A. Gondela, K. Walczak / Tetrahedron: Asymmetry 16 (2005) 2107–2112
2111
(
CDCl ), d (ppm) = 16.65, 28.99, 53.64, 55.39, 90.26,
46.32; H, 5.30; N, 14.73. Found: C, 46.55; H, 5.61; N,
14.45.
3
113.26, 148.02, 150.15, 158.89, 170.12. Anal. Calcd for
C H N O (237.22): C, 50.63; H, 4.67; N, 17.71.
Found: C, 50.38; H, 4.47; N, 17.57.
1
0
11
3
4
4.6.5. (S)-(ꢀ)-3-Phenyl-2-(3-methyl-5-nitrouracil-1-yl)prop-
1
ionic acid 8e. Yield 0.15 g (50%); R = 0.81 (A). H
f
4
.6. Synthesis of 2-(3-methyl-5-nitrouracil-1-yl)alkanoic
NMR (DMSO-d ), d (ppm) = 3.17 (s, 3H, N–CH ),
6
3
acids 8a–f from a-amino acids 7a–f (general procedure)
3.37 (dd, 1H, J = 9.9 Hz, J = 14.1 Hz, CH ), 3.47 (dd,
1H, J = 5.7 Hz, J = 14.1 Hz, CH ), 5.41 (dd, 1H,
J = 5.7 Hz, J = 9.9 Hz, CH), 7.16–7.32 (m, 5H, Ar),
2a
2b
The suitable a-amino acid 7a–f (2.0 mmol) was dissolved
in water (1.0 ml) and an equimolar amount of triethyl-
amine added (2 mmol). The mixture was stirred at ambi-
ent temperature for 30 min and then 3-methyl-5-nitro-1-
0
13
9.06 (s, 1H, H-6 ), 13.4 (br s, 1H, OH). C NMR
(DMSO-d ), d (ppm) = 28.38, 34.93, 63.21, 124.36,
6
126.92, 128.59 (2C), 129.07 (2C), 136.47, 147.71,
149.18, 153.66, 169.26. Anal. Calcd for C H N O
6
(
4-nitrophenyl)uracil 4a (1.0 mmol) and DMF (3.0 ml)
were added. During the reaction, triethylamine
1.0 mmol), which was necessary for the shift of beta-
1
4
13
3
(319.27): C, 52.67; H, 4.10; N, 13.16. Found: C, 52.95;
H, 4.50; N, 12.88.
(
ine-triethylammonium salt equilibrium towards the free
amine, was periodically added via syringe. The resulting
yellowish-brown mixture was stirred until the decay of
4.6.6. (S)-(ꢀ)-3-(4-Hydroxyphenyl)-2-(3-methyl-5-nitro-
uracil-1-yl)propionic acid 8f. Yield 0.19 g (57%);
1
the substrate (48–72 h, TLC, MeOH/CHCl , 20:80).
3
R = 0.81 (A). H NMR (DMSO-d ), d (ppm) = 3.14
f
6
The solvents were evaporated under reduced pressure,
and the resulting residue diluted in water (10 ml), acidi-
fied with 5% aq HCl and decolourized with charcoal.
Water was evaporated under reduced pressure and the
yellow residue purified on a silica gel column using the
(s, 3H, N–CH ), 3.24 (d, 1H, J = 5.4 Hz, CH ), 5.23
0
3
2
(d, 1H, J = 5.4 Hz, CH), 6.62 (d, 2H, J = 8.7 Hz, H-2 ,
0
0
0
H-6 ), 6.96 (d, 2H, J = 8.7 Hz, H-3 , H-5 ), 8.82 (s, 1H,
H-6 ), 9.43 (br s, 1H, OH–Ar), COOH—not observed.
00
1
3
C NMR (DMSO-d ), d (ppm) = 28.33, 35.81, 62.93,
6
mixture of MeOH and CHCl (1:1) as eluent (System
3
A). After recrystallization from methanol, an analytical
sample was obtained.
115.26 (2C), 123.25, 127.15, 130.18 (2C), 148.25,
149.82, 153.89, 156.11, 169.99. Anal. Calcd for
C H N O (335.27): C, 50.16; H, 3.91; N, 12.53.
1
4
13
3
7
Found: C, 49.85; H, 4.25; N, 12.17.
4
0
.6.1. 2-(3-Methyl-5-nitrouracil-1-yl)acetic acid 8a. Yield
1
.2 g (87%); R = 0.38 (A). H NMR (DMSO-d ), d
f
6
(
9
ppm) = 3.22 (s, 3H, NCH ), 4.36 (s, 2H, CH ),
References
3
2
0
13
.21 (s, 1H, H-6 ), OH—not observed. C NMR
(
1
DMSO-d ), d (ppm) = 28.20, 52.61, 123.76, 149.70,
1. Petersen, M.; Wengel, J. Trends Biotech. 2003, 21, 74–
81.
6
49.78, 154.37, 169.08. Anal. Calcd for C H N O
7
7
3
6
2
3
4
. Larsen, H. J.; Bentin, T.; Nielsen, P. E. Biochem. Biophys.
Acta 1999, 1489, 159–166.
(229.15): C, 36.69; H, 3.08; N, 18.34. Found: C, 36.97;
H, 3.06; N, 18.67.
¨
. Pooga, M.; Land, T.; Bartfai, T.; Langel, U. Biomol. Eng.
001, 17, 183–192.
2
4
8
1
.6.2. (S)-(+)-2-(3-Methyl-5-nitrouracil-1-yl)propionic acid
b. Yield 0.14 g (58%); R = 0.58 (A); MS ESI [M+
. Hyrup, B.; Egholm, M.; Nielsen, P. E.; Wittung, P.;
Norden, B.; Buchardt, O. J. Am. Chem. Soc. 1994, 116,
7964–7970; Ganesh, K. N.; Nielsen, P. E. Curr. Org.
Chem. 2000, 4, 931–943.
f
+
1
] = 244 (14). H NMR (DMSO-d ), d (ppm) = 1.54
6
(
d, 3H, J = 7.2 Hz, CH ), 3.22 (s, 3H, N–CH ), 5.03
3 3
0
(
observed.
q, 1H, J = 7.2 Hz, CH), 9.07 (s, 1H, H-6 ), OH—not
C NMR (DMSO-d ), d (ppm) = 17.10,
5. Altman, K. H.; Chesi, Ch. S.; Garcia-Echeverria, C.
Bioorg. Med. Chem. Lett. 1997, 7, 1119–1122.
6. Maison, W.; Schlemminger, I.; Westerhoff, O.; Martens, J.
Bioorg. Med. Chem. 2000, 8, 1343–1360.
1
3
6
2
1
8.38, 45.11, 57.65, 124.20, 147.52, 149.69, 154.18,
71.57. Anal. Calcd for C H N O (243.18): C, 39.51;
8
9
3
6
7
. Longley, D. B.; Harkin, D. P.; Johnston, P. G. Nature
Rev. 2003, 3, 330–338.
H, 3.73; N, 17.28. Found: C, 39.37; H, 3.46; N,
1
7.07.
8
. Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.;
Nitta, I.; Baba, M.; Shigeta, S.; Walker, R. T.; De Clercq,
E.; Miyasaka, T. J. Med. Chem. 1992, 35, 337–345.
4
8
.6.3. (R)-(ꢀ)-2-(3-Methyl-5-nitrouracil-1-yl)propionic acid
c. Yield 0.12 g (50%); R = 0.58 (A). Anal. Calcd for
f
9. Trusule, M.; Kupce, E.; Augustane, I.; Verovskii, N. V.;
Lukevics, E.; Baumane, L.; Gavars, R.; Stradins, J. Khim.
Geterotsikl. Soedin. 1991, 12, 1687–1694.
C H N O (243.18): C, 39.51; H, 3.73; N, 17.28. Found:
8
9
3
6
C, 39.17; H, 3.44; N, 16.97.
1
0. Copik, A.; Suwi n´ ski, J.; Walczak, K.; Bronikowska, J.;
Czuba, Z.; Kr o´ l, W. Nucleosides, Nucleotides Nucleic
Acids 2002, 21, 377–383.
4.6.4. (S)-(+)-4-Methyl-2-(3-methyl-5-nitrouracil-1-yl)penta-
noic acid 8d. Yield 0.13 g (46%); R = 0.16 (MeOH/
f
1
11. Nielsen, P.; Dreiøe, L. H.; Wengel, J. Bioorg. Med. Chem.
995, 3, 19–28.
CHCl , 2:8). H NMR (DMSO-d ), d (ppm) = 0.88 (d,
3
6
1
2. Lee, K. H.; Chen, Y. L.; Huang, B. R.; Tzeng, Ch. Ch.;
3
1
H, J = 6.6 Hz, CH ), 0.89 (d, 3H, J = 6.6 Hz, CH ),
.44–1.58 (m, 1H, CH), 1.76–2.00 (m, 2H, CH ), 3.22
3
3
1
2
Zhu, Q. Y.; Chou, T. Ch. Nucleosides Nucleotides 1991,
0, 1407–1416.
(
Hz, CH), 9.01 (s, 1H, H-6 ), OH—not observed.
s, 3H, N–CH ), 5.03 (dd, 1H, J = 4.5 Hz, J = 10.5
3
1
0
13
C
1
3. Ouchi, T.; Jokei, S.; Fujie, H.; Chikashita, H.; Inoi, T. J.
Heterocycl. Chem. 1984, 21, 1023–1024.
NMR (DMSO-d ), d (ppm) = 21.30, 22.99, 24.43,
6
2
1
8.47, 48.62, 59.88, 124.25, 147.41, 150.10, 154.04,
71.50. Anal. Calcd for C H N O (285.26): C,
14. Esposito, A.; Perino, M. G.; Taddei, M. Eur. J. Org.
Chem. 1999, 931–936.
1
1
15
3
6