Stereocontrolled Synthesis of Key Advanced Intermediates toward Simplified Acetogenin Analogues

Article abstract of DOI:10.1021/jo990772h

The stereo- and enantiocontrolled synthesis of substituted β-hydroxy ethers based on glycol and catechol bearing an alkyne group and a series of substituents is reported. These substrates were designed to mimic the bis-THF array of annonaceous acetogenins and to provide an access to simplified and modified analogues. The key steps of the synthesis involve the condensation of the nonracemic mesylate of solketal with ethylene glycol and catechol, followed by an alkylation with a glycidyl derivative. Under appropriate conditions, the reaction is completely stereoselective and allows the synthesis of all the diastereomers. After the epoxide was opened with triethylsilylacetylene, the second epoxide was unmasked and reacted with a series of alkyl, aryl, amine, and alcohol reagents. A series of 28 analogues was prepared having a glycol or a catechol core, a stereodefined configuration of the flanking hydroxyl groups, and an acetylenic appendage suitable for a coupling to a lactone-bearing fragment.

Full text of DOI:10.1021/jo990772h

6782
J . Org. Chem. 1999, 64, 6782-6790
Ster eocon tr olled Syn th esis of Key Ad va n ced In ter m ed ia tes
tow a r d Sim p lified Acetogen in An a logu es
Yvan Le Hue´rou,† J ulien Doyon, and Rene´ L. Gre´e*
Laboratoire de Synthe`ses et d’Activations de Biomole´cules, CNRS, ESA 6052, ENSCR,
Avenue du Ge´ne´ral Leclerc, 35700 Rennes-Beaulieu, France
Received May 11, 1999
The stereo- and enantiocontrolled synthesis of substituted â-hydroxy ethers based on glycol and
catechol bearing an alkyne group and a series of substituents is reported. These substrates were
designed to mimic the bis-THF array of annonaceous acetogenins and to provide an access to
simplified and modified analogues. The key steps of the synthesis involve the condensation of the
nonracemic mesylate of solketal with ethylene glycol and catechol, followed by an alkylation with
a glycidyl derivative. Under appropriate conditions, the reaction is completely stereoselective and
allows the synthesis of all the diastereomers. After the epoxide was opened with triethylsilylacet-
ylene, the second epoxide was unmasked and reacted with a series of alkyl, aryl, amine, and alcohol
reagents. A series of 28 analogues was prepared having a glycol or a catechol core, a stereodefined
configuration of the flanking hydroxyl groups, and an acetylenic appendage suitable for a coupling
to a lactone-bearing fragment.
In tr od u ction
resistant cell ligns.7 Some of the acetogenins have been
shown to be strong inhibitors of the NADH: ubiquinone
reductase (complex I) in the mitochondrial membrane
and of the NADH oxidase in the plasmic membrane.8 This
interference with respiration and ATP production leads
to the rapid death of the cell. The acetogenins, however,
do not appear to be inhibitors of tyrosine kinase; they
have no action on the cell cycle and have no DNA-
damaging effects.9
Considering the potential of this class of compounds
as therapeutic agents or as biological tools and the
important synthetic efforts reported to date,10 we found
it surprising that little attention had been paid so far to
find out the relative contributions of the various consti-
tutional parts of the molecule to the biological activity.11
We initiated a program toward the synthesis of simplified
and modified acetogenin analogues, the final aim being
to better understand the structure-activity relationships.
The Annonaceae form a large family of trees, shrubs,
or lianas commonly found in tropical and subtropical
areas.1 The medicinal, cosmetic and culinary values2 of
these plants have been recognized by the indigenous
populations for a long time: the leaves, roots, bark, or
fruits have been used in various preparations for the
treatment of numerous ailments such as sleep disorder
and fever, as an antiseptic, or against fungi or parasitic
infestations.3 Since the isolation of the first acetogenin
uvaricine 1 by J ollad et al.,4 over 230 new acetogenins
have been discovered and their broad spectrum of activity
revealed: antitumoral, antimalarial, pesticidal, antibacte-
rial, or immunosuppressive.5 Their very potent cytotox-
icity (often nM) has made them a promising new lead
for cancer chemotherapy6 and possibly against multidrug-
* To whom correspondence should be addressed. E-mail: gree@ensc-
rennes.fr. Tel: 33 299 87 13 83. Fax: 33 299 87 13 84. doyon@univ-
rennes1.fr. Tel: 33 299 87 13 95.
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S. M.; Sudhakaran Nair, C. R.; Nair, G. R.; Thankamani, V.; Hisham,
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† Current address: Department of Chemistry and Biochemistry,
Campus box 215, Boulder, Colorado, 80309-0215.
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10.1021/jo990772h CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/17/1999

Intermediates toward Simplified Acetogenin Analogues
J . Org. Chem., Vol. 64, No. 18, 1999 6783
Among the five subfamilies of acetogenins the B1
subtype (adjacent bis-THF)12 represents the most potent
and has been intensely studied. The structures and the
relative stereochemistries have been established by
partial or total synthesis, by NMR analysis, Mosher ester
techniques,13 and/or combinations thereof.14 This class
was thus chosen as the model system for this study.
The length and difficulties inherent to the synthesis
of the central bis-THF unit is well documented. Thus,
the first objective was to develop an efficient synthesis
of simpler bis-ether analogues (Figure 1).
This simplification should, in the end, shed some light
on the importance of the rigidity of the system, which
might be important if the recognized cation sequestration
ability of these compounds plays indeed a role in the
mechanism of action, membrane transit, and molecular
recognition.15 The second objective we deemed necessary
to achieve was the control of the stereochemistry of the
flanking hydroxyl groups. As we have learned from the
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F igu r e 1. Simplification strategy for the synthesis of aceto-
genin analogues.
natural systems, this point can be critical for the biologi-
cal activity, especially with respect to the selectivity. The
third and final dimension to be realized was the ability
to introduce a great variety of substituents in the
southern fragment. Limited studies7b,16 have shown that
a shortening of this chain results in diminished activity,
but no further modifications have been explored so far.
In this paper, we describe the stereocontrolled synthesis
in both enantiomeric forms of the precursors to simplified
acetogenin analogues consisting of glycol and catechol
ethers and bearing natural and modified southern chains.
Str a tegy. The realization of these objectives entails
the following requirements: (1) The central part must be
readily accessible from both glycols and catechols. (2) The
absolute and relative configuration of the two hydroxyl
groups must be perfectly controlled and introduced at will
into any configuration. (3) The introduction of the south-
ern end (Figure 1) must be done from a common inter-
mediate. (4) An alkyne function must be present at the
northern end to allow a coupling to a lactone- bearing
synthon.
Retrosynthetically (Scheme 1), the most obvious way
to introduce the northern and southern fragments was
through the opening of an epoxide. These reactions are
well documented for a variety of nucleophiles including
those we have chosen (alkynes, alkyls, aryls, amines, and
alcohols). However, the introduction of the upper and
lower fragments requires that the accepting groups (the
epoxides) be introduced or revealed sequentially to avoid
regioselectivity and chemoselectivity issues to surface at
the coupling stage. The next issue to be considered was
the requirement for complete control and ready access
to any desired diastereoisomer. The latent element of
symmetry (either σ or C2) was therefore the key issue to
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1998, 54, 2401. (c) Reference 10b

6784 J . Org. Chem., Vol. 64, No. 18, 1999
Le Hue´rou et al.
Sch em e 1
Sch em e 2
be dealt with. We felt that an early desymmetrization of
the glycol or catechol with an orthogonally masked
epoxide followed by the introduction of an epoxide or
epoxide precursor was the most practical approach in
terms of stereochemical control and chemoselectivity.
Among the epoxide precursors, diols, alkenes, and alde-
hydes are the most obvious, through epoxidation for the
alkene, selective activation for the diol, and sulfonium
chemistry for the latter. Since the Sharpless epoxidation
methodology produces only low ee or de on allyl ether,17
we chose to have the stereochemistry of the diol already
set up in the reagent during the alkylation. Solketal,
which is readily available in both enantiomeric forms,18a
was selected as the masked epoxide and an activated
glycidyl ether as the second partner. This approach
turned out to be quite successful.
Sch em e 3
Resu lts a n d Discu ssion
Solketal was first activated as its mesylate18b,c and then
treated with sodium ethyleneglycoxide at 140 °C for 12
h to produce very cleanly the monoalkylated glycol (-)-3
in 91% yield. No bis-alkylation product could be detected.
In contrast, the reaction of catechol in the presence of
NaH in THF led to the complete recovery of the starting
mesylate. The less reactive catechol yielded itself to
alkylation only after 24 h at 100 °C in DMF with NaH
as the base. In this case, 10% of the bis alkylation product
(-)-6 and 21% of starting material are also recovered.
They are easily separated from the product (-)-5 by
simple recrystallization. The use of K2CO3 instead of NaH
gave a greater proportion of the bis-alkylated product
with the same overall yield (Scheme 2).
which is known to be an ambielectrophile, reacting either
at the chloride- or at the epoxide-bearing centers. In the
former case, the result is a retention of configuration at
the central carbon atom while an inversion takes place
in the latter via intramolecular chloride displacement by
the alkoxide generated.20
Treatment of glycidyl ether (-)-3 with optically pure
epichlorohydrin under phase-transfer conditions (Scheme
3)21,19 produced compound (-)-7 in 78% yield with no
detectable amount of a second diastereomer. At this
point, the regioselectivity and therefore the relative
stereochemistry of this epoxide could not be established
unambiguously. They were, however, clearly demon-
strated later on in the synthesis through MPA-ester
analysis (vide infra). Again, the reactivity of the phenol
proved quite different from the parent alkyl (-)-5. Under
the same conditions, a 7:3 mixture of diastereomers (8/
9) was obtained corresponding to inversion and retention
With this first alkylation achieved, we turned to the
introduction of the glycidyl fragment. The opening of
epichlorohydrin by alkoxides is a well-known industrial
process used in the synthesis of fatty glycidyl ethers.19
This chemistry makes use of racemic epichlorohydrin,
(17) Hoyes, T. R.; Tan, L. Synlett 1996, 615.
(19) (a) Urata, K.; Takaishi, N. J . Am. Oil Chem. Soc. 1996, 73, 831.
(b) Urata, K.; Takaishi, N. J . Am. Oil Chem. Soc. 1994, 71, 1027. (c)
Szo¨nyi, F.; Cambon, A. Tenside Surf Det. 1994, 31, 124.
(20) Klunder, J . M.; Ko, S. Y.; Sharpless, K. B. J . Org. Chem. 1986,
51, 3710.
(18) (a) Solketal, in both enantiomeric forms was obtained from
CHEMI spa, Via del Lavoratori, 54, 20092 Cinisello Balsamo (MI),
Italy, at ca. $500/kg. (b) Kawakami, Y.; Asai, T.; Umeyama, K.;
Yamashita, Y. J . Org. Chem. 1982, 47, 3581. (c) Newcomb, B. Can. J .
Chem. 1951, 29, 805.
(21) Plusquellec, D. ENSC-Rennes, personal communication

Intermediates toward Simplified Acetogenin Analogues
J . Org. Chem., Vol. 64, No. 18, 1999 6785
Ta ble 1. Alk yla tion of Ca tech ol w ith 2 u n d er Va r iou s
Con d ition s
equiv
base
of 4
(equiv)
solvent T (°C) time (h) % 2 % 5 % 6
2
2
0.7
NaH (2)
K2CO3 (2)
NaH (0.75)
THF
DMF
DMF
20
100
100
12
24
24
100
10 52
10 62
32
21
Ta ble 2. Alk yla tion of Mon osu bstitu ted Ca tech ol w ith
Glycid yl Ch lor id e a n d Tosyla te
a
Key: (A) 50% NaOH/hexane, TBABr, 40 °C, 12 h; (B) NaH,
DMF, rt.
of configuration, respectively, at the central carbon atom.
Similar results have been observed by McLure22 under
slightly different conditions. Following McLure’s condi-
tions and switching to the antipodal tosylate, we could
achieve a clean alkylation to produce (-)-8 in 80% yield
with complete retention of the glycidyl configuration
instead of inversion as in the case of 3 (Table 2). The
enantiomers (+)-7 and (+)-8 were readily prepared from
the corresponding reagent’s enantiomers. Having in hand
these bifunctional compounds, the stage was set for the
introduction of the northern and southern chains. Al-
though we could introduce at will either chain at this
stage and produce both enantiomers depending on the
order of addition, we could appreciate the gain in
convergency that would result by introducing the alkyne
first while working with two enantiomeric series instead
of just one, the greater diversity being introduced at the
later stages of the sequence.
Epoxide opening by acetylides or trialkylsilylacetylides
in the presence of Lewis acids23 such as BF3‚Et2O24 or
Me3Ga25 is a well-precedented reaction. After some
optimization of the relative stoichiometries of the re-
agents, conditions were found to generate 70-80% yield
of the desired silyl-protected homopropargylic alcohol 10
and 11. Deprotection of the acetonide proceeded unevent-
fully. Selective tosylation at the primary position of the
triol was realized via the dibutylstannylene acetal26 in
90% yield in both series to give 12 and 13. We had
expected that the coupling of the various chain might be
realized27 at this stage of the synthesis. Unfortunately,
only complex mixtures were obtained under all the
conditions examined, with the notable exception of
amines for which the reaction worked well. We resorted
F igu r e 2. Determination of the absolute and relative stereo-
chemistries of the epoxide via their MPA esters. 1H NMR shift
differences.
to generate the epoxide whose reactivity was expected
to be more predictable. We then attempted the formation
of the epoxide by treatment of the tosylate 12 in meth-
anolic K2CO3 at 0 °C, only to find, as we should have
feared, a mixture of protected 14a and deprotected 15
epoxides (1:1). The sanction of this ratio taught us that
although rapid, this deprotection was not as kinetically
favored as epoxide formation since the epoxide was
always present. In light of this kinetic edge, we reasoned
that a more robust protecting group might better survive
the conditions. Thus, the sequence was repeated with
triethylsilyl-protected acetylene and under the same
conditions, a 90% yield of the epoxide was realized with
no trace of cleavage. Care must however be exercized in
maintaining the temperature low to avoid methanol
addition onto the epoxide (Scheme 4). The sequence was
similarly applied in the catechol series to give 16.
As noted earlier, although we could perform the second
alkylation with complete stereoselectivity, we still re-
quired a firmly grounded confirmation. Suitable crystal-
linity for X-ray analysis could not be realized with the
various derivatives prepared, and recourse was made to
MPA-esters.28 These esters were preferred over the more
traditional MTPA (Mosher esters) for the greater ∆ppm
and better reliability. The results for the two series are
shown in Figure 2 and are in full agreement with the
stereochemistry represented.
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Shanzer, A. Tetrahedron Lett. 1980, 21, 221. (c) Pereyre, M.; Quintard,
J .-P.; Rham, A. Tin in Organic Synthesis; Butterworths: London, 1987;
p 261. (d) Boons, G.-J .; Castle, G. H.; Clase, J . A.; Grice, P.; Ley, S. V.;
Pinel, C. Synlett 1993, 913.
(27) Bonini, C.; Federici, C.; Rossi, L.; Righi, G. J . Org. Chem. 1995,
60, 4803.
Cou p lin g of th e Ep oxid es 14 a n d 16 w ith Va r iou s
Nu cleop h iles. We now had in hand multigram quanti-
(28) (a) Latypov, S. K.; Seco, J . M.; Quin˜oa, E.; Riguera, R. J . Org.
Chem. 1996, 61, 8569. (b) Duret. P; Waechter, A.-I.; Figade`re, B.;
Hocquemiller, R.; Cave´, A. J . Org. Chem. 1998, 63, 4717.

6786 J . Org. Chem., Vol. 64, No. 18, 1999
Le Hue´rou et al.
Sch em e 4a
a
Key: (a) HCCSiR3, BuLi, BF3‚Et2O, THF, -78 °C; (b) p-TsOH, MeOH, 0 °C; (c) Bu2Sn(OMe)2, toluene, heat, then 0 °C, TsCl; (d)
K2CO3, MeOH, 0 °C.
ties of two simplified bis-THF surrogates in both enan-
tiomeric forms and were ready for the introduction of the
southern fragments. The series of substituents was
selected on the basis of the known membrane affinity of
the acetogenins; starting from the natural C9 normal
alkyl chain present in the natural product, we introduced
various aryl groups bearing an electron-withdrawing
group (CF3), an electron-donating group (p-MeO), or
unsubstituted (Ph, 2-Nph). While keeping a lipophilic
character they should be susceptible to engage further
polar or electrostatic interactions. Next, a series of
secondary amines was introduced that are expected to
increase the chelating strength of the central part yet to
remain liposoluble. Finally, a cholesteryl appendage was
grafted.
Sch em e 5
The reaction of the Grignard reagents in the presence
of copper(I) salts proceeded cleanly in the great majority
of the cases with yields in the 70-85% range (Table 3,
and Scheme 5). In a few instances (entries 12 and 14),
along with the expected product, variable amounts of the
bromohydrin were also produced. The copolarity of the
two products thwarted chromatographic separation, and
despite numerous experiments we were unable to pin-
point the parameters on which to act to suppress its
occurrence. Resort was made to a chemical separation:
the amine derivatives being part of our targets, we
reasoned that these side products could be put to a useful
contribution. Treatment of the mixture of product and
the bromohydrin with piperidine in methanol at 40 °C
for 12 h resulted in complete conversion of the side
product into the now easily separable amino alcohol with
no adverse effect on the other product.
The introduction of various secondary amines was
uneventfully realized29 in near-quantitative yield produc-
ing compounds of very high purity. Unsaturated or
(29) (a) Seki, T.; Takezaki, T.; Ohuchi, R.; Ohuyabi, H.; Ishimori,
T.; Yasuda, K. Chem. Pharm. Bull. 1994, 42, 1609. (b) Press, J . B.;
Falitico, R.; Hajos, Z. G.; Sawyers, R. A.; Kanojia, R. M.; Williams, L.;
Haertlein, B.; Kauffan, J . A.; Lakas-Weiss, C.; Salata, J . J . J . Med.
Chem. 1992, 35, 4509.

Intermediates toward Simplified Acetogenin Analogues
J . Org. Chem., Vol. 64, No. 18, 1999 6787
Ta ble 3. Rea ction of Va r iou s Nu cleop h iles w ith
Ep oxid es 14 a n d 16
Con clu sion s
In this paper, we have described a general strategy for
the synthesis of a family of simplified acetogenin ana-
logues. We have concentrated on the design of bis-ether
mimicks of the central THF rings present in the natural
products, consisting of ethylene glycol and catechol
ethers. Starting from solketal, we have established a
seven-step sequence giving access to the key epoxides 14b
and 16b with complete stereocontrol in 35% and 26%
yield, respectively. These two epoxides have been ef-
ficiently coupled to a series of alkyls, aryls, amines, and
alcohols to produce a panel of 28 acetogenin precursor
analogues.
products
(yield, %)
entry
1
nucleophile
C9H19MgBr
conditions
(+)-14b
CuBr‚MS,
THF,
0 °C, 1 h
(+)-20a (74)
2
3
4
5
(-)-14b
(+)-16b
(-)-16b
(+)-14b
(-)-20a (71)
(+)-22a (70)
(-)-22a (64)
(+)-20b (86)
PhMgBr
CuBr‚MS,
THF,
0 °C, 3 h
6
7
(-)-14b
(+)-16b
(-)-20b (71)
(+)-22b (85)
CuBr‚MS,
THF,
The first part of this study disclosed herein constitutes
the first attempt toward a comprehensive mapping of the
structure-activity relationship of the acetogenins, with
an emphasis on the simplification of the synthetically
challenging central bis-THF part. Further studies are in
progress for the synthesis of fully functionalized ana-
logues and of southern chain analogues in the natural
bis-THF series as well. These and the relevant biological
data will be reported in due course.
0 °C, 1 h
8
9
(-)-16b
(+)-14b
(-)-22b (86)
(+)-20c (76)
p-MeO(C6H4)- CuBr‚MS,
MgBr
THF,
0 °C, 12 h
10
11
12
(-)-14b
(-)-16b
(-)-14b
(-)-20c (71)
(-)-22c (77)
(-)-20d (25-80),
(-)-21 (0-70)
p-CF3(C6H4)- CuBr‚MS,
MgBr
THF,
0 °C, 2 h
13
14
(-)-16b
(+)-14b
(-)-22d (80)
(+)-20e (71),
(+)-21 (15)
We hope that, once completed, these studies will shed
a new light on the biological activity and the therapeutic
potential of this class of compounds.
2-NphMgBr
CuBr‚MS,
THF,
0 °C, 1 h
15
16
17
(-)-14b
(-)-16b
(+)-14b
(-)-20e (80)
(+)-22ea (78)
(+)-20f (98)
piperidine
MeOH,
40 °C
Exp er im en ta l Section
18
19
20
(-)-14b
(-)-16b
(-)-20f (98)
(-)-22f (97)
(+)-20g (96)
Gen er a l P r oced u r es. All dry solvents were freshly dis-
tilled under nitrogen from the recommended drying agent.
Toluene and methanol were distilled from sodium, ether, DME
and THF were distilled from sodium benzophenenone ketyl,
dichloromethane was distilled from CaH2, and triethylamine
was distilled from KOH. DMF was dried over 4A MS and then
distilled under reduced pressure. Other reagents and solvents
were used as received from the commercial suppliers. All
reactions were performed with dry solvents and under a dry
argon or nitrogen atmosphere unless specified. External bath
temperatures are reported. Melting points are uncorrected.
FTIR was recorded on NaCl plates as thin films or as KBr
pellets, specific rotation was measured at 20 °C in 1 mL quartz
microcells, and the concentration is expressed in g/dL. El-
emental analyses were done at the Service de Microanalyse
de Gif-sur-Yvette (ICSN). MS were performed by Centre
Re´gional de Mesures Physiques de l’Ouest. 1H, 13C, and 19F
NMR spectra were recorded in the specified solvent.
(+)-14b Bu2NH
MeOH,
40 °C
21
22
23
(-)-14b
(-)-16b
(-)-14b
(-)-20g (97)
(-)-22g (97)
(-)-20h (86)
Oct2NH
uracil
MeOH,
20 °C
24
25
26
(-)-16b
(+)-16b
rac-14b
(-)-22h (87)
(+)-22h (90)
rac-20i (0)
K2CO3,
MeOH,
heat
27
28
rac-14b
(-)-14b
indole
cholesterol
rac-20j (0)
(-)-20k (36)
BF3‚Et2O,
CH2Cl2,
rt
29
30
(+)-14b
(-)-16b
(-)-20k ′a
(-)-22k (38)
a
(4R)-5,6-Isop r op ylid en e-3-oxa -1,5,6-tr ih yd r oxyh exa n ol
((-)-3) an d (4S)-5,6-Isopr opyliden e-3-oxa-1,5,6-tr ih ydr oxy-
h exa n ol ((+)-3). Sodium (650 mg, 28.2 mmol) was carefully
added to freshly distilled ethylene glycol (30 mL) at room
temperature under argon atmosphere. After complete dissolu-
tion of the sodium, the solution was cooled to 0 °C, and the
mesylate (-)-2 was added dropwise. The reaction was stirred
for 12 h at 140 °C, cooled, and quenched with saturated
aqueous NH4Cl. The aqueous phase was extracted with CH2-
Cl2, and the combined organic phases were washed with brine,
dried (MgSO4), and evaporated to yield 3.98 g (91%) of (-)-3
as a colorless oil: FTIR (film) 3525, 1257, 1214, 1126, 1056
In all cases, except these two, the sign of the optical totation
is the same for product and starting material.
deactivated amines (entries 27 and 28) could, however,
not be introduced under these conditions. The opening
of epoxide by alcohols under Lewis acid catalysis is a well-
documented reaction and usually produces good yields
of the hydroxyethers. In our hands, these methods failed
to provide the expected products. We suspect that a
combination of intra- and intermolecular homocoupling
leading to various oligomers and macrocyclized products
is responsible for the low yields observed; the oxygen-
rich neighboring region is probably templating the Lewis
acid-catalyzed process. We turned to the method de-
scribed by Bittmann,30 which proved the most satisfac-
tory. The desired ethers were thus obtained albeit in
moderate to low yields.
cm-1; [R]20 -6.5 (c 3.7, CHCl3); 1H NMR (CDCl3, 400 MHz) δ
D
4.34-4.26 (m, 1H), 4.06 (dd, 1H, J ) 8.3, 6.5 Hz), 3.73 (dd,
1H, J ) 8.3, 6.4 Hz), 3.75-3.72 (m, 2H), 3.64-3.59 (m, 2H),
3.57 (dd, 1H, J ) 10.2, 6.0 Hz), 3.54 (dd, 1H, J ) 10.2, 5.0
Hz), 2.99 (t, 1H, J ) 5.7 Hz), 1.43 (s, 3H), 1.36 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 109.5, 74.8, 72.9, 72.2, 66.5, 61.6,
26.7, 25.3; HRMS (EI) for C7H13O4 (M - CH3)+ calcd 161.0814,
found 161.0813.
Th e (4S)-5,6-isopr op yliden e-3-oxa -1,5,6-tr ih ydr oxyh ex-
a n ol ((+)-3) was prepared analogously from (+)-2 and also
(30) (a) Guivildasky, P. N.; Bittmann, R. J . Am. Chem. Soc. 1989,
111, 3077. (b) Guivildasky, P. N.; Bittmann, R. J . Org. Chem. 1989,
54, 4643.
gave satisfactory analytical results: [R]20 +6 (c 2.2, CHCl3).
D

6788 J . Org. Chem., Vol. 64, No. 18, 1999
Le Hue´rou et al.
1-[(2S)-2,3-Dih yd r oxy-2,3-isop r op ylid en ep r op oxy]-2-
h yd r oxyben zen e ((-)-5) a n d 1-[(2R)-2,3-Dih yd r oxy-2,3-
isop r op ylid en ep r op oxy]-2-h yd r oxyben zen e ((+)-5). To a
washed suspension of NaH (504 mg, 21 mmol) in 70 mL of
anhydrous DMF at room temperature was added dropwise
catechol (2.2 g, 20 mmol) in 15 mL of DMF. The solution was
stirred for 30 min at the same temperature, and (-)-2 (5.9 g,
28 mmol) in 15 mL of DMF was added dropwise. The reaction
mixture was then stirred for 24 h at 110 °C, cooled, and
quenched with 50 mL of saturated aqueous NH4Cl. The organic
layer was separated, and the aqueous phase was extracted
with ether (3 × 50 mL). The combined organic phases were
extracted with 10% NaOH aqueous solution, and the combined
aqueous phases were neutralized with a 10% HCl aqueous
solution. The aqueous phase was then extracted with ether,
and the combined organic phases washed with brine, dried
(MgSO4), and evaporated. After recrystallization (ether/hex-
ane), 2.75 g (62%) of (-)-5 was isolated as colorless crystals:
mp 48 °C; FTIR (film) 3450, 1597, 1520, 1250, 1155, 1111, 973,
786 cm-1; [R]20D +2 (c 5.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
δ 6.97-6.79 (m, 4H), 6.38 (bs, 1H), 4.52-4.44 (m, 1H), 4.15
(dd, 1H, J ) 8.6, 6.6 Hz), 4.08 (dd, 1H, J ) 10.7, 4.6 Hz), 4.03
(dd, 1H, J ) 10.2, 5.6 Hz), 3.89 (dd, 1H, J ) 8.1, 5.6 Hz), 1.47
(s, 3H), 1.49 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 146.7, 145.9,
122.8, 120.0, 115.4, 114.3, 110.0, 74.1, 71.1, 66.1, 26.6, 25.2;
HRMS (EI) for C12H16O4 (M+) calcd 224.1049, found 224.1048.
Th e 1-[(2R)-2,3-d ih yd r oxy-2,3-isop r op ylid en ep r opoxy]-
2-h yd r oxyben zen e ((+)-5) was prepared from (+)-2 analo-
gously and also gave satisfactory analytical results: [R]20D -2.1
(c 5.9, CHCl3).
(m, 4H), 4.53-4.45 (m, 1H), 4.23 (dd, 1H, J ) 11.2, 3.1 Hz),
4.17 (dd, 1H, J ) 8.2, 6.1 Hz), 4.11 (dd, 1H, J ) 9.7, 5.1 Hz),
4.03-3.95 (m, 3H), 3.39-3.34 (m, 1H), 2.88 (dd, 1H, J ) 4.6,
4.6 Hz), 2.75 (dd, 1H, J ) 5.1, 2.6 Hz), 1.47 (s, 3H), 1.40 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 148.8, 148.7, 122.0, 121.9,
115.1, 115.0, 109.6, 74.0, 70.2, 70.0, 66.9, 50.2, 44.7, 26.7, 25.4;
HRMS (EI) for C15H20O5 (M+) calcd 280.1311, found 280.1308.
Th e 1-[(2R)-2,3-dih ydr oxy-2,3-isop r op yliden ep r op oxy]-
2-[(2S)-2,3-ep oxyp r op oxy]ben zen e ((+)-8) was prepared
analogously from (+)-5 and (S)-(+)-glycidyl tosylate and also
gave satisfactory analytical results: [R]20D +21.2 (c 3.6, CHCl3).
Gen er al P r ocedu r e 1. Open in g of Epoxides by Lith iu m
(Tr ieth ylsilyl)a cetylid e. To a solution of (triethylsilyl)-
acetylene in anhydrous THF at -78 °C under argon atmo-
sphere was added dropwise a solution of n-butyllithium (1.6
M in hexane). After 30 min, freshly distilled BF3‚Et2O was
added dropwise, the solution was stirred for 15 min, and then
the epoxide in THF was added slowly. The reaction mixture
was then stirred for 3 h at -78 °C and quenched with
saturated aqueous NH4Cl. The aqueous phase was extracted
with ether, and the combined organic phases were washed with
brine and dried (MgSO4) before evaporation of the volatiles.
The resulting oil was purified by silica gel chromatography
(elution with 5% MeOH in CH2Cl2) to give the corresponding
(triethylsilyl)alkyne derivative.
(4R,11R)-6,9-Dioxa -11,12-isop r op ylid en e-4,11,12-tr ih y-
dr oxy-1-(tr ieth ylsilyl)-dodec-1-yn e ((-)-10b) an d (4S,11S)-
6,9-Dioxa -11,12-isop r op ylid en e-4,11,12-tr ih yd r oxy-1-(tr i-
et h ylsilyl)d od ec-1-yn e ((+)-10b ). According to general
procedure 1, (TES)acetylene (3.3 mL, 18 mmol) in 6 mL of
THF, n-BuLi (10.6 mL, 17 mmol), BF3‚Et2O (2.3 mL, 19 mmol),
epoxide (-)-7 (2 g, 8.6 mmol) in 3 mL of THF were employed:
(2R,9R)-1,2-E p oxy-9,10-d ih yd r oxy-4,7-d ioxa -9,10-iso-
p r op ylid en ed eca n e ((-)-7) a n d (2S,9S)-1,2-Ep oxy-9,10-
d ih yd r oxy-4,7-d ioxa -9,10-isop r op ylid en ed eca n e ((+)-7).
To alcohol (-)-3 (3.9 g, 22.2 mmol) were successively added at
room temperature 4 g (51 mmol) of a 50% NaOH aqueous
solution, tetrabutylammonium bromide (709 mg, 2.2 mmol),
and 40 mL of hexane. (R)-(-)-epichlorohydrin (4 mL, 51.1
mmol) was then added dropwise, and the resulting suspension
was stirred for 12 h at 60 °C. After cooling, the solution was
diluted with 250 mL of ether, and 60 mL of water then
extracted with ether. The combined organic phases were
washed with brine, dried (MgSO4), and evaporated to yield 4
g (78%) of (-)-7 as a colorless oil: FTIR (film) 1255, 1214, 1140,
colorless oil (76%); FTIR (film) 3382, 1239, 1122, 727 cm-1
;
[R]20 -14.6 (c 3.45, CHCl3); 1H NMR (CDCl3, 400 MHz) δ
D
4.32-4.25 (m, 1H), 4.06 (dd, 1H, J ) 8.2, 6.1 Hz), 3.98-3.89
(m, 1H), 3.73 (dd, 1H, J ) 8.1, 6.6 Hz), 3.71-3.61 (m, 5H),
3.58 (dd, 1H, J ) 10.2, 5.6 Hz), 3.52 (dd, 1H, J ) 10.2, 6.1
Hz), 3.49 (dd, 1H, J ) 11.7, 6.7 Hz), 2.80 (d, 1H, J ) 4.6 Hz),
2.53 (dd, 1H, J ) 17.3, 6.1 Hz), 2.45 (dd, 1H, J ) 16.8, 7.1
Hz), 1.42 (s, 3H), 1.36 (s, 3H), 0.98 (t, 9H, J ) 8.1 Hz), 0.57 (q,
6H, J ) 8.1 Hz); 13C NMR (CDCl3, 100 MHz) δ 109.5, 103.6,
84.4, 74.7, 74.1, 72.3, 70.8, 70.7, 68.9, 66.7, 26.8, 25.4, 24.9,
7.5, 4.5; HRMS (EI) for C18H33O5Si (M - CH3)+ calcd 357.2097,
found 357.2107.
1105 cm-1; [R]20 -14.4 (c 3.45, CHCl3); 1H NMR (CDCl3, 400
D
MHz) δ 4.32-4.25 (m, 1H), 4.06 (dd, 1H, J ) 8.1, 6.1 Hz), 3.79
(dd, 1H, J ) 11.7, 2.6 Hz), 3.76-3.62 (m, 5H), 3.59 (dd, 1H,
J ) 10.2, 6.1 Hz), 3.51 (dd, 1H, J ) 10.2, 5.6 Hz), 3.42 (dd,
1H, J ) 11.7, 5.6 Hz), 3.19-3.13 (m, 1H), 2.79 (dd, 1H, J )
5.1, 5.1 Hz), 2.61 (dd, 1H, J ) 4.6, 2.6 Hz), 1.42 (s, 3H), 1.36
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 109.3, 74.7, 72.3 71.9,
70.9, 70.6, 66.7, 50.8, 44.1, 26.8, 25.4; HRMS (EI) for C10H17O5
(M - CH3)+ calcd 217.1076, found 217.1083.
Th e (4S,11S)-6,9-d ioxa -11,12-isop r op ylid en e-4,11,12-
tr ih yd r oxy-1-(tr ieth ylsilyl)d od ec-1-yn e ((+)-10b) was pre-
pared analogously from (+)-7 and also gave satisfactory
analytical results: [R]20 +16.7 (c 5.2, CHCl3).
D
1-[(2S)-2,3-Dih yd r oxy-2,3-isop r op ylid en ep r op oxy]-2-
[(2R)-2-h yd r oxy-5-(t r iet h ylsilyl)p en t -4-yn oxy]b en zen e
((-)-11b) an d 1-[(2R)-2,3-dih ydr oxy-2,3-isopr opyliden epr o-
poxy]-2-[(2S)-2-h ydr oxy-5-(tr ieth ylsilyl)pen t-4-yn oxy]ben -
zen e ((+)-11b). According to general procedure 1, (TES)-
acetylene (1.7 mL, 9.5 mmol) in 3 mL of THF, n-BuLi (6.3 mL,
10.1 mmol), BF3‚Et2O (0.89 mL, 7.2 mmol), and epoxide (-)-7
(1.67 g, 6 mmol) in 1 mL of THF were employed: colorless oil
Th e (2S,9S)-1,2-ep oxy-9,10-d ih yd r oxy-4,7-d ioxa -9,10-
isop r op ylid en ed eca n e ((+)-7) was prepared analogously
from (+)-3 and (S)-(+)-epichlorohydrin and also gave satisfac-
tory analytical results: [R]20 +16.5 (c 3.5, CHCl3).
D
1-[(2S)-2,3-Dih yd r oxy-2,3-isop r op ylid en ep r op oxy]-2-
[(2R)-2,3-ep oxyp r op oxy]ben zen e ((-)-8) a n d 1-[(2R)-2,3-
Dih ydr oxy-2,3-isopr opyliden epr opoxy]-2-[(2S)-2,3-epoxy-
p r op oxy]ben zen e ((+)-8). To a washed suspension of NaH
(275 mg, 11 mmol) in 15 mL of anhydrous DMF was added
dropwise at room temperature 2.34 g (10 mmol) of (-)-5 in 7
mL of DMF. The solution was stirred for 30 min, and 2 g (8.8
mmol) of (R)-(-)-glycidyl tosylate in 7 mL of DMF was added
dropwise. The reaction mixture was then stirred for 72 h at
room temperature and quenched with saturated aqueous NH4-
Cl. The aqueous phase was extracted with ether, and the
combined organic phases were washed with a 10% NaOH
aqueous solution and brine and dried (MgSO4). After evapora-
tion of the volatiles, the resulting solid was purified by silica
gel chromatography (elution with 20% AcOEt in toluene) to
give a white solid. This solid was recrystallized from ether/
hexane to yield (-)-8 (1.98 g, 80%) as colorless crystals: mp
(78%); FTIR (film) 3473, 2174, 1594, 1503, 845, 738 cm-1; [R]20
D
-32.2 (c 4.7, CHCl3); 1H NMR (CHCl3, 400 MHz) δ 6.96-6.91
(m, 4H), 4.52-4.46 (m, 1H), 4.20 (dd, 1H, J ) 9.5, 3.7 Hz),
4.14 (dd, 1H, J ) 8.2, 6.4 Hz), 4.16-4.12 (m, 1H), 4.05-4.02
(m, 2H), 4.00 (dd, 1H, J ) 9.5, 6.7 Hz), 3.95 (dd, 1H, J ) 8.2,
5.5 Hz), 3.29 (d, 1H, J ) 4.9 Hz), 2.66 (dd, 1H, J ) 17.1, 5.5
Hz), 2.57 (dd, 1H, J ) 16.8, 7.6 Hz), 1.47 (s, 3H), 1.39 (s, 3H),
0.97 (t, 9H, J ) 8.1 Hz), 0.57 (q, 6H, J ) 8.1 Hz); 13C NMR
(CHCl3, 100 MHz) δ 148.89, 148.86, 122.1, 122.0, 115.2, 115.0,
109.8, 103.3, 84.6, 74.1, 72.8, 70.3, 68.5, 66.5, 26.6, 25.2, 24.7,
7.5, 4.4; HRMS (EI) for C23H36O5Si (M+) calcd 420.2332, found
420.2317.
Th e 1-[(2R)-2,3-dih ydr oxy-2,3-isopr op ylid en ep r op oxy]-
2-[(2S )-2-h yd r oxy-5-(t r ie t h ylsilyl)p e n t -4-yn oxy]b e n -
zen e ((+)-11b) was prepared analogously from (+)-8 and also
gave satisfactory analytical results: [R]20D +31.3 (c 4.5, CHCl3).
Gen er a l P r oced u r e 2. Dep r otection of Diols. To a
solution of the acetonide in 100 mL of MeOH at room
temperature was added p-TsOH‚H2O. The reaction mixture
38 °C; FTIR (film) 1593, 1504, 1454, 1372, 846, 749 cm-1; [R]20
D
-21.1 (c 5.3, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 6.99-6.89

Intermediates toward Simplified Acetogenin Analogues
J . Org. Chem., Vol. 64, No. 18, 1999 6789
was stirred for 12 h at the same temperature, triethylamine
was added, the volatiles were removed under vacuo, and the
resulting oil was purified by silica gel chromatography (elution
with 5% MeOH in AcOEt) to give the corresponding depro-
tected derivative.
84.4, 74.0, 71.4, 70.6, 70.5, 70.3, 68.8, 68.1, 24.8, 21.6, 7.4, 4.4;
HRMS (FAB) for C23H39O7SSi (M + H)+ calcd 487.2186, found
487.2186.
Th e (4S,11S)-6,9-d ioxa -12-(p-tolu en esu lfon yl)-4,11,12-
tr ih yd r oxy-1-(tr ieth ylsilyl)d od ec-1-yn e ((+)-12b) was pre-
pared analogously from the triol obtained from (+)-10b and
also gave satisfactory analytical results: [R]20 +7.5 (c 3.05,
CHCl3)
(4R,11S)-6,9-Dioxa -4,11,12-tr ih yd r oxy-1-(tr ieth ylsilyl)-
d od ec-1-yn e a n d (4S,11R)-6,9-Dioxa -4,11,12-tr ih yd r oxy-
1-(tr ieth ylsilyl)d od ec-1-yn e. According to general procedure
2, acetonide (-)-10b (3 g, 8 mmol), TsOH, H2O (150 mg, 0.8
mmol), and triethylamine (5 mL) were employed: colorless oil
1-[(2R)-2,3-Dih yd r oxy-3-(p-tolu en esu lfon yl)p r op oxy]-
2-[(2R )-2-h yd r oxy-5-(t r ie t h ylsilyl)p e n t -4-yn oxy]b e n -
zen e ((-)-13b) a n d 1-[(2S)-2,3-d ih yd r oxy-3-(p-tolu en esu l-
fon yl)p r op oxy]-2-[(2S)-2-h yd r oxy-5-(tr ieth ylsilyl)p en t-4-
yn oxy]ben zen e ((+)-13b). According to general procedure 3,
the triol was obtained from (-)-11b (2.8 g, 7.4 mmol) in 250
mL of toluene, (dibutyl)tin(dimethoxide) (1.77 mL, 7.7 mmol),
triethylamine (0.06 mL), and p-toluenesulfonyl chloride (2 g,
10.3 mmol): colorless oil (91%); FTIR (film) 3422, 2173, 1595,
(86%); FTIR (film) 3382, 2173, 1122, 1047, 727 cm-1; [R]20
D
-12.9 (c 4.3, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 3.99-3.91
(m, 1H), 3.91-3.84 (m, 1H), 3.79 (d, 1H, J ) 4.8 Hz), 3.72-
3.59 (m, 8H), 3.61 (dd, 1H, J ) 9.9, 4.0 Hz), 3.58 (dd, 1H, J )
10.1, 6.4 Hz), 3.51 (dd, 1H, J ) 9.9, 7.0 Hz), 3.17 (d, 1H, J )
6 Hz), 2.53 (dd, 1H, J ) 16.8, 5.6 Hz), 2.44 (dd, 1H, J ) 16.9,
7.6 Hz) 0.97 (t, 9H, J ) 8.1 Hz), 0.58 (q, 6H, J ) 8.1 Hz); 13C
NMR (CDCl3, 100 MHz) δ 103.6, 84.3, 74.2, 72.9, 70.6, 70.54,
70.51, 68.9, 63.8, 24.8, 7.4, 4.3; HRMS (FAB) for C16H33O5Si
(M + H)+ calcd 333.2097, found 333.2088.
1503, 1125, 1019, 831, 738 cm-1; [R]20 -15.6 (c 6.3, CHCl3);
D
1H NMR (CDCl3, 400 MHz) δ 7.78 (d, 2H, J ) 8.2 Hz), 7.31 (d,
2H, J ) 8.2 Hz), 6.99-6.85 (m, 4H), 4.21-4.08 (m, 5H), 4.04
(dd, 1H, J ) 9.8, 3.4 Hz), 4.00-3.94 (m, 2H), 3.60 (d, 1H, J )
4.4 Hz), 3.27 (d, 1H, J ) 4.2 Hz), 2.60 (dd, 1H, J ) 16.9, 5.6
Hz), 2.52 (dd, 1H, J ) 16.9, 7.5 Hz), 2.42 (s, 3H), 0.97 (t, 9H,
J ) 8.1 Hz), 0.57 (q, 6H, J ) 8.1 Hz). 13C NMR (CDCl3, 100
MHz) δ 148.9, 148.6, 145.1, 132.4, 129.9, 127.9, 122.7, 122.4,
115.9, 115.6, 102.9, 84.9, 72.9, 70.5, 69.9, 68.6, 67.9, 24.8, 21.6,
7.4, 4.3; HRMS (EI) for C27H38O7SSi (M+) calcd 534.2107, found
534.2106.
Th e (4S,11R)-6,9-d ioxa -4,11,12-tr ih yd r oxy-1-(tr ieth yl-
silyl)d od ec-1-yn e was prepared analogously from (+)-10b
and also gave satisfactory analytical results: [R]20 +12.3
D
(c 2.95, CHCl3).
1-[(2S)-2,3-Dih ydr oxypr opoxy]-2-[(2R)-2-h ydr oxy-5-(tr i-
et h ylsilyl)p en t -4-yn oxy]ben zen e a n d 1-[(2R)-2,3-d ih y-
d r oxyp r op oxy]-2-[(2S)-2-h yd r oxy-5-(tr ieth ylsilyl)p en t-4-
yn oxy]ben zen e. According to general procedure 2, acetonide
(-)-11b (3.3 g, 7.85 mmol), TsOH, H2O (150 mg, 0.8 mmol),
and triethylamine (5 mL) were employed: colorless oil (90%);
Th e 1-[(2S)-2,3-d ih yd r oxy-3-(p -t olu en esu lfon yl)p r o-
poxy]-2-[(2S)-2-h ydr oxy-5-(tr ieth ylsilyl)pen t-4-yn oxy]ben -
zen e ((+)-13b) was prepared analogously from the triol
obtained from (+)-11b and also gave satisfactory analytical
FTIR (film) 3453, 2174, 1594, 1503, 1125, 1033, 738 cm-1
;
[R]20 -27.5 (c 4.55, CHCl3); 1H NMR (CDCl3, 400 MHz) δ
D
results: [R]20 +15.9 (c 4.6, CHCl3).
D
6.98-6.88 (m, 4H), 4.22 (dd, 1H, J ) 9.1, 2.5 Hz), 4.18-4.10
(m, 2H), 4.08-4.00 (m, 4H), 3.98 (dd, 1H, J ) 9.1, 7.6 Hz),
3.85-3.73 (m, 2H), 3.32 (t, 1H, J ) 5.1 Hz), 2.63 (dd, 1H, J )
16.8, 5.6 Hz), 2.54 (dd, 1H, J ) 16.8, 8.1 Hz), 0.97 (t, 9H, J )
8.1 Hz), 0.57 (q, 6H, J ) 8.1 Hz); 13C NMR (CDCl3, 100 MHz)
δ 148.8, 148.5, 122.4, 122.1, 115.4, 114.6, 103.1, 84.8 72.7, 72.4,
70.1, 68.6, 63.9, 24.7, 7.4, 4.3; HRMS (EI) for C20H32O5Si (M+)
calcd 380.2019, found 380.2004.
Gen er a l P r oced u r e 4. F or m a tion of Ep oxid es. To a
solution of the tosylate in MeOH/CH2Cl2 10/1 at 0 °C was
added K2CO3. The suspension was stirred for 1 h at the same
temperature, and the volatiles were removed in vacuo. The
resulting white paste was dissolved in CH2Cl2, washed with
water, dried (MgSO4), and after evaporation purified by silica
gel chromatography (elution with 5% MeOH in CH2Cl2) to give
the corresponding epoxy derivative.
Th e 1-[(2R)-2,3-d ih yd r oxyp r op oxy]-2-[(2S)-2-h yd r oxy-
5-(tr ieth ylsilyl)p en t-4-yn oxy]ben zen e was prepared analo-
gously from (+)-11b and also gave satisfactory analytical
(4R,11S)-6,9-Dioxa -11,12-ep oxy-4-h yd r oxy-1-(tr ieth yl-
silyl)d od ec-1-yn e ((-)-14b) a n d (4S,11R)-6,9-Dioxa -11,12-
ep oxy-4-h yd r oxy-1-(t r iet h ylsilyl)d od ec-1-yn e ((+)-14b).
According to general procedure 4, tosylate (-)-12b (750 mg,
1.5 mmol) in 5 mL of MeOH and 0.5 mL of CH2Cl2, and K2-
CO3 (470 mg, 3.4 mmol) were employed: colorless oil (87%);
results: [R]20 +23.5 (c 4.85, CHCl3).
D
Gen er a l P r oced u r e 3. Selective P r im a r y Tosyla tion .
(Dibutyl)tin(dimethoxide) was added to the triol in anhydrous
toluene at room temperature, and half of the solvent was
distilled. The reaction mixture was cooled to -15 °C, and
triethylamine and p-toluenesulfonyl chloride were successively
added before the solution was allowed to reach room temper-
ature. The reaction mixture was stirred for 17 h and quenched
with water, and the aqueous phase was extracted with ether.
The combined organic phases were washed with brine and
dried (MgSO4), and the volatiles were removed under vacuo.
The resulting oil was purified by silica gel chromatography
(elution with CH2Cl2 then 5% MeOH in CH2Cl2) to give the
corresponding tosylated derivative.
FTIR (film) 3442, 2173, 1105, 1017 cm-1; [R]20 -11 (c 3.3,
D
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 3.99-3.90 (m, 1H), 3.82
(dd, 1H, J ) 11.7, 3.0 Hz), 3.74-3.63 (m, 5H), 3.51 (dd, 1H,
J ) 9.6, 7.1 Hz), 3.43 (dd, 1H, J ) 11.2, 5.6 Hz), 3.20-3.13
(m, 1H), 2.80 (t, 1H, J ) 4.6 Hz), 2.73 (d, 1H, J ) 4.6 Hz),
2.62 (dd, 1H, 4.6, 2.6 Hz), 2.53 (dd, 1H, J ) 16.8, 5.6 Hz), 2.46
(dd, 1H, J ) 16.8, 7.6 Hz), 0.97 (t, 9H, J ) 8.1 Hz), 0.57 (q,
6H, J ) 8.1 Hz); 13C NMR (CDCl3, 100 MHz) δ 103.6, 84.5,
74.1, 71.9, 70.8, 70.6, 68.8, 50.8, 44.2, 24.8, 7.4, 4.4; HRMS
(EI) for C16H31O4Si (M + H)+ calcd 315.1992, found 315.1995.
Anal. Calcd for C16H30O4Si: C, 61.11; H, 9.61. Found: C, 60.53;
H, 9.61.
(4R,11R)-6,9-Dioxa-12-(p-tolu en esu lfon yl)-4,11,12-tr ih y-
d r oxy-1-(tr ieth ylsilyl)d od ec-1-yn e ((-)-12b) a n d (4S,11S)-
6,9-Dioxa -12-(p -t olu en esu lfon yl)-4,11,12-t r ih yd r oxy-1-
(tr ieth ylsilyl)d od ec-1-yn e ((+)-12b). According to general
procedure 3, the triol was obtained from (-)-10b (1.16 g, 4
mmol) in 150 mL of toluene, (dibutyl)tin(dimethoxide) (1 mL,
4.4 mmol), triethylamine (0.03 mL), and p-toluenesulfonyl
chloride (991 mg, 5.2 mmol): colorless oil (88%); FTIR (film)
Th e (4S,11R)-6,9-d ioxa -11,12-ep oxy-4-h yd r oxy-1-(t r i-
eth ylsilyl)d od ec-1-yn e ((+)-14) was prepared analogously
from (+)-12b and also gave satisfactory analytical results:
[R]20 +10 (c 3.0, CHCl3).
D
1-[(2S)-2,3-Ep oxyp r op oxy]-2-[(2R)-2-h yd r oxy-5-(tr ieth -
ylsilyl)p en t -4-yn oxy]ben zen e ((-)-16b ) a n d 1-[(2R)-2,3-
E p oxyp r op oxy]-2-[(2R)-2-h yd r oxy-5-(t r iet h ylsilyl)p en t -
4-yn oxy]ben zen e ((+)-16b). According to general procedure
4, tosylate (-)-13b (1.84 mg, 3.4 mmol) in 25 mL of MeOH,
2.5 mL of CH2Cl2, and K2CO3 (1 g, 7.5 mmol) were employed:
colorless oil (89%); FTIR (film) 3442, 2173, 1594, 1503, 1019,
3422, 2173, 1189, 1097, 1018, 815 cm-1; [R]20 -7.8 (c 3.65,
D
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, 2H, J ) 8.2 Hz),
7.35 (d, 2H, J ) 8.2 Hz), 4.09-3.96 (m, 3H), 3.95-3.87 (m,
1H), 3.66-3.59 (m, 5H), 3.56 (dd, 1H, J ) 10.1, 4.0 Hz), 3.51
(dd, 1H, J ) 10.1, 5.6 Hz), 3.47 (dd, 1H, J ) 10.0, 7.1 Hz),
3.26 (d, 1H, J ) 5.4 Hz), 2.98 (d, 1H, J ) 4.6 Hz), 2.50 (dd,
1H, J ) 16.8, 5.7 Hz), 2.45 (s, 3H), 2.42 (dd, 1H, J ) 16.8, 7.2
Hz), 0.97 (t, 9H, J ) 8.1 Hz), 0.57 (q, 6H, J ) 8.1 Hz); 13C
NMR (CDCl3, 100 MHz) δ 144.9, 132.5, 129.8, 127.9, 103.4,
738 cm-1; [R]20 -20.4 (c 5.1, CHCl3); 1H NMR (CDCl3, 400
D
MHz) δ 6.99-6.93 (m, 4H), 4.29 (dd, 1H, J ) 11.2, 3.0 Hz),
4.21 (dd, 1H, J ) 9.2, 3.1 Hz), 4.18-4.11 (m, 1H), 4.02 (dd,
1H, J ) 9.2, 6.6 Hz), 3.95 (dd, 1H, J ) 11.7, 6.1 Hz), 3.41-
3.35 (m, 1H), 3.24 (d, 1H, J ) 4.6 Hz), 2.92-2.89 (m, 1H), 3.76

6790 J . Org. Chem., Vol. 64, No. 18, 1999
Le Hue´rou et al.
(dd, 1H, J ) 4.6, 2.5 Hz), 2.67 (dd, 1H, J ) 17.3, 5.6 Hz), 2.58
(dd, 1H, J ) 16.8, 7.1 Hz), 0.97 (t, 9H, J ) 8.1 Hz), 0.58 (q,
6H, J ) 8.1 Hz); 13C NMR (CDCl3, 100 MHz) δ 149.0, 148.7,
122.5, 122.0, 115.7, 115.3, 103.3, 84.7, 72.8, 70.7, 68.4, 50.4,
44.6, 24.7, 7.4, 4.3; HRMS for C20H30O4Si (M+) calcd 362.1913,
found 362.1926.
(t, 9H, J ) 7.8 Hz), 0.56 (q, 6H, J ) 7.8 Hz); 13C NMR (CDCl3,
100 MHz) δ 170.2, 148.71, 148.69, 136.0, 128.7, 128.6, 127.1,
122.1, 122.0, 115.5, 115.0, 101.9, 84.9, 82.4, 71.0, 70.2, 68.8,
57.4, 50.2, 44.7, 22.2, 7.4, 4.3; HRMS(EI) for C29H38O6Si (M+)
calcd 510.2438, found 510.2446.
1-[(2S)-2,3-Ep oxyp r op oxy]-2-[(2R)-2-h yd r oxy-2-O-[(2S)-
2-m eth oxy-2-ph en ylacetate)-5-(tr ieth ylsilyl)pen t-4-yn oxy]-
ben zen e ((-)-18b). According to general procedure 5, alcohol
(-)-16b (30 mg, 0.083 mmol), (S)-(+)-MPA (22 mg, 0.135
mmol), DCC (38 mg, 0.18 mmol), and DMAP (5 mg, 0.04 mmol)
were employed: colorless oil (64%); FTIR (film) 2361, 2177,
1753, 1502, 1115, 736 cm-1; [R]20D +11 (c 7.0, CHCl3); 1H NMR
(CDCl3, 400 MHz) δ 7.45-7.41 (m, 2H), 7.36-7.30 (m, 3H),
6.96-6.89 (m, 4H), 5.37-5.31 (m, 1H), 4.77 (s, 1H), 4.29 (dd,
1H, J ) 10.8, 3.9 Hz), 4.23 (dd, 1H, J ) 10.7, 5.8 Hz)-), 4.21
(dd, 1H, J ) 11.2, 3.3 Hz), 3.99 (dd, 1H, J ) 11.2, 5.5 Hz),
3.41 (s, 3H), 3.35-3.31 (m, 1H), 2.87 (dd, 1H, J ) 5.0, 4.2 Hz),
2.74 (dd, 1H, J ) 5.0, 2.6 Hz), 2.64 (dd, 1H, J ) 17.0, 7.3 Hz),
2.55 (dd, 1H, J ) 17.0, 5.3 Hz), 0.92 (t, 9H, J ) 7.8 Hz), 0.52
(q, 6H, J ) 7.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 170.1, 148.9,
148.8, 135.9, 128.7, 128.6, 127.1, 122.2, 122.1, 115.7, 115.1,
101.7, 84.9, 82.3), 71.1, 70.3, 68.9, 57.4, 50.2, 44.7, 21.9, 7.4,
4.3; HRMS (EI) for C29H38O6Si (M+) calcd 510.2438, found
510.2446.
Th e 1-[(2R)-2,3-ep oxyp r op oxy]-2-[(2R)-2-h yd r oxy-5-
(tr ieth ylsilyl)p en t-4-yn oxy]ben zen e ((+)-16b) was pre-
pared analogously from (+)-13b and also gave satisfactory
analytical results: [R]20 +19.8 (c 4.65, CHCl3).
D
Gen er a l P r oced u r e 5. Meth oxym a n d elic Ester s Syn -
th esis. To the alcohol in 1 mL of anhydrous CH2Cl2 at room
temperature were successively added methoxymandelic acid,
DCC, and DMAP. The solution was strirred for 12 h at room
temperature and then filtrated. The filtrate after concentration
was purified by silica gel chromatography (elution with 50%
ether in hexane) to give the corresponding mandelic ester.
(4R,11R)-6,9-Dioxa -11,12-ep oxy-4-h yd r oxy-4-O-((2R)-
2-m e t h oxy-2-p h e n yla ce t a t e )-1-(t r ie t h ylsilyl)-d od e c-1-
yn e ((-)-17a ). According to general procedure 5, alcohol (-)-
14b (20 mg, 0.064 mmol), (R)-(-)-MPA (17 mg, 0.1 mmol), DCC
(29 mg, 0.14 mmol), and DMAP (4 mg, 0.032 mmol) were
employed: colorless oil (61%); FTIR (film) 2361, 2177, 1762,
1
1111, 729 cm-1; [R]20 -38.5 (c 7.5, CHCl3); H NMR (CDCl3,
D
400 MHz) δ 7.47-7.43 (m, 2H), 7.38-7.31 (m, 3H), 5.16-5.10
(m, 1H), 4.78 (s, 1H), 3.70 (dd, 1H, J ) 11.6, 2.9 Hz), 3.54 (d,
2H, J ) 5 Hz), 3.50-3.30 (m, 4H), 3.42 (s, 3H), 3.35 (dd, 1H,
J ) 11.6, 5.8 Hz), 3.14-3.09 (m, 1H), 2.78 (dd, 1H, J ) 5.1,
4.2 Hz), 2.65 (dd, 1H, J ) 17.2, 6.6 Hz), 2.59 (dd, 1H, J ) 5.0,
2.7 Hz), 2.57 (dd, 1H, J ) 17.1, 5.9 Hz), 0.98 (t, 9H, J ) 7.8
Hz), 0.57 (q, 6H, J ) 7.8 Hz); 13C NMR (CDCl3, 100 MHz) δ
170.2, 136.1, 128.7, 128.5, 127.2, 102.3, 84.5, 82.4, 71.8, 71.6,
70.8, 70.7, 70.5, 57.3, 50.8, 44.2, 22.1, 7.4, 4.4; HRMS (EI) for
Gen er a l P r oced u r e 6. Op en in g of Ep oxid es w ith Gr ig-
n a r d Rea gen t. A 1 M solution of the Grignard in anhydrous
THF or ether was added dropwise to a suspension of CuBr‚
Me2S in THF at 0 °C under an argon atmosphere. The solution
was then stirred for 10 min, and the epoxide in THF was added
dropwise. The reaction mixture was stirred for a range of 1-12
h at 0 °C and then quenched with saturated aqueous NH4Cl.
The aqueous phase was extracted with ether, and the com-
bined organic phases were washed with brine and dried
(MgSO4) before evaporation of the volatiles. The resulting oil
was purified by silica gel chromatography (elution with 2%
MeOH in CH2Cl2) to give the corresponding open derivative.
Gen er a l P r oced u r e 7. Op en in g of E p oxid es w it h
Secon d a r y Am in es. To the amine in anhydrous MeOH at
room temperature was added dropwise the epoxide in MeOH.
The solution was stirred for 12 h at 40 °C, and the solvent
and excess amine were removed under vacuo to give the
corresponding amino derivative.
C
25H38O6Si (M+) calcd 462.2438, found 462.2438.
(4R,11R)-6,9-Dioxa -11,12-ep oxy-4-h yd r oxy-4-O-[(2S)-
2-m e t h oxy-2-p h e n yla ce t a t e ]-1-(t r ie t h ylsilyl)d od e c-1-
yn e ((-)-17b). According to general procedure 5, alcohol (-)-
14b (20 mg, 0.064 mmol), (S)-(+)-MPA (17 mg, 0.1 mmol), DCC
(29 mg, 0.14 mmol), and DMAP (4 mg, 0.032 mmol) were
employed: Colorless oil (64%); FTIR (film) 2177, 1762, 1111,
729 cm-1; [R]20 +10.6 (c 7.5, CHCl3); 1H NMR (CDCl3, 400
D
MHz) δ 7.47-7.43 (m, 2H), 7.38-7.31 (m, 3H), 5.18-5.11 (m,
1H), 4.79 (s, 1H), 3.77 (dd, 1H, J ) 11.6, 2.9 Hz), 3.70 (m, 2H),
3.67-3.55 (m, 4H), 3.43 (s, 3H), 3.41 (dd, 1H, J ) 11.8, 6.0
Hz), 3.17-3.12 (m, 1H), 2.79 (dd, 1H, J ) 4.9, 4.1 Hz), 2.61
(dd, 1H, J ) 5.0, 2.7 Hz), 2.49 (dd, 1H, J ) 17.1, 7.0 Hz), 2.43
(dd, 1H, J ) 16.9, 5.3 Hz), 0.95 (t, 9H, J ) 7.8 Hz), 0.53 (q,
6H, J ) 7.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 170.2, 136.0,
128.7, 128.6, 127.1, 102.1, 84.5, 82.5, 71.9, 71.4, 70.82, 70.78,
70.6, 57.4, 50.8, 44.2, 21.9, 7.4, 4.3; HRMS (EI) for C25H38O6Si
(M+) calcd 462.2438, found 462.2441.
Gen er a l P r oced u r e 8. Op en in g of E p oxid es w it h
Ch olester ol. To cholesterol and the epoxide in anhydrous
CH2Cl2 at room temperature was added BF3‚Et2O. The sus-
pension was stirred for 72 h at room temperature, and the
solvent was evaporated. The resulting white paste was purified
by silica gel chromatography (elution 5% MeOH in CH2Cl2) to
give the corresponding cholesteryl derivative.
Ack n ow led gm en t. This research was supported by
Laboratoires Servier, the CNRS, and the Ministe`re de
l’Education Supe´rieure et de la Recherche. Y.L.H.
thanks Laboratoire Servier and Drs. Renard and Pfeiffer
for a graduate fellowship. We thanks Profs. Gesson and
Figade`re for fruitful discussions. In addition, we thank
Pierre Guenot for recording the mass spectra.
1-[(2S)-2,3-Ep oxyp r op oxy]-2-[(2R)-2-h yd r oxy-2-O-[(2R)-
2-m eth oxy-2-ph en ylacetate]-5-(tr ieth ylsilyl)pen t-4-yn oxy]-
ben zen e ((-)-18a ). According to general procedure 5, alcohol
(-)-16b (37 mg, 0.1 mmol), (R)-(-)-MPA (27 mg, 0.16 mmol),
DCC (45 mg, 0.22 mmol), and DMAP (8 mg, 0.05 mmol) were
employed: colorless oil (63%); FTIR (film) 2361, 2177, 1753,
1502, 1115, 736 cm-1; [R]20 -36.0 (c 7.5, CHCl3); 1H NMR
D
(CDCl3, 400 MHz) δ 7.46-7.44 (m, 2H), 7.34-7.27 (m, 3H),
6.96-6.84 (m, 3H), 6.77-6.72 (m, 1H), 5.37-5.30 (m, 1H), 4.81
(s, 1H), 4.14 (dd, 1H, J ) 11.2, 3.3 Hz), 4.10 (m, 2H), 3.92 (dd,
1H, J ) 11.2, 5.4 Hz), 3.43 (s, 3H) 3.31-3.27 (m, 1H), 2.85
(dd, 1H, J ) 5.0, 4.2 Hz), 2.82 (dd, 1H, J ) 17.1, 6.8 Hz), 2.73
(dd, 1H, J ) 17.1, 5.7 Hz), 2.72 (dd, 1H, J ) 5.0, 2.7 Hz), 0.96
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of all compounds described and characterization for
compounds 20a -k and 22a -k . This material is available free
of charge via the Internet at http://pubs.acs.org.
J O990772H