Enantioselective synthesis of 4-hydroxy-D-pyroglutamic acid derivatives by an asymmetric 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/S0957-4166(02)00072-1

The 1,3-dipolar cycloaddition of a chiral nitrone derived from glyoxylic acid and protected D-ribosyl hydroxylamine with the acrylamide of Oppolzer's sultam provides a perfectly stereoselective approach to protected (2R,4R)-4-hydroxy-D-pyroglutamic acid.

Full text of DOI:10.1016/S0957-4166(02)00072-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 167–172
Enantioselective synthesis of 4-hydroxy-
D
-pyroglutamic acid
derivatives by an asymmetric 1,3-dipolar cycloaddition
Pedro Merino,a,* Julia Revuelta,a Tomas Tejero,a Ugo Chiacchio,b,* Antonio Rescifina,b
Anna Pipernoc and Giovanni Romeoc
aDepartamento de Qu´ımica Orga´nica, ICMA, Facultad de Ciencias, Universidad de Zaragoza, E-50009 Zaragoza, Spain
bDipartimento di Scienze Chimiche, Universita` di Catania, Viale Andrea Doria 6, Catania 95125, Italy
cDipartimento Farmaco-Chimico, Universita` di Messina, Via SS. Annunziata, Messina 98168, Italy
Received 21 January 2001; accepted 13 February 2002
Abstract—The 1,3-dipolar cycloaddition of a chiral nitrone derived from glyoxylic acid and protected
D-ribosyl hydroxylamine
with the acrylamide of Oppolzer’s sultam provides a perfectly stereoselective approach to protected (2R,4R)-4-hydroxy-D-pyro-
glutamic acid. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
nes.4 In addition, compounds 2 are an entry to 4-substi-
tuted glutamic acids of biological importance.5
Pyroglutamic acids (the cyclic forms of the glutamic
acids) 1 and their derivatives have a wide range of
synthetic applications.1 Protected derivatives of 1 (Fig.
1) have been used for the asymmetric synthesis of a
number of natural and pharmacologically interesting
products.2 However, in spite of this synthetic activity
with compounds 1, 4-hydroxy pyroglutamic acids 2
have not received attention until recently.3 Compounds
Preparation of compound 2a in homochiral form can
be accomplished by oxidation of the enolate derived
from protected L
-pyroglutamic acid.6 Very recently, a
multigram scale preparation has been reported for both
2a and its trans isomer 2b, starting from trans-4-
hydroxy-
allow preparation of
L
-amino acid starting materials in both cases.8 One of
L
-proline.7 These syntheses, however, only
L
-isomers due to the availability of
2, formally derived from the natural
L
-series, and their
enantiomers ent-2, in their protected forms, are useful
our laboratories has reported an approach to ent-2a
based on nitrone chemistry.9 The approach used the
furan ring as a surrogate of the carboxylic function; so
subsequent ruthenium-mediated oxidation was needed
to deliver the desired pyroglutamates.10
synthons since they are highly functionalized pyrrolidi-
2. Results and discussion
Herein, we describe the use of a chiral glyoxylic acid
derived nitrone, in which the carboxyl group is already
present, as a suitable material for a straightforward
approach to 4-hydroxy-D-pyroglutamic acid deriva-
tives.11 This method obviates the need for metal-
assisted oxidations.
Nitrone 3 was easily prepared in situ as previously
described by one of us12 and made to react with methyl
acrylate 4a in a sealed tube for 18 h. After evaporation
and purification, two adducts 5a and 6a, in a 2:1 ratio,
and 80% chemical yield were obtained and separated
Figure 1. Pyroglutamic acids and their 4-hydroxy derivatives.
* Corresponding authors. Tel.: +34 976 762 075; fax: +34 976 762
075; e-mail: pmerino@posta.unizar.es
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00072-1

168
P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 167–172
(see Section 4). When the reaction was carried out with
the Oppolzer’s sultam derived acrylamide 4b,13 the
5b:6b ratio increased to 20:1 (Scheme 1).
As shown in Fig. 3, the trans adducts 5 could be formed
by exo attack on the (E)-nitrone, or by endo attack on
the (Z)-nitrone. Similarly, the minor cis adducts 6
could be formed by endo attack on the (E)-nitrone or
by exo attack on the (Z)-nitrone. The nitrone cycload-
ditions with monosubstituted electron-poor dipolar-
ophiles (such as methyl acrylate 4a and acrylamide 4b),
capable of secondary orbital interactions,14 proceed
through endo transition states.15 According to this rule,
one might expect the preferred path to involve endo
attack on the (Z)-nitrone, and not exo attack on the
(E)-nitrone. Previous results with configurationally sta-
ble (Z)-nitrones9,16 showed that changing from methyl
acrylate 4a to acrylamide 4b afforded greater amounts
of trans-isomers, thus supporting the hypothesis that
bulky groups at the carbonyl moiety of the dipolar-
ophile favour endo attack of (Z)-nitrones. Admittedly,
this interpretation is speculative and the possibility of
E-exo attack should not be discarded.17
The diastereomeric ratios of the products were deter-
mined by HPLC and NMR spectroscopy on crude
mixtures. In both cases a preference for trans adducts
was observed. The regiochemistry of the adducts was
readily deduced from 1H NMR data. In each case,
there was one proton signal at 4.55–5.11 ppm which
corresponded to the H5 proton; the alternative regioiso-
mers are not reported to show a resonance at this
chemical value. The relative stereochemistry of com-
pounds 5 and 6 were determined by extensive NOEDS
experiments (Fig. 2).
Thus, for trans adduct 5a, irradiation of H4a (2.47 l)
gave rise to a NOE effect for the geminal proton H4b
(2.81 l; 28%) and for H3 (4.16 l; 10%), while irradia-
tion of H4b gave rise to a positive NOE effect for H4a
(25%) and H5 protons (4.55 l; 13%): these data unam-
biguously indicate a syn relationship between H4a and
H3 and between H4b and H5 protons, respectively.
Conversely, in the cis adduct 6a irradiation of H4a (2.70
l) produced a positive NOE effect for the geminal
proton H4b (2.87 l; 33%), for H3 (4.19 l; 9%) and H5
(4.77 l; 12%); moreover, the irradiation of H5 gave rise
to a positive enhancement for H4a (7%) and H3 (0.5%),
so indicating a cis topological arrangement between H5,
H4a and H3 protons.
The preferential diastereofacial Re selectivity (induced
by the sugar moiety) observed in the cycloaddition with
methyl acrylate 4 is in agreement with previously
reported data.12,18,19 In the reaction of 3 with 4b, the
For trans adduct 5b irradiation of H5 (5.11 l) gave rise
to a positive enhancement of H4b (2.82 l; 5%), while
irradiation of H3 (4.28 l) produced a positive NOE for
H4a (2.87 l; 6%). Instead, for cis compound 6b the
irradiation of H5 (4.74 l) gave rise to a NOE effect for
H4a (2.45 l; 5%) and for H3 (3.95 l; 1%), thus indicat-
ing a cis relationship between these protons.
The predominant Re-face attack at the nitrone carbon
was confirmed by chemical correlation as discussed
below.
The observed stereochemical results are in good agree-
ment with the precedents existing for cycloaddition
reactions of nitrones bearing an electron-withdrawing
group at the nitrone carbon atom, which exist as mix-
tures of E and Z isomers.12
Figure 2. Selected NOEs observed for compounds 5 and 6.
Scheme 1.

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 167–172
169
Figure 3. The four possible attacks to (E)- and (Z)-3. S*=1-deoxy-5-[(tert-butyldiphenylsilyl)oxy]-2,3-O-isopropylidene-
1,4-pentofuranose-1-yl; R=OMe; Oppolzer’s sultam.
D
-ribo-
sultam moiety favors Re face attack of the alkene, and
the ribosyl group again has a tendency for Re face
attack of the nitrone. As shown in Fig. 3, the formation
of (3R,5R)-5 as the predominant adduct comes from a
Re–Re attack either by an E-exo or a Z-endo attack.
Compounds 5 and 6 were converted to the target
4-hydroxy-D-pyroglutamic acid derivatives in a one-
flask procedure consisting of four sequential steps
(Scheme 2). Elimination of the sugar moiety by acidic
hydrolysis and subsequent N–O cleavage by
hydrogenolysis gave unprotected ethyl 4-hydroxy-D-
pyroglutamates 7 and 9. We did not observe, in any
case, competitive formation of the corresponding lac-
tone by intramolecular cyclization with the hydroxyl
group at C(4). In this respect, the formation of lactams
versus lactones is clearly favoured, as has been
described elsewhere.10 In situ protection of these com-
pounds with tert-butyldimethylsilyl (TBDMS) and tert-
butoxycarbonyl (Boc) groups afforded the protected
compounds 8 and 10. In the case of compounds 5b and
6b it was possible to recover the Oppolzer’s sultam in
near to 60% yield.
Scheme 2. (i) HCl, EtOH, rt, 6 h; (ii) Pd(OH)2/C, MeOH, H2,
2000 psi, rt, 48 h; (iii) TBDMSCl, imidazol, DMF, 70°C, 3 h;
(iv) Boc2O, DMAP, Et3N, CH2Cl2, rt, overnight.
Confirmation of the absolute stereochemistry came
from an alternative synthesis. Starting from cis-4-
hydroxy-
procedure for trans-4-hydroxy-
D
-proline8 and following the recently reported
L
-proline,7 compound 8
was prepared (Scheme 3). The physical and spectro-
scopic properties of the obtained compound were iden-
tical to those obtained from the cycloadducts 5a and
5b. Similarly, starting from trans-4-hydroxy-L-proline,
compound 10 was synthesized. The physical and spec-
troscopic properties of this compound were identical to
those obtained from the cycloadducts 6a and 6b. Thus,
the absolute configuration of 8 and 10 could be unam-
biguously assigned.
3. Conclusions
In summary, we have developed a five-step asymmetric
synthesis of protected 4-hydroxy-
using -ribose and Oppolzer’s sultam as highly efficient
chiral auxiliaries. In fact, this approach has led to the
D
-pyroglutamic acid 8
Scheme 3. (i) 1. EtOH, HCl, reflux, 2. (Boc)2O, Et3N,
CH2Cl2; (ii) TBDMSCl, imidazole, DMF; (iii) RuO2(cat),
NaIO4, EtOAc/H2O.
D

170
P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 167–172
preparation of the target compound (protected
(2S,4R)-4-hydroxypyroglutamic acid) in more
0.92 (t, 3H, J=7.1 Hz), 0.98 (s, 9H), 1.27 (s, 3H), 1.42
(s, 3H), 2.47 (dt, 1H, J=8.1, 12.9 Hz), 2.81 (ddd, 1H,
J=1.8, 8.8, 12.9 Hz), 3.63 (dd, 1H, J=5.3, 10.6 Hz),
3.68 (s, 3H), 3.74 (dd, 1H, J=8.6, 10.6 Hz), 3.78 (dd,
1H, J=7.1, 10.8 Hz), 3.91 (dd, 1H, J=7.1, 10.8 Hz),
4.15 (ddd, 1H, J=1.7, 5.3, 8.6 Hz), 4.16 (dd, 1H,
J=1.8, 8.1 Hz), 4.55 (dd, 1H, J=8.1, 8.8 Hz), 4.57 (d,
1H, J=1.3 Hz), 4.68 (dd, 1H, J=1.7, 6.3 Hz), 4.83 (dd,
1H, J=1.3, 6.3 Hz), 7.28–7.60 (m, 10H). 13C NMR
(CDCl3, 125 MHz) l 13.9, 19.2, 25.0, 26.7, 26.8, 34.2,
52.5, 61.4, 62.4, 64.1, 77.6, 82.1, 84.1, 87.5, 98.4, 112.4,
127.7, 127.7, 129.7, 129.7, 133.3, 133.4, 135.5, 135.5,
170.4, 172.1. Anal. calcd for C32H43NO8Si: C, 64.30; H,
7.25; N, 2.34. Found: C, 64.56; H, 7.01; N, 2.40%.
a
efficient way (d.r.=20:1) than that reported previously
(d.r.=6:1).9 The synthesis avoids low temperature reac-
tions, oxidations and difficult purifications, thus mak-
ing it amenable for large-scale preparations. Further
studies related to the utility of the product 8 as a chiral
building block will be reported in due course.
4. Experimental
The reaction flasks and other glass equipment were
heated in an oven at 130°C overnight and assembled in
a stream of Ar. All reactions were monitored by TLC
on silica gel 60 F254; the position of the spots was
detected with 254 nm UV light or by spraying with one
of the following staining systems: 50% methanolic sul-
furic acid, 5% ethanolic fosfomolibdic acid and iodine.
Preparative column chromatography was performed on
columns of silica gel (60–240 mesh) and with solvents
that were distilled prior to use. Preparative centrifugally
accelerated radial thin-layer chromatography (PCAR-
TLC) was performed with a Chromatotron® Model
7924 T (Harrison Research, Palo Alto, CA, USA); the
rotors (1 or 2 mm layer thickness) were coated with
silica gel Merck grade type 7749, TLC grade, with
binder and fluorescence indicator (Aldrich 34, 644–6)
and the eluting solvents were delivered by the pump at
a flow rate of 0.5–1.5 mL min−1. Melting points were
4.1.2. (3S,5R)-5-Acetyl-2-[5-(tert-butyldiphenylsilyl)-1-
deoxy-2,3-O-isopropylidene-D-ribo-1,4-pentofuranose-1-
yl]-isoxazolidine-3-carboxylic acid ethyl ester 6a. 6a
(0.807 g, 27%); HPLC: tR 10.8 min; sticky oil; [h]2D5=
1
+45 (c 0.20, CHCl3); H NMR (CDCl3, 500 MHz) l
1.02 (t, 3H, J=7.1 Hz), 1.05 (s, 9H), 1.33 (s, 3H), 1.50
(s, 3H), 2.70 (ddd, 1H, J=8.6, 10.1, 13.2 Hz), 2.87
(ddd, 1H, J=2.1, 4.4, 13.2 Hz), 3.72 (dd, 1H, J=5.4,
10.9 Hz), 3.74 (s, 3H), 3.84 (dd, 1H, J=8.1, 10.9 Hz),
3.89 (dd, 1H, J=7.1, 10.6 Hz), 3.98 (dd, 1H, J=7.1,
10.6 Hz), 4.19 (dd, 1H, J=2.1, 8.6 Hz), 4.24 (ddd, 1H,
J=1.6, 5.4, 8.1 Hz), 4.48 (d, 1H, J=1.4 Hz), 4.76 (dd,
1H, J=1.6, 6.2 Hz), 4.77 (dd, 1H, J=4.4, 10.1 Hz),
4.90 (dd, 1H, J=1.4, 6.2 Hz), 7.36–7.66 (m, 10H). 13C
NMR (CDCl3, 125 MHz) l 13.9, 19.2, 24.9, 26.6, 26.8,
34.0, 52.5, 61.2, 61.4, 63.9, 76.5, 81.9, 83.87, 87.3, 98.4,
112.7, 127.8, 127.8, 129.8, 129.8, 133.2, 133.3, 135.5,
135.5, 170.4, 170.5. Anal. calcd for C32H43NO8Si: C,
64.30; H, 7.25; N, 2.34. Found: C, 64.12; H, 7.11; N,
2.56%.
1
uncorrected. H and 13C NMR spectra were recorded
on a Varian Unity or on a Bruker 300 instrument in
CDCl3 at 55°C. Chemical shifts are reported in ppm (l)
relative to CHCl3 (l=7.26) in CDCl3. Optical rotations
were taken at 25°C on a Perkin–Elmer 241 polarimeter.
Elemental analysis were performed on a Perkin Elmer
240B microanalyzer. Methyl acrylate 3a was purchased
(Aldrich) and distilled prior to use. Nitrone 312 and
acrylamide 4b20 were prepared according the reported
procedures.
4.1.3. (3R,5R)-2-[5-(tert-Butyldiphenylsilyl)-1-deoxy-2,3-
O - isopropylidene - D - ribo - 1,4 - pentofuranose - 1 - yl] - 5-
[(1S,5R,7R)-10,10-dimethyl-3,3-dioxo-3l6-thia-4-aza-
tricyclo[5.2.1.01,5]decane-4-carbonyl]-isoxazolidine-3-car-
boxylic acid ethyl ester 5b. 5b (2.272 g, 57%); HPLC: tR
8.6 min; white solid; mp=55–56°C; [h]2D5=−62 (c 1.31,
4.1. Cycloaddition of nitrone 3 with dipolarophiles 4a
and 4b
1
CHCl3); H NMR (CDCl3, 500 MHz) l 0.96 (t, 3H,
A
solution of 5-(tert-butyldiphenylsilyl)-1-deoxy-1-
J=7.3 Hz), 0.97 (s, 3H), 1.04 (s, 9H), 1.19 (s, 3H), 1.29
(s, 3H), 1.30–1.41 (m, 2H), 1.46 (s, 3H), 1.82–1.95 (m,
3H), 2.03 (dd, 1H, J=7.7, 13.9 Hz), 2.29 (ddd, 1H,
J=4.7, 7.3, 13.9 Hz), 2.82 (ddd, 1H, J=1.8, 8.4, 13.1
Hz), 2.87 (dt, 1H, J=7.7, 13.1 Hz), 3.43 (d, 1H, J=
13.9 Hz), 3.52 (d, 1H, J=13.9 Hz), 3.69 (dd, 1H,
J=5.1, 10.6 Hz), 3.80 (dd, 1H, J=8.8, 10.6 Hz), 3.81
(dq, 1H, J=7.3, 10.6 Hz), 3.91 (dd, 1H, J=4.7, 7.7
Hz), 3.96 (dq, 1H, J=7.3, 10.6 Hz), 4.24 (ddd, 1H,
J=1.1, 5.1, 8.8 Hz), 4.28 (dd, 1H, J=1.8, 7.7 Hz), 4.64
(s, 1H), 4.75 (dd, 1H, J=1.1, 6.2 Hz), 4.86 (d, 1H,
J=6.2 Hz), 5.11 (dd, 1H, J=7.7, 8.4 Hz), 7.35–7.66 (m,
10H). 13C NMR (CDCl3, 125 MHz) l 13.8, 19.1, 19.9,
20.9, 25.1, 26.4, 26.6, 26.7, 32.0, 32.9, 37.8, 44.7, 47.7,
48.7, 53.0, 61.2, 63.3, 64.0, 65.5, 78.0, 82.6, 83.9, 87.7,
97.8, 112.1, 127.6, 127.7, 129.6, 129.7, 133.4, 133.4,
135.4, 135.5, 169.7, 170.3. Anal. calcd for
C41H56N2O10SSi: C, 61.78; H, 7.08; N, 3.51. Found: C,
61.93; H, 6.89; N, 3.62%.
hydroxyamino-2,3-O-isopropylidene- -ribo-1,4-pento-
D
furanose (5 mmol), dipolarophile (15 mmol and 6 mmol
of 4a and 4b, respectively) and ethyl glyoxylate (150
mmol, 50% solution in toluene) was heated at 75°C, in
a sealed tube (18 h and 40 h for 4a and 4b, respec-
tively). The reaction mixture was evaporated and the
residue was purified by column flash chromatography
(cyclohexane/ethyl acetate, 4:1), and then by HPLC
(n-hexane/2-propanol, 97:3). Preparative HPLC was
,
performed with a microsorb silica DYNAMAX-100 A
(21×250 mm) column, with
instrument.
a Varian Pro Star
4.1.1. (3R,5R)-5-Acetyl-2-[5-(tert-butyldiphenylsilyl)-1-
deoxy-2,3-O-isopropylidene- -ribo-1,4-pentofuranose-1-
D
yl]-isoxazolidine-3-carboxylic acid ethyl ester 5a. 5a
(1.582 g, 53%); HPLC: tR 11.2 min; sticky oil; [h]2D5=
1
−12 (c 1.01, CHCl3); H NMR (CDCl3, 500 MHz) l

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 167–172
171
4.1.4. (3S,5R)-2-[5-(tert-Butyldiphenylsilyl)-1-deoxy-2,3-
O - isopropylidene - - ribo - 1,4 - pentofuranose - 1 - yl] - 5-
magnesium sulfate and evaporated to give crude 8,
which is purified by radial chromatography (hexane/
EtOAc, 9:1, Rf=0.27) to afford pure 8 as an oil (0.187
D
[(1S,5R,7R)-10,10-dimethyl-3,3-dioxo-3l6-thia-4-aza-
tricyclo[5.2.1.01,5]decane-4-carbonyl]-isoxazolidine-3-car-
boxylic acid ethyl ester 6b. 6b (0.120 g, 3%); HPLC: tR
7.2 min; sticky oil; [h]2D5=−51 (c 0.34, CHCl3); 1H
NMR (CDCl3, 500 MHz) l 0.97 (s, 3H), 1.07 (s, 9H),
1.18 (s, 3H), 1.26 (t, 3H, J=7.2 Hz), 1.29 (s, 3H),
1.32–1.39 (m, 2H), 1.51 (s, 3H), 1.84–1.96 (m, 2H), 2.00
(dd, 1H, J=7.7, 13.8 Hz), 2.03–2.11 (m, 2H), 2.45 (ddd,
1H, J=8.6, 9.5, 12.6 Hz), 2.99 (ddd, 1H, J=4.0, 6.4,
12.6 Hz), 3.38 (d, 1H, J=13.5 Hz), 3.47 (d, 1H, J=13.5
Hz), 3.78 (dd, 1H, J=7.2, 10.6 Hz), 3.83 (dd, 1H,
J=5.7, 10.6 Hz), 3.89 (dd, 1H, J=4.8, 7.7 Hz), 3.95
(dd, 1H, J=6.4, 9.5 Hz), 4.18 (q, 2H, J=7.2 Hz), 4.19
(ddd, 1H, J=4.0, 5.7, 7.2 Hz), 4.54 (dd, 1H, J=4.0, 6.1
Hz), 4.74 (dd, 1H, J=4.0, 8.6 Hz), 4.91 (dd, 1H,
J=1.4, 6.1 Hz), 5.06 (d, 1H, J=1.4 Hz), 7.37–7.70 (m,
10H). 13C NMR (CDCl3, 125 MHz) l 14.1, 19.3, 19.9,
21.2, 25.3, 26.3, 26.8, 27.2, 33.2, 34.7, 38.3, 45.0, 47.7,
48.6, 53.2, 60.4, 61.3, 64.9, 65.9, 76.0, 81.2, 83.5, 87.4,
96.9, 112.6, 127.6, 127.6, 127.7, 127.7, 129.5, 129.6,
133.7, 133.7, 135.5, 135.5, 135.6, 135.7, 169.5, 169.7.
Anal. calcd for C41H56N2O10SSi: C, 61.78; H, 7.08; N,
3.51. Found: C, 61.84; H, 6.92; N, 3.40%.
1
g, 52%). [h]2D5=+44 (c 0.45, CHCl3); H NMR (CDCl3,
300 MHz) l 0.11 (s, 3H), 0.15 (s, 3H), 0.88 (s, 9H), 1.23
(t, 3H, J=7.3 Hz), 1.49 (s, 9H), 1.95 (dt, 1H, J=6.8,
13.1 Hz), 2.54 (dt, 1H, J=7.8, 13.1 Hz), 4.18 (dq, 1H,
J=7.3, 10.7 Hz), 4.22 (dq, 1H, J=7.3, 10.7 Hz), 4.26
(dd, 1H, J=6.8, 7.8 Hz), 4.41 (dd, 1H, J=6.8, 7.8 Hz).
13C NMR (CDCl3, 75.5 MHz) l −5.4, −4.6, 14.0, 18.9,
25.6, 27.9, 32.1, 55.7, 61.6, 70.5, 83.7, 149.8, 170.4,
171.4. Anal calcd for C18H33NO6Si C, 55.79; H, 8.58;
N, 3.61. Found: C, 55.93; H, 8.32; N, 3.97%.
The same procedure was applied to 5b (0.42 g, 0.53
mmol) and pure 8 (0.115 g, 56%) was obtained. The
physical and spectroscopic properties were identical to
those obtained for the compound prepared from 5a.
4.2.2. 1-tert-Butyl 2-ethyl (2S,4R)-4-[(tert-butyldi-
methylsilyl)oxy]-5-oxo-pyrrolidine-1,2-dicarboxylate 10.
The same procedure described above for the conversion
of 5a to 8 was applied to 6a (0.130 g, 0.21 mmol). After
radial chromatography (hexane/EtOAc, 9:1, Rf=0.21)
of the crude product, pure 10 (0.044 g, 54%) was
obtained as an oil. [h]2D5=+39 (c 0.32, CHCl3); 1H
NMR (CDCl3, 300 MHz) l 0.08 (s, 3H), 0.13 (s, 3H),
0.85 (s, 9H), 1.25 (t, 3H, J=7.2 Hz), 1.45 (s, 9H), 2.16
(dt, 1H, J=9.8, 13.2 Hz), 2.30 (ddd, 1H, J=1.5, 8.3,
13.2 Hz), 4.29 (q, 2H, J=7.2 Hz), 4.38 (dd, 1H, J=8.3,
10.0 Hz), 4.51 (dd, 1H, J=1.5, 9.6 Hz). 13C NMR
(CDCl3, 75.5 MHz) l −5.3, −4.5, 14.1, 18.2, 25.6, 27.9,
32.2, 55.1, 61.7, 69.7, 83.7, 149.5, 171.2, 172.0. Anal.
calcd for C18H33NO6Si: C, 55.79; H, 8.58; N, 3.61.
Found: C, 55.62; H, 8.67; N, 3.72%.
4.2. Reduction of compounds 5 and 6
4.2.1. 1-tert-Butyl 2-ethyl (2R,4R)-4-[(tert-butyldi-
methylsilyl)oxy]-5-oxo-pyrrolidine-1,2-dicarboxylate 8. A
solution of 5a (0.57 g, 0.93 mmol) in ethanol (7 mL)
was treated with concentrated HCl (1.2 mL) at ambient
temperature and the resulting solution is stirred until no
starting material remained (hexane/EtOAc, 4:1, Rf=
0.32) (ca. 6 h). The reaction mixture was poured into a
saturated aqueous solution of sodium carbonate (35
mL) and extracted with EtOAc (4×25 mL). The organic
layers were combined, dried over magnesium sulfate
and evaporated on a rotary evaporator to give a residue
which was taken up in ethanol (20 mL), treated with
Pearlman’s catalyst, Pd(OH)2–C (60 mg) and stirred
under hydrogen at ambient temperature and 2000 psi.
After 48 h, the reaction mixture was filtered through
Celite, which was washed with ethanol, and the filtrate
was evaporated under reduced pressure to give crude 7.
The formation of 7 was confirmed by TLC (hexane/
EtOAc, 1:1, Rf=0.12 or EtOAc/MeOH, 5:1, Rf=0.62).
The same procedure was applied to 6b (0.21 g, 0.26
mmol) and pure 10 (0.115 g, 59%) was obtained. The
physical and spectroscopic properties were identical to
those obtained for the compound prepared from 6a.
Acknowledgements
The authors are grateful to D.G.I. (Project CASAN-
DRA, MCYT, Madrid), D.G.A. (Project P116-2001,
Zaragoza), M.U.R.S.T. (Roma), and Italian C.N.R.
(Roma), for their financial supports; Chiacchio Maria
Assunta and Rossella Anita Sanfilippo for their techni-
cal assistance.
Crude 7 was dissolved in DMF (9 mL) and treated with
imidazole (0.378 g) and TBDMSCl (0.452 g, 3 mmol).
The resulting solution was stirred at 70°C until no
starting material was observed by TLC (ca. 3 h).
Methanol (3 mL) and water (30 mL) were added and
the resulting mixture was extracted with EtOAc (3×25
mL). The organic layers were combined, dried (magne-
sium sulfate) and evaporated under reduced pressure to
give crude 4, which was dissolved in CH2Cl2 (15 mL)
and treated with Boc2O (0.41 g, 1.86 mmol), Et3N (0.15
mL, 1 mmol) and DMAP (0.122 g, 1 mmol). The
reaction mixture was stirred at ambient temperature
overnight, at which time 1N KHSO4 (15 mL) was
added. The organic layer was separated, washed with
water (1×15 mL) and brine (1×15 mL), dried over
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