N. Wild, U. Groth
FULL PAPER
3
H, CHCH
3
), 1.38 (t, 3
J
H,H ϭ 7.0 Hz, 3 H, CH
3
CH
2
O), 2.13
(NH
2
CH), 61.3 (CH
3
CH
2
O), 115.3 (py-C-3), 119.7 (py-C-5), 145.8
3
3
(dsept, JH,H ϭ 3.5 Hz, 1 H, CHCH
3
), 3.01 (d, JH,H ϭ 4.7 Hz, 2 (py-C-2), 149.9 (py-C-4), 164.3 (py-C-6), 165.1 (py-CO
2
), 174.8
): ν˜ ϭ 2963, 1745 (CO
) ppm. IR (CCl R), 1717
2 4 2
H, CH
3
2
), 3.56 (t, 3JH,H ϭ 3.5 Hz, 1 H, 2-H), 3.66 (s, 3 H, OCH
3
), (NH CHCO
2
(CO R), 1613, 1461, 1371, 1355, 1253, 1178, 1057, 1029 cm . MS
2
3
Ϫ1
.68 (s, 3 H, OCH
3
), 3.88 (s, 3 H, py-OCH
3
), 3.90 (q,
J
H,H
ϭ
ϩ
ϩ
7
J
.0 Hz, 2 H, CH
3
CH
2
O), 4.26 (s, 1 H, CϭCH(Z)H), 4.29 (q, (70 eV): m/z (%) ϭ 282 (5) [M ], 223 (66) [M Ϫ CO
2
CH
Ϫ OCH
3
], 195
],
3
ϩ
ϩ
H,H ϭ 4.7 Hz, 1 H, 5-H), 5.40 (s, 1 H, CϭCH(E)H), 6.43 (s, 1 H,
): 149 (100) [M Ϫ CO
], CO CH CH Ϫ C NO
(94) [M Ϫ C
3
ϩ
H
6
NO
2
], 177 (23) [M Ϫ CO
CH CH Ϫ CO CH
], 88 (38) [C
2
CH
2
CH
3
3
py-3-H), 7.10 (s, 1 H, py-5-H) ppm. 13C NMR (100 MHz, CDCl
δ ϭ 14.6 (CH CH O), 16.5 (CH ), 18.9 (CH ), 31.5 [CH(CH
), 52.2 and 52.4 (OCH ), 53.0 (py-OCH
0.5 (C-5), 63.2 (CH CH O), 83.9 (CϭCH ), 111.5 (py-C-3), 114.0
], 121 (49) [M
NO ]. C13H N O
2 18 2 5
ϩ
Ϫ
3
2
2
3
2
3
ϩ
3
2
3
3
3
)
2
2
2
3
3
H
6
2
3
H
6
3
6
9.3 (CH
2
3
3
), 55.7 (C-2), (282.29): calcd. C 55.31, H 6.43, N 9.92; found C 55.15, H 6.78,
N 9.55.
3
2
2
(
py-C-5), 149.7 (py-C-2), 149.8 (py-C-4), 158.7 (CϭN), 161.9 (Cϭ
N), 162.9 (py-C-6), 163.9 (CϭCH ) ppm. IR (CCl
): ν˜ ϭ 2944,
696 (CϭCOR), 1604, 1462, 1438, 1393, 1371, 1313, 1286, 1240,
2
4
3
(
1
-(6-Carboxy-2-oxo-4-pyridyl)-
1): A solution of 11 (0.03 g, 0.11 mmol) and LiOH (0.06 g,
.59 mmol) in MeOH/H O (3:1, 5 mL) was stirred at room tem-
L-alanine [(S)-(؊)-Acromelobic Acid]
1
1
(
Ϫ1
ϩ
198, 1174, 1054 cm . MS (70 eV): m/z (%) ϭ 375 (61) [M ], 360
2
ϩ
ϩ
50) [M Ϫ CH
3
], 332 (36) [M Ϫ CH(CH
3
)
2
], 193 (100)
perature for 16 h. The reaction mixture was neutralized with 2
ϩ
ϩ
[C H14NO ], 141 (99) [C H N O ]. C20H N O (375.46):
11 2 6 8 2 2 29 3 4
HCl and the solvent was removed in vacuo. The residue was dis-
solved in CHCl (5 mL), treated with TMSI (0.11 g, 0.53 mmol)
3
calcd. C 63.98, H 7.79, N 11.19; found C 64.05, H 7.27, N 11.35.
2R,5S)-5-[(2-Ethoxycarbonyl-6-methoxy-4-pyridyl)methyl]-2-iso-
propyl-3,6-dimethoxy-2,5-dihydropyrazine (10): Ozonized oxygen
was bubbled through a cooled solution (Ϫ78 °C) of (1-ethoxyvinyl)-
pyridine 9 (0.26 g, 0.70 mmol) and a few milligrams of Sudan III
and refluxed for 16 h. After addition of MeOH (20 mL), the solu-
tion was refluxed for a further 16 h. Solvent removal in vacuo and
(
purification of the crude compound by DOWEX MAC-3 ion ex-
change resin using water as eluent followed by DOWEX Re-
tardion 11A8 resin chromatography and lyophilization afforded
2 2
in CH Cl (25 mL) until the red colour disappeared. Dimethyl sulf-
(
S)-(Ϫ)-acromelobic acid (1, 0.02 g, 71%) as a pale yellow solid.
ide (0.09 g, 1.40 mmol) was added and the reaction mixture was
stirred at room temperature for 16 h. Solvent removal in vacuo
gave a crude product which was purified by chromatography using
petroleum ether/EtOAc (10:1) as eluent to give 10 (0.18 g, 69%) as
23
D
1
[α]
ϭ Ϫ133.1 (c ϭ 0.051, H
2
O). H NMR (600 MHz, D
2
O): δ ϭ
3
2
3
.09 (dd,
J
H,H ϭ 7.7,
JH,H ϭ 14.5 Hz, 1 H, CH ), 3.22 (dd,
2
3
2
3
J
H,H ϭ 5.9, JH,H ϭ 14.5 Hz, 1 H, CH
2
), 4.18 (dd, JH,H ϭ 5.9,
), 6.75 (s, 1 H, py-3-H), 7.05 (s, 1 H,
py-5-H) ppm. 13C NMR (150 MHz, D
O): δ ϭ 35.1 (CH ), 52.8
CH), 111.4 (py-C-3), 122.7 (py-C-5), 137.2 (py-C-2), 150.9
py-C-4), 163.6 (py-C-6), 164.0 (CO H), 171.2 (CO H) ppm. IR
KBr): ν˜ ϭ 3181, 3174, 3169, 3167, 3163, 1620 cm . UV: λmax
O) ϭ 225 and 310 nm. C (226.19): calcd. C 47.79, H
.46, N 12.39; found C 47.92, H 4.23, N 12.08.
3JH,H ϭ 7.8 Hz, 1 H, CHNH
2
a colorless oil. [α]2
400 MHz, CDCl
0
3
ϭ ϩ30.7 (c ϭ 0.99, EtOH). H NMR
1
D
2
2
3
(
3
): δ ϭ 0.61 (d, JH,H ϭ 6.8 Hz, 3 H, CHCH
3
),
), 1.37 (t, JH,H ϭ 7.0 Hz, 3
O), 2.13 (dsept, JH,H ϭ 3.5 Hz, 1 H, CHCH ), 3.06
(
(
(
(
NH
2
3
3
.93 (d, JH,H ϭ 7.0 Hz, 3 H, CHCH
3
2
2
Ϫ1
3
H, CH
3
CH
2
3
(
dd, 3
J
H,H ϭ 5.8, 2
JH,H ϭ 12.9 Hz, 2 H, CH
2
), 3.57 (t, 3JH,H
ϭ
H
2
9 10 2 5
H N O
3
.4 Hz, 1 H, 2-H), 3.64 (s, 3 H, OCH
3
), 3.68 (s, 3 H, OCH
3
), 3.95
4
(
s, 3 H, py-OCH
J
3
), 4.27 (q, 3
JH,H ϭ 4.4 Hz, 1 H, 5-H), 4.31 (q,
3
4
H,H ϭ 7.0 Hz, 2 H, CH
3
2
CH O), 6.66 (d, JH,H ϭ 1.2 Hz, 1 H,
4
13
py-3-H), 7.53 (d, JH,H ϭ 0.8 Hz, 1 H, py-5-H) ppm. C NMR
(
3
(
1
100 MHz, CDCl
1.6 [CH(CH ], 39.1 (CH
OCH ), 55.5 (C-5), 60.6 (C-2), 61.4 (CH
21.0 (py-C-5), 144.7, 150.3, 161.7, 163.9, 164.2, 165.3 ppm. IR
): ν˜ ϭ 2961, 1744, 1719, 1701, 1616, 1564, 1440, 1373, 1244
3
): δ ϭ 14.2 (CH
3
CH
2
O), 16.5 (CH
3
), 18.9 (CH
3
),
3
)
2
2
), 52.3 (OCH
3
), 52.4 (OCH
3
), 53.5 Acknowledgments
3
3 2
CH O), 115.7 (py-C-3),
We thank Dr. A. Jonczyk, Merck KG, for providing us with a
sample of the bis(lactim) ether of cyclo(--Val-Gly-) (8). We are
indebted to the Fonds der Deutschen Chemischen Industrie and to
the European Commission, Directorate XXII, for providing finan-
cial support.
(
(
(
CCl
4
Ϫ1
ϩ
C-OR), 1057 cm . MS (70 eV): m/z (%) ϭ 377 (40) [M ], 334
ϩ
ϩ
54) [M
Ϫ
CH(CH
], 141 (100) [C
(377.43): calcd. C 60.46, H 7.21, N 11.13; found C
3 2 3
) ], 195 (99) [C10H12NO ], 183 (97)
ϩ
2
ϩ
ϩ
[C
9
H
15
N
2
O
6 8 2 2 7 7
H N O ], 122 (59) [C H NO ].
C
19
H
27
N
3
O
5
60.15, H 7.03, N 11.00.
[
[
1]
2]
A. F. Parsons, Tetrahedron 1996, 52, 4149Ϫ4174.
4
-[(2-Ethoxycarbonyl-6-methoxy-4-pyridyl)methyl]-L-alanine Methyl
K. Yamano, K. Hashimoto, H. Shirahama, Heterocycles 1992,
Ester (11): 0.5 HCl (1 mL) was added to a stirred solution of 10
80.4 mg, 0.21 mmol) in MeCN (5 mL). The reaction mixture was
stirred at room temperature for 45 min. The solvent was removed
under reduced pressure, CH Cl (5 mL) was added to the residue,
3
4, 445Ϫ448.
(
[
3]
K. Yamano, H. Shirahama, Tetrahedron 1993, 49, 2427Ϫ2436.
J. E. Baldwin, M. R. Spyvee, R. C. Whitehead, Tetrahedron
Lett. 1994, 35, 6575Ϫ6576.
[4]
2
2
and the solution was adjusted to pH ϭ 9 by the addition of concd.
ammonia. Solvent removal in vacuo gave a crude yellow oil which
was purified by chromatography using petroleum ether/EtOAc
[5] [5a]
M. Adamczyk, S. R. Akireddy, R. E. Reddy, Org. Lett.
2000, 2, 3421Ϫ3423. [ M. Adamczyk, S. R. Akireddy, R. E.
5b]
[
5c]
Reddy, Tetrahedron: Asymmetry 2001, 12, 2385Ϫ2387.
M.
(1:500) as eluent to give 11 (51.7 mg, 86%) as a pale yellow solid.
Adamczyk, S. R. Akireddy, R. E. Reddy, Tetrahedron 2002,
2
3
1
58, 6951Ϫ6963.
[
1
α]
D
ϭ Ϫ2.9 (c ϭ 0.72, EtOH). H NMR (400 MHz, CDCl
3
): δ ϭ
),
), 3.06 (dd,
), 3.72 (s, 3 H, CO CH ),
), 3.98 (s, 3 H, py-OCH ), 4.38 (q,
CH O), 6.75 (s, 1 H, py-3-H), 7.54 (s, 1
H, py-5-H) ppm. C NMR (100 MHz, CDCl ): δ ϭ 14.3
CH CH O), 40.1 (CH ), 52.3 (CO CH ), 53.7 (py-OCH ), 54.9
[
[
6]
7]
3
For a review, see: R. M. Williams, Synthesis of optically active
α-amino acids, Pergamon Press, New York, 1989, p. 1 ff.
C. Ma, X. Liu, X. Li, J. Flippen-Anderson, S. Yu, J. M. Cook,
J. Org. Chem. 2001, 66, 4525Ϫ4542.
.39 (t, JH,H ϭ 7.4 Hz, 3 H, CH
3
CH
H,H ϭ 5.5, 2
JH,H ϭ 13.3 Hz, 1 H, CH
2 2
O), 1.71 (br. s, 2 H, NH
.83 (dd, 3
2
J
2
3
2
J
H,H ϭ 5.1, JH,H ϭ 13.7 Hz, 1 H, CH
2
2
3
3
.69Ϫ3.76 (m, 1 H, CHNH
J
2
3
[8]
[9]
V. Ojea, M. Ruiz, G. Shapiro, E. Pombo-Villar, J. Org. Chem.
3
H,H ϭ 7.4 Hz, 2 H, CH
3
2
2
000, 65, 1984Ϫ1995.
13
3
P. Dalla Croce, C. La Rosa, E. Pizzatti, Tetrahedron: Asym-
metry 2000, 11, 2635Ϫ2642.
(
3
2
2
2
3
3
4448
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4445Ϫ4449