Systematic Construction of a Monotetrahydrofuran-Ring Library in Annonaceous Acetogenins by Asymmetric Alkynylation and Stereodivergent Tetrahydrofuran-Ring Formation

Article abstract of DOI:10.1002/chem.200305185

All eight diastereoisomers of the monotetrahydrofuran-ring cores of annonaceous acetogenins have been synthesized through utilization of asymmetric alkynylation and stereodivergent one-pot tetrahydrofuran-ring formation. In all cases, the asymmetric alkyn

Full text of DOI:10.1002/chem.200305185

FULL PAPER
Systematic Construction of a Monotetrahydrofuran-Ring Library in
Annonaceous Acetogenins by Asymmetric Alkynylation and Stereodivergent
Tetrahydrofuran-Ring Formation
Naoto Kojima, Naoyoshi Maezaki,* Hiroaki Tominaga, Mikito Asai, Minori Yanai, and
Tetsuaki Tanaka*[a]
1
Abstract: All eight diastereoisomers of
the monotetrahydrofuran-ring cores of
annonaceous acetogenins have been
synthesized through utilization of asym-
metric alkynylation and stereodivergent
one-pot tetrahydrofuran-ring formation.
In all cases, the asymmetric alkynylation
proceeded with very high diastereose-
lectivity to give eight kinds of optically
pure tetrahydrofuran core from a com-
mon a-oxyaldehyde. We also describe a
comparison of the HNMR, 13C NMR,
and CD spectral data of the eight
isomers and give full details of the
tetrahydrofuran-ring construction in-
cluding a model study of asymmetric
alkynylation.
Keywords: alkynylations ¥ cycliza-
tion ¥ polyketides ¥ stereodivergent
synthesis ¥ synthetic methods
form).[3] Furthermore, it is known that some acetogenins
inhibit multidrug-resistant cancer cells with an ATP-driven
transporter system (ATP ˆ adenosine triphosphate).[4] Over
350 acetogenins have been isolated from various annonaceae
plants so far. Most of them are characterized by having one to
three tetrahydrofuran (THF) ring(s) with various stereo-
chemistries in the center of a long hydrocarbon chain with an
a,b-unsaturated g-lactone moiety at the end. The number and
stereochemistry of the THF rings are known to affect the kind
of effective tumor cell lines for growth inhibition.[1] Therefore,
systematic synthesis of the poly-THF-ring core would be
important to establish a structure activity relationship.
Reiterative strategy is an effective approach to synthesize
the poly-THF-ring cores, because of their repeated structure.
This methodology is advantageous in terms of economics
(reuse of the same reagents) and ease of operation. Pioneer-
Introduction
Annonaceous acetogenins (Scheme 1) are a new class of
natural polyketides that have attracted worldwide attention
due to their broad spectrum of biological activity; this activity
includes cytotoxic, antitumor, immunosuppressive, antimalar-
ial, and antifeedant effects.[1, 2] Some of these compounds are
Scheme 1. Representative structure of annonaceous acetogenins, where
n ˆ 1 3 and R, R' ˆ hydrocarbon chains with oxygenated moieties and/or
double bonds.
¡
ing works have been reported by the groups of Figadere,
¡
promising candidates for new types of antitumor drugs
possessing potent inhibitory activity against NADH:ubiqui-
none oxidoreductase of the respiratory chain (mitochondrial
complex I), the main gate of energy production in the cell
(NADH ˆ nicotinamide adenine dinucleotide, reduced
Casiraghi, and Koert. Figadere et al. and Casiraghi and co-
workers independently reported a unique reiterative proce-
dure through Lewis acid promoted C-glycosydation with a
2-(trimethylsilyloxy)furan-type C4 unit.[5] Although their
procedure was useful to construct varied collections of the
poly-THF-ring cores, it lacked stereoselectivity. Koert et al.
developed a reiterative method with use of nucleophilic
addition of a 3,4-isopropylidenedioxybutyl anion to a-oxy-
aldehyde.[6] Both syn and anti adducts were synthesized with
good diastereoselectivities by changing the metal species.
However, the non-chelation-controlled addition with an
organozinc reagent gave low yields due to decomposition of
the reagent under the Lewis acidic reaction conditions. In
addition, the diastereoselectivity was low in the cases where
the a-oxyaldehyde was mismatched with the C4 unit.[6b]
[a] Dr. N. Maezaki, Prof. Dr. T. Tanaka, N. Kojima, H. Tominaga, M. Asai,
M. Yanai
Graduate School of Pharmaceutical Sciences
Osaka University, 1-6 Yamadaoka, Suita
Osaka 565-0871 (Japan)
Fax : (‡81)6-6879-8214
E-mail: maezaki@phs.osaka-u.ac.jp, t-tanaka@phs.osaka-u.ac.jp
Supporting information for this article is available on the WWW under
http://www.chemeurj.org or from the author.
4980
¹ 2003 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
DOI: 10.1002/chem.200305185
Chem. Eur. J. 2003, 9, 4980 4990

4980 4990
Table 1. Effect of the protecting group of the a-oxyaldehyde on asym-
metric alkynylation.[a]
During the course of our synthetic study of annonaceous
acetogenins,[7] we planned a systematic synthesis of the poly-
THF-ring cores based on asymmetric alkynylation of a-
oxyaldehyde with a 3-butyne-1,2-diol derivative, as depicted
in Scheme 2. In a preliminary communication, we demon-
PG
Yield [%] (anti:syn)[b]
(1R,2S)-NME
(1S,2R)-NME
TBS
TES
TIPS
Bn
92 (80:20)
52 (69:31)
79 (53:47)
85 (61:39)
70 (59:41)
86 (8:92)
82 (20:80)
76 (18:82)
85 (24:76)
58 (19:81)
MEM
Scheme 2. Strategy of systematic synthesis of poly-THF ring cores. PG ˆ
[a] Conditions: Zn(OTf)2 (2.2 equiv), Et3N (2.4 equiv), NME (2.4 equiv),
toluene, RT. Abbreviations: TBS ˆ tert-Butyldimethylsilyl, TES ˆ trie-
thylsilyl, TIPS ˆ triisopropylsilyl, Bn ˆ benzyl, MEM ˆ (2-methoxyeth-
oxy)methyl, OTf ˆtrifluoromethanesulfonate, NMEˆN-methylephedrine.
Protecting group.
strated a highly stereodivergent and stereoselective synthesis
of monoTHF-ring cores.[7c] Herein, we report the systematic
synthesis of all eight isomers of the THF-ring core with two
flanking secondary alcohols, and we discuss the comparison of
1
[b] Determined from HNMR spectroscopic data (500 MHz, CDCl 3).
controlled by the chirality of the reagent rather than that of
1
their HNMR, 13C NMR, and CD spectral data.
14]
the a-oxyaldehyde in all cases.[12
The TBS-protected a-
oxyaldehyde afforded the best results in terms of both yield
and diastereoselectivity. Thus, we decided to employ the TBS
group as the protecting group of the a-oxyaldehyde in further
investigations.
Results and Discussion
We attempted to prepare the C4 unit, 3-butyne-1,2-diol (13),
from d-mannitol by the procedure reported by Gooding,
Cooper and co-workers.[15] However, the yield of the Wittig
reaction of 2,3-O-isopropylidene-d-glyceraldehyde (10) in the
Corey Fuchs sequence was poor and not reproducible
(Scheme 3). The problem was overcome by adopting Rassat×s
Our strategy for the systematic synthesis of the THF cores is
outlined in Scheme 2. One key step is asymmetric alkynyla-
tion of the a-oxyaldehyde 4 with the chiral alkyne C4 unit 5,
both enantiomers of which are readily prepared from natural
products in enantiomerically pure form. We expected high
diastereoselectivity from the prominent stereodifferentiating
ability of the method of Carreira and co-workers, and
convenient stereocontrol was also anticipated by changing
the chiral ligand.[8] The employment of alkynylation is
advantageous since the unreacted acetylide can be reused
even if the reaction requires excess reagent. Such reuse is
impossible in the case of an organometallic reagent generated
by halogen metal exchange reaction. Another key step is the
stereodivergent THF-ring formation, by which four kinds of
THF-ring core can be synthesized from two common pre-
cursors by changing the protocol (pathways a and b). More-
over, the terminal alcohol in the resulting THF-ring core 2
becomes a junction with the next C4 unit 5 by oxidation to an
aldehyde. Therefore, our strategy can potentially be applied
to the synthesis of poly-THF-ring cores 1.[9]
Scheme 3. Preparation of the C4 unit 14. a) TH F, 08C; b) nBuLi, THF,
À788C ! RT; c) Dowex 50W, MeOH, 358C, 83% over 2 steps; d) BnBr,
NaH, nBu4NI, THF, 08C ! RT, 84 %.
Initially, we examined the effect of the protecting group of
the a-oxyaldehyde on the reagent-controlled asymmetric
alkynylation with the benzyl ether of propargyl alcohol 7[10]
(Table 1). We selected silyl ethers[11a] (TBS, TES, and TIPS)
and alkyl ethers[11b] (Bn and MEM) as protecting groups for
(S)-6 (PG ˆ H), taking into account its application to the total
synthesis of the annonaceous acetogenins. The asymmetric
alkynylation was carried out by using Zn(OTf)2, and Et3N in
the presence of (1R,2S)- or (1S,2R)-NME according to the
protocol of Carreira and co-workers. As a result, we found
that the stereochemistry of the asymmetric alkynylation was
procedure. Thus, C1-elongation of the aldehyde 10 was
accomplished by using (Ph3PCHBr2)Br and tBuOK,[16] to give
dibromoolefin 11 in good yield and with excellent reprodu-
cibility.[17] Next, the resulting 11 was converted into the diol 13
without isolation of volatile acetonide 12 by the modified
Gooding protocol.[15a] Diol 13 was protected with dibenzyl
ethers to give a protected alkyne 14, which has the advantage
of reducing the number of steps since the deprotection and
reduction of the triple bond can take place simultaneously.
Chem. Eur. J. 2003, 9, 4980 4990
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4981

N. Maezaki, T. Tanaka et al.
FULL PAPER
Table 2. Asymmetric alkynylation of aldehyde 6 with chiral alkyne (S)-14.
Table 3. Asymmetric alkynylation of aldehyde 20 with alkynes 7 or (S)-
14.[a]
Entry
Alkyne
NME
Yield [%]
anti:syn[b]
1
2
3
4
7
7
1R,2S
1S,2R
1R,2S
1S,2R
54
25
trace
trace
3: > 97
64:36
(S)-14
(S)-14
Aldehyde
NME
Major product
Yield [%]
anti:syn[a]
(S)-6
(S)-6
(R)-6
(R)-6
1R,2S
1S,2R
1R,2S
1S,2R
15a
15b
15c
15d
58
15
66
25
84:16
39:61
8:92
[a] Conditions: Alkyne (2.0 equiv), Zn(OTf)2 (2.2 equiv), Et3N (2.4 equiv),
NME (2.4 equiv), toluene, RT. [b] Determined from 1HNMR spectro-
scopic data (500 MHz, CDCl3).
73:27
1
[a] Determined from HNMR spectroscopic data (500 MHz, CDCl 3).
We next investigated the asymmetric alkynylation with the
chiral C4 unit 14 (Table 2). The stereochemistry of the major
product was mainly subject to the chirality of the chiral ligand
rather than that of the aldehyde or the alkyne.[12, 13] In
particular, a combination of the alkyne (S)-14 with (R)-6
provided better yield and selectivity than the corresponding
combination of (S)-14 with (S)-6.[18]
compared with the yield of alkynylation of the aldehyde 6.
Based on the model study, a combination of the R-configured
aldehyde and S-configured alkyne was adopted. However, the
reaction became sluggish when the substrates 20 and (S)-14
were employed. In spite of the matched pair, only a trace
amount of the adduct was obtained, and most of 20 decom-
posed during the long reaction time (entries 3 and 4).
(R)-2-Silyloxytetradecanal 20 was prepared as shown in
Scheme 4. Optically pure (R)-tetradecane-1,2-diol (16) was
prepared by kinetic resolution of (Æ)-tetradecene oxide with
We assumed that steric bulkiness of the dibenzyl moiety in
alkyne (S)-14 impeded the reaction. Therefore, we tried a
coupling reaction of the aldehyde 20 and various 3-butyn-1,2-
diol derivatives with lesser steric demands (Table 4). Unpro-
tected diol 13 (entry 1) and diacetyl derivative 22 (entry 2)[21]
afforded no adduct. On the other hand, cyclohexylidene
acetal 23[22] afforded the syn adduct 24a in good yield and with
high diastereoselectivity, but the yield and selectivity for the
anti-adduct 24b were only moderate (entries 3 and 4).[20]
Furthermore, selective deacetalization of 24 was difficult
due to the presence of the acid-sensitive TBS group.
Eventually, we found that a benzylidene acetal is the best
protecting group. The benzylidene acetal 25 was readily
prepared by an acetal-exchange reaction of 3-butyne-1,2-diol
Scheme 4. Preparation of aldehyde 20. a) PvCl, pyridine, CH2Cl2, 08C !
RT, 85%; b) TBSCl, imidazole, DMF, 08C ! RT, quantitative; c) DIBAL-
H , CHCl2, À788C, quantitative; d) Dess Martin periodinane, CH2Cl2,
2
Table 4. Asymmetric alkynylation of aldehyde 20 with various alkynes.
RT, 96 %. Pv ˆ Pivalate, DMF ˆ N,N-dimethylformamide, DIBAL-H ˆ
diisobutylaluminum hydride.
Jacobsen×s salen manganese catalyst.[19] The diol 16 was
converted into 18 by selective protection of the primary
alcohol to give pivalate 17 followed by silylation of the
secondary alcohol. Treatment of 18 with DIBAL-Hat À788C
furnished primary alcohol 19 in quantitative yield. This was
then oxidized to form a-oxyaldehyde 20 in 96% yield.
Next, asymmetric alkynylation with the long-chain alde-
hyde 20 was investigated. The stereochemistry of the asym-
metric alkynylation depended on the chirality of the reagent
(Table 3, entries 1 and 2).[20] Aldehyde (R)-20 and (1R,2S)-
NME seem to be a matched pair, as expected from the results
shown in Table 1. However, the yield was low to moderate
Entry
Alkyne
NME
Yield [%]
anti:syn[a]
1
2
3
4
13
22
23
23
1R,2S
1R,2S
1R,2S
1S,2R
no reaction
trace
93
3: > 97
85:15
43
1
[a] Determined from HNMR spectroscopic data (500 MHz, CDCl 3).
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THF-Ring Formation
4980 4990
(13) in good yield to give an approximately 1:1 mixture of
diastereomeric isomers 25a and 25b,[23] which can be sepa-
rated by column chromatography (Scheme 5).
Scheme 5. Preparation of alkyne 25. a) PhCH(OMe)2, CSA, THF, reflux,
88%. CSA ˆ (‡)-10-camphorsulfonic acid.
Scheme 6. Synthesis of acetals 27a and 27b. a) TBAF, THF, RT; b) Me2-
C(OMe)2, pTsOH¥ H 2O, CH2Cl2, RT, 94% over 2 steps from 26a, 97%
over 2 steps from 26b. TBAF ˆ tetrabutylammonium fluoride, pTs ˆ 4-
toluenesulfonyl ˆ tosyl.
Table 5 shows the results of the asymmetric alkynylation of
the aldehyde 20 with the alkynes 25a and 25b. The C2
stereogenic centers in the alkynes 25a and 25b did not show
remarkable effects on either the yield or the selectivity
(entries 1 and 2). In both reactions, the syn adduct 26a
Table 5. Asymmetric alkynylation of aldehyde 20 with alkynes 25a and
25b.
Scheme 7. Synthesis of THF-ring moiety 31a. a) H2, 10% Pd/C, EtOAc,
RT, 94%; b) TrisCl, pyridine, CH2Cl2, 08C ! RT, 87 %; c) K2CO3, MeOH,
08C ! RT, 70%. Tris ˆ 2,4,6-triisopropylbenzenesulfonyl.
Entry
Alkyne
NME
Yield [%]
anti:syn[a]
1
2
3
4
2S,4S
1R,2S
1R,2S
1R,2S
1S,2R
74
86
96
3: > 97
5:95
3: > 97
94:6
2R,4S
2RS,4S
2RS,4S
quantitative
1
[a] Determined from HNMR spectroscopic data (500 MHz, CDCl 3).
predominated over the anti adduct 26b. The results indicate
that separation of 25a and 25b is not required in a practical
operation. In fact, the syn adduct 26a was obtained in
excellent yield with very high diastereoselectivity by using a
mixture of 25a and 25b (entry 3).[24, 25] We also found that the
anti adduct 26b can be obtained in good yield and with
acceptable diastereoselectivity by using the antipode of NME
(entry 4).[26]
The stereochemistry of the coupling products 26a and 26b
was determined by comparison of the coupling constants with
related compounds (Scheme 6).[13] The adducts 26a and 26b
were respectively converted into diacetonides 27a and 27b by
desilylation and subsequent acetalization. The coupling con-
stants (J5,6 ˆ 7.3 Hz in 27a and J5,6 ˆ 5.5 Hz in 27b) were
identical with those of the related substrates.[27] Moreover, an
NOE was observed between the two protons at the C5 and C6
positions in 27b, but not in 27a.
With the syn and anti adducts 26a and 26b in hand, we
examined the stereodivergent THF-ring formation. The syn-
thesis of the 2,5-trans-fused THF ring with 26a by pathways a
and b is depicted in Schemes 7 and 8.
Scheme 8. Synthesis of THF-ring moiety 31b. a) H2, 10% Pd/C, Et3N,
EtOAc, RT, quantitative; b) pTsCl, pyridine, 08C ! RT, 96 %; c) H2, 10%
Pd/C, EtOAc, RT; d) NaH, THF, 0 ! 408C, 78% over 2 steps.
Hydrogenation of the triple bond accompanied by depro-
tection of the benzylidene acetal with 10% Pd/C in EtOAc
afforded a saturated alcohol 28 in good yield. Selective
sulfonylation of the primary alcohol with TrisCl furnished the
sulfonate 29 in 87% yield. Upon treatment of 29 with K2CO3
in MeOH, THF-ring formation proceeded smoothly via
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4983

N. Maezaki, T. Tanaka et al.
FULL PAPER
epoxide 30 in a one-pot reaction, to give the trans/threo isomer
31a in 70% yield (Scheme 7, pathway a).[28]
Alternatively, the trans/erythro isomer 31b was synthesized
through pathway b (Scheme 8). An attempt to obtain 34 by
tosylation of 26a accompanied by simultaneous reduction of
the triple bond and the benzylidene acetal was unsuccessful,
presumably due to hydrogenolysis of the tosyl group. Selec-
tive hydrogenation of the triple bond in the presence of Et3N
as a catalyst poison[29] followed by tosylation of the secondary
alcohol transformed 26a into tosylate 33 in 96% yield over
two steps. Reductive deacetalization and subsequent intra-
molecular Williamson reaction with NaHin THF promoted
THF-ring formation rather than tetrahydropyran-ring forma-
tion and led to the production of 31b in 78% yield over two
steps.[30]
Scheme 9. Synthesis of THF-ring moieties 31c and 31d by pathways a or b,
as depicted in Schemes 7 and 8.
Table 7. Oxidation of alcohols 31a d to aldehydes 35a d.
The deprotection of the benzylidene acetal and the THF-
ring formation can also be performed in a one-pot operation
with a comparative yield by changing the solvent of hydro-
genation to THF (Table 6, entry 2). We found that the yield
was remarkably improved when 34 was present in high
concentration, and 31b could be obtained in quantitative yield
(entry 3).
Alcohol
Product
Yield [%]
31a
31b
31c
31d
35a
35b
35c
35d
86
85
93
76
Table 6. One-pot THF-ring formation of 33.
Entry
1
Conditions
Concentration [m][a]
Yield [%]
78
by the modified Mosher method.[12] Since selective depro-
tection of the TMS group is possible, these adducts would be
useful for the synthesis of various monoTHF-ring acetogenins.
Representative chemical shifts in the 1Hand 13C NMR
spectral data of 36 39a and 36 39b are summarized in
Tables 9 and 10. These eight compounds exhibited a charac-
teristic signal pattern and their signals are distinguishable.
Almost no signal due to other diastereomeric isomers was
observed in each spectrum, a fact which indicates the high
purity of these products.
1) Pd/C, H2, EtOAc
2) NaH, THF
Pd/C, H2, THF
then NaH
Pd/C, H2, THF
then NaH
0.025
2
3
0.025
0.049
75
quantitative
[a] Concentration of 34 in the THF-ring formation step.
In a similar manner, a cis/erythro isomer 31c and a cis/threo
isomer 31d were synthesized from the common anti adduct
26b in 73 and 57% overall yield, respectively (Scheme 9).
Next, we examined the conversion of 31a d into the THF
cores with two flanking secondary alcohols, whose structure is
frequently found in natural
Figure 1 shows a comparison of the CD spectra of the eight
diastereoisomers. The difference in stereochemistry affects
the maximum wavelength and the intensity, so the diaster-
monoTHF-ring
acetogenins.
Table 8. Asymmetric alkynylation of aldehydes 35a d with trimethylsilylacetylene.[a]
Oxidation of the terminal pri-
mary alcohol of 31a d was
carried out with Dess Martin
periodinane[31] to furnish the a-
tetrahydrofuranic
aldehydes
35a d in good yield (Table 7).
Trimethylsilylacetylene was
then diastereoselectively intro-
duced to the a-tetrahydrofu-
Aldehyde
NME
Product
Yield [%]
Selectivity[b]
a-OH:b-OH
A
B
ranic aldehydes 35a
d (Ta-
trans
trans
trans
trans
cis
cis
cis
cis
threo
threo
1R,2S
1S,2R
1R,2S
1S,2R
1R,2S
1S,2R
1R,2S
1S,2R
36a
36b
37a
37b
38a
38b
39a
39b
70
72
75
69
61
71
79
66
3: > 97
> 97:3
3: > 97
> 97:3
3: > 97
> 97:3
3: > 97
94:6[c]
ble 8). The reaction proceeded
with predictable selectivities,
and the diastereoselectivity
was very high in all cases, giving
all eight diastereomers 36 39a
and 36 39b with high optical
purity.[32] The stereochemistry
of the adducts was confirmed
erythro
erythro
erythro
erythro
threo
threo
1
[a] TMS ˆ trimethylsilyl. [b] Determined from HNMR spectroscopic data (500 MHz, CDCl 3). [c] Calculated
from yield of product.
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Chem. Eur. J. 2003, 9, 4980 4990

THF-Ring Formation
4980 4990
Table 9. Representative 1HNMR spectral data of 36 39a and 36 39b
(500 MHz, CDCl3).
synthesis of eight diastereomeric isomers. The asymmetric
alkynylation proceeded, almost exclusively, to give syn and
anti adducts with predictable selectivity by changing the chiral
ligand. Since the antipodes of all chiral materials (alkyne,
aldehyde, NME) are available, the antipodes of each isomer
could theoretically be synthesized. Thus, our methodology
could be widely used for the synthesis of various annonaceous
acetogenins. Application of our strategy to the synthesis of
biologically active acetogenins is under way. Those results will
be reported elsewhere.
Stereochemistry
A/B/C
OHC3-HC4-HC7-HC8-H
threo/trans/threo (36a)
erythro/trans/threo (36b)
erythro/trans/erythro (37a) 2.33 4.36
threo/trans/erythro (37b)
threo/cis/erythro (38a)
erythro/cis/erythro (38b)
erythro/cis/threo (39a)
threo/cis/threo (39b)
2.47 4.18
2.35 4.39
4.04
4.12
4.10
4.03
3.99
4.09
4.11
4.03
3.91
4.04
4.03
3.92
3.90
3.92
3.97
3.98
3.57
3.56
3.78
3.78 3.81
3.79
3.85
3.62
3.58
2.43 4.18
2.67 4.17
2.87 4.48
3.05 4.50
2.85 4.18
Experimental Section
General: Melting points are uncorrected. Optical rotations were measured
by using a JASCO DIP-360 digital polarimeter. 1HNMR spectra were
recorded in CDCl3 solution with a JEOL JNM-GX500 spectrometer
(500 MHz). 13C NMR spectra were recorded in CDCl3 solution with a
JEOL JNM-AL300 spectrometer (75 MHz). All signals are expressed as
ppm downfield from tetramethylsilane as an internal standard (d value).
The following abbreviations are used: brˆ broad, s ˆ singlet, d ˆ doublet,
t ˆ triplet, q ˆ quartet, qn ˆ quintet, sep ˆ septet, and m ˆ multiplet. IR
absorption spectra (FT: diffuse reflectance spectroscopy) were recorded
with KBr powder with a Horiba FT-210 IR spectrometer, and only
noteworthy absorptions (cmÀ1) are listed. Mass spectra were obtained with
a JEOL JMS-600Hand a JEOL JMS-700 mass spectrometer. Column
chromatography was carried out by using Kanto Chemical silica gel 60N
(spherical, neutral, 63 210 mm). Flash column chromatography was
carried out by using Merck silica gel 60 (40 63 mm). All air- or moisture-
sensitive reactions were carried out in flame-dried glassware under an
atmosphere of Ar or N2. All solvents were dried and distilled according to
standard procedures. All organic extracts were dried over anhydrous
MgSO4, filtered, and concentrated with a rotary evaporator under reduced
pressure. Known compounds (S)-6,[11] 7,[10] 10,[15] 16,[19] 22,[21] and 23[22] were
synthesized according to the literature methods. Experimental procedures
and characterization data for 8, 9, 14, 15, 21, 24a, and 24b are included in
the Supporting Information.
Table 10. Representative 13C NMR spectral data of 36 39a and 36 39b
(75 MHz, CDCl3).
Stereochemistry
A/B/C
C3
C4
C7
C8
threo/trans/threo (36a)
erythro/trans/threo (36b)
erythro/trans/erythro (37a)
threo/trans/erythro (37b)
threo/cis/erythro (38a)
erythro/cis/erythro (38b)
erythro/cis/threo (39a)
threo/cis/threo (39b)
65.6
65.0
65.2
65.4
66.5
65.4
65.3
65.8
82.0
81.4
81.5
82.0
81.9
81.3
81.3
81.7
82.9
83.5
83.6
82.6
82.8
82.4
81.9
82.4
74.9
75.0
73.0
72.9
73.0
73.0
74.6
74.5
Preparation of 11 with (Ph3PCHBr2)Br: tBuOK (6.42 g, 57.2 mmol) was
added to
a solution of (Ph3PCHBr2)Br (31.0 g, 60.2 mmol) in THF
(250 mL) with stirring at 08C. After 10 min at RT, a solution of 10
(3.92 g, 30.1 mmol) in THF (50 mL) was added to the mixture at 08C. After
10 min, the reaction was quenched with brine. The solvent was evaporated
prior to extraction with n-hexane. The combined organic layers were
washed with water and brine prior to drying and solvent evaporation.
Purification by column chromatography on silica gel (hexane/EtOAc (5:1))
yielded 11 (8.32 g, 97%) as a yellow oil. The spectral data were identical
with those previously reported.[15a]
Preparation of 13: nBuLi (88.8 mL, 1.56m in n-hexane, 139 mmol) was
added to a solution of 11 (18.0 g, 62.9 mmol) in THF (180 mL) with stirring
at À788C over 1 h, then the mixture was allowed to warm to 108C over 1 h.
Et2O (110 mL) and water (110 mL) were added to the mixture at RT. After
15 min, the aqueous layer was extracted with Et2O. Dowex 50W (18.0 g)
and MeOH(150 mL) were added to the combined organic layers with
stirring at RT, and the whole reaction mixture was stirred at 358C for 15 h.
Dowex 50W was filtered off and the filtrate was concentrated under
reduced pressure. Purification by column chromatography on silica gel
(hexane/EtOAc (3:2 ! 2:3)) yielded 13 (4.49 g, 83%). The spectral data
were identical with those previously reported.[15a]
Figure 1. CD spectral data for 36 39a and 36 39b.
eomers can thereby be differentiated. The maximum wave-
length of the trans isomers and the cis isomers was observed at
about 184.4 and 183.4 nm, respectively. The intensity of the
spectra for the trans isomers was generally stronger than that
of the cis isomers.
(R)-2-Hydroxytetradecanyl pivalate (17): Pivaloyl chloride (5.55 mL,
45.0 mmol) was added to a solution of 16 (6.91 g, 30.0 mmol) in pyridine
(30 mL) and CH2Cl2 (30 mL) with stirring at 08C. After 5 min, the whole
mixture was stirred at RT for 15 h. Concentration followed by azeotropic
removal of pyridine with toluene was repeated three times. Purification by
column chromatography on silica gel (hexane/EtOAc (5:1)) yielded 17
(8.01 g, 85%) as a white powder. M.p. 40.1 42.28C (n-hexane/EtOAc);
Conclusion
We have developed a highly stereoselective and stereodiver-
gent synthesis of the cores of monoTHF-ring acetogenins
based on asymmetric alkynylation of a chiral a-oxyaldehyde
with a C4 unit. We have also demonstrated the stereodivergent
1
[a]2D6 ˆ À2.3 (c ˆ 1.59, CHCl3); HNMR: d ˆ 0.88 (t, J ˆ 7.0 Hz, 3H), 1.22
(s, 9H), 1.26 1.31 (m, 20H), 1.43 1.52 (m, 2H), 2.00 (brs, 1H), 3.81 3.85
(m, 1H), 3.97 (dd, J ˆ 11.6, 6.7 Hz, 1H), 4.13 (dd, J ˆ 11.6, 3.1 Hz,
Chem. Eur. J. 2003, 9, 4980 4990
www.chemeurj.org
¹ 2003 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
4985

N. Maezaki, T. Tanaka et al.
FULL PAPER
1H) ppm; 13C NMR: d ˆ 14.1, 22.7, 25.3, 27.2 (3C), 29.3, 29.5, 29.55 (2C),
29.63 (2C), 29.7, 31.9, 33.4, 38.9, 68.6, 70.2, 178.7 ppm; IR (KBr): nÄ ˆ 3535,
(dd, J ˆ 8.2, 6.7 Hz, 1H), 4.87 (ddd, J ˆ 6.7, 5.2, 1.8 Hz, 1H), 5.87 (s, 1H),
7.40 7.44 (m, 3H), 7.55 7.58 (m, 2H) ppm; 13C NMR: d ˆ 65.9, 70.8, 74.3,
80.8, 105.1, 126.8 (2C), 128.3 (2C), 129.4, 136.8 ppm; IR (KBr): nÄ ˆ 2121,
‡
1703 cmÀ1; MS (FAB): m/z: 315 [M‡H] ; HRMS (FAB): m/z calcd for
‡
‡
‡
C19H39O3: 315.2899; found: 315.2909 [M‡H] .
1070 cmÀ1; MS (EI): m/z: (%): 174 (27.9) [M] , 173 (36.0) [M À H] , 78
(100); HRMS (EI): m/z calcd for C11H10O2: 174.0681; found: 174.0688
(R)-2-(tert-Butyldimethylsilyloxy)tetradecanyl pivalate (18): Imidazole
(3.40 g, 50.0 mmol) was added to a solution of 17 (7.86 g, 25.0 mmol) in
DMF (25 mL) with stirring at 08C. After 5 min, TBSCl (7.54 g, 50.0 mmol)
was added to the mixture with stirring at 08C. After 2 h at RT, the mixture
was quenched with water and extracted with EtOAc. The combined organic
layers were washed with water and brine prior to drying and solvent
evaporation. Purification by column chromatography on silica gel (hexane/
‡
[M] .
General procedure of the asymmetric alkynylation (Table 5, Entry 3): A
flask was charged with Zn(OTf)2 (2.18 g, 6.01 mmol). Vacuum (5 mmHg)
was applied and heated to 1208C for 12 h. After the flask was cooled to RT,
the vacuum was released. N-Methylephedrine (1.17 g, 6.55 mmol), toluene
(6 mL), and Et3N (0.912 mL, 6.55 mmol) were added to the flask with
stirring at RT. After 3 h, a solution of 25 (951 mg, 5.46 mmol, 25a:25b ˆ
1:1) in toluene (0.3 mL) was added to the mixture at RT. After 15 min, a
solution of 20 (935 mg, 2.73 mmol) in toluene (0.3 mL) was added to the
mixture with stirring at RT. The reaction mixuture was stirred for 43 h. The
reaction was quenched with saturated NH4Cl and the mixture was
extracted with EtOAc. The combined organic layers were washed with
brine prior to drying and solvent evaporation. Purification by column
chromatography on silica (hexane/EtOAc (50:1 ! 20:1)) yielded
(2RS,4S,3'R,4'R)-26a (1.36 g, 96%, anti:syn ˆ 3: > 97) as a colorless oil.
EtOAc (10:1)) yielded 18 (11.7 g, quantitative) as a colorless oil. [a]D26
ˆ
‡1.7 (c ˆ 1.28, CHCl3); 1HNMR: d ˆ 0.06 (s, 3H), 0.07 (s, 3H), 0.87 (t, J ˆ
6.4 Hz, 3H), 0.88 (s, 9H), 1.20 (s, 9H), 1.25 1.39 (m, 20H), 1.42 1.52 (m,
2H), 3.83 (qn, J ˆ 5.5 Hz, 1H), 3.94 (dd, J ˆ 11.0, 5.5 Hz, 1H), 3.97 (dd, J ˆ
11.0, 5.5 Hz, 1H) ppm; 13C NMR: d ˆ À4.7, À4.6, 14.1, 18.0, 22.7, 24.9, 25.8
(3C), 27.2 (3C), 29.3, 29.5, 29.55, 29.63 (2C), 29.66, 29.70, 31.9, 34.6, 38.7,
68.1, 70.1, 178.5 ppm; IR (KBr): nÄ ˆ 1734 cmÀ1; MS (FAB): m/z: 429
‡
[M‡H] ; HRMS (FAB): m/z calcd for C25H53O3Si: 429.3764; found:
‡
429.3774 [M‡H] .
(R)-2-(tert-Butyldimethylsilyloxy)tetradecanol (19): DIBAL-H(1.0 m in
toluene, 40.0 mL, 40.0 mmol) was added to a solution of 18 (8.58 g,
20.0 mmol) in CH2Cl2 (210 mL) with stirring at À788C. After 25 min,
saturated Rochelle salt was gradually added to the mixture, and the whole
mixture was stirred at RT for 0.5 h. After solvent evaporation, the mixture
was extracted with EtOAc. The combined organic layers were washed with
water and brine prior to drying and solvent evaporation. Purification by
column chromatography on silica gel (hexane/EtOAc (5:1)) yielded 19
(6.96 g, quantitative) as a colorless oil. [a]2D6 ˆ À8.4 (c ˆ 1.34, CHCl3);
1HNMR: d ˆ 0.07 (s, 6H), 0.86 (t, J ˆ 7.0 Hz, 3H), 0.89 (s, 9H), 1.25 1.30
(m, 20H), 1.43 1.50 (m, 2H), 2.01 (brs, 1H), 3.42 (dd, J ˆ 11.0, 5.5 Hz,
1H), 3.53 (dd, J ˆ 11.0, 3.7 Hz, 1H), 3.70 (m, 1H) ppm; 13C NMR: d ˆ
À4.6, À4.5, 14.1, 18.0, 22.7, 25.3, 25.8 (3C), 29.3, 29.5, 29.55, 29.62 (2C),
29.64, 29.8, 31.9, 34.0, 66.2, 72.9 ppm; IR (KBr): nÄ ˆ 3329 cmÀ1; MS (FAB):
(2S,4S)-4-[(3'R,4'R)-4'-(tert-Butyldimethylsilyloxy)-3'-hydroxy-1'-hexade-
cynyl]-2-phenyl-1,3-dioxolane [(2S,4S,3'R,4'R)-26a]: The procedure was
same as that used for preparation of (2RS,4S,3'R,4'R)-26a. Colorless oil;
[a]2D5 ˆ ‡34.7 (c ˆ 1.17, CHCl3); 1HNMR: d ˆ 0.12 (s, 3H), 0.15 (s, 3H),
0.88 (t, J ˆ 7.0 Hz, 3H), 0.92 (s, 9H), 1.26 1.31 (s, 20H), 1.50 1.69 (m, 2H),
2.56 (d, J ˆ 7.3 Hz, 1H), 3.76 (td, J ˆ 6.1, 4.3 Hz, 1H), 3.99 (dd, J ˆ 7.9,
6.4 Hz, 1H), 4.29 4.31 (m, 1H), 4.36 (dd, J ˆ 7.9, 6.7 Hz, 1H), 4.93 (ddd,
J ˆ 6.7, 6.4, 1.8 Hz, 1H), 5.96 (s, 1H), 7.36 7.40 (m, 3H), 7.46 7.48 (m,
2H) ppm; 13C NMR: d ˆ À4.52, À4.45, 14.0, 18.0, 22.6, 25.0, 25.8 (3C),
29.2, 29.4, 29.46, 29.54 (2C), 29.57, 29.64, 31.8, 33.6, 64.7, 65.8, 71.1, 75.2, 81.9,
86.6, 103.5, 126.5 (2C), 128.2 (2C), 129.3, 136.6 ppm; IR (KBr): nÄ ˆ 3510,
‡
2251, 1107 cmÀ1; MS (FAB): m/z: 539 [M‡Na] ; HRMS (FAB): m/z calcd
‡
for C31H52NaO4Si: 539.3533; found: 539.3540 [M‡Na] .
(2R,4S)-4-[(3'R,4'R)-4'-(tert-Butyldimethylsilyloxy)-3'-hydroxy-1'-hexa-
decynyl]-2-phenyl-1,3-dioxolane [(2R,4S,3'R,4'R)-26a]: The procedure
was same as that used for preparation of (2RS,4S,3'R,4'R)-26a. Colorless
oil; [a]2D4 ˆ ‡7.5 (c ˆ 1.40, CHCl3); 1HNMR: d ˆ 0.10 (s, 3H), 0.13 (s, 3H),
0.88 (t, J ˆ 6.7 Hz, 3H), 0.91 (s, 9H), 1.26 1.31 (m, 20H), 1.47 1.65 (m,
2H), 2.51 (d, J ˆ 7.3 Hz, 1H), 3.73 (td, J ˆ 6.1, 4.3 Hz, 1H), 4.07 (dd, J ˆ 7.9,
5.5 Hz, 1H), 4.18 (dd, J ˆ 7.9, 6.7 Hz, 1H), 4.26 (ddd, J ˆ 7.3, 4.3, 1.2 Hz,
1H), 4.88 (ddd, J ˆ 6.7, 5.5, 1.2 Hz, 1H), 5.86 (s, 1H), 7.36 7.40 (m, 3H),
7.51 7.53 (m, 2H) ppm; 13C NMR: d ˆ À4.5, À4.4, 14.1, 18.1, 22.6, 25.0,
25.8 (3C), 29.3, 29.47, 29.50, 29.57 (2C), 29.61, 29.7, 31.9, 33.6, 64.7, 66.4, 70.6,
75.2, 81.6, 86.2, 104.9, 126.8 (2C), 128.2 (2C), 129.3, 137.0 ppm; IR (KBr):
‡
m/z: 345 [M‡H] ; HRMS (FAB): m/z calcd for C20H45O2Si: 345.3189;
‡
found: 345.3185 [M‡H] .
(R)-2-(tert-Butyldimethylsilyloxy)tetradecanal (20): Dess Martin period-
inane (1.48 g, 3.48 mmol) was added to a solution of 19 (800 mg, 2.32 mmol)
in CH2Cl2 (12 mL) with stirring at 08C. After 15 min at RT, the mixture was
filtered through silica gel and the filtrate was evaporated. Purification by
column chromatography on silica gel (hexane/EtOAc (10:1)) yielded 20
(765 mg, 96%) as a colorless oil. [a]2D4 ˆ ‡24.5 (c ˆ 1.69, CHCl3); 1HNMR:
d ˆ 0.04 (s, 3H), 0.05 (s, 3H), 0.85 (t, J ˆ 6.7 Hz, 3H), 0.90 (s, 9H), 1.23
1.42 (m, 20H), 1.53 1.63 (m, 2H), 3.93 (td, J ˆ 6.1, 1.2 Hz, 1H), 9.55 (dd,
J ˆ 1.8, 1.2 Hz, 1H) ppm; 13C NMR: d ˆ À5.1, À4.7, 14.1, 18.1, 22.6, 24.6,
25.7 (3C), 29.3, 29.40, 29.41, 29.5, 29.59, 29.61, 29.64, 31.9, 32.6, 77.6,
‡
nÄ ˆ 3489, 2243, 1066 cmÀ1; MS (FAB): m/z: 539 [M‡Na] ; HRMS (FAB):
‡
m/z calcd for C31H52NaO4Si: 539.3533; found: 539.3546 [M‡Na] .
‡
204.0 ppm; IR (KBr): nÄ ˆ 1738 cmÀ1; MS (FAB): m/z: 365 [M‡Na] ;
(2RS,4S)-4-[(3'S,4'R)-4'-(tert-Butyldimethylsilyloxy)-3'-hydroxy-1'-hexa-
decynyl]-2-phenyl-1,3-dioxolane (26b): The procedure was same as that
used for preparation of (2RS,4S,3'R,4'R)-26a. Colorless oil; [a]2D6 ˆ ‡33.6
(c ˆ 1.09, CHCl3); 1HNMR: d ˆ 0.10 (s, 3H), 0.11 (s, 3H), 0.88 (t, J ˆ
6.7 Hz, 3H), 0.91 (s, 4.5H), 0.92 (s, 4.5H), 1.28 1.43 (m, 20H), 1.56 1.69
(m, 2H), 2.32 (d, J ˆ 5.5 Hz, 0.5H), 2.37 (d, J ˆ 6.1 Hz, 0.5H), 3.75 (ddd,
J ˆ 7.3, 5.5, 3.7 Hz, 0.5H), 3.78 (ddd, J ˆ 7.3, 5.5, 3.7 Hz, 0.5H), 3.99 (dd, J ˆ
7.9, 6.1 Hz, 0.5H), 4.07 (dd, J ˆ 7.9, 5.5 Hz, 0.5H), 4.19 (dd, J ˆ 7.9, 6.7 Hz,
0.5H), 4.367 (dd, J ˆ 7.9, 6.7 Hz, 0.5H), 4.374 4.42 (m, 1H), 4.91 (ddd, J ˆ
6.7, 5.5, 1.2 Hz, 0.5H), 4.96 (ddd, J ˆ 6.7, 6.1, 1.2 Hz, 0.5H), 5.87 (s, 0.5H),
5.96 (s, 0.5H), 7.37 7.39 (m, 3H), 7.47 7.49 (m, 1H), 7.52 7.54 (m,
1H) ppm; 13C NMR: (2R)-26b: d ˆ À4.6, À4.4, 14.0, 18.0, 22.6, 25.27, 25.8
(3C), 29.3, 29.46, 29.50 (2C), 29.55, 29.59, 29.64, 31.8, 32.4, 65.8, 66.0, 71.1,
74.8, 82.9, 83.1, 103.5, 126.5 (2C), 128.2 (2C), 129.4, 136.5 ppm; (2S)-26b:
d ˆ À4.6, À4.4, 14.0, 18.0, 22.6, 25.33, 25.8 (3C), 29.3, 29.46, 29.50 (2C),
29.55, 29.59, 29.64, 31.8, 32.3, 66.0, 66.3, 70.7, 74.8, 84.2, 84.8, 104.9, 126.8
(2C), 128.2 (2C), 129.3, 137.1 ppm; IR (KBr): nÄ ˆ 3462, 2241, 1097 cmÀ1; MS
HRMS (FAB): m/z calcd for C20H42NaO2Si: 365.2852; found: 365.2873
‡
[M‡Na] .
(2RS,4S)-4-Ethynyl-2-phenyl-1,3-dioxolane (25): Benzaldehyde dimethyl
acetal (0.175 mL, 1.16 mmol) and (‡)-10-camphorsulfonic acid (13.5 mg,
0.058 mmol) were added to a solution of 13 (50.0 mg, 0.581 mmol) in THF
(4 mL) with stirring at RT. After 1 h under reflux conditions, the reaction
was quenched with Et3N and the solvent was evaporated. NaBH4 (33.0 mg,
0.872 mmol) was added to the solution of the residue in MeOH(3.0 mL)
with stirring at 08C. After 30 min at RT, the reaction was quenched with
water and the solvent was evaporated. The residue was extracted with
EtOAc. The combined organic layers were washed with brine prior to
drying and solvent evaporation. Purification by column chromatography on
silica gel (hexane/EtOAc (100:1 ! 10:1)) yielded 25 (89.2 mg, 88%,
25a:25b ˆ 1:1). Analytical samples of 25a and 25b were purified by
column chromatography on silica gel (hexane/EtOAc (100:1 ! 10:1)). 25a:
Colorless powder; m.p. 51.0 53.08C; [a]2D6 ˆ ‡86.3 (c ˆ 1.17, CHCl3);
1HNMR: d ˆ 2.63 2.64 (m, 1H), 4.04 (dd, J ˆ 7.9, 6.1 Hz, 1H), 4.38 (dd,
J ˆ 7.9, 6.7 Hz, 1H), 4.93 (td, J ˆ 6.4, 1.8 Hz, 1H), 6.05 (s, 1H), 7.43 7.46
(m, 3H), 7.54 7.55 (m, 2H) ppm; 13C NMR: d ˆ 65.3, 70.8, 74.7, 80.9, 103.4,
‡
(FAB): m/z: 517 [M‡H] ; HRMS (FAB): m/z calcd for C31H53O4Si:
‡
517.3713; found: 517.3705 [M‡H] .
126.4 (2C), 128.1 (2C), 129.3, 136.3 ppm; IR (KBr): nÄ ˆ 2119, 1066 cmÀ1
;
(2S,5R,6R)-1,2:5,6-Di-O-isopropylidene-octadec-3-yne-1,2,5,6-tetrol
(27a): TBAF (1.0m in THF, 0.192 mL, 0.192 mmol) was added to a solution
of 26a (50.0 mg, 0.0967 mmol) in THF (0.5 mL) with stirring at RT. After
1.5 h, water (0.7 mL) and Et2O (1.7 mL) were added to the reaction
mixture, and the aqueous layer was extracted with Et2O. The combined
‡
‡
MS (EI): m/z: (%): 174 (37.2) [M] , 173 (48.4) [M À H] , 97 (14.6) [M À
‡
C6H5] , 78 (100); HRMS (EI): m/z calcd for C11H10O2: 174.0681; found:
174.0683 [M] . 25b: Colorless oil; [a]2D6 ˆ ‡37.5 (c ˆ 1.21, CHCl3);
‡
1HNMR: d ˆ 2.57 (d, J ˆ 1.8 Hz, 1H), 4.15 (dd, J ˆ 8.2, 5.2 Hz, 1H), 4.20
4986
¹ 2003 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 4980 4990

THF-Ring Formation
4980 4990
organic layers were washed with water and brine prior to drying and solvent
evaporation. Me2C(OMe)2 (9.6 mL, 78.0 mmol) and a catalytic amount of
pTsOH¥ H 2O were added to the solution of the crude product in CH2Cl2
(6 mL) with stirring at RT. After 18 h, saturated NaHCO3 and CH2Cl2 were
added, and the organic layer was washed with brine prior to drying and
solvent evaporation. Purification by flash column chromatography on silica
gel (hexane/EtOAc (30:1)) yielded 27a (36.0 mg, 94%) as a pale yellow oil.
[a]2D8 ˆ ‡26.8 (c ˆ 1.55, CHCl3); 1HNMR: d ˆ 0.88 (t, J ˆ 7.0 Hz, 3 H),
1.20 1.51 (m, 20H), 1.38 (s, 3H), 1.40 (s, 3H), 1.45 (s, 3H), 1.48 (s, 3H),
1.60 1.64 (m, 2H), 3.93 (dd, J ˆ 7.9, 6.1 Hz, 1H), 4.00 (td, J ˆ 7.3, 6.4 Hz,
1H), 4.16 (dd, J ˆ 7.9, 6.1 Hz, 1H), 4.24 (dd, J ˆ 7.3, 1.2 Hz, 1H), 4.76 (td,
J ˆ 6.1, 1.2 Hz, 1H) ppm; 13C NMR: d ˆ 14.1, 22.7, 25.7, 25.9, 26.13, 26.16,
27.1, 29.3, 29.46, 29.54, 29.60, 29.63 (2C), 29.64, 31.9, 32.4, 65.5, 69.8, 70.4,
81.4, 82.7, 83.9, 109.7, 110.4 ppm; IR (KBr): nÄ ˆ 1063 cmÀ1; MS (FAB): m/z:
25.6, 26.0 (3C), 27.7, 27.8, 29.3, 29.59 (2C), 29.63 (2C), 29.7, 29.8, 31.9, 33.0,
64.9, 75.0, 79.4, 82.1 ppm; IR (KBr): nÄ ˆ 3421, 1068 cmÀ1; MS (FAB): m/z:
‡
415 [M‡H] ; HRMS (FAB): m/z calcd for C24H51O3Si: 415.3608; found:
‡
415.3600 [M‡H] .
(2RS,4S)-4-[(3'R,4'R)-4'-(tert-Butyldimethylsilyloxy)-3'-hydroxyoctade-
canyl]-2-phenyl-1,3-dioxolane (32): A mixture of 26a (300 mg, 0.580 mmol)
and Et3N (0.040 mL, 0.290 mmol) in EtOAc (6 mL) was hydrogenated on
10% Pd/C (15 mg) with stirring at RT for 2.5 h. The Pd/C was filtered off
and the filtrate was concentrated under reduced pressure. Purification by
column chromatography on silica gel (hexane/EtOAc (7:1)) yielded 32
(301 mg, quantitative) as a colorless oil. [a]2D4 ˆ ‡2.5 (c ˆ 1.00, CHCl3);
1HNMR: d ˆ 0.07 0.09 (m, 6H), 0.87 0.90 (m, 12H), 1.26 (m, 21H),
1.38 1.51 (m, 1.58H), 1.60 1.68 (m, 1.42H), 1.72 1.95 (m, 2H), 2.21 (d,
J ˆ 6.7 Hz, 0.42H), 2.23 (d, J ˆ 6.7 Hz, 0.58H), 3.44 3.53 (m, 2H), 3.64 (t,
J ˆ 6.7 Hz, 0.58H), 3.70 (t, J ˆ 7.3 Hz, 0.42H), 4.12 (t, J ˆ 7.0 Hz, 0.42H),
4.20 4.28 (m, 1.58H), 5.81 (s, 0.42H), 5.93 (s, 0.58H), 7.35 7.39 (m, 3H),
7.46 7.50 (m, 2H) ppm; 13C NMR: d ˆ À4.6, À4.1, 14.1, 18.1, 22.6, 25.0,
25.9 (3C), 29.3, 29.5 (2C), 29.59 (2C), 29.63, 29.8, 30.0 (0.58C), 30.2 (0.42C),
30.57 (0.42C), 30.64 (0.58C), 31.9, 33.8, 70.1 (0.42C), 70.7 (0.58C), 72.6
(0.58C), 72.7 (0.42C), 75.26 (0.42C), 75.29 (0.58C), 76.8 (0.58C), 77.6
(0.42C), 103.0 (0.58C), 104.0 (0.42C), 126.3 (1.16C), 126.6 (0.84C), 128.3
(2C), 129.0 (0.42C), 129.2 (0.58C), 137.8 (0.42C), 138.4 (0.58C) ppm; IR
‡
395 [M‡H] ; HRMS (FAB): m/z calcd for C24H43O4: 395.3161; found:
‡
395.3167 [M‡H] .
(2S,5S,6R)-1,2:5,6-Di-O-isopropylidene-octadec-3-yne-1,2,5,6-tetrol
(27b): The procedure was the same as that used for preparation of 27a.
Pale yellow oil; [a]2D8 ˆ À6.6 (c ˆ 1.35, CHCl3); 1HNMR: d ˆ 0.88 (t, J ˆ
6.7 Hz, 3H), 1.26 1.54 (m, 20H), 1.34 (s, 3H), 1.38 (s, 3H), 1.48 (s, 3H),
1.51 (s, 3H), 1.63 1.70 (m, 1H), 1.73 1.79 (m, 1H), 3.92 (dd, J ˆ 7.9,
6.1 Hz, 1H), 4.06 (td, J ˆ 6.7, 5.8 Hz, 1H), 4.16 (dd, J ˆ 7.9, 6.1 Hz, 1H), 4.76
(dd, J ˆ 5.8, 1.2 Hz, 1H), 4.77 (td, J ˆ 6.1, 1.2 Hz, 1H) ppm; 13C NMR: d ˆ
14.1, 22.7, 25.90, 25.93, 26.1 (2C), 27.9, 29.3, 29.48, 29.54, 29.62 (2C), 29.64
(2C), 30.7, 31.9, 65.5, 69.2, 69.9, 78.1, 82.0, 85.0, 109.5, 110.3 ppm; IR (KBr):
‡
(KBr): nÄ ˆ 3562, 1070 cmÀ1; MS (FAB): m/z: 521 [M‡H] ; HRMS (FAB):
‡
m/z calcd for C31H57O4Si: 521.4026; found: 521.4015 [M‡H] .
(2RS,4S)-4-[(3'R,4'R)-4'-(tert-Butyldimethylsilyloxy)-3'-(p-toluenesulfo-
‡
nÄ ˆ 1065 cmÀ1; MS (FAB): m/z: 395 [M‡H] ; HRMS (FAB): m/z calcd for
noxyl)octadecanyl]-2-phenyl-1,3-dioxolane
(33):
pTsCl
(522 mg,
‡
C24H43O4: 395.3161; found: 395.3162 [M‡H] .
(2S,5R,6R)-6-(tert-Butyldimethylsilyloxy)octadecane-1,2,5-triol (28):
2.74 mmol) was added to a solution of 32 (285 mg, 0.548 mmol) in pyridine
(2 mL) with stirring at 08C. The stirring was continued at RT for 7 h. The
reaction was quenched with saturated NH4Cl, and the mixture was
extracted with EtOAc. The combined organic layers were washed with
water and brine prior to drying and solvent evaporation. Purification by
column chromatography on silica gel (hexane/EtOAc (10:1)) yielded 33
(354 mg, 96%) as a colorless oil. [a]2D5 ˆ ‡13.1 (c ˆ 0.73, CHCl3); 1HNMR:
d ˆ À0.01 (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H), 0.88 (t, J ˆ 7.0 Hz, 3H), 1.26
(m, 22H), 1.40 1.59 (m, 3H), 1.97 2.04 (m, 1H), 2.42 (s, 1.26H), 2.44 (s,
1.74H), 3.49 (dd, J ˆ 7.9, 6.7 Hz, 0.58H), 3.55 (dd, J ˆ 7.9, 6.7 Hz, 0.42H),
3.65 3.76 (m, 1H), 4.03 (dd, J ˆ 7.3, 6.7 Hz, 0.42H), 4.06 4.14 (m, 1H),
4.18 (dd, J ˆ 7.9, 6.1 Hz, 0.58H), 4.38 (ddd, J ˆ 9.2, 4.3, 3.1 Hz, 0.42H),
4.41 4.44 (m, 0.58H), 5.75 (s, 0.42H), 5.82 (s, 0.58H), 7.30 7.37 (m, 5H),
7.42 7.44 (m, 2H), 7.79 (t, 2H, J ˆ 8.2 Hz) ppm; 13C NMR: d ˆ À4.8, À4.6,
14.1, 17.9, 21.6, 22.6, 24.2 (0.42C), 24.3 (0.58C), 25.7 (3C), 25.9, 29.3, 29.5
(2C), 29.56, 29.61 (2C), 29.65, 29.43, 30.2, 31.9, 69.9 (0.42C), 70.5 (0.58C),
71.9 (0.58C), 72.0 (0.42C), 76.2 (0.58C), 76.8 (0.42C), 84.8, 102.9 (0.58C),
103.9 (0.42C), 126.3 (1.16C), 126.5 (0.84C), 127.8 (2C), 128.2 (0.84C), 128.3
(1.16C), 129.0 (0.58C), 129.2 (0.42C), 129.7 (2C), 134.2 (0.42C), 134.3
A
solution of 26a (1.21 g, 2.34 mmol) in EtOAc (23 mL) was hydrogenated
on 10% Pd/C (60.5 mg) with stirring at RT for 24 h. The Pd/C was filtered
off and the filtrate was concentrated under reduced pressure. Purification
by column chromatography on silica gel (hexane/EtOAc (1:4)) yielded 28
(1.14 g, 94%) as a colorless oil. [a]2D6 ˆ À5.7 (c ˆ 1.60, CHCl3); 1HNMR:
d ˆ 0.08 (s, 3H), 0.09 (s, 3H), 0.88 (t, J ˆ 7.0 Hz, 3H), 0.90 (s, 9H), 1.26 1.31
(m, 20H), 1.38 1.69 (m, 6H), 2.65 (brs, 1H), 3.23 (brs, 1H), 3.47 (dd, J ˆ
11.0, 7.6 Hz, 1H), 3.48 3.53 (m, 2H), 3.63 (dd, J ˆ 11.0, 3.1 Hz, 1H), 3.74
(ddd, J ˆ 11.0, 7.3, 4.3 Hz, 1H) ppm; 13C NMR: d ˆ À4.6, À4.2, 14.1, 18.1,
22.7, 24.8, 25.8 (3C), 29.3, 29.55, 29.57, 29.61 (3C), 29.64, 29.8, 29.9, 31.9, 33.7,
66.6, 72.0, 73.0, 75.4 ppm; IR (KBr): nÄ ˆ 3358, 1080 cmÀ1; MS (FAB): m/z:
‡
433 [M‡H] ; HRMS (FAB): m/z calcd for C24H53O4Si: 433.3713; found:
‡
433.3726 [M‡H] .
(2S,5R,6R)-6-(tert-Butyldimethylsilyloxy)-2,5-dihydroxyoctadecanyl
2',4',6'-triisopropylbenzenesulfonate (29): 2,4,6-Triisopropylbenzenesul-
fonyl chloride (1.05 g, 3.48 mmol) was added to a solution of 28 (500 mg,
1.16 mmol) in pyridine (2 mL) and CH2Cl2 (3 mL) at 08C with stirring.
After 20 h at RT, water was added to the reaction mixture, and the mixture
was extracted with EtOAc. The combined organic layers were washed with
brine prior to drying and solvent evaporation. Purification by column
chromatography on silica gel (hexane/EtOAc (5:1)) yielded 29 (704 mg,
87%) as a colorless oil. [a]D24 ˆ ‡0.12 (c ˆ 0.96, CHCl3); 1HNMR: d ˆ 0.07
(s, 3H), 0.08 (s, 3H), 0.87 0.89 (m, 12H), 1.25 (m, 39H), 1.36 1.65 (m,
4H), 1.70 1.75 (m, 1H), 2.41 (d, J ˆ 5.5 Hz, 1H), 2.87 (brs, 1H), 2.88 2.94
(m, 1H), 3.43 3.45 (m, 1H), 3.47 3.50 (m, 1H), 3.92 3.96 (m, 2H), 4.04
(dd, J ˆ 12.8, 7.3 Hz, 1H), 4.14 (sep, J ˆ 6.7 Hz, 2H), 7.19 (s, 2H) ppm;
13C NMR: d ˆ À4.7, À4.2, 14.1, 18.0, 22.6, 23.5, 24.66 (2C), 24.69 (2C), 24.74
(2C), 25.8 (3C), 29.3, 29.5 (3C), 29.6 (5C), 29.8 (2C), 31.9, 33.7, 34.2, 69.4,
72.6, 72.8, 75.4, 123.8 (2C), 129.1, 150.8 (2C), 153.8 ppm; IR (KBr): nÄ ˆ
(0.58C), 137.6 (0.42C), 138.2 (0.58C), 144.7 ppm; IR (KBr): nÄ ˆ 1068 cmÀ1
;
‡
MS (FAB): m/z: 697 [M‡Na] ; HRMS (FAB): m/z calcd for C38H62NaO6S-
‡
Si: 697.3934; found: 697.3907 [M‡Na] .
(2S,5S,6R)-6-(tert-Butyldimethylsilyloxy)-2,5-epoxyoctadecan-1-ol (31b):
A solution of 33 (55.0 mg, 0.0815 mmol) in EtOAc (1 mL) was hydro-
genated on 10% Pd/C (2.8 mg) with stirring at RT for 24 h. The Pd/C was
filtered off and the filtrate was concentrated under reduced pressure. The
residue was dissolved in THF (3 mL). NaH (62.6% in oil, 12.5 mg,
0.326 mmol) was added to the mixture with stirring at 08C. After 1 h at
408C, water was added to the reaction mixture, and the mixture was
extracted with EtOAc. The combined organic layers were washed with
brine prior to drying and solvent evaporation. Purification by column
chromatography on silica gel (hexane/EtOAc (10:1)) yielded 31b (26.4 mg,
78% in 2 steps) as a colorless oil. [a]2D8 ˆ À2.1 (c ˆ 1.17, CHCl3); 1HNMR:
d ˆ 0.06 (s, 6H), 0.86 0.89 (m, 12H), 1.23 1.38 (m, 22H), 1.60 1.69 (m,
1H), 1.82 1.97 (m, 4H), 3.46 (dd, J ˆ 11.6, 6.1 Hz, 1H), 3.62 (dd, J ˆ 11.6,
3.1 Hz, 1H), 3.75 3.78 (m, 1H), 3.90 (dt, J ˆ 10.4, 3.7 Hz, 1H), 4.05 4.10
(m, 1H) ppm; 13C NMR: d ˆ À4.5, À4.3, 14.1, 18.2, 22.7, 25.4, 25.9 (3C),
27.6, 29.3, 29.57 (2C), 29.59 (2C), 29.64, 29.7, 29.9, 31.9, 34.7, 65.0, 73.4, 79.5,
‡
3379, 1425, 1076 cmÀ1; MS (FAB): m/z: 699 [M‡H] ; HRMS (FAB): m/z
‡
calcd for C39H75O6SSi: 699.5054; found: 699.5059 [M‡H] .
(2R,5R,6R)-6-(tert-Butyldimethylsilyloxy)-2,5-epoxyoctadecan-1-ol
(31a): K2CO3 (71.9 mg, 0.520 mmol) was added to a mixture of 29 (72.4 mg,
0.104 mmol) with stirring at 08C. The whole mixture was stirred at 08C for
2 h and at RT for 39 h. Water was added to the reaction mixture. The
mixture was extracted with EtOAc, and the combined organic layers were
washed with brine prior to drying and solvent evaporation. Purification by
column chromatography on silica gel (hexane/EtOAc (10:1)) yielded 31a
(30.2 mg, 70%) as a colorless oil. [a]2D6 ˆ ‡4.4 (c ˆ 0.76, CHCl3); 1HNMR:
d ˆ 0.06 (s, 3H), 0.07 (s, 3H), 0.87 0.89 (m, 12H), 1.26 (m, 22H), 1.60 1.74
(m, 2H), 1.88 1.97 (m, 2H), 3.48 (dd, J ˆ 11.6, 6.1 Hz, 1H), 3.57 (ddd, J ˆ
7.0, 6.1, 4.0 Hz, 1H), 3.65 (dd, J ˆ 11.6, 2.7 Hz, 1H), 3.91 (dt, J ˆ 7.3, 6.1 Hz,
1H), 4.05 4.10 (m, 1H) ppm; 13C NMR: d ˆ À4.6, À4.2, 14.1, 18.3, 22.7,
‡
82.0 ppm; IR (KBr): nÄ ˆ 3462, 1051 cmÀ1; MS (FAB): m/z: 437 [M‡Na] ;
HRMS (FAB): m/z calcd for C24H50NaO3Si: 437.3426; found: 437.3430
‡
[M‡Na] .
One-pot THF-ring formation of 33: A solution of 33 (151 mg, 0.223 mmol)
in THF (3 mL) was hydrogenated on 10% Pd/C (15.1 mg) with stirring at
RT for 22 h. THF (1.8 mL) and NaH (62.6% in oil, 34.3 mg, 0.892 mmol)
were added to the mixture with stirring at 08C. After 2 h at 408C, water was
Chem. Eur. J. 2003, 9, 4980 4990
www.chemeurj.org
¹ 2003 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
4987

N. Maezaki, T. Tanaka et al.
FULL PAPER
added to the reaction mixture, and the mixture was extracted with EtOAc.
The combined organic layers were washed with brine prior to drying and
solvent evaporation. Purification by column chromatography on silica gel
(hexane/EtOAc (10:1)) yielded 31b (92.5 mg, quantitative) as a colorless
oil.
1HNMR: d ˆ 0.078 (s, 3H), 0.084 (s, 3H), 0.88 (t, J ˆ 6.7 Hz, 3H), 0.90 (s,
9H), 1.26 1.69 (m, 22H), 1.79 1.92 (m, 4H), 2.44 (brs, 1H), 3.47 (dt, J ˆ
10.4, 5.5 Hz, 1H), 3.59 (ddd, J ˆ 6.7, 6.1, 3.7 Hz, 1H), 3.76 (brd, J ˆ 11.0 Hz,
1H), 3.96 (td, J ˆ 6.7, 3.7 Hz, 1H), 4.05 4.09 (m, 1H) ppm; 13C NMR: d ˆ
À4.6, À4.4, 14.1, 18.2, 22.6, 25.6, 25.9 (3C), 27.3, 27.7, 29.3, 29.58, 29.61 (3C),
29.7, 29.8, 31.9, 34.0, 65.3, 74.7, 79.3, 81.2 ppm; IR (KBr): nÄ ˆ 3448,
(2R,5S,6R)-6-(tert-Butyldimethylsilyloxy)-2,5-epoxyoctadecan-1-ol (31c):
Compound 26b was converted into a triol by the same procedure as that
described for the conversion of 26a into 28. Colorless oil; [a]2D6 ˆ ‡5.6 (c ˆ
1.74, CHCl3); 1HNMR: d ˆ 0.07 (s, 3H), 0.08 (s, 3H), 0.88 (t, J ˆ 7.3 Hz,
3H), 0.90 (s, 9H), 1.26 (m, 20H), 1.33 1.65 (m, 6H), 2.87 (brs, 3H), 3.46
(dd, J ˆ 11.0, 7.3 Hz, 1H), 3.57 3.61 (m, 2H), 3.62 (dd, J ˆ 11.0, 3.1 Hz,
1H), 3.68 3.72 (m, 1H) ppm; 13C NMR: d ˆ À4.5, À4.4, 14.1, 18.0, 22.6,
25.6, 25.8 (3C), 28.6, 29.3, 29.59 (2C), 29.61 (2C), 29.64 (2C), 29.8, 30.8, 31.9,
66.9, 72.4, 75.1, 75.3 ppm; IR (KBr): nÄ ˆ 3321, 1084 cmÀ1; MS (FAB): m/z:
‡
1052 cmÀ1; MS (FAB): m/z: 415 [M‡H] ; HRMS (FAB): m/z calcd for
‡
C24H51O3Si: 415.3607; found: 415.3613 [M‡H] .
(3R,4R,7R,8R)-8-(tert-Butyldimethylsilyloxy)-4,7-epoxy-1-trimethylsilyl-
heneicos-1-yn-3-ol (36a): Dess Martin periodinane (1.48 g, 3.50 mmol)
was added to a solution of 31a (363 mg, 0.875 mmol) in CH2Cl2 (9 mL) and
pyridine (1 mL) with stirring at 08C. After stirring at RT for 1 h, the
mixture was filtered through silica gel and the filtrate was concentrated
under the reduced pressure. Purification by flash column chromatography
(hexane/EtOAc (30:1)) yielded 35a (309 mg, 86%) as a pale yellow oil. The
aldehyde was unstable and was therefore used immediately in the next step.
Aldehyde 35a was converted into 36a by the same procedure as that
described for the formation of (2RS,4S,3'R,4'R)-26a but with trimethylsi-
lylacetylene instead of 25. Colorless oil; [a]2D4 ˆ ‡12.9 (c ˆ 1.03, CHCl3);
1HNMR: d ˆ 0.06 (s, 3H), 0.08 (s, 3H), 0.17 (s, 9H), 0.88 (t, J ˆ 6.7 Hz,
3H), 0.89 (s, 9H), 1.23 1.45 (m, 22H), 1.67 (dq, J ˆ 11.9, 8.7 Hz, 1H),
1.75 1.83 (m, 1H), 1.89 1.96 (m, 1H), 2.02 2.08 (m, 1H), 2.47 (d, J ˆ
4.6 Hz, 1H), 3.57 (td, J ˆ 6.6, 3.7 Hz, 1H), 3.91 (td, J ˆ 8.2, 6.6 Hz, 1H), 4.04
(q, J ˆ 6.7 Hz, 1H), 4.18 (dd, J ˆ 6.7, 4.6 Hz, 1H) ppm; 13C NMR: d ˆ À4.6,
À4.1, À0.2 (3C), 14.1, 18.3, 22.7, 25.5, 26.0 (3C), 27.7, 28.3, 29.3, 29.57, 29.59,
29.63 (2C), 29.7, 29.8, 31.9, 33.0, 65.6, 74.9, 82.0, 82.9, 90.3, 103.7 ppm; IR
‡
433 [M‡H] ; HRMS (FAB): m/z calcd for C24H53O4Si: 433.3713; found:
‡
433.3719 [M‡H] . The triol was converted into a sulfonate by the same
procedure as that described for the conversion of 28 into 29. Colorless oil;
[a]2D4 ˆ ‡3.8 (c ˆ 0.73, CHCl3); 1HNMR: d ˆ 0.06 (s, 3H), 0.07 (s, 3H), 0.88
(t, J ˆ 6.7 Hz, 3H), 0.89 (s, 9H), 1.26 (m, 39H), 1.36 1.49 (m, 4H), 1.73
1.79 (m, 1H), 2.50 2.54 (m, 1H), 2.91 (sep, J ˆ 6.7 Hz, 1H), 3.48 3.50 (m,
1H), 3.56 3.61 (m, 2H), 3.87 3.91 (m, 1H), 3.98 4.00 (m, 2H), 4.14 (sep,
J ˆ 6.7 Hz, 2H), 7.19 (s, 2H) ppm; 13C NMR: d ˆ À4.5 (2C), 14.1, 18.0, 22.6
(2C), 23.5 (2C), 24.7 (2C), 25.5, 25.8 (3C), 28.1, 29.3, 29.5 (3C), 29.56 (3C),
29.59, 29.8 (2C), 30.6, 30.7, 31.8, 34.2, 69.6, 72.7, 74.7, 75.2, 123.7 (2C), 129.0,
150.8 (2C), 153.7 ppm; IR (KBr): nÄ ˆ 3446, 1425, 1074 cmÀ1; MS (FAB) m/
‡
z: 699 [M‡H] ; HRMS (FAB): m/z calcd for C39H75O6SSi: 699.5054;
‡
(KBr): nÄ ˆ 3429, 2175, 1074 cmÀ1; MS (FAB): m/z: 533 [M‡Na] ; HRMS
‡
found: 699.5046 [M‡H] . The sulfonate was converted into 31c by the
‡
(FAB): m/z calcd for C29H58NaO3Si2: 533.3822; found: 533.3846 [M‡Na] ;
same procedure as that described for the conversion of 29 into 31a.
Colorless oil; [a]2D4 ˆ À15.5 (c ˆ 0.53, CHCl3); 1HNMR: d ˆ 0.071 (s, 3H),
0.073 (s, 3H), 0.88 (t, J ˆ 6.7 Hz, 3H), 0.90 (s, 9H), 1.26 (m, 20H), 1.39 1.49
(m, 2H), 1.65 1.72 (m, 1H), 1.78 1.94 (m, 3H), 2.05 (t, J ˆ 6.7 Hz, 1H),
3.49 (ddd, J ˆ 11.6, 5.5, 4.9 Hz, 1H), 3.68 3.72 (m, 1H), 3.78 (td, J ˆ 5.5,
4.3 Hz, 1H), 3.85 (ddd, J ˆ 7.9, 6.7, 4.3 Hz, 1H), 3.99 4.04 (m, 1H) ppm;
13C NMR: d ˆ À4.4, À4.2, 14.1, 18.1, 22.7, 25.0, 25.8, 25.9 (3C), 27.2, 29.3,
29.57 (2C), 29.63 (2C), 29.7, 29.9, 31.9, 35.0, 65.7, 73.1, 79.4, 82.2 ppm; IR
20
CD (c ˆ 1.96  10À3, CHCl3) [q]
(nm): ‡1.7  104 (184.4).
max
(3S,4R,7R,8R)-8-(tert-Butyldimethylsilyloxy)-4,7-epoxy-1-trimethylsilyl-
heneicos-1-yn-3-ol (36b): The procedure was the same as that used for
preparation of 36a. Colorless oil; [a]2D4 ˆ ‡22.1 (c ˆ 1.04, CHCl3);
1HNMR: d ˆ 0.06 (s, 3H), 0.07 (s, 3H), 0.17 (s, 9H), 0.88 (t, J ˆ 6.7 Hz,
3H), 0.89 (s, 9H), 1.23 1.47 (m, 22H), 1.64 1.73 (m, 1H), 1.93 2.05 (m,
3H), 2.35 (d, J ˆ 6.7 Hz, 1H), 3.56 (ddd, J ˆ 7.3, 5.5, 4.3 Hz, 1H), 4.04 (ddd,
J ˆ 7.9, 6.1, 5.5 Hz, 1H), 4.12 (td, J ˆ 7.0, 3.7 Hz, 1H), 4.39 (dd, J ˆ 6.1,
3.7 Hz, 1H) ppm; 13C NMR: d ˆ À4.6, À4.2, À0.3 (3C), 14.1, 18.2, 22.7,
25.6, 25.9 (3C), 26.7, 27.6, 29.32, 29.58, 29.61 (3C), 29.64, 29.8, 31.9, 32.9,
‡
(KBr): nÄ ˆ 3481, 1063 cmÀ1; MS (FAB): m/z: 415 [M‡H] ; HRMS (FAB):
‡
m/z calcd for C24H51O3Si: 415.3608; found: 415.3614 [M‡H] .
(2S,5R,6R)-6-(tert-Butyldimethylsilyloxy)-2,5-epoxyoctadecan-1-ol
(31d): Compound 26b was converted into an alcohol by the same
procedure as that described for the conversion of 26a into 32. Colorless
oil; [a]2D8 ˆ ‡5.7 (c ˆ 1.31, CHCl3); 1HNMR: d ˆ 0.08 0.09 (m, 6H), 0.88
0.92 (m, 12H), 1.27 1.77 (m, 25H), 1.93 2.00 (m, 1H), 2.27 (s, 0.5H), 2.32
(s, 0.5H), 3.49 3.66 (m, 2.5H), 3.73 (t, J ˆ 7.3 Hz, 0.5H), 4.12 (t, J ˆ 7.3 Hz,
0.5H), 4.25 4.31 (m, 1.5H), 5.82 (s, 0.5H), 5.95 (s, 0.5H), 7.35 7.40 (m,
3H), 7.47 7.51 (m, 2H) ppm; 13C NMR: d ˆ À4.48, À4.45, 14.1, 18.0, 22.6,
25.5, 25.8 (3C), 27.5 (0.5C), 27.7 (0.5C), 29.3, 29.5, 29.56, 29.59 (2C), 29.62,
29.79, 29.84 (0.5C), 29.9 (0.5C), 30.91 (0.5C), 30.95 (0.5C), 31.9, 69.9 (0.5C),
70.6 (0.5C), 73.98 (0.5C), 74.02 (0.5C), 75.27 (0.5C), 75.30 (0.5C), 76.1
(0.5C), 76.9 (0.5H), 103.1 (0.5C), 104.0 (0.5C), 126.3, 126.6, 128.3, 129.0,
129.2, 137.7 (0.5C), 138.3 (0.5C) ppm; IR (KBr): nÄ ˆ 3507, 1068 cmÀ1; MS
65.0, 75.0, 81.4, 83.5, 90.5, 103.7 ppm; IR (KBr): nÄ ˆ 3410, 2175, 1090 cmÀ1
;
‡
MS (FAB): m/z: 533 [M‡Na] ; HRMS (FAB): m/z calcd for C29H58NaO3-
‡
Si2: 533.3822; found: 533.3823 [M‡Na] ; CD (c ˆ 1.96  10À3, CHCl3)
20
[q]
(nm): ‡3.6  104 (184.0).
max
(3R,4S,7S,8R)-8-(tert-Butyldimethylsilyloxy)-4,7-epoxy-1-trimethylsilyl-
heneicos-1-yn-3-ol (37a): The procedure was the same as that used for
preparation of 36a, but with (1S,2R)-NME instead of (1R,2S)-NME.
Colorless oil; [a]2D3 ˆ À18.6 (c ˆ 1.06, CHCl3); 1HNMR: d ˆ 0.049 (s, 3H),
0.052 (s, 3H), 0.17 (s, 9H), 0.88 (t, J ˆ 7.3 Hz, 3H), 0.89 (s, 9H), 1.23 1.43
(m, 22H), 1.89 2.05 (m, 4H), 2.33 (d, J ˆ 6.1 Hz, 1H), 3.78 (ddd, J ˆ 6.1,
5.5, 3.7 Hz, 1H), 4.03 (ddd, J ˆ 7.3, 6.7, 3.7 Hz, 1H), 4.10 (td, J ˆ 6.7, 3.7 Hz,
1H), 4.36 (dd, J ˆ 6.1, 3.7 Hz, 1H) ppm; 13C NMR: d ˆ À4.6, À4.2, À0.2
(3C), 14.1, 18.1, 22.7, 25.4, 25.5, 25.9 (3C), 26.9, 29.3, 29.55, 29.57, 29.62 (2C),
29.64, 29.8, 31.9, 34.7, 65.2, 73.0, 81.5, 83.6, 90.5, 103.9 ppm; IR (KBr): nÄ ˆ
‡
(FAB): m/z: 543 [M‡Na] ; HRMS (FAB): m/z calcd for C31H56NaO4Si:
‡
543.3846; found: 543.3851 [M‡Na] . The alcohol was converted into a
‡
3417, 2175, 1105 cmÀ1; MS (FAB): m/z: 533 [M‡Na] ; HRMS (FAB): m/z
tosylate by the same procedure as that described for the conversion of 32
into 33. Colorless oil; [a]D24 ˆ À9.7 (c ˆ 1.03, CHCl3); 1HNMR: d ˆ 0.002 (s,
1.5H), 0.006 (s, 1.5H), 0.022 (s, 1.5H), 0.023 (s, 1.5H), 0.847 (s, 4.5H), 0.854
(s, 4.5H), 0.88 (t, J ˆ 7.0 Hz, 3H), 1.19 1.52 (m, 23H), 1.63 1.72 (m, 2H),
1.90 1.96 (m, 1H), 2.44 (s, 3H), 3.50 (t, J ˆ 7.3 Hz, 0.5H), 3.57 (dd, J ˆ 7.3,
6.4 Hz, 0.5H), 3.84 3.87 (m, 1H), 4.00 (t, J ˆ 7.3 Hz, 0.5H), 4.03 4.09 (m,
1H), 4.11 (dd, J ˆ 7.3, 6.4 Hz, 0.5H), 4.45 4.52 (m, 1H), 5.75 (s, 0.5H), 5.85
(s, 0.5H), 7.32 (dd, J ˆ 8.6, 1.2 Hz, 2H), 7.36 7.39 (m, 3H), 7.42 7.45 (m,
2H), 7.79 (dd, J ˆ 7.9, 3.1 Hz, 2H) ppm; 13C NMR: d ˆ À4.81 (0.5C), À4.79
(0.5C), À4.78 (0.5C), À4.5 (0.5C), 14.1, 18.1, 21.5, 22.6, 23.7 (0.5C), 24.0
(0.5C), 25.4 (0.5C), 25.5 (0.5C), 25.8 (3C), 28.4 (0.5C), 28.8 (0.5C), 29.3,
29.4, 29.48, 29.51, 29.58 (2C), 29.62, 31.9, 34.3, 69.8 (0.5C), 70.3 (0.5C), 73.9
(0.5C), 74.0 (0.5C), 75.3 (0.5C), 76.0 (0.5C), 85.2 (0.5C), 85.3 (0.5C), 102.9
(0.5C), 103.9 (0.5C), 126.2, 126.5, 127.8 (2C), 128.21, 128.24, 129.0 (0.5C),
129.2 (0.5C), 129.6 (2C), 134.3, 137.6 (0.5C), 138.3 (0.5C), 144.6 ppm; IR
‡
calcd for C29H58NaO3Si2: 533.3822; found: 533.3855 [M‡Na] ; CD (c ˆ
20
1.96 Â 10À3, CH C3l) [q]
(nm): À3.9 Â 104 (184.6).
max
(3S,4S,7S,8R)-8-(tert-Butyldimethylsilyloxy)-4,7-epoxy-1-trimethylsilyl-
heneicos-1-yn-3-ol (37b): The procedure was the same as that used for
preparation of 36b. Colorless oil; [a]2D4 ˆ À10.3 (c ˆ 1.01, CHCl3);
1HNMR: d ˆ 0.056 (s, 3H), 0.062 (s, 3H), 0.17 (s, 9H), 0.88 (t, J ˆ 7.3 Hz,
3H), 0.89 (s, 9H), 1.23 1.40 (m, 22H), 1.76 1.87 (m, 2H), 1.95 (dq, J ˆ
11.6, 8.5 Hz, 1H), 2.01 2.07 (m, 1H), 2.43 (d, J ˆ 4.3 Hz, 1H), 3.78 3.81
(m, 1H), 3.92 (ddd, J ˆ 7.9, 6.1, 3.1 Hz, 1H), 4.03 (q, J ˆ 6.7 Hz, 1H), 4.18
(dd, J ˆ 6.7, 4.6 Hz, 1H) ppm; 13C NMR: d ˆ À4.6, À4.2, À0.2 (3C), 14.1,
18.1, 22.7, 25.2, 25.5, 26.0 (3C), 28.1, 29.3, 29.5, 29.56, 29.61 (2C), 29.64, 29.8,
31.9, 34.7, 65.4, 72.9, 82.0, 82.6, 90.2, 103.9 ppm; IR (KBr): nÄ ˆ 3410, 2175,
‡
1055 cmÀ1; MS (FAB): m/z: 533 [M‡Na] ; HRMS (FAB): m/z calcd for
‡
C29H58NaO3Si2: 533.3822; found: 533.3821 [M‡Na] ; CD (c ˆ 1.96  10À3
,
‡
(KBr): nÄ ˆ 1097 cmÀ1; MS (FAB): m/z: 697 [M‡Na] ; HRMS (FAB): m/z
20
CHCl3) [q]
(nm): À1.9 Â 104 (184.8).
‡
max
calcd for C38H62NaO6SiS: 697.3934; found: 697.3936 [M‡Na] . The tosylate
was converted into 31d by the same procedure as that described for the
conversion of 33 into 31b. Colorless oil; [a]2D8 ˆ À3.3 (c ˆ 1.02, CHCl3);
(3R,4R,7S,8R)-8-(tert-Butyldimethylsilyloxy)-4,7-epoxy-1-trimethylsilyl-
heneicos1-yn-3-ol (38a): The procedure was the same as that used for
4988
¹ 2003 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 4980 4990

THF-Ring Formation
4980 4990
preparation of 36a. Colorless oil; [a]2D3 ˆ À5.3 (c ˆ 0.90, CHCl3); 1HNMR:
d ˆ 0.08 (s, 3H), 0.09 (s, 3H), 0.17 (s, 9H), 0.88 (t, J ˆ 6.7 Hz, 3H), 0.90 (s,
9H), 1.23 1.33 (m, 20H), 1.38 1.44 (m, 1H), 1.47 1.51 (m, 1H), 1.78
1.84 (m, 2H), 1.85 1.92 (m, 1H), 1.97 2.05 (m, 1H), 2.67 (d, J ˆ 5.5 Hz,
1H), 3.79 (ddd, J ˆ 6.1, 4.9, 4.3 Hz, 1H), 3.90 (ddd, J ˆ 7.9, 6.1, 4.3 Hz, 1H),
3.99 (ddd, J ˆ 7.9, 6.1, 4.9 Hz, 1H), 4.17 (dd, J ˆ 6.1, 5.5 Hz, 1H) ppm;
13C NMR: d ˆ À4.4, À4.0, À0.2 (3C), 14.1, 18.1, 22.7, 24.9, 25.5, 25.9 (3C),
28.1, 29.3, 29.55, 29.61 (3C), 29.64, 29.9, 31.9, 35.0, 66.5, 73.0, 81.9, 82.8, 90.0,
103.9 ppm; IR (KBr): nÄ ˆ 3440, 2175, 1070 cmÀ1; MS (FAB): m/z: 511
Organic Natural Products, Vol. 70 (Ed.: W. Hertz), Springer-Verlag,
New York, 1997, pp. 81 288; d) L. Zeng, Q. Ye, N. H. Oberlies, G. Shi,
Z.-M. Gu, K. He, J. L. McLaughlin, Nat. Prod. Rep. 1996, 13, 275 306;
¬
e) M. C. Zafra-Polo, M. C. Gonzalez, E. Estornell, S. Sahpaz, D.
Cortes, Phytochemistry 1996, 42, 253 271; f) ™Annonaceous Aceto-
genins∫: Z.-M. Gu, G.-X. Zhao, N. H. Oberlies, L. Zeng, J. L.
McLaughlin, in Recent Advances in Phytochemistry, Vol. 29 (Eds.:
J. T. Arnason, R. Mata, J. T. Romeo), Plenum Press, New York, 1995,
pp. 249 310; g) X.-P. Fang, M. J. Rieser, Z.-M. Gu, G.-X. Zhao, J. L.
McLaughlin, Phytochem. Anal. 1993, 4, 27 67; h) J. K. Rupprecht, Y.-
H. Hui, J. L. McLaughlin, J. Nat. Prod. 1990, 53, 237 278.
‡
[M‡H] ; HRMS (FAB): m/z calcd for C29H59O3Si2: 511.4003; found:
‡
20
511.4003 [M‡H] ; CD (c ˆ 1.96  10À3, CHCl3) [q]
(nm): À1.5 Â 104
max
(183.4).
[2] For reviews of the synthesis of annonaceous acetogenins, see: a) G.
Casiraghi, F. Zanardi, L. Battistini, G. Rassu, Chemtracts-Organic
Chemistry 1998, 11, 803 827; b) M. C. Elliott, J. Chem. Soc. Perkin
(3S,4R,7S,8R)-8-(tert-Butyldimethylsilyloxy)-4,7-epoxy-1-trimethylsilyl-
heneicos-1-yn-3-ol (38b): The procedure was the same as that used for
preparation of 36b. Colorless oil; [a]2D2 ˆ ‡12.5 (c ˆ 1.00, CHCl3);
1HNMR: d ˆ 0.08 (s, 3H), 0.09 (s, 3H), 0.17 (s, 9H), 0.88 (t, J ˆ 7.3 Hz,
3H), 0.89 (s, 9H), 1.26 1.32 (m, 20H), 1.40 1.46 (m, 1H), 1.51 1.58 (m,
1H), 1.76 1.83 (m, 1H), 1.87 1.99 (m, 2H), 2.11 2.17 (m, 1H), 2.87 (d,
J ˆ 3.1 Hz, 1H), 3.85 (dt, J ˆ 6.7, 4.9 Hz, 1H), 3.92 (ddd, J ˆ 8.5, 5.5, 4.9 Hz,
1H), 4.09 (dt, J ˆ 7.9, 3.1 Hz, 1H), 4.48 (t, J ˆ 5.8 Hz, 1H) ppm; 13C NMR:
d ˆ À4.5, À4.2, À0.2 (3C), 14.1, 18.1, 22.6, 24.8, 25.93, 25.96 (3C), 26.02,
29.3, 29.5, 29.59 (3C), 29.63, 29.9, 31.9, 34.9, 65.4, 73.0, 81.3, 82.4, 90.5,
103.4 ppm; IR (KBr): nÄ ˆ 3442, 2177, 1051 cmÀ1; MS (FAB): m/z: 511
¡
Trans. 1 1998, 4175 4200; c) B. Figadere, Acc. Chem. Res. 1995, 28,
359 365; d) R. Hoppe, H.-D. Scharf, Synthesis 1995, 1447 1464;
e) U. Koert, Synthesis 1995, 115 132.
[3] E. Wolvetang, K. L. Johnson, K. Kramer, A. W. Linnane, FEBS Lett.
1994, 339, 40 44.
[4] N. H. Oberlies, V. L. Croy, M. L. Harrison, J. L. McLaughlin, Cancer
Lett. 1997, 15, 73 79.
[5] a) F. Zanardi, L. Battistini, G. Rassu, L. Pinna, M. Mor, N. Culeddu, G.
¡
Casiraghi, J. Org. Chem. 1998, 63, 1368 1369; b) B. Figadere, J.-F.
‡
¬
Peyrat, A. Cave, J. Org. Chem. 1997, 62, 3428 3429.
[M‡H] ; HRMS (FAB): m/z calcd for C29H59O3Si2: 511.4003; found:
‡
20
511.3981 [M‡H] ; CD (c ˆ 1.96  10À3, CHCl3) [q]
(nm): ‡0.27  104
[6] a) U. Koert, M. Stein, H. Wagner, Liebigs Ann. 1995, 1415 1426, and
references therein; b) U. Koert, H. Wagner, U. Pidun, Chem. Ber.
1994, 127, 1447 1457.
max
(183.4).
(3R,4S,7R,8R)-8-(tert-Butyldimethylsilyloxy)-4,7-epoxy-1-trimethylsilyl-
heneicos-1-yn-3-ol (39a): The procedure was the same as that used for
preparation of 36b. Colorless oil; [a]2D1 ˆ À37.5 (c ˆ 1.13, CHCl3);
1HNMR: d ˆ 0.08 (s, 3H), 0.10 (s, 3H), 0.16 (s, 9H), 0.88 (t, J ˆ 7.0 Hz,
3H), 0.91 (s, 9H), 1.26 1.33 (m, 20H), 1.41 1.48 (m, 1H), 1.63 1.70 (m,
1H), 1.77 1.90 (m, 2H), 1.96 (dq, J ˆ 12.8, 8.5 Hz, 1H), 2.11 2.17 (m, 1H),
3.05 (d, J ˆ 3.1 Hz, 1H), 3.62 (ddd, J ˆ 7.3, 6.1, 3.7 Hz, 1H), 3.97 (ddd, J ˆ
7.9, 6.7, 3.7 Hz, 1H), 4.11 (ddd, J ˆ 7.9, 4.9, 3.1 Hz, 1H), 4.50 (dd, J ˆ 3.7,
3.1 Hz, 1H) ppm; 13C NMR: d ˆ À4.6, À4.2, À0.2 (3C), 14.1, 18.3, 22.7,
25.4, 26.0 (3C), 26.1, 27.6, 29.3, 29.56, 29.60 (3C), 29.64, 29.8, 31.9, 34.2, 65.3,
74.6, 81.3, 81.9, 90.1, 103.7 ppm; IR (KBr): nÄ ˆ 3439, 2177, 1057 cmÀ1; MS
[7] a) N. Maezaki, N. Kojima, H. Tominaga, M. Yanai, T. Tanaka, Org.
Lett. 2003, 5, 1411 1414; b) N. Maezaki, N. Kojima, A. Sakamoto, H.
Tominaga, C. Iwata, T. Tanaka, M. Monden, B. Damdinsuren, S.
Nakamori, Chem. Eur. J. 2003, 9, 390 399; c) N. Maezaki, N. Kojima,
M. Asai, H. Tominaga, T. Tanaka, Org. Lett. 2002, 4, 2977 2980; d) N.
Maezaki, N. Kojima, A. Sakamoto, C. Iwata, T. Tanaka, Org. Lett.
2001, 3, 429 432.
[8] a) E. El-Sayed, N. K. Anand, E. M. Carreira, Org. Lett. 2001, 3, 3017
3020; b) N. K. Anand, E. M. Carreira, J. Am. Chem. Soc. 2001, 123,
9687 9688; c) H. Sasaki, D. Boyall, E. M. Carreira, Helv. Chim. Acta
¬
2001, 84, 964 971; d) D. Boyall, F. Lopez, H. Sasaki, D. Frantz, E. M.
‡
(FAB): m/z: 511 [M‡H] ; HRMS (FAB): m/z calcd for C29H59O3Si2:
Carreira, Org. Lett. 2000, 2, 4233 4236; e) D. E. Frantz, R. F‰ssler,
C. S. Tomooka, E. M. Carreira, Acc. Chem. Res. 2000, 33, 373 381;
f) D. E. Frantz, R. F‰ssler, E. M. Carreira, J. Am. Chem. Soc. 2000,
122, 1806 1807.
‡
20
511.4003; found: 511.4007 [M‡H] ; CD (c ˆ 1.96  10À3, CHCl3) [q]
max
(nm): À0.41 Â 104 (183.6).
(3R,4S,7R,8R)-8-(tert-Butyldimethylsilyloxy)-4,7-epoxy-1-trimethylsilyl-
heneicos-1-yn-3-ol (39b): The procedure was the same as that used for
preparation of 36a. Colorless oil; [a]2D2 ˆ À7.9 (c ˆ 1.00, CHCl3); 1HNMR:
d ˆ 0.078 (s, 3H), 0.083 (s, 3H), 0.17 (s, 9H), 0.88 (t, J ˆ 7.3 Hz, 3H), 0.90 (s,
9H), 1.23 1.45 (m, 21H), 1.58 1.65 (m, 1H), 1.77 (dq, J ˆ 12.2, 7.9 Hz,
1H), 1.81 1.93 (m, 2H), 2.00 (dq, J ˆ 12.8, 7.9 Hz, 1H), 2.85 (d, J ˆ 5.5 Hz,
1H), 3.58 (td, J ˆ 6.1, 4.3 Hz, 1H), 3.98 (ddd, J ˆ 7.9, 6.7, 4.3 Hz, 1H), 4.03
(dt, J ˆ 7.9, 5.5 Hz, 1H), 4.18 (t, J ˆ 5.5 Hz, 1H) ppm; 13C NMR: d ˆ À4.6,
À4.2, À0.2 (3C), 14.1, 18.2, 22.7, 25.4, 26.0 (3C), 27.1, 28.1, 29.3, 29.59, 29.61
(3C), 29.64, 29.8, 31.9, 33.9, 65.8, 74.5, 81.7, 82.4, 89.7, 104.3 ppm; IR (KBr):
[9] Application to bis-THF-ring cores has already been communicated,
see ref. [7a].
[10] X.-F. Ren, E. Turos, C. H. Lake, M. R. Churchill, J. Org. Chem. 1995,
60, 6468 6483.
[11] a) G. Cainelli, M. Panunzio, E. Bandini, G. Martelli, G. Spunta,
Tetrahedron 1996, 52, 1685 1698; b) L. Banfi, A. Bernardi, L.
Colombo, C. Gennari, C. Scolastico, J. Org. Chem. 1984, 49, 3784
3790.
[12] The absolute configurations of coupling products were determined by
the modified Mosher method. See: a) I. Ohtani, T. Kusumi, Y. Kashman,
H . Kakisawa,J. Am. Chem. Soc. 1991, 113, 4092 4096; b) J. A. Dale,
H . S. Mosher,J. Am. Chem. Soc. 1973, 95, 512 519; c) J. A. Dale, D. L.
Dull, H. S. Mosher, J. Org. Chem. 1969, 34, 2543 2549.
‡
nÄ ˆ 3405, 2175, 1078 cmÀ1; MS (FAB): m/z: 511 [M‡H] ; HRMS (FAB): m/
‡
z calcd for C29H59O3Si2: 511.4003; found: 511.4022 [M‡H] ; CD (c ˆ 1.96 Â
20
10À3, CH C3l) [q]
(nm): ‡1.5  104 (183.2).
max
[13] The signals of the C3 methine protons in the 1HNMR spectral data of
the syn adducts appeared upfield by 0.1 0.2 ppm relative to those in
the spectra of the anti adducts. On the other hand, the signals of the
OHprotons in the syn adducts appeared downfield by 0.1 0.2 ppm
relative to those in the anti adducts. The shifts were consistent for each
compound in this series.
[14] We found that a combination of the aldehyde (S)-6 with (1S,2R)-NME
provided better selectivity than the corresponding combination of (S)-
6 with (1R,2S)-NME. Carreira and co-workers also reported similar
results in the asymmetric alkynylation of (S)-6 with acetyl propargyl
alcohol,[8a] but the reaction mechanism was not mentioned.
[15] a) O. W. Gooding, C. C. Beard, D. Y. Jackson, D. L. Wren, G. F.
Cooper, J. Org. Chem. 1991, 56, 1083 1088. Other synthetic
procedures for 3-butyne-1,2-diol 13 were reported. See: b) O.
Yamada, K. Ogasawara, Synthesis 1995, 1291 1294; c) O. Yamada,
K. Ogasawara, Synlett 1995, 427 428; d) S. Takano, M. Setoh, O.
Yamada, K. Ogasawara, Synthesis 1993, 1253 1256.
Acknowledgement
We acknowledge financial support by
a Grant-in-Aid for Scientific
Research (C) from the Japan Society for the Promotion of Science
(Grant no.: 14572006) and grants from the Research Foundation for
Pharmaceutical Sciences and the Shorai Foundation for Science and
Technology. N.K. is grateful to Research Fellowships of the Japan Society
for the Promotion of Science for Young Scientists.
[1] For reviews on annonaceous acetogenins, see: a) F. Q. Alali, X.-X.
Liu, J. L. McLaughlin, J. Nat. Prod. 1999, 62, 504 540; b) M. C. Zafra-
¡
Polo, B. Figadere, T. Gallardo, J. R. Tormo, D. Cortes, Phytochemistry
1998, 48, 1087 1117; c) ™Acetogenins from Annonaceae∫: A. Cave, B.
Figadere, A. Laurens, D. Cortes, in Progress in the Chemistry of
¬
¡
Chem. Eur. J. 2003, 9, 4980 4990 www.chemeurj.org ¹ 2003 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
4989

N. Maezaki, T. Tanaka et al.
FULL PAPER
[16] P. Michel, D. Gennet, A. Rassat, Tetrahedron Lett. 1999, 40, 8575
8578.
very effective for obtaining reproducibility of the yield. Therefore, the
modified procedure was employed after this entry.
[17] During the course of our study, Pietruszka reported another solution
employing the Bestmann Ohira reagent for alkyne 13. See: J.
Pietruszka, A. Witt, J. Chem. Soc. Perkin Trans. 1 2000, 4293 4300.
[18] Koert reported a similar double stereodifferentiation in the substrate-
controlled addition of a-tetrahydrofuranic aldehyde with the chiral
3,4-isopropylidenedioxybutyl anion.[6b]
[19] a) S. E. Schaus, J. Branalt, E. N. Jacobsen, J. Org. Chem. 1998, 63,
4876 4877; b) P. S. Savle, M. J. Lamoreaux, J. F. Berry, R. D. Gan-
dour, Tetrahedron:Asymmetry 1998, 9, 1843 1846; c) M. Tokunaga,
J. F. Larrow, F. Kakiuchi, E. N. Jacobsen, Science 1997, 277, 936 938.
[20] Stereochemistries of coupling products were assigned by analogy with
the 1HNMR spectra of related compounds. The details are described
in ref. [13].
[25] Carreira and co-workers reported a catalytic version of the asym-
metric alkynylation.[8b] We examined the asymmetric alkynylation of
the aldehyde 20 with the alkyne 25 under the catalytic conditions but
the reaction did not proceed.
[26] The diastereomeric ratio based on the benzylidene acetal for 26a and
26b was almost the same as the ratio of 25a and 25b used.
[27] a) D. L. J. Clive, E.-S. Ardelean, J. Org. Chem. 2001, 66, 4841 4844;
b) M. Hirama, T. Shigemoto, S. Ito, J. Org. Chem. 1987, 52, 3342 3346.
[28] Recently, a one-pot THF-ring formation from the 1,2,5-triol deriva-
tives was reported by Forsyth and co-workers. See: a) A. B. Dounay,
G. J. Florence, A. Saito, C. J. Forsyth, Tetrahedron 2002, 58, 1865
1874; b) A. B. Dounay, C. J. Forsyth, Org. Lett. 2001, 3, 975 978.
[29] a) H. Sajiki, K. Hirota, Tetrahedron 1998, 54, 13981 13996; b) H.
Sajiki, Tetrahedron Lett. 1995, 36, 3465 3468.
[21] V. A. Engelhardt, J. E. Castle, J. Am. Chem. Soc. 1953, 75, 1734.
[22] J. Yoshida, M. Nakagawa, H. Seki, T. Hino, J. Chem. Soc. Perkin Trans.
1 1992, 343 350.
[30] U. Koert, M. Stein, H. Wagner, Chem. Eur. J. 1997, 3, 1170 1180, and
references therein.
[23] Stereochemistry of the benzylidene acetal was assumed by analogy the
1HNMR spectra of related compounds. See: a) T. B. Grindley, S.
Kusuma, T. S. Cameron, Can. J. Chem. 1986, 64, 2388 2396; b) N.
Baggett, K. W. Buck, A. B. Foster, M. H. Randall, J. M. Webber, J.
Chem. Soc. 1965, 3394 3440.
[31] S. Hoppen, S. B‰urle, U. Koert, Chem. Eur. J. 2000, 6, 2382 2396.
[32] The moderate yields in some entries were caused by base-promoted
deprotection of the TMS group in the coupling product and
subsequent coupling of the resulting acetylide with another aldehyde.
[24] Recently, Carreira and co-workers reported a modified procedure in
which Zn(OTf)2 was dried before use.[8d] We found that this protocol is
Received: May 27, 2003 [F5185]
4990
¹ 2003 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 4980 4990