Studies towards the total synthesis of solanoeclepin A: Synthesis and potato cyst nematode hatching activity of analogues containing the tetracyclic left-hand substructure

Article abstract of DOI:10.1039/b202020n

In our studies towards the total synthesis of solanoeclepin A, a natural hatching agent of potato cyst nematodes, three analogues containing the tetracyclic left-handed substructure have been synthesised. First, the synthesis of the parent tetracycle 2 in

Full text of DOI:10.1039/b202020n

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Studies towards the total synthesis of solanoeclepin A:
synthesis and potato cyst nematode hatching activity of
analogues containing the tetracyclic left-hand substructure†
1
Jorg C. J. Benningshof, Maarten IJsselstijn, Sabine R. Wallner, Anne L. Koster,
Richard H. Blaauw, Angeline E. van Ginkel, Jean-François Brière, Jan H. van Maarseveen,
Floris P. J. T. Rutjes and Henk Hiemstra*
Institute of Molecular Chemistry, Universiteit van Amsterdam, Nieuwe Achtergracht 129,
1018 WS Amsterdam, The Netherlands. E-mail: hiemstra@science.uva.nl
Received (in Cambridge, UK) 26th February 2002, Accepted 24th May 2002
First published as an Advance Article on the web 24th June 2002
In our studies towards the total synthesis of solanoeclepin A, a natural hatching agent of potato cyst nematodes,
three analogues containing the tetracyclic left-handed substructure have been synthesised. First, the synthesis of
the parent tetracycle 2 in enantiopure form is reported. Key steps are (1) chromium-mediated coupling of aldehyde
5 (see preceding paper in this issue) and vinyl triflate 6 to furnish an α,β-unsaturated lactone, which was transformed
into triene 4 in six-steps, (2) ring-closing metathesis of 4 to tetracycle 3 and (3) oxidative functionalisation of the least
substituted double bond of 3 to provide the fully functionalised tetracyclic left-handed substructure of solanoeclepin
A. The methodology developed was successfully applied in the synthesis of two more elaborate solanoeclepin A
analogues 9 and 11. Both compounds, prepared as mixtures of diastereomers, showed promising biological activity
in hatching activity tests.
Introduction
As described in the preceding paper1 our synthetic strategy
to prepare the tetracyclic left-handed substructure 2 of solano-
eclepin A (1)2 by using a McMurry coupling as the key step
failed. In this paper we present an alternative and successful
approach for the construction of the highly functionalised
seven-membered ring by using an olefin metathesis process to
provide 3. Target compound 2 was expected to be accessible
via oxidative functionalisation of the least substituted double
bond of diene 3, the latter being the product of a ring-
closing metathesis (RCM)3 reaction of divinyl compound 4. As
described in the previous paper1 a convergent approach can be
used to construct 4. To this end, aldehyde 5, which in this case
contains a vinyl functionality, and vinyl triflate ‡ 6 have to be
coupled. It was expected that aldehyde 5 would be readily avail-
able from compound 7, which should arise from the well known
hydroxy ester 8 reported in the previous paper (Scheme 1).1
To gain a better insight into the structure–activity relation-
ships (SAR) of the natural product, the second part of this
paper reports the syntheses and biological activity of two
more elaborate model compounds 9 and 11 (Scheme 2). As was
concluded from SAR studies of glycinoeclepin A,4 the hatching
agent of the soybean cyst nematode, a carboxylic acid group is
essential for hatching activity. For this reason it was decided
that solanoeclepin A analogues 9 and 11 should contain this
moiety properly attached to the tetracyclic left-handed sub-
structure. It was speculated that a cyclopropane ring5 could
Scheme 1
also be important for the hatching activity.
In order to gain rapid access to these analogues a non-
diastereoselective approach was chosen. Testing mixtures of
diastereomers would give a positive result even if only one of
the isomers were active. Once activity is found in one of the
mixtures, efforts can be made to elucidate the structure of
the active diastereomer. Therefore, compounds 9 and 11 were
synthesised by coupling enantiopure aldehyde 5 with racemic
vinyl triflates 10 and 12, respectively.
† Electronic supplementary information (ESI) available: further
experimental details. See http://www.rsc.org/suppdata/p1/b2/b202020n/
‡ The IUPAC name for triflate is trifluoromethanesulfonate.
DOI: 10.1039/b202020n
J. Chem. Soc., Perkin Trans. 1, 2002, 1701–1713
This journal is © The Royal Society of Chemistry 2002
1701

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Scheme 4 Reagents and conditions: a, Na, NH3, t-BuOH–THF 1 : 1,
Ϫ33 ЊC; b, HCl (aq); c, Pd/C–H2, EtOAc; d, TBDPSCl, imidazole,
DMF; e, LDA, THF, Ϫ78 ЊC; then HMPT, NCCO2Me, Ϫ78 ЊC,
10 min; f, NaH, (CF3SO2)2NPh, THF, 0 ЊC
rt.
Finally, reaction with N-phenyltrifluoromethanesulfonimide11
yielded vinyl triflate 10.
Scheme 2
Results and discussion
Synthesis of vinyl triflate 12
(E)-Alkene 2312 was expected to be a good precursor for a
Simmons–Smith cyclopropanation, which could lead to a trans-
disubstituted cyclopropane (Scheme 5). Treatment of allylic
Preparation of aldehyde 5
The first step in the synthesis of aldehyde 5 was THP protection
of the enantiopure hydroxy ester 81 to provide 13 (Scheme 3).
Scheme 3 Reagents and conditions: a, DHP, p-TsOH, CH2Cl2; b,
disiamylborane, THF, Ϫ20 ЊC; c, NaOH, H2O2; d, TBDPSCl,
imidazole, DMF; e, LiAlH4, THF; f, TPAP, NMO, acetone; g,
Ph3P=CH2, THF; h, HOAc, THF, H2O; i, SO3ؒpyridine, DMSO, Et3N,
CH2Cl2.
Hydroboration6 of 13 by using disiamyl§borane furnished, after
oxidative workup, alcohol 14 as the major product in a 76%
yield (89 : 11 regioselectivity). After protection of the secondary
hydroxy group of 14 as a TBDPS ether to give 15, the ester
function of 15 was readily reduced to the primary alcohol 16.
TPAP–NMO oxidation7 then gave aldehyde 17 in high yield.
Subsequent Wittig olefination afforded 7. To prepare the
required aldehyde the tetrahydropyranyl group was cleaved and
the resulting alcohol 18 was oxidised by applying a sulfur
trioxide, pyridine–DMSO oxidation.8 The developed sequence
was used to synthesise aldehyde 5 in enantiopure form ([α]2D2
ϩ19.2 10Ϫ1 × deg cm2 gϪ1 (c = 1.06, CHCl3)) in batches of 20 g
in 11% overall yield from furfural.
Scheme 5 Reagents and conditions: a, Zn(CH2I)2ؒDME, CH2Cl2, rt, 18
h; b, I2, PPh3, imidazole, toluene, acetonitrile (2 : 1); c, PPh3, toluene,
reflux; d, KOt-Bu, toluene, 70 ЊC, 30 min, then cyclohexane-1,4-dione
monoethylene ketal, 70 ЊC, 6 h; e, PtO2 (cat.), H2, EtOAc, 40 min;
f, p-TsOH (cat.), acetone, 40 ЊC; g, LDA, THF, Ϫ78 ЊC; then HMPT,
NCCO2Et, Ϫ78 ЊC; h, NaH, (CF3SO2)2NPh, THF, 0 ЊC
rt.
alcohol 23 with a Zn(CH2I)2ؒDME complex13 resulted in a
clean cyclopropanation reaction on a 37 mol scale to provide
the trans-cyclopropane 24 as a racemate. It is well-known that
this process can also be carried out in an enantioselective
fashion.14
Synthesis of vinyl triflate 10
The hydroxy group of 24 was then replaced by iodide.15
Treatment of iodide 25 with triphenylphosphine in refluxing
toluene gave phosphonium salt 26. For the Wittig reaction with
cyclohexane-1,4-dione monoethylene acetal the reaction con-
ditions appeared to be crucial for a successful transformation.16
Ylide formation by using potassium tert-butoxide at 70 ЊC was
followed, after 30 min, by addition of the ketone. Alkene 27 was
obtained in almost quantitative yield after 6 h. Clean hydrogen-
Vinyl triflate 10 was synthesised as shown in Scheme 4. Com-
mercially available 3-(4-methoxyphenyl)propan-1-ol (19) was
converted to hydroxyketone 20 by a literature procedure.9 The
hydroxy group of 20 was protected as silyl ether 21. Subsequent
acylation with methyl cyanoformate10 led to 22 which exists
1
completely in the enol form according to H NMR in CDCl3.
§ The IUPAC name for disiamyl is 1,2-dimethylprop-1-yl.
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Scheme 6 Reagents and conditions: a, CrCl2, NiCl2 (cat.), DMF, 50 ЊC, 18 h; b, LiAlH4, Et2O, rt, 30 min; c, TBDMSCl, imidazole, DMF; d, Ac2O,
pyridine, CH2Cl2; e, CSA (cat.), MeOH, 0 ЊC; f, TPAP, NMO, acetone; g, Ph3P=CH2, THF, 0 ЊC.
ation of the double bond was accomplished using a platinum
1
catalyst with careful monitoring of the reaction by H NMR.
Because the cyclopropane ring was prone to hydrogenolysis the
reaction was stopped after 30 min. Hydrolysis of the acetal in
28 was followed by introduction of the ester group by using
Mander’s procedure.10 Triflation11 of 30 afforded vinyl triflate
12 as a close to equimolar mixture of four diastereoisomers in
11 steps and 25% overall yield from (E)-but-2-ene-1,4-diol.
Seven-membered ring formation
The chromium-mediated coupling17 of aldehyde 5 and vinyl
triflate 6 afforded the α,β-unsaturated lactone 31 (Scheme 6).
Under the reaction conditions a mixture of diastereomers
(69 : 31) was found. The chromium-mediated couplings of
aldehyde 5 and vinyl triflates 10 and 12 gave lactones 32 and 33,
respectively, in a similar yield and diastereoselectivity. At this
point the α,β-unsaturated lactone 31 had to be converted into
RCM precursor 4. A highly efficient six-step procedure was
developed to accomplish this transformation. The sequence
started with a lithium aluminium hydride reduction of the
lactone. The resulting primary hydroxy group of 34 was
protected as a TBDMS ether (35) and the secondary hydroxy
group was then protected as an acetate to give compound 36.
Subsequently the allylic hydroxy group was selectively
deprotected by a catalytic amount of camphorsulfonic acid
(CSA) to afford alcohol 37. The latter was oxidised using
TPAP–NMO to give aldehyde 46, which in crude form was
subjected to a Wittig olefination resulting in RCM precursor
4 in a good overall yield of 67% over six steps. The use of
this protocol for the transformation of 32 and 33 resulted in a
six-step route to 48 and 50 in overall yields of 46% and 61%,
respectively.
When triene 4 was subjected to a catalytic amount of
Grubbs’ catalyst18 the cyclisation appeared to be extremely
slow. In fact one equiv. of this catalyst in hot toluene was
required to get a full conversion of the starting material. This
problem could be solved by using second generation
ruthenium-based catalysts 5119 or 5220 (Scheme 7). Gratifyingly,
only 15 mol% of the unsaturated imidazolin-2-yl catalyst (51)
in hot toluene effected quantitative ring closure of triene 4
after 16 h. Precursors 48 and 50 were somewhat more difficult
to cyclise. Eventually, treatment of these precursors with the
ruthenium catalysts demonstrated that the seven-membered
Scheme 7
ring can be efficiently constructed via RCM furnishing 54 and
55 in excellent yields.
Introduction of the oxygen substituents
Having the dienes 53–55 available, the least-substituted double
bond needed to be functionalised with oxygen substituents. The
first attempt at this involved the introduction of a 1,2-diketone
in one step using KMnO4 in acetic anhydride.21 This reagent
mixture led to complete cleavage of the C᎐C bond resulting in
᎐
a diacid. It was then decided to introduce the 1,2-diketone
via a milder three-step procedure. First the least hindered
double bond was dihydroxylated (Scheme 8). Remarkably,
catalytic osmium tetraoxide in the presence of stoichiometric
N-methylmorpholine N-oxide appeared to be fully inactive. It is
well-known that the reactivity of osmium tetraoxide can be
increased by the addition of tertiary amines.22 Recent studies on
the mechanistic details of amine-accelerated dihydroxylation
with osmium tetraoxide by Corey and coworkers23 suggested
that a 2 : 1 complex of DMAP and osmium tetraoxide could be
effective for this transformation. In fact, this reagent caused
smooth and selective dihydroxylation of the least hindered
J. Chem. Soc., Perkin Trans. 1, 2002, 1701–1713
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Scheme 8 Reagents and conditions: a, OsO4 (1 equiv.), DMAP (2 equiv.), t-BuOH–H2O (1 : 1), rt, 30 min; b, Na2SO3; c, Dess–Martin periodinane,
CH2Cl2 Ϫ20 ЊC
rt; d, Cu(OAc)2, MeOH, reflux; e, Ag2O, MeI, DMF.
double bond. The parent system 53 gave a 78 : 22 diastereo-
meric mixture of cis-diols 56. RCM products 54 and 55 were
also readily dihydroxylated, but the ratio of cis-diols could not
be determined due to the complexity of the isomer mixtures.
The next step was the oxidation of both hydroxy groups.
Direct double oxidation of the mixture of 56 to the 1,2-
diketone by using DMSO-based reagents did not lead to any
isolable products. The use of manganese dioxide or TPAP as
the oxidant was also unsuccessful. These reagents caused a
rapid oxidative cleavage of the C–C bond to give a dialdehyde
in an almost quantitative yield.24
Scheme 9 Reagents and conditions: a, HFؒpyridine, THF, 0 ЊC; b,
TPAP, NMO, acetone; c, K2CO3, MeOH.
Faced with these disappointing results, it became obvious
that simultaneous oxidation of both hydroxy groups to arrive at
the diketone was not possible. Fortunately, it appeared feasible
to oxidise the hydroxy groups separately. In analogy with liter-
ature reports,25 the more reactive allylic hydroxy group of
56–58 could be oxidised with Fétizon’s reagent26 to give
α-hydroxyketones 59, 60 and 61, respectively. It was then found
that the α-hydroxyketones could be obtained even more
efficiently from the diols by using 1 equiv. of the Dess–Martin
periodinane,27 if the reaction was carefully monitored to
prevent over-oxidation. The α-hydroxyketones were obtained as
single isomers, presumably by equilibration of H-6 under the
reaction conditions. In these isomers H-5 and H-6 have a trans-
configuration (J = 12 Hz) to allow intramolecular hydrogen
bond formation between the hydroxy group and the ketone.
The last step to the diketone was the oxidation of the second
hydroxy group. To prevent C–C bond cleavage as observed
in previous oxidative methods, an alternative oxidative agent
was used. It is known that α-hydroxyketones can be oxidised to
α-diketones by using cupric acetate.28 Even though to the best
of our knowledge cupric acetate has never been used for the
synthesis of seven-membered ring 1,2-diketones, this reagent
was investigated. Gratifyingly, treatment of the hydroxyketones
(59–61) with cupric acetate in refluxing methanol resulted in the
desired 1,2-diketones, which existed completely in the enol form
according to NMR data. Because these enols proved to be
rather unstable they were directly methylated. The significantly
more stable methyl enol ethers 63, 65 and 67 were obtained in
excellent yields.
ation. The X-ray analysis proved the structure of 2, including
the orientation of the hydroxy group which was introduced via
the chromium-mediated coupling (Fig. 1).
Fig. 1 ORTEP plot of the crystal structure of 2.
In the last few steps of the synthesis of the solanoeclepin
A analogue, 9, the two silyl ethers of 65 were hydrolysed using
TBAF, which was made slightly acidic by the addition of acetic
acid (Scheme 10). Diol 70 was subsequently oxidised to keto
Completion of the synthesis
To complete the synthesis of the tetracyclic left-handed
substructure 2 the silyl ether in 63 was cleaved (Scheme 9).
Subsequent oxidation of the liberated hydroxy group and
removal of the acetate group of 69 resulted in the desired
product (2), which was
a stable crystalline compound
(mp 173 ЊC) with a high optical rotation ([α]2D4 ϩ495 × 10Ϫ1 deg
cm2 gϪ1 (c = 0.6, CHCl3)).
Upon recrystallisation of 2 colourless crystals were obtained,
which appeared suitable for X-ray crystal structure determin-
Scheme 10 Reagents and conditions: a, TBAF, HOAc, THF, rt, 16 h;
b, TPAP, NMO, acetone; c, K2CO3, MeOH.
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acid 71. Surprisingly, the TPAP oxidation did not stop at the
aldehyde stage but went on to give the corresponding acid.
Methanolysis of the acetate resulted in the desired compound 9
as a 1 : 1 mixture of two enantiopure diastereomers. Reversed
phase thin layer chromatography afforded the pure diastereo-
meric mixture.
To complete the synthesis of analogue 11 a comparable
approach was used. After removal of the silyl ethers from 67
the resulting diol 72 was treated with TPAP–NMO (Scheme
11). In this case the oxidation stopped at the aldehyde stage and
Fig. 2 PCN hatching activity tests.
be concluded that a carboxylic acid function tethered to
compound 2, which itself is devoid of any hatching activity,
results in biologically active compounds. The role of the length
and the structure of this tether must await further studies.
These results will direct future design and syntheses of
new potentially biologically active solanoeclepin A model
compounds. Eventually, this approach might lead to synthetic-
ally well accessible and biologically active solanoeclepin A
analogues, which could lead to an environmentally benign
method to control PCN.
Conclusion
The syntheses of three solanoeclepin A model compounds
containing the tetracyclic left-handed substructure have been
reported. In a convergent approach these analogues were
assembled via a chromium-mediated coupling of aldehyde
5 with vinyl triflates 6, 10 and 12. The seven-membered ring
was constructed by using a ruthenium catalysed ring-closing
metathesis reaction. Oxidative functionalisation of the least
hindered double bond eventually led to the desired compounds.
The synthetic approach presented augurs well for a successful
completion of the total synthesis of the natural product as soon
as a properly functionalised vinyl triflate becomes available.
Two of the model compounds showed good hatching activity,
which is promising for the development of environmentally
benign methods to control potato cyst nematodes.
Scheme 11 Reagents and conditions: a, TBAF, HOAc, THF, rt, 16 h;
b, TPAP, NMO, acetone; c, NaClO2, 2-methylbut-2-ene, NaH2PO4,
t-BuOH–H2O (1 : 1); d, K2CO3, MeOH.
compound 73 was isolated. Oxidation of the aldehyde moiety
to the acid group was accomplished by using a buffered
solution of sodium chlorite.29 Methanolysis of the acetate then
gave 11, which was isolated as an approximately equimolar
mixture of four enantiopure isomers. Reversed phase thin layer
chromatography afforded the purified diastereomeric mixture
of 11.
Hatching activity tests
The solanoeclepin A model compounds 2, 9 and 11, prepared
as described in this paper, were tested for their biological
activity as hatching agents of potato cyst nematodes. As a
reference substance so-called Potato Root Diffuse (PRD) con-
taining natural hatching material was used. PRD is obtained by
collecting the extract of young, two to ten weeks old, potato
plants.
Experimental1
(1R,2S,4S)-3,3-Dimethyl-1-[(2R*)-tetrahydropyran-2-yloxy-
methyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid ethyl
ester (13)
To a solution of crude alcohol 81 (6.3 g, 20.2 mmol) in CH2Cl2
(150 mL) was added 3,4-dihydro-2H-pyran (4.6 mL, 51 mmol,
2.5 equiv.) and a catalytic amount of p-TsOHؒH2O (38 mg, 0.20
mmol, 1 mol%). The reaction mixture was stirred at rt for 16 h.
Then the reaction mixture was quenched by adding saturated
aqueous NaHCO3 (250 mL) and extracted with CH2Cl2
(3 × 250 mL). The combined organic layers were washed with
brine and subsequently dried over Na2SO4 and the solvent was
removed in vacuo. Column chromatography (petroleum ether–
EtOAc (8 : 2)) furnished the protected alcohol 13 (5.71 g,
18.4 mmol, 91%) as a colourless oil as a mixture of diastereo-
mers; Rf = 0.64 (petroleum ether–EtOAc (3 : 7)); IR 2945, 1737,
1032; 1H NMR (500 MHz) δ 6.48–6.45 (2H, m), 4.69 (0.5H, m),
4.59 (0.5H, m), 4.37 (1H, m), 4.25–4.12 (3H, m), 4.06–4.01 (1H,
m), 3.88–3.81 (1H, m) 3.53–3.51 (1H, m), 2.25 (1H, m), 1.81–
1.50 (6H, m), 1.28 (3H, m), 1.12 (3H, s), 1.06 (3H, s); 13C NMR
In the hatching activity tests30 potato cyst nematode (PCN)
eggs (ca. 300 eggs in 4 mL of water at pH = 4) were subjected to
the new compounds in a range of concentrations. These PCN
eggs were isolated from their protective cyst to increase their
biological response towards the hatching agent. The various
testing samples were obtained by diluting the following
stock solutions (N (relative concentration) = 1): 125 mg LϪ1 of
compound 2, 250 mg LϪ1of compound 9 and 500 mg LϪ1
of compound 11, 2, 10, 20 and 100 times.
After 10 days (the optimum hatching time30) the number of
PCN hatched was estimated (Fig. 2). In the in vivo tests two
of the synthesised solanoeclepin A analogues 9 and 11 showed
promising hatching activity. The hatching activity curves for
these compounds are similar to the one of PRD (with the
exception of the highest concentration of compound 9). It can
J. Chem. Soc., Perkin Trans. 1, 2002, 1701–1713
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(125 MHz) δ 171.8, 137.3, 136.9, 135.4, 135.3, 99.3, 98.9, 90.4,
89.7, 87.0, 86.9, 65.6, 65.6, 62.0, 62.0, 60.0, 59.8, 55.8, 55.2,
44.4, 44.1, 30.3, 30.3, 26.3, 26.2, 25.3, 25.3, 24.9, 24.8, 19.2,
19.2, 14.4, 14.3; HRMS (FAB) [M ϩ Hϩ] calcd for C17H27O5:
311.1859, found: 311.1851.
(125 MHz) δ 171.0, 170.6, 135.7, 135.6, 134.0, 134.0, 133.8,
133.8, 129.6, 129.6, 127.6, 99.2, 98.9, 91.7, 91.6, 87.3, 86.6, 72.0,
71.9, 68.3, 66.8, 62.1, 61.9, 59.8, 59.7, 59.6, 59.1, 47.9, 45.9,
43.2, 42.8, 30.5, 30.4, 26.8, 25.4, 25.3, 25.1, 25.1, 24.5, 24.5,
19.3, 19.2, 19.0, 14.3, 14.2; HRMS (FAB) [M ϩ Hϩ] calcd for
C33H47O6Si: 567.3142, found: 567.3123.
(1R,2S,4R,5S)-5-Hydroxy-3,3-dimethyl-1-[(2R*)-tetrahydro-
pyran-2-yloxymethyl]-7-oxabicyclo[2.2.1]heptane-2-carboxylic
acid ethyl ester (14)
(1R,2R,4R,5S)-5-{(tert-Butyldiphenylsilyloxy)-3,3-dimethyl-1-
[(2R*)-tetrahydropyran-2-yloxymethyl]-7-oxabicyclo[2.2.1]-
heptan-2-yl}methanol (16)
A solution of 2-methylbut-2-ene (33.5 mL of a 2.0 M solution
in THF, 67 mmol, 2 equiv.) in THF (30.2 mL) was cooled
to 0 ЊC and a borane–methyl sulfide complex (3.20 mL,
34.0 mmol) was added dropwise. The reaction mixture was
allowed to warm to rt and was stirred for 4 h giving a 0.5 M
solution of disiamylborane in THF.
A solution of ester 15 (5.6 g, 9.9 mmol) in Et2O (80 mL) was
cooled to Ϫ78 ЊC and lithium aluminium hydride (14.8 mL of
a 1.0 M solution in Et2O, 14.8 mmol, 1.5 equiv.) was added
dropwise. The reaction mixture was allowed to warm to rt
and was stirred for 15 min. Then the mixture was quenched by
adding EtOAc followed by saturated aqueous Na2SO4 (0.5 mL)
and was dried over Na2SO4 and filtered to remove any solids.
Evaporation of the solvent gave alcohol 16 (5.0 g, 9.4 mmol,
95%) as a colourless oil, as a 1 : 1 mixture of diastereomers; Rf =
0.14 (petroleum ether–Et2O (1 : 1)); IR 3474 (br), 3071, 2942,
A solution of alkene 13 (4.54 g, 14.6 mmol) in THF (10 mL)
was cooled to Ϫ60 ЊC. To this solution was added disiamyl-
borane (44 mL of a 0.5 M solution in THF, 22.0 mmol,
1.5 equiv.) and the colourless reaction mixture was stirred at
Ϫ20 ЊC for 16 h. The reaction was allowed to warm to 0 ЊC and
NaOH (32 mL of a 3.0 M solution, 96 mmol, 6.5 equiv.) was
carefully added, followed by H2O2 (14 mL of a 35 wt% solution
in water, 144 mmol, 10 equiv.). After stirring the reaction
mixture for 3 h, saturated aqueous NH4Cl (40 mL) was added
and the aqueous layer was extracted with EtOAc (3 × 75 mL).
The combined organic layers were washed with brine and
subsequently dried over Na2SO4 and the solvent was removed
in vacuo. Column chromatography (petroleum ether–EtOAc
(2 : 8)) afforded alcohol 14 (3.59 g, 10.9 mmol, 76%) as a colour-
less oil as a 1 : 1 mixture of diastereomers (and its other
regioisomer (378 mg, 1.15 mmol, 8%) as a 1 : 1 mixture of
diastereomers, as a colourless oil); Rf = 0.27 (Rf regioisomer =
0.46)(petroleum ether–EtOAc (3 : 7)); IR 3447 (br), 2954, 1737,
1
1113, 1068, 1033; H NMR (400 MHz) δ 7.73–7.63 (4H, m),
7.44–7.35 (6H, m), 4.69–4.65 (1H, m), 4.38–4.37 (1H, m), 4.20
(0.5H, d, J = 10.6 Hz), 4.14 (0.5H, d, J = 10.1 Hz), 3.90–3.83
(1.5H, m), 3.74–3.52 (1.5H, m), 3.48–3.41 (2H, m), 3.39–3.31
(1H, m), 2.03 (1H, m), 2.01–1.94 (1.5H, m), 1.79–1.72 (3H, m),
1.63–1.39 (4.5H, m), 1.06 (4.5H, s), 1.06 (4.5H, s), 0.81 (3H, s),
0.65 (3H, s); 13C NMR (100 MHz) δ 135.7, 135.7, 134.1, 134.0,
133.9, 129.6, 129.6, 127.6, 99.6, 99.4, 92.4, 92.3, 86.7, 86.4, 72.2,
72.0, 68.1, 67.5, 63.1, 62.9, 60.1, 60.0, 56.4, 48.2, 47.5, 41.3,
41.2, 30.5, 30.4, 26.8, 25.1, 24.6, 24.5, 22.9, 22.8, 19.7, 19.6,
19.0; HRMS (FAB) [M ϩ Hϩ] calcd for C31H45O5Si: 525.3036,
found: 525.3022.
1
1140, 1029; H NMR (400 MHz) δ (0.5H, m), 4.54 (0.5H, m),
(1R,2S,4R,5S)-5-(tert-Butyldiphenylsilyloxy)-3,3-dimethyl-1-
[(2R*)-tetrahydropyran-2-yloxymethyl]-7-oxabicyclo[2.2.1]-
heptane-2-carbaldehyde (17)
4.31 (1H, m), 4.17–4.08 (3H, m), 4.00 (1H, dd, J = 9.7, 7.1 Hz),
3.88–3.82 (1.5H, m), 3.78–3.73 (0.5H, m), 3.54–3.47 (1H, m),
2.33 (0.5H, s), 2.32 (0.5H, s), 2.20 (0.5H, dd, J = 13.8, 7.0 Hz),
2.09–2.00 (1H, m) 1.95 (0.5H, br s), 1.85 (0.5H, d, J = 13.8 Hz),
1.79–1.42 (6H, m), 1.28–1.23 (3H, m), 1.19 (1.5H, s), 1.19
(1.5H, s), 1.05 (3H, s); 13C NMR (100 MHz) δ 170.8, 170.5,
99.6, 98.9, 91.9, 91.9, 87.5, 87.2, 71.3, 71.2, 67.9, 66.4, 62.3,
62.0, 60.4, 60.0, 59.9, 59.6, 47.0, 45.5, 43.2, 43.0, 30.5, 30.4,
25.4, 25.3, 25.2, 25.1, 19.3, 19.2, 14.4, 14.2; HRMS (FAB)
[M ϩ Hϩ] calcd for C17H29O6: 329.1964, found: 329.1960.
To a solution of alcohol 16 (4.8 g, 9.2 mmol) in acetone (40 mL)
were added NMO (1.6 g, 13.7 mmol, 1.6 equiv.) and TPAP
(40 mg, 0.11 mmol, 1.2 mol%). The reaction mixture was stirred
for 2 h and filtered over a thin pad of silica, followed by
exhaustive rinsing with EtOAc. Evaporation of the solvents
and column chromatography (petroleum ether–Et2O (4 : 1))
afforded aldehyde 17 (4.2 g, 8.1 mmol, 88%) as a colourless oil,
as a 1 : 1 mixture of diastereomers; Rf = 0.48 (petroleum ether–
1
Et2O (1 : 1)); IR 2939, 2858, 1713, 1111, 1068; H NMR (400
(1R,2S,4R,5S)-5-(tert-Butyldiphenylsilyloxy)-3,3-dimethyl-1-
[(2R*)-tetrahydropyran-2-yloxymethyl]-7-oxabicyclo[2.2.1]-
heptane-2-carboxylic acid ethyl ester (15)
MHz) δ 9.63 (0.5H, d, J = 6.2 Hz), 9.60 (0.5H, d, J = 6.2 Hz),
7.68 (2H, d, J = 7.8 Hz), 7.63 (2H, d, J = 7.8 Hz), 7.46–7.36 (6H,
m), 4.69 (0.5H, m), 4.63 (0.5H, m), 4.35 (1H, dd, J = 6.6, 2.0
Hz), 4.09 (0.5H, d, J = 11.4 Hz), 4.02 (0.5H, d, J = 11.4 Hz),
3.82–3.62 (3H, m), 3.58–3.49 (1H, m), 1.92 (0.5H, dd, J = 13.0,
6.9 Hz), 1.89–1.49 (8.5H, m), 1.07 (9H, s), 1.02 (1.5H, s), 1.02
(1.5H, s), 0.69 (1.5H, s), 0.68 (1.5H, s); 13C NMR (100 MHz)
δ 203.5, 135.8, 135.7, 133.9, 133.7, 129.8, 129.7, 127.7, 98.8,
98.7, 91.9, 89.2, 89.0, 72.2, 71.7, 67.2, 66.4, 65.9, 65.7, 61.7,
61.4, 46.0, 45.2, 44.4, 44.3, 30.0, 30.0, 25.3, 25.3, 25.1, 25.0,
24.9, 19.0, 18.8, 18.6.
To a solution of alcohol 14 (3.65 g, 11.1 mmol) in CH2Cl2
(150 mL) was added TBDPSCl (6.37 mL, 24.5 mmol,
2.2 equiv.) and imidazole (2.50 g, 36.7 mmol, 3.3 equiv.). The
reaction mixture was stirred for 16 h at rt. Then the reaction
mixture was poured into water (100 mL) and after separation
of the organic layer the aqueous layer was extracted with
EtOAc (2 × 200 mL). The combined organic layers were washed
with brine and subsequently dried over Na2SO4 and the solvent
was removed in vacuo. Column chromatography (petroleum
ether–Et2O (9 : 1)) afforded the protected alcohol 15 (5.59 g,
9.88 mmol, 89%) as a colourless oil, as a 1 : 1 mixture of dia-
stereomers; Rf = 0.76 (petroleum ether–Et2O (1 : 1)); IR 2946,
(1R,2S,4R,5S)-tert-Butyl{6,6-dimethyl-4-[(2R*)-tetrahydro-
pyran-2-yloxymethyl]-5-vinyl-7-oxabicyclo[2.2.1]heptan-2-
yloxy}diphenylsilane (7)
1
1740, 1113, 1071, 1032; H NMR (500 MHz) δ 7.70–7.64 (4H,
m), 7.45–7.36 (6H, m), 4.74 (0.5H, m), 4.51 (0.5H, m), 4.39–
4.35 (1H, m), 4.14–3.99 (4H, m), 3.88–3.84 (0.5H, m), 3.80–3.75
(0.5H, m), 3.65 (0.5H, s), 3.64 (0.5H, s), 3.63–3.51 (1H, m), 2.16
(0.5H, s), 2.15 (0.5H, s), 2.11 (0.5H, dd, J = 12.9, 6.8 Hz), 2.00
(0.5H, d, J = 12.4 Hz), 1.89 (0.5H, dd, J = 12.9, 6.8 Hz), 1.80–
1.71 (2H, m), 1.64–1.44 (4.5H, m), 1.22 (1.5H, t, J = 7.0 Hz),
1.21 (1.5H, t, J = 7.0 Hz), 1.07 (4.5H, s), 1.06 (4.5H, s), 0.88
(1.5H, s), 0.87 (1.5H, s), 0.76 (1.5H, s), 0.74 (1.5H, s); 13C NMR
A solution of methyltriphenylphosphonium bromide (7.52 g,
21.1 mmol, 2.55 equiv.) in THF (200 mL) was cooled to 0 ЊC
and n-BuLi (12.8 mL of a 1.6 M solution in hexanes, 20.5
mmol, 2.5 equiv.) was added. The yellow suspension was stirred
at 0 ЊC for 1 h and then aldehyde 17 (4.31 g, 8.25 mmol) in THF
(50 mL) was added via a double tipped needle. The reaction
mixture was allowed to warm to rt and stirring was continued
for 2 h. The reaction was then quenched by adding acetone
1706
J. Chem. Soc., Perkin Trans. 1, 2002, 1701–1713

View Article Online
(colour changed from yellow to white). The reaction mixture
was diluted with Et2O (200 mL) and was washed with water
(200 mL). After separation of the organic layer the aqueous
layer was extracted with Et2O (2 × 200 mL). The combined
organic layers were washed with brine and subsequently dried
over Na2SO4 and the solvent was removed in vacuo. Column
chromatography (petroleum ether–EtOAc (9 : 1)) afforded
protected alcohol 7 (3.82 g, 7.34 mmol, 89%) as a colourless oil,
as a mixture of diastereomers; Rf = 0.64 (petroleum ether–Et2O
(1 : 1)); IR 3071, 2943, 2860, 1113, 1070; 1H NMR (500 MHz)
δ 7.71–7.67 (4H, m), 7.45–7.37 (6H, m), 5.70–5.59 (1H, m),
4.97–4.94 (1H, m), 4.85–4.80 (1.5H, m), 4.59 (0.5H, m), 4.40
(1H, m), 3.97–3.92 (1H, m), 3.85–3.81 (0.5H, m), 3.76–3.74
(0.5H, m), 3.69–3.61 (2H, m), 3.54–3.50 (1H, m), 2.12 (0.5H, d,
J = 13.0 Hz), 1.95–1.44 (8.5H, m), 1.08 (4.5H, s), 1.08 (4.5H, s),
0.81 (1.5H, s), 0.80 (1.5H, s), 0.66 (1.5H, s), 0.64 (1.5H, s);
13C NMR (125 MHz) δ 136.4, 135.8, 135.8, 135.7, 135.7, 134.3,
134.3, 134.1, 134.1, 129.6, 129.5, 127.6, 127.6, 116.6, 116.2,
98.8, 98.6, 91.9, 91.8, 88.4, 87.7, 72.4, 72.3, 67.2, 65.7, 62.0,
61.5, 61.4, 60.7, 45.3, 43.7, 42.7, 42.7, 30.5, 30.4, 26.9,
26.8, 25.6, 25.5, 25.1, 25.0, 24.5, 24.4, 19.2, 19.0, 18.9); HRMS
(FAB) [M ϩ Hϩ] calcd for C32H45O4Si: 521.3087, found:
521.3050.
4-[3-(tert-Butyldiphenylsilyloxy)propyl]cyclohexanone (21)
To a solution of ketone 20 (13 g, 83 mmol, prepared according
to the literature9) in DMF (70 mL) were added imidazole
(11.3 g, 166 mmol, 2 equiv.) and TBDPSCl (22.8 g, 83 mmol,
1 equiv.). After stirring the solution at rt for 16 h, the mixture
was poured into water (150 mL). After separation of the
organic layer the aqueous layer was extracted with EtOAc (3 ×
50 mL). The combined organic layers were washed with brine
and dried over Na2SO4. Evaporation of the solvent and column
chromatography (petroleum ether–EtOAc (4 : 1)) afforded
ketone 21 (30 g, 76 mmol, 91%) as a colourless oil; Rf = 0.22
(petroleum ether–EtOAc (9 : 1)); IR 2931, 2858, 1716, 1428,
1111; 1H NMR (400 MHz) δ 7.67–7.65 (4H, m), 7.45–7.36 (6H,
m), 3.67 (2H, t, J = 6.4 Hz), 2.38–2.23 (4H, m), 2.04–1.97 (2H,
m), 1.67–1.58 (3H, m), 1.41–1.32 (4H, m), 1.05 (9H, s); 13C
NMR (100 MHz) δ 212.3, 135.5, 133.9, 129.5, 127.5, 63.8, 40.7,
35.5, 32.6, 31.5, 30.0, 26.7, 19.0.
rac-5-[3-(tert-Butyldiphenylsilyloxy)propyl]-2-hydroxycyclohex-
1-enecarboxylic acid methyl ester (22)
A solution of ketone 21 (7.47 g, 19 mmol) in THF (15 mL) was
cooled to Ϫ78 ЊC. To this solution was added LDA (21.0 mL of
a 1.0 M solution in THF, 21.0 mmol, 1.1 equiv.) and the
reaction mixture was allowed to warm to 0 ЊC in ca. 1 h. After
cooling the reaction mixture to Ϫ78 ЊC, HMPT (3.4 mL,
28.5 mmol, 1.5 equiv.) was added followed by methyl
cyanoformate (2.51 mL, 28.5 mmol, 1.5 equiv.) and stirring was
continued at Ϫ78 ЊC for 10 min. The reaction was quenched by
pouring it into water. After separation of the organic layer the
aqueous layer was extracted with Et2O (3 × 30 mL). The com-
bined organic layers were washed with brine and subsequently
dried over Na2SO4. Evaporation of the solvent and column
chromatography (petroleum ether–Et2O (9 : 1)) afforded ester
22 (9.2 g). The crude product was used in the next step; Rf =
0.42 (petroleum ether–EtOAc (9 : 1)); IR 3071, 2931, 2857,
(؉)-(1R,2S,4R,5S)-[5-(tert-Butyldiphenylsilyloxy)-3,3-
dimethyl-2-vinyl-7-oxabicyclo[2.2.1]heptan-1-yl]methanol (18)
Protected alcohol 7 (1.9 g, 3.7 mmol) was dissolved in a mixture
of HOAc–THF–water (4 : 2 : 1 v/v/v) (35 mL) and heated at 60
ЊC for 16 h. Evaporation of the solvents and column chrom-
atography (petroleum ether–Et2O (4 : 1)) afforded alcohol 18
(1.5 g, 3.4 mmol, 96%) as a colourless oil; Rf = 0.43 (petroleum
ether–Et2O (1 : 1)); [α]2D0 ϩ18.9 (c = 1.02, CHCl3); IR 3459 (br),
1
3071, 2958, 1112, 1077; H NMR (400 MHz) δ 7.69–7.58 (4H,
m), 7.42–7.33 (6H, m), 5.67 (1H, ddd, J = 17.0, 10.4, 10.3 Hz),
4.99 (1H, dd, J = 10.0, 2.1 Hz), 4.87 (1H, dd, J = 16.9, 2.0 Hz),
4.39 (1H, dd, J = 6.8, 2.2 Hz), 3.84 (1H, d, J = 12.3 Hz), 3.64
(1H, s), 3.59 (1H, d, J = 12.3 Hz), 1.99 (1H, d, J = 12.7 Hz), 1.87
(1H, br s), 1.82 (1H, dd, J = 12.8, 6.9 Hz), 1.74 (1H, d, J = 10.7
Hz), 1.07 (9H, s), 0.80 (3H, s), 0.61 (3H, s); 13C NMR (100
MHz) δ 135.9, 135.8, 135.7, 134.1, 133.9, 129.7, 129.6, 127.6,
116.9), 92.0, 88.9, 72.5, 62.4, 60.4, 44.3, 43.2, 26.9, 24.9, 24.3,
19.0; HRMS (EI) calcd for C27H36O3Si: 436.2434, found:
436.2433.
1
1659, 1616, 1214, 1119; H NMR (400 MHz) δ 12.14 (1H, s),
7.69–7.66 (4H, m), 7.43–7.36 (6H, m), 3.76 (3H, s), 3.67 (2H, t,
J = 6.4 Hz), 2.42–2.37 (1H, m), 2.30–2.05 (2H, m), 1.86–1.73
(2H, m), 1.65–1.52 (3H, m), 1.51–1.42 (3H, m), 1.06 (9H, s); 13
C
NMR (100 MHz) δ 176.1, 172.9, 172.8, 135.0, 134.0, 133.9,
132.0, 130.8, 129.8, 129.5, 129.4, 127.5, 96.9, 63.9, 63.7, 51.2,
35.0, 32.9, 33.2, 30.0, 28.8, 27.9, 27.8, 26.8, 19.1; HRMS (FAB)
[M ϩ Hϩ] calcd for C27H37O4Si: 453.2461, found: 453.2468.
(؉)-(1R,2S,4R,5S)-5-(tert-Butyldiphenylsilyloxy)-3,3-dimethyl-
2-vinyl-7-oxabicyclo[2.2.1]heptanecarbaldehyde (5)
rac-5-[3-(tert-Butyldiphenylsilyloxy)propyl]-2-trifluoromethyl-
sulfonyloxycyclohex-1-enecarboxylic acid methyl ester (10)
To a solution of alcohol 18 (1.0 g, 2.3 mmol) in CH2Cl2 (10 mL)
was added DMSO (2.6 mL, 36.6 mmol, excess) and triethyl-
amine (1.8 mL, 12.9 mmol, 6 equiv.) followed by SO3ؒpyridine
(1.2 g, 7.5 mmol, 3 equiv.). The orange reaction mixture was
stirred at rt for 3 h. Then the reaction mixture was diluted by
adding Et2O (30 mL) and quenched with saturated aqueous
NH4Cl (30 mL). After separation of the organic layer the aque-
ous layer was extracted with Et2O (2 × 30 mL). The combined
organic layers were washed with brine and subsequently dried
over Na2SO4 and the solvent was removed in vacuo. Column
chromatography (petroleum ether–Et2O (4 : 1)) afforded alde-
hyde 5 (829 mg, 1.9 mmol, 83%) as a light yellow oil; Rf = 0.52
(petroleum ether–Et2O (1 : 1)); [α]2D2 ϩ19.2 (c = 1.06, CHCl3); IR
3072, 2961, 2858, 1732, 1111, 1068; 1H NMR (400 MHz) δ 9.84
(1H, s), 7.68 (2H, d, J = 6.4 Hz), 7.62 (2H, d, J = 6.5 Hz),
7.46–7.37 (6H, m), 5.54 (1H, ddd, J = 17.0, 10.4, 10.3 Hz), 5.02
(1H, dd, J = 10.1, 1.8 Hz), 4.90 (1H, dd, J = 16.9, 1.6 Hz), 4.39
(1H, dd, J = 6.8, 2.2 Hz), 3.77 (1H, s), 2.13–2.02 (2H, m), 1.80
(1H, d, J = 12.8 Hz), 1.06 (9H, s), 0.84 (3H, s), 0.62 (3H, s);
13C NMR (100 MHz) δ 203.2, 138.7, 138.6, 137.8, 137.6, 136.7,
136.5, 132.8, 132.8, 132.5, 130.7, 130.5, 121.0, 95.4, 95.2, 74.2,
64.5, 46.7, 45.9, 29.8, 27.9, 27.1, 22.0; HRMS (FAB) [M ϩ Hϩ]
calcd for C27H35O3Si: 435.2355, found: 435.2339.
A solution of β-ketoester 22 (9.2 g) in THF (50 mL) was cooled
to 0 ЊC. To this solution was carefully added NaH (0.85 g of
a 60% dispersion in mineral oil, 21 mmol, 1.1 equiv.) and
stirring was continued for 30 min. Then N-phenyltrifluoro-
methanesulfonimide(3.8g,21mmol,1.1equiv.)wasaddedinone
portion and the reaction mixture was allowed to warm to rt in ca.
90 min. Then the reaction mixture was carefully poured into
saturated aqueous NaHCO3 (40 mL) and after separation
of the organic layer, the aqueous layer was extracted with Et2O
(3 × 30 mL). The combined organic layers were washed with
brine and subsequently dried over Na2SO4. Evaporation of the
solvent and column chromatography (petroleum ether–EtOAc
(4 : 1)) purification afforded vinyl triflate 10 23 (5.5 g, 9.4 mmol,
50% over 2 steps) as a colourless oil; Rf = 0.42 (petroleum ether–
EtOAc (9 : 1)); IR 3072, 2931, 2858, 1730, 1426, 1211; 1H NMR
(400 MHz) δ 7.69–7.64 (4H, m), 7.46–7.35 (6H, m), 3.81 (3H, s),
3.68 (2H, t, J = 6.4 Hz), 2.64–2.63 (1H, m), 2.60–2.41 (2H, m),
2.08–2.00 (1H, m), 1.87–1.83 (1H, m), 1.64–1.53 (3H, m),
1.42–1.22 (3H, m), 1.06 (9H, s); 13C NMR (100 MHz) δ 164.9,
151.6, 135.5, 133.8, 129.5, 127.6, 122.1, 118.5 (q, J = 317 Hz),
63.7, 52.0, 32.2, 31.9, 31.2, 29.7, 28.3, 28.0, 26.8, 19.1; HRMS
(FAB) [M ϩ Hϩ] calcd for C28H36F3O6SSi: 585.1954, found:
585.1928.
J. Chem. Soc., Perkin Trans. 1, 2002, 1701–1713
1707

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(R*,R*)-[2-(tert-Butyldiphenylsilyloxymethyl)cyclopropyl]-
methanol (24)
1.1 equiv.) in toluene (80 mL) was heated to 70 ЊC. To this
suspension was added KOt-Bu (15.0 mL of a 1.0 M solution in
THF, 15 mmol, 1.0 equiv.) and stirring was continued at 70 ЊC
for 30 min. To the brown solution was added cyclohexane-1,4-
dione monoethylene ketal (2.30 g, 14.7 mmol) and the reaction
mixture was stirred at 70 ЊC for 6 h. Then the reaction mixture
was poured into water (150 mL) and after separation
of the organic layer the aqueous layer was extracted with Et2O
(3 × 150 mL). The combined organic layers were washed with
brine and subsequently dried over Na2SO4. Evaporation of the
solvent and column chromatography (petroleum ether–Et2O
(9 : 1)) afforded alkene 27 (6.53 g, 14.1 mmol, 95%) as a colour-
less oil; Rf = 0.58 (petroleum ether–Et2O (1 : 1)); IR 3071, 2954,
1117, 1078; 1H NMR (500 MHz) δ 7.68–7.65 (4H, m), 7.44–7.35
(6H, m), 4.61 (1H, d, J = 9.0 Hz), 3.97 (4H, s), 3.65 (1H, dd,
J = 10.7, 5.8 Hz), 3.55 (1H, dd, J = 10.7, 6.3 Hz), 2.38 (2H, t, J =
6.2 Hz), 2.20 (2H, t, J = 6.2 Hz), 1.69–1.65 (4H, m), 1.39–1.34
(1H, m), 1.04 (9H, s), 0.91–0.85 (1H, m), 0.63–0.59 (1H, m),
0.47–0.42 (1H, m); 13C NMR (125 MHz) δ 135.6, 135.6, 134.7,
129.5, 127.6, 127.6, 127.5, 125.6, 109.0, 66.7, 64.2, 36.1, 35.3,
33.2, 26.8, 25.5, 22.6, 19.2, 15.3, 11.6; HRMS (FAB) [M ϩ Hϩ]
calcd for C29H39O3Si: 463.2668, found: 463.2677.
A solution of 1,2-dimethoxyethane (10.4 mL, 100 mmol,
3 equiv.) in CH2Cl2 (250 mL) was cooled to Ϫ15 ЊC. To this
solution was added Et2Zn (100 mL of a 1.0 M solution in
hexanes, 100 mmol, 3 equiv.) and after 10 min CH2I2 (16.2 mL,
200 mmol, 6 equiv.) was added dropwise at such a rate as to
keep the temperature below Ϫ10 ЊC (approximately 30 min).
The clear solution was stirred at Ϫ20 ЊC for 30 min and allylic
alcohol 23 (12.2 g, 37 mmol)12 in CH2Cl2 (60 mL) was added
dropwise. The reaction mixture was stirred at rt for 18 h and
was then carefully poured into saturated aqueous NaHCO3
(200 mL). After separation of the organic layer the aqueous
layer was extracted with EtOAc (3 × 150 mL). The combined
organic layers were washed with brine and subsequently dried
over Na2SO4. Evaporation of the solvent and column chrom-
atography (petroleum ether–Et2O (3 : 1
1 : 1)) afforded
cyclopropane 24 (9.6 g, 28 mmol, 76%) as a colourless oil; Rf =
0.61 (Et2O); IR 3310 (br), 3070, 2959, 2859, 1112, 1076; H
1
NMR (400 MHz) δ 7.68–7.65 (4H, m), 7.43–7.36 (6H, m), 3.69
(1H, dd, J = 10.8, 5.4 Hz), 3.47–3.41 (3H, m), 1.37 (1H, br s),
1.05 (9H, s), 0.97–0.94 (2H, m), 0.46–0.39 (2H, m); 13C NMR
(100 MHz) δ 135.6, 133.8, 129.6, 127.6, 66.5, 66.4, 26.9, 19.3,
19.2, 19.2, 7.7; HRMS (FAB) [M ϩ Hϩ] calcd for C21H29O2Si:
341.1937, found: 341.1933.
(R*,R*)-tert-Butyl[2-(1,4-dioxaspiro[4.5]decan-8-ylmethyl)-
cyclopropylmethoxy]diphenylsilane (28)
To a solution of alkene 27 (6.49 g, 14.0 mmol) in EtOAc was
added PtO2 (80 mg, 0.35 mmol, 2.5 mol%). The reaction
mixture was stirred under a hydrogen atmosphere (1 atm) for
40 min. Filtration over a thin pad of Celite® and evaporation
of the solvent gave acetal 28 (6.41 g, 13.8 mmol, 98%) as a
colourless oil; Rf = 0.57 (petroleum ether–Et2O (1 : 1)); IR 3070,
(R*,R*)-tert-Butyl[(2-iodomethylcyclopropyl)methoxy]-
diphenylsilane (25)
A solution of cyclopropane 24 (9.4 g, 28 mmol) in dry toluene
(150 mL) and acetonitrile (75 mL) was cooled to 0 ЊC. To this
solution was added triphenylphosphine (10.7 g, 41 mmol,
1.5 equiv.) and stirring was continued at 0 ЊC for 10 min. Then
imidazole (7.6 g, 112 mmol, 4 equiv.) was added. After stirring
at 0 ЊC for 15 min, iodine (10.7 g, 42 mmol, 1.5 equiv.) was
added in portions of ca. 0.5 g in approximately 45 min. The
yellow–brown solution was stirred at 0 ЊC for 30 min. Then the
reaction mixture was poured into saturated aqueous Na2S2O3.
After separation of the organic layer the aqueous layer was
extracted with Et2O (2 × 200 mL). The combined organic layers
were washed with brine and subsequently dried over Na2SO4
and the solvent was removed in vacuo. Column chromatography
(petroleum ether–Et2O (4 : 1)) afforded iodide 25 (9.5 g,
21 mmol, 75%) as a colourless oil; Rf = 0.73 (petroleum ether–
Et2O (2 : 1)); IR 3064, 2932, 2855, 1105, 1072; 1H NMR
(400 MHz) δ 7.68–7.66 (4H, m), 7.43–7.36 (6H, m), 3.63 (1H,
dd, J = 10.8, 5.5 Hz), 3.49 (1H, dd, J = 10.8, 6.1 Hz), 3.13 (2H,
dd, J = 7.7, 3.4 Hz), 1.24–1.18 (1H, m), 1.05 (9H, s), 1.04–0.99
(1H, m), 0.74–0.72 (1H, m), 0.46–0.43 (1H, m); 13C NMR (100
MHz) δ 135.5, 133.7, 133.6, 129.6, 127.5, 65.6, 26.8, 26.7, 21.0,
19.2, 15.2, 12.5; HRMS (FAB) [M ϩ Hϩ] calcd for C21H28IOSi:
451.0954, found: 451.0946.
1
2933, 2859, 1109; H NMR (400 MHz) δ 7.68–7.65 (4H, m),
7.42–7.35 (6H, m), 3.94 (4H, s), 3.67 (1H, dd, J = 10.7, 5.7 Hz),
3.36 (1H, dd, J = 10.7, 7.2 Hz), 1.91–1.70 (4H, m), 1.55–1.49
(3H, m), 1.46–1.34 (1H, m), 1.32–1.14 (3H, m), 1.04 (9H, s),
0.79–0.74 (1H, m), 0.58–0.52 (1H, m), 0.29–0.22 (1H, m), 0.19–
0.16 (1H, m); 13C NMR (100 MHz) δ 135.6, 134.8, 134.1, 134.0,
129.5, 127.6, 127.5, 109.2, 67.7, 64.2, 64.1, 40.5, 37.1, 34.5, 30.3,
30.1, 26.8, 21.0, 19.2, 15.4, 9.5; HRMS (FAB) [M ϩ Hϩ] calcd
for C29H41O3Si: 465.2825, found: 465.2810.
(R*,R*)-4-[2-(tert-Butyldiphenylsilyloxymethyl)cyclopropyl-
methyl]cyclohexanone (29)
To a solution of acetonide 28 (6.39 g, 13.8 mmol) in acetone
(150 mL) was added p-TsOH (100 mg, 0.52 mmol, 4 mol%).
The reaction mixture was stirred at 40 ЊC for 7 h and then
saturated aqueous NaHCO3 was added to the reaction mixture.
The aqueous layer was extracted with Et2O (3 × 150 mL). The
combined organic layers were washed with brine and
subsequently dried over Na2SO4. Evaporation of the solvent
and column chromatography (petroleum ether–Et2O (6 : 1))
afforded ketone 29 (4.41 g, 10.5 mmol, 76%) as a colourless oil;
Rf = 0.42 (petroleum ether–Et2O (2 : 1)); IR 3070, 2931, 2858,
(R*,R*)-[2-(tert-Butyldiphenylsilyloxymethyl)cyclopropyl-
methyl]triphenylphosphonium iodide (26)
1
To a solution of iodide 25 (9.1 g, 20.4 mmol) in toluene
(100 mL) was added triphenylphosphine (5.8 g, 22 mmol,
1.1 equiv.). The colourless solution was stirred at 100 ЊC and
after 16 h a white product precipitated. The precipitate was
collected by filtration and was rinsed with cold toluene.
Recrystallisation of the product from hot toluene afforded
phosphonium salt 26 (12.2 g, 17.1 mmol, 84%) as a white
amorphous solid. Mp 205–206 ЊC; 1H NMR (400 MHz,
CD3OD) δ 7.88–7.66 (15H, m), 7.56–7.51 (4H, m), 7.46–7.35
(6H, m), 3.60–3.32 (4H, m), 1.06–1.00 (2H, m), 0.95 (9H, s),
0.69–0.64 (1H, m), 0.51–0.47 (1H, m).
1715, 1110, 1064; H NMR (400 MHz) δ 7.68–7.65 (4H, m),
7.44–7.35 (6H, m), 3.74 (1H, dd, J = 10.7, 5.4 Hz), 3.34 (1H, dd,
J = 10.7, 7.4 Hz), 2.37–2.27 (4H, m), 2.23–2.18 (1H, m),
2.12–2.08 (1H, m), 1.83–1.76 (1H, m), 1.45–1.36 (4H, m), 1.05
(9H, s), 0.83–0.81 (1H, m), 0.59–0.57 (1H, m), 0.33–0.29 (1H,
m), 0.23–0.19 (1H, m); 13C NMR (100 MHz) δ 212.4, 135.5,
134.0, 133.9, 129.5, 127.6 (Ar), 67.6, 40.9, 40.8, 39.7, 36.9, 32.8,
32.5, 26.8, 21.1, 19.2, 15.3, 9.4; HRMS (FAB) [M ϩ Hϩ] calcd
for C27H37O2Si: 421.2563, found: 421.2574.
5-[2-(tert-Butyldiphenylsilyloxymethyl)-(R*,R*)-cyclopropyl-
methyl]-2-hydroxycyclohex-1-enecarboxylic acid ethyl ester (30)
(R*,S*)-tert-Butyl[2-(1,4-dioxaspiro[4.5]decan-8-ylidene-
methyl)cyclopropylmethoxy]diphenylsilane (27)
Following the same procedure as described for the preparation
A white suspension of phosphonium salt 26 (11.36 g, 16 mmol,
of 22, ketone 29 (2.4 g, 5.7 mmol) was converted to β-ketoester
1708
J. Chem. Soc., Perkin Trans. 1, 2002, 1701–1713

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30 (2.4 g, 4.8 mmol, 84%). Column chromatography (petroleum
ether–Et2O (9 : 1)) afforded β-ketoester 30 as an equimolar
mixture of two diastereomers as a colourless oil; Rf = 0.76
(petroleum ether–Et2O (1 : 1)); IR 3070, 2931, 2858, 1651, 1615,
1216, 1111; 1H NMR (400 MHz) δ 12.2 (0.5H, s), 12.2 (0.5H, s),
7.68–7.65 (4H, m), 7.43–7.35 (6H, m), 4.21–4.15 (2H, m), 3.74
(0.5H, dd, J = 10.7, 5.5 Hz), 3.65 (0.5H, dd, J = 10.7, 5.8 Hz),
3.47 (0.5H, dd, J = 10.8, 6.6 Hz), 3.33 (0.5H, dd, J = 10.6, 7.4
Hz), 2.45–2.42 (1H, m), 2.28 (2H, m), 1.99–1.82 (2H, m),
1.70–1.61 (1H, m), 1.47–1.43 (1H, m), 1.33–1.19 (5H, m), 1.05
(4.5H, s), 1.04 (4.5H, s), 0.99–0.79 (1H, m), 0.62–0.60 (1H, m),
0.35–0.28 (1H, m), 0.22–0.19 (1H, m); 13C NMR (100 MHz)
δ 172.6, 171.8, 171.6, 135.7, 135.5, 134.0, 133.9, 133.8, 129.5,
129.4, 127.4, 97.1, 97.1, 67.6, 67.2, 60.0, 40.0, 39.8, 34.4, 34.1,
28.9, 28.8, 28.7, 27.6, 27.5, 26.8, 26.7, 21.1, 20.7, 19.1, 19.1,
15.1, 14.6, 14.2, 9.7, 9.2; HRMS (FAB) [M ϩ Hϩ] calcd for
C30H43O4Si: 493.2774, found: 493.2792.
(؉)-(S)-[(1R,2S,4R,5S)-5-(tert-Butyldiphenylsilyloxy)-3,3-
dimethyl-2-vinyl-7-oxabicyclo[2.2.1]heptan-1-yl](2-hydroxy-
methylcyclohex-1-enyl)methanol (34)
To a solution of lactone 31 (330 mg, 0.61 mmol) in Et2O (4 mL)
was rapidly added lithium aluminium hydride (1.0 mL of a
1.0 M solution in Et2O, 1 mmol, 1.7 equiv.) in one portion at rt.
The reaction mixture was stirred for 30 min and then quenched
by adding EtOAc and few drops of saturated aqueous Na2SO4.
The reaction mixture was dried over Na2SO4 and filtration and
evaporation of the solvent gave diol 34 (314 mg, 0.57 mmol,
93%) as a colourless viscous oil; Rf = 0.28 (petroleum ether–
Et2O (1 : 3)); [α]1D9 = ϩ15.2 (c = 2.03, CHCl3); IR 3420 (br), 3071,
1
2929, 2857, 1113; H NMR (400 MHz) δ 7.64–7.61 (4H, m),
7.43–7.36 (6H, m), 5.94 (1H, ddd, J = 16.9, 10.4, 10.3 Hz), 5.19
(1H, dd, J = 10.1, 2.1 Hz), 5.08 (1H, s), 5.07 (1H, dd, J = 17.0,
2.0 Hz), 4.38 (1H, d, J = 11.2 Hz), 4.32 (1H, dd, J = 6.5, 1.5 Hz),
3.63 (1H, s), 3.60–3.52 (1H, m), 3.41–3.28 (1H, br s), 2.61–2.52
(1H, m), 2.31–2.10 (2H, m), 2.08–1.99 (2H, m), 1.93 (1H, d,
J = 10.1 Hz), 1.89 (1H, dd, J = 13.5, 7.3 Hz), 1.69–1.60 (4H, m),
1.05 (9H, s), 0.81 (3H, s), 0.67 (3H, s); 13C NMR (100 MHz)
δ 136.5, 136.3, 135.8, 135.7, 134.0, 133.8, 132.7, 129.7, 129.7,
127.7, 116.6, 91.4, 90.6, 72.8, 69.8, 63.1, 62.0, 44.2, 43.4, 29.7,
28.9, 26.9, 26.3, 25.0, 24.3, 22.6, 19.0; HRMS (FAB) [M ϩ Naϩ]
calcd for C34H46NaO4Si: 569.3063, found: 569.3080.
5-[2-(tert-Butyldiphenylsilyloxymethyl)-(R*,R*)-cyclopropyl-
methyl]-2-trifluoromethylsulfonyloxycyclohex-1-enecarboxylic
acid ethyl ester (12)
Following the same procedure as described for the preparation
of 10, β-ketoester 30 (2.4 g, 4.9 mmol) was converted to vinyl
triflate 12. Column chromatography (petroleum ether–Et2O
(9 : 1)) afforded vinyl triflate 12 (2.9 g, 4.7 mmol, 95%) as an
equimolar mixture of two diastereomers as a colourless oil; Rf =
0.67 (petroleum ether–Et2O (2 : 1)); IR 3073, 2934, 2859, 1729,
(؉)-(S)-[2-(tert-Butyldimethylsilyloxymethyl)cyclohex-1-enyl]-
[(1R,2S,4R,5S)-5-(tert-butyldiphenylsilyloxy)-3,3-dimethyl-2-
vinyl-7-oxabicyclo[2.2.1]heptan-1-yl]methanol (35)
1
1415, 1208; H NMR (400 MHz) δ 7.67–7.65 (4H, m, Ar–H),
7.44–7.35 (6H, m), 4.26 (2H, q, 7.1 Hz), 3.74 (0.5H, dd, J =
10.7, 5.4 Hz), 3.68 (0.5H, dd, J = 10.7, 5.5 Hz), 3.40 (0.5H, dd,
J = 10.7, 6.9 Hz), 3.32 (0.5H, dd, J = 10.7, 7.5 Hz), 2.68–2.60
(1H, m), 2.46–2.32 (2H, m), 2.17–2.05 (1.5H, m), 1.98–1.92
(0.5H, m), 1.71–1.56 (1H, m), 1.48–1.17 (6H, m), 1.04 (4.5H, s),
1.03 (4.5H, s), 0.95–0.77 (1H, m), 0.59–0.53 (1H, m), 0.36–0.28
(1H, m), 0.23–0.18 (1H, m); 13C NMR (100 MHz) δ 164.5,
151.2, 151.1, 135.5, 135.3, 133.8, 133.8, 131.9, 131.8, 129.5,
129.5, 127.5, 122.6, 122.5, 118.3 (q, J = 317 Hz), 67.5, 67.1, 61.3,
39.0, 38.9, 33.2, 32.9, 32.4, 32.1, 28.3, 28.2, 27.9, 27.8, 26.7,
26.6, 21.0, 20.7, 19.2, 14.9, 14.4, 13.8, 9.5, 9.1; HRMS (FAB)
[M ϩ Hϩ] calcd for C31H40F3O6SSi: 625.2267, found: 625.2267.
To a solution of diol 34 (312 mg, 0.55 mmol) in DMF (8 mL)
were added imidazole (112 mg, 1.65 mmol, 3 equiv.) and
TBDMSCl (166 mg, 1.10 mmol, 2 equiv.). The reaction mixture
was stirred at rt for 16 h and then poured in water (25 mL). The
aqueous layer was extracted with EtOAc (3 × 25 mL)
and the combined organic layers were washed with brine
and subsequently dried over Na2SO4. After evaporation of the
solvent and column chromatography purification (petroleum
ether–Et2O (9 : 1)) alcohol 35 (323 mg, 0.48 mmol, 89%) was
obtained as a colourless oil. Alcohol 35 could be used crude in
the next reaction; Rf = 0.63 (petroleum ether–Et2O (1 : 1)); [α]1D9
ϩ6.14 (c = 1.32, CHCl3); IR 3471 (br), 3071, 2930, 2857, 1095;
1H NMR (400 MHz) δ 7.69–7.63 (4H, m), 7.45–7.36 (6H, m),
5.66 (1H, ddd, J = 17.0, 10.4, 10.3 Hz), 5.01 (1H, dd, J = 10.0,
2.1 Hz), 4.83 (1H, dd, J = 16.9, 2.1), 4.37 (1H, dd, J = 6.7,
1.7 Hz), 3.96–3.93 (2H, m), 3.73–3.69 (1H, m), 3.52 (1H, s),
2.40 (1H, br s), 2.04 (1H, d, J = 12.7 Hz), 1.92–1.86 (1H, m),
1.77–1.59 (5H, m,), 1.41–1.32 (4H, m), 1.06 (9H, s), 0.91 (9H,
s), 0.75 (3H, s), 0.60 (3H, s), 0.07 (6H, s); 13C NMR (100 MHz)
δ 136.3, 135.8, 135.8, 134.2, 134.0, 129.6, 129.6, 127.6, 116.6,
92.5, 90.7, 72.6, 72.4, 61.1, 61.0, 43.6, 41.5, 27.6, 26.9, 26.6,
26.1, 25.1, 24.3, 21.1, 20.6, 18.9, 18.3, Ϫ5.34, Ϫ5.35.
(؉)-(3S)-3-[(1R,2S,4R,5S)-5-(tert-Butyldiphenylsilyloxy)-3,3-
dimethyl-2-vinyl-7-oxabicyclo[2.2.1]heptan-1-yl]-4,5,6,7-tetra-
hydroisobenzofuran-1(3H)-one (31)
To a solution of aldehyde 5 (280 mg, 0.65 mmol) in DMF
(10 mL) was added vinyl triflate 6 (419 mg, 1.38 mmol,
2.1 equiv.) followed by CrCl2 (320 mg, 2.61 mmol, 4 equiv.) and
NiCl2 (2.4 mg, 18.5 µmol, ca. 1 mol%). The resulting green
reaction mixture was stirred at 50 ЊC for 18 h. After cooling the
mixture to 0 ЊC it was quenched by adding saturated aqueous
NH4Cl (3 mL) followed by water (15 mL). The aqueous mixture
was extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with brine and subsequently dried over
Na2SO4 and the solvent was removed in vacuo. Column
chromatography (petroleum ether–Et2O (9 : 1)) afforded
diastereomeric lactone 31 (223 mg, 0.41 mmol, 64%) and its
isomer (104 mg, 0.19 mmol, 28%) as colourless viscous oils; Rf =
0.51 (Rf isomer = 0.32) (petroleum ether–Et2O (1 : 1)); [α]2D1
ϩ47.9 (c = 0.99, CHCl3); IR 3071, 2933, 2857, 1760, 1111, 1010;
1H NMR (400 MHz) δ 7.65 (2H, d, J = 7.9 Hz), 7.55 (2H, d,
J = 7.9 Hz), 7.46–7.31 (6H, m), 5.67 (1H, ddd, J = 17.0, 10.4,
10.3 Hz), 5.13 (1H, dd, J = 10.1, 1.9 Hz), 5.07–5.03 (2H, m),
4.31 (1H, d, J = 5.9 Hz), 3.58 (1H, s), 2.87–2.80 (1H, m), 2.38–
2.22 (3H, m), 2.00 (1H, d, J = 10.6 Hz), 1.77–1.63 (6H, m), 1.05
(9H, s), 0.78 (3H, s), 0.65 (3H, s); 13C NMR (100 MHz) δ 160.9,
135.7, 135.6, 134.8, 133.9, 133.4, 129.8, 128.1, 127.8, 127.7,
118.7, 92.2, 88.0, 80.9, 71.5, 61.6, 42.3, 40.9, 26.8, 25.5, 24.8,
24.6, 21.7, 21.6, 20.2, 18.3; HRMS (FAB) [M ϩ Hϩ] calcd for
C34H43O4Si: 543.2931, found: 543.2931.
(؉)-(S)-Acetic acid [2-(tert-butyldimethylsilyloxymethyl)-
cyclohex-1-enyl][(1R,2S,4R,5S)-5-tert-butyldiphenylsilyloxy)-
3,3-dimethyl-2-vinyl-7-oxabicyclo[2.2.1]heptan-1-yl]methyl ester
(36)
To a solution of alcohol 35 (387 mg, 0.59 mmol) in CH2Cl2 (2
mL) was added acetic anhydride (0.5 mL, 5.3 mmol, 10 equiv.)
and pyridine (200 µL, 2.5 mmol, 5 equiv.) and stirring was con-
tinued at rt for 16 h. To get full conversion the reaction mixture
was stirred at 50 ЊC for 3 h. Then the mixture was poured into
saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc
(3 × 20 mL). The combined organic layers were washed with
brine and subsequently dried over Na2SO4. Evaporation of the
solvent gave acetate 36 (377 mg, 0.54 mmol, 92%) as an oil.
Acetate 36 was used crude in the next reaction; Rf = 0.66
(petroleum ether–Et2O (1 : 1)); [α]2D0 ϩ15.5 (c = 1.25, CHCl3); IR
3072, 2931, 2857, 1747, 1234, 1113; 1H NMR (400 MHz)
J. Chem. Soc., Perkin Trans. 1, 2002, 1701–1713
1709

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δ 7.66–7.61 (4H, m), 7.42–7.35 (6H, m), 5.74 (1H, s), 5.65 (1H,
ddd, J = 16.9, 10.4, 10.2 Hz), 4.96 (1H, dd, J = 10.0, 2.3 Hz),
4.79 (1H, dd, J = 16.9, 2.2 Hz), 4.47 (1H, d, J = 12.9 Hz), 4.33
(1H, dd, J = 6.5, 1.7 Hz), 4.13 (1H, d, J = 12.9 Hz), 3.54 (1H, s),
2.40–2.31 (1H, m), 2.17–1.99 (3H, m), 1.94 (3H, s), 1.87–1.81
(2H, m), 1.72 (1H, d, J = 12.6 Hz), 1.59–1.53 (4H, m), 1.04 (9H,
s), 0.92 (9H, s), 0.75 (3H, s), 0.63 (3H, s), 0.11 (3H, s), 0.10 (3H,
s); HRMS (FAB) [M ϩ Hϩ] calcd for C42H63O5Si2: 703.4214,
found: 703.4210.
in THF (10 mL) was added via a double tipped needle. The
reaction mixture was stirred for 45 min and then quenched by
adding saturated aqueous NaHCO3. The aqueous layer was
extracted with EtOAc (3 × 30 mL). The combined organic
layers were washed with brine and subsequently dried over
Na2SO4 and the solvent was removed in vacuo. Column
chromatography (petroleum ether–Et2O (9 : 1)) afforded triene
4 (483 mg, 0.83 mmol, 92%) as an oil; Rf = 0.76 (petroleum
ether–Et2O (1 : 1)); [α]2D1 ϩ8.51 (c = 2.1, CHCl3); IR 3072, 2932,
2858, 1747, 1234, 1113, 1027; 1H NMR (400 MHz) δ 7.66–7.60
(4H, m), 7.42–7.34 (6H, m), 7.03 (1H, dd, J = 17.3, 11.1 Hz),
5.85 (1H, s), 5.70 (1H, ddd, J = 16.9, 10.3, 10.3 Hz), 5.21 (1H, d,
J = 17.2 Hz), 5.03 (1H, d, J = 11.1 Hz), 4.97 (1H, dd, J = 10.1,
2.3 Hz), 4.80 (1H, dd, J = 16.9, 2.2 Hz), 4.33 (1H, dd, J = 6.0,
2.2 Hz), 3.63 (1H, s), 2.32–2.18 (4H, m), 1.95 (3H, s), 1.85–1.83
(3H, m), 1.65–1.54 (4H, m), 1.02 (9H, s), 0.78 (3H, s), 0.66 (3H,
s); 13C NMR (100 MHz) δ 169.3, 136.6, 135.7, 135.7, 134.3,
134.1, 132.7, 132.3, 129.6, 129.6, 127.6, 127.6, 116.2, 111.7,
91.4, 89.8, 73.5, 71.8, 62.0, 44.3, 42.6, 28.3, 26.8, 25.5, 25.3,
24.7, 22.5, 22.4, 20.7, 19.0; HRMS (FAB) [M ϩ Hϩ] calcd for
C37H49O4Si: 585.3400, found: 585.3400.
(S)-Acetic acid [(1R,2S,4R,5S)-5-tert-butyldiphenylsilyloxy)-
3,3-dimethyl-2-vinyl-7-oxabicyclo[2.2.1]heptan-1-yl](2-hydroxy-
methylcyclohex-1-enyl)methyl ester (37)
A solution of protected alcohol 36 (428 mg, 0.61 mmol) in
MeOH (20 mL) was cooled to 0 ЊC. To this solution were added
a few crystals of CSA and stirring was continued at 0 ЊC for 2 h.
Then saturated aqueous NaHCO3 (3 mL) was added to quench
the reaction followed by water (15 mL). The aqueous layer was
extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with brine and subsequently dried over
Na2SO4 and the solvent was removed in vacuo. Crude allylic
alcohol 37 (364 mg, 0.62 mmol, 100%) was obtained as a
colourless oil; Rf = 0.18 (petroleum ether–Et2O (1 : 1)); IR 3505
(؉)-(2S,3R,5S,10R,19S)-Diene 53
1
(br), 3070, 2930, 2856, 1743, 1234, 1113, 1019; H NMR (400
A solution of triene 4 (300 mg, 513 µmol) in toluene (70 mL,
7.3 mM) was thoroughly degassed with argon. Then catalyst 51
(64 mg, 75 µmol, 15 mol%) was added and the brown reaction
mixture was stirred at 70 ЊC for 16 h. After cooling to rt
the solvent was removed in vacuo. Column chromatography
(petroleum ether–Et2O (9 : 1)) afforded diene 53 (283 mg,
509 µmol, 99%) as an oil; Rf = 0.75 (petroleum ether–Et2O
(1 : 1)); [α]2D2 ϩ78.0 (c = 0.79, MeOH); IR 2941, 2860, 1740,
1240, 1108; 1H NMR (500 MHz) δ 7.68–7.60 (4H, m), 7.43–7.38
(6H, m), 5.70 (1H, d, J = 11.7 Hz), 5.50 (2H, m), 4.44 (1H, m),
3.62 (1H, s), 2.47–2.42 (1H, m), 2.05 (3H, s), 1.98–1.90 (3H, m),
1,87 (1H, d, J = 7.0 Hz), 1.67–1.49 (6H, m), 1.05 (9H, s),
0.67 (6H, s); HRMS (FAB) [M ϩ Hϩ] calcd for C35H45O4Si:
557.3087, found: 557.3095.
MHz) δ 7.64–7.61 (4H, m), 7.44–7.37 (6H, m), 5.98 (1H, s), 5.67
(1H, ddd, J = 16.9, 10.4, 10.3 Hz), 4.98 (1H, dd, J = 10.1, 2.3
Hz), 4.80 (1H, dd, J = 16.9, 2.2 Hz), 4.44 (1H, d, J = 11.5 Hz),
4.34 (1H, dd, J = 6.6, 1.5 Hz), 3.68 (1H, d, J = 11.6 Hz), 3.64
(1H, s), 2.58–2.51 (1H, m), 2.09–1.97 (3H, m), 1.94 (3H, s), 1.91
(1H, dd, J = 12.9, 6.6 Hz), 1.87 (1H, d, J = 10.6 Hz), 1.72 (1H, d,
J = 12.9 Hz), 1.64–1.52 (4H, m), 1.05 (9H, s), 0.78 (3H, s), 0.66
(3H, s); 13C NMR (100 MHz) δ 169.5, 137.5, 136.0, 135.7,
135.7, 133.8, 129.8, 129.7, 129.4, 127.7, 127.7, 116.6, 91.7, 89.1,
71.7, 71.6, 62.8, 61.4, 43.3, 42.4, 29.1, 26.7, 26.1, 25.5, 24.7,
22.5, 22.5, 20.6, 18.9; HRMS (FAB) [M ϩ Naϩ] calcd for
C36H48NaO5Si: 611.3169, found: 611.3168.
(؊)-(S)-Acetic acid [(1R,2S,4R,5S)-5-tert-butyldiphenylsilyl-
oxy)-3,3-dimethyl-2-vinyl-7-oxabicyclo[2.2.1]heptan-1-yl]-
(2-formylcyclohex-1-enyl)methyl ester (46)
(2S,3R,5R,6S,7R,10R,19S)- and (2S,3R,5R,6R,7S,10R,19S)-
Diol 56
To a solution of allylic alcohol 37 (367 mg, 0.62 mmol) in
acetone (20 mL) were added NMO (110 mg, 0.94 mmol,
1.5 equiv.) and TPAP (6.6 mg, 18 µmol, 3 mol%). The dark
mixture was stirred for 2 h and filtered over a thin pad of silica
followed by exhaustive rinsing with EtOAc. Evaporation of the
solvent gave aldehyde 46 (353 mg, 0.60 mmol, 97%) as an oil; Rf
= 0.68 (petroleum ether–Et2O (1 : 1)); [α]2D0 Ϫ35.5 (c = 1.75,
CHCl3); IR 3071, 2935, 2859, 1750, 1672, 1228, 1111; 1H NMR
(500 MHz) δ 10.18 (1H, s), 7.66–7.58 (4H, m, Ar–H), 7.44–7.36
(6H, m), 6.23 (1H, s), 5.65 (1H, ddd, J = 16.9, 10.5, 10.0 Hz),
5.01 (1H, dd, J = 10.0, 1.7 Hz), 4.84 (1H, dd, J = 16.9, 2.0 Hz),
4.35 (1H, d, J = 6.6 Hz), 3.54 (1H, s), 2.37–2.18 (4H, m), 1.99
(3H, s), 1.95 (1H, dd, J = 12.7, 6.6 Hz), 1.87 (1H, d, J = 10.7
Hz), 1.66–1.59 (5H, m), 1.02 (9H, s), 0.74 (3H, s), 0.63 (3H, s);
13C NMR (125 MHz) δ 191.3, 169.4, 151.3, 136.6, 135.7, 135.6,
133.9, 133.8, 129.7, 129.7, 127.7, 127.6, 117.1, 91.3, 88.2, 71.6,
71.5, 61.5, 43.7, 42.8, 28.3, 26.7, 25.1, 24.5, 22.7, 21.9, 21.3,
20.5, 19.0 (C(CH3)3); HRMS (FAB) [M ϩ Hϩ] calcd for
C36H47O5Si: 587.3193, found: 587.3179.
To a vigorously stirred solution of diene 53 (162 mg, 291 µmol)
in tert-butanol (7 mL) was added DMAP (71.2 mg, 580 µmol,
2 equiv.). Then OsO4 (7.4 mL of a 1 wt% solution in water
(291 µmol, 1 equiv.)) was added in one portion to the reaction
mixture. The reaction mixture turned brown immediately and
stirring was continued for 30 min. Then Na2SO3 (189 mg,
1.50 mmol, 5 equiv.) was added in one portion. After stirring
for 30 min, the reaction mixture was filtered over a thin pad of
silica to remove the solids and rinsed with MeOH (30 mL).
Evaporation of the solvents in vacuo and column chrom-
atography (petroleum ether–Et2O (1 : 3)) afforded a 78 : 22
mixture of cis-diols 56 (145 mg, 246 µmol, 84%) as a white
solid; Rf = 0.05 (petroleum ether–Et2O (1 : 1)); IR (KBr) 3436
1
(br), 3184, 2932, 1737, 1603, 1240, 1111; H NMR (500 MHz)
δ 7.66 (2H, d, J = 7.8 Hz), 7.62 (2H, d, J = 7.8 Hz), 7.44–7.35
(6H, m), 5.76 (0.2H, s), 5.46–5.41 (0.7H, m), 5.41–5.30 (0.6H,
m), 4.55–4.48 (1H, m), 4.42–4.40 (0.8H, dd, J = 6.8, 2.9 Hz),
4.33–4.32 (0.2H, dd, J = 4.4, 2.9 Hz), 4.10 (1H, s), 3.70 (0.2H,
s), 3.58 (0.8H, s), 2.48–2.40 (0.7H, m), 2.34–2.31 (0.8H, m), 2.20
(1H, s), 2.07–2.01 (5.5H, m), 1.99–1.90 (2H, m), 1.89–1.80 (1H,
m), 1.73–1.43 (4H, m), 1.16 (3H, s), 1.04 (9H, s), 0.69 (3H, s);
HRMS (FAB) [M ϩ Hϩ] calculated for C35H47O6Si: 591.3142,
found: 591.3142.
(؉)-(S)-Acetic acid [(1R,2S,4R,5S)-5-(tert-butyldiphenylsilyl-
oxy)-3,3-dimethyl-2-vinyl-7-oxabicyclo[2.2.1]heptan-1-yl]-
(2-vinylcyclohex-1-enyl)methyl ester (4)
To a suspension of methyltriphenylphosphonium bromide
(860 mg, 1.90 mmol, 2.1 equiv.) in THF (15 mL) at 0 ЊC was
added dropwise n-BuLi (1.13 mL of a 1.6 M solution in
hexanes, 1.80 mmol, 2.0 equiv.). The yellow suspension was
stirred at 0 ЊC for 1 h and aldehyde 46 (530 mg, 0.90 mmol)
(؉)-(2S,3R,5S,6R,10R,19S)-ꢀ-Hydroxyketone 59
To a solution of the mixture of cis-diols 56 (37.8 mg, 64.0 µmol)
in CH2Cl2 (2 mL) at Ϫ20 ЊC was added Dess–Martin reagent
(35 mg, 83 µmol, 1.3 equiv.). The reaction mixture was allowed
1710
J. Chem. Soc., Perkin Trans. 1, 2002, 1701–1713

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to warm to rt in 1 h and was stirred for another 2 h. The
reaction was quenched by adding saturated aqueous NaHCO3
(3 mL) and saturated aqueous Na2SO3 (3 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with brine and subsequently dried
over Na2SO4 and the solvent was removed in vacuo. Column
chromatography (petroleum ether–Et2O (3 : 1)) afforded α-
hydroxyketone 59 (31.1 mg, 52 µmol, 81%) as a white solid [α]2D2
ϩ11.8 (c = 0.91, CHCl3); Rf = 0.54 (petroleum ether–Et2O
pyridine, 0.2 mL) was added and the reaction mixture was
allowed to warm to rt. After stirring the mixture at rt for 3 h,
the reaction was carefully quenched with saturated aqueous
NaHCO3 (3 mL) and extracted with CH2Cl2 (3 × 5 mL). The
combined organic layers were washed with brine and sub-
sequently dried over Na2SO4 and the solvent was removed
in vacuo. Column chromatography (petroleum ether–Et2O (1 : 1
1 : 9)) afforded alcohol 68 (12.3 mg, 34.0 µmol, 77%) as a
white solid; Rf = 0.23 (Et2O); [α]2D2 ϩ227.3 (c = 1.1, CHCl3); IR
1
1
(1 : 1)); IR 3458, 2937, 1746, 1645,1232, 1079; H NMR (400
3470 (br), 2935, 1743, 1645, 1237; H NMR (500 MHz) δ 5.17
MHz) δ 7.66 (2H, d, J = 7.7 Hz), 7.62 (2H, d, J = 7.7 Hz), 7.46–
7.37 (6H, m), 5.30 (1H, s), 4.77 (1H, dd, J = 12.2, 1.8 Hz), 4.46
(1H, dd, J = 6.9, 3.1 Hz), 3.72 (1H, d, J = 1.8 Hz), 3.67 (1H, s),
2.82–2.70 (1H, m), 2.58–2.49 (1H, m), 2.30–2.20 (1H, m), 2.04
(3H, s), 2.03–1.96 (1H, m), 1.86 (1H, dd, J = 11.2, 6.9 Hz),
1.80–1.45 (6H, m), 1.19 (3H, s), 1.06 (9H, s), 0.66 (3H, s); 13C
NMR (125 MHz) δ 203.3, 169.6, 150.5, 135.8, 135.7, 134.7,
133.6, 133.6, 129.9, 129.8, 127.7, 127.7, 93.4, 85.4, 76.7, 73.8,
72.4, 54.3, 49.0, 43.2, 32.7, 26.9, 25.4, 23.7, 22.4, 21.9, 21.5,
21.1, 19.0; HRMS (FAB) [M ϩ Hϩ] calcd for C35H45O6Si:
589.2985, found: 589.2966.
(1H, s), 4.39 (1H, dd, J = 6.9, 1.7 Hz), 3.91 (1H, s), 3.59 (3H, s),
2.67–2.61 (2H, m), 2.24–2.18 (2H, m), 1.98 (3H, s), 1.91–1.87
(1H, m), 1.79–1.61 (5H, m), 1.36 (3H, s), 1.29 (3H, s); 13C NMR
(125 MHz) δ 190.5, 170.3, 146.6, 145.6, 138.7, 138.6, 91.9, 86.9,
74.7, 70.8, 59.5, 45.9, 44.7, 31.3, 26.3, 24.4, 21.9, 21.7, 21.5,
20.8; HRMS (FAB) [M ϩ Hϩ] calcd for C20H27O6: 363.1808,
found: 363.1825.
(؉)-(3R,10R,19S)-Ketone 69
To a solution of alcohol 68 (11.4 mg, 31.5 µmol) in acetone
(3 mL) were added NMO (8.8 mg, 75.2 µmol, 2.4 equiv.) and
a catalytic amount of TPAP. The dark mixture was stirred for
30 min and the reaction mixture was filtered over a thin pad of
silica followed by exhaustive rinsing with EtOAc. The solvent
was removed in vacuo. Column chromatography (pentane–Et2O
(4 : 1)) afforded ketone 69 (10.4 mg, 28.8 mmol, 91%) as an oil;
Rf = 0.42 (petroleum ether–Et2O (1 : 1)); [α]2D2 ϩ423 (c = 1.3,
CHCl3); IR 2935, 1769, 1746, 1643, 1233; 1H NMR (500 MHz)
δ 5.23 (1H, s), 3.88 (1H, s), 3.62 (3H, s), 2.67–2.62 (2H, m), 2.48
(1H, d, J = 16.8 Hz), 2.22 (1H, d, J = 16.6 Hz), 2.18–2.14 (1H,
m), 2.01 (3H, s), 1.92–1.88 (1H, m), 1.71–1.57 (4H, m),
1.44 (3H, s), 1.29 (3H, s); 13C NMR (125 MHz) δ 207.3, 189.9,
170.1, 147.0, 144.0, 139.0, 138.5, 88.8, 86.8, 74.0, 59.6, 46.4,
44.6, 31.3, 26.4, 23.5, 21.8, 21.6, 20.9, 20.7; HRMS (FAB) [M ϩ
Hϩ] calcd for C20H25O6: 361.1651, found: 361.1648.
(؉)-(2S,3R,10R,19S)-Enol ketone 62
To a solution of α-hydroxyketone 59 (23.4 mg, 39.8 µmol) in
MeOH (2 mL) was added cupric acetate monohydrate (31.2 mg,
172 µmol, 4.3 equiv.). The blue mixture was stirred at 60 ЊC for
6 h. Then the green mixture was cooled to rt and quenched with
water (10 mL) followed by extraction with CH2Cl2 (3 × 10 mL).
The combined organic layers were washed with brine and
subsequently dried over Na2SO4 and the solvent was removed in
vacuo. Column chromatography (petroleum ether–Et2O (4 : 1))
afforded enol ketone 62 (17.4 mg, 29.7 µmol, 75%) as a white
solid; Rf = 0.61 (petroleum ether–Et2O (1 : 1)); [α]2D3 ϩ122.6 (c =
1
1.6, CHCl3); IR 3385, 2934, 1742, 1604, 1236, 1078; H NMR
(500 MHz) δ 7.68 (2H, d, J = 6.6 Hz), 7.63 (2H, d, J = 6.6 Hz),
7.46–7.38 (6H, m), 6.45 (1H, s), 5.24 (1H, s), 4.43 (1H, dd, J =
6.8, 2.7 Hz), 3.74 (1H, s), 2.76–2.64 (2H, m), 2.26–2.22 (1H, m),
1.98 (3H, s), 1.97–1.91 (1H, m), 1.78–1.75 (1H, m), 1.70–1.57
(5H, m), 1.19 (3H, s), 1.08 (9H, s), 0.84 (3H, s); 13C NMR (125
MHz, C6D6) δ 188.7, 170.6, 146.3, 141.1, 136.9, 136.9, 134.8,
134.8, 134.5, 130.9, 130.9, 129.2, 129.0, 92.7, 87.9, 75.9, 73.7,
46.5, 45.6, 33.2, 27.8, 27.5, 24.4, 22.8, 22.5, 20.8, 20.5, 20.0;
HRMS (FAB) [M ϩ Hϩ] calcd for C35H43O6Si: 587.2829, found:
587.2822.
(؉)-(3R,10R,19S)-Ketone 2
To a solution of ketone 69 (8.0 mg, 22 µmol) in MeOH (2 mL)
was added K2CO3 (7.5 mg, 54 µmol, 2.5 equiv.). The reaction
mixture was stirred at rt for 1 h. Then the reaction mixture was
poured into saturated aqueous NaHCO3 and extracted with
CH2Cl2 (3 × 5 mL). The combined organic layers were washed
with brine and subsequently dried over Na2SO4 and the solvent
was removed in vacuo. Column chromatography (pentane–Et2O
(2 : 3)) afforded alcohol 2 (5.8 mg, 18 µmol, 82%) as a white
solid which was recrystallised from pentane–Et2O to give
colourless crystals; Rf = 0.24 (petroleum ether–Et2O (1 : 3)); mp
172.5–173.5 ЊC; [α]2D4 ϩ 495 (c = 0.6, CHCl3); IR 3474 (br), 2935,
(؉)-(2S,3R,10R,19S)-Methyl enol ether 63
To a solution of enol ketone 62 (17.2 mg, 29.3 µmol) in DMF
(0.5 mL) was added iodomethane (200 µL, 3.2 mmol,
109 equiv.) and Ag2O (80 mg, 346 µmol, 12 equiv.) and the
resulting gray suspension was stirred at rt for 16 h. Then the
reaction mixture was filtered over a thin pad of Celite® and the
filtrate was washed with Et2O (20 mL). Evaporation and
column chromatography (petroleum ether–Et2O (3 : 1))
afforded methyl enol ether 63 (16.8 mg, 28.0 µmol, 95%) as an
oil; Rf = 0.52 (petroleum ether–Et2O (1 : 1)); [α]2D2 ϩ152.6
1
1767, 1642; H NMR (500 MHz) δ 4.26 (1H, s), 3.88 (1H, s),
3.63 (3H, s), 2.70–2.65 (1H, m), 2.52–2.46 (1H, m), 2.37 (1H, d,
J = 16.8 Hz), 2.32 (1H, br s), 2.19 (1H, d, J = 16.8 Hz), 2.17–
2.13 (1H, m), 1.98–1.91 (1H, m), 1.73–1.61 (4H, m), 1.45 (3H,
s), 1.23 (3H, s); 13C NMR (125 MHz) δ 207.9, 189.2, 147.3,
142.5, 140.2, 138.3, 89.2, 88.9, 74.4, 59.8, 46.5, 44.3, 32.1, 26.3,
23.6, 22.0, 21.7, 21.1; HRMS (FAB) [M ϩ Hϩ] calcd for
C18H23O5: 319.1546, found: 319.1548.
1
(c = 1.1, CHCl3); IR 2935, 1743, 1642, 1236, 1080; H NMR
(500 MHz) δ 7.74 (2H, d, J = 6.6 Hz), 7.64 (2H, d, J = 6.6 Hz),
7.47–7.39 (6H, m), 5.13 (1H, s), 4.39 (1H, dd, J = 6.8, 2.4 Hz),
3.69 (1H, s), 3.48 (3H, s), 2.68–2.59 (2H, m), 2.15–2.11 (1H, m),
1.95 (3H, s), 1.84–1.80 (2H, m), 1.77–1.65 (5H, m), 1.18 (3H, s),
1.08 (9H, m), 0.81 (3H, s); 13C NMR (125 MHz) δ 190.6, 170.3,
146.7, 145.7, 139.5, 137.8, 135.8, 135.7, 133.7, 133.6, 129.9,
129.8, 127.8, 127.8, 91.7, 86.5, 75.0, 71.6, 59.4, 46.0, 44.2, 31.1,
26.9, 26.3, 24.3, 21.9, 21.7, 21.0, 20.8, 19.0; HRMS (FAB)
[M ϩ Hϩ] calcd for C36H45O6Si: 601.2985, found: 601.3024.
Crystallographic data for 2:¶ C18H22O5, Mr = 318.3643, ortho-
rhombic, P212121, a = 7.8483(9), b = 8.1518(10), c = 24.541(5) Å,
V = 1570.1(4) Å3, Z = 4, Dx = 1.35 g cmϪ3, λ(Cu-Kα) = 1.5418 Å,
µ(Cu-Kα) = 8.0 cmϪ1, F(000) = 680, 243 K, final R = 0.044 for
1829 observed reflections.
(2S,3R,10R,13R,19S)- and (2S,3R,10R,13S,19S)-Diol 70
To a solution of methyl enol ether 65 (see supplementary
information) (21 mg, 24 µmol) in THF (1 mL) was added
(؉)-(2S,3R,10R,19S)-Alcohol 68
¶ CCDC reference number 149470. See http://www.rsc.org/suppdata/
p1/b2/b202020n/ for crystallographic files in .cif or other electronic
format.
A solution of protected alcohol 63 (26.3 mg, 43.8 µmol) in THF
(3 mL) was cooled to 0 ЊC. Then HFؒpyridine (70% HF–30%
J. Chem. Soc., Perkin Trans. 1, 2002, 1701–1713
1711

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HOAc (1 drop) followed by tetrabutylammonium fluoride
(160 µL of a 1 M solution in THF, 160 µmol, 6 equiv.) and the
reaction mixture was stirred at rt for 16 h. Evaporation and
1H NMR (400 MHz) δ 9.09 (0.25H, d, J = 5.2 Hz), 9.07 (0.25H,
d, J = 5.2 Hz), 9.03 (0.25H, d, J = 5.4 Hz), 9.02 (0.25H, d, J = 5.4
Hz), 5.26 (0.25H, s), 5.25 (0.25H, s), 5.21 (0.5H, s), 3.88 (1H, s),
3.64 (0.75H, s), 3.62 (0.75H, s), 3.61 (1.5H, s), 2.95–2.90 (0.5H,
m), 2.75–2.63 (1H, m), 2.47 (1H, d, J = 16.7 Hz), 2.32–2.03 (4H,
m), 2.01 (1.5H, s), 2.00 (1.5H, s), 1.99–1.81 (1.5H, m), 1.69–1.47
(4H, m), 1.45 (1.5H, s), 1.44 (1.5H, s), 1.30 (1.5H, s), 1.29
(1.5H, s), 0.95–0.79 (3H, m); 13C NMR (100 MHz) δ 207.1,
207.0, 200.8, 200.7, 189.9, 189.3, 170.2, 147.1, 147.0, 144.6,
144.5, 139.4, 139.3, 138.2, 138.1, 88.8, 86.9, 86.5, 73.8,
73.6, 59.7, 59.6, 46.5, 46.4, 44.7, 44.4, 39.0, 38.9, 38.8, 38.7,
33.1, 33.0, 33.0, 32.1, 32.0, 31.5, 30.5, 30.4, 30.4, 30.3, 27.8,
27.6, 26.9, 23.5, 21.0, 20.9, 20.7, 20.6, 20.4, 20.2, 15.3, 15.1,
15.0; HRMS (FAB) [M ϩ Hϩ] calcd for C25H31O7: 443.2070,
found: 443.2069.
purification by column chromatography (Et2O
EtOAc)
afforded diol 70 (9.5 mg, 23 µmol, 99%) as a 1 : 1 mixture of two
diastereomers as a colourless oil; Rf = 0.11 (EtOAc); IR 3417
(br), 2928, 1740, 1633, 1238, 1030; 1H NMR (400 MHz) δ 5.19
(0.5H, s), 5.16 (0.5H, s), 4.38 (1H, d, J = 5.3 Hz), 3.90 (1H, s),
3.64–3.62 (2H, m), 3.60 (1.5H, s), 3.56 (1.5H, s), 2.71–2.61 (1H,
m), 2.37–2.10 (3H, m), 1.98 (1.5H, s), 1.96 (1.5H, s), 1.81–1.73
(2H, m), 1.68–1.52 (3H, m), 1.49–1.36 (4H, m), 1.35 (1.5H, s),
1.35 (1.5H, s), 1.22 (3H, s); HRMS (FAB) [M ϩ Hϩ] calcd for
C23H33O7: 421.2226, found: 421.2233.
(3R,10R,13R,19S)- and (3R,10R,13S,19S)-Acid 9
To a solution of diol 70 (9.5 mg, 23 µmol) in acetone (1 mL)
were added NMO (9.8 mg, 84 µmol, 3.6 equiv.) and tetra-
propylammonium perruthenate (2.8 mg, 7.6 µmol, 0.3 equiv.).
The reaction mixture was stirred at rt for 16 h. The reaction
mixture was filtered over a thin pad of silica and rinsed with
EtOAc–HOAc (1000 : 1). Evaporation of the solvent gave acid
71. Then the crude acid was dissolved in MeOH (0.5 mL) and
K2CO3 (400 µL of a 0.1 M solution in MeOH, 40 µmol,
1.7 equiv.) was added. The reaction mixture was stirred at rt for
3 h. Filtration over a thin pad of silica and evaporation of the
solvent gave solanoeclepin A analogue 9 as a 1 : 1 mixture of
two diastereomers, which were purified by reversed phase thin
layer chromatography (Merck RP-18 F254s) Rf = 0.53 (H2O–
MeCN (1 : 1)) to give the pure product (3.5 mg, 9.0 µmol, 40%);
(3R,10R,13R,19S,20R,22R)-, (3R,10R,13R,19S,20S,22S)-,
(3R,10R,13S,19S,20R,22R)- and (3R,10R,13S,19S,20S,22S)-
Acid 11
To a solution of aldehyde 73 (6.5 mg, 15 µmol) in tert-butanol
(0.1 mL) and 2-methyl-2-butene (0.1 mL) was added a solution
of NaClO2 (8.0 mg, 88 µmol, 5.9 equiv.) and NaH2PO4 (8.1 mg,
68 µmol, 4.5 equiv.) in H2O (0.1 mL). This reaction mixture was
stirred at rt for 2 h and then filtered over a thin pad of silica.
Evaporation of the solvent gave the crude acid (HRMS (FAB)
[M ϩ Hϩ] calcd for C25H31O8: 459.2019, found: 459.2032). The
crude acid was dissolved in MeOH (0.5 mL). To this solution
was added K2CO3 (400 µL of a 0.1 M solution in MeOH,
40 µmol, 2.6 equiv.) and stirring was continued at rt for 3 h.
Filtration over a thin pad of silica and evaporation gave crude
acid 11, which was further purified by reversed phase thin layer
chromatography (Merck RP-18 F254s) to give solanoeclepin
A analogue 11 (4.3 mg, 10 µmol, 66%) as an equimolar mixture
of four diastereomers as a white solid; Rf = 0.53 (H2O–MeCN
1
IR 3445 (br), 2932, 1771, 1698, 1632; H NMR (400 MHz,
CD3OD) δ 4.24 (0.5H, s), 4.22 (0.5H, s), 3.87 (1H, s), 3.59
(1.5H, s), 3.56 (1.5H, s), 2.52–2.45 (2H, m), 2.31–2.10 (6H, m),
1.69–1.53 (5H, m), 1.43 (3H, s), 1.26 (3H, s); 13C NMR (125
MHz) δ 207.1 (C-2), 189.1, 188.9 (C-7), 176.4 (C-21), 147.3,
147.0, 140.9, 139.9, 139.8, 139.7, 137.4, 137.3, 89.2, 89.1, 88.8,
88.7, 74.3, 64.8, 46.6, 46.5, 44.4, 43.9, 35.2, 34.9, 33.4, 33.2,
33.2, 32.5, 32.3, 29.3, 29.2, 28.1, 27.7, 23.6, 21.6, 21.1; HRMS
(FAB) [M ϩ Hϩ] calcd for C21H27O7: 391.1757, found:
391.1725.
1
(1 : 1)). IR 3395 (br), 2932, 1766, 1693, 1632; H NMR (500
MHz) δ 4.30 (0.25H, s), 4.29 (0.25H, s), 4.28 (0.5H, s), 3.88 (1H,
s), 3.66 (0.75H, s), 3.65 (0.75H, s), 3.62 (1.5H, s), 2.98–2.96
(0.5H, m), 2.57–2.53 (1.5H, m), 2.36 (1H, d, J = 16.9 Hz), 2.36–
2.14 (3H, m), 1.90–1.82 (2H, m), 1.69–1.52 (3H, m), 1.45 (3H,
s), 1.39–1.63 (2H, m), 1.29 (1.5H, s), 1.26 (1.5H, s), 0.89–0.80
(2H, m); 13C NMR (125 MHz) δ 207.7, 189.0, 188.8, 178.7,
147.4, 147.2, 140.8, 139.8, 139.8, 137.5, 137.1, 89.3, 89.0, 88.9,
74.2, 73.8, 65.4, 46.6, 46.5, 44.4, 44.0, 39.4, 39.2, 33.5, 33.4,
33.1, 33.0, 33.0, 32.9, 32.5, 32.0, 28.1, 27.7, 23.6, 21.6, 21.5,
21.1, 20.1, 16.3; HRMS (FAB) [M ϩ Hϩ] calcd for C23H29O7:
417.1913, found: 417.1917.
(2S,3R,10R,13R,19S,20R,22R)-, (2S,3R,10R,13R,19S,20S,-
22S)-, (2S,3R,10R,13S,19S,20R,22R)- and (2S,3R,10R,13S,-
19S,20S,22S)-Diol 72
Following the same procedure as described for the preparation
of 70, the TBDPS groups of enol ketone 67 (18 mg, 20 µmol
were removed. Column chromatography (Et2O
EtOAc)
afforded diol 72 (9.1 mg, 20 µmol, 99%) as a as an equimolar
mixture of four diastereomers as a colourless oil; Rf = 0.13
(EtOAc); IR 3520 (br), 2964, 2856, 1739, 1720, 1633, 1238,
1065; 1H NMR (400 MHz) δ 5.19–5.16 (1H, m), 4.40–4.38 (1H,
m), 3.60 (1H, s), 3.59 (1.5H, s), 3.57 (1.5H, s), 3.48–3.43 (2H,
m), 2.71–2.62 (1H, m), 2.37–2.10 (4H, m), 2.04 (1.5H, s), 1.98
(1.5H, s), 1.86–1.46 (7H, m), 1.25 (3H, s), 1.22 (1.5H, s), 1.21
(1.5H, s), 0.89–0.83 (1H, m), 0.67–0.65 (1H, m), 0.41–0.39 (1H,
m), 0.2–0.30 (1H, m); HRMS (EI) calcd for C25H34O7:
446.2305, found: 446.2300.
Acknowledgements
The HLB Research Center, Wijster, The Netherlands, is kindly
acknowledged for performing the hatching activity tests.
J. Fraanje and K. Goubitz of our Institute are kindly thanked
for the X-ray crystal structure determination. These invest-
igations are supported (in part) by the Netherlands Research
Council for Chemical Sciences (CW) with financial aid from the
Netherlands Technology Foundation (STW).
(3R,10R,13R,19S,20R,22R)-, (3R,10R,13R,19S,20S,22S)-,
(3R,10R,13S,19S,20R,22R)- and (3R,10R,13S,19S,20S,22S)-
Aldehyde 73
Notes and references
1 J. C. J. Benningshof, R. H. Blaauw, A. E. van Ginkel, J. H. van
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Trans. 1, 2002, preceding paper (DOI: 10.1039/b201987f ).
To a solution of diol 72 (9.1 mg, 20 µmol) in acetone (1 mL)
were added NMO (5 mg, 42 µmol, 2.1 equiv.) and tetrapro-
pylammonium perruthenate (3.1 mg, 8.5 µmol, 0.4 equiv.). The
reaction mixture was stirred at rt for 6 h and filtered over a thin
pad of silica followed by exhaustive rinsing with EtOAc.
Evaporation of the solvent afforded aldehyde 73 (6.5 mg,
15 µmol, 77%) as an equimolar mixture of four diastereomers
as a white solid; IR 2932, 1769, 1744, 1704, 16.43, 1233;
2 For recent advances in our synthetic efforts towards solanoeclepin
A, see R. H. Blaauw, J.-F. Brière, R. de Jong, J. C. J. Benningshof,
A. E. van Ginkel, F. P. J. T. Rutjes, J. Fraanje, K. Goubitz, H. Schenk
and H. Hiemstra, Chem. Commun., 2000, 1463; J. C. J. Benningshof,
R. H. Blaauw, A. E. van Ginkel, F. P. J. T. Rutjes, J. Fraanje,
K. Goubitz, H. Schenk and H. Hiemstra, Chem. Commun., 2000,
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A. E. van Ginkel, F. P. J. T. Rutjes, J. Fraanje, K. Goubitz, H. Schenk
1712
J. Chem. Soc., Perkin Trans. 1, 2002, 1701–1713

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