A facile route to bulladecin-type acetogenins - Total synthesis of asimilobin and correction of the configuration of its tetrahydrofuran segment

Article abstract of DOI:10.1002/(SICI)1099-0690(200001)2000:2<349::AID-EJOC349>3.0.CO;2-J

The most efficient method for the synthesis of the trans/threo/trans- bis(tetrahydrofuran) (THF) ring unit was established, and the first total synthesis of (-)-asimilobin and its diastereomer was then accomplished in twelve and fourteen steps, respectively, from trans-1,5,9-decatriene, by a convergent route with a Wittig reaction as the key step. By virtue of these synthetic results, the absolute configuration of the bis(THF) unit in naturally occurring asimilobin should be corrected.

Full text of DOI:10.1002/(SICI)1099-0690(200001)2000:2<349::AID-EJOC349>3.0.CO;2-J

FULL PAPER
A Facile Route to Bulladecin-Type Acetogenins – Total Synthesis of Asimilobin
and Correction of the Configuration of Its Tetrahydrofuran Segment
Zhi-Min Wang,*[a] Shi-Kai Tian,[a] and Min Shi*[a]
Keywords: Sharpless asymmetric dihydroxylation / Asimilobin / Tetrahydrofuran ring / Wittig reaction / Annonaceous
acetogenins
The most efficient method for the synthesis of the trans/
threo/trans-bis(tetrahydrofuran) (THF) ring unit was
a convergent route with a Wittig reaction as the key step. By
virtue of these synthetic results, the absolute configuration
established, and the first total synthesis of (–)-asimilobin and of the bis(THF) unit in naturally occurring asimilobin should
its diastereomer was then accomplished in twelve and
be corrected.
fourteen steps, respectively, from trans-1,5,9-decatriene, by
Our first target compound is asimilobin, a relatively rare
bulladecin-type acetogenin.[1b] Asimilobin was isolated by
McLaughlinЈs group, both from the seeds of Asimina trilo-
ba[7a] and from the bark of Goniothalamus giganteus (An-
nonaceae),[7b] and showed cytotoxicity values comparable
with adriamycin against six human solid-tumor cell lines.
The absolute configuration of asimilobin was determined to
be 1a (Figure 2) by spectroscopic analysis.[7a] The striking
characteristic of this compound is the adjacent trans/threo/
trans-bis(THF) ring core with only one threo-flanking
hydroxy group at the α-position.
Introduction
In the past few years, considerable attention was paid to
the rapidly growing class of naturally occurring Annona-
ceous acetogenins, due to their broad spectrum of biological
activities such as cytotoxic, antitumor, antimicrobial, anti-
malarial, antifeedant, pesticidal, and immunosuppressive
effects.[1] This class of polyketide-derived fatty acids was
isolated from the Annonaceae family of tropical and sub-
tropical trees. They are characterized by the presence of one
to three THF rings in the center of a long hydrocarbon
chain which has a butenolide moiety at the end. Their po-
tent biological activity as well as their unique and diverse
structures make Annonaceous acetogenins attractive targets
for synthetic chemists.
Stereocontrolled construction of the THF units played a
central role in the reported total syntheses of Annonaceous
acetogenins.[2][3] Recently, several reports showed more con-
venient approaches to various THF units.[4] One of these
reports, by Sinha, is on a very effective and useful synthetic
method for the stereocontrolled construction of bis- or
tris(THF) units by the oxidative cyclization of trans,-
trans,trans-trienol with CF3CO2ReO3. [4h] Because we are
interested in the stereocontrolled construction of such THF
units, we successfully synthesized all the configurations of
mono- and bis(THF) units[5] (Figure 1). One of these THF
units was already used in the total synthesis of (ϩ)-rollinias-
tatin (1) by Koert.[6] To explore more efficient routes, in
order to establish large chemical libraries of Annonaceous
acetogenins for comprehensive biological screening, the to-
tal syntheses by routine organic procedures of several other
types of such interesting compounds are being carried out
in our laboratory.
Figure 2. Asimilobin
We have already reported the first total synthesis of (Ϫ)-
asimilobin (1a) and (ϩ)-asimilobin (1b), and the correction
of the absolute configuration of naturally occurring asimi-
lobin as a preliminary communication.[8] In this paper we
will describe the full details of this total synthesis. As shown
in Scheme 1, a convergent route to 1a with a Wittig reaction
as a key step was adopted. The two segments 2a and 3,
can be synthesized from trans-1,5,9-decatriene (5) and -
glutamic acid, respectively.
Results and Discussion
In our earlier efforts towards the stereocontrolled con-
struction of THF units, we developed a much more efficient
synthetic method to the trans/threo/trans-bis(THF) ring
building block 4a, which had been synthesized previously
with 80% de in fifteen steps by Wagner and Koert.[9] Com-
pound 4a could be synthesized according to our method in
only two steps, in which metal-catalyzed asymmetric ap-
proaches were utilized (Scheme 2). Regioselective oxidation
of the starting material 5 by the Sharpless asymmetric dihy-
droxylation (AD) reaction,[10] installed the two primitive
Figure 1. mono- and bis-(THF) units in Annonaceous acetogenins
[a]
Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032, China
Eur. J. Org. Chem. 2000, 349Ϫ356
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0102Ϫ349 $ 17.50ϩ.50/0
349

Z.-M. Wang, S-K. Tan, M. Shi
FULL PAPER
group by catalytic hydrogenation over Pd/C, led to the
bis(THF) ring segment 11a.
The preparation of the other segment 3 is shown in
Scheme 3. Epoxide 6[17] was opened by lithium alkynylide,
prepared from compound 12 in the presence of BF3·OEt2,
and the resulting alcohol 13 was treated with MOMCl/
iPr2NEt to give compound 14. Aldol condensation of the
enolate prepared from ester 14 with the aldehyde 15[18] pro-
duced adduct 16 (mixture of diastereomers). Protection of
the newly generated hydroxy group in compound 16 as a
methoxymethyl ether and subsequent treatment with a 1:3
mixture of 9% aqueous H2SO4 and THF[18] afforded lac-
tone 17. Bromination of the propargyl alcohol 17 gave com-
pound 18, which was then treated with PPh3 to afford the
Wittig salt 3.
Scheme 1. Retrosynthesis of Asimilobin
stereogenic centers in more than 94% ee[11] in the bis(THF)
ring backbone. The resulting dienediol 7a was smoothly ox-
idized and cyclized when Co(modp)2 [bis(1-morpholinocar-
bamoyl-4,4-dimethyl-1,3-pentanedionato)cobalt(II)][14] was
used as a catalyst under oxygen, and the C2-symmetric com-
pound 4a[12] was formed in 96% de,[13] as determined by
GC/MS analysis of its dimethyl ether. To the best of our
knowledge, this synthetic route is much shorter and more
efficient than any other reported in the literature so far.[9]
Scheme 3. Conditions: a) 12, BuLi, THF, Ϫ78°C, then BF3·OEt2,
then 6, 83%; b) MOMCl, iPr2NEt, CH2Cl2, 86%; c) LDA, THF,
Ϫ78°C, then 15, 80%; d) 9% H2SO4, THF, 65% (two steps); e)
PPh3, CBr4, CH2Cl2, 89%; f) PPh3, PhH, 87%
The coupling reaction between aldehyde 2a, newly pre-
pared from alcohol 11a, and the ylide prepared from Wittig
salt 3 in situ gave enyne 19a[19] (Scheme 4). Compound 19a
was hydrogenated in the presence of Pd/C and then treated
with DBU[18] to afford compound 20a. Deprotection of 20a
with BF3·OEt2 gave the title compound 1a. Thus, the total
synthesis of 1a was accomplished in twelve steps and in a
total yield of 2.0% from trans-1,5,9-decatriene (5). This, to
the best of our knowledge, is the shortest synthetic route
for the total synthesis of naturally occurring Annonaceous
acetogenins with one or two THF rings.[2][3]
Scheme 2. Conditions: a) K3Fe(CN)6, K2CO3, MeSO2NH2,
(DHQ)2PHAL, K2OsO2(OH)4, tBuOH/H2O (1:1), 0°C; 57%; b)
Co(modp)2, TBHP, O2, iPrOH, 78%; c) NaH, BnBr, THF, 71%; d)
Swern oxidation; e) CH3(CH2)13MgCl, CuBr·SMe2, Et2O, Ϫ78 to
0°C; 49% (two steps); f) MOMCl, iPr2NEt, CH2Cl2; 87%; g) H2,
Pd/C, EtOH, 93%
The spectral data of the obtained target compound, (Ϫ)-
asimilobin (1a), are consistent with those of naturally oc-
curring asimilobin reported in the literature.[7] However, the
Diol 4a was monoprotected as the benzyl ether 8a. Swern specific rotation is discrepant: our synthetic sample of 1a:
20
20
oxidation of the resulting alcohol 8a gave an aldehyde, [α]D ϭ Ϫ11.4 (c ϭ 0.70, CHCl3), [α]D ϭ Ϫ11.9 (c ϭ
which was allowed to react with CH3(CH2)13MgCl in the 0.43, CH2Cl2); naturally occurring asimilobin: ref.[7a]
presence of CuBr·SMe2,[15] to give compound 9a[16] (9a and [α]D ϭ ϩ6.0 (c ϭ 0.05, CHCl3); ref.[7b] [α]D ϭ ϩ11.3 (c ϭ
9b were separated by column chromatography, 9a/9b ϭ 1.00, CH2Cl2).
7.1:1). Protection of the secondary alcohol 9a as a meth-
We are certain that the stereochemistry of our synthetic
oxymethyl ether, and subsequent removal of the benzyl sample is that of (Ϫ)-asimilobin (1a), because the absolute
350
Eur. J. Org. Chem. 2000, 349Ϫ356

A Facile Route to Bulladecin-Type Acetogenins
FULL PAPER
The synthetic route to compound 1b (Scheme 5) is similar
to that of compound 1a, but has two distinct differences.
Firstly, we used the chiral ligand (DHQD)2PHAL instead
of (DHQ)2PHAL to introduce the first two stereogenic cen-
ters by Sharpless AD reaction. Secondly, to improve the
selectivity in the construction of C-18 stereogenic center,
we selected to reduce ketone 21 with -Selectride, to afford
alcohol 9c with much higher stereoselectivity (17:1). The
total synthesis of 1b was then accomplished in fourteen
steps and in a total yield of 1.7% from trans-1,5,9-decatri-
ene (5).
Scheme 4. Conditions: a) Swern oxidation; b) 3, tBuOK, THF, Ϫ78
to 0°C, 32% (two steps); c) Pd/C, H2, EtOH; d) DBU, THF, 56%
(two steps); e) BF3·OEt2, DMS, 79%
configuration of dienediol 7a was confirmed by an alterna-
tive preparation,[11] and both the stereogenic centers in the
butenolide segment came from enantiomerically pure natu-
ral products. The consistency of the spectral data, and the
large discrepancy in specific rotation suggest that the two
compounds are enantiomers or diastereomers. The fact that
the relative configurations of the two stereogenic regions
[THF ring segment (C10ϪC18) and butenolide segment (C-
4 and C-34)] in naturally occurring asimilobin are the same
as those of our synthetic sample, and the fact that there is
1
no interference in the H and 13C NMR spectral data be-
tween the two stereogenic regions (since they are separated
by a five-carbon chain), allows us to conclude that only
three isomers (1b؊d, Figure 3) could have the same spectral
data as those of compound 1a. Only one of them, however,
corresponds to the structure of naturally occurring asimilo-
bin. Considering that the butenolides in Annonaceous ace-
togenins usually have the (4R,34S) configuration, which
was further unambiguously confirmed by synthetic mod-
els,[7a] the THF ring segment of the naturally occurring asi-
milobin is more likely to have the absolute configuration
opposite to that of compound 1a. The more probable struc-
ture of naturally occurring asimilobin is therefore 1b. To
confirm this and to examine the feasibility of utilizing this
route to synthesize the other diastereomers of compound
1a, we carried out the total synthesis of compound 1b.
Scheme 5. Conditions: a) K3Fe(CN)6, K2CO3, MeSO2NH2,
(DHQD)2PHAL, K2OsO2(OH)4, tBuOH/H2O (1:1), 0°C, 59%; b)
Co(modp)2, TBHP, O2, iPrOH, 80%; c) NaH, BnBr, THF, 64%; d)
Swern oxidation; e) CH3(CH2)13MgCl, THF, Ϫ78 to 0°C, 72%
(two steps); f) -Selectride, THF, Ϫ78°C, 68% (two steps); g)
MOMCl, iPr2NEt, CH2Cl2, 83%; h) H2, Pd/C, EtOH, 91%: i) 3,
tBuOK, THF, Ϫ78 to 0°C, 28% (two steps); j) DBU, THF, 63%
(two steps); k) BF3·OEt2, DMS, 76%
We found that the obtained synthetic sample of (ϩ)-asi-
milobin (1b)[20] {[α]D24 ϭ ϩ6.4 (c ϭ 0.36, CHCl3); [α]D24 ϭ
ϩ7.0 (c ϭ 0.10, CH2Cl2)},[8] had the same spectral data as
those of compound 1a, and a specific rotation which was
very close to the specific rotation reported in the litera-
ture.[7a] It is well known that the optical rotation is depen-
dent on solvent and concentration. We therefore carefully
measured the specific rotation of 1b again in the same con-
24
centration of chloroform and dichloromethane {[α]D
ϭ
ϩ6.7 (c ϭ 0.05, CHCl3); [α]D24 ϭ ϩ7.9 (c ϭ 1.0, CH2Cl2)}.
We are therefore convinced that the absolute configuration
of the bis(THF) ring segment of naturally occurring asimi-
lobin is opposite to that reported in the literature. Its cor-
rect absolute configuration should be that of 1b.
Figure 3. Possible structures of Asimilobin
Eur. J. Org. Chem. 2000, 349Ϫ356
351

Z.-M. Wang, S-K. Tan, M. Shi
FULL PAPER
300 MHz): δ ϭ 1.52Ϫ1.68 (m, 2 H), 1.70Ϫ1.85 (m, 2 H), 1.91Ϫ2.05
(m, 4 H), 2.49 (br, s, 2 H), 3.50 (dd, J ϭ 11.8, 5.3 Hz, 2 H), 3.71
(dd, J ϭ 11.8, 2.6 Hz, 2 H), 3.85Ϫ3.95 (m, 2 H), 4.10Ϫ4.21 (m, 2
H). Ϫ EI-MS; m/z: 171, 153, 101. Ϫ C10H18O4 (202.2): calcd. C
59.39, H 8.97; found: C 59.32, H 8.94.
Conclusion
We have developed: (i) an efficient synthetic method for
the stereocontrolled construction of adjacent trans/threo/
trans-bis(THF) ring units, (ii) a short and convenient route
to couple this key intermediate with other building blocks,
and (iii) the first total synthesis of (Ϫ)-asimilobin and (ϩ)-
asimilobin in twelve and fourteen steps, respectively, from
the achiral starting materials 5. To study the relationship
between structure and biological activity, the syntheses of
asimilobin analogs are in progress.
(2S,5S,6S,9S)-1-Benzyloxy-2,5;6,9-diepoxy-1-decanol (8a): To
a
solution of diol 4a (1.01 g, 5.00 mmol) in dry THF (50 mL) at 0°C
was added NaH (120 mg, 5.00 mmol); the reaction mixture was
stirred for 1 h, then a solution of benzyl bromide (855 mg,
0.596 mL, 5.00 mmol) in THF (2 mL) was added dropwise over
10 min. After stirring for 8 h, the solvent was removed under re-
duced pressure. To the obtained residue was added water and
EtOAc. After separation, the aqueous layer was extracted with
EtOAc. The combined organic extracts were dried with MgSO4 and
concentrated under reduced pressure. The residue was purified by
flash chromatography (EtOAc/petroleum ether, 2:3) to give 8a
(1.03 g, 71%) as a colorless oil. Ϫ [α]D20 ϭ Ϫ6.3 (c ϭ 1.00, CHCl3).
Experimental Section
General: Optical rotations were determined in solutions of either
CHCl3 or CH2Cl2, at room temperature, and with a PerkinϪElmer-
241 MC digital polarimeter; [α]D values are given in units of 10Ϫ1
Ϫ
1H NMR (CDCl3, 300 MHz): δ ϭ 1.55Ϫ1.81 (m, 4 H),
1.91Ϫ2.10 (m, 4 H), 3.46Ϫ3.57 (m, 3 H), 3.70 (dd, J ϭ 11.7, 3.2 Hz,
1 H), 3.86Ϫ3.96 (m, 2 H), 4.09Ϫ4.17 (m, 1 H), 4.18Ϫ4.26 (m, 1
H), 4.56 (s, 2 H), 7.25Ϫ7.39 (m, 5 H). Ϫ 13C NMR (CDCl3,
75 MHz): δ ϭ 27.47, 28.44, 28.70, 28.79, 64.64, 72.79, 73.39, 78.48,
79.95, 82.20, 82.21, 127.62, 127.68, 128.36, 138.45. Ϫ EI-MS; m/z
(%): 293 [MHϩ] (11.0), 261 (3.21), 201 (26.6). Ϫ IR (neat): ν˜ ϭ
3426, 1601, 1495 cmϪ1. Ϫ HRMS: calcd. for C17H24O4 292.1675;
found 292.1678.
deg cm2 gϪ1. Ϫ H NMR and 13C NMR spectra were determined
1
on solutions in CDCl3, with tetramethylsilane (TMS) as internal
standard, at 300 MHz and 75 MHz, respectively, with a Bruker
AMX-300 spectrometer. Ϫ IR spectra were determined on neat
samples, or on solutions in CHCl3, with a PerkinϪElmer 983 spec-
trometer. Ϫ Mass spectra were recorded with an HP-5989 instru-
ment. High-mass spectra were recorded with a Finnigan MAϩ in-
strument. Ϫ Microanalyses were performed with a CarloϪErba
1106 analyzer. Ϫ Organic solvents were dried by standard methods
when necessary. Commercially obtained reagents were used without
further purification. Ϫ All reactions were monitored by TLC with
Huanghai 60F254 silica-gel-coated plates. Ϫ Flash column chroma-
tography was carried out with 300Ϫ400-mesh silica gel.
(2S,5S,6S,9S,10S)-1-Benzyloxy-2,5;6,9-diepoxy-10-tetracosanol
(9a): To
a solution of oxalyl chloride (125 mg, 0.086 mL,
0.98 mmol) in dry CH2Cl2 (10 mL) at Ϫ78°C under nitrogen was
added DMSO (153 mg, 0.140 mL, 1.96 mmol) as a solution in
CH2Cl2 (1 mL). After stirring for 10 min, a solution of 8a (181 mg,
0.620 mmol) in CH2Cl2 (2 mL) was added and the reaction mixture
was stirred for 2 h. Triethylamine (0.50 mL) was then added and
the mixture was allowed to warm to room temperature. After 1 h,
the reaction was quenched with water and extracted with CH2Cl2.
The organic extracts were washed with saturated brine and dried
with MgSO4. After concentration under reduced pressure, the
crude aldehyde was obtained. Freshly prepared CH3(CH2)13MgCl
(0.20 , 9.3 mL, 1.86 mmol) in ether was added to a solution of
CuBr·SMe2 (382 mg, 1.86 mmol) in SMe2 (4 mL) at Ϫ40°C under
nitrogen. After stirring for 15 min, the reaction mixture was cooled
to Ϫ78°C and added to a solution of the above-mentioned alde-
hyde in ether (2 mL). The reaction mixture was stirred for 1 h and
allowed to warm to room temperature. Saturated aqueous am-
monium chloride was added and the mixture was extracted with
ether. The organic layers were washed with saturated brine and
dried with MgSO4. After concentration under reduced pressure, the
residue was purified by flash chromatography (EtOAc/petroleum
ether, 1:15) to give 9a (149 mg, 49%) and 9b (21 mg, 6.9%), both
(5S,6S)-1,9-Decadiene-5,6-diol (7a): To a well-stirred solution of
(DHQ)2PHAL (1.09 g, 1.40 mmol), K2OsO2(OH)4 (309 mg,
0.840 mmol), K3Fe(CN)6 (139 g, 421 mmol), K2CO3 (58.1 g,
421 mmol), and MeSO2NH2 (13.3 g, 140 mmol) in tBuOH/H2O
(1:1) (1400 mL) at 0°C was added triene 5 (19.1 g, 140 mmol).
After stirring vigorously for 12 h, the reaction was quenched with
Na2SO3 (140 g) and extracted with EtOAc. The organic layers were
dried with MgSO4 and then concentrated under reduced pressure.
The residue was purified by flash chromatography (EtOAc/petro-
leum ether, 1:10) to give 7a (13.6 g, 57%) as a colorless oil. Ϫ
[α]D20 ϭ Ϫ21.3 (c ϭ 3.30, CHCl3). Ϫ 1H NMR (CDCl3, 300 MHz):
δ ϭ 1.48Ϫ1.68 (m, 4 H), 2.10Ϫ2.39 (m, 4 H), 2.37 (br, s, 2 H),
3.42Ϫ3.53 (m, 2 H), 4.98 (dm, J ϭ 10.0 Hz, 2 H), 5.04 (dm, J ϭ
17.3 Hz, 2 H), 5.83 (ddt, J ϭ 17.3, 10.0, 6.6 Hz, 2 H). Ϫ 13C NMR
(CDCl3, 75 MHz): δ ϭ 29.87, 32.56, 73.82, 114.91, 138.23. Ϫ EI-
MS; m/z (%):171 [MHϩ] (14.5), 153 (100), 135 (50.0), 85 (14.3). Ϫ
IR (neat) ν˜ ϭ 3402, 1639 cmϪ1. Ϫ HRMS: calcd. for C10H18O2
170.1307; found 170.1309.
13
as colorless oils. Ϫ 9a: [α]D ϭ Ϫ11.4 (c ϭ 2.42, CHCl3). Ϫ 1H
(2S,5S,6S,9S)-2,5;6,9-Diepoxydecane-1,10-diol (4a): To a solution
of 7a (1.70 g, 10.0 mmol) in iPrOH (250 mL) were added Co(m-
NMR (CDCl3, 300 MHz): δ ϭ 0.88 (t, J ϭ 6.9 Hz, 3 H), 1.15Ϫ1.36
(m, 24 H), 1.36Ϫ1.45 (m, 2 H), 1.58Ϫ1.80 (m, 4 H), 1.90Ϫ2.11 (m,
odp)2 (2.16 g, 4.00 mmol) and tBuOOH (1.80 g, 20.0 mmol); the 4 H), 2.51 (br, s, 1 H), 3.34Ϫ3.43 (m, 1 H), 3.47 (dd, J ϭ 10.0,
reaction mixture was heated at 60°C under pure oxygen for 3 h,
before it was cooled to room temperature. Saturated aqueous
4.9 Hz, 1 H), 3.53 (dd, J ϭ 10.0, 5.2 Hz, 1 H), 3.80Ϫ3.98 (m, 3 H),
4.19Ϫ4.24 (m, 1 H), 4.57 (s, 2 H), 7.27Ϫ7.39 (m, 5 H). Ϫ 13C NMR
Na2S2O3 (10 mL) was added to the reaction mixture and the re- (CDCl3, 75 MHz): δ ϭ 14.19, 22.75, 25.72, 28.42, 28.50, 28.80,
sulting solution was stirred for a further 10 min. iPrOH was evapo-
rated under reduced pressure. The residue was extracted with
EtOAc. The organic extracts were dried with MgSO4 and concen-
trated under reduced pressure. The residue was purified by flash
chromatography (MeOH/petroleum ether, 1:10) to give 4a (1.57 g
28.91, 29.42, 29.73, 31.98, 33.49, 72.80, 73.37, 74.12, 78.57, 81.96,
81.97, 83.12, 127.57, 127.70, 128.37, 138.45. Ϫ EI-MS; m/z (%):
489 [MHϩ] (2.44), 471 (11.0), 397 (9.03), 381 (18.8). Ϫ IR (neat):
ν˜ ϭ 3466, 1495, 1466 cmϪ1. Ϫ C31H52O4 (488.7): calcd. C 76.18,
13
H 10.72; found C 75.79, H 10.91. Ϫ 9b: [α]D ϭ Ϫ9.8 (c ϭ 2.50,
78%) as a colorless oil. Ϫ [α]D18 ϭ ϩ18.5 (c ϭ 0.80, CHCl3) {ref.[9]
:
CHCl3). Ϫ H NMR (CDCl3, 300 MHz): δ ϭ 0.88 (t, J ϭ 6.9 Hz,
1
20
[α]D ϭ ϩ12.5 (c ϭ 0.80, CHCl3)}. Ϫ 1H NMR (CDCl3, 3 H), 1.15Ϫ1.45 (m, 26 H), 1.58Ϫ1.67 (m, 2 H), 1.68Ϫ1.86 (m,
352
Eur. J. Org. Chem. 2000, 349Ϫ356

A Facile Route to Bulladecin-Type Acetogenins
FULL PAPER
20
2 H), 1.86Ϫ2.11 (m, 4 H), 2.21 (br, s, 1 H), 3.48 (dd, J ϭ 10.0, Ϫ [α]D ϭ Ϫ5.4 (c ϭ 1.25, CHCl3). Ϫ 1H NMR (CDCl3,
5.1 Hz, 1 H), 3.55 (dd, J ϭ 10.0, 4.9 Hz, 1 H), 3.85Ϫ3.96 (m, 4 H), 300 MHz): δ ϭ 1.49Ϫ1.69 (m, 3 H), 1.69Ϫ1.97 (m, 5 H), 2.35Ϫ2.59
4.17Ϫ4.26 (m, 1 H), 4.56 (s, 2 H), 7.27Ϫ7.39 (m, 5 H). Ϫ 13C NMR (m, 4 H), 3.48Ϫ3.58 (m, 1 H), 3.67 (s, 3 H), 3.68Ϫ3.89 (m, 2 H),
(CDCl3, 75 MHz): δ ϭ 14.19, 22.75, 24.54, 26.11, 28.41, 28.85,
4.17Ϫ4.34 (m, 2 H), 4.79 (t, J ϭ 3.1 Hz, 1 H), period Ϫ EI-MS;
29.42, 29.62, 31.98, 32.46, 71.24, 72.77, 73.40, 78.49, 82.45, 82.63, m/z (%): 271 [MHϩ] (1.0), 253 (0.3), 239 (1. 8), 201 (0.2). Ϫ IR
82.64, 127.57, 127.70, 128.37, 138.45. Ϫ EI-MS; m/z (%): 489
[MHϩ] (3.19), 487 (2.19), 471 (16.6), 397 (14.0), 381 (30.0). Ϫ IR
(neat): ν˜ ϭ 3466, 1495, 1466 cmϪ1. Ϫ HRMS: calcd. for C31H52O4
488.3866; found 488.3879.
(neat): ν˜ ϭ 3440, 2232, 1734 cmϪ1. Ϫ HRMS: calcd. for C13H18O4
[M Ϫ CH3OH] 238.1205; found 238.1192.
Methyl (4S)-4-(Methoxymethoxy)-8-O-(tetrahydropyran-2-yl)-6-oc-
tynoate (14): This compound was prepared by the same procedure
as that used for the preparation of 10a. Ether 14 was obtained as
(2S,5S,6S,9S,10S)-1-Benzyloxy-2,5;6,9-diepoxy-10-(methoxy-
methoxy)tetracosane (10a): Ethyldiisopropylamine (221 mg,
0.300 mL, 1.71 mmol) was added to a solution of 9a (355 mg,
0.686 mmol) in dry CH2Cl2 (4 mL) at 0°C, followed by the addition
of chloromethyl methyl ether (110 mg, 0.100 mL, 1.37 mmol). The
reaction mixture was stirred at room temperature for 1 d and was
then quenched with water and extracted with CH2Cl2. The organic
layers were washed with saturated brine and dried with MgSO4.
After concentration, the residue was purified by flash chromatogra-
phy (EtOAc/petroleum ether, 1:20) to give 10a (328 mg, 90%) as a
20
a colorless oil (8.94 g, 86%). Ϫ [α]D ϭ Ϫ33.6 (c ϭ 1.92, CHCl3).
Ϫ
1H NMR (CDCl3, 300 MHz): δ ϭ 1.49Ϫ1.64 (m, 4 H),
1.64Ϫ2.08 (m, 4 H), 2.37Ϫ2.55 (m, 4 H), 3.37 (s, 3 H), 3.48Ϫ3.56
(m, 1 H), 3.66 (s, 3 H), 3.65Ϫ3.74 (m, 1 H), 3.76Ϫ3.87 (m, 1 H),
4.15Ϫ4.31 (m, 2 H), 4.62 (d, J ϭ 7.0 Hz, 1 H), 4.69 (d, J ϭ 7.0 Hz,
1 H), 4.78 (t, J ϭ 3.2 Hz, 1 H), period Ϫ EI-MS; m/z (%): 315
[MHϩ], 283 (0.6), 253 (0.7), 231 (7.4). Ϫ IR (neat): ν˜ ϭ 2239,
1736 cmϪ1. Ϫ HRMS: calcd. for C16H26O6 314.1729; found
314.1762.
13
colorless oil. Ϫ [α]D ϭ Ϫ25.0 (c ϭ 1.17, CHCl3). Ϫ 1H NMR
Methyl (2RS,4S)-2-{[(1RS,2S)-1-Hydroxy-2-O-(tetrahydropyran-2-
yl)]propyl}-4-(methoxymethoxy)-8-O-(tetrahydropyran-2-yl)-6-
octynoate (16): To a solution of diisopropylamine (1.28 g, 1.77 mL,
12.7 mmol) in dry THF (40 mL) was added a solution of nBuLi
(2.5 , 4.25 mL, 10.6 mmol) at Ϫ78°C under nitrogen. The mixture
was stirred for 15 min and a solution of 14 (2.78 g, 8.85 mmol) in
THF (5 mL) was added. After stirring for 30 min, a solution of
newly prepared aldehyde 15 (1.67 g, 10.6 mmol) in THF (5 mL)
was added to the reaction solution. The reaction mixture was
stirred for 30 min and quenched with aqueous ammonium chloride
solution. After warming to room temperature, the mixture was ex-
tracted with EtOAc. The organic layer was washed with saturated
brine and dried with MgSO4. After concentration under reduced
pressure, the residue was purified by flash chromatography (EtOAc/
petroleum ether, 1:5) to give 16 (3.36 g, 80%) as a colorless oil. Ϫ
(CDCl3, 300 MHz): δ ϭ 0.88 (t, J ϭ 6.9 Hz, 3 H), 1.20Ϫ1.35 (m,
24 H), 1.35Ϫ1.54 (m, 2 H), 1.61Ϫ1.81 (m, 4 H), 1.87Ϫ2.07 (m, 4
H), 3.39 (s, 3 H), 3.45 (dd, J ϭ 10.0, 4.9 Hz, 1 H), 3.51 (dd, J ϭ
10.0, 5.2 Hz, 1 H), 3.44Ϫ3.53 (m, 1 H), 3.88Ϫ3.99 (m, 2 H),
4.00Ϫ4.07 (m, 1 H), 4.18Ϫ4.23 (m, 1 H), 4.56 (s, 2 H), 4.67 (d, J ϭ
6.8 Hz, 1 H), 4.81 (d, J ϭ 6.8 Hz, 1 H), 7.27Ϫ7.39 (m, 5 H). Ϫ
13C NMR (CDCl3, 75 MHz): δ ϭ 14.17, 22.76, 25.77, 28.28, 28.85,
29.43, 29.74, 29.91, 31.10, 32.00, 55.77, 72.98, 73.37, 78.53, 79.73,
81.63, 81.63, 81.71, 96.84, 127.55, 127.71, 128.38, 138.61. Ϫ EI-
MS; m/z (%): 531 [Mϩ Ϫ H] (5.42), 501 (25.8), 471 (46.7), 455
(37.4). Ϫ IR (neat): ν˜ ϭ 1495, 1466 cmϪ1. Ϫ C33H56O5 (532.8):
calcd. C 74.39, H 10.59; found C 74.32, H 10.94.
(2S,5S,6S,9S,10S)-2,5;6,9-Diepoxy-10-(methoxymethoxy)-1-tetra-
cosanol (11a): To a solution of 10a (176 mg, 0.331 mmol) in EtOH
(5 mL) was added 10% Pd/C (30 mg); the mixture was hydrogen-
ated under 1 atm pressure at 40°C for 10 h. After filtration and
concentration, the residue was purified by flash chromatography
(EtOAc/petroleum ether, 1:3) to give 11a (136 mg, 93%) as a color-
less oil. Ϫ [α]D14 ϭ Ϫ11.9 (c ϭ 2.35, CHCl3). Ϫ 1H NMR (CDCl3,
300 MHz): δ ϭ 0.88 (t, J ϭ 6.9 Hz, 3 H), 1.20Ϫ1.35 (m, 24 H),
1.35Ϫ1.54 (m, 2 H), 1.61Ϫ1.82 (m, 4 H), 1.87Ϫ2.08 (m, 4 H), 3.40
(s, 3 H), 3.43Ϫ3.57 (m, 2 H), 3.63Ϫ3.74 (m, 1 H), 3.88Ϫ3.98 (m,
2 H), 4.00Ϫ4.10 (m, 1 H), 4.10Ϫ4.25 (m, 1 H), 4.67 (d, J ϭ 6.8 Hz,
1 H), 4.81 (d, J ϭ 6.8 Hz, 1 H). Ϫ 13C NMR (CDCl3, 75 MHz):
δ ϭ 14.18, 22.76, 25.77, 27.54, 28.12, 28.53, 28.78, 29.44, 29.74,
31.05, 32.01, 55.79, 64.84, 79.78, 79.98, 81.84, 81.85, 96.90, period
Ϫ EI-MS; m/z (%): 411 (12.5), 381 (26.0), 365 (10.4), 309 (16.9). Ϫ
IR(neat): ν˜ ϭ 3426 cmϪ1. Ϫ C26H50O5 (442.7): calcd. C 70.54, H
11.38; found C 70.40, H 11.50.
20
1
[α]D ϭ Ϫ3.2 (c ϭ 2.0, CHCl3). Ϫ H NMR (CDCl3, 300 MHz):
δ ϭ 1.25 (d, J ϭ 6.4 Hz, 3 H), 1.49Ϫ1.64 (m, 8 H), 1.64Ϫ1.87 (m,
4 H), 1.98Ϫ2.11 (m, 1 H), 2.13Ϫ2.28 (m, 1 H), 2.49Ϫ2.58 (m, 2
H), 2.88Ϫ2.97 (m, 1 H), 3.38 (s, 3 H), 3.48Ϫ3.56 (m, 2 H), 3.68 (s,
3 H), 3.65Ϫ3.74 (m, 2 H), 3.75Ϫ3.97 (m, 3 H), 4.15Ϫ4.31 (m, 2
H), 4.60Ϫ4.70 (m, 3 H), 4.80Ϫ4.85 (m, 1 H). Ϫ EI-MS: m/z 389
(3.4), 357 (5.4), 305 (1.5), 273 (4.5). Ϫ IR (neat): ν˜ ϭ 3462, 2223,
1734 cmϪ1. Ϫ C24H40O9 (472.6): calcd. C 61.00, H 8.53; found C
61.12, H 8.61.
(3RS,4RS,5S)-3-[(2S)-6-Hydroxy-2-(methoxymethoxy)-4-hexynyl]-
4-(methoxymethoxy)-5-methyldihydrofuran-2(3H,4H,5H)-one (17):
The newly generated hydroxy group in 16 (3.24 g, 6.86 mmol) was
protected by an MOM ether, in a similar manner to that used for
the preparation of 10a. The obtained product was dissolved in
THF (50 mL), and 9% sulfuric acid (18 mL) was added. The reac-
tion mixture was stirred at room temperature for 16 h and extracted
Methyl
(4S)-4-Hydroxy-8-O-(tetrahydropyran-2-yl)-6-octynoate with EtOAc. The organic layer was washed with saturated brine
(13): To a solution of 12 (6.72 g, 48.0 mmol) in dry THF (95 mL)
and dried with MgSO4. After concentration under reduced press-
was added a solution of nBuLi (2.5  in hexane, 19.2 mL, ure, the residue was purified by flash chromatography (EtOAc/
48.0 mmol) at Ϫ78°C under nitrogen. The mixture was stirred for
20 min and BF3·OEt2 (6.0 mL, 48.0 mmol) was added. After stir-
petroleum ether, 1:3) to give 17 (1.42 g, 65%) as a colorless oil. Ϫ
[α]D20 ϭ Ϫ32.5 (c ϭ 1.10, CHCl3). Ϫ 1H NMR (CDCl3, 300 MHz):
ring for a further 15 min, a solution of epoxide 6 (5.21 g, δ ϭ 1.48 (d, J ϭ 6.4 Hz, 3 H), 1.83Ϫ2.08 (m, 1 H), 2.20Ϫ2.33 (m,
40.0 mmol) in THF (20 mL) was added dropwise. The reaction 1 H), 2.55Ϫ2.60 (m, 2 H), 2.85Ϫ2.92 (m, 1 H), 3.38 (s, 3 H), 3.41
mixture was stirred for 30 min and quenched with aqueous am-
monium chloride solution. After warming to room temperature,
the mixture was extracted with EtOAc. The organic layers were
washed with saturated brine and dried with MgSO4. After concen-
tration, the residue was purified by flash chromatography (EtOAc/
petroleum ether, 1:10), to give 13 (8.94 g, 83%) as a colorless oil.
(s, 3 H), 3.88Ϫ4.00 (m, 2 H), 4.20Ϫ4.28 (m, 2 H), 4.30Ϫ4.35 (m,
1 H), 4.65Ϫ4.78 (m, 4 H). Ϫ EI-MS: m/z 255 (0.43), 247 (5.92),
217 (4.57). Ϫ IR (neat): ν˜ ϭ 3434, 2225, 1772 cmϪ1. Ϫ HRMS:
calcd. for C11H19O6 [M Ϫ CH2CϵCCH2OH] 247.1182; found
247.1180. Ϫ C15H24O7 (316.4): calcd. C 56.95, H 7.65; found C
56.72, H 7.56.
Eur. J. Org. Chem. 2000, 349Ϫ356
353

Z.-M. Wang, S-K. Tan, M. Shi
FULL PAPER
(3RS,4RS,5S)-3-[(2S)-6-Bromo-2-(methoxymethoxy)-4-hexynyl]-4-
(methoxymethoxy)-5-methyldihydrofuran-2(3H,4H,5H)-one (18): To
a solution of 17 (432 mg, 1.37 mmol) in dry CH2Cl2 (5 mL) was
added CBr4 (684 mg, 2.06 mmol) and PPh3 (431 mg, 1.64 mmol) at
0°C. After being stirred for 5 min, the mixture was purified by flash
chromatography (EtOAc/petroleum ether, 1:6) to give 18 (461 mg,
89%) as a colorless oil. Ϫ [α]D20 ϭ Ϫ41.9 (c ϭ 0.80, CHCl3). Ϫ 1H
NMR (CDCl3, 300 MHz): δ ϭ 1.48 (d, J ϭ 6.4 Hz, 3 H), 1.86Ϫ2.03
(m, less than 1 H), 2.18Ϫ2.27 (m, more than 1 H), 2.59Ϫ2.65 (m,
2 H), 2.85Ϫ2.92 (m, 1 H), 3.38 (s, 3 H), 3.41 (s, 3 H), 3.85Ϫ3.98
(m, 2 H), 3.92 (t, J ϭ 1.2 Hz, 2 H), 4.33Ϫ4.40 (m, 1 H), 4.66Ϫ4.76
(m, 4 H). Ϫ EI-MS; m/z (%): 379 [MHϩ] (0.872), 348 (0.94), 346
EI-MS; m/z: 591, 531, 449. Ϫ IR (neat): ν˜ ϭ 1757 cmϪ1. Ϫ for
C39H70O8 (667.0): calcd. C 70.23, H 10.58; found C 70.34, H 10.35.
(؊)-Asimilobin (1a): To a solution of 20a (16 mg, 0.024 mmol) in
SMe2 (5 mL) was added BF3·OEt2 (0.20 mL) at 0°C. The reaction
mixture was stirred at room temperature for 30 min, quenched with
water, and extracted with EtOAc. The organic layer was washed
with saturated brine and dried with MgSO4. After concentration
under reduced pressure, the residue was purified by flash chroma-
tography (EtOAc/petroleum ether, 1:1) to give 1 (11 mg, 79%) as a
20
20
white waxy solid. Ϫ [α]D ϭ Ϫ11.4 (c ϭ 0.70, CHCl3); [α]D
ϭ
Ϫ11.9 (c ϭ 0.43, CH2Cl2); ref.[7a]: [α]D ϭ ϩ6.0 (c ϭ 0.05, CHCl3);
ref.[7b]: [α]D ϭ ϩ11.3 (c ϭ 1.00, CH2Cl2). Ϫ 1H NMR (CDCl3,
300 MHz): δ ϭ 0.88 (t, J ϭ 7.0 Hz, 3 H), 1.20Ϫ1.36 (m, 30 H),
1.36Ϫ1.54 (m, 6 H), 1.43 (d, J ϭ 7.0 Hz, 3 H), 1.54Ϫ1.72 (m, 5 H),
1.89Ϫ2.06 (m, 3 H), 2.34Ϫ2.45 (m, 1 H), 2.53 (dm, J ϭ 15.0 Hz, 1
H), 3.34Ϫ3.44 (m, 1 H), 3.76Ϫ3.90 (m, 4 H), 3.90Ϫ3.98 (m, 1 H),
5.06 (q, J ϭ 7.0 Hz, 1 H), 7.18Ϫ7.21 (m, 1 H). Ϫ 13C NMR
(CDCl3, 75 MHz): δ ϭ 14.19, 19.16, 22.77, 25.56, 25.63, 25.69,
25.75, 26.11, 28.49, 28.79, 28.83, 28.99, 29.43, 29.53, 29.76, 32.01,
32.14, 33.46, 33.57, 35.74, 37.39, 69.97, 74.25, 78.04, 79.98, 81.33,
82.12, 83.20, 131.20, 151.90, 174.65. Ϫ EI-MS; m/z (%): 579 [MHϩ]
(14.4), 561 [M Ϫ OH] (15.7), 543 (19.7), 527 (13.1), 525 (13.9). Ϫ
IR (CHCl3): ν˜ ϭ 3422, 1747 cmϪ1. Ϫ UV: λmax ϭ 209 nm (EtOH);
ref.[7b]: λmax ϭ 209 nm (EtOH). Ϫ HRMS: calcd. for C35H62O6
578.4546; found 578.4502. Ϫ C35H62O6 (578.9): calcd. C 72.62, H
10.80; found C 72.47, H 10.54.
(0.93), 247 (4.02), 217 (3.81). Ϫ IR (neat): ν˜ ϭ 2233, 1771 cmϪ1
.
Ϫ HRMS: calcd. for C11H19O6 [M Ϫ CH2CϵCCH2Br]: 247.1182;
found 247.1167.
Preparation of Phosphonium Salt 3: To a solution of 18 (276 mg,
0.728 mmol) in dry benzene (2 mL) was added PPh3 (197 mg,
0.750 mmol) and the reaction mixture was stirred at room tempera-
ture for 14 h, ether (30 mL) was then added to the reaction mixture
which was then stirred for 5 min. The precipitate was isolated by
filtration and dried in vacuum to give 3 as a yellowish powder.
(3RS,4RS,5S)-3-[(2S,8S,11S,12S,15S,16S)-8,11;12,15-Diepoxy-
2,16-bis(methoxymethoxy)tricosa-4-yn-6-enyl]-4-(methoxymethoxy)-
5-methyldihydrofuran-2(3H,4H,5H)-one (19a): The above-men-
tioned salt 3 was added to dry THF (8 mL) and cooled to Ϫ78°C
under argon. After adding tBuOK (72 mg, 0.64 mmol), the mixture
was allowed to warm to Ϫ50°C, stirred for 15 min, and then cooled
again to Ϫ78°C. Freshly prepared aldehyde 2a [from 11a (111 mg,
0.25 mmol) by Swern oxidation] was added as a solution in THF
(1 mL), and the reaction mixture was further stirred for another
1 h. After warming to room temperature, the reaction was
quenched with water and extracted with EtOAc. The organic layer
was washed with saturated brine and dried with MgSO4. After con-
centration under reduced pressure, the residue was purified by flash
chromatography (EtOAc/petroleum ether, 1:3) to give 19a (57 mg,
(5R,6R)-1,9-Decadiene-5,6-diol (7b): The procedure was the same
as that used for the preparation of 7a, except that chiral ligand
(DHQD)2PHAL was added instead of (DHQ)2PHAL. To a well-
stirred solution of (DHQD)2PHAL (218 mg, 0.28 mmol), K2O-
sO2(OH)4 (62 mg, 0.17 mmol), K3Fe(CN)6 (27.7 g, 83.90 mmol),
K2CO3 (11.6 g, 84.1 mmol), and MeSO2NH2 (2.66 g, 28.0 mmol)
in tBuOH/H2O (1:1) (280 mL) at 0°C was added triene 5 (3.82 g,
28.10 mmol). After being stirred vigorously for 12 h, the reaction
was quenched with Na2SO3 (60 g) and extracted with EtOAc. The
organic layers were dried with MgSO4 and then concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy (EtOAc/petroleum ether, 1:10) to give 7b (2.82 g, 59%) as a
1
32%) as a colorless oil. Ϫ H NMR (CDCl3, 300 MHz): δ ϭ 0.88
(t, J ϭ 6.9 Hz, 3 H), 1.20Ϫ1.36 (m, 24 H), 1.36Ϫ1.54 (m, 2 H),
1.48 (d, J ϭ 6.4 Hz, 3 H), 1.58Ϫ1.80 (m, 3 H), 1.88Ϫ2.07 (m, 5
H), 2.16Ϫ2.27 (m, 2 H), 2.61Ϫ2.70 (m, 2 H), 2.86Ϫ2.94 (m, 1 H),
3.37Ϫ3.45 (m, 9 H), 3.48Ϫ3.57 (m, 1 H), 3.86Ϫ3.99 (m, 4 H),
4.00Ϫ4.10 (m, 1 H), 4.31Ϫ4.40 (m, 1 H), 4.67Ϫ4.78 (m, 5 H), 4.82
(d, J ϭ 6.9 Hz, 1 H), 4.88Ϫ4.98 (m, 1 H), 5.45Ϫ5.53 (m, 1 H),
5.84Ϫ5.96 (m, 1 H). Ϫ EI-MS; m/z (%): 723 [MHϩ] (2.17), 691
(4.12), 661 (3.43), 646 (6.72), 631 (7.31), 616 (8.12). Ϫ IR (neat):
ν˜ ϭ 1774 cmϪ1. Ϫ C41H70O10 (723.0): calcd. C 68.11, H 9.76; found
C 68.07, H 9.50.
20
colorless oil. Ϫ [α]D ϭ ϩ22.0 (c ϭ 4.00, CHCl3). Ϫ The spectral
data are the same as those of 7a.
(2R,5R,6R,9R)-2,5;6,9-Diepoxydecane-1,10-diol (4b): This com-
pound was synthesized from 7b by the same procedure as that used
20
for the preparation of 4a. Ϫ [α]D ϭ Ϫ20.1 (c ϭ 1.20, CHCl3). Ϫ
The spectral data are the same as those of 4a.
Diastereomers 9c and 9d: These were synthesized from 4b by a pro-
cedure similar to that used for the preparation of 9a and 9b, except
(5S)-3-[(2R,8R,11S,12S,15S,16S)-8,11;12,15-Diepoxy-2,16-bis- that CuBr·SMe2 was not added during the Grignard reaction step.
(methoxymethoxy)tricosyl]-5-methylfuran-2(5H)-one (20a): To To a solution of oxalyl chloride (61 mg, 0.042 mL, 0.48 mmol) in
a
solution of 19a (41 mg, 0.057 mmol) in EtOH (2 mL) was added dry CH2Cl2 (5 mL) at Ϫ78°C under nitrogen was added DMSO
10% Pd/C (10 mg); the reaction mixture was stirred under 1 atm (75 mg, 0.067 mL, 0.96 mmol) as a solution in CH2Cl2 (1 mL).
pressure of hydrogen at room temperature for 7 h. After filtration After being stirred for 10 min, a solution of the monobenzyl ether
and concentration, the residue was dissolved in THF (5 mL), and
DBU (50 mg) was added. The reaction mixture was stirred over-
of 4b (70 mg, 0.24 mmol) in CH2Cl2 (2 mL) was added and the
reaction mixture was stirred for 2 h. Triethylamine (1.0 mL) was
night at room temperature. After removal of the solvent, the residue then added and the mixture was allowed to warm to room tempera-
was purified by flash chromatography (EtOAc/petroleum ether, 1:3) ture. After 1 h, the reaction was quenched with water and extracted
20
to give 20a (21 mg, 56%) as a colorless oil. Ϫ [α]D ϭ Ϫ24.1 (c ϭ
with CH2Cl2. The organic extracts were washed with saturated
1.00, CHCl3). Ϫ 1H NMR (CDCl3, 300 MHz): δ ϭ 0.88 (t, J ϭ brine and dried with MgSO4. After being concentrated under re-
6.9 Hz, 3 H), 1.20Ϫ1.36 (m, 30 H), 1.36Ϫ1.54 (m, 8 H), 1.43 (d, duced pressure, the crude aldehyde was obtained. Freshly prepared
J ϭ 7.0 Hz, 3 H), 1.58Ϫ1.75 (m, 3 H), 1.90Ϫ2.07 (m, 3 H), 2.51 CH3(CH2)13MgCl (0.48 , 2.0 mL, 0.96 mmol) in ether was cooled
(d, J ϭ 5.8 Hz, 2 H), 3.35Ϫ3.42 (m, 6 H), 3.47Ϫ3.56 (m, 1 H), to Ϫ78°C under nitrogen and the solution was added to a solution
3.75Ϫ3.97 (m, 4 H), 3.98Ϫ4.07 (m, 1 H), 4.67Ϫ4.78 (m, 3 H), 4.82 of the above-mentioned aldehyde in THF (2 mL). The reaction
(d, J ϭ 6.9 Hz, 1 H), 4.98Ϫ5.08 (m, 1 H), 7.18Ϫ7.21 (m, 1 H). Ϫ mixture was stirred for 1 h and allowed to warm to room tempera-
354
Eur. J. Org. Chem. 2000, 349Ϫ356

A Facile Route to Bulladecin-Type Acetogenins
FULL PAPER
ture. Saturated aqueous ammonium chloride was added and the
mixture was extracted with ether. The organic layers were washed
with saturated brine and dried with MgSO4. After being concen-
trated under reduced pressure, the residue was purified by flash
chromatography (EtOAc/petroleum ether, 1:15), which gave 9c and
9d as a colorless oil. They were immediately used for the next reac-
tion.
[M Ϫ H Ϫ Na], 528. Ϫ IR (CHCl3): ν˜ ϭ 3430, 1750 cmϪ1. Ϫ
HRMS: calcd. for C35H62O6 578.4546; found 578.4528.
Ϫ
C35H62O6 (578.9): calcd. C 72.62, H 10.80; found C 72.38, H 10.64.
Acknowledgments
We thank the National Natural Sciences Foundation of China and
the Shanghai-Unilever Research & Development Fund for finan-
cial support.
(2R,5R,6R,9R,10R)-1-Benzyloxy-2,5;6,9-diepoxy-10-tetracosanol
(9c): A pair of diastereomers (9c ϩ 9d) (484 mg, 0.992 mmol) was
oxidized by the Swern method to give ketone 21. To a solution of
21 in THF (5 mL) was slowly added a solution of -Selectride (1.0
, 2.0 mL, 2.0 mmol) at Ϫ78°C under argon. After the reaction
mixture was stirred for 1 h, MeOH (2 mL) was added slowly. The
reaction mixture was allowed to warm to room temperature and it
was concentrated under reduced pressure. The residue was purified
by flash chromatography (EtOAc/petroleum ether, 1:15) to give 9c
(328 mg, 68%) and 9d (19 mg, 4%), both as colorless oils. Ϫ 9c:
[α]D20 ϭ ϩ14.7 (c ϭ 2.10, CHCl3). Ϫ Its spectral data are the same
as those of 9a.
[1]
Recent reviews: [1a] A. Cave, B. Figadere, A. Laurens, D. Cortes
´
`
in Progress in the Chemistry of Organic Nature Products (Ed.:
W. Hertz), Natural, Springer Verlag; Wien, New York, 1997,
[1b]
vol. 70, pp. 81Ϫ288. Ϫ
L. Zeng, Q. Ye, N. H. Oberlies, G.
Shi, Z.-M. Gu, K. He, J. L. McLaughlin, Nat. Prod. Rep. 1996,
13, 275Ϫ306.
[2]
[2a]
Recent syntheses (after 1996):
A. Yazbak, S. C. Sinha, E.
Keinan, J. Org. Chem. 1998, 63, 5863Ϫ5868. Ϫ [2b] S. C. Sinha,
A. Sinha, S. C. Sinha, E. Keinan, J. Am. Chem. Soc. 1998, 120,
[2c]
˚
S. E. Schaus, J. Branalt, E. N. Jacobsen, J.
[2d]
4017Ϫ4020. Ϫ
Org. Chem. 1998, 63, 4876Ϫ4877. Ϫ
J. A. Marshall, H. Ji-
[2e]
(2R,5R,6R,9R,10R)-2,5;6,9-Diepoxy-10-(methoxymethoxy)-1-tetra-
cosanol (11b): This compound was synthesized from 9c according
to the same procedure as that used for the preparation of 11a. Ϫ
[α]D20 ϭ ϩ12.8 (c ϭ 2.40, CHCl3). Ϫ Its spectral data are the same
as those of 11a.
ang, Tetrahedron Lett. 1998, 39, 1493Ϫ1496. Ϫ
J. A. Mar-
shall, K. W. Hinkle, Tetrahedron Lett. 1998, 39, 1303Ϫ1306. Ϫ
[2f]
S. Hanessian, T. A. Grillo, J. Org. Chem. 1998, 63,
[2g]
1049Ϫ1057. Ϫ
B. M. Trost, T. L. Calkins, C. G. Bochet,
Angew. Chem. 1997, 109, 2746Ϫ2748; Angew. Chem. Int. Ed.
[2h]
Engl. 1997, 36, 2632Ϫ2635. Ϫ
S. C. Sinha, A. Sinha, S. C.
(3RS,4RS,5S)-3-[(2S,8R,11R,12R,15R,16R)-8,11;12,15-Diepoxy-
2,16-bis(methoxymethoxy)tricosa-4-yn-6-enyl]-4-(methoxymethoxy)-
5-methyldihydrofuran-2(3H,4H,5H)-one (19b): The procedure used
Sinha, E. Keinan, J. Am. Chem. Soc. 1997, 119, 1204Ϫ1206. Ϫ
[2i] J. A. Marshall, M. Chen, J. Org. Chem. 1997, 62, 5996Ϫ6000.
[2j]
Ϫ
J. A. Marshall, K. W. Hinkle, J. Org. Chem. 1997, 62,
[2k]
5989Ϫ5995. Ϫ
H. Makabe, A. Tanaka, T. Oritani, Tetra-
[2l
1
was the same as that used for the preparation of 19a. Ϫ H NMR
hedron Lett. 1997, 38, 4247Ϫ4250. Ϫ
T. R. Hoye, Z. Ye, J.
(CDCl3, 300 MHz): δ ϭ 0.88 (t, J ϭ 6.9 Hz, 3 H), 1.20Ϫ1.36 (m,
24 H), 1.36Ϫ1.54 (m, 2 H), 1.48 (d, J ϭ 6.4 Hz, 3 H), 1.58Ϫ1.80
(m, 3 H), 1.88Ϫ2.07 (m, 5 H), 2.16Ϫ2.27 (m, 2 H), 2.61Ϫ2.70 (m,
2 H), 2.86Ϫ2.94 (m, 1 H), 3.37Ϫ3.45 (m, 9 H), 3.48Ϫ3.57 (m, 1
H), 3.86Ϫ3.99 (m, 4 H), 4.00Ϫ4.10 (m, 1 H), 4.31Ϫ4.40 (m, 1 H),
4.67Ϫ4.78 (m, 5 H), 4.82 (d, J ϭ 6.9 Hz, 1 H), 4.88Ϫ4.98 (m, 1
H), 5.45Ϫ5.53 (m, 1 H), 5.84Ϫ5.96 (m, 1 H). Ϫ EI-MS; m/z: 723
[MHϩ]. Ϫ IR (neat): ν˜ ϭ 1774 cmϪ1. Ϫ C41H70O10 (723.0): calcd.
C 68.11, H 9.76; found C 68.32, H 9.61.
Am. Chem. Soc. 1996, 118, 1801Ϫ1802.
[3]
[4]
[3a]
Reviews on syntheses:
B. FigadŁre, Acc. Chem. Res. 1995,
[3b]
28, 359. Ϫ
U. Koert, Synthesis 1995, 115Ϫ132.
[4a] S. C. Sinha, A. Sinha, A. Yazbak, E. Keinan, J. Org. Chem.
[4b]
1996, 61, 7640Ϫ7641. Ϫ
E. Keinan, A. Sinha, A. Yazbak,
S. C. Sinha, S. C. Sinha, Pure Appl. Chem. 1997, 69, 423Ϫ430.
[4c]
Ϫ
K. Li, S. Vig, F. M. Uchum, Tetrahedron Lett. 1998, 39,
2063Ϫ2066. Ϫ [4d] H. Zhang, M. Seepersaud, S. Seepersaud, D.
R. Mootoo, J. Org. Chem. 1998, 63, 2049Ϫ2052. Ϫ [4e] B. Figa-
`
´
dere, J.-F. Peyrat, A. Cave, J. Org. Chem. 1997, 62, 3428Ϫ3429.
[4f]
Ϫ
T. B. Towne, F. E. McDonald, J. Am. Chem. Soc. 1997,
[4g]
119, 6022Ϫ6028. Ϫ
J.-P. Gesson, B. Ronoux, E. Schulten,
[4h]
(5S)-3-[(2R,8S,11R,12R,15R,16R)-8,11;12,15-Diepoxy-2,16-bis-
(methoxymethoxy)tricosyl]-5-methylfuran-2(5H)-one (20b): The pro-
cedure was the same as that used for the preparation of 20a. Ϫ
[α]D26 ϭ ϩ2.7 (c ϭ 0.55, CHCl3). Ϫ 1H NMR (CDCl3, 300 MHz):
δ ϭ 0.88 (t, J ϭ 6.9 Hz, 3 H), 1.20Ϫ1.36 (m, 30 H), 1.36Ϫ1.54 (m,
8 H), 1.43 (d, J ϭ 7.0 Hz, 3 H), 1.58Ϫ1.75 (m, 3 H), 1.90Ϫ2.07
(m, 3 H), 2.51 (d, J ϭ 5.8 Hz, 2 H), 3.35Ϫ3.42 (m, 6 H), 3.47Ϫ3.56
(m, 1 H), 3.75Ϫ3.97 (m, 4 H), 3.98Ϫ4.07 (m, 1 H), 4.67Ϫ4.78 (m,
3 H), 4.82 (d, J ϭ 6.9 Hz, 1 H), 4.98Ϫ5.08 (m, 1 H), 7.18Ϫ7.21 (m,
1 H). Ϫ EI-MS; m/z: 591, 531, 449. Ϫ IR (neat): ν˜ ϭ 1757 cmϪ1. Ϫ
C39H70O8 (667.0): calcd. C 70.23, H 10.58; found C 70.42, H 10.68.
Tetrahedron Lett., 1997, 38, 5811Ϫ5814. Ϫ
S. C. Sinha, E.
Keinan, S. C. Sinha, J. Am. Chem. Soc. 1998, 120, 9076Ϫ9077.
Z.-M. Wang, S.-K. Tian, M. Shi, Tetrahedron: Asymmetry,
1999, 10, 2551Ϫ2562.
[5]
[6]
U. Koert, Tetrahedron Lett. 1994, 35, 2517Ϫ2520.
[7] [7a]
M. H. Woo, K. Y. Cho, Y. Zhang, L. Zeng, Z.-M. Gu, J. L.
[7b]
McLaughlin, J. Nat. Prod. 1995, 58, 1533Ϫ1542. Ϫ
Y.
Zhang, L. Zeng, M.-H. Woo, Z.-M. Gu, Q. Ye, F.-E. Wu, J. L.
McLaughlin, Heterocycles 1995, 41, 1743Ϫ1755.
Z.-M. Wang, S.-K. Tian, M. Shi, Tetrahedron Lett. 1999, 40,
977Ϫ1000.
H. Wagner, U. Koert, Angew. Chem. 1994, 106, 1939; Angew.
Chem. Int. Ed. Engl. 1994, 33, 1873Ϫ1875 and citation therein.
H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483Ϫ2547.
The absolute configuration and ee of 7a were confirmed by
comparing them with the specific optical rotation of its enanti-
omer 7b, prepared from (2S,3S)-1,4-dichlorobutan-2,3-diol: K.
P. M. Vanhessche, Z.-M. Wang, K. B. Sharpless, Tetrahedron
Lett. 1994, 35, 3469Ϫ3472.
[8]
[9]
[10]
[11]
(؉)-Asimilobin (1b): The procedure was the same as that used for
the preparation of 1a. Ϫ [α]D24 ϭ ϩ6.4 (c ϭ 0.36, CHCl3); [α]D24 ϭ
24
ϩ7.0 (c ϭ 0.10, CH2Cl2); [α]D ϭ ϩ6.7 (c ϭ 0.05, CHCl3);
24
1
[α]D ϭ ϩ7.9 (c ϭ 1.0, CH2Cl2). Ϫ H NMR (CDCl3, 300 MHz):
δ ϭ 0.88 (t, J ϭ 7.0 Hz, 3 H), 1.20Ϫ1.36 (m, 30 H), 1.36Ϫ1.54 (m,
6 H), 1.43 (d, J ϭ 7.0 Hz, 3 H), 1.54Ϫ1.72 (m, 5 H), 1.89Ϫ2.06
(m, 3 H), 2.34Ϫ2.45 (m, 1 H), 2.53 (dm, J ϭ 15.0 Hz, 1 H),
3.34Ϫ3.44 (m, 1 H), 3.76Ϫ3.90 (m, 4 H), 3.90Ϫ3.98 (m, 1 H), 5.06
(q, J ϭ 7.0 Hz, 1 H), 7.18Ϫ7.21 (m, 1 H). Ϫ 13C NMR (CDCl3,
300 MHz): δ ϭ 14.19, 19.20, 22.77, 25.56, 25.64, 25.69, 25.76,
26.12, 28.49, 28.78, 28.82, 28.98, 29.44, 29.53, 29.77, 32.01, 32.15,
33.48, 33.60, 35.75, 37.41, 69.98, 74.25, 78.03, 79.98, 81.31, 82.13,
83.20, 131.27, 151.87, 174.65. Ϫ FABMS; m/z: 602 [MH ϩ Na],
600 [MNa Ϫ H], 580 [M ϩ 2 H], 578 [Mϩ], 560 [M Ϫ H2O], 544
Eur. J. Org. Chem. 2000, 349Ϫ356
355

Z.-M. Wang, S-K. Tan, M. Shi
FULL PAPER
[12]
1
The H NMR spectral data and the sign of optical rotation of
3.68 (dd, J ϭ 11.7, 3.1 Hz, 1 H), 3.78Ϫ3.87 (m, 1 H), 3.88Ϫ3.98
(m, 1 H), 4.06Ϫ4.22 (m, 2 H), 4.56 (s, 2 H), 7.25Ϫ7.39 (m, 5
H). Ϫ 13C NMR (CDCl3, 75 MHz): δ ϭ 27.50, 27.69, 28.33,
28.89, 64.66, 72.81, 73.39, 78.60, 80.05, 82.13, 82.66, 127.70,
127.71, 128.39, 138.47. Ϫ 8e: 1H NMR (CDCl3, 300 MHz): δ ϭ
1.73Ϫ1.84 (m, 3 H), 1.84Ϫ2.02 (m, 5 H), 3.41Ϫ3.56 (m, 3 H),
3.74 (dd, J ϭ 11.7, 2.8 Hz, 1 H), 3.84Ϫ3.96 (m, 2 H), 4.05Ϫ4.18
(m, 2 H), 4.56 (s, 2 H), 7.25Ϫ7.39 (m, 5 H). Ϫ 13C NMR
(CDCl3, 75 MHz): δ ϭ 27.32, 27.97, 28.18, 28.70, 65.43, 72.50,
73.36, 78.48, 80.06, 81.59, 81.89, 127.60, 127.77, 128.38, 138.24.
S. Inoki, T. Mukaiyama, Chem. Lett. 1990, 67Ϫ70.
K. Mead, T. L. MacDonald, J. Org. Chem. 1985, 50, 422Ϫ424.
The relative configuration of compound 9a was confirmed by
comparing the chemical shifts of the proton and the carbon
atom located at C-18 with those of naturally occurring asimilo-
bin (see ref.[7]).
compound 4a are the same as those reported in the literature
(see ref.[9]).
[13]
1
The H and 13C NMR spectra of compound 8a, the monoben-
zyl ether of diol 4a, were compared to those of all its possible
diastereomers, 8c, 8d,[5] and 8e (U. Koert, M. Stein, H. Wagner,
Liebigs Ann. 1995, 1415Ϫ1426), and no other diastereomer was
detected. 8c: 1H NMR (CDCl3, 300 MHz): δ ϭ 1.69Ϫ1.85 (m,
3 H), 1.85Ϫ1.97 (m, 3 H), 1.97Ϫ2.10 (m, 2 H), 3.46Ϫ3.57 (m,
3 H), 3.77 (dd, J ϭ 11.7, 2.8 Hz, 1 H), 3.86Ϫ3.94 (m, 1 H),
3.95Ϫ4.03 (m, 1 H), 4.08Ϫ4.16 (m, 1 H), 4.19Ϫ4.28 (m, 1 H),
4.56 (s, 2 H), 7.25Ϫ7.39 (m, 5 H). Ϫ 13C NMR (CDCl3,
75 MHz): δ ϭ 27.35, 28.79, 28.79, 28.80, 65.68, 72.57, 73.38,
[14]
[15]
[16]
[17]
J. P. Vigneron, R. Meric, M. Larcheveque, A. Debel, G. Ku-
nesch, P. Zagatti, M. Gallois, Tetrahedron Lett. 1982, 23,
5051Ϫ5054.
Z.-J. Yao, Y.-L. Wu, J. Org. Chem. 1995, 60, 1170Ϫ1176.
That the (Z) isomer predominated [(Z)/(E) > 5:1], was shown
by H NMR (CDCl3, 300 MHz) spectral analysis.
[18]
[19]
1
[20]
The ee of 7b (over 94%) and the de of 4b (over 95%) were con-
firmed by the same methods as used before.[11][13]
Received June 16, 1999
78.76, 80.16, 81.67, 81.98, 127.67, 127.67, 128.39, 138.42. Ϫ 8d:
1H NMR (CDCl3, 300 MHz): δ ϭ 1.55Ϫ1.77 (m, 3 H),
1.77Ϫ1.90 (m, 2 H), 1.90Ϫ2.04 (m, 3 H), 3.42Ϫ3.57 (m, 3 H),
[O99359]
356
Eur. J. Org. Chem. 2000, 349Ϫ356