J. Wehbe et al. / Tetrahedron: Asymmetry 14 (2003) 1123–1126
1125
3. Conclusion
(2S,3S)-2b (minor isomer): Rf=0.41 (EtOAc/petroleum
ether, 1/1); H NMR (250 MHz, C6D6): l 0.8 (s, 3H),
1
We can conclude that for the threo compounds, the
(2S,3R) isomer is effectively the active isomer and also
that the stereogenicity of the b carbon is important, the
(2S,3S) enantiomer being less active than the (2S,3R)
isomer.
1.08 (t, 3H, J=7.1 Hz), 1.25 (s, 3H), 1.35 (d, 3H,
J=6.8 Hz), 1.45 (s, 9H), 1.7 (s, 3H), 1.85 (m, 1H), 1.97
(d, 1H, J=10.1 Hz), 2.25 (t, 1H, J=5.9 Hz), 2.39 (m,
3H), 2.52 (m, 2H), 2.88 (s, 1H), 3.12 (m, 1H), 4.06 (q,
2H, J=7.1 Hz), 4.41 (d, 1H, J=6.2 Hz); MS (ESI) m/z:
396.3 (M+H)+, 813.5 (2M+Na+).
4. Experimental
4.2. Synthesis of (2S,3R)-3a and (2S,3S)-3b
Melting points were obtained using a Bu¨chi 510 capil-
lary apparatus and are uncorrected. H NMR spectra
were recorded at 250 MHz using Bru¨cker AC250
instrument. For H NMR spectra recorded in CDCl3
1
Citric acid solution (15%, 4.4 ml, 2.1 mmol) was added
to a solution of Schiff base (0.8 g, 2 mmol) in THF (5.8
ml). The mixture was stirred at room temperature for 4
days. After evaporation of the solvent, the residue was
dissolved in H2O (10 ml) and washed with Et2O (3×15
ml). The aqueous phase was adjusted to pH 7 using
Na2CO3 and the amino ester was extracted with Et2O
(3×5 ml). The organic phase was dried (MgSO4) and
evaporated under reduced pressure to give a yellow oil.
1
chemical shifts are quoted in parts per million and are
referenced to the residual solvent peak. The following
abbreviations are used: s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; br, broad. Coupling constants
are reported in hertz (Hz). Low resolution mass spectra
were recorded on micromass electrospray instrument
with only molecular ion and other major peaks being
reported. Flash chromatography was carried out using
E-Merck silica gel (Kieselgel 60, 230–400 mesh) as
stationary phase. Thin layer chromatography was car-
ried out on aluminium plates pre-coated with Merck
silica gel 60F254 which were visualized by quenching of
UV fluorescence or by staining with a 10% methanol
phosphomolybdic acid solution followed by heat.
Preparative HPLC were performed on a Waters delta
4000 apparatus equipped with a Delta-Pack C18
column (15 Mm, 40×100 nm) and a UV detector, using
a linear gradient of CH3CN in H2O with 0.1% TFA
from 0 to 100% in 15 min. THF was distilled from
sodium/benzophenone ketyl. Reagents were supplied
from commercial sources (Aldrich, Fluka). The Schiff
base 1 was prepared as previously described.8
(2S,3R)-3a: Yield 50% Rf=0.25 (EtOAc/petroleum
1
ether, 1/1); H NMR (250 MHz, C6D6): l 1.01 (d, 3H,
J=7 Hz), 1.08 (t, 3H, J=7.1 Hz), 1.42 (s, 9H), 2.34
(dd, 1H, J=14.3 Hz, 6.8 Hz), 2.63 (dd, 1H, J=14.3 Hz,
6.5 Hz), 2.69 (m, 1H), 3.43 (d, 1H, J=3.4 Hz), 4.06 (q,
2H, J=7.1 Hz); MS (ESI) m/z: 246.2 (M+H)+, 190.1
(M−tBu+H)+.
(2S,3S)-3b: Yield 67% Rf=0.1 (EtOAc/petroleum ether,
1
1/1); H NMR (250 MHz, C6D6): l 1.09 (t, 3H, J=7.1
Hz), 1.1 (d, 3H, J=6.4 Hz), 1.45 (s, 9H), 2.26 (dd, 1H,
J=14.9 Hz, 8.7 Hz), 2.5 (m, 1H), 2.67 (dd, 1H, J=14.9
Hz, 4.5 Hz), 3.17 (d, 1H, J=5.7 Hz), 4.06 (q, 2H,
J=7.1 Hz); MS (ESI) m/z: 246.2 (M+H)+, 190.1 (M−
tBu+H)+.
4.1. Synthesis of (2S,3R)-2a and (2S,3S)-2b
4.3. Synthesis of (2S,3R) 5a and (2S,3S) 5b tert-butyl-
3-methylpyroglutamates
A solution of CH3MgBr in Et2O (3.07 ml, 9.24 mmol)
was added at −30°C to chiral Schiff base 1 (2 g, 7.1
mmol) dissolved in anhydrous THF (15 ml); DBU (1.4
ml, 9.24 mmol) was added and the mixture stirred
during 20 min after which ethyl crotonate (1.06 ml, 8.52
mmol) was introduced and the reaction followed by
TLC. After 30 min a NH4Cl saturated solution (5 ml)
was added and the aqueous phase extracted with
EtOAc. The combined extracts were dried (Mg SO4),
evaporated under reduced pressure and the residue
purified by silica gel column chromatography (Et2O/
CH2Cl2/petroleum ether 3/7/2). Two diastereomers
were separated, the (2S,3R) isomer (major, 42% yield)
and the (2S,3S) isomer (minor, 33% yield) as yellow
oils.
On standing at room temperature for 12 h, 3a and 3b
cyclised to afford the corresponding pyroglutamates in
quantitative yield.
1
(2S,3R)-5a: H NMR (400 MHz, CDCl3) l: 1.05 (d,
3H, J=7 Hz), 1.42 (s, 9H), 2 (dd, 1H, J=16.5 Hz, 6.8
Hz), 2.41 (d.d, 1H, J=16.5 Hz, 8.1 Hz), 2.73 (m, 1H),
4.05 (d, 1H, J=7.5 Hz), 6.2 (s, 1H). 13C NMR (400
MHz, CDCl3): l 16.03, 28.5, 33.1, 38.28, 60.86, 82.91,
170.27, 178.06; MS (FAB+) m/z: 200 (M+H)+, 399
(2M+H)+. HRMS: m/z calcd for C10H18NO3 200.1287,
found 200.1284.
(2S,3R)-2a (major isomer): Rf=0.48 (EtOAc/petroleum
1
1
(2S,3R)-5b: H NMR (400 MHz, CDCl3): l 1.21 (d,
ether, 1/1); H NMR (250 MHz, C6D6): l 0.82 (s, 3H);
3H, J=6.1 Hz), 1.4 (s, 9H), 1.97 (m, 1H), 2.48 (m, 2H),
3.65 (d, 1H, J=5.7 Hz), 6.4 (s, 1H). 13C NMR (400
MHz, CDCl3) l: 20.38, 38.37, 34.64, 38.6, 63.5, 82.69,
171.15, 177.35; MS (FAB+) m/z: 200 (M+H)+, 399
(2M+H)+. HRMS: m/z calcd for C10H18NO3 200.1287,
found 200.1284.
1.05 (t, 3H, J=7.2 Hz), 1.23 (s, 3H), 1.30 (d, 3H,
J=6.8 Hz), 1.43 (s, 9H), 1.67 (s, 3H), 1.88 (m, 1H), 1.91
(d, 1H, J=4.4 Hz), 2.25 (t, 1H, J=5.9 Hz), 2.35 (m,
1H), 2.6 (m, 3H), 2.84 (m, 2H), 3.1 (m, 1H), 4.08 (q,
2H, J=7.1 Hz), 4.2 (d, 1H, J=6.2 Hz); MS (ESI) m/z:
396.3 (M+H)+, 813.5 (2M+Na+).