Efficient synthesis of (S)-3,4-dihydro-2-pivaloyloxymethyl-2H-pyrrole 1-oxide

Article abstract of DOI:10.1016/S0957-4166(02)00110-6

A convenient synthesis of the title nitrone is reported. The sequence starts from ethyl L-pyroglutamate as the source of chirality and the key step is the generation of an unstable α-methoxy-N-carboxylate ion, which readily decomposes to an imine. The oxidation of the imine with methyl(trifluoromethyl)dioxirane provides the enantiopure nitrone, which is trapped with dimethyl acetylenedicarboxylate.

Full text of DOI:10.1016/S0957-4166(02)00110-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 437–445
Efficient synthesis of
(S)-3,4-dihydro-2-pivaloyloxymethyl-2H-pyrrole 1-oxide
Fe´lix Busque´,a Pedro de March,a,* Marta Figueredo,a Josep Font,a,* Timothy Gallagherb and
Sergio Mila´na
aDepartament de Qu´ımica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Spain
bSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Received 18 February 2002; accepted 1 March 2002
Abstract—A convenient synthesis of the title nitrone is reported. The sequence starts from ethyl L-pyroglutamate as the source of
chirality and the key step is the generation of an unstable a-methoxy-N-carboxylate ion, which readily decomposes to an imine.
The oxidation of the imine with methyl(trifluoromethyl)dioxirane provides the enantiopure nitrone, which is trapped with
dimethyl acetylenedicarboxylate. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
In relation to an ongoing program on alkaloid synthe-
sis, we wanted to develop a convenient access to an
enantiopure 2-substituted 3,4-dihydro-2H-pyrrole 1-
oxide 1 (Fig. 1). Preparations of a few chiral nitrones
with this structure are described in the literature,
namely 2 (R=Me),6 3,7 48 and 5.9 However, all are
prepared in racemic form and through methodologies
which cannot be modified easily to provide enantiose-
lective routes, since they all start from achiral materials.
Nitrones are among the most synthetically useful 1,3-
dipolar species, because their cycloaddition reactions
with alkenes or alkynes yield isoxazolidines or isoxazo-
lines, respectively, which are suitable intermediates for
the synthesis of bioactive compounds, mainly alka-
loids.1 Stereoselective synthesis is a major goal in
organic chemistry and many efforts have been devoted
to the preparation of enantiopure cycloadducts derived
from 1,3-dipoles. Nevertheless, progress in the develop-
ment of asymmetric versions of the 1,3-dipolar cycload-
dition reaction lags far behind the advances reached in
the closely related Diels–Alder process. Particularly
noticeable is the relatively small number of successful
1,3-dipolar cycloadditions compared to those of Diels–
Alder reactions performed in the presence of enantio-
pure catalysts.2 Thus, most syntheses of enantiopure
isoxazolidines achieved through a 1,3-dipolar cycload-
dition process start from either a chiral non-racemic
dipolarophile or nitrone.2 During the last years, our
research group has been active in this field and we have
focused on all three possible approaches to the issue:
use of enantiopure catalysts,3 homochiral dipolar-
ophiles4 and homochiral nitrones.5
Obviously, a prolinate or proline itself are appealing
and inexpensive starting materials for the synthesis of a
nitrone of general structure 1, but direct oxidation of
* Corresponding authors. Tel.: 34-935811258; fax: 34-935811265
(P.de M.); tel.: 34-935811255; fax: 34-935811265 (J.F.); e-mail:
pere.demarch@uab.es; josep.font@uab.es
Figure 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00110-6

438
F. Busque´ et al. / Tetrahedron: Asymmetry 13 (2002) 437–445
proline or its esters with several reagents affords either
the conjugated or the unsubstituted achiral nitrones 6
or 7.10 We have reported the synthesis of the hydroxy-
methyl substituted nitrone 8,5b formed via direct oxida-
tion of prolinol, and a preliminary note describing the
preparation of the pivaloyloxymethyl derivative 9.5a
Herein, we give full details for the preparation of 9,
including a new and improved synthesis of this nitrone.
To the best of our knowledge there are no other reports
NMR spectrum, this new compound showed an
absorption at l 7.70 corresponding to the imine pro-
ton.22,23 The moderate yield of the reduction is proba-
bly due to the low stability of 14.
According to the literature precedents, the oxidation of
an imine to a nitrone can be carried out either directly
using permanganate ion,24 dioxiranes,25 oxaziridinium
tetrafluoroborates,26 or peracids,25a or through a two-
step procedure involving the generation25a,27 and rear-
rangement of an oxaziridine under various reaction
conditions.27a–d,27g,28 Oxidation of the aldimine 14 with
permanganate ion under heterogeneous conditions or
with Oxone® did not provide the target nitrone 2
(R=Et), but treatment of 14 with m-CPBA led to a ca.
1:1 mixture of diastereoisomeric oxaziridines 15 as evi-
denced by the presence of two singlets at l 4.55 and
of
enantiomerically
pure
C(5)-monosubstituted
aldonitrones. Homochiral, 5-substituted ketonitrones
have been described by Oppolzer’s group,11 and the
remaining enantiopure five-membered cyclic nitrones
reported in the literature contain additional oxygen
functionalities at C(3) and/or C(4).12
1
2. Results and discussion
4.60 in the H NMR spectrum attributed to C(5a)H.
When this mixture was heated at 70°C, the signal at l
4.55 had completely disappeared after 1 h, while that at
l 4.60 vanished after heating for 3 h, and the only
product observed was the known pyrrole 16,22 forma-
tion of which is favoured by the acidity of the C(3)
proton situated a to the ester group. Based on these
observations we tentatively assigned the first singlet to
the cis oxaziridine, which should decompose faster con-
sidering the stereoelectronic requirements of the pro-
cess. Unfortunately, all attempts to effect the desired
rearrangement of 15 to nitrone 2 under thermal
activation27b,27d or in the presence of silica gel27a,28c
failed and only pyrrole 16 was detected.
Considering these literature precedents, our first
attempts were directed towards the development of an
enantioselective synthesis of 2 (R=Et) starting from
(+)-ethyl
L
-pyroglutamate, 10 (Scheme 1), which can
either be purchased or easily prepared.13 Thiolactam
(+)-11 was prepared in 90% yield by reaction of 10 with
Lawesson’s reagent,14 although racemic15 and enantio-
pure 1116 had already been prepared by other method-
ologies. Reaction of 11 with iodomethane gave the
hydroiodide 12, which upon treatment with aqueous
NaHCO317 afforded the imidothiolate 13 as a colourless
oil in 84% overall yield. Evidence of the imidothiolate
moiety are the absorptions of the methyl group at l
2.50 and that of the imine carbon atom at l 176.9 in
Since the presence of an ester moiety in the target
enantiopure nitrone was not essential for our synthetic
plans, we decided to focus our attention on a new
target nitrone with the same carbon framework, but
with a hydroxymethyl group as the substituent at posi-
tion two, namely 8 or its protected variant 9. The first
step in this alternative route was the reduction of the
ester functionality of thiolactam 11 with lithium boro-
hydride (Scheme 2), the same reagent previously used
1
the H and 13C NMR spectra, respectively. Since we
found a unique precedent18 regarding the desulfurisa-
tion of a non-aromatic imidothiolate to an imine we
tested several reducing agents for the conversion of 13
into 14. Attempts to achieve this transformation with
Al–Hg,18 HSnBu3,19 or Ni(BH4)2,20 were unsuccessful,
but the use of commercial W-2 Raney-Ni21 furnished
1
the dihydropyrrole 14 in 40% isolated yield. In its H
Scheme 1. (a) Lawesson’s reagent, THF, rt, 1 h, 90%; (b) ICH3, acetone, rt, 18 h, 87%; (c) NaHCO3, H2O, 97%; (d) W-2
Raney-Ni, acetone, ref., 1 h, 40%; (e) KMnO4, CH2Cl2/H2O or Oxone®, acetone; (f) m-CPBA, CDCl3, 0°C, 30 min; (g) 70°C,
CDCl3.

F. Busque´ et al. / Tetrahedron: Asymmetry 13 (2002) 437–445
439
t
Scheme 2. (a) LiBH4, THF, rt, 18 h, 90%; (b) ICH3, acetone, rt, 18 h, 92%; (c) NaHCO3, H2O, 83%; (d) BuCOCl, DMAP, py,
CH2Cl2, rt, 1 day, 92%; (e) W-2 Raney-Ni, acetone, ref., 1 h, 34%; (f) m-CPBA, CH2Cl2, 0°C, 1 h, 72%; (g) D, hw or SiO2; (h)
TFMD, CH2Cl2, −78°C, 1 h; (i) DMAD, CH2Cl2, rt, 18 h, 62% from 21.
for the reduction of the analogous lactam.29 The new
compound 17, isolated in 90% yield as a colourless
solid, presents two double doublets at l 3.54 and 3.76
in its 1H NMR spectrum for the methylene group of the
primary alcohol. Thiolactam 17 was converted into the
hydroiodide 18 and this into the imidothiolate 19,
which was isolated as a colourless oil in 76% overall
yield. Although a synthesis of 19 has already been
described,30 our sequence improves the reported overall
yield from 32 to 62% starting from 10. The hydroxyl
group in 19 was then protected as the pivaloyl ester
using the conventional methodology31 providing the
new pyrroline 20 in 92% yield. Reduction of 20 was
best carried as above using W-2 Raney-Ni to give the
unstable imine 21 in 34% yield. Its structural identifica-
under thermal27b,27d or photochemical28a,b conditions or
by treatment with silica gel27a,28c were unsuccessful.
Additionally, oxidation of the imine 21 with dimethyl-
dioxirane at a range of temperatures between −78 and
−20°C did not afford the desired nitrone 9.25 Either no
reaction took place or decomposition products were
mainly detected. Nevertheless, the oxidation of 21 could
be satisfactorily accomplished using methyl(trifluoro-
methyl)dioxirane.32 Monitoring the reaction by 1H
NMR analysis of the reaction mixture showed the
progressive decrease of the imine signal at l 7.60, while
a new absorption at l 6.97 simultaneously increased
accordingly to the formation of nitrone 9. Addition of
dimethyl acetylenedicarboxylate to the crude nitrone
solution at room temperature afforded a single cycload-
duct 23 in 62% overall yield from imine 21. The assign-
ment of the stereochemistry of 23 stands on the
following significant NOE experiments: (a) irradiation
of C(3a)H at l 4.85 caused an enhancement of the
signal of C(4)Hb at l 2.30; (b) presaturation of this last
proton resulted in an increase of the signal correspond-
ing to C(5)Hb at l 1.54; (c) irradiation of C(6)H at l
3.56 produced an enhancement of C(5)Ha at l 1.92,
but not of C(5)Hb; and (d) irradiation of C(5)Hb
increases only the signals corresponding to C(4)Hb and
C(5)Ha. The enantiomeric purity of 23 ([h]2D5=−167.5
1
tion was based on the absorptions at l 7.60 in its H
NMR spectrum due to the imine proton and the signal
at l 167.8 in the 13C NMR spectrum corresponding to
the imine carbon atom. In this reaction some unreacted
20 was recovered which had an identical specific rota-
tion value as the starting 20. This observation indicates
that no racemization took place during the reduction
process, in spite of the strong basic medium.
With the aim of preparing the corresponding oxaziridi-
nes, the first oxidation assays of imine 21 were per-
formed using m-CPBA.25a,27a–d,27g These reactions
yielded ca. 1:3 mixtures of diastereoisomeric com-
pounds 22a and 22b, respectively. The stereochemical
assignment is only tentative, based on the assumption
that the oxidation takes place preferentially on the less
hindered face of 21 and also on the following NMR
data: proton C(3)H in 22b is shifted upfield (l 3.37)
compared to isomer 22a (l 3.76), while the opposite
occurs for the methylenic protons of the substituent at
C(3) (l 4.22 for 22b and l 4.08 and 4.16 for 22a). These
observations are in agreement with a higher steric con-
gestion for C(3)H in 22b and for the methylene unit in
22a. Unfortunately, all efforts to isomerise 22 to 9
1
(c 7.5, CHCl3)) was established as ]95% by H NMR
analysis using europium(III) tris[3-(trifluoromethyl-
hydroxymethylene)-(−)-camphorate] as chiral shift
reagent and employing racemic 23, prepared from
racemic 10, as a standard. Racemic 23 showed two sets
of signals for the methylenoxy group at C(6), each
methoxy group and the tert-butyl unit. For cycloadduct
(−)-23, prepared from enantiomerically pure lactam
(S)-10, only one set of signals was observed in the
presence of Eu(tfc)3.
The results so far obtained completed the synthetic
sequence from (+)-ethyl pyroglutamate 10 to the target

440
F. Busque´ et al. / Tetrahedron: Asymmetry 13 (2002) 437–445
nitrone 9 with an overall yield of ca. 12%. Undoubt-
edly, the main drawback of the synthesis was the
desulfurisation step, the yield of which we were unable
to improve despite the many efforts dedicated to this
end. Therefore, we decided to develop an alternative
synthesis of imine 21, according to the pathway
depicted in Scheme 3. Ethyl pyroglutamate, 10, was
reduced to alcohol 24,33 available also commercially, in
90% yield. Protection of the primary alcohol as the
pivaloate ester was achieved in 83% yield. The presence
5.10 and two singlets at l 3.30 and 3.35. The mixture of
diastereoisomers 28 was treated with tert-
butyldimethylsilyl trifluoromethanesulfonate36 to give
the corresponding silyl carbamates 29 as an oily mate-
rial. The analysis of the 1H NMR spectrum of 29
reveals the presence of two rotamers for each stereoiso-
mer: four doublets in the region l 4.80–5.20 and four
singlets between l 3.20 and 3.60 are observed. We
envisaged the N-trialkylsilyloxycarbonyl group of 29 as
a masked form of an N-carboxylate ion 30,36 that
should be an extremely unstable species, accessible by
cleavage of the silyl carbamate with fluoride ion. Con-
sequently, we decided to treat the mixture of isomers 29
with tetrabutylammonium fluoride in the hope that the
carboxylate 30 would spontaneously decarboxylate to
form the imine 21. We were certainly pleased to isolate
enantiopure 21 in 72% overall yield from the methoxy
aminal 28. To the best of our knowledge, this is the first
example of synthesis of an imine from a N-Boc pro-
tected amide.
1
of a singlet at l 1.15 in the H NMR spectrum of 25
and two absorptions at l 178.4 and 178.6 in its 13C
NMR spectrum revealed the formation of the desired
ester. Prior to the reduction of the lactam group, the
nitrogen atom was protected as the tert-butyl carba-
mate using standard methodology.34 The new com-
pound 26, isolated as a solid in 88% yield, shows two
singlets at l 1.07 and 1.41 in the proton NMR spec-
trum and a signal at l 149.1 in the 13C NMR spectrum,
in agreement with the presence of a carbamate moiety.
Carefully controlled reduction of 26 with DIBAL-H35
at −78°C for 4 h followed by treatment of the crude
product with saturated aqueous ammonium chloride
provided a mixture of diastereoisomeric aminals 27 in
87% yield. The NMR spectra of this mixture are com-
plicated by the slow equilibrium between rotamers of
the carbamate function at room temperature in the
CDCl3 solution, but a broad signal at l 5.46 in the
proton NMR spectrum is clearly diagnostic for an
aminal proton. The crude material was treated with
anhydrous methanol in the presence of a catalytic
amount of p-toluenesulfonic acid35 to afford a mixture
of the methoxy derivatives 28 in 88% yield. Their
purification by column chromatography allowed the
isolation of pure samples of each isomer. In the proton
NMR spectrum, the less polar isomer shows a unique
set of signals with a broad absorption at l 5.18 and a
singlet at l 3.27 characteristic of the aminal proton and
the methoxy group, respectively, while the second elut-
ing isomer presents a ca. 1:1 mixture of two carbamate
rotamers, evidenced by two broad signals at l 4.90 and
The overall yield for the conversion of 26 into 21 is
55%, completing an efficient synthesis of enantiopure
imine 21, which is formed in 40% yield starting from
commercially available 24.
During these synthetic studies, a series of new enantio-
pure 3,4-dihydro-2H-pyrrole derivatives have been pre-
pared. In particular, for the target nitrone a new syn-
thesis has been developed, markedly improving upon
the preliminary sequence.
3. Experimental
Reaction mixtures were stirred magnetically. The
organic extracts were dried over anhydrous sodium
sulfate. Reaction solutions were concentrated using a
rotary evaporator at 5–10 Torr. Flash chromatography
was performed using Merck silica gel (230–400 mesh).
Infrared spectra were recorded on a Nicolet 5 ZDX
c
a
b
O
CH2OCOtBu
O
CH2OH
O
CO2Et
N
H
N
H
N
H
25
10
24
HO
H3CO
d
e
O
CH2OCOtBu
CH2OCOtBu
CH2OCOtBu
H
H
N
Boc
N
Boc
N
Boc
26
27
28
CH3O
H
g
CH3O
H
CH2OCOtBu
f
CH2OCOtBu
CH2OCOtBu
N
N
N
CO2SitBuMe2
C O
21
-
O
29
30
t
Scheme 3. (a) LiBH4, THF, rt, 48 h, 90%; (b) BuCOCl, DMAP, py, CH2Cl2, rt, 1 day, 83%; (c) (Boc)2O, Et3N, CH2Cl2, rt, 1
day, 88%; (d) DIBAL, THF, −78°C, 4 h, 87%; (e) p-TsOH, MeOH, rt, 30 min, 88%; (f) CF3SO3SitBuMe2, 2,6-lutidine, CH2Cl2,
rt, 10 min; (g) nBu4NF, THF, rt, 1 h, 72% from 28.

F. Busque´ et al. / Tetrahedron: Asymmetry 13 (2002) 437–445
441
spectrophotometer. 1H and 13C NMR spectra were
3.4. Ethyl (3S,5aR)- and (3S,5aS)-tetrahydro-
pyrrolo[1,2-b]oxaziridine-3-carboxylate 15
recorded on Bruker AC-250-WB or AM-400-WB instru-
ments at 250 or 400 MHz and 62.5 or 100 MHz,
respectively, in CDCl3 solutions. Only those spectra
recorded in the Bruker AM-400-WB are specified. Mass
spectra were performed on a Hewlett–Packard 5985B
instrument at 70 eV; only peaks with higher intensity
than 20% are reported, unless they belong to molecular
ions or to significant fragments.
A solution of imine 14 (20 mg, 0.14 mmol) in CDCl3
(0.6 mL) at 0°C was treated with m-CPBA (95% purity,
1
25 mg, 0.14 mmol). After 30 min the H NMR analysis
of the mixture showed the presence of a ca. 1:1 mixture
1
of cis- and trans-15; cis-15: H NMR l 1.26 (t, J=6.5
Hz, 3H, CH3), 1.80 (m, 2H), 2.05 (m, 1H), 2.40 (m,
1H), 3.80 (dd, J=10.4 Hz, J%=1.6 Hz, 1H, H-3), 4.25
(q, J=6.5 Hz, 2H, OCH2), 4.55 (s, 1H, H-5a); trans-15:
1H NMR l 1.22 (t, J=6.5 Hz, 3H, CH3), 1.80 (m, 2H),
2.05 (m, 1H), 2.40 (m, 1H), 4.05–4.20 (m, 1H, H-3 and
q, J=6.5 Hz, 2H, OCH2), 4.60 (s, 1H, H-5a).
3.1. Ethyl (S)-4,5-dihydro-2(3H)-thioxopyrrole-5-
carboxylate 11
A solution of ethyl L
-pyroglutamate13 (2.00 g, 12.7 mmol)
in anhydrous THF (30 mL) under nitrogen atmosphere
was treated with Lawesson’s reagent (2.56 g, 6.33 mmol).
The reaction mixture was kept at rt for 1 h. Flash
chromatography of the crude material (4.60 g) using
hexane/ethyl acetate (3:2) as eluent afforded 1116 as a
solid (1.98 g, 11.4 mmol, 90%); mp 35–36°C (lit.16a mp
43–45°C; lit.16b yellow oil). [h]2D0=+12.5 (c 4.0, ethanol).
On heating this sample at 70°C the signals of cis-15
disappeared after 1 h, and the absorptions of trans-15
disappeared after 3 h. The only observable new signals
corresponded to pyrrole 16;22 1H NMR l 1.30 (t,
J=6.5 Hz, 3H, CH3), 4.28 (q, J=6.5 Hz, 2H, OCH2),
6.20 (dd, J=6.4 Hz, J%=2.8 Hz, 1H, H-4), 6.84 (m, 1H,
H-3), 6.91 (m, 1H, H-5).
3.2. Ethyl (S)-3,4-dihydro-5-methylthio-2H-pyrrole-2-
carboxylate 13
3.5. (S)-4,5-Dihydro-5-hydroxymethylpyrrole-2(3H)-
thione 17
To a solution of 11 (1.97 g, 11.4 mmol) in acetone (40
mL), iodomethane (0.70 mL, 11.3 mmol) was added
slowly and the mixture was stirred at rt overnight. A
colourless precipitate was formed. Ether (30 mL) was
added and the solid was filtered and washed with ether
(2×10 mL) yielding the hydroiodide 12 (3.11 g, 9.9 mmol,
87%), which was dissolved in CH2Cl2 (30 mL). This
solution was washed with saturated aqueous NaHCO3
(2×60 mL) and removal of the organic solvent yielded
compound 13 as a colourless oil (1.80 g, 9.6 mmol, 84%
from 11). An analytical sample was obtained by distilla-
tion; bp 92–93°C/2 Torr; IR (film) 2982, 2932, 1738,
To a solution of thiolactam 11 (1.70 g, 9.83 mmol) in
THF (20 mL) at 0°C, a solution of LiBH4 in THF (2.0
M, 5.4 mL, 10.7 mmol) was slowly added. The mixture
was kept at rt overnight, then cooled at 0°C and
neutralised with 20% aqueous acetic acid (8 mL). The
organic solvent was removed under vacuum, the formed
precipitate was filtered off and the aqueous solution was
introduced in a Dowex 50WX8-400 column previously
washed with HCl 2M (150 mL) and water (150 mL).
Elution with water afforded a colourless solid (2.01 g),
which was washed with hot acetone (50 mL). The acetone
solution was concentrated to yield a solid (1.56 g).
Purification by flash chromatography using chloroform/
methanol (18:1) as eluent afforded 17 as a colourless solid
(1.17 g, 8.96 mmol, 90%); mp 124–125°C; IR (KBr) 3217,
1
1585, 1188 cm−1; H NMR l 1.28 (t, J=5.7 Hz, 3H,
CH3), 2.18 (m, 1H, H-3), 2.23 (m, 1H, H-3), 2.50 (s, 3H,
SCH3), 2.74 (m, 2H, H-4), 4.21 (q, J=5.7 Hz, 2H,
OCH2), 4.70 (dd, J=5.2 Hz, J%=4.8 Hz, 1H, H-2); 13C
NMR l 13.7/14.1 (CH3/SCH3), 27.6 (C-3), 38.6 (C-4),
60.9 (OCH2), 73.5 (C-2), 172.7 (CO), 176.9 (C-5); MS
(m/z): 187 (M+, 19), 114 (100), 100 (33). Anal. calcd for
C8H13NO2S: C, 51.31; H, 7.00; N, 7.48; S, 17.12. Found:
C, 51.29; H, 6.99; N, 7.47; S, 17.02%. [h]2D0=+80.6 (c 6.0,
CHCl3).
1
2972, 2928, 2876, 1536, 1289 cm−1; H NMR l 1.84 (m,
1H, H-4), 2.26 (m, 1H, H-4), 2.91 (m, 2H, H-3), 3.54 (dd,
J=11.0 Hz, J%=8.0 Hz, 1H, CH2O), 3.76 (dd, J=11.0
Hz, J%=3.5 Hz, 1H, CH2O), 4.06 (m, 1H, H-5), 8.60 (br
s, 1H, NH); 13C NMR l 25.9 (C-4), 44.3 (C-3), 64.7/65.5
(C-5/CH2O), 206.9 (C-2); MS (m/z): 131 (M+, 91), 100
(100), 67 (45). Anal. calcd for C5H9NOS: C, 45.78; H,
6.91; N, 10.68; S, 24.44. Found: C, 45.80; H, 6.86; N,
10.58; S, 24.35%. [h]2D0=+13.4 (c 1.9, acetone).
3.3. Ethyl (S)-3,4-dihydro-2H-pyrrole-2-carboxylate 14
A mixture of 13 (550 mg, 2.9 mmol) and commercial W-2
Raney-Ni (5.5 g) in acetone (40 mL) was heated at reflux
for 1 h. The solution was filtered through Celite® and the
solid was extracted with boiling ethyl acetate (30 mL) for
15 min. The combined filtrates were concentrated to
afford an oil (290 mg), which was purified by flash
chromatography using ethyl acetate as eluent furnishing
the following fractions: starting 13 (30 mg) and imine 14
as an unstable colourless oil (165 mg, 1.17 mmol, 40%);
1H NMR l 1.20 (t, J=6.2 Hz, 3H, CH3), 2.05 (m, 2H,
H-3), 2.60 (m, 2H, H-4), 4.18 (q, J=6.2 Hz, 2H, OCH2),
4.67 (m, 1H, H-2), 7.70 (s, 1H, H-5). [h]2D0=+14.1 (c 8.5,
CHCl3).
3.6. (S)-3,4-Dihydro-2-hydroxymethyl-5-methylthio-2H-
pyrrole 19
To a solution of 17 (1.01 g, 7.71 mmol) in acetone (25
mL), iodomethane (0.70 mL, 11.3 mmol) was added
slowly and the mixture was stirred at rt overnight. A
colourless precipitate was formed. Ether (20 mL) was
added and the solid was filtered and washed with ether
(2×10 mL) yielding the hydroiodide 18 (1.93 g, 7.07
mmol, 92%), that was dissolved in ethyl acetate (30
mL). This solution was washed with saturated aqueous

442
F. Busque´ et al. / Tetrahedron: Asymmetry 13 (2002) 437–445
NaHCO3 (2×20 mL) and removal of the organic sol-
vent yielded compound 1930 as a colourless oil (855 mg,
5.90 mmol, 76% from 17); IR (KBr) 3364, 2928, 2874,
3.9. (3S,5aS)- and (3S,5aR)-3-Pivaloyloxymethyltetra-
hydropyrrolo[1,2-b]oxaziridine 22a and 22b
1
1587, 1100 cm−1; H NMR l 1.72 (m, 1H, H-3), 2.09
A solution of imine 21 (90 mg, 0.49 mmol) in CH2Cl2
(5.0 mL) at 0°C under a nitrogen atmosphere was
treated with m-CPBA (95% purity, 89 mg, 0.50 mmol)
previously dried over anhydrous MgSO4. The mixture
was kept at this temperature for 1 h. The solvent was
removed, the residue (210 mg) was dissolved in CHCl3
and the solution was washed with 10% aqueous
Na2CO3 (2×10 mL). Removal of the solvent yielded a
colourless oil identified as a 1:3 mixture of 22a and 22b,
respectively (70 mg, 0.35 mmol, 72%); IR (film) 2972,
2875, 1730, 1284, 1157 cm−1; 13C NMR l 20.8/21.5
(C-4/C-5), 27.0 and 27.3 (C(CH3)3), 38.8 (C(CH3)3),
64.2/64.7/65.5 (CH2O/C-3), 81.1 and 81.3 (C-5a), 178.4
(CO); MS (m/z): 200 (M++1, 1), 97 (31), 84 (100), 57
(m, 1H, H-3), 2.15 (br s, 1H, OH), 2.40 (s, 3H, SCH3),
2.65 (m, 2H, H-4), 3.49 (dd, J=11.0 Hz, J%=7.5 Hz,
1H, CH2O), 3.83 (dd, J=11.0 Hz, J%=2.7 Hz, 1H,
CH2O), 4.15 (m, 1H, H-2); 13C NMR l 13.6 (SCH3),
27.4 (C-3), 38.6 (C-4), 66.6 (CH2O), 70.8 (C-2), 174.1
(C-5); MS (m/z): 145 (M+, 18), 114 (100), 61 (35).
[h]2D0=+97.2 (c 5.3, CHCl3); lit.30 [h]2D0=+78.1 (c 2.2,
CHCl3).
3.7. (S)-3,4-Dihydro-5-methylthio-2-pivaloyloxymethyl-
2H-pyrrole 20
1
(83); 22a: H NMR (from the mixture) l 1.18 (s, 9H,
To a solution of 19 (400 mg, 2.76 mmol), DMAP (130
mg, 1.0 mmol) and pyridine (0.45 mL, 5.60 mmol) in
CH2Cl2 (25 mL) at 0°C, pivaloyl chloride (0.69 mL,
5.60 mmol) was added slowly and the mixture was
stirred at rt for 1 day. The solvent was removed, the
solid (1.80 g) was dissolved in CHCl3 (20 mL) and the
solution was washed with saturated aqueous NaHCO3
(2×20 mL). Flash chromatography of the crude mate-
rial (800 mg) using hexane/ethyl acetate (4:1) as eluent
afforded 20 as a colourless oil (580 mg, 2.53 mmol,
92%); IR (KBr) 2970, 2874, 1734, 1591, 1285, 1157
tBu), 1.50–1.80 (m, 2H), 1.80–2.10 (m, 1H), 2.35 (dd,
J=14.6 Hz, J%=10.0 Hz, 1H, H-5), 3.76 (m, 1H, H-3),
4.08 (dd, J=11.7 Hz, J%=5.9 Hz, 1H, CH2O), 4.16 (dd,
J=11.7 Hz, J%=4.4 Hz, 1H, CH2O), 4.57 (s, 1H, H-5a);
1
t
22b: H NMR (from the mixture) l 1.20 (s, 9H, Bu),
1.50–1.80 (m, 2H), 1.80–2.10 (m, 1H), 2.40 (dd, J=14.6
Hz, J%=8.0 Hz, 1H, H-5), 3.37 (dq, J=10.3 Hz, J%=6.6
Hz, 1H, H-3), 4.22 (d, J=6.6 Hz, 2H, CH2O), 4.57 (s,
1H, H-5a).
3.10. (S)-3,4-Dihydro-2-pivaloyloxymethyl-2H-pyrrole
1-oxide 9
1
t
cm−1; H NMR l 1.10 (s, 9H, Bu), 1.76 (m, 1H, H-3),
2.10 (m, 1H, H-3), 2.38 (s, 3H, SCH3), 2.60 (m, 2H,
H-4), 4.13 (d, J=5.1 Hz, 2H, CH2O), 4.27 (m, 1H,
H-2); 13C NMR l 13.6 (SCH3), 26.4 (C-3), 27.4
(C(CH3)3), 38.6/38.7 (C-4/C(CH3)3), 66.6 (CH2O), 70.8
(C-2), 174.3 (C-5), 178.3 (CO); MS (m/z): 230 (M++1,
20), 127 (73), 114 (100), 80 (51), 61 (25), 57 (88), 55
(20), 41 (57). Anal. calcd for C11H19NO2S: C, 57.61; H,
8.35; N, 6.11; S, 13.98. Found: C, 57.72; H, 8.39; N,
5.82; S, 13.73%. [h]2D0=+22.6 (c 10.6, CHCl3).
A solution of imine 21 (130 mg, 0.71 mmol) in CH2Cl2
(10 mL) at −78°C and protected from the light was
treated with a solution of TFMD in trifluoroacetone32
(438 mM, 1.9 mL, 0.85 mmol). After 1 h the solvent
was removed and the oily residue (154 mg) was iden-
1
tified as nitrone 9 and used immediately; H NMR l
t
1.18 (s, 9H, Bu), 2.12 (m, 1H, H-3), 2.39 (m, 1H, H-3),
2.65 (m, 2H, H-4), 4.10 (m, 1H, H-2), 4.32 (dd, J=10.7
Hz, J%:1.0 Hz, 1H, CH2O), 4.60 (dd, J=10.7 Hz,
J%:1.0 Hz, 1H, CH2O), 6.97 (s, 1H, H-5). Several other
minor absorptions were also observed.
3.8. (S)-3,4-Dihydro-2-pivaloyloxymethyl-2H-pyrrole 21
from 20
3.11. Dimethyl (3aS,6S)-3a,4,5,6-tetrahydro-6-pivaloyl-
oxymethylpyrrolo[1,2-b]isoxazole-2,3-dicarboxylate 23
A mixture of 20 (440 mg, 1.92 mmol) and commercial
W-2 Raney-Ni (4.5 g) in acetone (40 mL) was heated at
reflux for 1 h. The solution was filtered through Celite®
and the solid was extracted with boiling ethyl acetate
(30 mL) for 15 min. The combined filtrates were con-
centrated to afford an oil (320 mg), that was purified by
flash chromatography using hexane/ethyl acetate (1:2)
as eluent and furnishing the following fractions: start-
ing 20 (55 mg) and imine 21 (106 mg, 0.58 mmol, 34%
considering the recovered 20) as an unstable colourless
oil. Recovered 20: [h]2D0=+22.2 (c 2.7, CHCl3); 21: IR
(film) 2971, 2875, 1728, 1697, 1461, 1156 cm−1; 1H
To a solution of nitrone 9 (154 mg) in CH2Cl2 (10 mL),
dimethyl acetylenedicarboxylate (0.15 mL, 1.12 mmol)
was added and the mixture was kept at rt overnight.
Flash chromatography of the crude material (270 mg)
using hexane/ethyl acetate (2:1) as eluent afforded
adduct 23 (151 mg, 0.44 mmol, 62% from imine 21); IR
(film) 2961, 2912, 1754, 1727, 1656, 1286, 1137 cm−1; 1H
t
NMR (400 MHz) l 1.15 (s, 9H, Bu), 1.54 (m, 1H,
H-5b), 1.92 (m, 1H, H-5a), 2.04 (m, 1H, H-4a), 2.30
(m, 1H, H-4b), 3.56 (m, 1H, H-6), 3.72 (s, 3H, OCH3),
3.85 (s, 3H, OCH3), 4.15 (dd, J=11.3 Hz, J%=5.6 Hz,
1H, CH2O), 4.19 (dd, J=11.3 Hz, J%=5.6 Hz, 1H,
t
NMR l 1.10 (s, 9H, Bu), 1.53 (m, 1H, H-3), 1.93 (m,
1H, H-3), 2.55 (m, 2H, H-4), 4.17 (d, J=5.1 Hz, 2H,
CH2O), 4.27 (m, 1H, H-2), 7.60 (s, 1H, H-5); 13C NMR
CH2O), 4.85 (br t, J3a,4b:J3a,4a:6.1 Hz, 1H, H-3a); 13
C
l
23.1 (C-3), 27.0 (C(CH3)3), 37.0 (C-4), 38.7
NMR l 27.1 (C(CH3)3), 24.7/30.4 (C-4/C-5), 38.7
(C(CH3)3), 51.8/53.1 (2×OCH3), 64.8 (CH2O), 69.1/69.5
(C-3a/C-6), 109.1 (C-3), 151.4 (C-2), 162.6/168.8 (2×
CO2Me), 178.2 (COt2Bu); MS (m/z): 341 (M+, 2), 256
(C(CH3)3), 66.5 (CH2O), 71.5 (C-2), 167.8 (C-5), 178.3
(CO); MS (m/z): 184 (M++1, 41), 57 (100), 41 (55).
[h]2D0=+64.4 (c 6.7, CHCl3).

F. Busque´ et al. / Tetrahedron: Asymmetry 13 (2002) 437–445
443
1
t
(100), 224 (29), 149 (94), 84 (24), 71 (54), 57 (55). Anal.
calcd for C16H23NO7: C, 56.30; H, 6.79; N, 4.10.
Found: C, 56.11; H, 6.90; N, 3.91%. [h]2D0=−167.5 (c
7.5, CHCl3).
mmol, 87%); H NMR l 1.10 (s, 9H, Bu), 1.37 (s, 9H,
OtBu), 1.75–1.95 (m, 4H, H-3, H-4), 3.81 (br s, 1H,
OH), 3.90–4.05 (m, 2H, CH2O), 4.15 (dd, J=10.6 Hz,
J%=3.4 Hz, 1H, H-5), 5.46 (m, 1H, H-2); 13C NMR l
25.8 (C-4), 27.0 (C(CH3)3), 28.2 (OC(CH3)3), 30.9 (C-
3), 38.6 (C(CH3)3), 55.8 (C-5), 64.6 (CH2O), 80.6
(OC(CH3)3), 82.5 (C-2), 154.4 (NCO), 178.0 (CO).
Anal. calcd for C15H27NO5: C, 59.78; H, 9.03; N, 4.65.
Found: C, 59.64; H, 9.19; N, 4.61%.
3.12. (S)-4,5-Dihydro-5-pivaloyloxymethyl-2(3H)-
pyrrolone 25
To a solution of 2433 (5.58 g, 48.5 mmol), DMAP (5.92
g, 48.5 mmol) and pyridine (5.10 mL, 63.3 mmol) in
CH2Cl2 (280 mL) at 0°C, pivaloyl chloride (11.9 mL,
96.9 mmol) was added slowly and the mixture was
stirred at rt for 1 day. The solvent was removed and the
solid was extracted with ethyl acetate (20 mL). Filtra-
tion of the residual solid and removal of the solvent
yielded an oil. Purification by flash chromatography
using ethyl acetate as eluent afforded 25 as a colourless
solid (8.01 g, 40.2 mmol, 83%); mp 64–65°C; IR (KBr)
3.15. (2R,5S)- and (2S,5S)-N-(tert-Butoxycarbonyl)-2-
methoxy-5-pivaloyloxymethylpyrrolidine 28
To a solution of 27 (400 mg, 1.33 mmol) in methanol (5
mL) at 0°C, was added p-TsOH (10 mg) and the
mixture was stirred at rt for 30 min. The solvent was
removed, the oil was dissolved in CH2Cl2 (25 mL) and
the resulting solution was washed with saturated
aqueous NaHCO3 (10 mL) and brine (5 mL). Removal
of the organic solvent yielded compound 28 as a mix-
ture of diastereoisomers (368 mg, 1.17 mmol, 88%).
Pure samples of each isomer as colourless oils were
obtained by flash chromatography using hexane/ethyl
1
3255, 2973, 1730, 1652, 1286, 1166 cm−1; H NMR l
t
1.15 (s, 9H, Bu), 1.80 (m, 1H, H-4), 2.25 (m, 3H, H-4,
2H-3), 3.85 (m, 2H, H-5, CH2O), 4.18 (dd, J=10.2 Hz,
J%=2.9 Hz, 1H, CH2O), 6.30 (br s, 1H, NH); 13C NMR
l
23.5 (C-4), 27.6 (C(CH3)3), 30.0 (C-3), 38.3
1
(C(CH3)3), 53.3 (C-5), 67.2 (CH2O), 178.4/178.6 (C-2/
CO); MS (m/z): 200 (M++1, 5), 97 (32), 84 (100). Anal.
calcd for C10H17NO3: C, 60.28; H, 8.60; N, 7.03.
Found: C, 60.19; H, 8.65; N, 6.88%. [h]2D0=+32.0 (c 5.2,
CHCl3).
acetate (4:1) as eluent. Major and less polar isomer: H
NMR l 1.17 (s, 9H, Bu), 1.45 (s, 9H, OtBu), 1.70–2.10
t
(m, 4H, H-3, H-4), 3.27 (s, 3H, OCH3), 4.00 (br m, 2H,
CH2O), 4.30 (br m, 1H, H-5), 5.18 (br d, 1H, H-2); 13C
NMR l 27.1 (C(CH3)3), 28.3 (OC(CH3)3), 31.4/32.1
(C-4/C-3), 38.8 (C(CH3)3), 55.2/56.2 (OCH3/C-5), 66.0
(CH2O), 80.4 (OC(CH3)3), 89.4 (C-2), 178.3 (CO).
3.13. (S)-N-(tert-Butoxycarbonyl)-4,5-dihydro-5-pival-
oyloxymethyl-2(3H)-pyrrolone 26
1
Minor and more polar isomer: H NMR l 1.17 (s, 9H,
tBu), 1.43 (s, 9H, OtBu), 1.70–2.00 (m, 3H, H-3, H-4),
2.20 (m, 1H, H-3/H-4), 3.30 (s)+3.35 (s) (3H, OCH3),
3.90–4.10 (m, 3H, CH2O, H-5), 4.90 (br s)+5.10 (br s)
(1H, H-2). Mixture of diastereoisomers: Anal. calcd for
C16H29NO5: C, 60.92; H, 9.27; N, 4.44. Found: C,
60.66; H, 9.93; N, 4.36%.
To a solution of 25 (2.58 g, 12.9 mmol), (Boc)2O (5.63
g, 25.8 mmol) and triethylamine (1.79 mL, 12.9 mmol)
in CH2Cl2 (20 mL) at 0°C, another solution of DMAP
(3.15 g, 25.8 mmol) in CH2Cl2 (10 mL) was added
slowly and the mixture was stirred at rt for 1 day. Flash
chromatography of the crude material using hexane/
ethyl acetate (1:1) as eluent afforded 26 as a solid (3.40
3.16. (2R,5S)- and (2S,5S)-N-(tert-Butyldimethylsilyl-
oxycarbonyl)-2-methoxy-5-pivaloyloxymethylpyrrolidine
29
1
g, 11.3 mmol, 88%); mp 62–63°C; H NMR l 1.07 (s,
t
9H, Bu), 1.41 (s, 9H, OtBu), 1.81 (m, 1H, H-4), 2.05
(m, 1H, H-4), 2.29 (ddd, J=17.6 Hz, J%=9.8, J%%=2.5
Hz, 1H, H-3), 2.53 (dt, J3,3=17.6 Hz, J3,4=10.7 Hz,
To a solution of 28 (1.57 g, 5.00 mmol) and 2,6-lutidine
(2.31 mL, 19.9 mmol) in CH2Cl2 (25 mL) at 0°C,
tert-butyldimethylsilyl trifluoromethanesulfonate (3.43
mL, 14.9 mmol) was added slowly and the mixture was
stirred at rt for 10 min. The solvent was removed, the
oil was dissolved in ethyl ether (40 mL) and the solu-
tion was washed with saturated aqueous NH4Cl (40
mL) and brine (30 mL). Partial distillation of volatile
components from the crude material afforded a residue
containing a mixture of diastereoisomers 29 contam-
J
3,4=9.7 Hz, 1H, H-3), 3.98 (m, 1H, CH2O), 4.23 (m,
2H, H-5, CH2O); 13C NMR l 20.6 (C-4), 26.8
(C(CH3)3), 27.7 (OC(CH3)3), 31.3 (C-3), 38.4
(C(CH3)3), 55.8 (C-5), 64.4 (CH2O), 82.8 (OC(CH3)3),
149.1 (NCOO), 173.7/177.6 (C-2/CO). Anal. calcd for
C15H25NO5: C, 60.17; H, 8.42; N, 4.68. Found: C,
60.42; H, 8.33; N, 4.58%. [h]2D0=−40.5 (c 5.1, CHCl3).
3.14. (2R,5S)- and (2S,5S)-N-(tert-Butoxycarbonyl)-2-
hydroxy-5-pivaloyloxymethylpyrrolidine 27
1
inated with silylated compounds; H NMR l 0.24 (s,
6H, SiMe2), 0.91 (s, 9H, SitBu), 1.12 (s, 9H, OtBu),
1.70–2.15 (m, 4H, H-3, H-4), 3.23 (s)+3.27 (s)+3.35
(s)+3.61 (s) (3H, OCH3), 3.85–4.15 (m, 2H, CH2O),
4.24 (m, 1H, H-5), 4.88 (d)+5.02 (d)+5.11 (d)+5.21 (d)
(1H, H-2).
To a solution of 26 (300 mg, 1.00 mmol) in dry THF (3
mL) at −78°C, a solution of DIBAL-H in THF (1.0 M,
1.1 mL, 1.10 mmol) was slowly added. The mixture was
stirred at −78°C for 4 h, quenched with saturated
aqueous NH4Cl (2 mL) and allowed to warm to rt. The
mixture was extracted with ethyl acetate (3×20 mL).
Flash chromatography of the crude material using hex-
ane/ethyl acetate (4:1) as eluent afforded a mixture of
diastereoisomers 27 as a colourless oil (263 mg, 0.87
3.17. Preparation of 21 from 29
A solution of 29 (1.50 g, 4.00 mmol) in THF (15 mL)
at 0°C, was treated with tetra-n-butylammonium

444
F. Busque´ et al. / Tetrahedron: Asymmetry 13 (2002) 437–445
fluoride in THF (1.0 M, 4.0 mL, 4.0 mmol) and the
mixture was stirred at rt for 1 h. The solvent was
removed, the oil was dissolved in CH2Cl2 (20 mL) and
the solution was washed with saturated aqueous NH4Cl
(20 mL) and brine (10 mL). Flash chromatography of
the crude material using hexane/ethyl acetate (1:1) as
eluent afforded 21 as a colourless oil (659 mg, 3.60
mmol, 72% from 28). For physical and spectroscopic
data of 21 see Section 3.8.
11. (a) Oppolzer, W.; Bochet, C. G.; Merifield, E. Tetra-
hedron Lett. 1994, 35, 7015–7018; (b) Oppolzer, W. Pure
Appl. Chem. 1994, 66, 2127–2130.
12. (a) Golik, J.; Wong, H.; Krishnan, B.; Vyas, D. M.;
Doyle, T. W. Tetrahedron Lett. 1991, 32, 1851–1854; (b)
Ballini, R.; Marcantoni, E.; Petrini, M. J. Org. Chem.
1992, 57, 1316–1318; (c) Cicchi, S.; Goti, A.; Brandi, A.
J. Org. Chem. 1995, 60, 4743–4748; (d) Giovannini, R.;
Marcantoni, E.; Petrini, M. J. Org. Chem. 1995, 60,
5706–5707; (e) van der Broek, L. A. G. M. Tetrahedron
1996, 52, 4467–4478; (f) Mccaig, A. E.; Meldrum, K. P.;
Wightman, R. H. Tetrahedron 1998, 54, 9429–9446; (g)
Closa, M.; Wightman, R. H. Synth. Commun. 1998, 28,
3443–3450; (h) Goti, A.; Cicchi, S.; Cacciarini, M.; Car-
dona, F.; Fedi, V.; Brandi, A. Eur. J. Org. Chem. 2000,
3633–3645; (i) Cicchi, S.; Marradi, M.; Goti, A.; Brandi,
A. Tetrahedron Lett. 2001, 42, 6503–6505.
Acknowledgements
We gratefully acknowledge financial support of DGES
(project PB97-0215) and CIRIT (1999SGR-00091). We
also thank DGES for a grant to S.M. and CIRIT for a
grant to F.B. We acknowledge Marc Comas for scaling
up some of the described reactions.
13. Smith, M. B.; Dembofsky, B. T.; Son, Y. C. J. Org.
Chem. 1994, 59, 1719–1725.
14. (a) Andersen, T. P.; Rasmussen, P. B.; Thomsen, I.;
Lawesson, S.-O.; Jørgensen, P.; Lindhardt, P. Liebigs
Ann. Chem. 1986, 269–279; (b) Nagao, Y.; Dai, W.-M.;
Ochiai, M.; Tsukagoshi, S.; Fujita, E. J. Org. Chem.
1990, 55, 1148–1156.
References
1. (a) Tufariello, J. J. 1,3-Dipolar Cycloaddition Chemistry;
John Wiley & Sons: New York, 1984; Vol. 2, Chapter 9;
(b) Torssell, K. B. G. Nitrile Oxides, Nitrones, and
Nitronates in Organic Synthesis; VCH Verlagsgesellschaft:
Weinheim, 1988.
2. (a) Frederickson, M. Tetrahedron 1997, 53, 403–425; (b)
Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863–909.
3. (a) Bayo´n, P.; de March, P.; Espinosa, M.; Figueredo,
M.; Font, J. Tetrahedron: Asymmetry 2000, 11, 1757–
1765; (b) Bayo´n, P.; de March, P.; Figueredo, M.; Font,
J.; Medrano, J. Tetrahedron: Asymmetry 2000, 11, 4269–
4278.
15. Bachi, M. D.; Breiman, R.; Meshulam, H. J. Org. Chem.
1983, 48, 1439–1444.
16. (a) Drauz, K. H.; Kleemann, A.; Martens, J. Ger. Offen.
DE 3117830; Chem. Abstr. 1983, 98, 143266a; (b) Honda,
T.; Kimura, M. Org. Lett. 2000, 2, 3925–3927.
17. Barton, D. H. R.; Ollis, W. D. Comprehensive Organic
Chemistry; Pergamon Press: Oxford, 1979; Vol. 2, pp.
489–490 and Vol. 3, pp. 448–452.
18. Confalone, P. N.; Huie, E. M.; Ko, S. S.; Cole, G. M. J.
Org. Chem. 1988, 53, 482–487.
19. Buynak, J. D.; Rao, M. N.; Pajouhesh, H.; Chan-
drasekaran, R. Y.; Finn, K.; de Meester, P.; Chu, S. C. J.
Org. Chem. 1985, 50, 4245–4252.
20. Boar, R. B.; Hawkins, D. W.; McGhie, J. F.; Barton, D.
H. R. J. Chem. Soc., Perkin Trans. 1 1973, 654–657.
21. Duhamel, P.; Kotera, M. J. Org. Chem. 1982, 47, 1688–
1691.
22. Pretsch, E.; Clerc, T.; Seibl, J.; Simon, W. Tablas para la
elucidacio´n estructural por me´todos espectrosco´picos;
Springer-Verlag Ibe´rica: Barcelona, 1998.
4. (a) Busque´, F.; de March, P.; Figueredo, M.; Font, J.;
´
Monsalvatje, M.; Virgili, A.; Alvarez-Larena, A.; Piniella,
J. F. J. Org. Chem. 1996, 61, 8578–8585; (b) de March,
P.; Escoda, M.; Figueredo, M.; Font, J.; Alvarez-Larena,
A.; Piniella, J. F. J. Org. Chem. 1997, 62, 7781–7787; (c)
Alibe´s, R.; Busque´, F.; de March, P.; Figueredo, M.;
Font, J.; Gambino, M. E.; Keay, B. A. Tetrahedron:
Asymmetry 2001, 12, 1747–1756.
´
5. (a) de March, P.; Figueredo, M.; Font, J.; Gallagher, T.;
Mila´n, S. J. Chem. Soc., Chem. Commun. 1995, 2097–
2098; (b) Closa, M.; de March, P.; Figueredo, M.; Font,
J. Tetrahedron: Asymmetry 1997, 8, 1031–1037.
6. Baldwin, J. E.; Chan, M. F.; Gallacher, G.; Otsuka, M.
Tetrahedron 1984, 40, 4513–4525.
7. Grigg, R.; Markandu, J.; Perrior, T.; Surendrakumar, S.;
Warnock, W. J. Tetrahedron 1992, 48, 6929–6952.
8. (a) Lathbury, D. C.; Gallagher, T. J. Chem. Soc., Chem.
Commun. 1986, 1017–1018; (b) Lathbury, D. C.; Shaw,
R. W.; Bates, P. A.; Hursthouse, M. B.; Gallagher, T. J.
Chem. Soc., Perkin Trans. 1 1989, 2415–2424.
9. Tufariello, J. J.; Mullen, G. B.; Tegeler, J. J.; Trybulski,
E. J.; Wong, S. C.; Ali, Sk. A. J. Am. Chem. Soc. 1979,
101, 2435–2442.
10. (a) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987,
28, 2383–2386; (b) Murahashi, S.-I.; Mitsui, H.; Shiota,
T.; Tsuda, T.; Watanabe, S. J. Org. Chem. 1990, 55,
1736–1744; (c) Murahashi, S.-I.; Imada, Y.; Ohtake, H. J.
Org. Chem. 1994, 59, 6170–6172.
23. Gibson, N. J.; Forrester, A. R. J. Chem. Soc., Perkin
Trans. 1 1995, 491–499.
24. Christensen, D.; Jørgensen, K. A. J. Org. Chem. 1989, 54,
126–131.
25. (a) Boyd, D. R.; Coulter, P. B.; McGuckin, M. R.;
Sharma, N. D.; Jennings, W. B.; Wilson, V. E. J. Chem.
Soc., Perkin Trans. 1 1990, 301–306; (b) Crandall, J. K.;
Reix, T. J. Org. Chem. 1992, 57, 6759–6764.
26. Hanquet, G.; Lusinchi, X. Tetrahedron 1994, 50, 12185–
12200.
27. (a) Lee, T. D.; Keana, J. F. W. J. Org. Chem. 1976, 41,
3237–3241; (b) Padwa, A.; Koehler, K. F. Heterocycles
1986, 24, 611–615; (c) Christensen, D.; Jørgensen, K. A.;
Hazell, R. G. J. Chem. Soc., Perkin Trans. 1 1990,
2391–2397; (d) Huber, R.; Vasella, A. Tetrahedron 1990,
46, 33–58; (e) Vidal, J.; Guy, L.; Ste´rin, S.; Collet, A. J.
Org. Chem. 1993, 58, 4791–4793; (f) Martiny, L.;
Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1995,
699–704; (g) Lin, Y.-M.; Miller, M. J. J. Org. Chem.
1999, 64, 7451–7458.

F. Busque´ et al. / Tetrahedron: Asymmetry 13 (2002) 437–445
445
28. (a) Bjørgo, J.; Boyd, D. R.; Campbell, R. M.; Neill, D.
C. J. Chem. Soc., Chem. Commun. 1976, 162–163; (b)
Iwano, Y.; Kawamura, Y.; Horie, T. Chem. Lett. 1995,
67–68; (c) Berranger, T.; Langlois, Y. J. Org. Chem.
1995, 60, 1720–1726.
29. Silverman, R. B.; Levy, M. A. J. Org. Chem. 1980, 45,
815–818.
30. Marco, J. L. J. Heterocycl. Chem. 1986, 23, 1059–1062.
31. Greene, T. W.; Whuts, P. G. M. Protective Groups in
Organic Synthesis; John Wiley & Sons: New York,
1991.
J. Org. Chem. 1988, 53, 3890–3891; (b) Ferrer, M.;
Sa´nchez-Baeza, F.; Casas, J.; Messeguer, A. Tetra-
hedron Lett. 1994, 35, 2981–2984.
33. (a) Saijo, S.; Wada, M.; Himizu, J.; Ishida, A. Chem.
Pharm. Bull. 1980, 28, 1449–1458; (b) Otsuka, M.;
Masuda, T.; Haupt, A.; Ohno, M.; Shiraki, T.; Sugiura,
Y; Maeda, K. J. Am. Chem. Soc. 1990, 112, 838–845.
34. Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem.
1983, 48, 2424–2426.
35. Langlois, N.; Rojas, A. Tetrahedron 1993, 49, 77–82.
36. Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870–
876.
32. (a) Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R.