Conformationally constrained analogues of diacylglycerol (DAG). Part 19: Asymmetric syntheses of (3R)- and (3S)-3-hydroxy-4,4-disubstituted heptono-1,4-lactones as protein kinase C (PK-C) ligands with increased hydrophilicity

Article abstract of DOI:10.1016/S0040-4020(02)00477-5

The stereospecific introduction of (R)- and (S)-OH groups at position C-3 of two diacylglycerol γ-lactones (DAG-lactones) previously identified as strong protein kinase C (PK-C) ligands is presented. The compounds were designed to investigate whether the extra OH group in a specific orientation could establish an additional hydrogen bond with the C1 domain of PK-C, thus providing a DAG analogue with reduced lipophilicity. The OH groups were introduced following two different diastereoselective multistep syntheses starting from diacetone-D-glucose. The PK-C binding affinities for the new compounds were weaker in comparison to those of the parent compounds, suggesting that the extra OH does not engage efficiently in hydrogen bonding at the receptor.

Full text of DOI:10.1016/S0040-4020(02)00477-5

TETRAHEDRON
Pergamon
Tetrahedron 58 /2002) 5335±5345
Conformationally constrained analogues of diacylglycerol ꢀDAG).
Part 19: Asymmetric syntheses of ꢀ3R)- and ꢀ3S)-3-hydroxy-4,4-
disubstituted heptono-1,4-lactones as protein kinase C ꢀPK-C)
ligands with increased hydrophilicityq
Kassoum Nacro,a,² Jeewoo Lee,b Joseph J. Barchi, Jr.,a Nancy E. Lewin,c Peter M. Blumbergc
and Victor E. Marqueza,p
aLaboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA
bLaboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
cLaboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, Bethesda,
MD 20892, USA
Received 12 February 2002; revised 30 April 2002; accepted 2 May 2002
AbstractÐThe stereospeci®c introduction of /R)- and /S)-OH groups at position C-3 of two diacylglycerol g-lactones /DAG-lactones)
previously identi®ed as strong protein kinase C /PK-C) ligands is presented. The compounds were designed to investigate whether the extra
OH group in a speci®c orientation could establish an additional hydrogen bond with the C1 domain of PK-C, thus providing a DAG analogue
with reduced lipophilicity. The OH groups were introduced following two different diastereoselective multistep syntheses starting from
diacetone-d-glucose. The PK-C binding af®nities for the new compounds were weaker in comparison to those of the parent compounds,
suggesting that the extra OH does not engage ef®ciently in hydrogen bonding at the receptor. q 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction and background
and which binds stereospeci®cally to the C1 domain of
the enzyme.2,3 The third group of atypical isozymes /z and
i/l) does not respond to DAG or to phorbol esters.2,3
The 11 members of the protein kinase C /PK-C) family of
isozymes have attracted much attention in recent years
because of their individual involvement in cell growth,
apoptosis, cell differentiation and malignant transformation.
PK-C isozymes, which are functionally serine/threonine
kinases, can be divided into three groups based on structural
features and cofactor requirement. Both classical isoforms
/a, bI, bII and g) and novel isozymes /d, 1, h, and u) are
responsive to diacylglycerol /DAG) and to the potent
exogenous tumor promoter, the phorbol esters.2,3 Physio-
logically, these PK-C isozymes become activated and trans-
locate from the cytosol to the membrane in response to the
lipophilic second-messenger DAG, which is generated as a
product of receptor-coupled phosphoinositide metabolism
Although non-speci®c hydrophobic interactions between
the ligand /DAG/phorbol esters) and the phospholipids in
the membrane are critical for ef®cient membrane insertion
and activation, it is likely that distinct ligand±protein inter-
actions, particularly those occurring within the C1 domain,
can additionally control isozyme speci®city. The combi-
nation of these speci®c and non-speci®c hydrophobic inter-
actions appears to act in concert as a sub-cellular
localization signal. Recently, we have synthesized a potent
isozyme-selective DAG-lactone analogue /1)1 containing a
hydroxamate moiety that showed remarkable isozyme
selectivity between PK-Ca and d in various cellular assays.4
We surmised that because of the compound's reduced lipo-
philicity /log Pˆ3.58) relative to other DAG-lactones, such
as 2 /log Pˆ5.89),5 speci®c protein-ligand interactions
became dominant and allowed differences between
isozymes to be revealed. This important change in the
properties of compound 1 was probably due to the direct
involvement of the additional OH group in hydrogen
bonding at the receptor.1 Such an interaction is a very
important since a non-binding, free OH group would
otherwise become solvated with water molecules and resist
q See Ref. 1.
Keywords: protein kinase C; diacylglycerol; DAG-lactones; carbohydrate
chemistry; log P.
Corresponding author. Address: Laboratory of Medicinal Chemistry,
p
Center for Cancer Research, NCI-Frederick, 376 Boyles St., Bldg. 376
Rm 104, Frederick, MD 21702-1201, USA. Tel.: 11-301-846-5954; fax:
11-301-846-6033; e-mail: marquezv@dc37a.nci.nih.gov
Present address: Albany Molecular Research Inc., 21 Corporate Circle,
P.O. Box 15098, Albany, NY 12212-5098, USA.
²
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/02)00477-5

5336
K. Nacro et al. / Tetrahedron 58 12002) 5335±5345
Table 1. Apparent Ki and calculated log P values15 for the new ligands assayed as inhibitors of PDBU binding to PK-Ca
Compounds
3a
3b
4a
4b
5a
5b
Ki /nM)a
Log P
20.80^2.1
5.63
26.90^3.7
5.63
273^12
4.50
290^20
4.50
5580^130
4.50
NDb
4.50
a
Ki are mean^SEM, nˆ3 experiments.
b
ND, not determined, 27.2^1.0% inhibition at 100 mM.
binding in a lipophilic environment. To further explore this
concept, we set out to modify the structure of other known,
high af®nity DAG-lactone ligands /3a,b)6 by introducing an
extra OH group elsewhere in the molecule, viz. in the
lactone ring /4a,b and 5a,b). It was expected that these
more hydrophilic DAG-lactones /Table 1) might also
uncover additional isozyme-speci®c contacts similar to
those observed with 1. An additional structural considera-
tion for incorporating the extra OH group to compounds
3a,b came from examining the structure of the ingenol
esters, which represent another important group of PK-C
ligands.7 Indeed, the potent ingenol ester 3-O-tetradecanoyl-
ingenol /3-TI)8 has an OH group in the southern poly-
hydroxylated region of the molecule, which is in the same
relative position to the hydroxymethyl group as in 4a,b and
5a,b. Such an extra OH group is lacking in 3a,b and in the
phorbol ester 12-tetradecanoylphorbol-13-acetate /TPA).
Both stereochemical orientations /4a,b and 5a,b) for the
newly created center were explored utilizing two different
synthetic approaches starting from cheap and plentiful
acetone-d-glucose. The biological results indicate that the
extra OH in the S-con®guration /5a and b) produced a large
decrease in binding af®nity /ca. 200 fold) relative to the
parent compounds /3a and b). However, the OH in the
R-con®guration resulted in only a 10-fold loss in binding
af®nity. Taken together these results indicate that the extra
OH does not engage ef®ciently in binding at the receptor
and contributes negatively to the partitioning of the
compounds into the lipid milieu.
2. Results and discussion
2.1. Synthesis of ꢀ3R)-3-hydroxy-4,4-disubstituted
heptono-1,4-lactones
The approach to the synthesis of 4a,b relied on accessing the
key intermediates 16a,b where the requisite lactone's
stereogenic centers are embedded in a tricyclic ring system
/Scheme 1). Commercially available acetone-d-glucose was
used as the starting material. The ®rst three steps of the
synthesis leading to compound 7 have already been
described,10 and the success of the approach was based on
the regioselective opening of the epoxide ring of 7 with
sodium benzylate to give intermediate 8. The ensuing
protection of the newly created tertiary alcohol with p-meth-
oxybenzyl /PMB) chloride proceeded well to give
compound 9 in excellent yield. Mono-deprotection of bis-
ketal 9 to diol 10 was smoothly achieved under mild hydro-
lytic conditions, which selectively removed the more labile
5,6-O-isopropylidene group. Silyl-ether protection of the
newly generated primary alcohol gave compound 11,
which after PCC oxidation produced the expected ketone
12. Wittig reaction of ketone 12 with C14H29PPh3Br and
n-BuLi in THF gave the expected mixture of Z- and
E-ole®ns /13a,b) in low yield /34%). This is the only low-
yielding step of the synthesis, which is attributed to the
sterically congested ketone and the bulky phosphonium
salt. The protective silyl and p-methoxybenzyl groups
were sequentially removed to give ®rst 14a,b as a mixture
of isomers, and then 15a and b which were separated
chromatographically as individual Z- and E-isomers in 55
and 43% yields, respectively. At this stage of the synthesis,
complete characterization of both geometric isomers was
not possible, but it could be later established unequivocally
by association with the correct geometric isomer identi®ed
after lactonization /vide infra). The remaining steps of the
synthesis were performed separately for each individual
isomer. The primary hydroxyl group in 15a and b was
®rst oxidized into an aldehyde and allowed to react intra-
molecularly with the tertiary alcohol to give the expected
lactol intermediate, which was oxidized in situ to afford 16a
or b in excellent yield. As in previous cases with this class of
lactones, the geometry of the exocyclic double bond was
1
assigned by H NMR.9 For these cisoid enone systems, the
b-cis vinyl proton /E-isomer 16b, dˆ6.85) normally reso-
nates in a 0.3±0.9 ppm range down®eld from the corre-
sponding b-trans proton /Z-isomer 16a, dˆ6.47).9 Such a
difference was consistently maintained throughout the rest
of the synthesis. The remaining 2,3-O-isopropylidene group
was hydrolyzed under acidic conditions with 2N HCl in
THF to give diols 17a and b, respectively, which upon
oxidative cleavage with sodium metaperiodate afforded
compounds 18a and b. Wittig coupling of 18a and b with
triphenylphosphoranylidene acetate provided exclusively

K. Nacro et al. / Tetrahedron 58 12002) 5335±5345
5337
Scheme 1. /a) PhCH2OH, NaH, THF, 98%; /b) p-MeOPhCH2Cl /PMBCl), NaH, Bu4NI, THF, 96%; /c) 2N HCl, EtOH, 95%; /d) t-BuSiMe2Cl /TBDMSCl),
Ê
imidazole, CH2Cl2±DMF, 99%; /e) PCC, 4 A molecular sieves, CH2Cl2, 80%; /f) C14H29PPh3Br, n-BuLi, THF, 34%; /g) n-Bu4NF, THF; /h) DDQ, CH2Cl2±
H2O, 98% two steps; /i) MnO2, CH2Cl2, 94%; /j) 2N HCl, THF, 758C; /k) NaIO4, MeOH±H2O; /l) PPh3vCHCO2CH3, CH2Cl2, 56±60%, three steps; /m)
BCl3, CH2Cl2, 2788C, 46±87%.
compounds 19a /Z,E-isomer) and 19b /E,E-isomer) in 60%
overall yield for the last three steps. Finally, removal of the
benzyl group afforded the desired targets 4a and b. During
the ®nal deblocking step of 19a with BCl3 some of the
desired Z,E-isomer 4a isomerized to the more stable E,E-
isomer 4b, even when the reaction was quenched with
NaHCO3 and a neutral buffer was used during work up.
The results were the same when MeOH was employed to
quench the reaction.
and 25 /62%). One-dimensional NOE spectroscopy was
used to assign the position of the TBDPS protecting group
in 24 and 25. Spectra in CDCl3 were well dispersed for 24,
but the methyl groups in 25 overlapped in this solvent,
prompting us to reexamine the spectrum of 25 in benzene-
d6. Several shifts in resonance position were observed in this
solvent, including a large separation of the methyl singlets
that permitted selective irradiation of each signal for assign-
ment purposes. The relatively rigid nature of the bicyclic
ring system in compounds 24 and 25 aided in the assign-
ments. Highly diagnostic was the enhancement of only one
of the methyl signals of the isopropylidene group after
irradiation of either H-1 or H-2 /carbohydrate numbering).
For this reason, this methyl signal was assigned to the
methyl group oriented toward the exo face of the bicyclic
system /Fig. 1). Observed NOEs to the remaining methyl
group included those from the CH2 group at C-4 oriented
toward the endo side of the ring system. Since the assign-
ment of the methylene bearing the free OH group was also
obvious from the observed coupling to the hydroxyl proton
/and sharpening of these signals after D2O exchange), it
remained a simple matter to distinguish which CH2O
functional group was on the `bottom' /endo) half of the
molecule. All other NOEs /Fig. 1) were in agreement with
the assigned structures. The observed NOEs were also
corroborated by limited molecular modeling using the
INSIGHT/DISCOVER package /Accelerys, Inc., San
Diego, CA). Energy minimization of compound 24 revealed
2.2. Synthesis of ꢀ3S)-3-hydroxy-4,4-disubstituted
heptono-1,4-lactones
Diacetone-d-glucose /6) was readily converted to 1,2:5,6-
di-O-isopropylidene-3-O-benzyl-a-d-allofuranose /20) and
1,2-O-ispropylidene-3-O-benzyl-a-d-allofuranose
/21)
according to published methods /Scheme 2).11,12 Oxidation
of 21 with sodium metaperiodate gave the corresponding
aldehyde 22, which was condensed as a crude product
with formaldehyde and aqueous NaOH to give crystalline
23 identical to the material described by Moffatt et al.13 The
Cannizzaro reaction was modi®ed slightly to give almost
quantitative yields of 23, by allowing the reaction to take
place in the presence of an excess of formaldehyde
/2±4 equiv.) and adding the 1 M NaOH solution last. One
of the primary hydroxyl groups in 23 was singly protected
with t-butyldiphenylsilyl /TBDPS) chloride to give a
combined quantitative yield of diastereoisomers 24 /38%)

5338
K. Nacro et al. / Tetrahedron 58 12002) 5335±5345
Scheme 2. /a) 2N HCl/EtOH; /b) NaIO4, MeOH/H2O, 72% /two steps); /c) H2CO, 1N NaOH, Dioxane, 94%; /d) t-BuSiPh2Cl /TBDPSCl), n-BuLi, THF,
100%; /e) PhCH2Br /BnBr), NaH, THF, 76%; /f) n-Bu4NF, THF, 94%; /g) DMSO, DCC, CHCl2CO2H; /h) Ph3PCHCO2Me, CH2Cl2 85% /two steps); /i) 0.2N
HCl, MeOH, 75%; /j) /ClCO)2, DMSO, Et3N, CH2Cl2; /k) BrPh3PC14H29, n-BuLi, THF 31% /two steps); /l) 0.1N HCl, THF/H2O, 87%; /m) MnO2, CH2Cl2,
64%; /n) BCl3, CH2Cl2, 2788C, 96%.
Figure 1. Diagnostic NOEs in compounds 24 and 25.

K. Nacro et al. / Tetrahedron 58 12002) 5335±5345
5339
that the protons of the endo-oriented methyl group and those
on the methylene unit of the endo-oriented CH2 at C-4 may
from the abundant chiral template, diacetone-d-glucose.
Relative to the parent DAG-lactones /3a and b), the new
compounds bind to PK-C with poorer binding af®nities.
Although the extra OH group reduced lipophilicity /log P)
by ca. 10-fold, it also lowered the binding af®nity for PK-Ca
suggesting that the additional polar group does not contri-
bute to the overall binding. Rather, the extra OH group
hinders the effectual partitioning of the molecules into the
lipid environment of the enzyme. These results strongly
support the concept that the addition of extra polar groups
to an otherwise strong ligand leads to a severe penalty of
desolvationÐespecially in a hydrophobic pocketÐif the
group does not engage in effective interactions with the
receptor.
Ê
be as little as 3.2±3.5 A apart. The remaining free hydroxyl
group in 24 was then protected as a benzyl ether to give 26,
and the TBDPS protective group was removed to give 27.
This was the preferred strategy, rather than using compound
25 directly, based on the robustness of the benzyl group
relative to the TBDPS group. The primary alcohol in 27
was oxidized under mild conditions to aldehyde 28, which
was immediately reacted with triphenylphosphoranylidene
acetate to give ole®n 29 /85% two steps). The ensuing acid-
catalyzed methanolysis of 29 proceeded smoothly to give
30a,b /75%) as a mixture of a,b-anomers. Although it was
possible to pursue the synthesis with the mixture, it proved
more convenient to separate the anomers at this stage and
to carry out the oxidation separately. The pure b-anomer
/singlet at d 5.03) was oxidized to give ketone 31, which
upon treatment with tetradecyltriphenylphosphonium bro-
mide and n-BuLi gave a mixture of geometric isomers
32a,b /31% two steps). Hydrolysis of the methyl glycoside
gave a mixture of four compounds /33a,b), which after
Swern oxidation gave the expected mixture of geometric
isomers /34a and b), which were then separated by column
chromatography. Finally, removal of the benzyl protective
group with BCl3 gave the desired target compounds 5a and
b. During this last step, a similar isomerization to the one
reported during the deprotection of 19a into mixtures of 4a
and b led to the isomerization of the less stable E,Z-isomer
5a into the more stable EE-isomer 5b regardless of the
method used for quenching the reaction. These compounds
are separable by column chromatography, and, as before,
the b-cis vinyl proton of the E,E-isomer 5b /dˆ7.08) reso-
nates ca. 0.5 ppm down®eld from the corresponding b-trans
proton in the E,Z-isomer 5a /dˆ6.60).9
4. Experimental
4.1. General procedures
All chemical reagents were commercially available.
Melting points were determined on a MelTemp II apparatus,
Laboratory Devices, USA, and are uncorrected. Silica gel
chromatography was performed on silica gel 60, 230±
400 mesh /E. Merck). 1H and 13C NMR spectra were
recorded on a Bruker AC-250 instrument at 250 and
62.9 MHz, respectively. Spectra are referenced to the
1
solvent in which they were run /7.24 ppm for H CDCl3).
One-dimensional NOE spectra were collected on a Varian
spectrometer with a three channel INOVA console at
500 MHz using an inverse detection H-X probe /Nalorac
corp., Martinez, CA.) with an actively shielded Z-axis
gradient. NOE's were obtained using the excitation
sculpting of selective pulses /Double Pulsed Field Gradient
Spin Echo NOE, DPFGSE-NOE) method of Scott et al.,16
employing a homospoil gradient pulse for randomization of
magnetization prior to the relaxation delay /Varian pulse
sequence NOESY1D from the CHEMPACK suite of
programs, provided by Krish Krishnamurthy, Eli Lilly and
Company, Indianapolis, IN). The probehead temperature
was maintained at 258C and no attempt was made to
deoxygenate the samples. Sech180 shaped pulses were
used for selective excitation of speci®c resonances. For
1D experiments, 128 increments were collected and the
FIDs were Fourier transformed using no apodization or
special processing functions. Distances were not quanti®ed
since qualitative measurements were suf®cient for assign-
ment purposes. Infrared spectra were recorded on a Perkin±
Elmer 1600 series FT-IR. Optical rotations were recorded
on a Perkin±Elmer model 241 polarimeter at room tempera-
ture with a path lengthˆ1 dm. Positive ion fast-atom
bombardment mass spectra /FAB-MS) were obtained on a
VG 7070E mass spectrometer at an accelerating voltage of
6 kV and a resolution of 2000. Glycerol was used as the
sample matrix and ionization was effected by a beam of
xenon atoms. Elemental analyses were performed by
Atlantic Microlab, Inc., Atlanta, GA.
2.3. Biological results
The binding af®nities of 4a,b and 5a,b relative to 3a,b were
measured in terms of the ability of the ligands to displace
bound [20-3H]phorbol 12,13-dibutyrate /PDBU) from a
recombinant PK-C a-isozyme as previously described
/Table 1).14 The inhibition curves obtained for these ligands
were of the type expected for competitive inhibition, and the
ID50 values were determined by ®t of the data points to the
theoretical non-cooperative competition curve. The Ki's for
inhibition of binding were calculated from the ID50 values.
A comparison between compounds 4a,b and the parent
DAG-lactones 3a,b revealed a 10-fold reduction in binding
af®nity which is indicative of the lack of involvement of the
extra OH group in effectively hydrogen bonding with the
receptor. A comparison between 5a and 3a revealed an even
greater drop in af®nity, ca. 268-fold. This means that the
`down', 3-/S)-OH in 5a is in a worse disposition to engage
in effective H-bonding with the receptor than the `up',
3-/R)-OH in either 4a or 4b, which experienced only
10-fold reductions in binding af®nity relative to the parent
DAG-lactones /3a and b).
4.1.1. Methyl ꢀ2Z)-3-[ꢀ2S)-2-ꢀhydroxymethyl)-5-oxo-4-
tetradecylideneꢀ2-2,3-dihydrofuryl)]prop-2-enoate ꢀ3a)
and methyl ꢀ2E)-3-[ꢀ2S)-2-ꢀhydroxymethyl)-5-oxo-4-
tetradecylideneꢀ2-2,3-dihydrofuryl)]prop-2-enoate ꢀ3b).
These compounds were prepared essentially as described
3. Conclusion
We have described the enantiospeci®c synthesis of four
highly functionalized DAG-lactones /4a,b, 5a, and b)

5340
K. Nacro et al. / Tetrahedron 58 12002) 5335±5345
in Ref. 9 except that myristyl aldehyde was used instead of
oleyl aldehyde. Anal. calcd for C23H38O5: C, 70.01; H, 9.71.
Found /3a): C, 70.13; H, 9.80. Found /3b): C, 70.11; H,
9.76.
4.1.5. 1-{ꢀ1R,2R,3R,5S)-4-[ꢀ4-Methoxyphenyl)methoxy]-
7,7-dimethyl-2,6,8-trioxa-4-[ꢀphenylmethoxy)methyl]bi-
cyclo[3.3.0]-3-yl}ꢀ1R)-ethane-1,2-diol ꢀ10). A solution of 9
/2.0 g, 4 mmol) in ethanol /90 ml) was treated with 2N HCl
solution /10 ml) and stirred for 16 h at room temperature.
The reaction mixture was neutralized with solid NaHCO3
and concentrated under vacuum. The residue was dissolved
in EtOAc, dried /MgSO4), ®ltered, and concentrated under
vacuum. The residue was puri®ed by silica gel ¯ash column
chromatography with hexanes/ethyl acetate mixtures of
1/1±1/2 as eluants to give 10 /1.74 g, 95%) as an oil:
4.1.2. 1,2:5,6-Di-O-isopropylidene-3-C-hydroxymethyl-
3,30-anhydro-a-d glucofuranose or 7-[ꢀ4R)-2,2-di-
methylꢀ1,3-dioxolan-4-yl)]-ꢀ1R,5S,7R,8R)-3,3-dimethyl-
2,4,6-trioxaspiro[bicyclo[3.3.0]octane-8,20-oxirane ꢀ7).
This compound was prepared from diacetone-d-glucose
/6) following the procedure described by Funabashi et al.10
22
[a]D ˆ117.528 /c 1.33, CHCl3); IR /neat) 3418
1
4.1.3. 3-[ꢀ4R)-2,2-Dimethylꢀ1,3-dioxolan-4-yl)]-ꢀ1R,2R,
3R,5S)-7,7-dimethyl-4,6,8-trioxa-2-[ꢀphenylmethoxy)-
methyl]bicyclo[3.3.0]octan-2-ol ꢀ8). A solution of benzyl
alcohol /7.94 g, 73.46 mmol) in THF /147 ml) was treated
with sodium hydride /60%, 2.94 g, 73.46 mmol) and stirred
for 30 min at room temperature. To this mixture, a solution
of 7 /10.00 g, 36.73 mmol) in THF /147 ml) was added
dropwise and then re¯uxed for 36 h. The reaction was
cooled to room temperature and quenched with acetic acid
/4.21 ml). The mixture was ®ltered and concentrated under
vacuum, and the remaining benzyl alcohol was removed by
distillation in a Kugelrohr apparatus under high vacuum.
The residue was puri®ed by silica gel ¯ash column chroma-
tography with hexanes/ethyl acetate mixtures of 3/1 and 2/1
as eluants to give pure 8 /13.72 g, 36.07 mmol, 98%) as a
/OH) cm21; H NMR /CDCl3) d 7.25±7.40 /m, 5H), 7.19
/d, 2H), 6.83 /d, 2H), 5.81 /d, 1H, Jˆ3.7 Hz), 4.42±4.72 /m,
5H), 3.98±4.15 /m, 3H), 3.65±3.85 /m, 6H), 1.49 /s, 3H),
1.28 /s, 3H); 13C NMR /CDCl3) d 158.81, 136.25, 130.03,
128.34, 128.22, 127.90, 113.53, 112.29, 104.15, 84.91,
84.43, 81.95, 73.66, 73.31, 67.38, 64.86, 64.01, 54.97,
26.77, 26.23. Anal. calcd for C25H32O8: C, 65.20; H, 7.01.
Found: C, 65.08; H, 7.03.
4.1.6. 1-{ꢀ1R,2R,3R,5S)-4-[ꢀ4-Methoxyphenyl)methoxy]-
7,7-dimethyl-2,6,8-trioxa-4-[ꢀphenylmethoxy)methyl]bi-
cyclo[3.3.0]-3-yl}-ꢀ1R)-2-ꢀ1,1,2,2-tetramethyl-1-silapro-
poxy)ethan-1-ol ꢀ11). Procedure 1. A solution of 10
/5.53 g, 12 mmol) in CH2Cl2 /160 ml) was treated with
triethylamine /10.04 ml, 72 mmol) and 4-dimethylamino-
pyridine /0.146 g, 1.2 mmol) followed by tert-butyl-
dimethylsilyl chloride /2.71 g, 18 mmol). The solution
was stirred at room temperature for 48 h, concentrated
under vacuum, and the residue was puri®ed by silica gel
¯ash column chromatography with a mixture of hexanes/
ethyl acetate /3/1) as eluant to give 11 /6.07 g, 88%) as an
22
white solid: mp 85±868C; [a]D1 ˆ122.308 /c 2.0, CHCl3);
IR /CHCl3) 3386 /OH) cm21; H NMR /CDCl3) d 7.20±
7.40 /m, 5H), 5.85 /d, 1H, Jˆ3.5 Hz), 4.63 /AB d, 1H,
Jˆ12.0 Hz), 4.58 /AB d, 1H, Jˆ12.0 Hz), 4.40 /d, 1H,
Jˆ3.5 Hz), 4.33 /m, 1H), 4.07 /dd, 1H, Jˆ8.7, 6.2 Hz),
3.99 /dd, 1H, Jˆ8.7, 5.3 Hz), 3.77 /m, 3H), 2.83 /br s,
1H), 1.48 /s, 3H), 1.35 /s, 3H), 1.32 /s, 6H); 13C NMR
/CDCl3) d 137.72, 128.28, 127.70, 127.61, 112.39,
109.04, 104.72, 85.40, 81.22, 80.66, 73.47, 72.52, 68.93,
67.26, 27.16, 26.66, 26.51, 25.18. Anal. calcd for
C20H28O7: C, 63.14; H, 7.42. Found: C, 63.32; H, 7.45.
22
oil: [a]D ˆ117.068 /c 1.87, CHCl3); IR /neat) 3448
1
/OH) cm21; H NMR /CDCl3) d 7.20±7.40 /m, 5H), 7.19
/d, 2H), 6.83 /d, 2H), 5.79 /d, 1H, Jˆ3.6 Hz), 4.50±4.76 /m,
5H), 3.62±4.02 /m, 9H), 1.47 /s, 3H), 1.30 /s, 3H), 0.87 /s,
9H), 0.51 /s, 6H); 13C NMR /CDCl3) d 158.89, 137.54,
130.96, 128.41, 128.32, 127.75, 113.65, 112.16, 104.43,
86.04, 82.54, 82.49, 73.62, 68.61, 68.12, 65.84, 64.76,
55.21, 27.02, 26.58, 25.94, 18.38, 25.33, 25.37. Anal.
calcd for C31H46O8Si: C, 64.78; H, 8.07. Found: C, 64.68;
H, 8.06.
4.1.4. {3-[ꢀ4R)-2,2-Dimethylꢀ1,3-dioxolan-4-yl)]-ꢀ1R,2R,
3R,5S)-2-[ꢀ4-methoxyphenyl)methoxy]-7,7-dimethyl-4,6,
8-trioxabicyclo[3.3.0]oct-2-yl}ꢀphenylmethoxy)methane
ꢀ9). A solution of 8 /5.84 g, 15.35 mmol) in THF /150 ml)
was treated with sodium hydride /60%, 2.46 g, 61.4 mmol)
and stirred for 20 min at room temperature. 4-Methoxy-
benzyl chloride /4.16 ml, 30.7 mmol) and tetrabutylammo-
nium iodide /2.83 g, 7.68 mmol) were added to this mixture,
which was then re¯uxed for 3 h. After cooling to room
temperature, the reaction mixture was ®ltered through a
short pad of silica gel and further eluted with ether. The
combined ®ltrate was concentrated under vacuum and the
residue was puri®ed by silica gel ¯ash column with hexanes/
ethyl acetate mixtures of 5/1±3/1 as eluants to give 9
Procedure 2. A solution of 10 /11.31 g, 25.56 mmol) in
CH2Cl2 /76.8 ml) was treated with imidazole /3.85 g,
56.49 mmol) and stirred for 1 h at room temperature.
Then, CH2Cl2 /38.4 ml), DMF /38.4 ml) and tert-butyl-
dimethylsilyl chloride /4.29 g, 28.49 mmol) were added
successively, and the resulting solution was stirred at
room temperature for 19 h. Following the addition of diethyl
ether /300 ml), the solution was extracted with water
/3£30 ml), dried over MgSO4, ®ltered and concentrated
under vacuum. The residue was puri®ed by silica gel ¯ash
chromatography with hexanes/ethyl acetate mixtures of
9/1±4/1 as eluants to afford 11 /13.99 g, 99%) as an oil
identical to the material obtained under procedure 1.
22
/7.38 g, 96%) as an oil: [a]D ˆ114.608 /c 2.02, CHCl3);
1H NMR /CDCl3) d 7.20±7.40 /m, 5H), 7.19 /d, 2H), 6.83
/d, 2H), 5.82 /d, 1H, Jˆ3.5 Hz), 4.50±4.77 /m, 5H), 4.40
/q, 1H), 3.80±4.06 /m, 5H), 3.78 /s, 3H), 1.49 /s, 3H),
1.37 /s, 3H), 1.31 /s, 6H); 13C NMR /CDCl3) d 158.87,
138.09, 131.02, 128.40, 128.23, 127.55, 113.63, 112.24,
108.51, 104.92, 86.21, 83.39, 82.42, 73.54, 73.31, 68.83,
66.88, 66.17, 55.19, 27.18, 26.59, 26.53, 25.34. Anal.
calcd for C28H36O8: C, 67.18; H, 7.25. Found: C, 67.22;
H, 7.25.
4.1.7. 1-{ꢀ1R,2R,3R,5S)-4-[ꢀ4-Methoxyphenyl)methoxy]-
7,7-dimethyl-2,6,8-trioxa-4-[ꢀphenylmethoxy)methyl]bi-
cyclo[3.3.0]-3-yl}-ꢀ1R)-2-ꢀ1,1,2,2-tetramethyl-1-silapro-
poxy)ethan-1-one ꢀ12). A solution of 11 /5.00 g,
8.70 mmol) in CH2Cl2 /87 ml) was cooled to 08C and treated

K. Nacro et al. / Tetrahedron 58 12002) 5335±5345
5341
Ê
with 4 A molecular sieves /10 g) and pyridinium chloro-
as a crude oil /1.62 g), which was used directly in the next
step.
chromate /5.63 g, 26.10 mmol). After stirring for 40 min
at room temperature, the reaction mixture was diluted
with ether /300 ml) and treated with a mixture of celite
and silica. After stirring for a short time, the suspension
was ®ltered through a short pad of silica gel and further
eluted with ether. The combined ®ltrate was concentrated
under vacuum and the residue was puri®ed by silica gel ¯ash
column chromatography with hexanes/ethyl acetate /9/1) as
eluant to give 12 /4.00 g, 80%) as a white solid: mp 55.4±
The above mixture of products /1.62 g, ,2.39 mmol) was
dissolved in CH2Cl2/H2O /120 ml/6.5 ml) and treated
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone /0.814 g,
3.59 mmol). After stirring overnight at room temperature,
the reaction mixture was dried /MgSO4), ®ltered through a
short pad of silica gel using hexanes/ethyl acetate /1/2) as
eluant, and the ®ltrate was concentrated under vacuum. The
residue was puri®ed by silica gel ¯ash column chroma-
tography with hexanes/ethyl acetate mixtures of 3/1±2/1
as eluants to give 15a /E-isomer, 0.533 g, 43%) and 15b
/Z-isomer, 0.684 g, 55%) as oils.
22
56.78C; [a]D ˆ122.698 /c 1.08, CHCl3); IR /neat) 1735
/CvO) cm21; 1H NMR /CDCl3) d 7.20±7.40 /m, 5H), 7.12
/d, 2H), 6.81 /d, 2H), 5.93 /d, 1H, Jˆ3.2 Hz), 4.77 /d, 1H,
Jˆ3.2 Hz), 4.50±4.75 /m, 6H), 4.35 /s, 1H), 4.02 /AB d,
1H, Jˆ10.9 Hz), 3.93 /AB d, 1H, Jˆ10.9 Hz), 3.78 /s, 3H),
1.46 /s, 3H), 1.34 /s, 3H), 0.84 /s, 9H), 20.04 /d, 6H); 13C
NMR /CDCl3) d 206.47, 158.95, 137.83, 130.58, 128.63,
128.20, 127.52, 113.61, 112.81, 105.59, 88.62, 86.09, 81.18,
73.54, 68.97, 68.87, 67.19, 55.10, 27.15, 26.49, 25.73,
18.35, 25.50, 25.54. Anal. calcd for C31H44O8Si: C,
65.00; H, 7.74. Found: C, 65.09; H, 7.75.
22
Compound 15a. [a]D ˆ14.428 /c 0.86, CHCl3); IR /neat)
1
3355 /OH) cm21; H NMR /CDCl3) d 7.20±7.40 /m, 5H),
5.94 /d, 1H, Jˆ3.6 Hz), 5.58 /t, 1H, Jˆ7.4 Hz), 4.57 /s, 2H),
4.41 /d, 1H, Jˆ3.6 Hz), 4.34 /s, 1H), 4.13 /s, 2H), 3.79 /AB
d, 1H, Jˆ9.5 Hz), 3.42 /AB d, 1H, Jˆ9.5 Hz), 3.11 /br s,
2H), 2.00±2.25 /m, 2H), 1.49 /s, 3H), 1.32 /s, 3H), 1.15±
1.40 /m, 22H), 0.86 /irregular t, 3H); 13C NMR /CDCl3) d
137.57, 137.46, 133.02, 128.38, 127.83, 127.63, 112.23,
104.25, 85.21, 84.79, 81.49, 73.76, 69.67, 56.10, 31.87,
29.63, 29.56, 29.44, 29.30, 29.25, 27.58, 27.03, 26.42,
22.64, 14.07. Anal. calcd for C31H50O6: C, 71.78; H, 9.72.
Found: C, 71.89; H, 9.68.
4.1.8.
3-{ꢀ1E)-1-[ꢀ1,1,2,2-Tetramethyl-1-silapropoxy)-
methyl]pentadec-1-enyl}-ꢀ1R,2R,3R,5S)-2-[ꢀ4-methoxy-
phenyl)methoxy]-7,7-dimethyl-4,6,8-trioxabicyclo[3.3.0]-
oct-2-yl)ꢀphenylmethoxy)methane and 3-{ꢀ1Z)-1-[ꢀ1,1,
2,2-tetramethyl-1-silapropoxy)methyl]pentadec-1-enyl}-
ꢀ1R,2R,3R,5S)-2-[ꢀ4-methoxyphenyl)methoxy]-7,7-di-
methyl-4,6,8-trioxabicyclo[3.3.0]oct-2-yl)ꢀphenylmeth-
oxy)methane ꢀ13a and 13b). A solution of tetra-
decylphosphonium bromide /7.54 g, 13.97 mmol) in THF
/87.3 ml) was cooled to 2258C and treated with n-butyl-
lithium /1.6 M in hexanes, 8.1 ml, 12.9 mmol). After
stirring for 1.5 h, the temperature reached 2108C. The
reaction mixture was then cooled to 2308C before proceed-
ing to add dropwise a solution of 12 /2.00 g, 3.71 mmol) in
toluene /40 ml). While stirring for 2.5 h, the reaction
mixture temperature was allowed to warm up to 08C, and
15 h later to reach room temperature. The reaction mixture
was diluted with toluene /200 ml) and treated with a satu-
rated solution of aqueous ammonium chloride /35 ml) and
brine /5 ml). The aqueous layer was extracted with diethyl
ether and the combined organic phases were washed succes-
sively with a saturated solution of aqueous sodium bicarbo-
nate /60 ml), brine /2£60 ml), dried over MgSO4, ®ltered
and concentrated. The residue was puri®ed by silica gel
¯ash column chromatography with hexanes/ethyl acetate
/9/1) as eluant to give a mixture of 13a and b /0.94 g,
34%) as an oil.
22
Compound 15b. [a]D ˆ227.58 /c 0.16, CHCl3); IR /neat)
1
3336 /OH) cm21; H NMR /CDCl3) d 7.20±7.40 /m, 5H),
5.95 /d, 1H, Jˆ3.6 Hz), 5.75 /br t, 1H), 4.89 /s, 1H), 4.59
/AB d, 1H, Jˆ12.2 Hz), 4.54 /AB d, 1H, Jˆ12.2 Hz), 4.43
/d, 1H, Jˆ3.6 Hz), 4.25 /AB d, 1H, Jˆ11.4 Hz), 3.95 /AB d,
1H, Jˆ11.4 Hz), 3.79 /AB d, 1H, Jˆ9.3 Hz), 3.40 /AB d,
1H, Jˆ9.3 Hz), 2.86 /br s, 2H), 1.80±2.10 /m, 2H), 1.52
/s, 3H), 1.34 /s, 3H), 1.15±1.40 /m, 22H), 0.86
/irregular t, 3H); 13C NMR /CDCl3) d 137.66, 137.55,
132.81, 128.36, 127.76, 127.60, 112.25, 104.33, 84.80,
82.25, 77.72, 73.81, 69.88, 64.29, 31.87, 29.61, 29.52,
29.42, 29.30, 29.26, 27.91, 27.10, 26.44, 22.64, 14.07.
Anal. calcd for C31H50O6: C, 71.78; H, 9.72. Found: C,
71.66; H, 9.78.
4.1.10. ꢀ1R,2R,6R,8S)-10,10-Dimethyl-3,7,9,11-tetraoxa-
2-[ꢀphenylmethoxy)methyl]-5ꢀZ)-tetradecylidenetricyclo-
[6.3.0.0k2,6l]undecan-4-one ꢀ16a). A solution of 15a
/0.16 g, 0.308 mmol) in CH2Cl2 /20 ml) was treated with
activated MnO2 /1.6 g, 18.5 mmol) and stirred at room
temperature for 36 h. The reaction mixture was ®ltered
and concentrated under vacuum. The residue was puri®ed
by silica gel ¯ash column chromatography with hexanes/
ethyl acetate /4/1) as eluant to give the Z-isomer 16a
4.1.9.
ꢀ1R,2R,3R,5S)-3-[ꢀ1E)-2-Hydroxy-1-tetradecyl-
ideneethyl]-7,7-dimethyl-4,6,8-trioxa-2-[ꢀphenylmethoxy)-
methyl]bicyclo[3.3.0]octan-2-ol ꢀ15a) and ꢀ1R,2R,3R,5S)-
3-[ꢀ1Z)-2-Hydroxy-1-tetradecylideneethyl]-7,7-dimethyl-
4,6,8-trioxa-2-[ꢀphenylmethoxy)methyl]bicyclo[3.3.0]-
octan-2-ol ꢀ15b). A solution of 13a,b /1.8 g, 2.39 mmol) in
THF /100 ml) was treated with tetra-n-butylammonium
¯uoride /1.0 M in THF, 4.78 ml, 4.78 mmol). After
stirring for 5 h at room temperature, the reaction
mixture was concentrated under vacuum. The residue was
dissolved in diethyl ether, ®ltered through a short pad of
silica gel and further eluted with ether. The ®ltrate was
concentrated under vacuum to afford a mixture of 14a,b
22
/0.15 g, 94%) as an oil: [a]D ˆ18.708 /c 0.23, CHCl3);
IR /neat) 1770 /CvO), 1679 /CvC) cm21 1H NMR
;
/CDCl3) d 7.20±7.40 /m, 5H), 6.47 /t, 1H, Jˆ7.7 Hz),
5.96 /d, 1H, Jˆ3.7 Hz), 4.89 /s, 1H), 4.67 /d, 1H, Jˆ
3.7 Hz), 4.55 /AB d, 1H, Jˆ12.0 Hz), 4.49 /AB d, 1H,
Jˆ12.0 Hz), 3.87 /AB d, 1H, Jˆ11.0 Hz), 3.82 /AB d,
1H, Jˆ11.0 Hz), 2.55±2.80 /m, 2H), 1.48 /s, 3H), 1.32 /s,
3H), 1.15±1.45 /m, 22H), 0.86 /irregular t, 3H); 13C NMR
/CDCl3) d 167.59, 149.33, 137.45, 128.30, 127.69, 127.32,
127.03, 113.61, 106.50, 90.32, 83.49, 83.30, 73.76, 69.20,
31.88, 29.62, 29.49, 29.36, 29.32, 29.19, 28.58, 27.89,

5342
K. Nacro et al. / Tetrahedron 58 12002) 5335±5345
27.28, 26.83, 22.65, 14.09. Anal. calcd for C31H46O6: C,
72.34; H, 9.01. Found: C, 72.46; H, 8.99.
cooling, the reaction mixture was neutralized with solid
NaHCO3 /1.68 g) and concentrated under vacuum. The
residue was dissolved in ethyl acetate, dried /MgSO4), and
concentrated under vacuum. The residue was puri®ed by
silica gel ¯ash column chromatography with hexanes/ethyl
acetate mixtures of 1/1±2/1 as eluants to give diol 17b as an
oil.
4.1.11. ꢀ1R,2R,6R,8S)-10,10-Dimethyl-3,7,9,11-tetraoxa-
2-[ꢀphenylmethoxy)methyl]-5ꢀE)-tetradecylidenetricyclo-
[6.3.0.0k2,6l]undecan-4-one ꢀ16b). A solution of 15b
/0.14 g, 0.27 mmol) in CH2Cl2 /20 ml) was treated with
manganese dioxide /0.94 g, 10.8 mmol) and reacted in the
same manner as for 16a to give 16b /0.13 g, 94%) as an oil:
The above diol was dissolved in a mixture of MeOH /16 ml)
and H2O /8 ml) and cooled to 08C. The solution was treated
with sodium metaperiodate /0.2 g, 0.93 mmol) and stirred
for 4 h at room temperature. The reaction mixture was
concentrated, diluted with ethyl acetate, ®ltered, and concen-
trated. The residue was puri®ed by silica gel ¯ash column
chromatography with hexanes/ethyl acetate mixtures of 1/1±
3/2 as eluants to give aldehyde 18b as an oil.
22
[a]D ˆ128.828 /c 0.17, CHCl3); IR /neat) 1775 /CvO),
1686 /CvC) cm21; 1H NMR /CDCl3) d 7.20±7.40 /m, 5H),
6.85 /ddd, 1H, Jˆ7.96, 7.96, 1.0 Hz), 5.96 /d, 1H, Jˆ
3.7 Hz), 5.20 /d, 1H, Jˆ0.9 Hz), 4.68 /d, 1H, Jˆ3.7 Hz),
4.55 /AB d, 1H, Jˆ12.2 Hz), 4.47 /AB d, 1H, Jˆ12.2 Hz),
3.86 /AB d, 1H, Jˆ10.9 Hz), 3.81 /AB d, 1H, Jˆ10.9 Hz),
2.20±2.40 /m, 2H), 1.49 /s, 3H), 1.33 /s, 3H), 1.15±1.45 /m,
22H), 0.86 /irregular t, 3H); 13C NMR /CDCl3) d 168.73,
146.13, 137.38, 128.34, 127.69, 127.64, 127.27, 113.60,
106.67, 90.82, 83.49, 79.36, 73.60, 69.23, 31.84, 29.99,
29.56, 29.40, 29.28, 29.15, 28.26, 27.25, 26.70, 22.61,
14.04. Anal. calcd for C31H46O6: C, 72.34; H, 9.01.
Found: C, 72.09; H, 8.96.
The above aldehyde was dissolved in CH2Cl2 /20 ml) and
the solution was treated with methyl /triphenylphospho-
ranylidene)acetate /0.31 g, 0.93 mmol). After stirring at
room temperature for 24 h, the reaction mixture was
concentrated and the residue was puri®ed by silica gel
¯ash column chromatography with hexanes/ethyl acetate
/3/1) as eluant to give 19b as an oil /0.070 g, 60% from
4.1.12.
Methyl
ꢀ2E)-3-{ꢀ2S,3R)-3-hydroxy-5-oxo-2-
1
[ꢀphenylmethoxy)methyl]-4ꢀZ)-tetradecylideneꢀ2-2,3-di-
hydrofuryl)}prop-2-enoate ꢀ19a). A solution of Z-isomer
16a /0.12 g, 0.23 mmol) in THF /10 ml) was treated with
2N HCl solution /9.3 ml) and heated overnight at 758C.
After cooling, the reaction mixture was neutralized with
solid NaHCO3 /1.68 g) and concentrated under vacuum.
The residue was dissolved in ethyl acetate, dried,
/MgSO4) and concentrated under vacuum to give crude
diol 17a /156 mg) as an oil.
15b): H NMR /CDCl3) d 7.20±7.40 /m, 5H), 7.02 /d,
1H, Jˆ15.8 Hz), 6.95 /m, 1H), 6.26 /d, 1H, Jˆ15.8 Hz),
5.00 /d, 1H, Jˆ1.1 Hz), 4.53 /AB d, 1H, Jˆ12.1 Hz), 4.47
/AB d, 1H, Jˆ12.1 Hz), 3.73 /s, 3H), 3.62 /AB d, 1H,
Jˆ10.0 Hz), 3.41 /AB d, 1H, Jˆ10.0 Hz), 2.25±2.45 /m,
2H), 1.15±1.50 /m, 22H), 0.86 /irregular t, 3H).
4.1.14. Methyl ꢀ2E)-3-{ꢀ2S,3R)-3-hydroxy-2-ꢀhydroxy-
methyl)-5-oxo-4ꢀZ)-tetradecylideneꢀ2-2,3-dihydrofuryl)}-
prop-2-enoate ꢀ4a).
A
solution of 19a /0.029 g,
The above diol was dissolved in a mixture of MeOH /14 ml)
and H2O /7.1 ml) and cooled to 08C. The solution was
treated with sodium metaperiodate /0.39 g, 1.84 mmol)
and stirred at room temperature for 4 h. The reaction
mixture was concentrated, diluted with ethyl acetate,
®ltered, and concentrated to give intermediate aldehyde
18a as an oil.
0.058 mmol) in CH2Cl2 /2.76 ml) was cooled to 2788C
and treated dropwise with boron trichloride /1.0 M,
0.28 ml, 0.28 mmol). After stirring for 2 h at 2788C, the
reaction mixture was quenched with saturated NaHCO3
solution /0.28 ml) and immediately partitioned between
ether and a pH 7 buffer solution. The organic layer was
washed with pH 7 buffer /3£5 ml), dried /MgSO4), and
concentrated under vacuum. The residue was puri®ed by
silica gel ¯ash column chromatography with hexanes/ethyl
acetate /2/1) as eluant to give the E,Z-isomer 4a /0.011 g,
46%) and the E,E-isomer 4b /0.013 g, 54%) both as white
The above aldehyde was dissolved in CH2Cl2 /20 ml) and
the solution was treated with methyl /triphenylphospho-
ranylidene)acetate /0.31 g, 0.93 mmol). After stirring at
room temperature for 24 h, the reaction mixture was
concentrated and the residue was puri®ed by silica gel
¯ash column chromatography with hexanes/ethyl acetate
/3/1) as eluant to give 19a as an oil /0.062 g, 0.124 mmol,
53%) and a small amount of the E,E-isomer 19b /0.008 g,
22
solids. 4a: mp 71.8±73.38C; [a]D ˆ128.68 /c 0.21,
1
CHCl3); H NMR /CDCl3) d 7.01 /d, 1H, Jˆ15.9 Hz),
6.49 /m, 1H), 6.15 /d, 1H, Jˆ15.9 Hz), 4.98 /br s, 1H),
3.72±3.77 /m, 5H), 3.35 /m, 2H), 2.65 /irregular q, 2H),
1.22±1.42 /m, 22H), 0.85 /irregular t, 3H); 13C NMR
/CDCl3) d 167.62, 166.10, 149.71, 142.00, 127.24,
123.47, 87.44, 71.55, 64.40, 51.94, 31.89, 29.64, 29.51,
29.39, 29.32, 29.25, 28.78, 27.90, 22.65, 14.08; FAB MS
/m/z, relative intensity) 411 /MH1, 100), 393 /MH12H2O,
38.8), 369 /MH1242, 18.0). Anal. calcd for C23H38O6: C,
67.29; H, 9.33. Found: C, 67.13; H, 9.34.
1
0.016 mmol, 7.8%). Compound 19a: H NMR /CDCl3) d
7.24±7.30 /m, 5H), 7.02 /d, 1H, Jˆ15.8 Hz), 6.47 /dt, 1H,
Jˆ8.0, 1.7 Hz), 6.21 /d, 1H, Jˆ15.8 Hz), 4.87 /dd, 1H,
Jˆ7.3, 1.11 Hz), 4.53 /s, 2H), 3.72 /s, 3H), 3.65 /AB d,
1H, Jˆ10.1 Hz), 3.51 /AB d, 1H, Jˆ10.1 Hz), 2.65±2.80
/m, 2H), 2.1 /d, 1H, Jˆ7.3 Hz), 1.16±1.40 /m, 22H), 0.86
/irregular t, 3H).
4.1.15. Methyl ꢀ2E)-3-{ꢀ2S,3R)-3-hydroxy-2-ꢀhydroxy-
methyl)-5-oxo-4ꢀE)-tetradecylideneꢀ2-2,3-dihydrofuryl)}-
4.1.13.
Methyl
ꢀ2E)-3-{ꢀ2S,3R)-3-hydroxy-5-oxo-2-
[ꢀphenylmethoxy)methyl]-4ꢀE)-tetradecylideneꢀ2-2,3-di-
hydrofuryl)}prop-2-enoate ꢀ19b). A solution of E-isomer
16b /0.12 g, 0.23 mmol) in THF /10 ml) was treated with
2N HCl solution /10 ml) and heated at 758C for 48 h. After
prop-2-enoate ꢀ4b).
A
solution of 19b /0.063 g,
0.126 mmol) in CH2Cl2 /6 ml) was cooled to 2788C and
treated with boron trichloride /1.0 M, 0.6 ml, 0.6 mmol).
After stirring for 90 min at 2788C, the reaction mixture

K. Nacro et al. / Tetrahedron 58 12002) 5335±5345
5343
was quenched with saturated NaHCO3 solution /0.6 ml) and
immediately partitioned between ether and a pH 7 buffer
solution. The organic layer was washed with pH 7 buffer
several times, dried /MgSO4), and concentrated under
vacuum. The residue was puri®ed by silica gel ¯ash column
chromatography with hexanes/ethyl acetate /3/2) as eluant
to give E,E-isomer 4b /0.045 g, 87%) as a white solid: mp
4.1.17.
1-ꢀ{ꢀ1S,3R,4S,5R)-7,7-Dimethyl-2,6,8-trioxa-4-
ꢀphenylmethoxy)-3-[ꢀphenylmethoxy)-methyl]bicyclo-
[3.3.0]oct-3-yl}methoxy)-2,2-dimethyl-1,1-diphenyl-1-
silapropane ꢀ26). A solution of 24 /3.18 g, 5.79 mmol) in
24 ml of THF at 08C was treated with 60% NaH suspended
in mineral oil /0.46 g, 11.6 mmol). The solution was stirred
at 08C for 1 h, and following the addition of benzyl bromide
/0.76 ml, 6.37 mmol) and n-Bu4NI /0.21 g, 0.58 mmol), the
reaction mixture was allowed to reach room temperature
and was stirred for 3 h. The entire mixture was ®ltered
through a short pad of silica gel and the collected ®ltrate
was dried under reduced pressure and puri®ed by silica gel
¯ash chromatography with hexanes/ethyl acetate mixtures
of 9/1, 7/1 and 4/1 as eluants to give three products. The
®rst, minor product corresponded to the benzylated ether of
diastereoisomer 25, which probably arose through rearran-
gement of the silyl group prior to benzylation. The second
product was the desired compound 26 /2.82 g, 76%), and
the third product /0.79 g) was the tribenzylated analogue
resulting from NaH-catalyzed desilylation of 24 followed
by complete benzylation.
22
59.4±60.68C; [a]D ˆ166.078 /c 0.28, CHCl3); IR /neat)
3485 and 3352 /OH), 1757 and 1724 /CvO), 1671
;
/CvC) cm21
1H NMR /CDCl3) d 7.02 /d, 1H, Jˆ
15.8 Hz), 7.00 /m, 1H), 6.26 /d, 1H, Jˆ15.8 Hz), 5.05 /br
s, 1H), 3.74 /s, 3H), 3.72 /m, 2H), 2.30±2.50 /m, 2H), 2.03
/br s, 1H), 1.50 /m, 2H), 1.10±1.40 /m, 20H), 0.86 /irregular
t, 3H); 13C NMR /CDCl3) d 168.82, 166.36, 149.63, 141.63,
128.78, 123.22, 88.48, 69.99, 66.03, 51.98, 31.90, 29.63,
29.50, 29.38, 28.38, 22.67, 14.10; FAB MS /m/z, relative
intensity) 411.4 /MH1, 50.6), 393.4 /MH12H2O, 11.0).
Anal. calcd for C23H38O6: C, 67.29; H, 9.33. Found: C,
67.20; H, 9.29.
4.1.16. {3-[ꢀ2,2-Dimethyl-1,1-diphenyl-1-silapropoxy)-
methyl]-ꢀ1S,3R,4S,5R)-7,7-dimethyl-2,6,8-trioxa-4-
ꢀphenylmethoxy)bicyclo[3.3.0]oct-3-yl}methan-1-ol ꢀ24)
22
Compound 26. Oil, [a]D1 ˆ16.458 /c 0.89, CHCl3); IR
and
{3-[ꢀ2,2-dimethyl-1,1-diphenyl-1-silapropoxy)-
/neat) 2934±2858 cm21; H NMR /CDCl3) d 7.80±7.33
/m, 20H), 5.85 /d, 1H, Jˆ3.9 Hz), 4.79±4.53 /m, 5H),
4.29 /d, 1H, Jˆ5.3 Hz), 4.16 /AB d, 2H, Jˆ1.7 Hz), 3.80
/AB q, 2H, Jˆ10.2 Hz), 1.39 and 1.37 /singlets, 6H),
1.12 /s, 9H); 13C NMR /CDCl3) d 138.07, 137.84,
135.74, 135.59, 133.47, 133.24, 129.34, 128.18, 128.11,
127.57, 127.43, 113.19, 104.15, 87.62, 79.60, 78.18,
73.63, 72.38, 72.01, 64.67, 26.85, 26.59, 26.34, 19.29.
Anal. calcd for C39H46O6Si: C, 73.32; H, 7.26. Found: C,
73.42; H, 7.33.
methyl]-ꢀ1S,3S,4S,5R)-7,7-dimethyl-2,6,8-trioxa-4-
ꢀphenylmethoxy)-bicyclo[3.3.0]oct-3-yl}methan-1-ol ꢀ25).
A solution of n-BuLi /2.5 M solution in hexane, 6 ml) was
added dropwise to a solution of 23 /4.42 g, 14.2 mmol) in
25 ml of THF at 2788C, followed by the addition of
t-BuPh2SiCl /4 g, 14.5 mmol). The resulting mixture was
stirred at 2788C for 30 min. After allowing it to warm to
room temperature, it was stirred for an additional 30 min
and then heated to re¯ux for 1 h. After the removal of the
volatiles under vacuum, the residue was puri®ed by silica
gel ¯ash chromatography with hexanes/ethyl acetate
mixtures of 4/1 and 2/1 as eluants to give a quantitative
yield of the two monoprotected diastereoisomers 24
/3.06 g, 5.58 mmol, 38%) and 25 /4.96 g, 9.04 mmol, 62%).
4.1.18. {ꢀ1S,3S,4S,5R)-7,7-Dimethyl-2,6,8-trioxa-4-ꢀphenyl-
methoxy)-3-[ꢀphenylmethoxy)methyl]-bicyclo[3.3.0]oct-
3-yl}methan-1-ol ꢀ27). A solution of n-Bu4NF /1 M, 7 ml)
was added dropwise to a solution of 26 /2.12 g, 3.32 mmol)
in 15 ml of THF at 08C. The reaction mixture was stirred at
room temperature overnight, concentrated under vacuum
and ®ltered through a short pad of silica gel. It was further
eluted with hexanes/ethyl acetate /1/1) and the ®ltrate was
concentrated under vacuum. The residual syrup was puri®ed
by silica gel ¯ash chromatography using hexanes/ethyl
acetate mixtures of 4/1 and 2/1 as eluants to afford 27
22
Compound 24. Oil, [a]D ˆ144.958 /c 1.01, CHCl3); IR
1
/neat) 3508 /OH), 2951±2855 cm21; H NMR /CDCl3) d
7.22±7.42 /m, 15H), 5.91 /d, 1H, Jˆ3.5 Hz), 4.90 /AB d,
1H, Jˆ11.9 Hz), 4.78 /irregular t, 1H, J,4.3 Hz), 4.60 /AB
d, 1H, Jˆ11.9 Hz), 4.52 /d, 1H, Jˆ5.1 Hz), 3.95±3.75 /2
overlapping quartets, 4H), 2.45 /broad s, 1H), 1.74 and 1.46
/singlets, 6H), 1.08 /s, 9H); 13C NMR /CDCl3) d 137.16,
135.45, 135.41, 133.05, 132.85, 129.60, 129.54, 128.42,
127.94, 127.64, 127.59, 127.54, 113.66, 104.38, 87.38,
79.05, 76.42, 72.50, 65.38, 63.01, 26.83, 26.78, 26.25,
19.18. Anal. calcd for C32H40O6Si: C, 70.04; H, 7.35.
Found: C, 69.82; H, 7.37.
22
/1.23 g, 93%) as an oil: [a]D ˆ176.628 /c 1.42, CHCl3);
IR /neat), 3530 /OH), 2937±2362 cm21; 1H NMR /CDCl3)
d 7.42±7.36 /m, 10H), 5.87 /d, 1H, Jˆ3.9 Hz), 4.87 /AB d,
1H, Jˆ11.7 Hz,), 4.73 /dd, 1H, Jˆ5.1, 3.9 Hz), 4.59 /m,
3H), 4.36 /d, 1H, Jˆ5.1 Hz), 4.01 /ABX dd, 1H, J,11.7,
,5.5 Hz), 3.92 /ABX dd, 1H, J,11.7, 7.5 Hz), 3.68 /AB q,
2H, Jˆ10.6 Hz), 2.47 /broad ABX t, 1H, J,6.7 Hz), 1.72
and 1.43 /singlets, 6H); 13C NMR /CDCl3) d 137.95,
137.32, 128.36, 128.23, 127.91, 127.71, 127.50, 113.43,
104.34, 86.43,78.79, 78.52, 73.54, 72.51, 71.57, 63.11,
26.71, 26.14. Anal. calcd for C23H28O6: C, 68.98; H, 7.05.
Found: C, 68.98; H, 7.13.
22
Compound 25. Oil, [a]D ˆ13.728 /c 1.36, CHCl3); IR
1
/neat) 3408 /OH), 3070±2857 cm21; H NMR /CDCl3) d
7.81±7.40 /m, 15H), 5.81 /d, 1H, Jˆ3.9 Hz), 4.75 /AB q,
2H, Jˆ11.9 Hz), 4.62 /br d, 1H, Jˆ2.9 Hz), 4.29±4.08 /m,
4H), 3.68 /br m, d after D2O exchange, 1H, Jˆ11.9 Hz),
2.05 /broad d, 1H), 1.34 /s, 6H), 1.14 /s, 9H); 13C NMR
/CDCl3) d 137.58, 135.70, 135.61, 133.14, 133.04,
129.49, 128.21, 127.70, 113.01, 103.92, 87.27, 78.74,
77.71, 72.46, 65.06, 64.22, 26.95, 26.28, 25.86, 19.25.
Anal. calcd for C32H40O6Si: C, 70.04; H, 7.35. Found: C,
70.28; H, 7.32.
4.1.19. Methylꢀ2E)-3-{ꢀ1S,3R,4S,5R)-7,7-dimethyl-2,6,8-
trioxa-4-ꢀphenylmethoxy)-3-[ꢀphenylmethoxy)methyl]-
bicyclo[3.3.0]oct-3-yl}prop-2-enoate ꢀ29). A solution of
27 /1.1 g, 2.72 mmol) in 6 ml of DMSO was treated at
room temperature with dicyclohexylcarbodiimide /DCC,

5344
K. Nacro et al. / Tetrahedron 58 12002) 5335±5345
2.25 g, 10.9 mmol) and dichloroacetic acid /0.11 ml,
1.36 mmol). The reaction mixture was stirred overnight,
diluted with Et2O and quenched by the careful addition of
oxalic acid /0.98 g, 2.72 mmol). The mixture was cooled to
2788C and the solids removed by ®ltration. The ®ltrate was
concentrated under vacuum to give 28 as a crude product
/1.5 g, ca. 2.72 mmol) which was used without further
puri®cation in the next step. Compound 28 was dissolved
in CH2Cl2 /30 ml) and the solution was cooled to 08C before
it was treated with triphenylphosphoralydene acetate
/3.64 g, 10.84 mmol). The cooling bath was removed and
the mixture was then stirred at room temperature overnight.
The solution was ®ltered through a short pad of silica gel
and the ®ltrate was concentrated under reduced pressure.
The residue was puri®ed by silica gel ¯ash chromatography
using hexanes/ethyl acetate 4/1 as eluant to give 29 /1.05 g,
The resulting solution was stirred overnight while allowing
the cooling bath to reach room temperature. The next day,
the solution was ®ltered through a pad of silica gel with
hexanes/ethyl acetate /2/1) as eluant. The ®ltrate was
concentrated under vacuum and the residue was puri®ed
by silica gel ¯ash column chromatography with hexanes/
ethyl acetate mixtures of 95/5, 9/1 and 4/1 as eluants to
give an inseparable mixture of compounds 32a and b
/0.797 g, 31%).
4.1.22. Compound 33a±d ꢀmixture of anomers and
geometric isomers). A stirred solution of compounds
32a,b /0.79 g, 1.30 mmol) in a mixture of THF /25 ml)
and water /10 ml) was cooled to 08C and treated dropwise
with concentrated HCl /0.32 ml). The solution was stirred
overnight while allowing the temperature to reach 108C.
Additional concentrated HCl /0.2 ml) was added and
stirring was continued at room temperature for 3 h. Solid
NaHCO3 was added until neutrality was achieved and the
mixture was ®ltered. The ®ltrate was concentrated under
vacuum and the residue was puri®ed by silica gel ¯ash
chromatography with hexanes/ethyl acetate mixtures of
9/1, 4/1 and 3/1 as eluants to give a mixture of 33a±d
/0.67 g, 87%).
22
85%) as an oil: [a]D ˆ12.258 /c 0.91, CHCl3); IR /neat)
2944, 1720 /CvO), 1656 cm21; 1H NMR /CDCl3) d 7.46±
7.27 /m, 11H), 6.34 /dd, 1H, Jˆ16.0, 0.6 Hz), 5.84 /d, 1H,
Jˆ3.6 Hz), 4.83 /AB d, 1H, Jˆ12.4 Hz), 4.71±4.59 /m,
2H), 4.65 /AB q, 2H, Jˆ12.2 Hz), 4.35 /d, 1H, Jˆ4.8 Hz),
3.81 /s, 3H), 3.42 /s, 2H), 1.55 and 1.36 /singlets, 6H); 13C
NMR /CDCl3) d 166.49, 145.64, 137.60, 137.41, 128.31,
128.23, 127.87, 127.85, 127.59, 127.52, 122.13, 113.28,
103.90, 85.79, 77.70, 77.52, 77.26, 73.50, 72.45, 71.66,
51.43, 25.92, 25.47. Anal. calcd for C26H30O7: C, 68.71;
H, 6.65. Found: C, 68.56; H, 6.60.
4.1.23.
methoxy)-2-[ꢀphenylmethoxy)methyl]-ꢀZ)-4-tetradecyl-
Methyl
ꢀ2E)-3-{ꢀ2S,3S)-5-oxo-3-ꢀphenyl-
ideneꢀ2-2,3-dihydrofuryl)}prop-2-enoate ꢀ24a) and
Methyl
4.1.20. Compound 30 ꢀmixture of anomers). A solution of
29 /3.95 g, 8.69 mmol) in MeOH /54 ml) was treated with
0.09N methanolic HCl /14.8 ml) and heated at 858C for
30 min. After cooling, the reaction mixture was neutralized
with solid NaHCO3, ®ltered and concentrated under
vacuum. The residue was puri®ed by silica gel ¯ash column
chromatography with ethyl acetate/hexanes mixtures of 1/1
and 2/1 as eluants to give 30 as a mixture of anomers. One
anomer was obtained pure /1.95 g, 52%), while the other
was isolated as an enriched mixture, still contaminated
with the more abundant anomer /0.85 g, 23%). The pure
ꢀ2E)-3-{ꢀ2S,3S)-5-oxo-3-ꢀphenylmethoxy)-2-
[ꢀphenylmethoxy)methyl]-ꢀE)-4-tetradecylideneꢀ2-2,3-di-
hydrofuryl)}prop-2-enoate ꢀ24b). A solution of 33a±d
/0.66 g, 1.11 mmol) in CH2Cl2 /30 ml) was treated with
activated MnO2 /4.53 g, 44.29 mmol). The mixture was
stirred at room temperature overnight, ®ltered, and the
®ltrate concentrated under vacuum. The residue was puri-
®ed by silica gel ¯ash chromatography with hexanes/ethyl
acetate /9/1) as eluant to give pure E,Z-isomer 34a /0.133 g,
21%), a mixture 34a and b /0.04 g, 6%), and pure
E,E-isomer 34b /0.243 g, 37%) as oils.
22
b-anomer was fully characterized: oil, [a]D ˆ252.718
22
Compounds 34a. Oil, [a]D ˆ22.578 /CHCl3, c 0.51); IR
/CHCl3, c 1.77); IR /neat) 3485 /OH), 3030±2930, 1720
1
1
/CvO), 1659 cm21; H NMR /CDCl3) d 7.40 /m, 10H),
/neat) 3422±2854, 1766 and 1726 /CvO), 1666 cm21; H
7.24 /d, 1H, Jˆ15.6 Hz), 5.67 /d, 1H, Jˆ15.6 Hz), 5.03
/s, 1H), 4.70 and 4.62 /singlets, 4H), 4.35 /d, 1H, Jˆ
4.8 Hz), 4.10 /d, 1H, Jˆ4.8 Hz), 3.83 /s, 3H), 3.52 /s,
2H), 3.41 /s, 3H); 13C NMR /CDCl3) d 166.75, 147.11,
137.65, 136.86, 128.42, 128.25, 128.04, 127.83, 127.59,
127.51, 120.87, 107.37, 85.05, 81.52, 74.81, 74.12, 73.53,
72.93, 55.01, 51.46. Anal. calcd for: C24H28O7: C, 67.28; H,
6.59. Found: C, 67.23; H, 6.50.
NMR /CDCl3) d 7.41±7.31 /m, 10H), 7.17 /d, 1H, Jˆ
15.7 Hz), 6.43 /broad t, 1H. J,8.03 Hz), 6.32 /d, 1H, Jˆ
15.75 Hz), 4.75 /broad s, 1H), 4.65 /AB q, 2H, Jˆ11.9 Hz),
4.59 /s, 2H), 3.83 /s, 3H), 3.55 /AB q, 2H, Jˆ10.2 Hz), 2.79
/irregular q, 2H, J,7.08 Hz), 1.34 /broad s, 22H), 0.97
/irregular t, 3H, J,6.35 Hz); 13C NMR /CDCl3) d 166.70,
166.00, 149.78, 141.96, 136.99, 136.94, 128.42, 128.32,
128.26, 127.92, 127.84, 127.76, 127.61, 125.47, 122.45,
85.72, 78.61, 73.69, 72.24, 71.18, 51.67, 31.86, 29.62,
29.60, 29.48, 29.34, 29.30, 29.19, 28.76, 27.84, 22.64,
14.07. Anal. calcd for C38H53O6: C, 75.22; H, 8.53. Found:
C, 75.18; H, 8.60.
4.1.21. Compounds 32a,b ꢀmixture of geometric
isomers). Starting with the pure anomer 30 /1.82 g,
4.25 mmol), Swern oxidation performed according to the
exact protocol of Yoshikawa et al.11 afforded the crude
keto compound 31 /1.81 g, IR /neat) 1724 cm21), which
was used directly for the next step without further puri®-
cation. Separately, a stirred solution of strictly anhydrous
tetradecyl phosphonium bromide /4.58 g, 8.49 mmol) in
THF /106 ml) was cooled to 2788C and treated dropwise
with n-BuLi /2.5 M in hexanes, 3.06 ml). Stirring continued
for 1.5 h and a solution of 31 /ca. 4.25 mmol) in THF
/10 ml) was transferred slowly to the solution of the ylide.
22
Compounds 34b. Oil, [a]D ˆ236.988 /CHCl3, c 0.53); IR
/neat): 2924±2855, 1767 and 1726 /CvO), 1673 cm21; 1H
NMR /CDCl3) d 7.43±7.33 /m, 10H), 7.25 /d, 1H, Jˆ
15.8 Hz), 7.08 /irregular t, 1H, J,7.69 Hz), 6.39 /d, 1H,
Jˆ15.8 Hz), 4.95 /s, 1H), 4.61 /s, 2H), 4.55 /AB q, 2H,
Jˆ11.2 Hz), 3.84 /s, 3H), 3.68 /AB d, 1H, Jˆ9.9 Hz),
3.48 /AB d, 1H, Jˆ9.9 Hz), 2.40±2.10 /m, 1H), 1.34 /br
s, 22H), 0.97 /irregular t, 3H, J,6.25 Hz); 13C NMR

K. Nacro et al. / Tetrahedron 58 12002) 5335±5345
5345
/CDCl3) d 168.24, 166.00, 148.66, 141.37, 136.85, 136.67,
128.37, 128.35, 128.01, 127.97, 127.91, 127.60, 126.72,
122.71, 86.43, 76.39, 73.74, 72.73, 71.51, 51.69, 31.86,
30.00, 29.60, 29.45, 29.32, 28.19, 22.64, 14.08. Anal.
calcd for C38H53O6: C, 75.22; H, 8.53. Found: C, 75.24; H,
8.54
168.98, 166.36, 149.37, 141.81, 128.66, 122.81, 88.64,
69.83, 65.81, 51.90, 31.84, 29.57, 29.51, 29.46, 29.34,
29.28, 28.33, 22.61, 14.04; FAB MS /m/z, relative intensity)
411 /MH1, 85.6), 393 /MH12H2O, 19.1). Anal. calcd for
C23H38O6: C, 67.29; H, 9.33. Found: C, 67.40; H 9.36.
References
4.1.24. Methyl ꢀ2E)-3-[ꢀ2S,3S)-3-hydroxy-2-ꢀhydroxy-
methyl)-5-oxo-ꢀZ)-4-tetradecylideneꢀ2-2,3-dihydrofuryl)]-
prop-2-enoate ꢀ5a). A stirred solution of 34a /112.2 mg,
0.199 mmol) in CH2Cl2 /9 ml) at 2788C was treated with
a solution of BCl3 /1 M in CH2Cl2, 904 ml) and maintained
at that temperature for 2 h. The reaction was quenched with
1 ml of MeOH and allowed to reach room temperature.
Volatiles were removed under reduced pressure and the
residue was puri®ed by silica gel ¯ash chromatography
with hexanes/ethyl acetate mixtures of 2/1 and 1/1 as eluants
to afford the E,E-isomer 5b /28 mg, 34%), a mixture of 5a
and b /35 mg, 43%) an the desired E,Z-isomer 5a /12 mg,
15%) as white solids. Overall yield 92%.
1. Lee, J.; Han, K.-C.; Kang, J.-H.; Pearce, L. L.; Lewin, N. E.;
Yan, S.; Benzaria, S.; Nicklaus, M. C.; Blumberg, P. M.;
Marquez, V. E. J. Med. Chem. 2001, 44, 4309±4312.
2. For a recent review, see: Newton, A. C. Chem. Rev. 2001, 101,
2353±2364.
3. For a recent review, see: Barry, O. P.; Kazanietz, M. G. Curr.
Pharm. Des. 2001, 7, 1725±1744.
4. Garcia-Bermejo, M. L.; Leskow, F. C.; Fujii, T.; Wang, Q.;
Blumberg, P. M.; Ohba, M.; Kuroki, T.; Han, K.-C.; Lee, J.;
Marquez, V. E.; Kazanietz, M. G. J. Biol. Chem. 2002, 277,
645±655.
5. Nacro, K.; Bienfait, B.; Lee, J.; Han, K.-C.; Kang, J.-H.;
Benzaria, S.; Lewin, N. E.; Bhattacharyya, D. K.; Blumberg,
P. M.; Marquez, V. E. J. Med. Chem. 2000, 43, 921±944.
6. These compounds were prepared essentially as described in
Ref. 9 except that myristyl aldehyde was used instead of oleyl
aldehyde. The biological activity is reported here for the ®rst
time.
22
Compound 5a. Mp 69.9±71.98C; [a]D ˆ230.458 /CHCl3,
c 0.22); IR /CHCl3) 3592 and 3406 /OH), 3021±2855, 1760
and 1721 /CvO), 1668 cm21; 1H NMR /CDCl3) d 7.14 /d,
1H, Jˆ15.8 Hz), 6.60 /dt, 1H, J,7.8, 1.7 Hz), 6.26 /d, 1H,
Jˆ15.8 Hz), 5.09 /d, 1H, Jˆ6.3 Hz), 3.89±3.83 /m, 5H),
3.21 /d, 1H, Jˆ7.5 Hz, D2O exchanged), 3.13 /m, 1H,
D2O exchanged), 2.79 /irregular q, 2H, J,7.24 Hz) 1.53±
1.33 /m, 22H), 0.96 /irregular t, 3H, J,6.35 Hz); 13C NMR
/CDCl3) d 167.17, 165.86, 149.64, 141.67, 127.20, 123.49,
87.19, 71.66, 64.54, 51.87, 31.85, 29.58, 29.47, 29.34,
29.29, 29.19, 28.73, 27.86, 22.62, 14.05; FAB MS /m/z,
relative intensity) 411 /MH1, 100), 393 /MH12H2O,
38.7). Anal. calcd for C23H38O6: C, 67.29; H, 9.33. Found:
C, 67.64; H, 9.43.
7. Zechmeister, K.; Brandl, F.; Hoppe, W.; Hecker, E.;
Opferkuch, H. J.; Adolf, W. Tetrahedron Lett. 1970, 4075±
4078.
8. Krauter, G.; von der Lieth, C.-W.; Schmidt, R.; Hecker, E.
Eur. J. Biochem. 1996, 242, 417±427.
9. Lee, J.; Sharma, R.; Wang, S.; Milne, G. W. A.; Lewin, N. E.;
Szallasi, Z.; Blumberg, P. M.; George, C.; Marquez, V. E.
J. Med. Chem. 1996, 39, 36±45.
10. Funabashi, M.; Sato, H.; Yoshimura, J. Bull. Chem. Soc. Jpn
1976, 49, 788±790.
4.1.24. Methyl ꢀ2E)-3-[ꢀ2S,3S)-3-hydroxy-2-ꢀhydroxy-
methyl)-5-oxo-ꢀE)-4-tetradecylideneꢀ2-2,3-dihydrofuryl)]-
prop-2-enoate ꢀ5b). A stirred solution of 34b /215.3 mg,
0.364 mmol) in CH2Cl2 /17 ml) at 2788C was treated with a
solution of BCl3 /1 M in CH2Cl2, 1.73 ml) in the same
manner as for 5a. Puri®cation by silica gel ¯ash chroma-
tography with the same solvent system afforded 5b /129 mg,
85%) and a mixture of 5a and b /27 mg, 18%).
11. Yoshikawa, M.; Okaichi, Y.; Cha, B. C.; Kitagawa, I.
Tetrahedron 1990, 46, 7459±7470.
12. Brimacombe, J. S.; Ching, O. A. Carbohydr. Res. 1968, 8, 82±
88.
13. Youssefyeh, R. D.; Verheyden, J. P.; Moffatt, J. G. J. Org.
Chem. 1979, 44, 1301±1309.
14. Sharma, R.; Lee, J.; Lewin, N. E.; Blumberg, P. M.; Marquez,
V. E. J. Med. Chem. 1996, 39, 19±28.
22
15. Meylan, W. M.; Howard, Ph. H. KOWWIN 1.63, Syracuse
Research Corp., http://esc.syrres.com.20; J. Pharm. Sci. 1995,
84, 83±92.
Compound 5b. Mp 55.6±57.88C; [a]D ˆ264.268 /CHCl3,
c 0.31); IR /CHCl3) 3587 and 3430 /OH), 3020±2855, 1757
and 1721 /CvO), 1674 cm21; 1H NMR /CDCl3) d 7.12 /d,
1H, Jˆ7.6 Hz), 7.08 /m, 1H), 6.34 /d, 1H, Jˆ15.6 Hz), 5.15
/d, 1H, Jˆ8.0 Hz), 3.83±3.74 /m, 5H), 2.56±2.45 /m, 4H),
1.59±1.34 /m, 22H), 0.96 /m, 3H); 13C NMR /CDCl3) d
16. Stott, K.; Stonehouse, J.; Hwang, T. L.; Keeler, J.; Shaka, A. J.
J. Am. Chem. Soc. 1995, 117, 4199±4200.