Stereospecific N-oxide-mediated monoprotection of trans-3,4-dihydroxypyrrolidine derivatives

Article abstract of DOI:10.1016/j.tetasy.2007.08.022

We found that the syntheses of O-monosubstituted 1-N-alkyl-trans-3,4-dihydroxypyrrolidines, normally faces serious obstacles due to poorly reactive hydroxy groups as a consequence of the presence of a highly basic pyrrolidine nitrogen atom, but that they

Full text of DOI:10.1016/j.tetasy.2007.08.022

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2165–2174
Stereospecific N-oxide-mediated monoprotection of
trans-3,4-dihydroxypyrrolidine derivatives
a
a
Dominik Rejman,a, Petr Kocˇalka, Milosˇ Budeˇsˇınsky,
´
*
´
b
a,
*
´
Ivan Barvık, Jr. and Ivan Rosenberg
aInstitute of Organic Chemistry and Biochemistry, Academy of Sciences, Flemingovo na´m. 2, 166 10 Prague 6, Czech Republic
bCharles University, Faculty of Mathematics and Physics, Institute of Physics, Ke Karlovu 5, 12116 Prague 2, Czech Republic
Received 2 July 2007; accepted 20 August 2007
Abstract—We found that the syntheses of O-monosubstituted 1-N-alkyl-trans-3,4-dihydroxypyrrolidines, normally faces serious obsta-
cles due to poorly reactive hydroxy groups as a consequence of the presence of a highly basic pyrrolidine nitrogen atom, but that they can
be obtained easily in high yields by conversion of 1-N-alkyl-trans-3,4-dihydroxypyrrolidines into the corresponding N-oxides. N-Oxida-
tion leads to the loss of the pyrrolidine nitrogen atom basicity and discrimination in the reactivity of the originally equivalent hydroxy
groups by at least one order of magnitude. The reaction of N-oxide derivatives with DMTrCl or TBDPSCl then proceeds in an almost
quantitative yield, rapidly, and stereospecifically on the hydroxy group which is in a cis-position to the N-oxide oxygen atom. In contrast
to the TBDPS derivative, the DMTr derivative could be easily deoxygenated with triphenylphosphine in high yield. The structures of the
products obtained were confirmed by 2D NMR experiments, and quantum-chemical calculations were performed to explain the reaction
mechanism of the stereospecific course of the reaction.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ether in THF, using sodium hydride to generate the alkox-
ide, led to a 61% yield of the monoprotected derivative.20
The benzoylation of 1-N-benzyl-trans-3,4-dihydroxypyrr-
olidine with benzoyl chloride in DMF, and in the presence
of triethylamine gave, by recycling of unreacted dihydroxy-
pyrrolidine and bis-benzoyl derivative, a final 90% yield of
the monobenzoyl derivative, but the authors did not spec-
ify the number of cycles.21
Enantiomeric trans-3,4-dihydroxypyrrolidines and their
derivatives are important precursors for the stereospecific
synthesis of biologically active compounds such as anti-
tumor agents1 and inhibitors of glycosidases,2 anti-protozoa
compounds,3 or as building blocks for the synthesis of chi-
ral catalysts.4 The pyrrolidine ring has also been employed
as a sugar mimic in analogues of nucleosides.5–18
An attempt to selectively protect one hydroxy group of
(3S,4S)-trans-1-N-benzyl-3,4-dihydroxypyrrolidine 1a18,22,23
with DMTr (dimethoxytrityl) or TBDPS (tert-butyl-
diphenylsilyl) protecting groups under various conditions,
has led to a moderate yield of the desired product which,
in our hands, has never exceeded 55%.18 The disubstituted
derivative and the unreacted starting material were always
present in the reaction mixture.
The synthesis of O-monosubstituted 1-N-alkyl-trans-3,4-
dihydroxypyrrolidines in high yields represent a serious
problem due to the presence of equally reactive hydroxy
groups. For instance, the silylation of 1-N-benzyl-trans-
3,4-dihydroxypyrrolidine with TBDMSCl in DMF in the
presence of imidazole afforded only 21% of the mono-
silylated product.19 However, the alkylation of the same
pyrrolidine derivative with chloromethyl-2-methoxyethyl
Based on the above-mentioned facts, the problem which
we wanted to address in this paper concerned the influence
of the N-oxide oxygen atom on the reactivity of the
otherwise equally reactive hydroxy groups in trans-3,4-
dihydroxypyrrolidine.
*
Corresponding authors. Tel.: +420 220 183 381; fax: +420 220 183 578
(I.R.); e-mail addresses: rejman@uochb.cas.cz; ivan@uochb.cas.cz
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.08.022

2166
D. Rejman et al. / Tetrahedron: Asymmetry 18 (2007) 2165–2174
2. Results and discussion
2.1. Synthesis
(3S,4S)-N-Benzyl-3,4-dihydroxypyrrolidine 1a18,22,23 was
converted to its 1-N-oxido derivative 4a by treatment with
a mixture of 30% hydrogen peroxide and ethanol (1:1)
overnight (Scheme 1). The N-oxide 4a was reacted with
DMTrCl or TBDPSCl, respectively, in pyridine. The reac-
tion was left to proceed overnight (quantitative conver-
sion), although the majority of starting material (ꢀ90%)
was consumed, in contrast to the dimethoxytritylation of
1a, within the first five minutes, as determined by HPLC
(for the reaction profile see Fig. 1).
We also attempted the tosylation and benzoylation of com-
pound 4a to obtain the appropriate mono-derivative, but in
this case the reaction gave a mixture of products.
An NMR study showed that only one diastereoisomeric
dimethoxytrityl derivative, 5a, was formed. It was subse-
quently silylated with TBDPSCl in pyridine to provide
compound 6, which in turn was detritylated with 80%
aqueous acetic acid to give silyl derivative 9. This com-
pound was also obtained as the only product by the oxida-
tion of 3 with hydrogen peroxide (Scheme 1). In this case,
the oxidation proceeded with 100% stereoselectivity. The
silyl derivative 7, with the same stereochemistry as 5a was
obtained from 4a and TBDPSCl. This compound was
dimethoxytritylated to give the fully protected compound
8. Both 8 and 9 served as compounds for assignment of
the configuration on the nitrogen atom of the N-benzyl-
N-oxido moiety. To confirm a more general validity of
the described procedure and in order to avoid the influence
of N-benzyl group on the stereochemical course of the
Figure 1. Kinetics of dimethoxytritylation of pyrrolidine 1a and 4a to
monodimethoxytrityl derivatives 2a and 5a, respectively.
reaction, 1-N-methyl-3,4-dihydroxypyrrolidine24 1b and
its N-oxido derivative 4b were prepared. Dimethoxytrityl-
ation of 4b to 5b proceeded in the same manner and with
the same stereochemistry (only one diastereoisomer was
formed), as in case of the 1-N-benzyl derivative 4a.
In order to obtain more information about the reaction
mechanism, we carried out an experiment with a diastereo-
isomeric mixture of (1RS,3R)-N-benzyl-3-hydroxypyrrol-
idine-N-oxides 11 and 12 (73:27) prepared by the
oxidation of (3S)-N-benzyl-3-hydroxypyrrolidine 107
Bn
R
N
R
Bn
O
N
N
N
ii
i
iii
9
TBDPSO
OH
O
HO
1a R= Bn
1b R= CH3
OH DMTrO
OH
2a R = Bn
2b R = CH3
HO
9
OTBDPS
3
v
iii
iv
X
Bn
O
Bn
O
R
O
N
Bn
O
R
N
N
N
N
i
i
ii
ii
TBDPSO
ODMTr TBDPSO
OH
HO
4a R= Bn
4b R= CH3
OH DMTrO
OH DMTrO
5a R= Bn
5b R= CH3
OTBDPS
8
7
6
Scheme 1. Reagents: (i) DMTrCl, pyridine; (ii) TBDPSCl, pyridine; (iii) 30% H2O2/EtOH 1:1; (iv) Ph3P, DCM; (v) 80% aq acetic acid.
Bn
N
Bn
N
Bn
O
O
Bn
O
Bn
ii
N
N
N
i
iii
+
73%
11
27%
HO
HO
HO
DMTrO
DMTrO
10
12
14
13
Scheme 2. Reagents: (i) 30% H2O2/EtOH 1:1; (ii) DMTrCl, pyridine; (iii) Ph3P, DCM.

D. Rejman et al. / Tetrahedron: Asymmetry 18 (2007) 2165–2174
2167
(Scheme 2). Dimethoxytritylation of the mixture of 11 and
12 afforded only one diastereoisomeric DMTr derivative
13, along with the unreacted compound 12.
carbon atoms bonded to nitrogen and also of the hydrogen
atoms at vicinal positions (0.8–1.6 ppm) in comparison
with analogous derivatives without oxygen. The larg-
est low-field effect (ca. 85 ppm) can be observed in 15N
NMR as it is documented on a pair of compounds: 1b
(ꢁ337.9 ppm) and 4b (ꢁ251.9 ppm).
We also attempted to remove the N-oxide oxygen atom
from O-DMTr derivatives 5a and 13, as well as from the
O-TBDPS derivative 7, using the reaction with triphenyl-
phosphine.25 Whereas the deoxygenation proceeded
smoothly in case of the DMTr derivatives 5a and 13, the
TBDPS derivative 7 was quite resistant; also the reduction
of 7 with samarium diiodide26 failed.
A much more difficult task was encountered with the deter-
mination of the configuration at the nitrogen atom of the
N-oxides due to the absence of relevant interproton cou-
pling constants and the possible flexibility of the pyrroli-
dine ring. Therefore, we had to combine the observed
endocyclic vicinal J(H,H) and NOE-contacts (from 2D-
ROESY spectra) in order to determine first the relative
(cis- and trans-) orientation of methylene hydrogen atoms
at the 2- and 5-positions to the substituents at the 3- and
4-positions, as well as the conformational features of the
pyrrolidine ring. Then we had to find the NOE contacts
of methyl protons of the N–CH3 group and/or methylene
protons of the N-benzyl group to the hydrogen atoms at
the 2- and 5-positions for the determination of configura-
tion at the nitrogen atom. The NMR analysis for com-
pound 5a is illustrated in Figure 2. The coupling pattern
observed in 2D-H,H-COSY spectrum and J(H,H) values
(see Fig. 2a) leads to the assignment of the endocyclic pro-
tons in the 2-, 3-, 4-, and 5-positions. The observed NOE
contacts H-4/H-2a, H-3/H-5a, and H-2b/H-5a indicate
mutual cis-orientation of those pairs of protons and lead
to the stereochemical assignment of methylene protons at
C-2 and C-5. Then, the NOE contacts between the hydro-
gens of N-benzyl methylene group and the hydrogen atoms
H-2b, H-5a define the configuration at the N-oxide nitro-
gen atom, as it is shown in Figure 2b.
2.2. NMR analysis
The structure and purity of all the pyrrolidine derivatives
were analyzed by means of 1H and 13C NMR spectra.
The presence of an oxygen atom in the N-oxides can be
detected indirectly by the low-field shifts (10–15 ppm) of
C6H5
CH2
C6H5
a
b
O
4.09
CH2
(2H)
O
NOE
NOE
12.8
2.92
H
3.21
H
10.8
N
H-2b
H-5a
H-5b
NOE
1.84
H
3.33
H
2
5
H-2a
1.5
8.2
4.2
4
3
4.05
H
OH
DMTrO
OH
6.8
NOE
NOE
H-3
9.0
DMTrO
H-4
H
4.86
5.0
Figure 2. NMR structure analysis of compound 5a: (a) Proton chemical
shifts and coupling constants (indicated with dashed arrows); (b) selected
non-trivial NOE’s allowing for the stereochemical assignment of
hydrogens at C-2, C-5 and determination of the relative configurations
of N-benzyl group and substituents (OH, ODMTr).
A similar approach was used to establish the configuration
of other N-oxides. No NOE contacts were observed
1
Table 1. H NMR parameters of compounds 1–14 (coupling constants J(H,H) are given in italics)
Compound solvent
H-2
H-20
H-3
H-4
H-5
H-50
1aa
2.76 dd
9.5; 4.4
2.70 dd
9.6; 6.0
2.32 dd
9.5; 5.9
2.24 dd
9.6; 4.0
1.56 dd
10.3; 4.5
1.61 dd
10.3; 4.1
2.38 dd
9.8; 4.1
3.35 dt
12.3; 2.3; 1.9
3.27 dd
11.8; 4.4
1.84 dd
12.8; 4.2
2.67 m
12.9; 2.8; 1.4
1.67 ddd
12.3; 4.5; 1.5
2.96 ddd
12.1; 4.2; 1.3
3.85 dd
5.9; 4.4
3.82 dd
6.0; 4.0
3.85 dd
5.9; 4.4
3.82 dd
6.0; 4.0
4.14 m
6.2; 5.9; 4.6; 3.1
4.12 m
6.1; 4.5; 2.8
4.10 m
6.0; 5.2; 3.8; 2.4
4.33 dt
2.4; 6.3; 6.1
3.94 dt
4.4; 1.0; 0.9
4.86 dq
9.0; 6.8; 5.0
4.62 ddd
6.7; 5.9; 3.6
5.33 dt
9.7; 6.0; 6.0
4.67 m
2.76 dd
9.5; 4.4
2.70 dd
9.6; 6.0
2.63 dd
9.5; 6.2
2.67 dd
9.6; 6.1
2.32 dd
9.5; 5.9
2.24 dd
9.6; 4.0
2.23 dd
9.5; 4.6
2.23 dd
9.6; 4.5
DMSO
1bb
DMSO
2ac
1.69 dd
10.3; 6.5
1.80 dd
10.3; 6.4
2.57 dd
9.8; 5.7
4.02 dd
12.3; 6.6
3.88 ddd
11.8; 6.6; 2.1
2.92 dd
12.8; 8.2
3.26 dd
12.9; 7.0
2.98 dd
12.3; 8.6
3.70 dd
12.1; 7.9
3.78 ddd
6.5; 4.5; 3.1
3.82 ddd
6.4; 4.1; 2.8
4.08 ddd
5.7; 4.1; 2.4
4.09 dt
6.6; 2.4; 2.3
4.38 ddd
6.6; 4.4; 1.0
4.05 ddd
8.2; 5.0; 4.2
4.18 ddd
7.0; 3.6; 2.8
4.33 m
DMSO
2bd
DMSO
3e
2.36 dd
9.8; 3.8
2.82 dd
9.8; 6.0
DMSO
4af
3.75 ddd
11.8; 6.3; 1.9
3.69 dd
11.2; 4.4
3.33 dd
10.8; 6.8
3.82 ddd
11.7; 5.9; 1.4
3.14 td
10.0; 9.7; 1.5
3.30 br dd
10.9; 7.3
3.45 dd
11.8; 6.1
3.25 ddd
11.2; 2.1; 0.9
3.21 dd
10.8; 9.0
3.45 dd
11.7; 6.7
2.52
DMSO
4bg
DMSO
5ah
DMSO
5bi
DMSO, 50 ꢁC
6j
DMSO
7k
8.6; 6.0; 4.5
4.24 dt
7.9; 4.2; 4.0
10.0; 6.0
3.20 ddd
10.9; 6.2; 1.3
DMSO
7.3; 6.2; 4.0
(continued on next page)

2168
D. Rejman et al. / Tetrahedron: Asymmetry 18 (2007) 2165–2174
Table 1 (continued)
Compound solvent
H-2
H-20
H-3
H-4
H-5
H-50
8l
2.60 um
ꢀ12.0; 6.6
3.76 dd
11.0; 4.4
2.65 dd
9.6; 6.2
2.44 um
4.56 td
4.74 br q
6.8; 6.4; 4.3
4.49 ddt
6.4; 4.9; <1.5; <1.5
1.53 m
13.0; 7.8; 5.6; 3.4
1.98 m
3.26 dd
12.0; 6.8
3.43 dd
11.6; 4.9
2.54 ddd
8.8; 7.8; 6.5
3.08 br dd
12.0; 6.4
3.47 ddd
11.6; 6.4; 1.9
2.38 ddd
8.8; 7.9; 5.6
CDCl3
9m
ꢀ12.0; 6.6
6.6; 6.6; 4.3
4.07 br d
4.4; <1.5
4.18 m
7.8; 6.2; 3.8; 3.4
3.06 dt
DMSO
10n
11.0; 1.9; <1.5
2.28 dd
9.6; 3.8
DMSO
13.0; 7.9; 7.8; 6.5
2.09 dddd
11o
3.40 dd
3.00 dd
4.26 m
3.51 td
3.28 ddd
DMSO (73%)
10.7; 4.3
10.7; 1.8
6.9; 4.3; 1.8; 0.9
13.6; 9.2; 8.0; 0.9
2.29 dddd
10.7; 10.7; 8.0
10.7; 9.2; 3.5
13.6; 10.7; 6.9; 3.5
1.65 ddt
12p
3.22 dd
3.19 dd
4.55 ddd
3.62 td
2.94 ddd
DMSO (27%)
11.0; 5.8
11.0; 6.4
7.9; 5.8; 2.3
13.2; 8.0; 2.3; 2.3
2.54 ddt
10.5; 10.5; 8.0
10.5; 7.9; 2.3
13.2; 10.5; 7.9; 7.9
2.35 m
13q
3.18 dd
2.43 m
4.30 td
3.30 td
3.18 m
DMSO, 50 ꢁC
12.5; 8.2
12.5; 3.3; 2.5
8.5; 8.2; 6.5
12.6; 11.4; 7.8; 6.5
2.00 m
11.4; 11.4; 6.6
11.4; 8.3
7.8; 2.5
12.6; 8.5; 8.3; 6.6
1.42 m
14r
2.17 dd
2.04 dd
4.03 m
2.37 ddd
2.24 ddd
DMSO
9.9; 6.8
9.9; 4.9
8.1; 6.8; 4.9; 4.3
13.4; 8.1; 5.7; 4.3
1.58 m
9.0; 8.1; 6.5
9.0; 7.5; 5.7
13.4; 8.1; 7.5; 6.5
Additional protons.
a NBn: 3.60 d (1H), 3.49 d (1H), 7.22–7.33 m (5H), OH: 4.56 b (2H).
b NCH3: 2.17 s, OH: 4.80 b (2H).
c Bn: 3.31 d (1H), 3.26 d (1H), 7.25 m (2H), 7.19 m (1H), 7.10 m (2H), ODMTr: 6.83 m (2H), 6.84 m (2H), 7.19 m (1H), 7.26 m (2H), 7.28 m (2H), 7.29 m
(2H), 3.71 s (3H), 3.715 s (3H).
d OH: 4.95 b (1H), ODMTr: 6.88 m (4H), 7.28 m (2H), 7.31 m (2H), 7.43 m (2H), 7.30 m (2H), 7.22 m (1H), 3.74 s (6H).
e NBn: 3.56 d (1H), 3.43 d (1H), 7.19–7.29 m (5H), OTBDPS: 1.01 s (9H), 7.36–7.46 m (6H), 7.59 m (2H), 7.65 m (2H), OH: 4.97 d (1H, J = 5.2).
f NBn: 4.64 d (1H), 4.67 d (1H), 7.36–7.42 m (3H), 7.57 m (2H).
g NCH3: 3.15 s (3H).
h NBn: 4.09 br s (2H), 7.27 m (2H), 7.28 m (2H), 7.34 m (1H), ODMTr: 6.81 m (2H), 6.83 m (2H), 7.20 m (1H), 7.27 m (2H), 7.33 m (2H), 7.48 m (4H), 3.72
s (3H), 3.73 s (3H).
i NCH3: 3.14 s (3H), ODMTr: 6.89 m (2H), 6.90 m (2H), 7.25 m (1H), 7.29 m (2H), 7.31 m (2H), 7.32 m (2H), 7.44 m (2H), 3.73 s (3H), 3.74 s (3H).
j NBn: 3.81 d (1H), 3.85 d (1H), 7.11 m (2H), 7.20 m (2H), 7.29 m (1H), OTBDPS: 7.81 m (2H), 7.67 m (2H), 7.55 m (1H), 7.50 m (1H), 7.48 m (2H), 7.42 m
(2H), 1.09 s (9H), ODMTr: 6.75 m (2H), 6.79 m (2H), 7.24 m (2H), 7.29 m (2H), 7.20–7.45 m (5H), 3.73 s (3H), 3.71 s (3H).
k NBn: 4.21 d (1H), 4.18 d (1H), 7.37–7.46 m (2H), 7.28 m (2H), 7.34 m (1H), OTBDPS: 7.65 m (2H), 7.60 m (2H), 7.37–7.46 m (5H), 7.34 m (1H), 1.10 s
(9H).
l NBn: 4.15 br d (1H), 3.98 br d (1H), 7.18–7.33 m (5H), OTBDPS: 7.74 m (2H), 7.67 m (2H), 7.48 m (1H), 7.45 m (1H), 7.38 m (2H), 7.37 m (2H), 1.10 s
(9H), ODMTr: 6.76 m (2H), 6.74 m (2H), 7.29 m (2H), 7.32 m (2H), 7.18–7.45 m (5H), 3.755 s (3H), 3.765 s (3H).
m NBn: 4.42 s (2H), 7.36–7.53 m (5H), OTBDPS: 0.98 s (9H), 7.36–7.53 m (6H), 7.52 m (2H), 7.57 m (2H).
n NBn: 3.56 d (1H), 3.51 d (1H), 7.21–7.32 m (5H).
o NBn: 4.39 d (1H), 4.35 d (1H), 7.38 m (3H), 7.56 m (2H).
p NBn: 4.38 d (1H), 4.33 d (1H), 7.38 m (3H), 7.56 m (2H).
q NBn: 4.25 d (1H), 4.22 d (1H), 7.20–7.40 m (5H), ODMTr: 6.84 m (2H), 6.86 m (2H); 7.20–7.40 m (9H), 3.742 s (3H), 3.735 s (3H).
r NBn: 3.39 d, 3.36 d, 7.17–7.28 m (5H), ODMTr: 6.85 m (2H), 6.86 m (2H), 7.25 m (2H), 7.26 m (2H), 7.39 m (2H), 7.17–7.28 m (3H).
between the aromatic hydrogens of substituents and pyrrol-
idine protons, obviously due to the preferred orientation of
the aromatic substituents out of the pyrrolidine ring. The
1H and 13C NMR data of compounds 1–14 are summa-
rized in Tables 1 and 2.
of both hydroxy groups which become chemically non-
equivalent due to their trans and cis orientations to the
N-oxide oxygen atom. The electron reach N-oxide oxygen
atom could be involved in the intramolecular hydrogen
bridge (Scheme 3) and thus influence the nucleophilicity
of the hydroxy group which is cis-oriented toward N-oxide
oxygen atom.
2.3. Reaction mechanism and molecular modeling
The NMR data clearly show that N-oxide oxygen atom in
compounds 5a, 5b, 13, and 7 is cis-oriented toward the
hydroxyl function bearing the DMTr or TBDPS groups.
The introduction of the N-oxide moiety into N-benzyl-3,4-
dihydroxypyrrolidine 1a completely changes the reactivity
The analysis of electrostatic potentials, molecular HOMO
orbitals, conformational energies, etc. of compounds 1b
and 4b supported the proposed reaction mechanism.
Firstly, comparison of electrostatic potentials clearly shows
(Fig. 3) that all potential nucleophilic centers (the N atom

D. Rejman et al. / Tetrahedron: Asymmetry 18 (2007) 2165–2174
Table 2. Carbon-13 NMR chemical shifts of compounds 1–14
2169
Compound solvent C-2
C-3
C-4
C-5
Other carbons
1a DMSO
1b DMSO
2a DMSO
60.92 77.69
62.72 77.65
59.01 80.60
77.69
77.65
76.79
60.92 NBn: 60.12, 138.98, 128.75(2), 128.29(2), 126.99
62.72 NCH3: 42.83
60.29 NBn: 59.83, 138.66, 128.63(2), 128.09(2), 126.82; ODMTr: 158.26(2), 145.94, 136.94,
136.48, 130.16(2), 130.03(2), 128.09(2), 127.89(2), 126.72, 113.29(2), 113.25(2),
86.01, 55.19(2)
2b DMSO
3 DMSO
61.38 81.06
60.68 80.28
77.25
77.86
62.44 NCH3: 42.39; ODMTr: 158.29(2), 145.83, 136.84, 136.57, 130.15(2), 130.08(2),
128.18(2), 127.94(2), 126.83, 113.35(2), 113.32(2), 86.16, 55.23(2)
60.82 Bn: 59.96, 139.07, 128.54(2), 128.24(2), 126.90; OTBDPS: 135.46(2), 135.36(2), 133.88,
133.49, 129.93, 129.92, 127.92(2), 127.89(2), 26.90(3), 18.96
71.08 Bn: 69.92, 130.40, 128.47(2), 132.88(2), 129.66
71.81 NCH3: 56.79
70.54 NBn: 71.29, 131.59, 127.59(2), 132.38(2), 128.64; ODMTr: 158.42, 158.39, 145.39, 136.40,
135.78, 130.29(2), 130.08(2), 128.11(2), 127.94(2), 126.86, 113.40(2), 113.33(2),
86.08, 55.20(2)
4a DMSO
4b DMSO
5a DMSO
71.99 76.08
77.34 77.61
72.17 77.77
76.28
78.37
74.57
5b DMSO
6 DMSO
73.38 77.91
71.53 77.36
74.80
77.14
71.44 NCH3: 56.96; ODMTr: 158.52(2), 144.86, 135.84, 135.57, 130.14(2), 130.05(2), 128.12(4),
127.14, 113.58(2), 113.55(2), 86.72, 55.26(2)
68.60 NBn: 71.53, 131.99(3), 128.07(2), 127.41; OTBDPS: 135.50(2), 135.47(2), 132.96, 132.87,
130.43, 130.28, 127.98(2), 127.87(2), 27.04(3), 18.88; ODMTr: 158.45, 158.43, 145.20,
136.16, 135.55, 130.20(2), 130.07(2), 128.07(4), 126.94, 113.32(2), 113.28(2), 86.16,
55.17, 55.16
7 DMSO
8 CDCl3
71.93* 77.83** 76.02** 71.84* NBn: 74.90*, 131.90, 132.47, 127.99(2), 128.75; OTBDPS: 135.54(2), 135.36(2), 133.36,
132.95, 130.09, 130.01, 127.94(2), 127.74(2), 28.86(3), 18.88
71.78 77.22
68.90 77.64
78.14
79.77
72.05 NBn: 73.56, 132.17(3), 128.00(2), 129.18; OTBDPS: 136.02(2), 135.87(2), 132.93, 132.85,
130.20, 129.97, 128.00(2), 127.89(2), 27.01(3), 19.16; ODMTr: 158.87, 158.82, 144.86,
136.07, 135.46, 130.16(2), 130.13(2), 128.28(2), 128.05(2), 127.09, 113.50(2), 113.43(2),
87.25, 55.19, 55.15
75.12 NBn: 69.88, 131.50, 128.08(2), 132.39(2), 129.01; OTBDPS: 135.25(2), 135.23(2), 132.88,
132.75, 130.22, 130.18, 128.08(2), 128.04(2), 26.77(3), 18.75
9 DMSO
10 DMSO
62.79 69.57
73.08 69.37
73.83 68.53
69.74 71.04
34.63
32.11
31.36
30.83
52.60 NBn: 59.93, 139.44, 128.65(2), 128.28(2), 126.90
65.76 NBn: 70.26, 129.99, 132.41(2), 128.66(2), 129.81
65.69 NBn: 70.85, 130.02, 132.51(2), 128.66(2), 129.87
65.18 NBn: 71.87, 131.02, 132.34(2), 127.96(2), 129.07; ODMTr: 158.44, 158.40, 145.27,
136.17, 135.94, 129.91(2), 129.84(2), 128.11(2), 127.82(2), 126.97, 113.54(2), 113.47(2),
86.64, 55.24(2)
11 D2O (77%)
12 D2O (23%)
13 DMSO
14 DMSO
60.46 73.15
32.79
52.29 NBn: 59.68, 139.00, 128.57(2), 128.18(2), 126.85; ODMTr: 158.25(2), 145.98, 136.84,
136.76, 129.90(2), 129.87(2), 127.98(2), 127.89(2), 126.73, 113.36(4), 86.15, 55.16(2)
,
* **
The signals with the same symbols may by mutually interchanged.
potential ellipsoid surrounded by positive values, does
not seem to be attractive for a cation.
O
N
O
N
O
N
Cl
HCl
H
O
H
O
RCl
R
OR
Bn
Electrostatic potential was ‘painted’ on the electron density
isosurface. Red represents negative regions around the
oxygen and nitrogen atoms and blue represents positive
regions around the hydrogen atoms.
Bn
Bn
R = DMTr or TBDPS
OH
OH
OH
Scheme 3.
Visualization of HOMO orbitals and HOMO frontier den-
sities shows (Fig. 4) that the most nucleophilic site in the
methylpyrrolidine 1b molecule is the nitrogen atom. In con-
trast, the HOMO orbitals in N-oxide 4b are equally divided
between the N-oxide and the cis-oriented hydroxy group.
as well as the oxygen atoms of both hydroxy groups) are
equally attractive for incoming cation in the case of the
N-methylpyrrolidine molecule 1b. They are situated on
the bottom of the separated funnel-shaped craters of nega-
tive potential values. In contrast, in the case of highly
polarized N-oxide 4b, there is a negative potential spread-
ing over the whole half-space involving the N-oxide oxygen
atom and cis-oriented ‘reactive’ hydroxy group making
them undoubtedly more accessible for a cation (to simplify
the calculation, we used Me3Si+ cation instead of TBDPSi+
or DMTr+ cations). On the other hand, the trans-oriented,
‘non-reactive’ hydroxy group, encapsulated in the zero
Finally, conformational energies of the speculative com-
plexes consisting of 1b and Me3Si+ cation confirmed that
the cation should be preferably localized at the nitrogen
atom (Fig. 5). In contrast, the cis-oriented, ‘reactive’
hydroxy group in 4b seemed to be the landing site. It
should be noted that the hydrogen atom of this hydroxyl
overjumped onto the N-oxide oxygen atom from where it
could be removed by the chloride anion or pyridine.

2170
D. Rejman et al. / Tetrahedron: Asymmetry 18 (2007) 2165–2174
Figure 3. Electrostatic potential isosurfaces for compounds 1b and 4b—zero (yellow), positive (blue), negative (red).
Figure 4. HOMO orbitals in the methylpyrrolidine 1b and N-oxide 4b.
Figure 5. The lowest energy transition state intermediates [1bÆMe3Si+] (a) and [4bÆMe3Si+] (b).
In summary, the electrostatic potential analysis showed
why the trans-oriented ‘non-reactive’ hydroxyl (trans to
N-oxide oxygen atom) is neglected by cations in 4b, and
the conformational energies showed that an incoming cat-
ion would be connected to 4b through the ‘reactive’ cis-hy-
droxy group, whereas the N-oxide oxygen atom would
assist by temporary adopting the incoming proton. More-
over, the HOMO orbitals uncovered that the nitrogen
atom, rather than both hydroxy groups, is the most nucleo-
philic site in 1b, thus providing an explanation for a differ-
ent reactivity toward electrophilic agents compared to 4b.
3. Conclusion
We have found that the presence of an N-oxido moiety in 1-
N-alkyl-trans-3,4-dihydroxypyrrolidine-N-oxides strongly
enhances the reactivity of only one of the two hydroxy
groups toward some of the electrophilic reagents, for
example, DMTrCl and TBDPSCl. A detailed NMR study
revealed that the hydroxy group, which is cis-oriented to
the N-oxide oxygen atom, is the highly reactive one. The
reaction mechanism was studied by ab initio calculation,
and the data obtained are in full agreement with the

D. Rejman et al. / Tetrahedron: Asymmetry 18 (2007) 2165–2174
2171
experimental data. These findings could be of practical use
for an efficient monoprotection of trans-dihydroxypyrrol-
idines and their further synthetic exploitation. Additional
studies on the reactivity enhancement caused by N-oxide
oxygen atom in another type of the hydroxylated hetero-
cyclic compounds are currently underway.
spots after heating). Preparative column chromatography
was carried out on a silica gel (40–60 lm; Fluka) neutral-
ized with triethylamine (1 mL/100 g), and the elution was
performed at the flow rate of 40 mL/min. The following
solvent systems were used for TLC and preparative chro-
matography: toluene–ethyl acetate 1:1 (T); chloroform–
ethanol 9:1 (C1); ethyl acetate–acetone–ethanol–water
6:1:1:0.5 (H3). The concentrations of the solvent systems
are provided in volume (v/v) percents. Mass spectra were
recorded on a ZAB-EQ (VG Analytical) instrument, using
FAB (ionization with Xe, accelerating voltage 8 kV). Glyc-
erol and thioglycerol were used as matrices. IR spectra
were measured in KBr tablets.
4. Experimental
4.1. Molecular modeling
Gas-phase quantum-mechanical calculations are a power-
ful tool for the investigation of N-oxide moieties.27–29
Therefore, ab initio geometry optimizations of several
model systems and subsequent calculations of electron den-
sities, electrostatic potentials, molecular HOMO, LUMO,
and natural orbitals were carried out at the HF level. The
6-31G(d) basis set was used. On this basis, the d-type func-
tions referred to as polarization functions enable to
describe precisely the geometry of the systems, in particular
those involving bonds between the electronegative atoms,
such as N–O. All calculations were performed with the
GAUSSIAN03 quantum chemistry software package.30
Results were visualized using VMD,31 WEBMO,32 and
4.4. (3S,4S)-1-N-Benzyl-3-dimethoxytrityloxy-4-hydroxy-
pyrrolidine 2a
4.4.1. Method A. Dimethoxytrityl chloride (2.2 g,
6.4 mmol) was added to a solution of 8a (0.84 g, 4.3 mmol)
in pyridine (50 mL). The reaction mixture was set aside at
rt for 2 d. Anhydrous methanol (1 mL) was added, and the
solution concentrated in vacuo. The product 2a was
obtained by chromatography on silica gel using a linear
gradient of toluene in petroleum ether followed by a linear
gradient of ethyl acetate in toluene in 52% yield (1.1 g,
2.23 mmol) as a yellow oil.
33
CHEMCRAFT programs.
4.2. NMR spectroscopy
4.4.2. Method B. Compound 5a (0.51 g, 1 mmol) was
treated with triphenylphosphine (1.3 g, 5 mmol) in DCM
(10 mL) at rt for 2 d. The product 2a was obtained by puri-
fication on silica gel using a linear gradient of ethyl acetate
in toluene in 75% yield (0.37 g, 0.75 mmol). HR-MS:
NMR spectra of the pyrrolidine derivatives were measured
on Varian UNITY-500 and Bruker AVANCE-500 spec-
trometers (1H at 500 MHz; 13C at 125.7 MHz) in CDCl3,
DMSO, and/or D2O. The chemical shifts are given in
1
d-scale [ppm] and the coupling constants in Hz. H NMR
(M+H)+ calcd for C32H33NO4, 495.2420; found,
20
spectra were referenced to tetramethylsilane (in CDCl3)
and/or residual signal of the solvent (d(DMSO) = 2.50
and d(D2O) = 4.80). 13C NMR spectra were referenced
either to the solvent peak (d(DMSO) = 39.7 and
d(CDCl3) = 77.0) or DSS as secondary standard (in
D2O). Structural assignment of protons and carbon atoms
was achieved using correlated homonuclear 1H,1H-2D-
495.2414. ½aꢂD ¼ þ35:8 (c 0.396, ethanol).
4.5. (3S,4S)-1-N-Methyl-3-dimethoxytrityloxy-4-hydroxy-
pyrrolidine 2b
A solution of compound 5b (0.086 g, 0.2 mmol) and tri-
phenylphosphine (0.52 g, 2 mmol) in DCM (2 mL) was
set aside at rt for 2 d. The product 2b was obtained by puri-
fication on silica gel using a linear gradient of ethyl acetate
in toluene in 38% yield (0.032 g, 0.076 mmol) as a yellow
oil. HR-MS: (M+H)+ calcd for C26H30NO4, 420.2169;
found, 420.2173.
1
1
COSY and heteronuclear H,13C-2D-HMQC and H,13C-
2D-HMBC spectra. The homonuclear H,1H-2D-ROESY
1
spectra were used for determination of the spatially close
hydrogen atoms and for the stereochemical assignment of
methylene protons. The 15N chemical shifts for compounds
1
1b and 4b were obtained from H,15N-2D-HMBC spectra
in DMSO and referenced to CH3NO2 as the external stan-
dard (in capillary). Optical rotations were measured on
polarimeter Autopol IV (Rudolph Res. Anal., USA) in eth-
anol at 589 nm.
4.6. (3S,4S)-1-N-Benzyl-3-tert-butyldiphenylsilyloxy-4-
hydroxypyrrolidine 3
1-N-Benzyl-3,4-dihydroxypyrrolidine17,21,22
1a
(2 g,
4.3. Synthesis
10.36 mmol) was treated with tert-butylchlorodiphenylsi-
lane (2.91 mL, 12 mmol) and imidazole (0.82 g, 12 mmol)
in pyridine (50 mL). The reaction mixture was stirred at
rt overnight (TLC in T and C1), quenched with methanol
(1 mL), and the solution was concentrated in vacuo. The
desired product 3 was obtained by chromatography on sil-
ica gel using a linear gradient of ethyl acetate in toluene in
22% yield (0.93 g, 2.24 mmol) as a yellowish thick oil. HR-
Unless stated otherwise, all used solvents were anhydrous.
Products were evaporated or lyophilized from dioxane, and
dried over phosphorus pentoxide at 50–70 ꢁC and 13 Pa.
TLC was performed on silica gel pre-coated aluminum
sheets UV 254 (Fluka). The compounds were detected by
UV light (254 nm), by heating (detection of DMTr group;
orange color), or by spraying with a 1% solution of ninhy-
drine to visualize pyrrolidines (they usually gave brown
MS: (M+H) calcd for C27H34NO2Si, 432.2359; found,
20
432.2350. ½aꢂD ¼ þ27:8 (c 0.416, ethanol).

2172
D. Rejman et al. / Tetrahedron: Asymmetry 18 (2007) 2165–2174
4.7. (3S,4S)-1-N-Benzyl-3,4-dihydroxy-1-N-oxidopyrrol-
idine 4a
the form of a yellowish foam. mmax(KBr) 3270 (OH); 2950
(CH3); 1463 (CH2); 1361 (N–CH3); 1087 (C–OH); 937
(N–O); 3056, 3034, 3001, 1608, 1582, 1509, 1446, 1252,
1222, 1178, 1116, 1014, 829, 791, 727, 635, 528, 585,
1492, 1155, 1002, 911, 756, 704, 617, 2908, 2836, 1301,
1033 (DMTr). HR-MS: (M+H) calcd for C26H30NO5,
436.2124; found, 436.2124.
1-N-Benzyl-3,4-dihydroxypyrrolidine17,21,22
1a
(5.3 g,
27.4 mmol) was treated with a 1:1 mixture of 30%
hydrogen peroxide and ethanol (30 mL) at rt overnight.
The mixture was diluted with water (100 mL) and applied
onto a column of Dowex 50 (H+, 50 mL). The resin was
washed with water (400 mL), and the product was eluted
with 3% aqueous ammonia. The desired compound was
obtained after evaporation in 95% yield (5.47 g,
26.14 mmol) as a colorless oil. HR-MS: (M+H) calcd for
C11H16NO3, 210.1130; found, 210.1130.
4.11. (1S,3S,4S)-1-N-Benzyl-4-tert-butyldiphenylsilyloxy-
3-dimethoxytrityloxy-1-N-oxidopyrrolidine 6
Dimethoxytrityl derivative 5a (0.5 g, 0.98 mmol) was trea-
ted with tert-butylchlorodiphenylsilane (1.04 mL, 4 mmol)
and imidazole (0.14 g, 2 mmol) in pyridine (10 mL) at rt
overnight. The reaction was quenched with methanol
(1 mL), concentrated at low temperature, and the desired
product 6 was obtained by chromatography on silica gel
using a linear gradient of ethanol in chloroform in 54%
yield (0.4 g, 0.53 mmol) as a yellowish foam. HR-MS:
4.8. (3S,4S)-3,4-Dihydroxy-1-N-methyl-1-N-oxidopyrrol-
idine 4b
A solution of iodine (5.4 g, 21 mmol) in THF (50 mL) was
slowly added to a vigorously stirred mixture of (3S,4S)-
3,4-dihydroxy-1-N-methylpyrrolidin-5,6-dione34
(1.23 g,
(M+H) calcd for C48H52NO5Si, 750.3615; found,
20
8.4 mmol) and sodium borohydride (1.7 g, 43 mmol) in
THF (150 mL) at 0 ꢁC for 2 h. The reaction mixture was
stirred at rt overnight, quenched by the slow addition of
3 M hydrochloric acid (20 mL) at 0 ꢁC, diluted with water
(200 mL) and applied onto a Dowex 50 (H+, 150 mL)
column. The resin was washed with water–ethanol mixture
(1:1) followed with 3% aqueous ammonia to afford (3S,4S)-
3,4-dihydroxy-1-N-methylpyrrolidine 1b. This product was
treated with a mixture of 30% hydrogen peroxide (10 mL)
and ethanol (10 mL) at rt overnight. The N-oxide 4b was
obtained after desalting on Dowex 50 (H+) in an 11% over-
all yield (0.125 g, 0.935 mmol) as a colorless oil. mmax(KBr)
3413, 3096, 2721 (OH); 2914, 2852 (CH2); 1438, 1412, 1352
(CH3); 1024 (C–OH); 962, 947 (N–O). HR-MS: (M+H)
calcd for C5H12NO3, 134.0817; found, 134.0813.
750.3589. ½aꢂD ¼ þ53:1 (c 0.199, ethanol).
4.12. (1S,3S,4S)-1-N-Benzyl-3-tert-butyldiphenylsilyloxy-
4-hydroxy-1-N-oxidopyrrolidine 7
The N-oxide 4a (2 g, 10.36 mmol) was treated with tert-
butylchlorodiphenylsilane (3.5 mL, 13.7 mmol) in pyridine
(100 mL) at rt overnight. Methanol (1 mL) was added, the
solvents were evaporated, and the residue was dissolved in
70% aqueous ethanol (100 mL), and applied onto a column
of Dowex 50 (H+, 50 mL). The resin was washed with 70%
ethanol (400 mL), and the desired compound was eluted
with a 3% aqueous ammonia–ethanol mixture (1:1). Com-
pound 7 was obtained in 98% yield (4.53 g, 10.12 mmol) as
a white foam. mmax(KBr) 2931 (CH2); 2857 (CH2); 2800
(OH); 1085 (C–OH); 936 (N–O); 3088, 2030, 1605, 1495,
1457, 1159, 757, 622 (Bn); 3070, 3048, 2931, 2857, 1596,
1589, 1568, 1488, 1428, 1332, 1188, 1113, 1105, 1026,
998, 918, 857, 740, 688, 613, 507, 489 (TBDPS). HR-MS:
(M+H) calcd for C27H34NO3Si, 448.2308; found, 448.2228.
4.9. (1S,3S,4S)-1-N-Benzyl-4-dimethoxytrityloxy-3-hydr-
oxy-1-N-oxidopyrrolidine 5a
N-Oxide 4a (0.748 g, 3.5 mmol) was treated with dimeth-
oxytrityl chloride (1.35 g, 4 mmol) in pyridine (35 mL) at
rt overnight. The reaction was quenched with methanol
(1 mL), concentrated at low temperature, and the residue
was subjected to column chromatography on silica gel
using a linear gradient of H3 in ethyl acetate. Dimethoxy-
trityl derivative 5a was obtained in 95% yield (1.7 g,
3.3 mmol) as an amorphous solid. mmax(KBr) 3239, 2636
(OH); 2934, 1463, 1374 (CH2); 1095 (COC); 1058 (C–
OH); 927 (N–O); 3061, 3035, 3002, 2953, 2908, 2836,
1608, 1583, 1509, 1491, 1457, 1446, 1301, 1251, 1223,
1177, 1156, 1115, 1033, 1012, 1001, 912, 829, 756, 791,
4.13. (1R,3S,4S)-1-N-Benzyl-4-tert-butyldiphenylsilyloxy-
3-dimethoxytrityloxy-1-N-oxidopyrrolidine 8
The silyl derivative 7 (0.5 g, 1.12 mmol) was treated with
dimethoxytrityl chloride (0.7 g, 2.07 mmol) in pyridine
(10 mL) at rt for 5 d. The reaction was quenched with
methanol (1 mL), solvents were evaporated, and product
8 was obtained by chromatography on silica gel using a lin-
ear gradient of ethanol in chloroform in 44% yield (0.367 g,
0.49 mmol) as a yellowish foam. HR-MS: (M+H) calcd for
20
727, 702, 618, 585, 528 (DMTr). HR-MS: (M+H) calcd
C48H52NO5Si, 750.3615; found, 750.3589. ½aꢂD ¼ þ37:6 (c
20
for C32H34NO5, 512. 2437; found, 512.2453. ½aꢂD ¼ þ31:4
0.507, ethanol).
(c 0.419, ethanol).
4.14. (1R,3S,4S)-1-N-Benzyl-3-tert-butyldiphenylsilyloxy-
4-hydroxy-1-N-oxidopyrrolidine 9
4.10. (3S,4S)-3-Dimethoxytrityloxy-4-hydroxy-1-N-methyl-
1-N-oxidopyrrolidine 5b
4.14.1. Method A. Compound 6 (0.4 g, 0.53 mmol) was
dissolved in 80% aqueous acetic acid (20 mL), the solution
then set aside for 2 h, concentrated in vacuo, and the resi-
due was co-evaporated with water and ethanol (3·). Prod-
uct 9 was obtained by column chromatography on silica gel
The title compound was prepared from N-oxide 4b (0.12 g,
0.902 mmol) and dimethoxytrityl chloride (0.34 g, 1 mmol)
in pyridine (10 mL) as described for the compound 5a.
Compound 5b was obtained 0.344 g (0.79 mmol, 88%) in

D. Rejman et al. / Tetrahedron: Asymmetry 18 (2007) 2165–2174
2173
using a linear gradient of ethanol in chloroform in 70%
yield (0.16 g, 0.37 mmol) as a white foam.
Complex Molecular Systems (LC512), MSMT NPV2:
2B06065, MSM0021620835 and ChemGen LC06077 (Min-
istry of Education, Youth and Sports of the Czech Repub-
lic) under Research Project Z40550506 is gratefully
4.14.2. Method B. Hydrogen peroxide (30%, 10 mL) was
added to a solution of 3 (0.93 g, 2.16 mmol) in ethanol
(20 mL). The solution was set aside at rt overnight, and
then applied on the column of Dowex 50 (H+, 50 mL).
The resin was washed with 50% aq ethanol (200 mL) to
remove hydrogen peroxide, and the desired product was
eluted with 3% ammonium hydroxide in 50% aq ethanol
(150 mL) to afford 95% yield (0.92 g, 2.051 mmol) of com-
pound 9 as a white foam. HR-MS: (M+H) calcd for
C27H34NO3Si, 448.2308; found, 448.2228.
´
acknowledged. Authors are indebted to Dr. Zdeneˇk Tocˇık
(IOCB) for valuable discussion, and the staff of the Depart-
ment of Mass Spectrometry (IOCB) for measurements of
HR-MS spectra.
References
1. Tsuzuki, Y.; Chiba, K.; Hino, K. Tetrahedron: Asymmetry
2001, 12, 1793–1799.
4.15. (1RS,3S)-1-N-Benzyl-3-hydroxy-1-N-oxidopyrrol-
idines 11 and 12
2. Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti, A.;
Picasso, S.; Vogel, P. J. Org. Chem. 1995, 60, 6806–6812.
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8. Kaspersen, F. M.; Biera¨ugel, H.; Pandit, U. K. Heterocycles
1974, 2, 15–19.
1-N-Benzyl-3-hydroxypyrrolidine 10 (1.5 g, 8.6 mmol) was
treated with a mixture of 30% hydrogen peroxide (15 mL)
and ethanol (15 mL) at rt overnight. The mixture was
diluted with water (30 mL) and applied onto a column of
Dowex 50 (H+, 30 mL). The resin was washed with water
(200 mL), and the desired compound was eluted with 3%
aqueous ammonia. After evaporation, 1.5 g (7.8 mmol) of
a mixture of N-oxides 11 and 12 were obtained in 90% yield
(1.5 g, 7.8 mmol) as a colorless oil. HR-MS: (M+H) calcd
for C11H16NO2, 194.1181; found, 194.1166.
4.16. (1R,3R)-1-N-Benzyl-3-dimethoxytrityloxy-1-N-oxido-
pyrrolidine 13
9. Kaspersen, F. M.; Pandit, U. K. J. Chem. Soc., Perkin Trans.
1 1975, 1617–1622.
10. Kaspersen, F. M.; Pandit, U. K. J. Chem. Soc., Perkin Trans.
1 1975, 1798–1802.
11. Ng, K.-M. E.; Orgel, L. E. J. Med. Chem. 1989, 32, 1754–
1757.
12. Peterson, M. L.; Vince, R. J. Med. Chem. 1991, 34, 2787–
2797.
13. Harnden, M. R.; Jarvest, R. L. Tetrahedron Lett. 1991, 32,
3863–3866.
14. Harnden, M. R.; Jarvest, R. L.; Parratt, M. J. J. Chem. Soc.,
Perkin Trans. 1 1992, 2259–2263.
15. Westwood, N. B.; Walker, R. T. Tetrahedron 1998, 54,
13391–13404.
The epimeric mixture of N-oxides 11 and 12 (0.24 g,
1.23 mmol) was treated with dimethoxytrityl chloride
(0.46 g, 1.4 mmol) in a mixture of DMF (4 mL) and pyri-
dine (20 mL) at rt for 1 h. The reaction was quenched with
methanol (0.2 mL), the solvents evaporated, and the resi-
due subjected to column chromatography on silica gel
using a linear gradient of H3 in ethyl acetate. The desired
product 13 was obtained in 74% yield (0.45 g, 0.91 mmol)
as a yellow foam. mmax(KBr) 928 (N–O); 2936, 1463, 1378
(CH2); 3058, 3034, 3000, 2952, 2907, 2835, 1608, 1582,
1509, 1492, 1457, 1446, 1352, 1224, 1178, 1154, 1117,
1099, 1082, 1014, 1003, 913, 829, 791, 754, 727, 702, 613,
´
´
´
´
16. Vaneˇk, V.; Budeˇsˇınsky, M.; Kavenova, I.; Rinnova, M.;
Rosenberg, I. Nucleosides Nucleotides Nucleic Acids 2003, 22,
1065–1067.
583, 523 (DMTr, Bn); HR-MS: (M+H) calcd for
20
17. Miyabe, H.; Kanehira, S.; Kume, K.; Kandori, H.; Naito, T.
Tetrahedron 1998, 54, 5883–5892.
C32H34NO4, 495.2410; found, 495.2408. ½aꢂD ¼ ꢁ20:1 (c
0.384, ethanol).
´
´
18. Rejman, D.; Kocˇalka, P.; Budeˇsˇınsky, M.; Pohl, R.; Rosen-
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4.17. (3R)-1-N-Benzyl-3-dimethoxytrityloxypyrrolidine 14
A solution of compound 13 (0.1 g, 0.2 mmol) and triphen-
ylphosphine (0.52 g, 2 mmol) in DCM (2 mL) was set aside
at rt overnight. The product 14 was obtained by purifica-
tion on silica gel using a linear gradient of ethyl acetate
in toluene in 92% yield (0.088 g, 0.184 mmol) as a thick yel-
low oil. HR-MS: (M+H) calcd for C32H34NO3, 480.2539;
found, 480.2529.
20. Cicchi, S.; Nunes, J.; Goti, A.; Brandi, A. Eur. J. Org. Chem.
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Support by Grants # 203/02/D150 and # 203/05/0827
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