: IR (film): nÄ ˆ 2922, 2852, 1750, 1466, 1042,
922 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 7.2 Hz, 3H), 1.2 1.6
(m, 40H), 1.40 (d, J ˆ 6.6 Hz, 3H), 2.26 (t, J ˆ 7.8 Hz, 2H), 3.38 (s, 6H),
3.48 3.70 (m, 10H), 4.66 (d, J ˆ 6.9 Hz, 2H), 4.75 (d, J ˆ 6.9 Hz, 2H), 4.99
(qd, J ˆ 6.6 Hz, 1.2 Hz, 1H), 6.98 ppm (d, J ˆ 1.2 Hz, 1H); 13C NMR
(150 MHz, CDCl3): d ˆ 173.88, 148.81, 134.44, 96.703, 96.059, 77.397, 76.280,
(KBr): nÄ ˆ 3466, 2924, 2854, 1736, 1464, 1112, 1042, 922 cmÀ1
;
1H NMR
(600 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 7.2 Hz, 3H), 1.25 1.48 (m, 38H), 1.53
(m, 2H), 1.62 (m, 2H), 2.30 (t, J ˆ 7.2 Hz, 2H), 3.30 (t, J ˆ 7.8 Hz, 1H), 3.38
(s, 3H), 3.48 3.54 (m, 3H), 3.58 3.78 (m, 6H), 3.67 (s, 3H), 4.66 (d, J ˆ
6.9 Hz, 1H), 4.77 ppm (d, J ˆ 6.9 Hz, 1H); HRMS for C33H66O7‡Na:
597.4700; found: 597.4704.
288
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2003, 9, No. 1

Annonaceous Acetogenin Analogues
282 290
74.162, 71.042, 70.799, 69.826, 69.225, 55.457, 55.214, 32.058, 31.929, 31.843,
29.768, 29.639, 29.553, 29.339, 29.210, 27.435, 25.489, 25.203, 22.684, 19.235,
14.111 ppm.
Compound 21: Tetrabutylammonium bisulfate (0.067 g) and aqueous 50%
NaOH solution (2 mL) were added to a stirred mixture of compound 12b
(0.67 g, 4.24 mmol) and (R)-epichlorohydrin (0.36 g). After being stirred
for 22 h at room temperature, the reaction mixture was diluted with ether
(20 mL). The organic layer was washed with saturated NH4Cl and brine,
and dried over Na2SO4. Removal of solvent and purification by column
chromatography gave 21 (0.7 g, 88%). [a]2D0 ˆ À8.5 (c ˆ 7.67 in CHCl3); IR
Compound 18b: The above protocol for 18c was employed for the
transformation of 17b to 18b: IR (film): nÄ ˆ 2924, 2854, 1752, 1466, 1112,
1042, 922 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.9 Hz, 3H),
1.2 1.6 (m, 40H), 1.40 (d, J ˆ 6.6 Hz, 3H), 2.26 (t, J ˆ 7.8 Hz, 2H), 3.38 (s,
6H), 3.5 3.7 (m, 10H), 4.65 (d, J ˆ 6.9 Hz, 2H), 4.76 (d, J ˆ 6.9 Hz, 2H),
4.99 (q, J ˆ 6.6 Hz, 1H), 6.98 ppm (s, 1H).
(KBr): nÄ ˆ 2924, 2853, 1466, 1210, 1043, 920 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d ˆ 0.84 (t, J ˆ 6.6 Hz, 3H), 1.20 1.52 (m, 18H), 2.57 (dd, J ˆ
2.6, Hz, 5.0 Hz, 1H), 2.78 (t, J ˆ 4.5 Hz, 1H), 3.15 (m, 1H), 3.35 (s, 3H),
3.33 3.78 (m, 9H), 4.62 (d, J ˆ 6.7 Hz, 1H), 4.73 ppm (d, J ˆ 6.7 Hz, 1H);
Compound 18a: The above protocol for 18c was employed for the
‡
transformation of 17a to 18a: IR (film): nÄ ˆ 2924, 1752, 1466, 1042 cmÀ1
;
MS (EI): m/z (%): 346 ([M] ), 306 (38.91), 285 (5.96), 225 (100.00), 207
1H NMR (600 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 7.2 Hz, 3H), 1.22 1.58 (m,
40H), 1.40 (d, J ˆ 6.6 Hz, 3H), 2.26 (t, J ˆ 7.2 Hz, 2H), 3.38 (s, 6H), 3.46
3.72 (m, 10H), 4.65 (d, J ˆ 6.6 Hz, 2H), 4.76 (d, J ˆ 6.6 Hz, 2H), 4.98 (q, J ˆ
6.6 Hz, 1H), 6.98 ppm (s, 1H).
(13.04), 188 (70.76), 91 (66.07); HRMS (FAB) for C19H38O5‡Na: 369.2611;
found: 369.2607.
Compound 22: To a stirred solution of trimethylsilyl acetylene (1.3 mL,
9.16 mmol) in THF (5 mL) at À788C were added nBuLi (1.6m, 5.73 mL,
9.16 mmol), BF3 ¥ Et2O (1.24 mL, 9.16 mmol), and compound 21 (1.2 g,
3.5 mmol) in THF (2 mL) successively. After being stirred for 2 h, the
reaction was quenched by adding saturated NaHCO3, and the mixture was
extracted with ether. The combined organic layers were washed with
saturated brine, concentrated and chromatographed to give the acetylene
intermediate. [a]2D0 ˆ À7.67 (c ˆ 1.25 in CHCl3); 1H NMR (300 MHz,
CDCl3): d ˆ 0.14 (s, 9H), 0.86 (t, J ˆ 6.9 Hz, 3H), 1.2 1.3 (m, 16H), 1.53
(m, 2H), 2.47 (t, J ˆ 6.9 Hz, 2H), 3.36 (s, 1H), 3.42 3.52 (m, 3H), 3.56
3.66 (m, 6H), 3.92 (m, 1H), 4.65 (d, J ˆ 6.8 Hz, 1H), 4.78 ppm (d, J ˆ
Compound (15S,24S,36S)-2c: MOM-protected compound 18c (316 mg) in
6n HCl/THF/CH3OH (2:1:2, 15 mL) was stirred for 16 h at room temper-
ature. The reaction mixture was quenched with 10% NaHCO3 and
extracted with ether. The extracts were washed with saturated aqueous
NH4Cl and brine, dried over Na2SO4 and concentrated under reduced
pressure. The crude product was further purified by column chromatog-
raphy on silica gel to afford 2c (186 mg, 68%). [a]1D8 ˆ ‡16.3 (c ˆ 2.17 in
CHCl3); IR (film): nÄ ˆ 2922, 2852, 1750, 1466, 1042, 922cmÀ1
;
1H NMR
(600 MHz, CDCl3): d ˆ 0.87 (t, J ˆ 7.2 Hz, 3H), 1.20 1.48 (m, 38H), 1.36
(d, J ˆ 7.2 Hz, 3H), 1.53 (quint, J ˆ 7.8 Hz, 2H), 2.26 (t, J ˆ 7.8 Hz, 2H), 2.50
(brs, 2H, OH), 3.31 (dd, J ˆ 9.6 Hz, 8.4 Hz, 2H), 3.52 (dd, J ˆ 9.6 Hz,
10.2 Hz, 2H), 3.61 (m, 4H), 3.75 3.81 (m, 2H), 4.98 (dq, J ˆ 1.2 Hz, 7.2 Hz,
1H), 6.97 ppm (d, J ˆ 1.2 Hz, 1H); 13C NMR (150 MHz, CDCl3): d ˆ
173.88, 148.81, 134.41, 78.11, 76.72, 71.27, 70.49, 34.44, 32.63, 29.85, 29.64,
29.55, 29.34, 29.21, 27.44, 25.49, 25.20, 22.68, 19.24, 14.11 ppm; MS (EI): m/z
‡
5.5 Hz, 1H); MS (EI): m/z (%): 413 ([M À OCH3] , 1.68), 363 (0.85), 307
(3.50), 271 (5.61), 227 (6.63), 183 (4.46), 167 (43.55).
Tetrabutylammonium fluoride (1.0m, 3.8 mL) was added to a solution of
the above intermediate in THF (10 mL). The reaction mixture was stirred
for 2 h, diluted with ether and worked up as usual to give the crude terminal
acetylene intermediate. Into the solution of this crude intermediate and
diisopropylethyl amine (2.8 mL) was injected MOMCl (2 mL). After being
stirred for 8 h, the mixture was diluted with ether, washed with water and
with saturated brine, dried over Na2SO4, concentrated, and purified by
‡
(%): 555 ([M‡H] , 2.30), 353 (7.68), 309 (30.67), 295 (100.00); HRMS for
C33H62O6‡Na: 577.4438; found: 577.4437.
Compound 2d: The above deprotection procedure was employed for the
transformation of 18d to 2d: [a]2D0 ˆ À87.4 (c ˆ 0.35 in CHCl3); 1H NMR
(600 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.9 Hz, 3H), 1.20 1.48 (m, 38H), 1.40
(d, J ˆ 6.6 Hz, 3H), 1.55 (quint, J ˆ 7.2 Hz, 2H), 2.15 (brs, 2H, OH), 2.26
(brt, J ˆ 7.8 Hz, 2H), 3.32 (dd, J ˆ 9.6 Hz, 8.4 Hz, 2H), 3.53 (dd, J ˆ 9.6 Hz,
2.4 Hz, 2H), 3.62 3.72 (m, 4H), 3.78 (m, 2H), 4.99 (dq, J ˆ 1.2 Hz, 6.6 Hz,
1H), 6.98 ppm (d, J ˆ 1.2 Hz, 1H); 13C NMR (150 MHz, CD3COCD3): d ˆ
173.936, 150.757, 134.124, 78.016, 76.745, 71.323, 70.621, 70.504, 34.551,
32.651, 30.546, 29.435, 28.222, 26.337, 25.781, 23.341, 19.468, 14.352 ppm;
column chromatography to give compound 22 in 66% overall yield. [a]D20
ˆ
‡9.69 (c ˆ 0.46 in CHCl3); IR (film): nÄ ˆ 3300, 2925, 1466, 1043, 922 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 0.90 (t, J ˆ 7.2 Hz, 3H), 1.20 1.62 (m,
18H), 1.98 (t, J ˆ 2 Hz, 1H), 2.38 2.52 (m, 2H), 3.37 (s, 3H), 3.38 (s, 3H),
3.4 3.9 (m, 10H), 4.65 (d, J ˆ 6.9 Hz, 1H), 4.73 (s, 2H), 4.75 ppm (d, J ˆ
6.9 Hz, 1H); HRMS for C23H44O6‡Na: 439.3029; found: 439.3024.
Compound 28: In succession, nBuLi (1.6m, 1.375 mL, 2.2 mmol), BF3 ¥ Et2O
(0.3 mL, 2.2 mmol) and 2717 (262 mg, 1.1 mmol) in THF (3 mL) were
added to a stirred solution of compound 22 (922 mg, 2.2 mmol) in THF
(4 mL) at À788C over a 20 30-minute interval. After being stirred for 3 h,
the reaction was quenched by adding saturated NaHCO3, and the mixture
was extracted with diethyl ether. The combined organic layers were washed
with saturated brine, dried over MgSO4, concentrated under vacuum, and
‡
MS (EI): m/z (%): 555 ([M‡H] , 0.35), 353 (5.21), 309 (21.85), 295
‡
‡
(100.00); MS (FAB): m/z 578 ([M‡1‡Na] ), 555 ([M‡1] ); HRMS for
C33H62O6Na: 577.4438; found: 577.4433.
Compound 2b: The above deprotection procedure was employed for the
transformation of 18b to 2b: [a]2D0 ˆ À6.9 (c ˆ 0.40 in CHCl3); IR (KBr):
purified by column chromatography to afford 28 (350 mg, 51%): [a]D20
ˆ
nÄ ˆ 3470, 2927, 1748, 1464, 1042, 922 cmÀ1
;
1H NMR (600 MHz, CDCl3):
À10.9 (c ˆ 2.19 in CHCl3); IR (KBr): nÄ ˆ 3467, 2924, 1753, 1460, 1039,
1
922 cmÀ1; H NMR (300 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.9 Hz, 3H), 1.26
d ˆ 0.88 (t, J ˆ 6.9 Hz, 3H), 1.20 1.48 (m, 38H), 1.40 (d, J ˆ 6.6 Hz, 3H),
1.55 (quint, J ˆ 7.2 Hz, 2H), 2.15 (brs, 2H, OH), 2.26 (brt, J ˆ 7.8 Hz, 2H),
3.32 (dd, J ˆ 9.6 Hz, 8.4 Hz, 2H), 3.53 (dd, J ˆ 2.4 Hz, 9.6 Hz, 2H), 3.62
3.72 (m, 4H), 3.78 (m, 2H), 4.99 (dq, J ˆ 1.2 Hz, 6.6 Hz, 1H), 6.98 ppm (d,
1.60 (m, 30H), 1.41 (d, J ˆ 6.9 Hz, 3H), 2.24 (t, J ˆ 7 Hz, 2H), 2.4 2.6 (m,
4H), 3.39 (s, 3H), 3.41 (s, 3H), 3.3 4.0 (m, 11H), 4.63 (d, J ˆ 6.6 Hz, 1H),
4.7 4.8 (m, 3H), 4.98 (q, J ˆ 6.9 Hz, 1H), 6.99 ppm (d, J ˆ 1.7 Hz, 1H);
13C NMR (75 MHz, CDCl3): d ˆ 14.061, 19.161, 20.982, 22.135, 22.621,
25.110, 25.414, 25.596, 27.341, 27.812, 29.269, 29.405, 29.557, 29.694, 31.849,
31.985, 36.235, 55.434, 70.034, 70.626, 70.868, 72.644, 74.101, 74.708, 76.165,
77.334, 95.895, 134.278, 148.832 ppm; MS (EI): m/z (%): 615 (7.11), 460
(5.57), 225 (66.74), 207 (8.64); HRMS (FAB) for C37H66O9‡Na: 677.4599;
found: 677.4603.
‡
J ˆ 1.2 Hz, 1H); MS (EI): m/z (%): 555 ([M‡1] , 0.48), 353 (5.08), 323
(0.30), 309 (20.55), 295 (100.00); 13C NMR (150 MHz, CD3COCD3): d ˆ
173.936, 150.757, 134.124, 78.16, 76.745, 71.323, 70.504, 34.551, 34.507,
32.651, 30.545, 29.435, 28.222, 26.337, 25.781, 23.341, 19.468, 14.352 ppm;
HRMS for C33H62O6‡Na: 577.4438; found: 577.4445.
Compound 2a: The above deprotection procedure was employed for the
transformation of 18a to 2a: [a]2D0 ˆ ‡3.4 (c ˆ 2.31 in CHCl3); IR (KBr):
Compound 20: A solution of NaOAc (0.88 g, 28 mmol) in H2O (15 mL) was
added dropwise to a solution of 28 (90 mg, 0.138 mmol) and para-
toluenesulfonyl hydrazone (1.77 g, 9.5 mmol) in dimethoxylethane
(15 mL) under reflux over 5 h. The reaction mixture was then cooled to
room temperature and poured into water. The mixture was extracted with
ether and the extracts were washed with brine, dried, and concentrated to
give a crude intermediate. The crude product obtained was then dissolved
into dimethyl sulfide (8 mL), cooled in an ice water bath and treated with
BF3 ¥ Et2O (0.78 mL, 6.15 mmol). After being stirred for 30 min, the
reaction mixture was quenched with saturated NaHCO3, and extracted
with ethyl acetate. The combined extracts were washed with water and then
saturated brine, dried, concentrated, and purified by column chromatog-
nÄ ˆ 3474, 2922, 1748, 1464, 1108, 1040, 922 cmÀ1
;
1H NMR (600 MHz,
CDCl3): d ˆ 0.88 (t, J ˆ 6.9 Hz, 3H), 1.20 1.50 (m, 38H), 1.40 (d, J ˆ 7.2 Hz,
3H), 1.55 (quint, J ˆ 6.6 Hz, 2H), 2.26 (brt, J ˆ 7.8 Hz, 2H), 3.32 (dd, J ˆ
9.6 Hz, 8.4 Hz, 2H), 3.53 (dd, J ˆ 9.6, 10.2 Hz, 2H), 3.60 3.72(m, 4H),
3.74 3.83 (m, 2H), 4.99 (dq, J ˆ 1.2 Hz, 7.2 Hz, 1H), 6.98 ppm (d, J ˆ
1.2 Hz, 1H); 13C NMR (150 MHz, CD3COCD3): d ˆ 174.259, 151.104,
134.272, 78.224, 75.136, 71.574, 70.297, 33.768, 32.611, 30.399, 29.702, 29.629,
29.584, 29.525, 29.348, 29.201, 27.430, 25.931, 25.708, 23.289, 19.430,
‡
14.339 ppm; MS (EI): m/z (%): 505 ([M‡1] , 0.38), 353 (5.86), 309
(22.75), 295 (100.00), 267 (4.39); HRMS for C33H62O6‡Na: 577.4438;
found: 577.4437.
Chem. Eur. J. 2003, 9, No. 1
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0901-0289 $ 20.00+.50/0
289

Y.-L. Wu et al.
FULL PAPER
raphy to give 20 (50 mg, 64%): [a]2D0 ˆ ‡18.7 (c ˆ 0.57 in CHCl3); IR
Zeng, Q. Ye, N. H. Oberlies, G. E. Shi, Z. M. Gu, K. He, J. L.
McLaughlin, Nat. Prod. Reports 1996, 275 306; d) A. Cave, B.
Figadere, A. Laurens, D. Cortes, Prog. Chem. Org. Nat. Prod. 1997, 70,
81 288; e) F. Q. Alali, X.-X. Liu, J. L. McLaughlin, J. Nat. Prod. 1999,
62, 504 540.
(KBr): nÄ ˆ 3420, 2922, 2852, 1741, 1465, 1325, 1150, 1084 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.7 Hz, 3H), 1.26 1.60 (m, 38H), 1.41
(d, J ˆ 6.9 Hz, 3H), 2.27 (dt, J ˆ 1.7 Hz, 6.6 Hz, 2H), 2.86 (brs, 3OH), 3.32
(dt, J ˆ 2.8 Hz, 8.9 Hz, 2H), 3.52 3.73 (m, 7H), 3.79 (m, 2H), 5.01 (dq, J ˆ
1.7 Hz, 6.9 Hz, 1H), 6.99 ppm (d, J ˆ 1.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d ˆ 14.128, 19.237, 22.703, 25.185, 25.495, 25.568, 25.633, 27.410,
29.130, 29.281, 29.346, 29.559, 29.584, 29.630, 29.710, 31.924, 32.885, 33.036,
37.346, 37.497, 70.094, 70.315, 70.510, 70.561, 71.736, 75.855, 75.903, 76.614,
[2] M. C. Gonzalez, J. R. Tormo, A. Bermejo, M. C. Zafra-polo, E.
Estornell, D. Cortes, Bioorg. Med. Chem. Lett. 1997, 7, 1113 1118 and
references therein.
[3] N. H. Oberlies, V. L. Croy, M. L. Harrison, J. L. McLaughlin, Cancer
Lett. 1997, 115, 73 79.
[4] For recent reviews, see: a) G. Cassiraghi, F. Zanardi, L. Battistini, G.
Rassu, G. Appendino, Chemtracts Org. Chem. 1998, 11, 803 827;
b) A. Tanaka, T. Oritani, J. Syn. Org. Chem. Jpn. 1997, 55, 877 885;
some recent publications: c) S. Baurle, U. Peters, T. Friedrich, U.
Koert, Eur. J. Org. Chem. 2000, 2207 2217; d) N. Maezaki, N. Kojima,
A. Sakamoto, C. Iwata, T. Tanaka, Org. Lett. 2001, 3, 429 432; e) S. D.
Burke, L. Jiang, Org. Lett. 2001, 3, 1953 1955; f) L. J. Dsouza, S. C.
Sinha, S. F. Lu, E. Keinan, S. C. Sinha, Tetrahedron 2001, 57, 5255
5265; g) H. Makabe, Y. Hattori, A. Tanaka, T. Oritani, Org. Lett. 2002,
4, 1083 1085.
[5] a) S. Sasaki, K. Muruta, H. Naito, H. Sugihara, K. Hiratani, M. Maeda,
Tetrahedron Lett. 1995, 36, 5571 5574; b) S. Sasaki, K. Muruta, H.
Naito, R. Maemura, E. Kawahara, M. Maeda, Tetrahedron 1998, 54,
2401 2410.
[6] H. Araya, Y. Fujimoto, K. Hirayama, J. Syn. Org. Chem. Jpn. 1994, 52,
765 777.
[7] J.-F. Peyrat, J. Mahuteau, B. Figadere, A. Cave, J. Org. Chem. 1997, 62,
4811 4815.
[8] Z.-J. Yao, H.-P. Wu, Y.-L. Wu, J. Med. Chem. 2000, 43(12), 2484 2487.
‡
134.317, 148.908, 173.895 ppm; MS (EI): m/z: 571 ([M‡1] ); HRMS (FAB)
for C33H62O7‡Na: 593.4387; found: 593.4397.
Compound 29: A solution of nBuLi in hexane (1.23 mL, 1.6m, 1.96 mmol)
was added to a solution of diisopropylamine (0.41 mL, 2.94 mmol) in THF
(6 mL) at 08C. The reaction mixture was stirred at 08C for 30 min and
cooled down to À788C, and (15S,24S)-17c (0.606 g, 0.981 mmol) in dry
THF (2.0 mL) was then added. After 30 min, O-THP-(R)-lactaldehyde
(232 mg, 1.47 mmol) in dry THF (6 mL) was added. The reaction mixture
was stirred for 2 h, quenched with saturated aqueous NH4Cl and diluted
with diethyl ether. The aqueous layer was extracted with diethyl ether three
times and the combined extracts were washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure. To the
resultant residue was added 9% H2SO4 (5 mL), and the mixture was stirred
for 48 h, quenched with 10% NaHCO3, and extracted with ether three
times. The extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. (CF3CO)2O (0.26 mL) was added to
the solution of the above residue in dry CH2Cl2 (5 mL) and Et3N (0.52 mL)
at 08C. The reaction mixture was stirred at room temperature for 8 h,
quenched with NaHCO3, and extracted with ether. The extracts were
washed with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by column chromatography on silica gel
(EtOAc/hexane ˆ 5:1 to 2:1) afforded 29 (0.378 mg, 60%) as a yellow oil.
[a]2D0 ˆ À25.8 (c ˆ 0.39 in CHCl3); IR (film): nÄ ˆ 2927, 2855, 1760, 1467,
¬
[9] Gree et al. published a synthetic endeavor aiming at similar targets:
¬
¬
Y. L. Huerou, J. Doyon, R. Gree, J. Org. Chem. 1999, 64, 6782 6790.
However, they only completed the construction of the two chiral
centers adjacent to the ethereal links without introducing the
butenolide moiety. In 2000 they reported the synthesis of a set of 16
simplified analogues with a ketolactone moiety instead of the usual
1
1319, 1145, 1111, 1040, 919 cmÀ1; H NMR (300 MHz, CDCl3): d ˆ 0.89 (t,
J ˆ 6.9 Hz, 3H), 1.21 1.58 (m, 40H), 1.42 (d, J ˆ 6.9 Hz, 3H), 2.28 (t, J ˆ
7.5 Hz, 2H), 3.39 (s, 6H), 3.46 3.76 (m, 10H), 4.67 (d, J ˆ 6.9 Hz, 2H), 4.77
(d, J ˆ 6.9 Hz, 2H), 5.01 (qd, J ˆ 7.1 Hz, 1.5 Hz, 1H), 7.00 ppm (d, J ˆ
1.8 Hz, 1H); 13C NMR (150 MHz, CDCl3): d ˆ 168.129, 148.830, 134.382,
96.677, 96.034, 79.235, 76.607, 76.264, 74.141, 71.030, 70.779, 55.465, 55.220,
32.059, 31.934, 31.835, 29.784, 29.644, 29.559, 29.352, 29.217, 27.443, 25.487,
¬
butenolide one: S. Rodier, Y. L. Huerou, B. Renoux, J. Doyon, P.
¬
Renard, A. Pirre, J.-P. Gesson, R. Gree, Bioorg. Med. Chem. Lett.
2000, 10, 1373 1375. Koert et al. reported the design, synthesis and
bioactivity of other analogues of annonaceous acetogenins: a) S.
Hoppen, U. Emde, T. Friedrich, L. Grubert, U. Koert, Angew. Chem.
2000, 112, 2184 2184; Angew. Chem. Int. Ed. 2000, 39, 2099 2102;
b) S. Arndt, U. Emde, S. B‰urle, T. Friedrich, L. Grubert, U. Koert,
Chem. Eur. J. 2001, 7, 993 1005.
‡
25.206, 22.702, 19.238, 14.132 ppm; MS (ESI): m/z: 665 ([M‡Na] ); HRMS
‡
(ESI) calcd for C37H70O8Na [M‡Na] : 665.4923; found 665.4963.
Compound 30: To a solution of 29 (0.161 g, 0.174 mmol) in dimethyl sulfide
(4 mL) was added BF3 ¥ Et2O (0.47 mL, 3.15 mmol) at 08C. The reaction
mixture was stirred at room temperature for 40 min and quenched with
saturated aqueous NaHCO3 (5.4 mL). The mixture was extracted with ethyl
acetate (3 Â 15 mL), and the extracts were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified by column chromatography to afford compound 30 (83 mg, 60%)
as a waxy solid. [a]2D5 ˆ À7.7 (c ˆ 0.78 in CHCl3); IR (film): nÄ ˆ 3506, 3415,
2916, 2850, 1751, 1738, 1655, 1470, 1327, 1141, 1118, 1100, 1031, 909, 881,
[10] Part of our synthetic endeavors of simplified annonaceous acetogenins
described in this paper has been published as a communication: B.-B.
Zeng, Y. Wu, Q. Yu, Y.-L. Wu, Y. Li, X.-G. Chen, Angew. Chem. 2000,
112, 2010 2013; Angew. Chem. Int. Ed. 2000, 39, 1934 1937.
[11] a) Z.-J. Yao, Y.-L. Wu, J. Org. Chem. 1995, 60(5), 1170 1176; b) Q.
Yu, Z.-J. Yao, X.-G. Chen, Y.-L. Wu, J. Org. Chem. 1999, 64(7), 2440
2445; c) T.-S. Hu, Q. Yu, Y.-L Wu, Y. Wu, J. Org. Chem. 2001, 66(3),
853 861.
[12] Y.-F. Wang, Y.-L. Wu, Hecheng Huaxue 1993, 1, 215 219 [Chem.
Abstr. 1994, 121, 133755p).
[13] a) N. Nagashima, M. Ohno, Chem. Lett. 1987, 141 144; b) H.-S. Byun,
E. R. Kumar, R. Bittman, J. Org. Chem. 1994, 59, 2630 2633; c) R.
1
720 cmÀ1; H NMR (300 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.9 Hz, 3H), 1.19
1.52 (m, 40H), 1.41 (d, J ˆ 6.9 Hz, 3H), 2.26 (t, J ˆ 7.8 Hz, 2H), 3.32 (dd,
J ˆ 8.4, 9.8 Hz, 2H), 3.54 (dd, J ˆ 2.7, 9.9 Hz, 2H), 3.61 3.73 (m, 4H),
3.76 3.83 (m, 2H), 5.00 (dq, J ˆ 1.8, 6.8 Hz, 1H), 6.99 ppm (d, J ˆ 1.5 Hz,
1H); 13C NMR (75 MHz, CDCl3): d ˆ 173.897, 148.837, 134.353, 76.597,
75.901, 70.515, 70.271, 33.019, 31.909, 29.689, 29.606, 29.559, 29.513, 29.327,
29.307, 29.186, 27.413, 25.555, 25.180, 22.687, 19.223, 14.107 ppm; MS (ESI):
¬
MartÌnez-Bernhardt, P. P. Castro, G. Godjoian, C. G. Gutierrez,
Tetrahedron 1998, 54, 8919 8932.
[14] Y.-C. Wang, F.-C. Liu, Synth. Commun. 1994, 24, 1265 1269.
[15] Similar strategies have been employed in the total synthesis of natural
acetogenins; see, e.g.: a) J. Marshall, H.-J. Jiang, J. Org. Chem. 1998,
63, 7066 7071; b) S. Hanessian, T. A. Grillo, J. Org. Chem. 1998, 63,
1049 1057.
[16] See, e.g. Q. Yu, Y.-K. Wu, Y.-L. Wu, J. Chem. Soc. Perkin Trans. 1 1999,
1183 1188 and references therein.
[17] a) M. H. Woo, L. Zeng, J. L. McLaughlin, Heterocycles, 1995, 41,
1731 1742; b) G.-X. Zhao, Z.-M. Gu, L. Zeng, J.-F. Chao, J. F.
Koslofski, K. V. Wood, J. L. McLaughlin, Tetrahedron, 1995, 51, 7149
7160.
‡
‡
m/z: 577 ([M‡Na] ); HRMS (ESI) calcd for C33H62O6Na [M‡Na] :
577.4438; found 577.4438.
Acknowledgements
We are grateful to the National Natural Science Foundation of China
(29790126), the Chinese Academy of Sciences (95-A1-504-03) and the
Ministry of Science and Technology of China (G2000077502) for financial
support.
[18] Q. Yu, Y.-K. Wu, L.-J. Xia, M.-H. Tang, Y.-L. Wu, Chem. Commun.
1999, 129 130.
[1] Reviews: a) J. K. Rupprecht, Y. H. Hui, J. L. McLaughlin, J. Nat.
Prod. 1990, 53, 237 278; b) X. P. Fang, M. J. Rieser, Z. M. Gu, G. X.
Zhao, J. L. McLaughlin, Phytochem. Analysis 1993, 4, 27 48; c) L.
Received: August 2, 2002 [F4311]
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