Synthesis of enantiomerically pure hydroxylated pyrroline N-oxides from d-ribose

Article abstract of DOI:10.1016/j.tetasy.2006.02.006

A convenient way to obtain enantiomerically pure hydroxylated pyrroline N-oxides is reported. The key step is the formation of ω-oxo enoates from d-ribose and a subsequent 1,3-azaprotio cyclotransfer reaction of the resulting oximino alkenoate derivatives

Full text of DOI:10.1016/j.tetasy.2006.02.006

Tetrahedron: Asymmetry 17 (2006) 829–836
Synthesis of enantiomerically pure hydroxylated pyrroline
N-oxides from D-ribose
Nikolaos G. Argyropoulos,* Theodoros D. Panagiotidis and John K. Gallos
Department of Chemistry, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece
Received 20 January 2006; accepted 6 February 2006
Available online 15 March 2006
Abstract—A convenient way to obtain enantiomerically pure hydroxylated pyrroline N-oxides is reported. The key step is the for-
mation of x-oxo enoates from D-ribose and a subsequent 1,3-azaprotio cyclotransfer reaction of the resulting oximino alkenoate
derivatives. The stereochemistry of the nitrones obtained is discussed in relation to that of the starting compounds.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
for example, N-alkylations, reductive aminations, lac-
tam formations, etc. are of common use for the nitrogen
bridgehead systems.4
The cycloaddition reaction of nitrones with olefins is one
of the most important methodologies for the synthesis
of many complex organic molecules.1 The concerted
process of this reaction, usually accompanied by a high
degree of regio- and stereoselectivity of the resulting
isoxazolidine cycloadducts, allows the creation of multi-
ple stereocenters in a single step, with complete control
of their relative configuration. These adducts can be
elaborated upon in a variety of ways, mainly originating
by cleavage of the labile N–O bond under mild reducing
conditions, leading to stereochemically well defined
open chain adducts.
The most general preparations of nitrones involve (i)
condensation of N-substituted hydroxylamines with car-
bonyl compounds; (ii) oxidation of secondary amines or
N,N-disubstituted hydroxylamines; and (iii) N-alkyl-
ation of oximes.1e The use of oximes as nitrone precur-
sors has found considerable application, but one
limitation is that a typical alkylation can be complicated
by the formation of oximino ethers as by-products.
However, an interesting variation of the alkylation pro-
cess is the reaction of oximes with electron poor alkenes
to give nitrones, a process that has been termed 1,3-
azaprotio cyclotransfer by Grigg et al.,5 who have also
systematically studied many other electrophilic induced
transformations of oximes to nitrones.6 The intramolec-
ular version of this transformation is given in Figure 1.
exo-trig Cyclization is presumably the most favorable
mode.7 According to this protocol, the synthesis of a
few chiral five- or six-membered cyclic nitrones has been
reported.2a–c Another interesting variation starting
from oximes and leading to chiral five-membered cyclic
Of particular importance are the enantiomerically pure
polyhydroxylated five- and six-membered cyclic nitrones
and their cycloaddition reactions. These compounds,
accessible either from sugars2 or from other sources,3
have found broad application in the synthesis of opti-
cally active nitrogenated compounds. In this respect,
densely substituted pyrrolidines or piperidines can be
obtained, by reacting a five- or six-membered cyclic nit-
rone and a suitable dipolarophile, followed by reductive
cleavage of the resulting isoxazolidine ring. A further
step toward the pyrrolizidine or indolizidine nucleus
can be accomplished, by intramolecular cyclization of
the resulting amino group and a proper functionality
already existing on the starting nitrone or dipolarophile
(e.g., an ester group). These intramolecular cyclizations,
X
X
H
N
O
O
N
*
Figure 1. Intramolecular 1,3-azaprotio cyclotransfer of alkenyl
Corresponding author. Tel.: +30 2310997871; fax: +30 2310997679;
oximes.
e-mail: narg@chem.auth.gr
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.02.006

830
N. G. Argyropoulos et al. / Tetrahedron: Asymmetry 17 (2006) 829–836
nitrones, involves an SN2 type intramolecular cycliza-
tion of c-mesyloxy or c-iodo-O-silylated oxime deriva-
tives.2e–i
13, 17, 18, and 21 (Schemes 2–5) following conventional
sugar transformations, all starting from the known D-
ribose monoacetonide 6.8 It is worth mentioning that the
alkene moiety, introduced by typical Wittig olefinations
has predominantly the Z-form in accordance to other a-
alkoxyaldehydes.9 However, in one case (Scheme 4) an
appreciable amount of the corresponding (E)-enoate
was also obtained. This fact allowed us to gain insight
regarding the influence of alkene form on the stereo-
chemistry of the final nitrone. All oxoenoates upon
treatment with hydroxylamine hydrochloride in the
presence of NaHCO3 afford the desired nitrones by a
spontaneous cyclization of the non-isolable oxime
derivatives.
The 1,3-azaprotio cyclotransfer process was also applied
to the synthesis of nitrones 1–5 described in this paper.
Nitrones 1 and 2 are in fact antipodes and their synthesis
was planned on the basis of manipulation of the stereo-
chemistry of the starting D-ribose. As regards the diaste-
reomeric pair of nitrones 3 and 4, their formation is
related to the stereochemistry (Z or E) of the alkene
precursors (Scheme 1).
O
N
O
N
MeO2C
CO2R
As outlined in Scheme 2, nitrone 110 was obtained by a
five-step reaction sequence starting from the D-ribose
monoacetonide and following conventional sugar trans-
formations, that is, NaBH4 reduction to ribitol 711 fol-
lowed by periodate oxidation12 to give L-erythrose
monoacetonide 8. Wittig olefination with the stable
methoxycarbonyl methylenetriphenyl phosphorane
(Ph3P@CHCOOCH3) followed by PDC oxidation13 of
the primary hydroxyl group of compound 9 gave the
key oxoenoate 10, which was finally transformed, by
cyclization of the non-isolable aldoxime 11 to the de-
sired nitrone 1 in 22% overall yield (based on the start-
ing D-ribose). It is noteworthy that some problems have
been encountered during the oxidation step of the pri-
mary hydroxyl group of compound 9. Various ap-
proaches such as Swern oxidation (DMSO/(COCl)2/
NEt3),14 or Collins oxidation15 have been tested, but
the results were not satisfactory. Best results were ob-
tained using pyridinium dichromate (PDC) in anhyd-
O
O
O
O
1
2: R = Me, 3: R =
t
Bu
O
N
CO2t-Bu
O
N
CO2Me
Ph3CO
O
O
O
O
4
5
Scheme 1.
2. Results and discussion
The key step for the synthesis of all the nitrones in this
study is the formation of the appropriate oxoenoates 10,
˚
rous acetic acid in the presence of molecular sieves 3 A.
2
O
OH
O
HO
OH
OH
OH
3
6
HO
HO
MeO2C
i
ii
iii
4
5
O
O
O
O
O
O
O
O
7
6
8
9
OH
N
iv
O
N
O
5
4
2
MeO2C
MeO2C
MeO2C
v
3
O
O
O
O
O
O
10
1
11
Scheme 2. Reagents and conditions: (i) NaBH4, MeOH, 0 °C, 1 h; (ii) NaIO4, t-BuOH, H2O, 25 °C; (iii) Ph3P@CHCO2Me, PhCOOH (cat.), CH2Cl2,
˚
reflux, 18 h; (iv) PDC, molecular sieves 3 A (powder), dry AcOH, CH2Cl2, 25 °C, 30 min; (v) NH2OHÆHCl, NaHCO3, MeOH, 25 °C, 12 h.
O
O
N
OH
O
OH
HO
HO
ii
i
iii
CO2CH3
CO2CH3
CO2CH3
O
O
O
O
O
O
O
O
12
6
13
2 (ent-1)
Scheme 3. Reagents and conditions: (i) Ph3P@CHCO2Me, PhCOOH (cat.), CH2Cl2, reflux, 18 h; (ii) NaIO4, t-BuOH, H2O, 25 °C, 15 h; (iii)
NH2OHÆHCl, NaHCO3, MeOH, 25 °C, 12 h.

N. G. Argyropoulos et al. / Tetrahedron: Asymmetry 17 (2006) 829–836
831
O
N
OH
O
HO
CO2tBu
CO2
t
Bu
CO2tBu
ii
iii
i
O
O
O
O
O
O
O
O
O
OH
HO
17
3
O
N
15
CO2
t
Bu
ii
O
O
CO2tBu
OH
HO
CO2tBu
6
iii
i
O
O
O
O
O
16
18
4
Scheme 4. Reagents and conditions: (i) Ph3P@CHCOOt-Bu 14, PhCOOH (cat.), CH2Cl2, reflux, 18 h; (ii) NaIO4, t-BuOH/H2O, 25 °C, 17 h; (iii)
NH2OHÆHCl, NaHCO3, MeOH, 25 °C, 12 h.
O
O
OH
OH
OH
HO
TrO
TrO
ii
CO2CH3
i
O
O
O
O
O
O
19
20
6
iii
O
N
OTr
O
TrO
iv
CO2CH3
CO2CH3
O
O
O
O
5
21
Scheme 5. Reagents and conditions: (i) Ph3CCl, DMF, NEt3, DMAP, 25 °C; (ii) Ph3P@CHCO2CH3, PhCOOH (cat.), CH2Cl2, reflux, 18 h; (iii)
˚
PDC, molecular sieves 3 A, dry AcOH, CH2Cl2, 25 °C, 0.5 h; (iv) NH2OHÆHCl, NaHCO3, EtOH, 25 °C, 2 h.
The reaction sequence to give nitrone 2 (ent-1) includes
the Wittig olefination of 6 followed by periodate oxida-
tion of the resulting diol group to the x-oxoenoate 13
and subsequent transformation to the nitrone 2 upon
treatment with hydroxylamine (Scheme 3). The overall
yield, starting from D-ribose was 27%. It should be men-
tioned that a minor inseparable amount of the (E)-iso-
mer of ester 12 was detected in the crude reaction
to separate these isomers and only a small fraction of
(Z)-isomer could be obtained in a pure state, their mix-
ture was subjected to periodate oxidation to give the
corresponding x-oxoenoates 17 and 18. Attempts to
separate these compounds also failed and only a part
of pure (Z)-enoate 17 but no pure (E)-enoate could be
obtained. Fortunately, treatment of the original mixture
with hydroxylamine gave the chromatographically sepa-
rable nitrones 3 and 4, in about the same ratio (ꢀ3:2) to
that of the starting esters 15 and 16. In an independent
experiment carried out starting from pure (Z)-enoate 17
only nitrone 3 was formed. This fact along with the ob-
served exclusive formation of anti nitrones 1 and 2 from
the corresponding (Z)-enoates 10 and 13 (Schemes 2
and 3) strongly support that nitrone 4 was exclusively
formed from (E)-enoate 18.
1
mixture (Z:E ꢀ 10:1). Its H NMR spectra show that
besides the main peaks for the cis olefinic protons at d
6.01 and 6.31 (J2,3 = 11.7 Hz) minor peaks appeared at
d 6.17 and 7.13 (J2,3 = 15.7 Hz), corresponding to the
2- and 3-H olefinic protons at trans position. Eventually
only the (Z)-isomer of compound 13 was isolated.
An analogous reaction sequence to that for nitrone 2,
was followed by the synthesis of diastereomeric nitrones
3 and 4 (Scheme 4). However, it has been observed that
the Wittig olefination of compound 6 with the stereo-
chemically congested stable phosphorane 14, gave
appreciable amounts of both (Z)- and (E)-enoates 15
and 16 in a ꢀ3:2 ratio. This was evidenced from the
1H NMR of the crude reaction mixture, where besides
the signals for the (Z)-isomer (see Experimental),
showed also typical signals for the trans olefinic protons
at d 6.16 (dd, J2,3 = 15.7, J2,4 = 1.5 Hz) and 7.13 (dd,
J2,3 = 15.7 and J3,4 = 4.7 Hz), corresponding to 2-H
and 3-H of the (E)-isomer 16. Since it was not possible
In order to widen the scope of this study, the synthesis of
the stereochemically congested nitrone 5 was also under-
taken. This nitrone was obtained in 40% overall yield by
an analogous four-step reaction sequence (Scheme 4),
involving tritylation, Wittig olefination, PDC oxidation,
and treatment with hydroxylamine. The cis-enoate 20
was exclusively formed affording finally the nitrone 5.
The proton assignment of all nitrones was based on dou-
ble resonance experiments, while their stereochemistry
was proposed on the basis of the values of coupling

832
N. G. Argyropoulos et al. / Tetrahedron: Asymmetry 17 (2006) 829–836
10%
20%
11%
O
O
H
CH2COOtBu
H
H
N
H
N
H
H
H
20%
4
3
4%
H
CH2COOtBu
O
O
5%
O
O
4
3
Figure 2. NOE results of nitrones 3 and 4.
constants J4,5 and also from NOE experiments. Thus for
nitrones 1–3 and 5, the observed coupling constants
(J4,5 = 1.0 Hz) are in accordance with a trans-arrange-
ment of 4-H and 5-H protons whereas the higher value
J4,5 = 5.9 Hz in isomer 4 is in accordance with a cis-
arrangement. Furthermore, NOE experiments carried
out on compounds 3 and 4 showed that the saturation
of 4-H and 5-H protons of compound 4 results in a
strong mutual enhancement. On the contrary, in isomer
3 the observed enhancements are much smaller, whereas
saturation of 4-H and CH2 resulted in a strong mutual
enhancement, supporting their syn proximity (Fig. 2).
ered as more kinetically controlled than TS D in accor-
dance with other close related radical cyclizations.17
3. Conclusion
A convenient way for the synthesis of polyhydroxylated
chiral five-membered cyclic nitrones has been reported.
Based on the intramolecular 1,3-azaprotio cyclotransfer
reaction of appropriate oximino alkenoates, it has been
established that the nature of the alkene moiety (Z- or
E-form) determines the course of the cyclization step.
In this way, it is possible to manipulate the stereo chem-
istry of the newly generated asymmetric center of the
nitrone nucleus, by controlling the stereochemistry of
the alkene part, so affording stereochemically defined
pyrrolidine derivatives. Further work is planned to
widen the scope of this process.
The exclusive formation of anti-nitrones 1, 2, 3, and 5,
when the pure (Z)-enoates 10, 13, 17, and 21 were used,
shows that the stereochemistry of the starting enoates
determines the cyclization course. On the other hand,
since both isomers 3 and 4 were obtained starting from
the mixture of (Z)- and (E)-oxoenoates 17 and 18, it is
reasonable to assume that compound 17 is transformed
exclusively to anti nitrone 3, and compound 18 to the
syn nitrone 4.16 Inspection of the possible transition states
for the cyclization step of the intermediate (Z)- and (E)-
oximes (Fig. 3) shows that for the (Z) derivatives the
syn-isomer (TS B) is stereochemically congested, thus
favoring the formation of anti isomer (TS A). On the
other hand, both transition states C and D can be con-
sidered to have a similar stereochemical environment,
although TS C leading to the nitrone 4, may be consid-
4. Experimental
4.1. General remarks
All melting points are uncorrected and were obtained
with a Kofler hot stage apparatus. The IR spectra were
obtained with a Perkin–Elmer 297 spectrophotometer,
as a thin film or Nujol mull as indicated. The NMR
spectra, reported in d units, were obtained in deuterio-
chloroform solutions, with tetramethylsilane as internal
standard, and recorded with a Brucker AM 300 spec-
trometer, operating at 300 MHz (1H) and 75 MHz
(13C). The mass spectra were measured with a VG TS-
250 spectrometer with ionization energy of 70 eV. Ele-
mental analyses were performed with a Perkin–Elmer
CHN 2400 automatic analyzer. Optical rotations were
Ot
Bu
O
OH
H
OH
N
N
O
O
O
O
O
H
CH3
¨
measured with an A. KRUSS Optronic P3002, operat-
H3C
OtBu
H3C
CH3
ing at 589 nm (l = 1 dm, 25 °C). Several intermediates
were not obtained in analytically pure form, so that
when it was possible, they were characterized only by
their NMR data.
A
B
OH
H
OH
OtBu
H
N
N
OtBu
O
O
O
O
O
4.2. Synthesis of nitrone 1
O
CH3
CH3
H3C
H3C
4.2.1. 2,3-O-Isopropylidene-D-ribofuranose 6. This was
prepared following standard procedure8 from D-ribose
(12.5 g, 83 mmol), dry acetone (125 mL), and sulfuric
acid (0.3 mL). Yield 15.3 g (97%).
D
C
Figure 3. Possible transition states for the synthesis of nitrones 3 and
4.

N. G. Argyropoulos et al. / Tetrahedron: Asymmetry 17 (2006) 829–836
833
4.2.2. (3aS,6aS)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]-
dioxol-4-ol 8. To a cooled (ice bath) solution of D-ri-
bose monoacetonide 6 (30.76 g, 0.162 mol) in reagent
grade MeOH (200 mL), NaBH4 (9.18 g, 0.24 mol) was
added in small portions with stirring. Stirring was con-
tinued for an additional hour, then the reaction mixture
concentrated to give the crude ribitol derivative 7, which
was used in the next step without further purification.
(dd, 1H, J = 6.7, 11.6 Hz, 3-H), 9.48 (d, 1H,
J = 2.8 Hz, CH@O). 13C NMR: d, 27.3, 25.2
[C(CH3)2], 51.8 (OCH3), 81.9, 75.8 (C-4, C-5), 111.5
(OCMe2O), 122.6 (C-2), 143.8 (C-3), 165.9 (COOCH3),
199.3 (CH@O), MS: m/z (%): 214 (28) [M+].
4.2.5.
(3aR,4R,6aS)-4-(2-Methoxy-2-oxoethyl)-2,2-di-
methyl-4,6a-dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-5-ium-
5-olate 1. To a solution of 10 (13.0 g, 60.75 mmol) in
reagent grade MeOH (150 mL) and H2O (200 mL),
NH2OHÆHCl (5.5 g, 79.1 mmol) and NaHCO3 (7.65 g,
0.9 mmol) were added. The mixture was stirred at
25 °C for 12 h, extracted with CH2Cl2, the organic phase
dried over Na2SO4, and the residue was chromato-
graphed on a silica gel column (eluent EtOAc/hexane,
To a stirred solution of compound 7 in t-BuOH/H2O
(300/200 mL), NaIO4 (139.1 g, 0.65 mol) was added in
portions. Stirring was continued overnight at rt, then
CH2Cl2 (500 mL) was added and the reaction mixture
neutralized with solid NaHCO3. The solids were filtered
off, and the aqueous phase extracted with CH2Cl2. The
resulting organic phase was dried over Na2SO4, concen-
trated, and chromatographed on a silica gel column
(eluent hexane/EtOAc, 3:1) to give pure compound 8
(20.5 g, 79% from the starting compound 6) as an oil.
Spectral data are in agreement with the literature
values.11
2:1) to give pure nitrone 1 (8.5 g, 66%) as an analytical
25
pure colorless oil. Data for compound 1: ½aꢁD ¼ þ11:0
1
(c 1.46, CHCl3). IR (film): 3030, 1715, 1565 cmꢂ1. H
NMR: d, 1.39 (s, 3H, CH3) 1.47 (s, 3H, CH3), 2.99
(dd, 1H, J = 4.1, 17.6 Hz, CH2COOCH3), 3.13 (dd,
1H, J = 6.2, 17.6 Hz, CH2COOCH3), 3.71 (s, 3H,
COOCH3), 4.26 (ddd, 1H, J = 4.1, 6.2, 1.0 Hz, 5-H),
4.86 (dd, 1H, J = 6.5, 1.0 Hz, 4-H), 5.37 (d, 1H,
J = 6.5 Hz, 3-H), 6.95 (s, 1H, 2-H). 13C NMR: d, 25.4,
26.9 [C(CH3)2], 32.9 (CH2COOCH3), 51.9 (OCH3),
75.5 77.9, 78.7 (C-3, C-4, C-5), 112 (OCMe2O), 133.2
(C-2), 170 (C@O), MS: m/z (%): 229 (89) [M+]. Anal.
Calcd for C10H15NO5 (229.236): C, 52.40; H, 6.60; N,
6.11. Found: C, 52.70; H, 6.56; N, 6.25.
4.2.3. Methyl (Z)-3-[(4R,5S)-5-(hydroxy methyl)-2,2-di-
methyl-1,3-dioxolan-4-yl]-2-propenoate 9. A solution of
compound 8 (20.5 g, 0.128 mol), methoxycarbonyl-
methylenetriphenylphosphorane (59.8 g, 0.179 mol) and
benzoic acid (1 g) in dry CH2Cl2 was refluxed for 18 h.
The solvent was removed in vacuo and the residue chro-
matographed on a silica gel, column eluting with hex-
ane/EtOAc (8:1) to give compound 9 (16.58 g, 60%) as
analytically pure solid.
4.3. Synthesis of nitrone 2 ent-1
Data for compound 9: Mp 27–29 °C (from CH2Cl2/hex-
4.3.1. Methyl (Z)-3-{(4S,5R)-5-[(1R)-1,2-dihydroxyethyl]-
25
ane). ½aꢁD ¼ ꢂ140 (c 1.2, CHCl3). IR (Nujol): 3480 (br),
2,2-dimethyl-1,3-dioxolan-4-yl}-2-propenoate
CH2Cl2 solution (ꢀ150 mL) of 2,3-O-isopropylidene-D-
ribofuranose (8.1 g, 43 mmol), methoxycarbonyl
12. A
1700, 1630 cmꢂ1. 1H NMR: d, 1.41 (s, 3H, CH3), 1.54 (s,
3H, CH3), 2.17 (br s, 1H, OH), 3.46 (dd, 1H, J = 5.1,
11.7 Hz, CH2OH), 3.61 (dd, 1H, J = 3.6, 11.7 Hz,
CH2OH), 3.74 (s, 3H, COOCH3), 4.58 (ddd, 1H,
J = 7.1, 5.1, 3.6 Hz, 5-H), 5.6 (dt, 1H, J = 7.1, 1.6 Hz,
4-H), 5.97 (dd, 1H, J = 11.6, 1.6 Hz, 2-H), 6.41 (dd,
1H, J = 7.1, 11.6 Hz, 3-H). 13C NMR: d, 24.6, 27.3,
[C(CH3)2], 51.6 (OCH3), 61.4 (C-6), 74.8 (C-5), 78.8
(C-4), 108.9 (OCMe2O), 120.5 (C-2), 147.6 (C-3), 166.4
(C-1). MS: m/z (%): 216 (14) [M+]. Anal. Calcd for
C10H16O5 (216.23): C, 55.55; H, 7.46. Found: C, 55.41;
H, 7.37.
6
methylenetriphenyl phosphorane (15.5 g, 46.5 mmol),
and benzoic acid (1 g) was refluxed for 18 h. The solvent
was removed in vacuum and the residue was chromato-
graphed on silica gel (eluent hexane/EtOAc, 2:1) to give
compound 12 (10.5 g), contaminated with a minor
amount of E-isomer and traces of triphenylphosphine
oxide; this was used in the next step without further puri-
fication. A pure sample of compound 12 has the follow-
ing spectral data: Data for compound 12: IR (film): 3400
1
(br), 1715, 1635 cmꢂ1. H NMR: d, 1.38 (s, 3H, CH3),
1.49 (s, 3H, CH3), 3.63–3.76 (m, 3H, 6-H, 7-H), 3.74
(s, 3H, CO2CH3), 4.32 (dd, 1H, J = 6.7, 7.3 Hz, 5-H),
5.62 (dt, 1H, J3,4 = J4,5 = 7.3 Hz, J2,4 = 1.1 Hz, 4-H),
6.01 (dd, 1H, J = 1.1, 11.7 Hz, 2-H) 6.31 (dd, 1H,
J = 7.3, 11.7 Hz, 3-H). 13C NMR: d, 25.2, 27.4
[C(CH3)2], 51.8 (OCH3), 63.9, 70.2, 74.2, 78.7 (C-4, C-
5, C-6, C-7), 109.3 (OCMe2O), 121.6 (C-2),146 (C-3),
167.5 (C@O), MS: m/z (%): 246 (75) [M+].
4.2.4. Methyl (Z)-3-[(4R,5R)-5-formyl-2,2-dimethyl-1,3-
dioxolan-4-yl]-2-propenoate 10. To a solution of com-
pound 9 (2.0 g, 9.26 mmol) in dry CH2Cl2 (50 mL)
pyridinium dichromate (PDC) (5.2 g, 13.8 mmol), acti-
˚
vated molecular sieves 3 A (powder) (3.65 g) and dry
acetic acid (0.46 mL) were successively added, under
an argon atmosphere. The mixture was stirred at rt for
0.5 h, filtered under vacuum and the filtrate concen-
trated and passed over a silica gel column eluted with
hexane/CH2Cl2/EtOAc (6:3:1) to obtain compound
4.3.2. Methyl (Z)-3-[(4S,5S)-5-formyl-2,2-dimethyl-1,3-
dioxolan-4-yl]-2-propenoate 13. A mixture of the above
crude compound 12 (10.0 g), t-BuOH (115 mL), water
(85 mL) and NaIO4 (18.3 g, 85.5 mmol) was stirred vig-
orously at rt for 18 h. The crude reaction mixture was
triturated with excess of CH2Cl2, the solids were filtered
off and the organic layer was washed with satu-
rated NaHCO3 solution and dried over Na2SO4. After
10 (1.46 g, 74%) as an oil. Data for compound 10:
25
½aꢁD ¼ þ16:3 (c 0.65, CHCl3). IR (film): 1700,
1650 cmꢂ1 1H NMR: d, 1.45 (s, 3H, CH3), 1.61 (s,
.
3H, CH3), 3.76 (s, 3H, COOCH3), 4.8 (dd, 1H,
J = 2.8, 7.7 Hz, 5-H), 5.82 (ddd, 1H, J = 1.7, 6.7,
7.7 Hz, 4-H), 5.99 (dd, 1H, J = 1.7, 11.6 Hz, 2-H), 6.25

834
N. G. Argyropoulos et al. / Tetrahedron: Asymmetry 17 (2006) 829–836
evaporation of the solvent the residue was chromato-
graphed on a silica gel column (eluent hexane/EtOAc,
16 (1.5 g, 5.2 mmol) dissolved in t-BuOH (40 mL) and
water (20 mL), NaIO4 (2.25 g, 10.5 mmol) was added
in portions. Stirring was continued at rt for 17 h, then
the mixture was neutralized (NaHCO3), extracted with
CH2Cl2, and dried over MgSO4. After removal of the
solvent the residue was quickly passed through a flash
silica gel column eluting with hexane/EtOAc 4:1 to give
a mixture of enoates 17 and 18 (0.9 g, 70%). An analyt-
ically pure sample of (Z)-enoate 17 (0.15 g, 75%) was ob-
tained from the (Z)-ester 15 (0.2 g, 0.7 mmol), following
3:1) to give compound 13 (4.2 g, 46% from compound
25
7) as an oil. Data for compound 13: ½aꢁD ¼ ꢂ15:5
(c 0.7, CHCl3). IR (film): 1700, 1650 cmꢂ1
.
1H
NMR: d, 1.45 (s, 3H, CH3), 1.61 (s, 3H, CH3), 3.76 (s,
3H, COOCH3), 4.8 (dd, 1H, J = 2.8, 7.7 Hz, 5-H),
5.82 (ddd, 1H, J = 1.7, 6.7, 7.7 Hz, 4-H), 5.99 (dd, 1H,
J = 1.7, 11.6 Hz, 2-H), 6.25 (dd, 1H, J = 6.7, 11.6 Hz,
3-H), 9.48 (d, 1H, J = 2.8 Hz, 6-H). 13C NMR: d,
25.2, 27.3 (C(CH3)2), 51.8 (OCH3), 75.8, 81.9 (C-4, C-
5), 111.5 (OCMe2O), 122.6 (C-2), 143.8 (C-3), 165.9
(CO2CH3), 199.3 (CH@O). MS: m/z (%): 214 (28) [M+].
the same procedure. Data for compound 17:
25
½aꢁD ¼ ꢂ6:35 (c 1.98, CHCl3). IR (film): 1720 (br),
1630 cmꢂ1 1H NMR: d, 1.43 (s, 3H, CH3), 1.60 (s,
.
3H, CH3), 1.49 [s, 9H, C(CH3)3], 4.88 (dd, 1H, J = 6.6,
3.0 Hz, 5-H), 5.81 (ddd, 1H, J = 6.6, 8.0, 2.4 Hz, 4-H),
5.88 (dd, 1H, J = 2.4, 11.5 Hz, 2-H), 6.14 (dd, 1H,
J = 6.6, 11.5 Hz, 3-H), 9.46 (d, 1H, J = 2.4 Hz, CH@O).
13C NMR: d, 25.0, 27.1, 28.0 (C(CH3)2, C(CH3)3),
75.5, 81.2, 81.7 (OCMe3, C-4, C-5), 111.1 (OCMe2O),
124.7 (C-3), 142.1 (C-4), 164.7 (CO2t-Bu), 198.9
(CH@O). MS: m/z (%) 256 (11) [M+]. Anal. Calcd for
C13H20O5 (256.29): C, 60.92; H, 7.89. Found: C, 60.67;
H, 7.64.
4.3.3.
(3aS,4S,6aR)-4-(2-Methoxy-2-oxoethyl)-2,2-di-
methyl-4,6a-dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-5-ium-
5-olate 2. To a solution of 9 (3.39 g, 15.85 mmol) in
reagent grade MeOH containing NaHCO3 (2 g, 23.76
mmol), NH2OHÆHCl (1.43 g, 20.6 mmol) was added.
The mixture was stirred at 25 °C for 12 h, extracted with
CH2Cl2, the organic phase dried over Na2SO4 and after
evaporation of the solvent, the residue was chromato-
graphed on a silica gel column, using a gradient from
EtOAc/hexane 2:1 to pure EtOAc and gave the nitrone
2 (2.4 g, 66%) as an analytically pure colorless oil. Data
4.4.3. (3aS,4S,6aR)-4-[2-(tert-Butoxy)-2-oxoethyl]-2,2-
dimethyl-4,6a-dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-5-
ium-5-olate 3 and (3aS,4R,6aR)-4-[2-(tert-butoxy)-2-oxo-
ethyl]-2,2-dimethyl-4,6a-dihydro-3aH-[1,3]dioxolo[4,5-
c]pyrrol-5-ium-5-olate 4. To a stirred solution of the
above mixture of (Z)- and (E)-esters 17 and 18 (0.54 g,
2.1 mmol) in methanol (15 mL), NH2OHÆHCl (0.2 g,
2.8 mmol), and NaHCO3 (0.3 g, 3.2 mmol) were succes-
sively added, with stirring at rt. Stirring was continued
for about 12 h, then the mixture extracted with CH2Cl2,
the organic phase was dried over MgSO4, concentrated,
and the residue was chromatographed on a silica gel col-
umn (eluent hexane/EtOAc, 1:4). Nitrone 3 (0.25 g) was
eluted first, followed by the nitrone 4 (0.17 g) both as
colorless oils. Total yield 70%. Following the same pro-
cedure from a pure sample of compound 17 (0.05 g,
25
for compound 2: ½aꢁD ¼ ꢂ12:4 (c 1.55, CHCl3). Anal.
Calcd for C10H15NO5 (229.23): C, 52.40; H, 6.60; N,
6.11. Found: C, 52.12; H, 6.57; N, 6.30. Spectral data
are identical to that of nitrone 1.
4.4. Synthesis of nitrones 3 and 4
4.4.1. (Z)- and (E)-tert-Butyl-3-{(4S,5R)-5-[(1R)-1,2-
dihydroxyethyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-2-pro-
penoates 15 and 16. These compounds were obtained
as a mixture from the reaction of 2,3-O-isopropylidene
D-ribofuranose 6 (1.98 g, 10.4 mmol) and phosphorane
14 (4.7 g, 12.5 mmol), according to the procedure
described for the synthesis of compound 12 and purified
by column chromatography (silica gel, hexane/EtOAc,
6:1) to give a mixture of both esters 15 and 16 (1.6 g,
70%) together with traces of Ph3PO, which was used
for the next step.
0.18 mmol) nitrone 3 was exclusively isolated in 68%
25
yield. Data for nitrone 3: ½aꢁD ¼ ꢂ3:1 (c 3.4, CHCl3).
1
IR (film): 3070, 1720, 1560 cmꢂ1. H NMR: d, 1.39 (s,
3H, CH3), 1.45 [s, 9H, C(CH3)3], 1.47 (s, 3H, CH3),
2.94 (d, 2H, J = 5.1 Hz, CH2CO2t-Bu), 4.21 (t, 1H,
J = 5.1 Hz, 5-H), 4.84 (d, 1H, J = 6.5 Hz, 4-H), 5.35
(d, 1H, J = 6.5 Hz, 3-H), 6.92 (s, 1H, 2-H). 13C NMR:
d, 28.0, 27.1, 25.6 [C(CH3)2, C(CH3)3], 34.5 (CH2CO2t-
Bu), 76.0, 78.2, 78.8, 82.0 (OCMe3, C-3, C-4, C-5),
112.0 (OCMe2O), 133.0 (C@N), 168.8 (CO2t-Bu). MS:
m/z (%): 271 (6) [M+]. Anal. Calcd for C13H21NO5
(271.31): C, 57.55; H, 7.80; N, 5.16. Found: C, 57.68;
H, 7.75; N, 4.96.
An analytically pure sample of Z-ester 15 was obtained
as a colorless oil after repeated chromatographic separa-
tions of the mixture of esters 15 and 16. Data of (Z)-
25
ester 15: ½aꢁD ¼ þ92:3 (c 1.24, CHCl3). IR (film):
1
3360–3260 (br), 1695 cmꢂ1. H NMR: d, 1.39 (s, 3H,
CH3), 1.51 (s, 3H, CH3), 1.48 (s, 9H, C(CH3)3), 3.63–
3.82 (m, 3H, 6-H, 7-H), 4.33 (dd, 1H, J = 6.5, 8.3 Hz,
5-H), 5.48 (ddd, 1H, J = 1.0, 6.5, 8.5 Hz, 4-H), 5.97
(dd, 1H, J = 1.0, 11.6 Hz, 2-H), 6.17 (dd, 1H, J = 8.5,
11.6 Hz, 3-H). 13C NMR: d, 26.0, 28.0 [C(CH3)3,
C(CH3)2], 64.9, 70.5 (C-6, C-7), 75.4, 79.8 (C-4, C-5),
83.0 (OCMe3), 110.2 (OCMe2O), 124.0 (C-3), 145.0
(C-2), 167.5 (C@O). MS: m/z (%): 231 (Mꢂt-Bu, 6).
Anal. Calcd for C14H24O6 (MW 288.34): C, 58.32; H,
8.39. Found: C, 58.19; H, 8.42.
25
Data for nitrone 4: ½aꢁD ¼ ꢂ62:1 (c 1.76, CHCl3). IR
(film): 3100, 1710, 1575 cmꢂ1 1H NMR: d, 1.38 (s,
.
3H, CH3), 1.43 (s, 3H, CH3), 1.48 (s, 9H, C(CH3)3),
2.77 (dd, 1H, J = 9.9, 17.1 Hz, CH2CO2t-Bu), 3.22
(dd, 1H, J = 4.6, 17.1 Hz, CH2CO2t-Bu ), 4.40–4.47
(m, 1H, 5-H), 5.0 (dd as t, 1H, J = 5.9 Hz, 4-H), 5.28
(d, 1H, J = 5.9 Hz, 3-H), 6.87 (s, 1H, 2-H). 13C NMR:
d, 25.7, 26.9, 27.8, 27.9 [C(CH3)2, C(CH3)3], 32.0
(CH2CO2t-Bu ), 71.5, 74.9, 77.7, 81.2 (OCMe3, C-3, C-
4.4.2. (Z)- and (E)-tert-Butyl-3-[(4S,5S)-5-formyl-2,2-
dimethyl-1,3-dioxolan-4-yl]-2-propenoate 17 and 18. To
a stirred solution of the above mixture of esters 15 and

N. G. Argyropoulos et al. / Tetrahedron: Asymmetry 17 (2006) 829–836
835
4, C-5), 111.9 (OCMe2O), 131.4 (C@N), 169.6 (C@O).
MS: m/z (%): 271 (22) [M+]. Anal. Calcd for
C13H21NO5 (271.31): C, 57.55; H, 7.80; N, 5.16. Found:
C, 57.66; H, 7.65, N, 4.86.
122.7, 127.2, 127.9, 128.5, 143.0, 143.3 (C-aromatic, C-2,
C-3), 165.6 (COOCH3), 203.7 (C@O). MS: m/z (%): 486
(23) [M+]. Anal. Calcd for C30H30O6 (486.56): C, 74.06,
H, 6.21. Found: C, 74.40; H, 6.30.
4.5. Synthesis of nitrone 5
4.5.4.
(3aS,4S,6aR)-4-(2-Methoxy-2-oxoethyl)-2,2-di-
methyl-6-[(trityloxy)methyl]-4,6a-dihydro-3aH-[1,3]diox-
olo[4,5-c]pyrrol-5-ium-5-olate 5. This compound was
obtained as oil in 90% yield, according to the procedure
described for compound 1 from compound 22 (0.70 g,
1.44 mmol), NH2OHÆHCl (0.135 g, 1.94 mmol), NaH-
CO3 (0.185 g, 2.2 mmol) in EtOH (20 mL) and purified
4.5.1. (3aR,6R,6aR)-2,2-Dimethyl-6-[(trityloxy)methyl]-
tetrahydrofuro[3,4-d][1,3]dioxol-4-ol 19. To a cooled
(0 °C) solution of compound 6 (7.0 g, 36.84 mmol) in
dry DMF (47 mL), dry NEt3 (10 mL), DMAP
(230 mg, 1.89 mmol) and trityl chloride (11.4 g,
41 mmol) were successively added with stirring under
an argon atmosphere. Stirring was continued at rt for
24 h, then the crude mixture poured on ice-water
(200 mL), extracted with CH2Cl2, the organic phase
was washed with a saturated NH4Cl solution, then with
water, dried over Na2SO4, and evaporated. Column
chromatography on silica gel (eluent hexane/EtOAc,
6:1) of the residue gave compound 19 (11 g, 69%) as
an oil; this was used without further purification in the
next step.
by column chromatography on silica gel (eluent hex-
25
ane/EtOAc, 3:1). Data for compound 5: ½aꢁD ¼ þ5:0
1
(c 0.38, CHCl3). IR (film): 1740, 1600 cmꢂ1. H NMR:
d, 1.45 (s, 3H, CH3), 1.46 (s, 3H, CH3), 2.87 (dd, 1H,
J = 6.9, 17.4 Hz, CH2COOCH3), 2.96 (dd, 1H, J = 4.3,
17.4 Hz, CH2COOCH3), 3.68 (s, 3H, COOCH3), 4.2
(s, 2H, TrOCH2), 4.26 (unresolved multiplet, 1H, 5-H),
4.73 (dd, 1H, J = 1.0, 6.5 Hz, 4-H), 5.57 (d, 1H,
J = 6.5 Hz, 3-H), 7.21–7.5 (m, 15H aromatic protons).
13C NMR: d, 25.8, 27.1 (C(CH3)2), 33.5 (CH2COOCH3),
52 (OCH3), 58.7 (C-5), 75.6, 76.7, 79.9 (CH2COOCH3,
C-3, C-4), 87.4 (CPh3), 112.0 (OCMe2O), 127.2, 127.9,
128.7, 143.3, 144.6 (C@N, aromatic carbons) 170.1
(C@O). MS: m/z (%): 471 (100) [M+ꢂ31]. Anal. Calcd
for C30H31NO6 (MW 501.57): C, 71.84; H, 6.23; N,
2.79. Found: C, 71.61; H, 6.15; N, 2.89.
4.5.2. Methyl (Z)-3-{(4S,5R)-5-[(1R)-1-hydroxy-2-(trityl-
oxy)ethyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-2-propenoate
20. Following the same procedure described for the
synthesis of compound 9 this compound was obtained
as an oil (1.54 g, 91%) from compound 19 (1.5 g,
3.47 mmol) and methoxycarbonylmethylenetriphenyl
phosphorane (1.70 g, 5 mmol) and purified by column
chromatography on silica gel (eluent hexane/CH2Cl2/
EtOAc, 7:3:1). Data for compound 20: IR (film):
Acknowledgments
3460 (br), 3080, 3050, 3020, 1715, 1640, 1590 cmꢂ1
.
We are grateful to the State Scholarship Foundation of
Greece for financial support.
1H NMR: d, 1.33 (s, 3H, CH3), 1.34 (s, 3H, CH3),
2.69 (d, 1H, J = 3.9 Hz, OH), 3.28 (m, 2H, TrOCH2),
3.69 (s, 3H, COOCH3), 3.69–3.74 (m, 1H, 6-H), 4.41
(dd, 1H, J = 6.5, 7.5 Hz, 5-H), 5.69 (ddd, 1H,
J = 6.5, 8.0, 1.5 Hz, 4-H), 5.92 (dd, 1H, J = 1.5,
10.5 Hz, 2-H), 6.18 (dd, 1H, J = 8.0, 10.5 Hz, 3-H),
7.2–7.46 (m, 15H, aromatic protons). 13C NMR: d,
27.5, 25.2 [C(CH3)2], 51.5 (OCH3), 64.8, 69.7, 74.0,
78.6, 86.6 (Ph3CO, TrOCH2, C-4, C-5, CHOH), 109.0
(OCMe2O), 121.5, 126.9, 127.7, 128.6, 143.7, 145.1
(C-2, C-3, C aromatic), 166.4 (CO2Me). MS: m/z (%):
488 (14) [M+]. Anal. Calcd for C30H32O6 (488.58): C,
73.75; H, 6.60. Found: C, 73.41; H, 6.40.
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