Studies towards the total synthesis of ouabagenin

Article abstract of DOI:10.1139/v05-042

An anionic cyclization strategy developed in our laboratory was used to produce a versatile and convergent synthesis of an advanced tetracyclic intermediate for the construction of ouabagenin and closely related analogs.

Full text of DOI:10.1139/v05-042

728
Studies towards the total synthesis of
ouabagenin1
Ling Chen and Pierre Deslongchamps
Abstract: An anionic cyclization strategy developed in our laboratory was used to produce a versatile and convergent
synthesis of an advanced tetracyclic intermediate for the construction of ouabagenin and closely related analogs.
Key words: organic chemistry, synthesis, cycloaddition, polycyclization, Michael reaction, Diels–Alder reaction, ste-
roids, oubain, ouabagenin, natural products.
Résumé : L’utilisation d’une réaction de cyclisation anionique développée dans nos laboratoires a permis d’élaborer
une route convergente et versatile d’un intermédiaire tétracyclique pour la synthèse de la ouabagénine et ses dérivés.
Mots clés : chimie organique, synthèse, cycloaddition, polycyclisation, reaction Michaël, reaction Diels–Alder, stéroï-
des, ouabaïne, ouabagénine, produits naturels.
Chen and Deslongchamps 740
Introduction
ouabagenin via anionic cyclization. The reaction of an α,β-
unsaturated β′-ketoester 2 with Nazarov intermediate 3 af-
forded, after decarboxylation and aldol condensation, steroid
6 with great control of stereochemistry (Scheme 1) (8).
These reactions, which led to the stereoselective generation
of five contiguous chiral centres, have laid a solid founda-
tion for the asymmetric total synthesis of ouabain or its
aglycone ouabagenin. The issues that remained unaddressed
were the methods of introduction of the 3- and 5-OH groups,
deoxygenation of the 7 position, synthesis of the butenolide
(for which there are excellent known methods in the litera-
ture (9)), along with some relatively straight forward func-
tional group transformations.
To achieve the total synthesis of 1b via the previously
stated strategy it was important to obtain an A-ring precursor
(α,β-unsaturated β′-ketoester) that would give comparable
selectivity to that obtained with 2 but with a better handle
for the introduction of the 3- and 5-OH groups. With this
goal in mind, we envisioned the potential use of compounds
A1–A3 (Scheme 2). A-ring precursors A1 and A2 could be
subjected to ozonolysis with concomitant Baeyer–Villager
oxidation to obtain the protected 3-OH group, thus relying
solely on an enone derived from the C-7 ketone as a handle
to introduce the 5-OH as illustrated. Alternatively, the use of
A3 would allow for reduction of an analogous enone to frag-
ment the ketal, affording a chiral allylic alcohol at C-3,
which would offer a variety of options for the introduction
of the C-5 OH.
Ouabain (1a), a cardioactive glycoside, was isolated from
the bark of the African ouabio tree (Acokanthera ouabio) by
Arnaud in 1888 (1). A similar compound was also isolated
from bovine and other mammalian sources and it has since
been established that the endogenous and the plant-derived
ouabain are in fact one and the same (2). Ouabagenin (1b),
the aglycone of ouabain, was isolated for the first time in
1942 by Mannich and Siewert (3), who proposed a structure
for the aglycone, and therefore the structure for ouabain as
well, which was later proven by Florey and Ehrenstein (4).
In 1988, a stereocontrolled approach to access 14-hydroxy
steroid skeletons was reported by our research group (5).
Under basic conditions, an α,β-unsaturated β′-ketoester can
react with a γ,δ-unsaturated β-ketoester (a Nazarov interme-
diate)3 to afford a tetracylic compound in good yield and
with excellent diastereoselectivity. This reaction is believed
to go through a cascade of anionic cyclization and aldol con-
densation known as anionic polycyclization, and would pro-
vide a very efficient way to construct highly oxygenated
polycyclic compounds such as ouabagenin.
There are many examples in the recent literature of stud-
ies towards the total synthesis of ouabagenin by various
methods from the groups of Overman (6) and Jung (7).
Herein we report some of our recent efforts at completing
this challenging total synthesis. In 2002, our group reported
an important development for the asymmetric synthesis of
Received 2 November 2004. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 23 June 2005.
L. Chen and P. Deslongchamps.2 Laboratoire de synthèse organique, Département de chimie, Institut de Pharmacologie de
Sherbrooke, Université de Sherbrooke, 3001, 12e Avenue nord, Sherbrooke, QC J1H 5N4, Canada.
1This article is part of a Special Issue dedicated to Professor Howard Alper.
2Corresponding author (e-mail: Pierre.Deslongchamps@USherbrooke.ca).
3These γ,δ-unsaturated β-ketoesters were originally studied by Ivan Nikolaevich Nazarov (1906–1957) in tandem Michael–aldol
reactions to form bicycles. We have named these compounds Nazarov intermediates in homage to his work. A representative
example available in english is: I.N. Nazarov and S.I. Zav’yalov. Zh. Obshch. Khim. 25, 477 (1955).
Can. J. Chem. 83: 728–740 (2005)
doi: 10.1139/V05-042
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Chen and Deslongchamps
729
Scheme 1. (a) Cs2CO3, CH2Cl2, r.t., 61%; (b) Pd(PPh3)4, morpholine, THF, r.t., 71%; (c) KHMDS, THF, reflux, 71%. 1a (R = α-L-
rhamnosyl (ouabain)); 1b (R = H (ouabagenin)).
1a, 1b
ring was opened with isopropyl magnesium chloride (16)
and N,O-dimethylhydroxyamine to give Weinreb amide 12
in 86% yield. The hydroxyl group of 12 was oxidized by the
Swern method (17) to afford aldehyde 13 in 75% yield. The
optimum yield for the Wittig reaction (92%) was obtained
with MePPh3Br and slightly less than 1 equiv. of potassium
bistrimethylsilylamide (KHMDS). The Weinreb amide (14)
was then reduced to the aldehyde (15) by diisobutylalumi-
num hydride (DIBAL-H) in 92% yield. The lithium dianion
of 2-bromoallylic alcohol (18) was added to the aldehyde to
afford the ring-closing metathesis (RCM) precursor 16 in
98% yield. The ring-closing metathesis reaction went
smoothly using Grubb’s second generation catalyst (19) to
deliver cyclohexene 17 in 73% yield. Oxidation of the diol
to the desired ketone aldehyde was effected by using 3 equiv.
of Dess–Martin periodinane to afford A3 in 80% yield.
With the three A-ring precursors (A1–A3) in hand, their
reactions with Nazarov intermediate 3 were investigated.
The preliminary results are summarized in Table 1. When
ring A1 was allowed to react with Nazarov intermediate 3 in
the presence of 2 equiv. of cesium carbonate (Table 1, entry
1), all starting material was consumed after 10 h by 1H
NMR (by TLC, the products overlapped with 3), but the de-
sired anionic cyclization adduct (18) was only isolated in 7%
Results and discussion
With the above synthetic strategy in mind, we proceeded
to synthesize the three targeted ring-A precursors proposed
above. Ring A1 was prepared as described in the literature
(10). Ring A2 was prepared from acid 7, an intermediate in
the synthesis of A1 (Scheme 3). Compound 7 was first con-
verted to the corresponding Weinreb amide (11), which was
then treated with methyl magnesium bromide to afford
methyl ketone 8 in 80% overall yield (12). Deprotection of
the acetal followed by acidic cyclization gave the cyclo-
hexenone 9 in 62% overall yield (13). The Baylis–Hillman
reaction between 9 and formaldehyde was used to introduce
the hydroxylmethyl group. This β-hydroxy ketone 10 can be
furnished in 54% yield. The hydroxyl group in 10 was then
oxidized with Dess–Martin periodinane (14) to afford the
desired aldehyde (A2) in 83% yield. Ring A2 proved to be
very unstable and was prepared immediately before use in
the next step.
The synthesis of A3, with its 3,4-hydroxyl groups pro-
tected as an acetonide for potential reductive fragmentation
to the allylic alcohol, began from 2-deoxy-D-ribose
(Scheme 4). The sugar was converted to the lactone (11) ac-
cording to the procedure in the literature (15). The lactone
© 2005 NRC Canada

730
Can. J. Chem. Vol. 83, 2005
Scheme 2.
via A1 and A2
1a, 1b
yield with other unwanted products. From the previous re-
sult, it was clear that A1 was not a good choice for the syn-
thesis.
in 36% overall yield (Scheme 5). The anionic cyclization re-
action between ring A3 and 3 was then repeated using
2 equiv. of cesium carbonate (as in the cases of the previous
A-ring precursors) to afford the desired anionic cyclization
product 21 in 78% yield with excellent stereoselectivity.
These results suggest the possibility that the reaction could
proceed via a double Michael process instead of a concerted
anionic cyclization. After decarboxylation of 21, compound
22 was obtained in 95% yield as a single diastereomer.
Based on the preliminary results from the above studies,
we decided to advance on the total synthesis of ouabagenin
with A3. The next step was to selectively reduce the alde-
hyde in compound 22. This could be achieved by either
LiAlH(OCEt3)3 (21) or LiAlH(O-t-Bu)3. The best yield was
obtained when the reaction was quenched with 5% acetic
acid to afford compound 23 in 99% yield.5
As expected, the reaction between ring A2 and Nazarov
intermediate 3 (Table 1, entry 2) was much faster than with
A1 owing to the more electron-withdrawing nature of the al-
dehyde with respect to the ester. After 2 h, the starting mate-
1
rials could not be detected by H NMR. The desired anionic
cyclization adduct (19) was isolated in 22% yield, along
with another diastereomer in 24% yield (stereochemistry not
determined). When subjected to the decarboxylation condi-
tions, anionic cyclization adduct 19 gave compound 20 in
72% yield.
Finally, the anionic cyclization between ring A3 and 3
was studied. Based on the previous work in our group (20),
a catalytic amount of cesium carbonate was used to avoid
the decomposition of A3. To our surprise, the only com-
pound isolated appeared to be a mono-Michael addition
product4 and treating this crude product with 1 equiv. of ce-
sium carbonate, produced the anionic cyclization adduct 21
The hydroxyl group in 23 was protected as a 2-
(trimethylsilyl)ethoxymethyl ether (SEM) ether (22). The
intramolecular aldol condensation was examined on 24 to
complete the steroid skeleton of ouabagenin. Several differ-
4 The mono-Michael product was isolated as a continually equilibrating mixture of diastereomers and keto–enol tautomers owing to the β-
1
ketoester and was therefore very difficult to completely characterize. Its structure was proposed based on the complex H NMR spectra of
this mixture (not given) and its subsequent reaction with Cs2CO3 to give the fully cyclized product (22), which was, after decarboxylation,
identical to that obtained via the one-step reaction. Based on these results, we feel that the assignment of the structure of a single Michael
addition product to compound 23 is a strong possibility, but certainly not an absolute.
5 Significantly lower yields were obtained when the reactions were quenched with aqueous ammonium chloride or HCl solutions or with wa-
ter alone.
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Chen and Deslongchamps
731
Scheme 3. (a) (i) Im2CO, DCM; (ii) MeONHMe·HCl, NEt3; (b) MeMgBr, THF, 0 °C, 80% for two steps; (c) 66% aq. AcOH, 40 °C;
(d) PTSA, toluene, 100 °C, 62% for two steps; (e) 37% HCHO, DMAP, THF, 54%; ( f ) Dess–Martin periodinane, DCM, 83%.
Scheme 4. (a) 2-Methoxypropene, PPTS, AcOEt, 70%; (b) Br2, CaCO3, CH3CN–H2O (5:1), 88%; (c) i-PrMgCl, MeNHOMe·HCl,
THF, –20 °C, 86%; (d) (COCl)2, DMSO, i-Pr2NEt, DCM, –78 °C, 75%; (e) MePPH3Br, KHMDS in toluene, THF, 0 °C, 92%;
( f ) DIBAL-H in toluene, THF, –78 °C, 92%; (g) t-BuLi in pentane, CH2CBrCH2OH, Et2O, 0 °C, 98%; (h) Grubb’s second generation
catalyst, DCM, 40 °C, 73%; (i) Dess–Martin periodinane, DCM, 80%.
2-Deoxy-D-ribose
ent bases were used, however, either product 25 or 26 result-
ing from β elimination was obtained under the conditions
shown in Table 2. By TLC, it appeared that the elimination
occurred before the desired aldol.
To circumvent the undesired β elimination, we proceeded
to reduce the carbonyl group at C-1 before attempting the
aldol. The selective reduction of the C-1 carbonyl group was
effected via a hydroxyl group directed reduction with
Me4NBH(OAc)3 (23), thus avoiding reduction of the other
two ketones, which were less hindered and would react more
rapidly with conventional reducing agents to afford com-
pound 27 in 96% yield (Scheme 6). Unfortunately, this di-
rected reduction allowed access to only the undesired α-OH
at the 1 position, but we were confident that this could be
easily corrected through a later oxidation–reduction se-
quence on the tetracycle. Thus, this diol (27) was protected
as an acetonide at which point the aldol condensation of 28
went smoothly, giving the desired product 29 in 86% yield.
At this point, our efforts were directed towards the instal-
lation of a hydroxyl group at C-5. As per our original plan,
this would be carried out via the reductive fragmentation of
the 7,5-enone. Several conditions were examined in attempt
to introduce the 5,6-double bond directly in compound 29.
Unfortunately, SeO2 with catalytic acetic acid, SeO2 in pyri-
dine, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in
benzene, and 2-iodoxybenzoic acid (IBX) in dimethylsulfoxide
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732
Can. J. Chem. Vol. 83, 2005
Table 1. Preliminary results of the reactions between A ring units and 3.
OTBDPS
OAc
OTBDPS
OAc
O
O
E
E
Cs2CO3, DCM
+
O
O
O
O
R
R
CO2All
CO2All
E = CO2Me or CHO
3
A1-A3
Entry
1
A ring units
Anionic cyclization (yield)a
Decarboxylation (yield)a
OTBDPS
OAc
O
O
O
E
O
H
O
OH
CO2All
A1
b
18
(7%)
OTBDPS
OTBDPS
OAc
OAc
H
O
O
O
O
O
O
H
2
O
H
O
O
OH
CO2All
A2
c
20
19
(72%)
(22%)
OTBDPS
OTBDPS
OAc
OAc
H
O
O
O
O
O
O
O
H
H
O
O
O
O
3
O
OH
O
O
O
CO2All
A3
21
(78%)
22
(95%)
aIsolated yield.
bAlong with three unidentified compounds.
cAlong with 24% of an unidentified diastereomer.
(DMSO) gave no reaction at all. Trapping 29 as a tert-
butyldimethylsilyl (TBS), enol ether 30 (24) and oxidation
with Pd(OAc)2 (25) over the course of 4 days allowed ac-
cess to the desired enone, but in poor yield and with
epimerization of the C-8 position. Fortunately, treatment of
30 with PhSeCl afforded phenyl selenide 31 in 71% yield
(26). Oxidative elimination of 31 with hydrogen peroxide
produced the desired compound 32 in 57% yield.
With compound 32 in hand, the reductive elimination was
attempted to remove the C-4 alkoxy group and introduce the
targeted allylic alcohol. In the presence of a catalytic amount
of acetic acid, 32 was treated with zinc dust in ethanol at re-
flux (27). The desired product 33 was obtained in 32% yield,
along with compound 29 in 29% yield. Compound 29,
which could be recycled, was obtained by the simple reduc-
tion of the double bond without the expected elimination.
Experimental
General
All the reactions were performed under a N2 atmosphere
with oven-dried glassware when necessary. Solvents were
distilled and dried according to standard procedures. Analyt-
ical TLC was performed on precoated glass plates
(0.25 mm) with silica gel 60F-250 (Merck). Flash chroma-
tography was performed with 230–400 mesh gel 60 (Merck).
1H and 13C NMR spectra were recorded on a Brüker AC-300
and are referenced with respect to the residual signals of the
solvent; they are described using standard abbreviations. IR
spectra were recorded on a PerkinElmer 1600 FT-IR. Mass
spectra were recorded on a ZAB-1F micromass spectrome-
ter.
Further optimization of this reaction is still required be-
fore undertaking the endgame of the synthesis, but we feel
that we have in hand a viable method for the synthesis of a
steroidal tetracycle with appropriate handles to complete the
total synthesis of ouabagenin (1b) or closely related ana-
logues for a structure activity relationship study.
␤-Hydroxyketone (10)
To a solution of 9 (20 mg, 0.147 mmol) in THF (0.25 mL)
was added 37% HCHO (66 µL, 0.88 mmol) and N,N-
dimethylaminopyridine (DMAP) (3.6 mg, 0.029 mmol). The
mixture was stirred at 60 °C for 16 h. It was directly purified
by preparative TLC (silica gel, hexanes – ethyl acetate
© 2005 NRC Canada

Chen and Deslongchamps
733
Scheme 5. (a) Cs2CO3 (0.2 equiv.), DCM, r.t. 2 h then Cs2CO3 (1.0 equiv.), DCM, r.t. 1 h, 36%; (b) Cs2CO3 (2.0 equiv.), DCM, r.t.
2 h, 60%; (c) Pd(PPh3)4, morpholine, THF, r.t., 95%; (d) LiAlH(O-t-Bu)3, THF, –78 °C or LiAlH(OCEt3)3, THF, 0 °C; (e) SemCl,
Imidazole, DCM, 71%.
temperature (r.t.) for 1 h. After removal of solvent in vacuo,
Table 2. Results of attempted aldol reactions.
the residue was purified by flash chromatography (silica gel,
Hex:EA = 1:1 with 1% acetic acid (AcOH)) to give ring A2
(11.7 mg, 83%) as a yellowish oil, which is very unstable
Product
(yield, %)
Entry
1
Reagent
Cs2CO3
Solvent
CH3CN
Temp.
Reflux
1
and should be used immediately for the next step. H NMR
26 (18)
(300 MHz, CDCl3) δ: 10.07 (1H, s), 7.82 (1H, dd, J = 2.6,
5.6 Hz), 4.90 (1H, br s), 4.81 (1H, br s), 2.80–2.43 (5H, m),
1.76 (3H, s).
2
3
4
Piperidine–AcOH
DBU
KHMDS
Benzene
Benzene
THF
r.t.
Reflux
Reflux
25 (20)
25 (95)
26 (22)
Weinreb amide (12)
(Hex:EA = 1:1)) to afford 10 (13 mg, 54%) as a colourless
oil. [α]2D0 –35.3 (c 1.62, CHCl3). IR (neat, cm–1) ν: 3416,
To a suspension of 11 (0.89 g, 5.17 mmol) and N,O-
dimethylhydroxylamine (0.80 g, 8.00 mmol) in THF
(10 mL) was added dropwise a 2 mol/L solution of i-
PrMgCl in THF (10.8 mL, 21.7 mmol) at –20 °C. The reac-
tion was stirred at –20 °C for 20 min. Aqueous (aq.) NH4Cl
solution (12 mL, satd. NH4Cl – H2O = 1:1) was added to
quench the reaction. It was extracted with a mixture of ether
and DCM (1:1, 5 × 20 mL), the combined organic layers
were dried over MgSO4 and concentrated. The residue was
purified by flash column chromatography (silica gel, EA) to
give 12 (1.04 g, 86%) as a colourless oil. [α]2D0 +33.0 (c
0.26, CHCl3). IR (thin film, cm–1) ν: 3444, 1659, 1644,
1
3083, 2920, 1668, 1434, 1384, 904. H NMR (300 MHz,
CDCl3) δ: 6.94 (1H, m), 4.80 (1H, br s), 4.74 (1H, br s),
4.24 (2H, br s), 2.75–2.26 (5H, m), 1.73 (3H, s). 13C NMR
(75 MHz, CDCl3) δ: 200.24, 146.2, 146.0, 138.0, 110.8,
61.6, 43.1, 42.0, 30.8, 20.4. EI-MS (70 eV) m/e: 166 (M+),
97 (100%). HR-MS calcd. for C10H14O2: 166.0994; found:
166.0991.
␣,␤-Unsaturated-␤′-ketoaldehyde (A2)
To a solution of 10 (14.3 mg, 0.036 mmol) in dichloro-
methane (DCM) (1 mL) was added Dess–Martin periodinane
(54.7 mg, 0.129 mmol). The mixture was stirred at room
1
1633. H NMR (300 MHz, CDCl3) δ: 4.66 (1H, dt, J = 5.9,
8.1 Hz), 4.31 (1H, t, J = 5.5 Hz), 3.70 (3H, s), 3.63 (2H, br
© 2005 NRC Canada

734
Can. J. Chem. Vol. 83, 2005
Scheme 6. (a) Me4NBH(OAc)3, CH3CN–AcOH, –20 to 0 °C, 96%; (b) 2-dimethoxypropane, CSA (cat.), acetone, 97%; (c) KHMDS in
toluene, THF, 86%; (d) TBSOTf, Et3N, DCM, –78 °C to r.t., 91%; (e) PhSeCl, 2,6-di-tert-butylpyridine, DCM, 9 h, 71%; ( f ) H2O2,
DCM, 1 h, 57%; (g) Zn, AcOH, EtOH.
d), 3.18 (3H, s), 2.94 (1H, dd, J = 5.3, 16.9 Hz), 2.77 (1H,
dd, J = 8.5, 16.8 Hz), 2.58 (1H, br s), 1.45 (3H, s), 1.36
(3H, s). 13C NMR (75 MHz, CDCl3) δ: 171.8, 107.7, 77.4,
73.2, 61.3, 61.1, 32.5, 32.0, 27.8, 25.1. EI-MS (70 eV) m/e:
218 (M+ – CH3), 144 (100%). HR-MS calcd. for C9H16NO5
(M+ – CH3): 218.1028; found: 218.1024.
layer was extracted with DCM (4 × 5 mL). The combined
organic layers were dried over MgSO4 and concentrated.
The residue was purified by flash column chromatography
(silica gel, EA) to afford 13 (150 mg, 75%) as a white solid.
Mp: 57–59 °C. [α]2D0 +14.1 (c 2.29, CHCl3). IR (thin film,
1
cm–1) ν: 1742, 1668, 1644. H NMR (300 MHz, CDCl3) δ:
9.69 (1H, dd, J = 0.5, 2.2 Hz), 4.81 (1H, q, J = 7.0 Hz), 4.53
(1H, dd, J = 2.3, 7.1 Hz), 3.67 (3H, s), 3.18 (3H, s), 2.90
(1H, dd, J = 6.7, 16.9 Hz), 2.67 (1H, dd, J = 7.2, 16.8 Hz),
1.56 (3H, s), 1.43 (3H, s). 13C NMR (75 MHz, CDCl3) δ:
202.4, 170.4, 110.3, 81.3, 74.2, 61.3, 32.4, 32.0, 27.4, 25.3.
EI-MS (70 eV) m/e: 216 (M+ – CH3), 144 (100%); HR-MS
calcd. for C9H14NO5 (M+ – CH3): 216.0875; found: 216.0872.
Aldehyde (13)
To a solution of (COCl)2 (0.084 mL, 0.96 mmol) in DCM
(3.0 mL) at –78 °C DMSO was added dropwise (0.148 mL,
2.09 mmol). It was then stirred for 10 min. To this mixture a
solution of 12 was added dropwise (204 mg, 0.870 mmol) in
DCM (1.0 mL) at –78 °C. The mixture was stirred for
30 min before diisopropylethylamine (DIPEA) (0.364 mL,
2.09 mmol) was added. It was stirred at r.t. for 15 min. Wa-
ter (3 mL) was added to quench the reaction. After stirring
for 5 min, the organic layer was separated. The aqueous
Weinreb amide (14)
CH3PPh3Br (6.10 g, 17.1 mmol) was dried under vacuum
at 110 °C for 2 h then cooled to r.t. THF (33 mL) was
© 2005 NRC Canada

Chen and Deslongchamps
735
added. To this suspension at 0 °C was slowly added
KHMDS (0.5 mol/L in toluene, 27.0 mL, 13.5 mmol) with
vigorous stirring. After addition, the temperature was raised
to r.t. and the mixture was stirred for 30 min. It was cooled
to –78 °C and a solution of 13 (3.29 g, 14.2 mmol) in THF
(33 mL) was transferred into the above suspension by can-
nula. The mixture was stirred at 0 °C for 1 h. Satd. aq.
NH4Cl (0.35 mL) was added to quench the reaction. Pentane
(132 mL) was added to precipitate the POPh3. After filtra-
tion, the filtrate was concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel,
Hex:EA = 1:2) to afford 14 (3.00 g, 92%) as a colourless oil.
[α]2D0 –3.5 (c 3.33, CHCl3). IR (thin film, cm–1) ν: 2986,
CDCl3) two isomers δ: 9.68 (1H, br s), 5.71–5.60 (1H, m),
5.30–5.16 (2H, m), 4.65–4.59 (2H, m), 2.67–2.58 (1H, m),
2.52–2.44 (1H, m), 1.43 (3H, s), 1.31 (3H, s). 13C NMR
(75 MHz, CDCl3) two isomers δ: 150.1, 149.2, 133.9, 133.6,
119.0, 118.6, 112.7, 112.0, 109.1, 79.7, 78.0, 74.8, 74.1,
70.9, 64.2, 64.1, 36.7, 36.1, 28.1, 28.0, 25.6, 25.5. EI-MS
(70 eV) m/e: 213 (M+ – CH3), 83 (100%). HR-MS calcd. for
C11H17O4 (M+ – CH3): 213.1127; found: 213.1131.
Cyclohexene (17)
A solution of 16 (617 mg, 2.70 mmol) in DCM (30 mL)
was degassed. To this solution was added Grubb’s second
generation catalyst (229 mg, 0.27 mmol). The mixture was
stirred at 40 °C overnight. After removal of the solvent in
vacuo, the residue was purified by flash column chromatog-
raphy (silica gel, 1% MeOH in EA) to afford 17 (395 mg,
1
2937, 1666, 1380, 1046. H NMR (300 MHz, CDCl3) δ:
5.81–5.70 (1H, m), 5.30–5.18 (2H, m), 4.73–4.64 (2H, m),
3.65 (3H, s), 3.14 (3H, s), 2.78 (1H, dd, J = 6.3, 16.7 Hz),
2.50 (1H, dd, J = 6.5, 16.6 Hz), 1.47 (3H, s), 1.36 (3H, s).
13C NMR (75 MHz, CDCl3) δ: 171.4, 134.0, 118.3, 108.4,
79.0, 74.3, 61.3, 33.4, 32.0, 27.9, 25.3. EI-MS (70 eV) m/e:
229 (M+), 83 (100%). HR-MS calcd. for C11H19NO4:
229.1314; found: 229.1319.
1
73%) as a green oil. Conformer a: H NMR (300 MHz,
CDCl3) δ: 5.67 (1H, dd, J = 1.3, 2.9 Hz), 4.57–4.51 (1H, m),
4.50–4.48 (1H, m), 4.29–4.23 (2H, m), 4.15–4.09 (1H, m),
2.46 (1H, ddd, J = 2.7, 3.8, 15.2 Hz), 2.01 (1H, ddd, J = 2.3,
4.5, 15.2 Hz), 1.45 (3H, s), 1.37 (3H, s). 13C NMR (75 MHz,
CDCl3) δ: 140.6, 122.6, 109.6, 72.8, 72.5, 65.3, 64.0, 31.9,
28.3, 26.5. Conformer b: IR (thin film, cm–1) ν: 3418, 2987,
Aldehyde (15)
1
2932, 1372, 1218, 1044. H NMR (300 MHz, CDCl3) δ:
To a solution of 14 (1.24 g, 5.41 mmol) in THF (40 mL)
was added 1.5 mol/L DIBAL-H in toluene (7.2 mL,
10.8 mmol) at –78 °C and the mixture was stirred at this
temperature for 1 h. Acetone (0.6 mL) was added to con-
sume the excess DIBAL-H and it was stirred for 5 min. The
reaction solution was transferred to a mixture of 0.5 mol/L
aq. tartaric acid and hexane (108 mL : 108 mL) by cannula,
then it was vigorously stirred for 30 min. The organic phase
was separated and washed with 45 mL of water and brine,
respectively. The combined aqueous phase was extracted
with 100 mL of 25% DCM in pentane. The combined or-
ganic phase was dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy (silica gel, Hex:EA = 2:1) to afford 15 (0.85 g, 92%)
as a clear oil. [α]2D0 –16.1 (c 1.68, CHCl3). IR (thin film, cm–1)
ν: 3085, 2988, 2937, 2733, 1728, 1645, 1372, 1249, 1217,
5.69 (1H, br s), 4.55–4.53 (2H, m), 4.50–4.45 (1H, m),
4.33–4.22 (2H, m), 2.39 (1H, dt, J = 4.9, 13.8 Hz), 1.85 (1H,
ddd, J = 3.2, 8.7, 13.8 Hz), 1.36 (6H, s). 13C NMR (75 MHz,
CDCl3) δ: 142.2, 123.7, 108.6, 72.2, 71.6, 65.5, 65.3, 35.1,
27.8, 26.1. EI-MS (70 eV) m/e: 185 (M+ – CH3), 95 (100%).
HR-MS calcd. for C9H13O4 (M+ – CH3): 185.0814; found:
185.0808.
␣,␤-Unsaturated-␤′-ketoaldehyde (A3)
To a solution of 17 (715 mg, 3.57 mmol) in DCM
(75 mL) was added Dess–Martin periodinane (4.54 g,
10.7 mmol). The mixture was stirred at r.t. for 1 h. It was fil-
tered through a short pad of silica gel (about 5 g), and
washed with a mixture of hexane, ethyl acetate, and AcOH
(50:50:1). The filtrate was concentrated in vacuo and the res-
idue was purified by flash column chromatography (silica
gel, Hex:EA:AcOH = 50:50:1) to afford A3 (560 mg, 80%)
as a colourless oil, which is not stable and should be used
directly in the next step. 1H NMR (300 MHz, CDCl3) δ: 10.1
(1H, br s), 7.30 (1H, dd, J = 2.2, 2.5 Hz), 4.89 (1H, dd, J =
4.8, 2.7 Hz), 4.70 (1H, m), 3.04 (1H, dd, J = 2.7, 7.6 Hz),
1
1167, 1050, 1004, 933, 869. H NMR (300 MHz, CDCl3) δ:
9.68 (1H, br s), 5.71–5.60 (1H, m), 5.30–5.16 (2H, m),
4.65–4.59 (2H, m), 2.67–2.58 (1H, m), 2.52–2.44 (1H, m),
1.43 (3H, s), 1.31 (3H, s). 13C NMR (75 MHz, CDCl3) δ:
199.9, 133.4, 118.8, 108.7, 78.6, 72.9, 45.1, 27.8, 25.3.
2.80 (1H, dd, J = 3.7, 7.5 Hz), 1.38 (3H, s), 1.29 (3H, s). 13
C
RCM precursor (16)
NMR (75 MHz, CDCl3) δ: 193.9, 188.9, 150.3, 128.9,
110.4, 73.1, 71.1, 39.3, 27.8, 26.3.
To
a solution of 2-bromoallylic alcohol (6.37 g,
46.5 mmol) in ether (154 mL) was slowly added a solution
of 1.47 mol/L t-BuLi in pentane (79 mL, 0.116 mol) at
−78 °C. It was quickly warmed to 0 °C and stirred at this
temperature for 4 h. 15 (2.64 g, 15.5 mmol) in ether (21 mL)
was added to this mixture at –78 °C, then it was stirred at
0 °C for 30 min. MeOH (4.4 mL) was added to quench the
reaction, followed by water (110 mL). The mixture was
stirred for 10 min. The organic layer was separated and the
aqueous layer was extracted with DCM (4 × 100 mL). The
combined organic phase was dried over MgSO4 and concen-
trated in vacuo. The residue was purified by flash column
chromatography (silica gel, Hex:EA = 1:2) to give 16
(3.48 g, 98%) as a colourless oil. IR (thin film, cm–1) ν:
Anionic cyclization adduct (18)
To a solution of 3 (29.4 mg, 0.0486 mmol) in DCM
(1 mL) was added Cs2CO3 (31.7 mg, 0.0972 mmol). The
mixture was stirred at r.t. for 10 min. A solution of A1
(19.0 mg, 0.0972 mmol) in DCM (1.0 mL) was added to the
above mixture over 10 min. The reaction mixture was stirred
at r.t. for 10 h. It was then filtered through a pad of Celite®
and washed with DCM. After removal of the solvent in
vacuo, the residue was purified by flash column chromatog-
raphy (silica gel, Hex:EA = 4:1) to afford 29 (2.8 mg, 7.2%)
1
as a colourless oil. H NMR (300 MHz, CDCl3) δ: 12.09
1
3418, 2987, 2932, 1372, 1218, 1044. H NMR (300 MHz,
(1H, s), 7.70–7.63 (4H, m), 7.42–7.38 (6H, m), 5.92
© 2005 NRC Canada

736
Can. J. Chem. Vol. 83, 2005
(1H, m), 5.53 (1H, m), 5.35–5.24 (2H, m), 4.93 (1H, s), 4.84
(1H, s), 4.68 (2H, m), 3.84–3.62 (2H, m), 3.60 (3H, s), 1.84
(3H, s), 1.05 (9H, s), 0.87 (3H, s).
film, cm–1) ν: 2934, 2859, 1746, 1732, 1711, 1659, 1651,
1230. 1H NMR (300 MHz, CDCl3) δ: 12.3 (1H, s), 9.40 (1H,
d, J = 1.8 Hz), 7.70–7.66 (4H, m), 7.43–7.38 (6H, m), 5.98–
5.84 (1H, m), 5.49 (1H, t, J = 8.8 Hz), 5.36–5.23 (2H, m),
4.78–4.61 (2H, m), 4.53 (1H, t, J = 5.0 Hz), 4.29 (1H, dd,
J = 5.2, 8.0 Hz), 3.68 (2H, ddd, J = 6.4, 10.3, 13.5 Hz), 3.58
(1H, d, J = 8.0 Hz), 3.08 (1H, dd, J = 6.1, 16.2 Hz), 2.75
(1H, dd, J = 1.4, 16.2 Hz), 2.68–2.54 (2H, m, H-17), 2.44–
2.05 (5H, m), 1.95 (1H, dd, J = 9.9, 14.9 Hz), 1.82 (3H, s),
1.76 (1H, dd, J = 1.3, 14.9 Hz), 1.55–1.48 (1H, m), 1.46
(3H, s), 1.32 (3H, s), 1.07 (9H, s), 0.86 (3H, s). 13C NMR
(75 MHz, CDCl3) δ: 222.1, 207.3, 197.4, 172.3, 170.6,
169.8, 135.6, 135.6, 133.3, 133.1, 131.7, 129.8, 129.7,
127.8, 127.8, 119.0, 109.5, 97.7, 78.1, 73.7, 70.0, 65.7, 64.3,
61.2, 49.3, 43.1, 40.6, 40.1, 39.8, 38.0, 36.5, 30.1, 27.8,
26.9, 25.7, 22.2, 20.7, 19.7, 19.2. CI-MS m/e: 818 (M +
Anionic cyclization adduct (19)
To a solution of 3 (36 mg, 0.059 mmol) in DCM (1 mL)
was added Cs2CO3 (40 mg, 0.122 mmol). The mixture was
stirred at r.t. for 10 min. A solution of aldehyde (14 mg,
0.085 mmol) in DCM (1 mL) was added to the above mix-
ture over 10 min. The reaction mixture was stirred at r.t. for
2 h. It was then filtered through a pad of Celite® and washed
with DCM. After removal of the solvent in vacuo, the resi-
due was purified by flash column chromatography (silica
gel, Hex:EA = 2:1) to afford an unidentified isomer
1
(11.2 mg) and 19 (10.3 mg, 22%) as a colourless oil. H
NMR (300 MHz, CDCl3) δ: 12.17 (1H, s), 9.29 (1H, d, J =
2.0 Hz), 7.70–7.68 (4H, m), 7.43–7.39 (6H, m), 5.99–5.86
(1H, m), 5.36–5.27 (3H, m), 4.95 (1H, s), 4.85 (1H, s), 4.72
(1H, dd, J = 6.0, 13.0 Hz), 4.62 (1H, dd, J = 6.0, 13.0 Hz),
3.74 (1H, dd, J = 5.7, 10.3 Hz), 3.63 (1H, dd, J = 6.5,
10.3 Hz), 3.26 (1H, dd, J = 3.5, 11.9 Hz), 2.96 (1H, dd, J =
6.5, 14.3 Hz), 2.84–2.49 (5H, m), 2.39–1.90 (7H, m), 1.88
(3H, s), 1.84 (1H, d, J = 1.4 Hz), 1.77 (3H, s), 1.66 (1H, m),
1.07 (9H, s), 0.87 (3H, s). 13C NMR (75 MHz, CDCl3) δ:
221.9, 210.2, 198.6, 172.1, 170.7, 170.3, 145.3, 135.6,
133.3, 133.2, 131.5, 129.7, 127.7, 119.4, 113.3, 98.3, 69.8,
65.6, 64.2, 63.5, 49.2, 43.6, 42.2, 40.7, 38.5, 37.5, 36.5,
33.1, 30.5, 29.1, 26.9, 22.4, 22.2, 20.9, 19.5, 19.2.
+
+
NH4 ). HR-MS calcd. for C45H60NO11Si (M + NH4 ):
818.3935; found: 818.3948.
Triketone (22)
To a solution of 21 (190 mg, 0.237 mmol) in THF was
added Pd(PPh3)4 (13.7 mg, 0.012 mmol) and morphiline
(0.103 mL, 1.19 mmol). The reaction mixture was stirred at
r.t. for 5 min at which time the reaction was complete by
TLC. After removal of the solvent in vacuo, the residue was
purified by flash column chromatography (silica gel,
Hex:EA = 1:1) to afford 22 (146 mg, 86%) as a white solid.
Mp: 139–142 °C. [α]2D0 +16.7 (c 0.33, CHCl3). IR (thin
film, cm–1) ν: 2932, 2859, 1738, 1731, 1714, 1471, 1428,
1372, 1223, 1112. 1H NMR (300 MHz, CDCl3) δ: 9.94
(1H, s), 7.68–7.59 (4H, m), 7.48–7.36 (6H, m), 5.39 (1H,
dd, J = 5.8, 9.0 Hz), 4.57 (1H, m), 4.08 (1H, dd, J = 5.5,
6.8 Hz), 3.69 (2H, ddd, J = 6.7, 10.5, 16.9 Hz), 3.08–2.98
(2H, m), 2.69 (1H, dd, J = 1.8, 15.8 Hz), 2.54–2.43 (4H, m),
2.38–2.25 (3H, m), 2.17–2.07 (2H, m), 1.96 (1H, dd, J =
10.3, 15.1 Hz), 1.89 (3H, s), 1.60–1.43 (2H, m), 1.38
(3H, s), 1.31 (3H, s), 1.07 (9H, s), 0.85 (3H, s). 13C NMR
(75 MHz, CDCl3) δ: 221.5, 206.4, 206.3, 200.6, 170.2,
135.6, 135.5, 133.3, 133.2, 129.8, 127.8, 109.6, 74.0, 74.0,
69.3, 64.4, 59.8, 49.2, 43.8, 43.3, 40.6, 39.5, 39.1, 39.0,
38.9, 36.4, 27.4, 26.9, 25.6, 22.2, 20.9, 19.2, 18.7. EI-MS
m/e: 701 (M+ – CH3), 495 (100%). HR-MS calcd. for
C40H49O9Si (M+ – CH3): 701.3146; found: 701.3140.
Triketone (20)
To a solution of 19 (10.3 mg, 0.0134 mmol) in THF
(1.5 mL) was added Pd(PPh3)4 (ca. 1 mg) and morphiline
(6.5 µL, 0.0745 mmol). The reaction mixture was stirred at
r.t. for 4 h. After removal of the solvent in vacuo, the residue
was purified by flash column chromatography (silica gel,
Hex:EA = 7:3) to afford 20 (6.6 mg, 72%) as a colourless
oil. IR (thin film, cm–1) ν: 2931, 2127, 1742, 1428, 1373,
1230, 1112, 910, 823, 736, 704. 1H NMR (300 MHz,
CDCl3) δ: 9.70 (1H, s), 7.70–7.65 (4H, m), 7.43–7.39
(6H, m), 5.20 (1H, dd, J = 6.7, 8.7 Hz), 4.89 (1H, s), 4.76
(1H, s), 3.72 (1H, dd, J = 6.6, 10.4 Hz), 3.67 (1H, dd, J =
6.6, 10.4 Hz), 2.98 (1H, q, J = 7.2 Hz), 2.90 (1H, m), 2.79
(1H, dd, J = 5.6, 14.0 Hz), 2.67 (1H, m), 2.53–1.94
(11H, m), 1.89 (3H, s), 1.76 (1H, m), 1.71 (3H, s), 1.59–
1.46 (2H, m), 1.07 (9H, s), 0.87 (3H, s). 13C NMR (75 MHz,
CDCl3) δ: 221.7, 208.4, 207.7, 199.7, 170.4, 145.4, 135.63,
135.55, 133.3, 133.17, 129.8, 127.8, 112.5, 77.2, 69.7, 65.0,
64.3, 49.4, 43.5, 43.1, 42.8, 42.3, 40.7, 40.3, 39.4, 36.5,
35.3, 30.1, 26.9, 22.1, 21.4, 21.0, 19.2, 19.0.
Alcohol (23)
To a solution of 22 (35.7 mg, 0.0498 mmol) in THF
(2.0 mL) at –78 °C was slowly added LiAlH[OC(C2H5)3]3
(0.50 mol/L in THF, 0.130 mL, 0.0650 mmol). The tempera-
ture was raised to 0 °C and the mixture was stirred at this
temperature for 1 h. Ether (5.0 mL) was added to dilute the
reaction solution, then 5% aq. AcOH (4.0 mL) was added to
quench the reaction. The mixture was stirred for 15 min. It
was extracted with ether (3 × 10 mL), the combined organic
layers were washed with satd. NaHCO3 (4.0 mL) and brine
(4.0 mL), and dried over MgSO4. After removal of the sol-
vent in vacuo, the residue was purified by flash column
chromatography (silica gel, Hex:EA = 1:1 with 0.5%
Anionic cyclization adduct (21)
To a solution of 3 (57 mg, 0.094 mmol) in DCM (4 mL)
was added Cs2CO3 (61 mg, 0.187 mmol). The mixture was
stirred at r.t. for 10 min. A solution of A3 (38 mg,
0.19 mmol) in DCM (2.0 mL) was added into this mixture
over 10 min. The reaction mixture was stirred at r.t. for 2 h.
It was then filtered through a pad of Celite® and washed
with DCM. After removal of the solvent in vacuo, the resi-
due was purified by flash column chromatography (silica
gel, Hex:EA = 2:1) to afford 21 (58 mg, 77%) as a white
foam. Mp: 57–59 °C. [α]D20 +30.4 (c 0.51, CHCl3). IR (thin
1
MeOH) to afford 23 (35.6 mg, 99%) as a colourless oil. H
NMR (300 MHz, CDCl3) at least two conformations in
CDCl3 δ: 7.72–7.59 (4H, m), 7.47–7.37 (6H, m), 5.20 (0.4H,
t, J = 9.2 Hz), 4.91 (0.6H, t, J = 8.8 Hz), 4.56–4.50 (1H, m),
© 2005 NRC Canada

Chen and Deslongchamps
737
4.18–3.71 (5H, m), 3.41 (0.6H, m), 3.21–3.03 (1H, m),
2.86–1.86 (13H, m), 1.83 (1.8H, s), 1.77 (1.2H, s), 1.42
(1.2H, s), 1.40 (1.8H, s), 1.33 (1.2H, s), 1.30 (1.8H, s), 1.09
(3.6H, s), 1.07 (5.4H, s), 0.98 (1.2H, s), 0.86 (1.8H, s).
Enone (26)
To a solution of 24 (15.3 mg, 18 µmol) in THF (1.8 mL)
was added KHMDS (0.5 mol/L in toluene, 18 µL, 9.0 µmol).
The mixture was heated to reflux for 30 min. It was filtered
through a pad of silica gel and washed with EA. The filtrate
was concentrated in vacuo and the residue was purified by
flash column chromatography (silica gel, Hex:EA = 16:9) to
give 26 as a colourless oil (4.3 mg, 28%) along with an un-
identified by-product (4.1 mg). [α]2D0 −45.8 (c 0.61, CHCl3).
IR (thin film, cm–1) ν: 3466, 3071, 2956, 1747, 1693, 1471,
SEM ether (24)
To a solution of 23 (45 mg, 0.0626 mmol) in DCM
(2.5 mL) was added DIPEA (0.164 mL, 0.939 mmol). The
solution cooled to 0 °C and 2-(trimethylsilyl)ethoxychloro-
methyl ether (SEMCl) (0.133 mL, 0.751 mmol) was added
dropwise. The mixture was stirred at r.t. for 16 h. It was di-
luted with DCM (30 mL) and washed with satd. NaHCO3
(5.0 mL). The aqueous layer was extracted with DCM (2 ×
10 mL). The combined organic layers were washed with
satd. NaHCO3 and brine (5.0 mL each) and dried over
MgSO4 and concentrated in vacuo. The residue was purified
by flash column chromatography (silica gel, Hex:EA = 2:1)
to afford 24 (37.5 mg, 71%) as a white foam. Mp: 48–51 °C.
[α]2D0 –6.1 (c 1.0, CHCl3). IR (thin film, cm–1) ν: 2955, 1742,
1715, 1240, 1112, 1059, 835, 704. 1H NMR (300 MHz,
CDCl3) δ: 7.68–7.61 (4H, m), 7.46–7.36 (6H, m), 4.97 (1H,
dd, J = 6.1, 9.3 Hz), 4.58 (2H, s), 4.50 (1H, dd, J = 5.7,
9.9 Hz), 4.02 (1H, dd, J = 5.7, 9.4 Hz), 3.95 (1H, d, J =
9.9 Hz), 3.70 (3H, ddd + d, J = 6.7, 10.5, 16.9 Hz and J =
9.6 Hz), 3.54 (2H, m), 3.08 (1H, dd, J = 6.0, 16.2 Hz), 2.75–
2.54 (4H, m), 2.50–2.02 (7H, m), 1.84 (3H, s), 1.83 (1H, m),
1.61–1.54 (2H, m), 1.42 (3H, s), 1.30 (3H, s), 1.06 (9H, s),
0.95–0.85 (2H, m), 0.89 (3H, s), 0.00 (9H, s). 13C NMR
(75 MHz, CDCl3) δ: 221.5, 208.0, 207.3, 170.5, 135.6,
135.5, 133.3, 133.2, 129.8, 127.8, 108.9, 95.3, 74.5, 73.1,
69.4, 65.6, 65.3, 64.4, 51.3, 49.1, 43.8, 43.8, 42.0, 40.8,
40.3, 39.6, 39.3, 38.6, 36.4, 27.9, 26.9, 25.5, 22.3, 20.9,
1
1428, 1378, 1231, 1112, 1036. H NMR (300 MHz, CDCl3)
δ: 7.66–7.62 (4H, m), 7.42–7.36 (6H, m), 6.68 (1H, dd, J =
2.0, 10.3 Hz), 6.01 (1H, dd, J = 2.2, 10.3 Hz), 4.92 (1H, dt,
J = 4.6, 11.0 Hz), 4.74 (1H, d, J = 16.7 Hz), 4.67 (1H, d, J =
16.7 Hz), 4.26 (1H, d, J = 9.8 Hz), 4.17 (1H, m), 3.99 (1H,
d, J = 9.8 Hz), 3.78–3.54 (5H, m), 2.89–2.64 (4H, m), 2.42
(1H, dd, J = 11.0, 13.1 Hz), 2.17–2.04 (1H, m), 1.95–1.56
(5H, m), 1.88 (3H, s), 1.16–1.08 (3H, m), 1.03 (9H, s), 0.99
(3H, s), 0.02 (9H, s). 13C NMR (75 MHz, CDCl3) δ: 211.5,
198.4, 169.5, 146.0, 135.6, 133.9, 129.5, 128.6, 127.6, 95.5,
82.0, 67.7, 67.2, 66.4, 65.6, 63.8, 52.9, 51.9, 50.9, 47.1,
46.3, 44.4, 43.8, 40.1, 32.6, 26.9, 24.5, 20.6, 19.2, 18.1,
15.4, –1.4. EI-MS m/e: 791 (MH+), 327 (100%). HR-MS
calcd. for C44H63O9Si2 (MH+): 791.4010; found: 791.3997.
Diol (27)
To a stirred solution of glacial AcOH (0.5 mL) was added
Me4NHB(OAc)3 (76 mg, 0.29 mmol) in two batches. It was
stirred at r.t. for 1.5 h and then cooled to 0 °C. It was trans-
ferred to a solution of 23 (20.8 mg, 0.029 mmol) in CH3CN
at 5 °C by cannula. The mixture was stirred at 5 °C for 3 h
before the temperature was raised to 0 °C and stirred at 0 °C
for 16 h. MeOH (0.10 mL) was added to quench the reac-
tion. The solvent was removed in vacuo. The residue was di-
luted with DCM (15 mL) and washed with satd. NaHCO3
(5.0 mL). The aqueous layer was extracted with DCM (2 ×
5.0 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The residue was purified
by flash column chromatography (silica gel, Hex:EA = 1:1
with 0.5% MeOH) to afford 27 (17.3 mg, 96%) as a white
solid, along with the recovered starting material (2.8 mg,
87% conversion (conv.)). Mp: 85–88 °C. IR (thin film, cm–1)
+
19.3, 18.9, 18.0, –1.4. CI-MS m/e: 866 (M + NH4 ), 849
(MH+). HR-MS calcd. for C47H69O10Si2 (MH+): 849.4429;
found: 849.4414.
Enone (25)
To a solution of 24 (7.1 mg, 0.008 36 mmol) in benzene
(1.0 mL) was added 1,8-diazabicyclo[5.4.0]undecene (DBU)
(0.62 µL, 0.00418 mmol). The mixture was heated to reflux
for 4 h. After removal of the solvent in vacuo, the residue
was purified by flash column chromatography (silica gel,
Hex:EA = 1:1) to afford 25 (6.3 mg, 95%) as a colourless
oil. [α]2D0 –33.4 (c 0.44, CHCl3). IR (thin film, cm–1) ν:
3444, 2955, 1739, 1682, 1470, 1428, 1372, 1248, 1112,
1
ν: 3453, 2933, 1730, 1428, 1371, 1244, 1112, 911, 733. H
NMR (300 MHz, CDCl3) at least two conformations in
CDCl3 δ: 7.69–7.61 (4H, m), 7.48–7.36 (6H, m), 5.75
(0.56H, d, J = 10.5 Hz), 5.46 (0.45H, d, J = 11.2 Hz), 4.34–
3.42 (7H, m), 2.80–1.98 (12H, m), 1.96 (3H, s), 1.94
(3H, s), 1.92–1.53 (4H, m), 1.45 (1.5H, s), 1.40 (1.8H, s),
1.31 (1.4H, s), 1.28 (1.3H, s), 1.27 (1.3H, s), 1.06 (4.5H, s),
1.05 (4.5H, s), 0.89 (2.3H, s), 0.85 (1.2H, s). 13C NMR
(75 MHz, CDCl3) at least two conformations in CDCl3 δ:
221.8, 210.4, 171.4, 135.6, 133.5, 133.3, 129.8, 129.7,
127.9, 127.8, 127.7, 79.2, 78.1, 75.4, 74.3, 72.7, 72.0, 71.1,
70.5, 70.1, 69.9, 68.4, 64.4, 64.1, 63.3, 62.2, 48.7, 44.9,
44.6, 44.2, 44.0, 43.1, 42.9, 40.6, 40.4, 40.0, 37.9, 37.5,
37.4, 37.1, 36.9, 36.7, 34.3, 34.0, 33.6, 32.8, 31.8, 31.4,
28.3, 28.1, 26.9, 25.9, 22.9, 22.6, 22.3, 21.3, 19.3, 18.3,
18.2. EI-MS m/e: 702 (M+ – H2O), 84 (100%). HR-MS
calcd. for C41H54O8Si (M+ – H2O): 702.3588; found:
702.3596.
1
1058. H NMR (300 MHz, CDCl3) δ: 7.68–7.63 (4H, m),
7.46–7.36 (6H, m), 6.67 (1H, dd, J = 2.1, 10.3 Hz), 6.02
(1H, dd, J = 2.0, 10.3 Hz), 4.95 (1H, dd, J = 4.2, 10.9 Hz),
4.60 (2H, s), 4.19 (1H, d, J = 9.6 Hz), 4.10 (1H, m), 3.78–
3.62 (3H, m), 3.60–3.48 (2H, m), 2.85 (1H, m), 2.73 (1H, br
d, J = 15.3 Hz), 2.53 (1H, dd, J = 5.3, 15.5 Hz), 2.46–1.99
(7H, m), 1.86 (3H, s), 1.84 (1H, dd, J = 10.6, 14.8 Hz),
1.56–1.52 (1H, m), 1.46 (1H, d, J = 14.2 Hz), 1.09 (9H, s),
0.97–0.84 (2H, m), 0.89 (3H, s), 0.01 (9H, s). 13C NMR
(75 MHz, CDCl3) δ: 221.4, 208.5, 198.2, 170.4, 147.2,
135.6, 133.4, 133.2, 129.85, 129.80, 128.5, 127.8, 95.3,
69.2, 67.2, 65.6, 64.4, 64.1, 52.1, 49.2, 45.4, 43.8, 42.3,
40.0, 38.8, 38.6, 36.4, 26.9, 22.2, 21.0, 19.3, 18.8, 18.0, −1.4.
EI-MS m/e: 733 (M+ – C4H9), 199 (100%). HR-MS calcd.
for C40H53O9Si2 (M+ – C4H9): 733.3228; found: 733.3242.
© 2005 NRC Canada

738
Can. J. Chem. Vol. 83, 2005
then tert-butyldimethylsilyltrifluoromethanesulfonate (TBSOTf)
(1.67 mL, 7.25 mmol) at 8 °C. The mixture was stirred at
this temperature for 20 min then the temperature was raised
to r.t. The mixture was then stirred at r.t. for 3 h. 2-Propanol
(0.50 mL) was added at 0 °C to consume the excess
TBSOTf. After stirring at r.t. for 10 min, satd. NaHCO3
(80 mL) was added. The mixture was extracted with ethyl
acetate (2 × 100 mL). The combined organic layers were
dried over Na2SO4 and concentrated. The residue was puri-
fied by flash column chromatography (silica gel, Hex:EA =
9:1 to 1:1) to give recovered 29 (80 mg, 71% (conv.) and 30
(225 mg, 100% based on recovered starting material
(borsm)) as a colourless oil. [α]2D0 +2.8 (c 0.21, CHCl3). IR
(neat, cm–1) ν: 3523, 3049, 2930, 2858, 1739, 1666, 1471,
Diacetonide (28)
To a solution of 27 (348 mg, 0.483 mmol) in acetone
(6.0 mL) was added DMP (1.2 mL, 9.76 mmol) and CSA
(11.2 mg, 0.0483 mmol). The mixture was stirred at r.t. for
1 h. Satd. NaHCO3 (20 mL) was added to quench the reac-
tion. It was extracted with ethyl acetate (1 × 50 mL, 2 ×
20 mL). The combined organic layers were washed with wa-
ter and brine (15 mL each) and dried over MgSO4. After
concentration in vacuo, the residue was purified by flash col-
umn chromatography (silica gel, Hex:EA = 2:1) to afford 28
(342 mg, 93%) as a colourless oil. [α]2D0 +11.0 (c 1.36,
CHCl3). IR (thin film, cm–1) ν: 2933, 2252, 1732, 1463,
1428, 1372, 1242, 1112, 912, 734, 704. 1H NMR (300 MHz,
CDCl3) δ: 7.65–7.61 (4H, m), 7.41–7.36 (6H, m), 5.63 (1H,
dt, J = 2.5, 11.7 Hz), 4.39 (1H, t, J = 4.3 Hz), 4.29 (1H, dd,
J = 4.4, 12.8 Hz), 4.12 (1H, d, J = 12.4 Hz), 3.83 (1H, dd,
J = 4.9, 10.2 Hz), 3.66 (1H, d, J = 12.4 Hz), 3.61–3.57
(2H, m), 2.82 (1H, m), 2.58–2.28 (6H, m), 2.21–1.96
(5H, m), 1.93 (3H, s), 1.96–1.92 (1H, m), 1.75–1.63
(2H, m), 1.49 (3H, s), 1.43 (3H, s), 1.29 (6H, s), 1.05
(9H, s), 0.90 (3H, s). 13C NMR (75 MHz, CDCl3) δ: 221.9,
209.1, 170.3, 135.7, 133.5, 133.3, 129.8, 127.8, 127.7,
108.2, 99.3, 75.0, 73.2, 71.8, 70.6, 64.8, 64.4, 48.9, 46.6,
45.5, 40.2, 39.2, 37.9, 37.8, 36.3, 34.2, 29.4, 28.4, 27.2,
26.9, 25.9, 22.6, 21.5, 19.3, 18.9. EI-MS m/e: 745 (M+ –
CH3), 703 (M+ – C4H9), 199 (100%). HR-MS calcd. for
C43H57O9Si (M+ – CH3): 745.3772; found: 745.3787.
1
1428, 1368, 1247, 1189, 1112, 1045, 866, 838, 759, 704. H
NMR (300 MHz, CDCl3) δ: 7.66–7.63 (4H, m), 7.44–7.34
(6H, m), 5.72 (1H, m), 5.09 (1H, dd, J = 1.2, 6.6 Hz), 4.45
(1H, t, J = 3.7 Hz), 4.37 (1H, s, OH), 4.22 (1H, dd, J = 4.1,
12.8 Hz), 3.99 (1H, d, J = 12.2 Hz), 3.88 (1H, dd, J = 5.1,
8.7 Hz), 3.68 (1H, J = 5.2, 9.9 Hz), 3.57 (1H, dd, J = 7.2,
9.8 Hz), 3.45 (1H, d, J = 12.3 Hz), 2.71 (1H, m), 2.36 (1H,
d, J = 11.8 Hz), 2.23–1.94 (5H, m), 1.89 (3H, s), 1.85–1.82
(1H, m), 1.74–1.60 (5H, m), 1.53 (3H, s), 1.46 (3H, s), 1.37
(3H, s), 1.35 (3H, s), 1.04 (9H, s), 0.91 (9H, s), 0.83 (3H, s),
0.23 (3H, s), 0.20 (3H, s). 13C NMR (75 MHz, CDCl3) δ:
170.0, 151.2, 135.6, 133.9, 129.53, 129.50, 127.6, 108.5,
106.3, 99.7, 83.5, 80.7, 73.7, 71.5, 70.7, 68.1, 65.2, 50.3,
46.0, 45.8, 44.6, 38.7, 37.2, 36.8, 36.0, 28.6, 28.5, 27.3,
26.9, 26.3, 26.1, 25.9, 21.6, 19.2, 18.8, 17.5, –3.8, –4.7. EI-
MS m/e: 859 (M+ – CH3), 817 (M+ – C4H9), 699 (100%).
HR-MS calcd. for C49H71O9Si (M+ – CH3): 859.4636;
found: 859.4648.
Aldol adduct (29)
To a solution of 28 (180 mg, 0.237 mmol) in THF
(22 mL) was added KHMDS (0.5 mol/L in toluene,
0.24 mL, 0.120 mmol). The mixture was heated to reflux
while stirring for 20 min. The reaction was monitored by
TLC. Upon completion, the reaction was cooled to r.t. aq.
NH4Cl (25 mL, satd. NH4Cl – water = 1:1) was added to
quench the reaction. It was extracted with ethyl acetate (1 ×
30 mL, 2 × 20 mL). The combined organic layers were
washed with water and brine (15 mL each) and dried over
MgSO4. After removal of the solvent in vacuo, the residue
was purified by flash column chromatography (silica gel,
Hex:EA = 7:3) to give 29 (154 mg, 86%) as a colourless oil.
[α]2D0 –6.5 (c 0.83, CHCl3). IR (thin film, cm–1) ν: 3534,
Phenylselenide (31)
To a solution of 30 (236 mg, 0.270 mmol) in DCM
(20 mL) was added 2,6-di-tert-butylpyridine (0.21 mL,
1.48 mmol) and PhSeCl (258 mg, 1.35 mmol). The mixture
was stirred at r.t. for 9 h. It was diluted with ether (100 mL)
and washed with satd. NaHCO3 (2 × 20 mL) and brine
(20 mL). The combined aqueous layers were extracted with
ether (20 mL) and the organic layer was washed with brine
(10 mL). The combined organic layers were dried over
Na2SO4 and concentrated in vacuo. The residue was purified
by flash column chromatography (silica gel, Hex:EA = 4:1)
to afford 30 (34 mg, 86% conv.) and 31 (150 mg, 71%
borsm) as a colourless oil. [α]2D0 –33.3 (c 0.45, CHCl3). IR
(thin film, cm–1) ν: 3561, 2978, 2875, 1736, 1702, 1467,
1
2933, 1732, 1699, 1472, 1428, 1383, 1249, 1112, 1045. H
NMR (300 MHz, CDCl3) δ: 7.67–7.63 (4H, m), 7.44–7.33
(6H, m), 5.54 (1H, dt, J = 5.4, 9.8 Hz), 4.48–4.41 (2H, m),
4.29 (1H, dd, J = 4.1, 12.7 Hz), 3.81–6.61 (4H, m), 3.51
(1H, s), 2.81 (1H, d, J = 12.3 Hz), 2.69 (1H, m), 2.55 (1H,
dd, J = 1.7, 15.5 Hz), 2.29–2.01 (5H, m), 1.96 (3H, s), 1.92–
1.75 (5H, m), 1.49 (3H, s), 1.46 (3H, s), 1.35 (3H, s), 1.33
(3H, s), 1.19 (1H, dd, J = 10.3, 13.7 Hz), 1.03 (9H, s), 0.99
(3H, s). 13C NMR (75 MHz, CDCl3) δ: 211.2, 170.2, 135.6,
134.0, 129.5, 127.6, 108.3, 99.6, 81.8, 75.1, 73.3, 70.9, 69.9,
66.6, 66.3, 52.0, 50.8, 46.4, 45.9, 42.4, 40.5, 40.0, 38.1,
33.6, 28.5, 28.1, 27.7, 26.9, 26.0, 24.4, 21.8, 19.2, 18.7,
15.3. EI-MS m/e: 745 (M+ – CH3), 199 (100%). HR-MS
calcd. for C43H57O9Si (M+ – CH3): 745.3772; found:
745.3779.
1
1230, 1093, 723, 649. H NMR (300 MHz, CDCl3) δ: 7.67–
7.63 (4H, m), 7.54–7.52 (2H, m), 7.43–7.27 (9H, m), 5.63
(1H, dt, J = 5.6, 10.0 Hz), 4.77 (1H, d, J = 12.6 Hz), 4.40
(1H, m), 4.30 (1H, dd, J = 3.9, 12.6 Hz), 3.98 (1H, d, J =
1.2 Hz), 3.92 (1H, d, J = 12.6 Hz), 3.80 (1H, m), 3.70
(1H, m), 3.62 (1H, dd, J = 5.0, 9.8 Hz), 3.50 (1H, d, J =
13.6 Hz), 3.36 (1H, s), 2.66 (1H, m), 2.21–1.97 (6H, m),
1.96 (3H, s), 1.93–1.75 (4H, m), 1.53 (3H, s), 1.49 (3H, s),
1.36 (3H, s), 1.32 (3H, s), 1.26 (1H, m), 1.04 (12H, s), 0.93–
0.86 (1H, m). 13C NMR (75 MHz, CDCl3) δ: 207.8, 170.1,
135.6, 135.2, 134.1, 129.43, 129.35, 129.1, 129.0, 127.5,
108.4, 99.3, 81.8, 76.3, 73.2, 70.5, 70.1, 67.3, 66.6, 51.2,
51.0, 49.6, 47.2, 46.3, 42.2, 41.2, 39.0, 33.5, 28.42, 28.38,
27.4, 26.9, 26.1, 24.5, 21.8, 19.2, 18.4, 15.2. EI-MS m/e:
Silylenol ether (30)
To a solution of 29 (276 mg, 0.36 mmol) in DCM
(12 mL) was added triethylamine (1.52 mL, 10.9 mmol) and
© 2005 NRC Canada

Chen and Deslongchamps
739
898 (M+
–
H2O), 369 (100%). HR-MS calcd. for
support from the Natural Sciences and Engineering Research
Council of Canada (NSERC) are highly appreciated. We
thank Dr. Andrew Corbett for his assistance in the prepara-
tion of this manuscript.
C50H62O8SiSe (M+ – H2O): 898.3379; found: 898.3366.
Enone (32)
To a solution of 31 (107 mg, 0.117 mmol) in DCM
(12 mL) was added H2O2 (12 mL) at 0 °C. The mixture was
stirred at r.t. for 1 h. It was diluted with ice water and ex-
tracted with DCM. The combined organic layers were
washed with water and brine then dried over Na2SO4. After
removing the solvent in vacuo, the residue was purified by
flash column chromatography to afford 32 (36.1 mg, 57%
borsm) as a colourless oil. [α]2D0 –40.0 (c 0.82, CHCl3). IR
(thin film, cm–1) ν: 3479, 2932, 2858, 1731, 1652, 1463,
1250, 1086. 1H NMR (300 MHz, CDCl3) δ: 7.69–7.60
(4H, m), 7.45–7.32 (6H, m), 5.97 (1H, s), 5.51 (1H, dt, J =
5.5, 10.3 Hz), 4.79 (1H, dd, J = 1.8, 12.7 Hz), 4.61–4.55
(2H, m), 4.47 (1H, s), 4.15 (1H, d, J = 12.3 Hz), 3.89 (1H,
d, J = 12.4 Hz), 3.68 (1H, m), 3.10 (1H, d, J = 12.9 Hz),
2.29 (2H, m), 2.06–1.93 (2H, m), 1.92 (3H, s), 1.91–1.70
(4H, m), 1.57 (3H, s), 1.54 (3H, s), 1.38 (6H, s), 1.34–1.05
(2H, m), 1.03 (12H, s). 13C NMR (75 MHz, CDCl3) δ:
204.8, 169.9, 160.5, 135.5, 134.2, 131.7, 129.4, 127.5,
109.8, 101.2, 83.0, 76.7, 74.7, 70.7, 67.3, 66.8, 66.7, 51.4,
49.9, 46.8, 42.8, 42.7, 33.1, 31.2, 28.5, 26.9, 24.7, 23.7,
21.5, 19.2, 19.1, 15.4. EI-MS m/e: 743 (M+ – CH3), 701
(M+ – C4H9), 485 (100%). HR-MS calcd. for C43H55O9Si
(M+ – CH3): 743.3615; found: 743.3623.
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A mixture of 32 (10.5 mg, 0.0138 mmol), Zn dust
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and EtOH (0.58 mL) in a sealed tube was heated to 80 °C
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was heated to reflux for another 2 h. After cooling the reac-
tion mixture to r.t., it was diluted with ethyl acetate and fil-
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(3.1 mg, 32%) as colourless oils. [α]2D0 −46.4 (c 0.28,
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1
703. H NMR (300 MHz, CDCl3) δ: 7.68–7.61 (4H, m),
7.44–7.33 (6H, m), 5.74 (1H, m), 5.65 (1H, dt, J = 5.3,
9.4 Hz), 5.29 (1H, m), 4.51 (1H, d, J = 12.6 Hz), 4.28 (1H,
dd, J = 5.4, 11.2 Hz), 3.92 (1H, d, J = 12.7 Hz), 3.72 (1H,
dd, J = 5.3, 9.9 Hz), 3.65 (1H, dd, J = 6.8, 9.9 Hz), 3.36
(1H, s), 2.75 (1H, d, J = 13.6 Hz), 2.68 (1H, m), 2.54–2.39
(2H, m), 2.28–2.13 (2H, m), 1.98 (3H, s), 1.97–1.69
(4H, m), 1.50 (3H, s), 1.39 (3H, s), 1.35–1.22 (3H, m), 1.03
(9H, s), 1.00 (3H, s), 0.87 (1H, m). 13C NMR (75 MHz,
CDCl3) δ: 211.1, 170.3, 135.6, 133.9, 129.5, 128.6, 127.7,
127.6, 99.5, 81.6, 77.2, 73.0, 69.6, 66.1, 65.9, 51.6, 50.7,
46.3, 45.0, 43.8, 42.3, 40.1, 37.4, 33.7, 29.7, 28.1, 28.0,
26.9, 24.4, 22.0, 19.2, 18.9, 15.5. EI-MS m/e: 671, 653, 569,
511, 493, 295, 199 (100%). HR-MS calcd. for C40H51O7Si
(M+ – OCH3): 671.3404; found: 671.3400.
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Acknowledgements
The research chair in organic chemistry granted to Pr. Pi-
erre Deslongchamps by BioChem Pharma Inc. and financial
© 2005 NRC Canada

740
Can. J. Chem. Vol. 83, 2005
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© 2005 NRC Canada