A short multigram asymmetric synthesis of prostanoid scaffolds

Article abstract of DOI:10.1016/S0040-4020(03)00920-7

Enantiomerically pure polysubstituted cyclopentanes which can be regarded as prostanoid scaffolds have been prepared by an efficient synthetic sequence readily applicable to the preparation of multigram quantities. The first key reaction is the diastereoselective allylmetallation of oxoamide 4 which is readily prepared from γ-butyrolactone and an enantiomerically pure 2,5-dimethylpyrrolidine. The second key-step is an intramolecular [2+2] cycloaddition of a keteneiminium salt leading to bicylo[3.2.0] heptanones. These intermediates have been easily transformed into a variety of prostanoid scaffolds of high enantiomeric purities.

Full text of DOI:10.1016/S0040-4020(03)00920-7

Tetrahedron 59 (2003) 6797–6812
A short multigram asymmetric synthesis of prostanoid scaffolds
†
Dominique Depre, Lian-Yong Chen and Leon Ghosez
a
a
a,b
,
,
*
´
´
aDepartment of Chemistry, University of Louvain, 1 Place Louis Pasteur, B-1348 Louvain-la-Neuve, Belgium
bEuropean Institute of Chemistry and Biology, IECB-ENSCPB, 16 Avenue Pey-Berland, F-33607 Pessac, France
Received 22 April 2003; revised 10 June 2003; accepted 10 June 2003
Dedicated to Professor K. C. Nicolaou for his outstanding contribution to chemistry and his friendship
Abstract—Enantiomerically pure polysubstituted cyclopentanes which can be regarded as prostanoid scaffolds have been prepared by an
efficient synthetic sequence readily applicable to the preparation of multigram quantities. The first key reaction is the diastereoselective
allylmetallation of oxoamide 4 which is readily prepared from g-butyrolactone and an enantiomerically pure 2,5-dimethylpyrrolidine. The
second key-step is an intramolecular [2þ2] cycloaddition of a keteneiminium salt leading to bicylo[3.2.0] heptanones. These intermediates
have been easily transformed into a variety of prostanoid scaffolds of high enantiomeric purities.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
various polycyclic systems.5 During the course of this
venture, we also showed that cycloaddition of olefins to
keteniminium salts derived from chiral amides took place
with a high level of stereoselectivity.6 It became soon
obvious to us that these highly selective asymmetric [2þ2]
cycloadditions could provide a short route to a wide variety
of enantiopure prostanoid scaffolds which should be useful
to medicinal chemists. We present here a detailed descrip-
tion of these studies which eventually led to multigram
syntheses of enantiopure polysubstituted cyclopentanes.7
As a class of compounds of considerable therapeutic
interest, the prostaglandin family of natural products has
provided one of the most dramatic areas of chemistry of our
generation.1 Natural prostaglandins exist in such minute
concentrations that extraction of commercial amounts from
natural sources is unpractical. A first total synthesis was
published by Corey et al. in 1969.2 Since then, many
research groups have been involved in synthetic studies of
these important natural products.1,3 However, as a result of
the metabolic instability and non-discriminating biological
properties of the natural prostaglandins, it soon became
clear that the synthesis of analogs with higher metabolic
stability and well-defined biological profile was highly
desirable. This stimulated a vast synthetic programme
aiming at the discovery of pharmacologically interesting
analogs of the natural prostaglandins. It also stimulated the
search for practical methods of synthesis of enantiomeri-
cally pure polysubstituted cylopentane rings, an essential
element of prostanoid structures.
2. Strategy
Our synthetic strategy is outlined in Scheme 1. As first
target, we selected the bicyclic lactone 1 carrying a
protected hydroxyl group and a vinyl substituent which
should be easily transformed into 1- or 2-carbon side-chains.
We were rather confident that conditions should be found to
generate regioselectively the lactone ring by a Baeyer–
Villiger oxidation of cyclobutanone 2.
For several years, our laboratory has been involved in this
synthetic endeavour.4 We had shown that intramolecular
[2þ2] cycloadditions of ketenes or keteneiminium salts to
carbon–carbon double bonds offered an easy access to
From the outset, it was anticipated that the control of the
absolute configuration of the three stereogenic centers
would not be possible with the help of a single chiral
inductor: we neither expected the secondary hydroxyl group
to dictate the stereochemical outcome of the cycloaddition
reaction nor the chiral pyrrolidine to control the facial
selectivity of the allylmetallation reaction. Thus, to deal
with the establishment of the desired configuration of the
three stereogenic centers, we expected to need: (1) a chiral
auxiliary for the stereoselective construction of the bridge-
head stereogenic centers by an intramolecular [2þ2]
cycloaddition reaction of a keteniminium salt 3, (2) a chiral
Keywords: [2þ2] cycloadditions; keteniminium salts; allylmetallation;
cyclobutanones; bicyclic lactones.
*
Corresponding author. Tel.: þ32-10-47-2915; fax: þ32-10-47-2944;
e-mail: ghosez@chim.ucl.ac.be
Present address: Johnson & Johnson Pharmaceutical Research &
†
Development, Division of Janssen Pharmaceutica N.V., Chemical
Development—Process Research, 30 Turnhoutsweg, B-2340 Beerse,
Belgium.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00920-7

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
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Scheme 1.
ligand for the diastereoselective allylmetallation of 4-
oxoamide 4. This strategy could give access to compounds
with the configuration of the natural prostaglandins but also
to their enantiomers or diastereomers.
The short sequence of Scheme 2 was applied to the
preparation of up to 73 g of protected alcohols. The
TADDOL ligand could be recovered after chromatography.
3.2. Cycloaddition reactions
The slow addition of triflic anhydride to a solution of amide 8
and 2,6-di-t-butyl-4-methylpyridine in 1,2-dichloroethane
(DCE) at room temperature generated the corresponding
keteneiminium salt 12 which underwent the intramolecular
cycloaddition reaction to give, after hydrolysis, the epimeric
cyclobutanones13aand13b(Scheme4).Theseparationofthe
epimeric cyclobutanones was effected by MPLC. Both di-t-
butyl-4-methylpyridine and 2,5-dimethylpyrrolidine could be
recovered after aqueous work-up (ca. .95% and 80–85%,
respectively). Similarly, the [2þ2]cycloadditionstarting from
11 gave good yields of epimeric cyclobutanones 14a and 14b
which could be readily separated by flash chromatography.
3. Results and discussion
3.1. Synthesis and allylmetallation of 4-oxoamide 4
The inexpensive g-butyrolactone was converted in 93%
yield into 3-oxoamide 4 by treatment with (2S,5S)-
dimethylpyrrolidine8 followed by Swern oxidation of the
intermediate alcohol 5 (Scheme 2). After aqueous work-up
and removal of the volatile products, the crude 3-oxoamide
4 was sufficiently pure to be directly used in the
allylmetallation step.
The reaction of 4 with pentadienylzinc bromide generated
from zinc dust and pentadienyl bromide9 yielded a quasi-
equimolecular (6–7¼1.1:1) mixture of diastereomeric
adducts. This observation experimentally confirmed the
inability of the chiral pyrrolidine to control the facial
selectivity of the allylmetallation reaction. After much trial
and error in order to improve the selectivity of formation of
6 using pentadienylzinc derivatives carrying various chiral
ligands,10 we turned to the class of chiral organotitanate
compounds developed by Hafner et al.11 The pentadienyl-
titanate reagent was prepared in situ from pentadienyl-
lithium and the corresponding (R,R)-chlorotitanate
derivative. The crude alcohol 6 was obtained in 95% yield
with a diastereomeric excess of 94%. A single recrystalliza-
tion gave enantiomerically pure 6 in 74% yield. Its epimer 7
was similarly obtained from the (S,S)-chlorotitanate. The
enantiomerically pure alcohols 6 and 7 were transformed
into derivatives 8–11 by standard procedures (Scheme 3).
Under the same conditions, amide 9 gave cyclobutanones
15a and 15b (Scheme 5). The two cyclobutanones were also
easily separated by flash chromatography.
The enantiomeric purity of cyclobutanones 13a,13b,
14a,14b and 15a,15b was measured by HPLC (Chiralpak
AD) using racemic standards of each diastereoisomer
obtained by preparative HPLC. The relative configurations
were assigned on the basis of the 3JH–H coupling constants
(Scheme 6).13
Thus, in the case of 13a and 14a, the low 3JH-1,H-2 values (0–
3 Hz) correspond to dihedral angles between 90 and 1108 in
agreement with an exo stereochemistry for the vinyl group.
This coupling constant was higher (7.5–7.6 Hz) for com-
pounds 13b and 14b indicating a dihedral angle around 308
between the two nuclei. This angle was that expected for an
endostereochemistryofthe vinyl substituent. Similar analyses
of the values of JH-2,H-3 and JH-3,H-4 allowed us to assign the
configuration of the silyloxy group. Since the absolute
configurations of the carbon atom bearing the silyloxy group
The structure and configuration of 7 and 10 were confirmed
by an X-ray diffraction analysis.12

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
6799
Scheme 2. Conditions: (a) (2S,5S)-dimethylpyrrolidine, Et3N, D, 95% crude; (b) oxalyl chloride, DMSO in DCM, 2788C then 5, Et3N, 2788C to room
temperature, 99% crude; (c) CH2vCH–CHvCH–CH2Br, Zn powder, THF, 508C, 93%; (d) 1,4-pendadiene, n-BuLi in THF, 2788C to room temperature,
then (R,R)-chorotitanate in THF–ether, 278 to 08C, then 4, NH4F, 2788C to room temperature; (e) same as (d) but with (S,S)-chlorotitanate.
were known from the X-ray diffraction studies of 7 and 10,
these studies also established the absolute configuration of the
other asymmetric centers of the bicyclic systems.
3.3. Baeyer–Villiger oxidations
Our next task was to transform the bicyclic cyclobutanones
into prostanoid synthons. The first subgoal involved the
insertion of an oxygen atom between the carbonyl group and
the vicinal bridgehead carbon atom through a Baeyer–
Villiger oxidation reaction. No problem of stereochemical
In conclusion, through these two key reactions, we had
achieved our goal to construct four bonds attached to the
five-membered ring in a stereocontrolled fashion.
Scheme 3.

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
6800
Scheme 4. Conditions: (a) triflic anhydride, 2,6-di-t-Bu-4-methylpyridine, 1,2-DCE, room temperature; (b) CCl4–H2O, D.
nature was expected here since these oxidations are known
to proceed with retention of configuration.14 On the other
hand, we were mindful that the insertion of the oxygen atom
might not occur with acceptable levels of regioselectivity.
The results are shown in Table 1.
with hydrogen peroxide in trifluoroethanol (entry 3), but
the reaction took several days.17 The use of a bulkier
reagent (entry 4) further decreased the reaction rate
without increasing the selectivity. We then applied the
best conditions (H2O2 –trifluoroethanol) to the other
bicyclic ketones. The selectivity was somewhat lower
for 13b, 14a and 14b (entries 5, 6, 7). Interestingly, the
oxidation of 15a,15b carrying an exo t-butyldiphenyl-
silyloxy substituent was completely selective in favour of
the formation of the desired lactone with both hydrogen
peroxide (entries 8, 10) and mCPBA (entry 9).18
Our initial studies were performed on compound 13a.
The reaction with mCPBA in the presence of sodium
hydrogen carbonate (entry 1), gave a mixture of lactone
16a and the corresponding regioisomer 17a in almost
quantitative yields but with disappointingly low selectiv-
ity.13,15 The oxidation by bis(trimethylsilyl)peroxide
(entry 2) was even less selective though this reagent
had been reported to oxidize the parent bicycloheptanone
with the exclusive formation of the type of g-lactone we
were interested in.16 The best selectivity was obtained
In each case the desired lactones were readily purified by
recrystallization. X-Ray diffraction analyses on lactones
16a, 16b and 16e confirmed the structural and stereo-
chemical assignments.19–21
Scheme 5.

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
6801
Scheme 6.
3.4. Transformations of the bicyclic lactones
The acetate probably originated from a silicagel-catalysed
trans-acetylation of alcohol 22 with ethyl acetate used for
the chromatographic separation. Treatment of the crude
alcohol with acetic anhydride in pyridine quantitatively
converted 22 into 23.
Our final task was to demonstrate that the enantiomerically
pure bicyclic lactones 16a–16f could be readily trans-
formed into a wide variety of prostanoid scaffolds. The
study was performed on compound 16a.
3.4.4. Wacker oxidation. When reacted under the con-
ditions of the Wacker oxidation,25,26 compound 16a gave
the enantiomerically pure ketone 24 in 76% yield together
with a small amount (17%) of aldehyde 25 (Scheme 10).
3.4.1. Oxidative cleavage of the vinyl substituent.
Compound 16a was converted in good yields into 18 after
ozonolysis and reductive treatment of the corresponding
ozonide with the borane–DMS complex (Scheme 7,
reaction a).22 Treatment of the intermediate ozonide with
DMS only gave aldehyde 19. Under the same conditions, a
2.1:1 mixture of 16a and 16b gave 19 and enal 20
(ratio<2.5:1).
3.5. Syntheses of precursors of 13-aza- or
13-oxaprostanoids
The vinyl group of 16a was readily transformed into a
carboxyl group by treatment with Jone’s reagent in the
presence of catalytic amount of osmium tetroxide.27
A
The formation of enal 20 probably resulted from a E2
elimination of t-butyldiphenylsilanol from the minor
aldehyde in which the acidic hydrogen a to the aldehyde
group and the silyloxygroup are in a trans relationship.
Curtius rearrangement of acid 26 provided an easy access to
an advanced precursor of the class of 13-azaprostaglandins.
Carbamate 27 was obtained in excellent yield from the
reaction of carboxylic acid 26 with diphenylphosphoryl
azide28 in the presence of benzyl alcohol. As a result of the
orthogonal protections, selective transformations of the
various functional groups embedded in 27 should be quite
easy. Indeed hydrogenolysis selectively cleaved the benzyl
carbamate group to give the free amine 28 in 98% yield.
3.4.2. Epoxidation of the vinyl substituent. A 4:1 mixture
of diastereomeric epoxides 21a and 21b was quantitatively
formed from the reaction of 16a with mCPBA (Scheme 8).
They were readily separated by flash chromatography on
silica gel. Both epoxides gave crystals which were
submitted to X-ray diffraction analyses.23
Our initial attempts to convert carboxylic acid 26 into a
precursor of the class of 13-oxaprostaglandins were less
successful: oxidative decarboxylation of 26 with lead
tetraacetate under many different conditions always led to
complex mixtures containing no alcohol 30 or its acetate.29
Fortunately, Barton’s radical oxidative decarboxylation
3.4.3. Hydroboration. Hydroboration of 16a using bromo-
borane–DMS complex24 followed by chromatography on
silica gel with ethyl acetate as eluent, gave a mixture of
alcohol 22 and the corresponding acetate 23 in 60 and 21%
yields, respectively (Scheme 9).

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
6802
Table 1. Baeyer–Villiger oxidations
Entry
Ketone
Conditions
Major product
Yield (%)
Regioisomer ratio 16–17
1
13a
mCPBA, NaHCO3, DCM, 08C, 30 min
96
3.4:1
2
3
4
(TMS)2O, TMSOTf (cat), DCM, 2158C, 15 h
H2O2, CF3CH2OH, 58C, 4–7 days
tBuOOH, CF3CH2OH, 58C, 11 days
82
89
52
1.5:1
13.3:1
13.3:1
5
6
7
13b
14a
14b
15a
H2O2, CF3CH2OH, 58C, 4–7 days
H2O2, CF3CH2OH, 58C, 4–7 days
H2O2, CF3CH2OH, 58C, 4–7 days
69
83
87
5.6:1
8.1:1
6.7:1
8
9
H2O2, CF3CH2OH, 58C, 4–7 days
94
94
Only one isomer
mCPBA, NaHCO3, DCM, 08C, 30 min
10
15b
H2O2, CF3CH2OH, 58C, 4–7 days
.98
Only one isomer
1
reaction30 provided us with a practical though not perfect
route towards alcohol 30. Acid 26 was first converted into
the activated ester 29 which was photolyzed in the presence
of oxygen and t-butylthiol to give an intermediate hydro-
peroxide which was reduced in situ with trimethylphosphite.
Alcohol 30 was obtained with a moderate 45% yield. When
the decomposition of ester 29 was carried out thermally,
yield dropped to 29% and a sulfide 31 (21%) was obtained
as a by-product. The sulfide probably originated from a
radical recombination in a solvent cage as previously
reported in other instances (Scheme 11).31
in 30 was supported by the fact that H and 13C NMR
spectra of 30 were found to be identical to those of the
alcohol resulting from the Baeyer–Villiger rearrangement
of 24.
4. Conclusion
The synthetic strategy using an asymmetric allylmetallation
of a functionalised aldehyde and an intramolecular [2þ2]
cycloaddition of a keteniminium salt provides a framework
for the enantiospecific access to polycyclic compounds.
This paper provides an illustration of the power of this
strategy. A short sequence of reactions which can easily be
scaled up led to a wide variety of prostanoid scaffolds in
enantiopure form. A proper choice of the chiral auxiliaries
The configuration of the carbon bearing the carbamoyl
substituent in 27 was assumed to be the same as in 26 since
the Curtius rearrangement is known to occur with retention
of configuration. The proposed configuration of the alcohol

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
6803
Scheme 7. Conditions: (a) O3, DCM, 2788C then H3B–DMS, 2788C to room temperature; (b) O3, DCM, 2788C then DMS.
Scheme 8.
Scheme 9.
should allow the preparation of all diastereomeric lactones
16. The main drawback of the present sequence is that it
requires two chiral auxiliaries to establish the desired
configurations of the stereogenic centers. In particular, it
would be desirable to avoid the use of the rather expensive
2,5-dimethylpyrrolidine. We have recently shown that this
was indeed possible.32 Further applications of this synthetic
strategy are presently under way.

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6804
Scheme 10.
Scheme 11. Conditions: (a) Jones reagent, OsO4 (cat), acetone, room temperature; (b) (PhO)2P(O)N3, Et3N, PhCH2OH, benzene, D; (c)
,
Et3N, toluene, room temperature (protected from light), filtration; (d) O2, t-BuSH, toluene, 500 W halogen lamp, room temperature then (MeO)3P; (e) O2, t-
BuSH, toluene, 808C then P(OMe)3.
´
5. Experimental
R. Flammang, Universite de Mons-Hainaut, Belgium.
Elemental analyses were performed in the laboratory of
Mr Stone at University College London, UK. Gas
chromatography (GC) analyses were performed on a
Carlo-Erba Fractovap 4160 chromatograph fitted with a
Heliflex AT-1 (30 m£0.25 mm int. B) or a Permabond SE-
52 (25 m£0.25 mm int. B) capillary column and a flame
ionisation detector using N2 as carrier gas. HPLC analyses
were performed on a Waters 600-E system fitted with a
column oven Merck Lichrojet and a variable-wavelength
UV detector set up at 220 nm. Chiralpak AD refers to a
Chiralpak AD column, 250 mm£4 mm int. B from Diacel.
Lichrospher Si60 refers to a Merck Lichrospher Si60 4 mm
column, 250£4.6 mm. Novapak C18 refers to a Novapak
C18 4 mm column, 300£3.9 mm int. B from Waters.
5.1. General
1H and 13C NMR spectra were recorded in deuteriochloro-
form on Varian Gemini-200, Varian Gemini-300 and
Brucker AM-500 spectrometers. 13C NMR spectra were
recorded in CDCl3 at 50, 75 or 125 MHz. Chemical shifts
are reported in ppm relative to tetramethylsilane or CDCl3.
Mass spectra (electron impact 70 eV) were recorded on a
Varian Mat-44 and on Finnigan Mat-TSQ 70 spectrometers.
Infra-red (IR) spectra were recorded on a Perkin–Elmer
1710 Fourier transform spectrometer. Absorption frequen-
cies are reported in cm21. High resolution mass spectra
(HRMS, electronic impact) were recorded by Professor

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
6805
Hypersil Phenyl refers to a Hypersil Phenyl 3 mm,
150£4.6 mm int. B from Chandon. Flash chromatography
separations were performed with silica gel Merck 60 230–
400 mesh. Preparative MPLC separations were performed
on a Prochrom LC-80 system with silica gel Merck 60 15–
40 mm. Solvents for reaction, extraction and chromatog-
raphy were of technical grade and distilled. Solvents for
reaction under anhydrous conditions were further distilled
on an appropriate drying agent.
solid). The isomer ratio was measured by HPLC (Chiralpak
AD 250£4.6 mm, hexane–isopropanol 25:1, flow 1 ml/min,
Rt 14.27 min (6), 17.10 min (7).
(2S,5S)-1-[(4R)-4-Hydroxy-5-vinylhept-6-enoyl]-2,5-di-
methylpyrrolidine 6. 84 ml (210 mmol) of a 2.5 M solution of
n-butyllithium in hexanes were added to a solution (2758C)
of 1,4-pentadiene (26.8 ml, 260 mmol) in 800 ml dry THF.
The resulting solution was allowed to warm up to 08C (1 h). It
was transferred at 2508C to awell stirred suspensionof141 g
(230 mmol) (R,R)-chlorotitanate in 3.4 l dry ether. The
reaction mixture was allowed to warm up to 2208C
(appearance of a brown colour) then cooled back to
2758C. 36.6 g (200 mmol) of 4 in 200 ml dry ether were
added and the mixture was allowed to react for 5 h at 2758C.
The resulting mixture was quenched with 1.85 l of 45%
aqueous NH4F and allowed to warm up to room temperature.
The suspension was filtered through Celite and the biphasic
filtrate was decanted. The aqueous layer was extracted with
ethyl acetate. The combined organic layers were dried over
magnesium sulphate and concentrated in vacuo. The residue
(160 g) was divided into 5 portions and filtered through 1 kg
silica (ether then ethyl alcohol–ether 1:19) to give 48.1 g 6
(95% yield, 94% d.e., white solid). Recrystallization from
ethyl acetate gave 37.1 g 6 with d.e. .98% (colourless
plates). TLC (ether) Rf 0.29. Mp 77–788C. [a]2D0¼27.0 (c:
1.0; CHCl3). Chiral-phase HPLC (Chiralpak AD, 2-propa-
5.1.1. (2S,5S)-1-(4-Hydroxybutanoyl)-2,5-dimethylpyr-
rolidine 5. A mixture of 17.4 ml (227 mmol) g-butyrolac-
tone, 45 g (454 mmol) (2S,5S)-dimethylpyrrolidine and
63 ml (907 mmol) triethylamine was refluxed for 2 days.
Then an additional portion (17.4 ml, 227 mmol) of g-
butyrolactone was added and the reflux was maintained until
complete conversion of the lactone. The mixture was
concentrated in vacuo to yield 81.0 g of 5 (96%, colourless
oil). 1H NMR (200 MHz) 4.23 (1H, m, J¼6.5 Hz), 4.04 (1H,
m, J¼6.7 Hz), 3.71 (2H, t, J¼5.6 Hz), 3.9 (1H, br), 2.52
(1H, d, J¼6.3 Hz), 2.51 (1H, d, J¼6.3 Hz), 2.23 (2H, m),
1.91 (2H, m, J¼5.9 Hz), 1.60 (2H, m), 1.19 (3H, d,
J¼6.2 Hz), 1.17 (3H, d, J¼6.6 Hz). 13C NMR (50 MHz)
172.2, 62.7, 53.9, 53.2, 32.6, 30.8, 29.0, 27.9, 21.5, 19.0. IR
nmax (thin film) 3403 (O–H), 1615 (CvO), 1422 (C–N
amide). MS m/z 185 (Mþ8), 141, 84. Calculated for
C10H19NO2: C, 64.83; H, 10.33; N, 7.56. Found: C, 64.90;
H, 10.68; N, 7.59. [a]2D0¼40.38 (c: 1.06; CHCl3).
1
nol–hexane 4:96, 1 ml/min, 208C) Rt 14.3 min. H NMR
(300 MHz) 5.88 (m, 2H), 5.14 (m, 4H), 4.21 (quint, 1H,
J¼6.7 Hz), 4.02 (quint, 1H, J¼6.6 Hz), 3.59 (ddd, 1H,
J¼9.4, 6.3, 2.9 Hz), 3.20 (br, 1H), 2.82 (q, 1H, J¼7 Hz), 2.51
(m, 2H), 2.04–2.26 (m, 2H), 1.92 (m, 1H), 1.73 (m, 1H),
1.50–1.63 (m, 2H), 1.18 (d, 3H, J¼4.4 Hz), 1.16 (d, 3H,
J¼4.4 Hz). 13C NMR (75 MHz) 172.1, 137.7, 137.4, 116.9,
116.5, 73.6, 55.2, 53.7, 53.2, 31.7, 30.8, 29.4, 29.0, 21.5,
19.0. IR nmax (KBr) 3226 (O–H), 1635 (CvC), 1599
(CvO), 1469, 1430. MS m/z 251 (Mþ8), 233 ([M2H2O]þ8),
184 ([M2C5H7]þ). Calculated for C15H25NO2: C, 71.67; H,
10.02; N, 5.57. Found: C, 71.74; H, 10.22; N, 5.53.
5.1.2. (2S,5S)-1-(4-Oxobutanoyl)-2,5-dimethylpyrroli-
dine 4. 30.5 ml (430 mmol) dry DMSO dissolved in
100 ml dichloromethane were added to a cold (2708C)
solution of oxalyl chloride (18.7 ml, 214 mmol) in 600 ml
dry dichloromethane over a period of 30 min and the
resulting mixture was stirred for 15 min at 2708C. Then, a
solution of 5 (39.8 g, 201 mmol) in 70 ml dichloromethane
was added in 5 min. After 20 min at 2708C, triethylamine
(137 ml, 988 mmol) was added and the reaction mixture
was allowed to warm up to room temperature. The reaction
mixture was worked-up with 700 ml water. The organic
layer was dried over magnesium sulphate, filtered and
concentrated in vacuo to give 4 (37.88 g, 96%, pale brown
(2S,5S)-1-[(4S)-4-Hydroxy-5-vinylhept-6-enoyl]-2,5-di-
methylpyrrolidine 7. Same procedure as for 6 starting from
1,4-pentadiene (0.88 ml, 8.53 mmol), 2.5 M n-butyllithium
(2.75 ml, 5.88 mmol) in hexanes, 4.81 g (7.85 mmol) (S,S)-
chlorotitanate and 1.20 g (6.55 mmol) 4. Purification by
flash chromatography (ether, then ether–ethyl alcohol 9:1)
gave 937 mg of 7 (57%, 92% d.e., white solid). Recrys-
tallization from ether–pentane gave 7 with d.e. .99%
(colourless crystals). TLC (ether) Rf 0.29. Mp 87–87.58C.
[a]2D0¼41.98 (c: 0.98; CHCl3). Chiral-phase HPLC (Chir-
alpak AD, 2-propanol–hexane 4:96, 1 ml/min, 208C) Rt
1
liquid). Crude 4 was used without further purification. H
NMR (200 MHz) 9.87 (1H, s), 4.20 (1H, m, J¼6.7 Hz), 4.08
(1H, m, J¼6.5 Hz), 2.85 (2H, m, J¼6 Hz), 2.63 (2H, m,
J¼6 Hz), 2.02–2.32 (2H, m), 1.49–1.66 (2H, m), 1.21 (3H,
d, J¼6.4 Hz), 1.15 (3H, d, J¼6.4 Hz). 13C NMR (50 MHz)
201.2, 169.3, 53.4, 53.1, 38.8, 30.7, 28.9, 27.2, 21.3, 18.9.
IR nmax (thin film) 1723 (CvO aldehyde), 1636 (CvO
amide), 1425. MS m/z 184 ([MþH]þ), 183 (Mþ8), 155, 84.
HRMS (EI) calculated for C10H17NO2: 183.125925. Found,
183.126454. [a]D20¼44.308 (c: 1.34; CHCl3).
1
17.1 min. H NMR (300 MHz) 5.81–5.97 (m, 2H), 5.08–
5.19 (m, 4H), 4.22 (quint, 1H, J¼6.6 Hz), 4.04 (quint, 1H,
J¼6.5 Hz), 3.68 (d, 1H, J¼4.0 Hz), 3.6 (m, 1H), 2.83 (q,
1H, J¼7.2 Hz), 2.40–2.62 (m, 2H), 2.04–2.27 (m, 2H),
1.92 (m, 1H), 1.49–1.77 (m, 3H), 1.17 (d, 3H, J¼6.4 Hz),
1.16 (d, 3H, J¼6.5 Hz). 13C NMR (75 MHz) 172.2, 137.7,
137.5, 116.9, 116.6, 73.6, 54.2, 53.9, 53.3, 31.7, 30.9, 29.7,
29.1, 21.6, 19.2. IR nmax (KBr) 3227 (O–H), 1635 (CvC),
1599 (CvO), 1469, 1430. MS m/z 252.2 ([MþH]þ), 251
(Mþ8), 233 ([M2H2O]þ8), 184 ([M2C5H7]þ). Calculated
for C15H25NO2: C, 71.67; H, 10.02; N, 5.57. Found: C,
71.75; H, 10.01; N, 5.46.
5.1.3. (2S,5S)-1-(4-Hydroxy-5-vinylhept-6-enoyl)-2,5-
dimethylpyrrolidine (617). A solution of 4 (366 mg,
2 mmol) and 5-bromo-penta-1,3-diene (735 mg, 5 mmol) in
8 ml THF was added dropwise in 30 min to a warm (608C)
suspension of 405 mg (6.2 mmol) zinc dust in 8 ml THF.
After 3 h at 608C, the reaction mixture was treated with
10 ml 1 M aqueous HCl and 2.5 ml ether. The dried organic
layer was concentrated in vacuo to give a residue which was
purified by flash chromatography (ether) to give 467 mg of a
mixture of 6 and 7 (93%, d.e. 7% in favour of 6, colourless

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6806
5.1.4. (2S,5S)-1-[(4R)-4-(tert-Butyldiphenylsilyloxy)-5-
vinylhept-6-enoyl]-2,5-dimethylpyrrolidine 8. A solution
of 6 (37.71 g, 150 mmol), tert-butyldiphenylsilyl chloride
(42.9 ml, 165 mmol) and imidazole (22.47 g, 330 mmol) in
700 ml DMF was stirred at 608C until complete conversion
of 6 (ca. 3 days). DMF was removed in vacuo and the
residue was treated with dichloromethane (1.9 l). The
resulting precipitate was filtered off through Celite and the
filtrate was concentrated under vacuum. The residue was
filtered through silica (ethyl acetate–petroleum ether 1:4) to
give 81 g of an oil. Removal of volatile impurities by bulb-
to-bulb distillation (708C/0.02 mbar) yielded 73.8 g pure 8
(100%, colourless to pale yellow oil). TLC (ethyl acetate–
petroleum ether 1:3) Rf 0.4. [a]2D0¼10.58 (c: 1.13; CH2Cl2).
1H NMR (300 MHz) 7.70 (m, 4H), 7.26–7.40 (m, 6H), 6.01
(ddd, 1H, J¼17.2, 10.5, 6.7 Hz), 5.83 (ddd, 1H, J¼17.8, 9.7,
7.5 Hz), 4.89–5.12 (m, 4H), 3.79 (dt, 1H, J¼7.6, 3.7 Hz),
4.10 (quint, 1H, J¼6.5 Hz), 3.47 (quint, 1H, J¼6.5 Hz),
2.90 (m, 1H), 2.27 (m, 1H), 2.01 (m, 2H), 1.68–1.90 (m,
3H), 1.46 (m, 2H), 1.06 (s, 9H), 1.08 (d, 3H, J¼6.3 Hz),
0.89 (d, 3H, J¼6.4 Hz). 13C NMR (75 MHz) 171.0, 137.8,
136.9, 136.0, 135.9, 134.4, 133.6, 129.7, 129.5, 127.5,
127.4, 116.9, 116.2, 76.7, 53.8, 53.2, 52.7, 31.7, 30.7, 29.9,
29.0, 27.0, 21.4, 19.6, 19.2. IR nmax (thin film) 1646 (CvO),
1462, 1426. MS m/z 489 (Mþ8), 432 ([M2t-Bu]þ).
Calculated for C31H43NO2Si: C, 76.02; H, 8.84; N, 2.85.
Found: C, 75.75; H, 8.90; N, 2.89.
TLC (ethyl acetate–pentane 3:7) Rf 0.25. Mp (ether–
1
pentane) 1138C. [a]D20¼41.7 (c: 1.05; CHCl3). H NMR
(200 MHz) 7.30–7.42 (m, 4H), 7.06 (tt, 1H, J¼7, 1.5 Hz),
6.70 (br, 1H), 5.74–5.93 (m, 2H), 5.08–5.17 (m, 4H), 4.95
(m, 1H, J¼8.5, 6, 4.1 Hz), 4.19 (quint, 1H, J¼6.6 Hz), 3.97
(quint, 1H, J¼6.4 Hz), 3.05 (m, 1H, J¼7.7, 5.8 Hz), 2.38
(m, 2H), 1.89–2.14 (m, 4H), 1.43–1.58 (m, 2H), 1.13 (d,
3H, J¼6.4 Hz), 1.12 (d, 3H, J¼6.3 Hz). 13C NMR
(50 MHz) 170.6, 153.4, 138.0, 136.5, 136.1, 129.1, 123.4,
118.6, 117.5, 117.3, 76.5, 53.5, 53.0, 52.8, 31.1, 30.8, 29.0,
21.5, 19.2, 17.7. IR nmax (KBr) 3240 (N–H), 3068, 2970,
1720 (CvO carbonate), 1617 (CvO amide), 1549, 1503,
1447, 1225. MS m/z 370 (Mþ8), 303 ([M2C5H7]þ), 184
([M2PhNCO–C5H7]þ). Calculated for C22H30N2O3: C,
71.32; H, 8.16; N, 7.56. Found: C, 71.10; H, 8.19; N, 7.76.
5.1.7. (2S,5S)-1-[(4R)-4-Benzoyloxy-5-vinylhept-6-
enoyl]-2,5-dimethylpyrrolidine 11. A solution 21.37 g
(85 mmol) of 6, 19.7 ml (170 mmol) benzoyl chloride and
17.2 ml (212 mmol) pyridine in 140 ml THF was stirred at
room temperature for 3 days then poured into 250 ml 1 M
aqueous HCl. The organic layer was washed with 140 ml
2 M aqueous NaOH and 140 ml of water, then dried over
magnesium sulphate, filtered and concentrated under
vacuum. The residue was purified by flash chromatography
(ethyl acetate–petroleum ether 1:3) to give 24.6 g 11 (81%,
pale yellow liquid). TLC (ethyl acetate–petroleum ether
3:1) Rf 0.38. [a]D20¼44.38 (c: 1.29; CHCl3). 1H NMR
(300 MHz) 8.04 (dd, 2H, J¼8.5, 1.4 Hz), 7.57 (tt, 1H,
J¼7.4, 1.4 Hz), 7.44 (m, 2H, J¼7.5 Hz), 5.81–5.94 (m,
2H), 5.26 (ddd, 1H, J¼9.5, 5.9, 3.5 Hz), 5.09–5.18 (m, 4H),
3.14 (q, 1H, J¼7.2 Hz), 3.17 (quint, 1H, J¼6.6 Hz), 3.10
(quint, 1H, J¼6.4 Hz), 2.36 (t, 2H, J¼7.7 Hz), 1.98–2.31
(m, 4H), 1.50 (m, 2H), 1.08 (d, 6H, J¼6.4 Hz). 13C NMR
(75 MHz) 170.4, 166.3, 136.5, 136.0, 132.9, 130.4, 129.6,
128.3, 117.5, 117.3, 76.0, 53.5, 53.0, 52.7, 31.1, 30.8, 29.0,
27.8, 21.5, 19.2. IR nmax (thin film) 1718 (CvO ester), 1636
(CvO amide), 1451, 1418. MS m/z 355 (Mþ8), 288
5.1.5. (2S,5S)-1-[(4S)-4-(tert-Butyldiphenylsilyloxy)-5-
vinylhept-6-enoyl]-2,5-dimethylpyrrolidine 9. Same pro-
cedure as for the synthesis of 8 starting with 377 mg
(1.5 mmol) of 7, 0.39 ml (1.5 mmol) of tert-butyldiphenyl-
silyl chloride and 224 mg (3.3 mmol) of imidazole. Yield:
677 mg of 9 (92%, colourless oil). TLC (ethyl acetate–
petroleum ether 1:3) Rf 0.43. [a]2D0¼3.268 (c: 1.35; CHCl3).
1H NMR (300 MHz) 7.67–7.79 (m, 4H), 7.33–7.43 (m,
6H), 5.98 (ddd, 1H, J¼17.2, 10.5, 6.7 Hz), 5.82 (ddd, 1H,
J¼17.3, 10.2, 8 Hz), 4.86–5.10 (m, 4H), 3.81 (dt, 1H,
J¼7.1, 4.3 Hz), 4.11 (quint, 1H, J¼6.7 Hz), 3.63 (quint, 1H,
J¼6.4 Hz), 2.90 (m, 1H), 2.26 (m, 1H), 1.99 (m, 2H), 1.67–
1.87 (m, 3H), 1.46 (m, 2H), 1.06 (s, 9H), 1.05 (d, 3H,
J¼6.7 Hz), 0.92 (d, 3H, J¼6.3 Hz). 13C NMR (75 MHz)
171.0, 137.7, 137.3, 136.1, 136.0, 134.8, 134.6, 129.6,
129.5, 127.5, 116.7, 116.2, 76.6, 53.6, 53.3, 52.9, 31.3, 30.9,
29.1, 27.2, 21.5, 19.6, 19.4. IR nmax (thin film) 1634 (CvO),
1427. MS m/z 432 ([M2t-Bu]þ), 199 ([Ph2SiOH]þ).
Calculated for C31H43NO2Si: C, 76.02; H, 8.84; N, 2.85.
Found: C, 75.70; H, 8.88; N, 2.96.
([M2C5H7]þ),
105
([PhCO]þ).
Calculated
for
C22H29NO3: C, 74.33; H, 8.22; N, 3.94. Found: C, 74.27;
H, 8.32; N, 3.88.
5.2. Intramolecular [212] cycloaddition
reactions—general procedure
Triflic anhydride (1.05 equiv. of a 0.66 M solution in DCE)
was added at room temperature over a period of 12 h to a
well stirred 0.06 M solution of amide 8, 9 or 11 in DCE
containing 1.20 equiv. of di-tert-butyl-methylpyridine. The
reaction mixture was stirred at room temperature for 24 h
then concentrated under vacuum. The residue was refluxed
in a biphasic mixture of water and CCl4 (2£11.5 l/mol) for
5 h to hydrolyse the intermediate cyclobutaneiminium salts.
Addition of 1.06 equiv. 1 M aqueous HCl, separation and
concentration of the organic layer left a residue which was
dissolved in ether (11.5 l/mol). The pyridium salts were
filtered off. The filtrate was dried over magnesium sulphate
and concentrated in vacuo. The crude product was purified
by flash chromatography or by MPLC to give the
corresponding cyclobutanones.
5.1.6. (2S,5S)-1-[(4R)-4-Anilinocarbonyloxy-5-vinylhept-
6-enoyl]-2,5-dimethylpyrrolidine 10. 0.11 ml (1 mmol) of
phenyl isocyanate was added to a solution of 126 mg
(0.5 mmol) of 6 in 1 ml benzene. The reaction mixture was
stirred at room temperature for 2 days. Volatile products
were removed in vacuo. The residue was treated with ethyl
acetate–aqueous 0.5 M HCl (3 mlþ1 ml). The biphasic
mixture was vigorously stirred at room temperature for 1 h.
The organic layer was dried over potassium carbonate,
filtered and concentrated in vacuo. The residue was purified
by filtration through a plug of silicagel (ethyl acetate–
pentane 3:7) to give 166 mg of 10 (90%, white powder).
Colourless needles suitable for X-ray diffraction analysis
were obtained by recrystallization from ether–pentane.
Recovery of 2,5-dimethylpyrrolidine. The aqueous layer
from the hydrolysis step was brought up to pH¼14 by

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
6807
adding sodium hydroxide at 08C. The resulting emulsion
was extracted with ether. The organic layer was dried over
potassium hydroxide. A stream of gaseous HCl was passed
at 08C through the solution to give the dimethylpyrrolidine
as its hydrochloride salt (ca. 83%).
separated by flash chromatography (ethyl acetate–hexane
3:97).
(1R,2R,3S,5S)-3-(tert-Butyldiphenylsilyloxy)-2-vinyl-bicy-
clo[3.2.0]heptan-6-one 15a. TLC (ethyl acetate–hexane
1:19) Rf 0.40. [a]2D0¼47.88 (c: 1.08; CHCl3). HPLC
(Lichrospher Si60, 2-propanol–hexane 0.3:99.7, 1 ml/min,
208C) Rt 7.7 min. Chiral-phase HPLC (Chiralpak AD, 2-
propanol–hexane 0.2:99.8, 0.4 ml/min, 208C) Rtent-15a
5.2.1. [212] Cycloaddition from 7. 1.20 g (2.13 mmol) of
7 gave after flash chromatography (ethyl acetate–petroleum
ether 1:9) 783 mg (94%, colourless gel) of a mixture of 13a
and 13b (13a–13b: 84:16 measured on MERCK LICHRO-
SPHER SiO2 4 mm, 250£4.6 mm, hexane–isopropanol,
99.7:0.3, flow 1 ml/min, Rt 10.24 min (13a) and 11.2 min
(13b). The separation of 13a and 13b was performed by
MPLC (ethyl acetate–petroleum ether 7:93). When the
reaction was carried out from 70 g (143 mmol) 7, 57.8 g of a
mixture of cyclobutanones were obtained. The separation by
MPLC gave 28.0 g 13a (50%, colourless gel), 3.18 g 13b
(6%, colourless gel), 4.58 g of 13a and 13b as a mixture
(8%), and 450 mg ent-15a (1%, colourless gel). No ent-15b
was isolated.
1
19.8 min, Rt15a 21.4 min. H NMR (500 MHz) 7.62–7.70
(m, 4H), 7.42 (m, 6H), 6.07 (ddd, 1H, J¼17.3, 10.5, 7.6 Hz),
5.14 (d, 1H, J¼10.5 Hz), 5.05 (d, 1H, J¼17.3 Hz), 4.43 (dt,
1H, J¼7.8, 5.4 Hz), 3.55 (m, 1H, J¼7.8, 2.7 Hz), 3.14 (ddd,
1H, J¼18.3, 9.3 Hz, 4), 2.81 (m, 1H, J¼2.8 Hz), 2.46 (m,
1H, J¼18.3, 3.7 Hz), 2.41 (m, 1H), 1.92 (ddd, 1H, J¼13.1,
5.5, 2.8 Hz), 1.85 (ddd, 1H, J¼13.1, 9.8, 7.6 Hz), 1.05 (s,
9H). 13C NMR (125 MHz) 212.3, 137.2, 135.7, 135.5, 133.9
(2£), 129.7, 127.5 (2£), 115.6, 76.8, 61.5, 53.9, 51.0, 34.9,
32.3, 26.8, 19.1. IR nmax (thin film) 1785 (CvO). MS m/z
333 ([M2t-Bu]þ). Calculated for C25H30O2Si: C, 76.87; H,
7.74. Found: C, 76.58; H, 7.71.
(1R,2R,3R,5S)-3-(tert-Butyldiphenylsilyloxy)-2-vinyl-bicy-
clo[3.2.0]heptan-6-one 13a. TLC (ethyl acetate–hexane
1:19) Rf 0.31. [a]2D0¼46.58 (c: 1.0; CHCl3). HPLC (Lichro-
spher Si60, 2-propanol–hexane 0.3:99.7, 1 ml/min, 208C)
Rt 10.1 min. Chiral-phase HPLC (Chiralpak AD, 2-propa-
nol–hexane 0.2:99.8, 0.5 ml/min, 208C) Rtent-13a 19.2 min,
(1R,2S,3S,5S)-3-(tert-Butyldiphenylsilyloxy)-2-vinyl-bicy-
clo[3.2.0]heptan-6-one 15b. TLC (ethyl acetate–hexane
1:19) Rf 0.33. [a]2D0¼55.08 (c: 1.08; CHCl3). HPLC (Lichro-
spher Si60, 2-propanol–hexane 0.3:99.7, 1 ml/min, 208C) Rt
8.7 min. Chiral-phase HPLC (Chiralpak AD, 2-propanol–
hexane 0.2:99.8, 0.5 ml/min, 208C) Rt15b 15.8 min, Rtent-15b
18.7 min. 1H NMR (500 MHz) 7.60–7.70(m, 4H), 7.30–7.50
(m, 6H), 5.68 (ddd, 1H, J¼18.4, 9.1, 7.6 Hz), 5.12 (m, 2H),
4.07(m, 1H, J¼10.4, 9.8,6.1 Hz), 3.44(m, 1H),2.91(ddd, 1H,
J¼18.3, 9.2, 4.6 Hz), 2.82 (m, 1H), 2.75 (m, 1H, J¼9.8,
7.6 Hz), 2.64 (ddd, 1H, J¼18.3, 4.3, 3.1 Hz), 1.92 (ddd, 1H,
J¼13.1, 6.1, 0.9 Hz), 1.71 (dt, 1H, J¼13.1, 10.4 Hz), 1.04 (s,
9H). 13C NMR (125 MHz) 212.1, 136.0, 135.9, 135.7, 134.0,
133.4, 129.6, 127.4, 117.5, 75.5, 60.5, 54.0, 47.5, 36.5, 30.5,
26.9, 19.1. IR nmax (thin film) 1780 (CvO). MS m/z 333
([M2t-Bu]þ). Calculated for C25H30O2Si: C, 76.87; H, 7.74.
Found: C, 76.47; H, 7.73.
1
Rt13a 22.8 min. H NMR (500 MHz) 7.62–7.70 (m, 4H),
7.40 (m, 6H), 5.44 (ddd, 1H, J¼17.3, 10.5, 7.6 Hz), 4.86 (d,
1H, J¼10.5 Hz), 4.78 (d, 1H, J¼17.3 Hz), 4.20 (d, 1H,
J¼3.7 Hz), 3.63 (m, 1H, J¼9.5, 6.8 Hz), 3.28 ((AB)MX,
2H, J¼18, 9.7, 3, 2.9, 1.6 Hz), 2.76 (m, 1H, J¼6.6 Hz), 2.71
(d, 1H, J¼7.7 Hz), 2.17 (d, 1H, J¼14.1 Hz), 1.85 (ddd, 1H,
J¼14.1, 9.6, 4.1 Hz), 1.50 (s, 9H). 13C NMR (125 MHz)
212.9, 138.9, 135.9, 135.8, 133.6, 133.3, 129.6, 127.6,
127.5, 114.6, 81.8, 63.5, 57.0, 52.5, 38.4, 33.4, 26.7, 18.8.
IR nmax (thin film) 1785 (CvO). MS m/z 390 (Mþ8), 333
([M2t-Bu]þ). Calculated for C25H30O2Si: C, 76.87; H,
7.74. Found: C, 76.74; H, 7.82.
(1R,2S,3R,5S)-3-(tert-Butyldiphenylsilyloxy)-2-vinyl-bicy-
clo[3.2.0]heptan-6-one 13b. TLC (ethyl acetate–hexane
1:19) Rf 0.24. [a]2D0¼72.48 (c: 1.0; CHCl3). HPLC (Lichro-
spher Si60, 2-propanol–hexane 0.3:99.7, 1 ml/min, 208C)
Rt 10.9 min. Chiral-phase HPLC (Chiralpak AD, 2-propa-
nol–hexane 0.2:99.8, 0.5 ml/min, 208C) Rtent-13b 18.8 min,
5.2.3. [212] Cycloaddition from 11. 20 g (56.3 mmol) 11
gave after flash chromatography (ethyl acetate–petroleum
ether 15:85) 10.34 g 14a (72%, pale yellow liquid) and
1.80 g 14b (13%, pale yellow solid).
(1R,2R,3R,5S)-3-Benzoyloxy-2-vinyl-bicyclo[3.2.0]heptan-
6-one 14a. TLC (ethyl acetate–petroleum ether 15:85) Rf
0.72. [a]2D0¼21.3 (c: 1.0; CHCl3). HPLC (Lichrospher Si60,
2-propanol–hexane 0.8:99.2, 1 ml/min, 208C) Rt 15.3 min.
1H NMR (500 MHz) 7.93 (d, 2H), 7.56 (t, 1H), 7.44 (t, 2H),
5.82 (ddd, 1H, J¼17.3, 10.5, 7 Hz), 5.44 (d, 1H, J¼4.6 Hz),
5.20 (d, 1H, J¼10.5 Hz), 5.16 (d, 1H, J¼17.3 Hz), 3.80 (m,
1H), 3.37 (ddd, 1H, J¼17.6, 9.7, 4.5 Hz), 3.02 (d, 1H,
J¼7 Hz), 3.02 (m, 1H, J¼4.1 Hz), 2.98 (m, 1H), 2.38 (d,
1H, J¼14.7 Hz), 2.20 (ddd, 1H, J¼14.7, 9.6, 4.6 Hz). 13C
NMR (125 MHz) 212.1, 165.5, 137.6, 133.0, 129.8, 129.5,
128.4, 115.8, 82.4, 63.7, 54.1, 52.6, 35.5, 43.3. IR nmax (thin
film) 1779 (CvO cyclobutanone), 1717 (CvO ester). MS
m/z 256 (Mþ8), 105 ([PhCO]þ). Calculated for C16H16O3: C,
74.98; H, 6.29. Found: C, 74.86; H, 6.16.
1
Rt13b 20.8 min. H NMR (500 MHz) 7.61–7.70 (m, 4H),
7.42 (m, 6H), 6.10 (ddd, 1H, J¼18.1, 10.3, 7.8 Hz), 5.13 (d,
1H, J¼10.3 Hz), 5.07 (d, 1H, J¼18.1 Hz), 4.38 (t, 1H,
J¼3.9 Hz), 3.55 (m, 1H), 3.53 (m, 1H, J¼3.9 Hz), 3.06 (m,
1H, J¼18.1, 10.0, 4.2 Hz), 2.90 (m, 1H, J¼6.5 Hz), 2.62 (td,
1H, J¼7.8, 7.6, 3.9 Hz), 2.04 (d, 1H, J¼13.7 Hz), 1.65 (ddd,
1H, J¼13.7, 9.4, 3.9 Hz), 1.05 (s, 9H). 13C NMR (125 MHz)
213.1, 136.2, 135.8, 133.6, 133.0, 129.6, 129.5, 127.5, 127.4
(2£), 127.3, 116.8, 78.9, 63.2, 52.1, 48.9, 39.4, 32.9, 26.9,
19.0. IR nmax (thin film) 1780 (CvO). MS m/z 390 (Mþ8),
333 ([M2t-Bu]þ), 205. Calculated for C25H30O2Si: C,
76.87; H, 7.74. Found: C, 76.52; H, 7.80.
5.2.2. [212] Cycloaddition from 8. 556 mg (0.99 mmol) of
8 gave after filtration through silicagel (ethyl acetate–
hexane 1:19) 350 mg (73%, colourless gel) of a mixture of
15a and 15b (15a–15b¼67:33). 15a and 15b were
(1R,2S,3R,5S)-3-Benzoyloxy-2-vinyl-bicyclo[3.2.0]heptan-
6-one 14b. TLC (ethyl acetate–petroleum ether 15:85) Rf

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
6808
0.47. Mp 133.48C. [a]2D0¼77.2 (c: 1.0; CHCl3). HPLC
J¼15.5, 6.9, 4.2 Hz), 1.05 (s, 9H). 13C NMR (75 MHz)
177.6, 136.2, 134.7, 133.5, 132.9, 129.8, 129.7, 127.6,
127.5, 118.5, 84.5, 77.2, 52.1, 41.6, 41.4, 31.2, 27, 19.1. IR
nmax (thin film) 1766 (CvO). MS m/z 349 ([M2t-Bu]þ).
Calculated for C25H30O3Si: C, 73.85; H, 7.43. Found: C,
73.65; H, 7.49.
(Lichrospher Si60, 2-propanol–hexane 0.8:99.2, 1 ml/min,
208C) Rt 35.3 min. H NMR (500 MHz) 7.90 (d, 2H), 7.55
1
(t, 1H), 7.44 (t, 2H), 5.95 (ddd, 1H, J¼18.4, 9.1, 7 Hz), 5.72
(t, 1H, J¼4.3 Hz), 5.19 (m, 2H), 3.77 (m, 1H), 3.34 (dt, 1H,
J¼18.3, 4.0 Hz), 3.20 (ddd, 1H, J¼18.3, 9.8, 4.0 Hz), 3.11
(m, 1H), 3.06 (m, 1H, J¼7.3 Hz), 2.40 (d, 1H, J¼14.7 Hz),
2.14 (ddd, 1H, J¼14.7, 9.5, 4.3 Hz). 13C NMR (125 MHz)
212.2, 165.6, 133.1, 132.9, 129.7, 129.4, 128.4, 118.2, 79.4,
63.3, 49.9, 48.8, 37.0, 32.5. IR nmax (KBr) 1773 (CvO
cyclobutanone), 1719 (CvO ester). MS m/z 256 (Mþ8), 105
([PhCO]þ). Calculated for C16H16O3: C, 74.98; H, 6.29.
Found: C, 74.75; H, 6.24.
5.3.3. (1S,5R,6R,7R)-7-(Benzoyloxy)-6-vinyl-2-oxabicy-
clo[3.3.0]octan-3-one 16c. 8.0 g (31.2 mmol) 14a gave
7.03 g (83%, colourless solid) of a mixture of 16c and 17c
(16c–17c¼89:11). Recrystallization (ethyl acetate–hexane
1:2) gave pure 16c (colourless crystals). TLC (ethyl
acetate–petroleum ether 1:1) Rf 0.78. Mp (ethyl acetate–
hexane) 69.68C. [a]D20¼228.78 (c: 1.00; CHCl3). HPLC
(Hypersil Phenyl, acetonitrile–water 40:60, 0.5 ml/min,
5.3. Baeyer–Villiger oxidations—general procedure
1
208C) Rt17c 9.7 min, Rt16c 15.6 min. H NMR (300 MHz)
Aqueous 35% hydrogen peroxide (4 equiv.) was added at
08C to a 0.4 M solution of cyclobutanone 13–15 in
trifluoroethanol. The resulting reaction mixture was then
stirred at 08C until complete conversion of the starting
material (ca. 4–7 days). The solvent was removed under
vacuum and the residue was dissolved in ether and extracted
with 1 M aqueous Na2S2O3 (2£2.7 l/mol). The organic layer
was dried over magnesium sulphate, concentrated in vacuo.
The crude product was purified by flash chromatography
then recrystallized to give pure lactones 16a–16f.
8.01 (dd, 2H, J¼8.7, 1.5 Hz), 7.57 (tt, 1H, J¼7.4, 1.6 Hz),
7.45 (t, 2H, J¼7.5 Hz), 5.76 (ddd, 1H, J¼17.6, 10, 7.2 Hz),
5.28 (m, 1H, J¼6.3, 5.6 Hz), 5.19 (d, 1H, J¼17.1 Hz), 5.17
(d, 1H, J¼10.4 Hz), 5.07 (td, 1H, J¼5.6, 1.9 Hz), 2.80–2.93
(m, 2H), 2.76 (q, 1H, J¼5.5 Hz), 2.60 (dt, 1H, J¼15.5, 6.5,
6 Hz), 2.53 (m, 1H, J¼15.9 Hz), 2.24 (ddd, 1H, J¼15.6, 4.7,
1.7 Hz). 13C NMR (75 MHz) 176.4, 166.0, 136.3, 133.3,
129.8, 129.6, 128.5, 117.5, 83.3, 78.9, 55.1, 42.2, 37.5, 34.9.
IR nmax (thin film) 1773 (CvO lactone), 1712 (CvO
benzoate). MS m/z 272 (Mþ8). Calculated for C16H16O4: C,
70.57; H, 5.92. Found: C, 70.30; H, 5.79.
5.3.1. (1S,5R,6R,7R)-7-(tert-Butyldiphenylsilyloxy)-6-
vinyl-2-oxabicyclo[3.3.0]octan-3-one
16a.
17.0 g
5.3.4. (1S,5R,6S,7R)-7-(Benzoyloxy)-6-vinyl-2-oxabicy-
clo[3.3.0]octan-3-one 16d. 1.0 g (3.9 mmol) 14b gave
920 mg (87%, colourless solid) of a mixture of 16d and
17d (16d–17d¼87:13). Recrystallization (ethyl acetate–
hexane 1:2) gave pure 16d (colourless crystals). TLC (ethyl
acetate–petroleum ether 1:1) Rf 0.7. Mp (ethyl acetate–
hexane) 133.48C. [a]D20¼240.18 (c: 0.99; CHCl3). HPLC
(Novapak C18, methanol–water 50:50, 0.5 ml/min, 208C)
(43.5 mmol) 13a gave after filtration through a plug of
silicagel 15.64 g (88%, colourless gel, which solidified after
a few hours) of a mixture of 16a and 17a (16a–17a¼91:8).
A recrystallization (ethyl acetate–hexane) gave pure 16a.
TLC (ethyl acetate–petroleum ether 1:4) Rf 0.44. Mp (ethyl
acetate–hexane) 668C. [a]2D0¼211.08 (c: 1.36; CHCl3).
HPLC (Novapak C18, methanol–water 80:20, 0.4 ml/min,
1
1
208C) Rt17a 45.8 min, Rt16a 47.8 min. H NMR (300 MHz)
Rt16d 27.8 min, Rt17d 32.2 min. H NMR (300 MHz) 7.95
7.66 (m, 4H), 7.35–7.47 (m, 6H), 5.43 (ddd, 1H, J¼17,
10.4, 7.7 Hz), 4.99 (d, 1H, J¼10.5 Hz), 4.97 (d, 1H,
J¼17 Hz), 4.83 (m, 1H, J¼6.9, 5.9, 3.4 Hz), 3.98 (q, 1H,
J¼5.6 Hz), 2.75 (dd, 1H, J¼18.8, 10.6 Hz), 2.45–2.62 (m,
3H), 2.02 (m, 2H), 1.05 (s, 9H). 13C NMR (75 MHz) 176.9,
137.5, 136, 135.9, 133.6, 133.4, 129.8, 127.6 (2£), 116.8,
83.3, 78.5, 58.1, 41.7, 40.4, 34.8, 26.9, 19. IR nmax (thin
film) 1774 (CvO), 1640, 1589, 1473, 1428. MS m/z 406
([M]þ8), 349 ([M2t-Bu]þ). Calculated for C25H30O3Si: C,
73.85; H, 7.43. Found: C, 73.64; H, 7.37.
(dd, 2H), 7.56 (tt, 1H, J¼7.3, 1.6 Hz), 7.45 (t, 2H,
J¼7.6 Hz), 5.89 (ddd, 1H, J¼17.3, 10.2, 7.5 Hz), 5.60 (t,
1H, J¼4.9, 4.1 Hz), 5.26 (d, 1H, J¼10.5 Hz), 5.22 (d, 1H,
J¼17 Hz), 5.19 (t, 1H, J¼7 Hz), 3.29 (m, 1H, J¼11.5, 8.9,
4.4 Hz), 2.96 (m, 1H), 2.89 (dd, 1H, J¼18.9, 4.4 Hz), 2.70
(dd, 1H, J¼18.9, 11.5 Hz), 2.47 (d, 1H, J¼15.9 Hz), 2.23
(ddd, 1H, J¼16.1, 6.5, 4.3 Hz). 13C NMR (75 MHz) 176.9,
165.9, 133.2, 132.3, 129.6, 128.5, 119.8, 84.1, 77.8, 50.0,
41.4, 39.7, 30.9. IR nmax (thin film) 1753 (CvO lactone),
1718 (CvO benzoate). MS m/z 272 (Mþ8). Calculated for
C16H16O4: C, 70.57; H, 5.92. Found: C, 70.47; H, 5.72.
5.3.2. (1S,5R,6S,7R)-7-(tert-Butyldiphenylsilyloxy)-6-
vinyl-2-oxabicyclo[3.3.0]octan-3-one
16b.
1.24 g
5.3.5. (1S,5R,6R,7S)-7-(tert-Butyldiphenylsilyloxy)-6-
126 mg
(3.17 mmol) 13b gave 865 mg (65%, colourless gel which
solidified after a few hours) of a mixture of 16b and 17b
(16b–17b¼85:15). Recrystallization (ethyl acetate–hexane
1:2) gave pure 16b (colourless crystals). TLC (ethyl
acetate–petroleum ether 1:4) Rf 0.33. Mp (ethyl acetate–
hexane) 99–99.58C. [a]2D0¼19.58 (c: 1.23; CHCl3). HPLC
(Novapak C18, methanol–water 80:20, 0.4 ml/min, 208C)
vinyl-2-oxabicyclo[3.3.0]octan-3-one
16e.
(0.32 mmol) 15a gave 125 mg 16e (94%, colourless
crystals). TLC (ethyl acetate–petroleum ether 1:4) Rf
1
0.58. [a]2D0¼6.28 (c: 1.00; CHCl3). H NMR (300 MHz)
7.62 (m, 4H), 7.34–7.46 (m, 6H), 5.99 (ddd, 1H, J¼17.5,
10.1, 8.5 Hz), 5.06–5.14 (m, 2H), 5.01 (m, 1H, J¼7.1, 7,
3.6 Hz), 4.43 (t, 1H, J¼3.8, 3.4 Hz), 3.02 (m, 1H, J¼9.8,
8.9, 1 Hz), 2.75 (dd, 1H, J¼18.1, 9.3 Hz), 2.33 (dd, 1H,
J¼18.3, 1.3 Hz), 2.14 (m, 1H, J¼8.8, 3.3 Hz), 2.10 (ddd,
1H, J¼15.6, 6.8, 1.1 Hz), 1.76 (dt, 1H, J¼15.2, 4.3, 3.5 Hz),
1.06 (s, 9H). 13C NMR (75 MHz) 176.9, 135.9, 135.7,
134.1, 133.2, 129.8, 127.7, 127.6, 117.4, 84.2, 77.7, 55.9,
42.4, 42.2, 33.3, 27.0, 19.4. IR nmax (thin film) 1772 (CvO).
1
Rt16b 38.7 min, Rt17b 43.1 min. H NMR (300 MHz) 7.68
(m, 4H), 7.34–7.46 (m, 6H), 6.06 (ddd, 1H, J¼17.2, 10.3,
8.5 Hz), 5.19 (d, 1H, J¼10.4 Hz), 5.08 (d, 1H, J¼17.2 Hz),
5.01 (t, 1H, J¼6.9, 6.8 Hz), 4.24 (m, 1H, J¼3.6 Hz), 2.96–
3.11 (m, 2H), 2.55–2.65 (m, 1H), 2.46 (m, 1H, J¼8.3,
3.5 Hz), 2.09 (d, 1H, J¼15.5, 1.5 Hz), 1.73 (ddd, 1H,

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
6809
MS m/z 349 ([M2t-Bu]þ). Calculated for C25H30O3Si: C,
73.85; H, 7.43. Found: C, 73.89; H, 7.43.
calculated for C20H19O4Si ([M2t-Bu]þ): 351.105263.
Found, 351.105927.
5.3.6. (1S,5R,6S,7S)-7-(tert-Butyldiphenylsilyloxy)-6-
63 mg
The reaction with 700 mg (1.72 mmol) of a mixture of 16a
and 16b gave 399 mg 19 (57%) and 61 mg 20 (23%,
unstable colourless gel, spectroscopic data identical to that
of literature33).
vinyl-2-oxabicyclo[3.3.0]octan-3-one
16f.
(0.15 mmol) 15b gave 66 mg 16f (100%, colourless gel
which solidified after a few hours). TLC (ethyl acetate–
petroleum ether 1:9) Rf 0.49. [a]2D0¼228.78 (c: 1.00;
CHCl3). 1H NMR (300 MHz) 7.61 (m, 4H), 7.34–7.47
(m, 6H), 5.37 (ddd, 1H, J¼17.5, 10.9, 8.4 Hz), 5.08 (dd, 1H,
J¼10.3, 1.4 Hz), 5.02 (ddd, 1H, J¼7.5, 5.7, 3.5 Hz), 4.97
(dd, 1H, J¼16.9, 1.9 Hz), 4.17 (m, 1H, J¼5.6, 5.5 Hz), 3.17
(m, 1H), 2.66 (td, 1H, J¼8.7, 8.3, 5.6 Hz), 2.54 (dd, 1H,
J¼18.7, 10.4 Hz), 2.36 (dd, 1H, J¼18.6, 3.7 Hz), 1.99–2.05
((AB)MX, 2H, J¼14.7, 5.6, 5.7, 3.4, 5.6 Hz), 1.06 (s, 9H).
13C NMR (75 MHz) 177.0, 135.8, 135.7, 134.7, 133.8,
133.5, 129.8, 127.7, 119.5, 83.7, 77.2, 54.7, 40.1, 39.9, 30.6,
27.0, 19.1. IR nmax (thin film) 1772 (CvO). MS m/z 349
([M2t-Bu]þ). Calculated for C25H30O3Si: C, 73.85; H,
7.43. Found: C, 73.65; H, 7.21.
5.3.9. Epoxidation reaction. 1.63 g (4 mmol) 16a and
2.21 g (8 mmol) mCPBA (technical grade) were dissolved
in 10 ml dichloromethane and the resulting mixture was
stirred overnight at room temperature then treated with 8 ml
1 M aqueous sodium thiosulphate. The aqueous layer was
dried over magnesium sulphate and concentrated in vacuo.
The crude product was purified by flash chromatography
(ethyl acetate–petroleum ether 4:6) to give 1.31 g 21a
(78%, colourless needles) and 326 mg 21b (19%, colourless
crystals).
(1S,5R,6S,7R)-7-(tert-Butyldiphenyl-silyloxy)-6-[(S)-oxi-
ran-2-yl]-2-oxabicyclo[3.3.0]octan-3-one 21a. TLC (ethyl
acetate–pentane 1:1) Rf 0.73. Mp 87.48C. [a]2D0¼227.38 (c:
1.19; CHCl3). 1H NMR (300 MHz) 7.66 (m, 4H), 7.37–7.48
(m, 6H), 4.87 (td, 1H, J¼6.8, 2.7 Hz), 4.17 (m, 1H, J¼5.1,
4.9 Hz), 2.81 (dd, 1H, J¼18.8, 11.2 Hz), 2.51–2.66 (m,
4H), 2.29 (dd, 1H, J¼4.6, 2.7 Hz), 2.09 (m, 1H, J¼15, 4.7,
2.4 Hz), 2.03 (m, 1H, J¼15.1, 6.1, 5.5 Hz), 1.85 (m, 1H,
J¼5.6, 5.2 Hz), 1.06 (s, 9H). 13C NMR (75 MHz) 176.8,
135.9, 135.8, 133.2, 130.0, 129.9, 127.8, 127.7, 83.6, 76.8,
56.2, 52.2, 45.8, 41.0, 38.5, 35.4, 26.7, 18.9. IR nmax (KBr)
1773 (CvO lactone). MS m/z 365 ([M2t-Bu]þ). Calculated
for C25H30O4Si: C, 71.05; H, 7.15. Found: C, 70.86; H, 7.27.
5.3.7. (1S,5R,6S,7R)-7-(tert-Butyldiphenylsilyloxy)-6-
hydroxymethyl-2-oxabicyclo[3.3.0]octan-3-one 18.
A
stream of ozone was passed through a solution of 16a
(900 mg, 2.21 mmol) in 80 ml dichloromethane at 2788C
until the apparition of a blue colour. Excess ozone was
removed with a stream of argon and the solution of ozonide
was quenched with 0.80 ml (8.84 mmol) borane–dimethyl
sulphide complex then warmed up to room temperature.
Addition of 1 ml 1 M aqueous HCl, stirring at room
temperature for 1 h and neutralization with NaHCO3 gave
a crude residue which was purified by flash chromatography
(ethyl acetate–cyclohexane 3:7) to give 667 mg of 18 (74%,
white solid). TLC (ethyl acetate–cyclohexane 1:1) Rf 0.34.
Mp 166.28C. [a]2D0¼232.58 (c: 1.23; CHCl3). 1H NMR
(300 MHz) 7.67 (m, 4H), 7.36–7.48 (m, 6H), 4.84 (dt, 1H,
J¼6.9, 4.4 Hz), 4.10 (q, 1H, J¼5.5 Hz), 3.37 (t, 2H,
J¼4.9 Hz), 2.80 (dd, 1H, J¼17.6, 9.9 Hz), 2.65 (m, 1H),
2.57 (dd, 1H, J¼17.6, 2.6 Hz), 2.08 (t, 2H, J¼5.5 Hz), 2.01
(m, 1H, J¼5.8, 5.6, 5.4 Hz), 1.05 (s, 9H). 13C NMR
(75 MHz) 177.0, 135.9, 135.8, 133.6, 133.4, 129.9 (2£),
127.8, 127.7, 83.8, 75.3, 61.8, 56.5, 40.8, 38.8, 35.5, 26.9,
19.0. IR nmax (KBr) 3488 (O–H), 1757 (CvO lactone). MS
m/z 353 ([M2t-Bu]þ). Calculated for C24H30O4Si: C,
70.20; H, 7.36. Found: C, 69.97; H, 7.32.
(1S,5R,6S,7R)-7-(tert-Butyldiphenyl-silyloxy)-6-[(R)-oxy-
ran-2-yl]-2-oxabicyclo[3.3.0]octan-3-one 21b. TLC (ethyl
acetate–pentane 1:1) Rf 0.52. Mp 101.48C. [a]2D0¼229.98
(c: 0.99; CHCl3). 1H NMR (300 MHz) 7.67 (m, 4H), 7.36–
7.48 (m, 6H), 4.95 (m, 1H, J¼7.1, 6.5 Hz), 4.18 (dt, 1H,
J¼5.3, 2.6 Hz), 2.88 (dd, 1H, J¼18.8, 11.7 Hz), 2.55–2.68
(m, 4H), 2.24 (dd, 1H, J¼4.5, 2.8 Hz), 2.13–2.21 (m, 2H),
1.91 (m, 1H, J¼15.4, 6.3, 5.2 Hz), 1.05 (s, 9H). 13C NMR
(75 MHz) 176.8, 135.9 (£2), 133.3, 133.2, 129.9 (£2), 127.8
(£2), 84.5, 76.6, 56.1, 51.8, 44.9, 41.0, 38.8, 36.1, 26.8,
18.9. IR nmax (KBr) 1759 (CvO lactone). MS m/z 365
([M2t-Bu]þ). Calculated for C25H30O4Si: C, 71.05; H,
7.15. Found: C, 70.76; H, 7.21.
5.3.8. (1S,5R,6R,7R)-7-(tert-Butyldiphenylsilyloxy)-6-
formyl-2-oxabicyclo[3.3.0]octan-3-one 19. Same as for
the synthesis of 18 using 1.76 ml (24 mmol) of dimethyl
sulphide to quench the ozonide. Purification by flash
chromatography (ethyl acetate–petroleum ether 1:1)
yielded 1.88 g 19 (77%, unstable colourless gel, becomes
yellow after a few hours). TLC (ethyl acetate–petroleum
ether 1:1) Rf 0.64. [a]2D0¼250.58 (c: 1.4; CHCl3).1H
NMR (300 MHz) 9.30 (s, 1H), 7.68 (m, 4H), 7.39–7.47
(m, 6H), 5.00 (t, 1H, J¼6.7 Hz), 4.52 (m, 1H), 3.32 (m,
1H), 2.92 (dd, 1H, J¼18.4, 11.2 Hz), 2.89 (br, 1H), 2.57
(dd, 1H, J¼18.4, 3.3 Hz), 2.23 (d, 1H, J¼15.4 Hz), 1.68
(ddd, 1H, J¼15.3, 6.3, 5.1 Hz), 1.07 (s, 9H). 13C NMR
(75 MHz) 198.6, 176.4, 135.9, 135.8, 132.9, 130.2, 130.1,
128.0, 127.9, 84.6, 74.6, 68.1, 40.7, 36.3, 35.8, 26.8, 18.9.
IR nmax (thin film) 1772 (CvO lactone), 1724 (CvO
aldehyde). MS m/z 351 ([M2t-Bu]þ). HRMS (EI)
5.3.10. Hydroboration reaction. 203 mg (0.5 mmol) of
16a were added to 0.25 ml (0.25 mmol) of a 1 M solution of
BH2Br–DMS complex in dichloromethane at 08C. After 2 h
at room temperature, 0.5 ml (3 mmol) of 6 M aqueous
sodium hydroxide, 0.5 ml ethyl alcohol and 0.11 ml
(1 mmol) of 30% hydrogen peroxide were successively
added. The resulting biphasic mixture was stirred at room
temperature for 1 h, then acidified with 6 M aqueous HCl
and extracted with ethyl acetate. The organic layer was
dried over magnesium sulphate and concentrated in vacuo.
The residue (276 mg, yellow oil) was purified by flash
chromatography (ethyl acetate–hexane 1:4 to 1:2) to give
47 mg 23 (21%, white solid) and 126 mg 22 (60%, white
solid). Acetylation of 22: 250 mg (0.59 mmol) 22, 0.11 ml
(1.18 mmol) acetic anhydride and 0.1 ml (1.18 mmol)
pyridine were stirred overnight at room temperature in

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
6810
1 ml THF. The reaction mixture was then diluted with ethyl
acetate (5 ml) and poured into 2 ml aqueous 1 M HCl. The
organic layer was dried over sodium carbonate and
concentrated under vacuum to give 260 mg crude 23
(100% pale yellow crystals) which did not require further
purification.
3.6 Hz), 2.22 (d, 1H, J¼15.3 Hz), 1.76 (ddd, 1H, J¼15, 4.7,
6.3 Hz), 1.73 (s, 3H), 1.07 (s, 9H). 13C NMR (75 MHz)
206.9, 176.7, 135.9, 133.0, 132.7, 130.2, 130.0, 128.0,
127.9, 85.3, 77.2, 68.6, 40.6, 38.7, 35.9, 29.3, 26.8, 19.0. IR
n
max (KBr) 1775 (CvO lactone), 1710 (CvO ketone). MS
m/z 365 ([M2t-Bu]þ). Calculated for C25H30O4Si: C,
71.05; H, 7.15. Found: C, 70.81; H, 7.13.
(1S,5R,6R,7R)-7-(tert-Butyldiphenylsilyloxy)-6-(2-hydro-
xyethyl)-2-oxabicyclo[3.3.0]octan-3-one 22. TLC (ethyl
acetate–petroleum ether 3:2) Rf 0.23. Mp 95–95.58C.
(1S,5R,6R,7R)-7-(tert-Butyldiphenylsilyloxy)-6-formyl-
methyl-2-oxabicyclo[3.3.0]octan-3-one 25. TLC (ethyl
acetate–petroleum ether 3:7) Rf 0.1. [a]2D0¼217.48 (c:
1.41; CHCl3). GC (Permabond SE-52, 100–2908C, 108C/
min) Rt 28.7 min. 1H NMR (300 MHz) 9.48 (t, 1H,
J¼1.3 Hz), 7.66 (m, 4H), 7.37–7.48 (m, 6H), 4.88 (td,
1H, J¼7, 2.7 Hz), 3.91 (q, 1H, J¼4.8 Hz), 2.84 (dd, 1H,
J¼18.6, 10.4 Hz), 2.71 (dd, 1H, J¼18.5, 3.5 Hz), 2.49 (m,
1H), 2.28–2.41 (m, 2H, J¼5.2, 1.3 Hz), 2.15 (ddd, 1H,
J¼17.1, 8.3, 1.5 Hz), 2.08 (m, 1H, J¼16.4 Hz), 1.98 (m, 1H,
J¼15.1, 6.6, 5.4 Hz), 1.05 (s, 9H). 13C NMR (75 MHz)
200.0, 176.8, 135.9, 135.8, 133.2, 129.9, 127.8, 127.7, 83.4,
78.2, 48.8, 46.5, 42.5, 40.2, 35.7, 26.8, 19.0. IR nmax (thin
film) 1768 (CvO lactone), 1727 (CvO aldehyde). MS m/z
365 ([M2t-Bu]þ). HRMS (EI) calculated for C21H21O4Si
([M2t-Bu]þ): 365.120913. Found, 365.120386.
1
[a]2D0¼227.28 (c: 1.93; CHCl3). H NMR (300 MHz) 7.68
(m, 4H), 7.37–7.49 (m, 6H), 4.92 (m, 1H, J¼7.4, 6.4,
1.8 Hz), 3.98 (m, 1H), 3.41–3.43 (m, 2H), 2.85 (dd, 1H,
J¼18.4, 10.9 Hz), 2.67 (dd, 1H, J¼18.4, 3.6 Hz), 2.55 (m,
1H, J¼10.9, 3.9 Hz), 2.09 (dd, 1H, J¼14.9, 3.1 Hz), 2.03
(m, 1H), 1.95 (ddd, 1H, J¼15.1, 6.6, 5.2 Hz), 1.29–1.37 (m,
3H), 1.05 (s, 9H). 13C NMR (75 MHz) 177.4, 135.9, 133.5,
133.4, 129.9, 129.8, 127.8, 127.7, 84.1, 78.8, 60.7, 51.7,
42.9, 40.2, 36.2, 35.8, 26.8, 19.0. IR nmax (KBr) 3557 (O–
H), 3439 (O–H), 1768 (CvO lactone). MS m/z 367 ([M2t-
Bu]þ). Calculated for C25H32O4Si: C, 70.71; H, 7.59.
Found: C, 70.44; H, 7.57.
(1S,5R,6R,7R)-6-(2-Acetoxyethyl)-7-(tert-butyldiphenylsi-
lyloxy)-2-oxabicyclo[3.3.0]octan-3-one 23. TLC (ethyl
acetate–petroleum ether 1:1) Rf 0.72. Mp (ethyl ether–
pentane) 108.5–109.58C. [a]2D0¼29.68 (c: 0.99; CHCl3). 1H
NMR (300 MHz) 7.65 (m, 4H), 7.36–7.47 (m, 6H), 4.92 (td,
1H, J¼7.1, 2.1 Hz), 3.96 (q, 1H, J¼4.1 Hz), 3.87 (t, 2H,
J¼6.6 Hz), 2.86 (dd, 1H, J¼18.3, 11 Hz), 2.62 (dd, 1H,
J¼18.1, 3.6 Hz), 2.55 (m, 1H), 2.08 ((A)BMX, 1H, J¼15.1,
3.8, 1.7 Hz), 1.99 (m, 1H), 1.99 (s, 3H), 1.94 (A(B)MX, 1H,
J¼15.1, 6.8, 5.1 Hz), 1.50 (m, 1H), 1.31 (m, 1H), 1.05 (s,
9H). 13C NMR (75 MHz) 176.8, 170.6, 136.0, 135.9, 133.5,
129.9 (2£), 127.8, 127.7, 83.9, 78.9, 62.4, 52.1, 42.8, 40.4,
36.1, 32.0, 26.9, 20.8, 19.0. IR nmax (KBr) 1763 (CvO
lactone), 1736 (CvO acetate). MS m/z 409 ([M2t-Bu]þ).
Calculated for C27H34O5Si: C, 69.49; H, 7.34. Found: C,
69.20; H, 7.39.
5.3.12. (1S,5R,6R,7R)-7-(tert-butyldiphenylsilyloxy)-3-
oxo-2-oxabicyclo[3.3.0]octane-6-carboxylic acid 26.
13.5 ml (36 mmol) of 2.67 M Jones reagent and 1.22 ml
(0.2 mmol) of a 4% aqueous solution of OsO4 were added to
4.07 g (10 mmol) of 16a in 50 ml acetone. The reaction
mixture was stirred at room temperature for 24 h. Addition
of 5 ml 2-propanol and 3 g sodium hydrogen sulphite then
of 100 ml water gave an homogeneous green solution after
90 min. Extraction with ethyl acetate and concentration of
the organic solution in vacuo gave a residue (4 g) which was
recrystallized from ethyl acetate–cyclohexane (3:10) to
give 3.39 g 26 (80%, white needles). Mp 144–1458C.
[a]2D0¼235.28 (c: 1.22; CHCl3). 1H NMR (300 MHz) 10.91
(br, 1H), 7.65 (m, 4H), 7.34–7.44 (m, 6H), 5.01 (t, 1H,
J¼7.6 Hz), 4.52 (m, 1H, J¼3 Hz), 3.19 (m, 1H, J¼11,
3.8 Hz), 2.90 (m, 1H, J¼3 Hz), 2.89 ((A)BX, 1H, J¼18.4,
11.3 Hz), 2.66 (A(B)X, 1H, J¼18.4, 3.8 Hz), 2.25 (d, 1H,
J¼14.7 Hz), 1.04 (s, 9H), 1.04 (dt, 1H, J¼14.7, 6.5, 5.1 Hz).
13C NMR (75 MHz) 177.5, 176.4, 135.9, 135.8, 132.8,
132.7, 130.0, 129.9, 127.8, 84.5, 77.6, 59.6, 40.8, 40.4, 35.6,
26.7, 18.9. IR nmax (KBr) 3100 (O–H), 1746 (CvO). MS m/
z 367 ([M2t-Bu]þ). Calculated for C24H28O5Si: C, 67.89;
H, 6.64. Found: C, 67.74; H, 6.83.
5.3.11. Wacker oxidation. A suspension of 72 mg
(0.4 mmol) palladium diacetate and 442 mg (4.46 mmol)
cuprous chloride in DMF water (2.8 mlþ0.8 ml was
vigorously stirred at room temperature under an oxygen
atmosphere for 90 min. The suspension became greenish
due to the oxidation of Cu(I) to Cu(II). Then 1.65 g
(4.06 mmol) 16a in 2 ml DMF was added and the reaction
mixture was stirred at room temperature until complete
conversion (ca. 2 days). Addition of 12 ml of 1 M aqueous
HCl and 12 ml ethyl acetate followed by separation of the
organic layer which was concentrated in vacuo. The residue
was purified by flash chromatography (ethyl acetate–
petroleum ether 3:7 then 4:6) to give 1.30 g 24 (76%,
white solid) and 290 mg 25 (17%, colourless gel).
5.3.13. (1S,5R,6R,7R)-7-(tert-Butyldiphenylsilyloxy)-6-
benzyloxycarbonylamino-2-oxabicyclo[3.3.0]octan-3-
one 27. A solution of 424 mg (1 mmol) of 26, 0.15 ml
(1.1 mmol) triethylamine, 0.41 ml benzyl alcohol and
0.24 ml (1.1 mmol) diphenylphosphoryl azide in 2 ml
benzene was refluxed for 24 h. Addition of 15 ml ethyl
acetate followed successively by 5 ml 1 M aqueous HCl,
5 ml 1 M aqueous NaOH and 5 ml water led to 27 (835 mg)
which was purified by flash chromatography (ethyl acetate–
petroleum ether 1:3 to 1:1). Yield: 415 mg (78%, colourless
solid). TLC (ethyl acetate–petroleum ether 1:3) Rf 0.24. Mp
126.5–1278C. [a]D20¼25.58 (c: 1.89; CHCl3). 1H NMR
(300 MHz) 7.64 (m, 4H), 7.26–7.46 (m, 11H), 5.00–5.03
(AB, 2H, J¼12.3 Hz), 4.84 (m, 1H, J¼7.2, 4.6 Hz), 4.47 (br,
(1S,5R,6R,7R)-6-Acetyl-7-(tert-butyldiphenylsilyloxy)-2-
oxabicyclo[3.3.0]octan-3-one 24. TLC (ethyl acetate–
petroleum ether 3:7) Rf 0.19. Mp 80–818C. [a]2D0¼276.38
(c: 1.58; CHCl3). GC (Permabond SE-52, 100–2908C,
108C/min) Rt 26.6 min. 1H NMR (300 MHz) 7.69 (m, 4H),
7.38–7.50 (m, 6H), 5.07 (t, 1H, J¼7.5, 6.3 Hz), 4.34 (m,
1H, J¼4.3, 1.5 Hz), 3.24 (m, 1H, J¼11, 3.1, 7 Hz), 3.05 (br,
1H), 2.90 (dd, 1H, J¼18.4, 11.5 Hz), 2.58 (dd, 1H, J¼18.4,

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D. Depre et al. / Tetrahedron 59 (2003) 6797–6812
6811
1H), 3.99 (q, 1H, J¼5.1 Hz), 3.87 (m, 1H, J¼6.9, 4.9 Hz),
2.67–2.81 (m, 3H), 2.04 (br, 2H), 1.03 (s, 9H). 13C NMR
(75 MHz) 176.5, 155.5, 136.1, 135.9, 133.1, 132.8, 130.0,
128.5, 128.3, 128.1, 127.8 (2£), 81.7, 77.2, 66.9, 64.9, 43.2,
39.1, 34.2, 26.7, 19.0. IR nmax (KBr) 3340 (N–H), 1744
(CvO lactone), 1711 (CvO carbonate). MS m/z 472
([M2t-Bu]þ). Calculated for C31H35NO5Si: C, 70.29; H,
6.66; N, 2.64. Found: C, 69.93; H, 6.71; N, 2.62.
acetate–petroleum ether 2:3) Rf 0.76. [a]2D0¼70.68 (c:
1
1.00; CHCl3). H NMR (300 MHz) 8.24 (dm, 1H, J¼4.9,
1.8, 0.9 Hz), 7.67 (m, 4H), 7.26–7.44 (m, 7H), 7.01 (d, 1H,
J¼8 Hz), 6.97 (dd, 1H, J¼7.2, 5 Hz), 5.06 (m, 1H, J¼7.4,
3.7 Hz), 4.30 (m, 2H), 2.95–3.08 (m, 3H), 2.12 (t, 2H,
J¼3.6 Hz), 1.05 (s, 9H). 13C NMR (75 MHz) 176.7, 157.3,
149.5, 136.0 (2£), 135.9, 133.2, 133.1, 129.8, 129.6, 127.6,
127.5, 122.5, 119.8, 84.3, 79.4, 56.9, 44.9, 40.2, 36.2, 26.8,
19.0. IR nmax (thin film) 1771 (CvO). MS m/z 432 ([M2t-
Bu]þ). HRMS (EI) calculated for C24H22NO3SSi ([M2t-
Bu]þ): 432.108969. Found, 432.108825.
5.3.14. (1S,5R,6R,7R)-6-Amino-7-(tert-butyldiphenylsilyl-
oxy)-2-oxabicyclo[3.3.0]octan-3-one 28. A solution of
100 mg (0.19 mmol) of 27 in 2 ml of methanol and 1 ml of
THF was hydrogenated at room temperature in the presence of
10 mg of 10% dry Pd/C catalyst. After completion of the
reaction (3 h), the catalyst was filtered off and the solvents
were removed under vacuum to give 73 mg of 28 (98%—
Acknowledgements
1
`
We thank the Fonds pour la Formation a la Recherche dans
l’Industrie et l’Agriculture (FRIA) for a PhD fellowship to
colourless film). H NMR (200 MHz) 7.64–7.69 (m, 4H),
7.37–7.45 (m, 11H), 4.95 (dt, 1H, J¼7.1, 2.0 Hz), 3.83 (m,
1H, J¼4.8, 4.2 Hz), 3.18 (t, 1H, J¼4.0 Hz), 2.65–2.78
((AB)X, 2H, J¼18.4, 10.4, 4.0 Hz), 2.48 (m, 1H), 2.20 (ddd,
1H, J¼15.0, 6.6, 5.6 Hz), 2.03 (dm, 1H, J¼15.1 Hz), 1.36 (br,
2H), 1.03 (s, 9H). 13C NMR (50 MHz) 177.1, 135.8, 135.7,
133.4, 133.2, 129.9 (2£), 127.8, 127.7, 83.5, 80.6, 65.6, 45.0,
39.1, 34.1, 26.7, 18.9. IRnmax (KBr)3377(N–H), 1770(CvO
lactone). MS m/z 396 ([MþH]þ).
´
D. Depre, and the Ministere de l’Education et de la
Recherche, Communaute franc¸aise de Belgique (action
`
´
´
concertee) and the University of Louvain for their generous
support. We are also indebted to Professor E. de Hoffmann
for the mass spectra, Dr Roland Touillaux for the meticulous
measurement and recording of high-field NMR spectra and
Professor J. P. Declercq and Dr B. Tinant for the X-ray
diffraction analyses.
5.3.15. Barton reaction on 26. 425 mg (1 mmol) of 26 and
0.24 ml (1 mmol) of triethylamine were successively added
at room temperature in the dark to a well stirred suspension
of 209 mg (1.1 mmol) of 32 in 10 ml toluene. After
complete conversion of 26 (ca. 45 min in the dark, reaction
followed by TLC), the precipitate was filtered off. The
resulting clear solution of 29 and a solution of 1 ml
(9 mmol) of tert-butyl thiol in 10 ml toluene were added
simultaneously into a reactor containing 10 ml toluene
through which an oxygen stream was passed. During the
addition, the reactor was either warmed up to 808C or
irradiated at room temperature with a 500-W halogen lamp.
The stream of oxygen was passed through the reaction
mixture for an additional hour after the end of the addition
of 29 and thiol. The reaction mixture was quenched with
0.25 ml (2.1 mmol) of trimethyl phosphite and stirred at
room temperature for 24 h. Volatile products were removed
under vacuum and the residue was purified by flash
chromatography (ethyl acetate–petroleum ether 15:85 to
40:60). Thermal reaction: 103 mg 31 (21%, colourless gel)
and 113 mg 30 (29%, white solid). Photochemical reaction:
190 mg 30 (45%, white solid).
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