J. Wehbe et al. / Tetrahedron: Asymmetry 15 (2004) 851–858
857
(0.078 g, 58%). Mp: 160–162 ꢁC. d.r.: 78/22 (1H NMR)
1H NMR (250 MHz, D2O): d 2.1 (m, 4H HCb and
CHd), 2.79 (m, 1H, CHc), 3.79 (m, 1H, CHa), 7.01
(d, 1H, J ¼ 512:2 Hz, P–H). 31P NMR (250 MHz, D2O)
d ¼ 22:21, 26.13. MS (ES) m=z 225.7 (M+Hþ), 451.1
(2M+H)þ.
mixture of two cyclic aminoesters. After recrystalliza-
tion (EtOAc/hexane 2/8), the major isomer 13a (2S,4S)
was isolated and characterized. Mp ¼ 69–72 ꢁC. IR:
1
1727 cmꢀ1, 1673 cmꢀ1. H NMR (250 MHz, CDCl3) see
Table 1. ½aꢁ ¼ ꢀ4:2 (c 5.7, C6D6). MS (ES) m=z 202
D
(M)t-Bu+H)þ, 258 (M+H)þ, 280 (M+Na)þ, 515.5
(2M+H)þ, 537.2 (2M+Na)þ.
4.5. Synthesis of 11, 12a, and 12b
12a provided 15a in 85% yield as a yellow oil. Rf : 0.23
(CH2Cl2/Et2O/petroleum ether 7/7/2). 1H NMR
(250 MHz, C6D6) d 1.4 (s, 2 · 9H, t-Bu), 1.6 (s, 2H,
NH2), 1.7–1.9 (m, 2H, H3), 2.8 (m, 1H, H4), 3.35 (m, 3H,
H5+H2), 3.7 (s, 3H, CH3), 5.1 (m, 1H, NH). MS (ES)
m=z 347.2 (M+H)þ.
To Schiff base 1 (0.61 g, 2.19 mmol) dissolved in anhy-
drous THF (10 mL) was added at )20 ꢁC 3 M CH3MgBr
(0.73 mL, 2.84 mmol). After stirring for 20 min, DBU
(0.42 mL, 2.4 mmol) was added and the mixture then
stirred for 30 min, after which the electrophile
(2.5 mmol) was added and the reaction maintained at
)20 ꢁC for 3 h monitored by TLC. The reaction was then
quenched with saturated NH4Cl (10 mL) and the mix-
ture extracted with EtOAc (3 · 10 mL); the organic lay-
ers were combined and dried over MgSO4, evaporated
and purified by silica gel column chromatography, to
afford compounds 11 and 12. From methyl itaconate as
electrophile (Scheme 1, R ¼ CO2Me), compound 11 was
obtained in 73% yield as a mixture of two unseparable
isomers using the eluent EtOAc/hexane 7/3. Rf : 0.5
(EtOAc/hexane 7/3 for column chromatography) 1H
NMR (250 MHz, C6D6): d 0.8 (s, 3H, CH3 minor), 0.9
(s, 3H, CH3 major), 1.21 (s, 3H, CH3 minor), 1.25 (s,
3H, CH3 major), 1.4 (2s, 2 · 9H, t-Bu), 1.71 (s, 3H, CH3
minor), 1.78 (s, 3H, CH3 major), 1.8–2.9 (m, 10H), 3.1
(m, 1H, CH4 minor), 3.3 (m, 1H, CH4 major), 3.4 (s, 3H,
CO2CH3 major), 3.42 (s, 3H, CO2CH3 minor), 4.45 (s,
3H, CO2CH3 major), 3.48 (s, 3H, CO2CH3 minor), 4.32
(dd, 1H, J ¼ 8:3 Hz, J ¼ 4:1 Hz, H2 minor), 4.45 (dd,
1H, J ¼ 10 Hz, J ¼ 3:85 Hz, H2 major). MS (ES) m=z
440.3 (M+H)þ, 462.30 (M+Na)þ.
12b afforded 15b in 85% yield. Rf : 0.13 (CH2Cl2/Et2O/
1
petroleum ether 7/7/2). H NMR (250 MHz, C6D6): d
1.45 (s, 2 · 9H, t-Bu), 1.75 (s, 2H, NH2), 2.21 (m, 2H,
H3), 2.85 (m, 1H, H4), 3.4 (m, 3H, H5+H2), 3.72 (s, 3H,
CH3 ), 5.2 (m, 1H, NH). MS (ES) m=z 347.2 (M+H)þ.
15a and 15b left at room temperature were quantita-
tively transformed into tert-butyl 4-(tert-butyloxycarb-
onylaminomethyl) pyroglutamates 16a and 16b.
16a (2S,4R) major isomer. Rf : 0.3 (CH2Cl2/Et2O/petro-
1
leum ether 7/7/2). H NMR (250 MHz, C6D6): d 1.5 (s,
2 · 9H, t-Bu), 1.75 (m, 1H, H3), 2.1 (m, 1H, H3), 2.2 (m,
1H, H5), 3.4 (m, 1H, H4), 3.6 (m, 2H, H2+H5), 5.9 (m,
1H, NH). MS (ES) m=z 259 (M)t-Bu+H)þ, 315.1
(M+H)þ, 336.9 (M+Na)þ, 629 (2M+H)þ, 651.2 (2M+
Na)þ 16b (2S,4S) minor isomer. Rf : 0.2 (CH2Cl2/Et2O/
1
petroleum ether 7/7/2). H NMR (250 MHz, C6D6): d
1.45 (s, 2 · 9H, t-Bu), 2.2 (m, 2H, H3), 2.72 (m, 2H, H5),
3.3 (m, 1H, H4), 4.0 (m, 1H, H2), 5.4 (m, 1H, NH). MS
(ES) m=z 259 (M)t-Bu+H)þ, 315.1 (M+H)þ, 336.9
(M+Na)þ, 629 (2M+H)þ, 651.2 (2M+Na)þ.
From methyl-2-(tert-butyloxycarbonyl aminomethyl)
acrylate (Scheme 2––R ¼ NHBoc) as the electrophile
12a and 12b were obtained in 75% yield as a mixture of
two diastereomers, which were separated by column
chromatography using as eluent CH2Cl2/Et2O/petro-
leum ether (7/7/2). 12a (2S,4R) yield ¼ 35%. Rf : 0.5
(CH2Cl2/Et2O/petroleum ether 7/7/2). 1H NMR
(250 MHz, C6D6): d 0.9 (s, 3H, CH3), 1.25 (s, 3H, CH3),
1.49 (s, 9H, t-Bu), 1.56 (s, 9H, t-Bu), 1.77 (s, 3H, CH3),
1.9–3.2 (s, 10H), 3.4 (m, 4H, CO2CH3+CH4), 4.55 (dd,
1H, J ¼ 9:4 Hz J ¼ 5:2 Hz, CH2), 5.45 (t, 1H,
J ¼ 8:2 Hz, NH). MS (ES) m=z 497.3 (M+H)þ, 519.3
(M+Na)þ 12b (2S,4S) yield ¼ 30%. Rf : 0.41 (CH2Cl2 M/
Et2O/petroleum ether 7/7/2).1H NMR (250 MHz, C6D6):
d 0.91 (s, 3H, CH3), 1.27 (s, 3H, CH3), 1.43 (s, 9H, tBu),
1.51 (s, 9H, tBu), 1.7 (s, 3H, CH3), 1.9–3.2 (m, 10H),
3.41 (m, 4H, CO2CH3+H4), 4.45 (dd, 1H, J ¼ 8:1 Hz,
J ¼ 4:7 Hz, H2), 4.9 (t, 1H, J ¼ 8:2 Hz, NH). MS (ES)
m=z 497.3 (M+H)þ, 519.3 (M+Na)þ.
4.7. Synthesis of 4-aminomethyl pyroglutamates 17a
(2S,4R) and 17b (2S,4S)
To 16a (or 16b) (0.06 g, 0.17 mmol) dissolved in THF
(1 mL) was added 2 M HCl (1 mL, 2 mmol) and the
mixture stirred 2 h at room temperature. After evapo-
ration of the solvent, the product was extracted into
EtOAc (3 · 5mL). The organic layer was dried and
evaporated under vacuum to afford 17a (or 17b) in 95%
1
yield as a white solid. 17a (2S,4R) H NMR (400 MHz,
D2O or CD3OD) see Table 2. Mp ¼ 83–85 ꢁC. 13C NMR
(400 MHz, D2O): d 29.08 (Cb), 39.11 (Cc), 40.40 (Cd),
54.56 (Ca), 175.87 (CO), 178.88 (COOH). MS (FABþ):
m=z ¼ 159:1 (M+H)þ, 383 (2M+H)þ HRMS (FABþ):
m=z calcd for C6H12NO4 (M+H)þ 159.0767, found
159.0783. ½aꢁ ¼ ꢀ11:2 (c 13.2, CD3OD).
D
1
17b (2S,4S) H NMR (400 MHz, D2O or CD3OD) see
Table 2. Mp ¼ 65–67 ꢁC. 13C NMR (400 MHz, D2O): d
29.30 (Cb), 37.80 (Cc), 40.24 (Cd), 54.35 (Ca), 176.46
(CO), 179.46 (COOH). MS (FABþ): m=z ¼ 159:1
(M+H)þ. HRMS (FABþ): m=z calcd for C6H12NO4
4.6. Hydrolysis of the Schiff bases 11, 12a, and 12b
Using the experimental procedure described for com-
pound 2; 13, 15a, and 15b were prepared. Compound 11
afforded 13 in 74% yield, as a white solid, which was a
(M+H)þ 159.0767, found 159.0765. ½aꢁ ¼ þ47:3 (c 5.2,
D
CD3OD).