13
5
Preparation of [1,2,3,4,5- C ]-5-Amino-4-oxopentanoic Acid
FULL PAPER
3
3
1
.87 (m, 2 H, OCH
2
), 3.47 (s, 2 H, CH
.99 (td, JH,H ϭ 4.11 Hz, CH CH CH), 1.28 (t, JH,H ϭ 7.21 Hz,
CH ): δ ϭ 201.4 (CϭO)
) ppm. 13C NMR (50 MHz, CDCl
66.5 (CϭO), 102.3 (CH), 64.42, 60.74, 48.66, 36.16, 26.85, OCH
3.51 ppm.
2
), 2.68 (t, 2 H, CH
2
CH
2
CH), (300 MHz, CDCl
3.51 (s, CH ), 2.88 (m,
2
H-H ϭ 6.52 Hz, 2 H, CH ), 1.28 (t, J
3
): δ ϭ 4.22 (q, JH-H ϭ 6.86 Hz, 2 H, OCH
2
CH
), 2.66 (t,
H-H ϭ 7.21 Hz, 3 H,
) ppm. C NMR (75 MHz, CDCl ): δ ϭ 36.54 ppm.
3
),
3
3
3
2
2
2
JC-H ϭ 128.6 Hz, 2 H, CH
2
3
3
OCH
1
1
2
3
3
J
1
3
2
CH
3
3
5
-(Acetylamino)-6-ethoxy-4,6-dioxohexanoic Acid (11): A solution
of NaNO (0.48 g, 7 mmol) in H O (10 mL) was added dropwise
13
Ethyl
[2,3,4,5,2Ј- C
5
]-5-(1Ј,3Ј-Dioxolan-2Ј-yl)-3-oxopentanoate
2
2
(
9A): Similarly, 8A (1.05 g, 8 mmol), activated Zn (2.00 g, 30 mmol) (45Ϫ60 min) to a cooled (0 °C) and stirred solution of 10 (1.00 g,
13
and ethyl [2- C]bromoacetate (3.36 g, 20 mmol) yielded 9A (1.50 g,
5.18 mmol) in glacial acetic acid (10 mL). The mixture was stirred
at 0Ϫ5 °C for 4 h and then at room temp. for 18 h. The mixture
1
8
1
3
1
5%). 1H NMR (200 MHz, CDCl
3
): δ ϭ 4.92 (dm,
74.7 Hz, 1 H, CH), 4.18 (q, JH,H ϭ 7.12 Hz, 2 H, OCH
J
C,H
ϭ
3
), was extracted with ethyl acetate (3 ϫ 50 mL), the combined organic
extracts were collected, washed with brine, and dried with MgSO
The solvent was removed under reduced pressure to yield 6-ethoxy-
CH), 5-oximino-4,6-dioxohexanoic acid (0.95 g, 4.27 mmol, 82%) as a
2
2
CH
3
1
.93 (m, 2 H, OCH
2
), 3.84 (m, 2 H, OCH
2
), 3.47 (dd,
J
C,H
ϭ
4
.
2
1
30.4, JC,H ϭ 5.84 Hz, 2 H, CH
2
), 2.68 (dm, JC,H ϭ 126.6 Hz, 2
CH), 1.99 (dm, JC,H ϭ 131.7 HZ, 2 H, CH CH
): δ ϭ light-yellow crystalline solid. H NMR (300 MHz, CDCl
1
H, CH
2
CH
2
2
1
1
2
4
.28 (t, 3 H, OCH
2
CH
3
) ppm. 13C NMR (50 MHz, CDCl
3
3
): δ ϭ
1
1JC-C ϭ 39.55 Hz, CϭO),) 103.4 (dd,
1
3
01.4 (t,
J
C-C
ϭ
J
J
C-C
ϭ
11.05 (br., COOH), 4.39 (q, JH-H ϭ 6.8 Hz, 2 H, CH ), 3.13 (t, 2
2
3.94, 2
J
C-C ϭ 5.86 Hz, CH), 49.45 (dd,
1
JC-C ϭ 38.08,
2
ϭ
13
H, CH
2
), 2.72 (t, 2 H, CH
2
), 1.34 (t, 3 H, CH
3
) ppm. C NMR
C-C
), 36.28 (tdd, JC-C ϭ JC-C ϭ 35.16, 2JC-C ϭ 5.85, (75 MHz, CDCl
1
1
): δ ϭ 193.2 (CϭO), 177.7 (CϭO), 161.1 (CϭO),
1
J
4.65 Hz, CH
2
3
2
C-C ϭ 13.91 Hz), 26.79 (ddd, 1
C-C ϭ 1
2
J
JC-C ϭ 43.95,
J
C-C
ϭ
149.5 (CϭN), 62.00, 31.79, 26.76, 13.40 ppm. Zn dust (2.09 g,
32 mmol) was added in portions to a solution of 6-ethoxy-5-oxim-
ino-4,6-dioxohexanoic acid (0.95 g, 4.27 mmol), acetic anhydride
5.86 Hz) ppm.
13
Ethyl [5- C]-5-(1Ј,3Ј-Dioxolan-2Ј-yl)-3-oxopentanoate (9B): Simi-
(
2.04 g, 20 mmol), and acetic acid (10 mL) over a period of 1 h.
1
larly, 8B (0.64 g, 5 mmol) yielded 9B (0.87 g, 4 mmol, 80%).
NMR (200 MHz, CDCl C-H ϭ 131.7 Hz,
): δ ϭ 1.99 (dm, 1
CH CH ): δ ϭ 26.88 ppm.
CH) ppm. 13C NMR (50 MHz, CDCl
H
The mixture was stirred at room temp. for 18Ϫ24 h, filtered, and
the residue was washed with ethyl acetate (3 ϫ 20 mL). The solvent
was evaporated under reduced pressure to yield 11 (0.90 g,
3
J
2
2
3
1
3
.59 mmol, 84%) as a light-brown oil. H NMR (200 MHz,
13
Ethyl [4- C]-5-(1Ј,3Ј-dioxolan-2Ј-yl)-3-oxopentanoate (9C): Simi-
3
3
CDCl ): δ ϭ 10.50 (br., COOH), 7.56 (br., NH), 5.27 (d, JH-H ϭ
1
larly, 8C (1.53 g, 12 mmol) yielded 9C (2.17 g, 10 mmol, 83%). H
3
6
2
CH
(
.86 Hz, CH-NH), 4.21 (q, JH-H ϭ 7.20 Hz, OCH
H, CH ), 2.75 (m, 2 H, CH ), 2.06 (s, 3 H, CH ), 1.29 (t, 3 H,
) ppm. 13C NMR (50 MHz, CDCl
): δ ϭ 197.9 (CϭO) 173.5
CϭO) 169.8 (CϭO) 160.0 (CϭO), 60.60, 60.48, 25.84, 25.00,
21.42, 13.48 ppm.
2 3
CH ), 3.02 (t,
1
3
NMR (200 MHz, CDCl
3
): δ ϭ 2.68 (dt, JC-H ϭ 126.6, JH-H
ϭ
2
2
3
7
.56 Hz, CH
2
CH
2
CH) ppm. 13C NMR (50 MHz, CDCl
01.8 (d, JC-C ϭ 41.05 Hz, CϭO), 36.16 (CH
3
): δ ϭ
1
3
3
2
2
CH CO) ppm.
2
α-Ethoxycarbonyl-β-oxoadipic Acid (10): CrO
to a solution of 9 (1.50 g, 6.78 mmol) in 50% AcOH in H
40 mL). The reaction mixture was stirred at room temp. for 16 h.
The mixture was extracted with diethyl ether (6 ϫ 100 mL), washed
with brine, and dried with MgSO . The solvent was evaporated
under reduced pressure to yield 10 as a light-yellowish oil (1.00 g,
3
(3.50 g) was added
2
O
1
3
[
(
1,2,3,4,5- C
11A): Similarly, 10A (1.00 g, 5.18 mmol) yielded [1,2,3,4,5- C
ethoxy-5-oximino-4,6-dioxohexanoic acid (0.95 g, 4.27 mmol, 82%)
5
]-5-(Acetylamino)-6-ethoxy-4,6-dioxohexanoic Acid
(
1
3
5
]-6-
4
1
as a light-yellow crystalline solid. H NMR (300 MHz, CDCl
3
):
ϭ
3
1
δ ϭ 4.39 (q,
37.4 Hz, CH
ϭ 6.86 Hz, OCH
J
H-H ϭ 6.87 Hz, OCH
2
CH
3
), 3.11 (dm,
J
C-H
3
1
8
7%) which crystallized after standing at 0 °C for 2 d. H NMR
1
1
2
), 2.72 (dm, JC-H ϭ 137.4 Hz, CH
2
), 1.34 (t, JH-H
) ppm. C NMR (75 MHz, CDCl ): δ ϭ
3 3
3
(
300 MHz, CDCl
3
): δ ϭ 4.22 (q, JH-H ϭ 6.86 Hz, 2 H, OCH
2
CH
), 2.66 (t,
H-H ϭ 7.21 Hz, 3 H,
) ppm. 13C NMR (75 MHz, CDCl
): δ ϭ 200.4 (CϭO),
77.5 (CϭO), 166.5 (CϭO), 60.97 (OCH CH ), 48.57 (CH ), 36.54
CH ), 27.12 (CH ), 13.45 (OCH CH ) ppm.
3
),
1
3
CH
3
2
3
.51 (s, 2 H, CH
2
), 2.88 (t, JH-H ϭ 6.18 Hz, 2 H, CH
H-H ϭ 6.52 Hz, 2 H, CH
), 1.28 (t, 3
CH
2
1
1
1
1
92.8 (dd, JC-C ϭ 62.53, JC-C ϭ 42.48 Hz, CϭO), 177.8 (d, JC-
3
J
2
J
1
2
C
ϭ 57.12 Hz, COOH), 149.5 (dd, JC-C ϭ 61.52, JC-C ϭ 11.72 Hz,
OCH
1
2
3
3
CϭN), 31.81 (td, JC-C ϭ JC-C ϭ 38.09, 2JC-C ϭ JC-C ϭ 11.73 Hz,
1
1
2
2
3
2
), 26.74 (dd, JC-C ϭ 55.67, 1JC-C ϭ 38.09 Hz, CH
1
CH
2
2
) ppm. Zn
(
2
2
2
3
dust (2.09 g, 32 mmol) was added in portions to a solution of
1
3
1
3
[1,2,3,4,5- C ]-6-ethoxy-5-oximino-4,6-dioxohexanoic acid (0.95 g,
[
2,3,4,5,6- C ]-α-Ethoxycarbonyl-β-oxoadipic Acid (10A): Similarly,
5
5
1
4.27 mmol), acetic anhydride (2.04 g, 20 mmol), and acetic acid
9
A (1.50 g, 6.78 mmol) yielded 10A (1.00 g, 87%). H NMR
3
(10 mL) over a period of 1 h. The mixture was stirred at room temp.
for 18Ϫ24 h, filtered, and the residue washed with ethyl acetate (3
ϫ 20 mL). The solvent was evaporated under reduced pressure to
(
3 2 3
300 MHz, CDCl ): δ ϭ 4.22 (q, JH-H ϭ 6.86 Hz, 2 H, OCH CH ),
1
2
1
3
1
7
2
5
3
.51 (dd, JC-H ϭ 130.4, JC-H ϭ 6.52 Hz, CH
2
), 2.88 (m, JC-H
ϭ
1
3
26.6 Hz, CH
2
), 2.66 (m, JC-H ϭ 128.6 Hz, CH
2
), 1.28 (t, JH-H
ϭ
1
) ppm. 1 C NMR (75 MHz, CDCl
3
yield 11A (0.90 g, 3.59 mmol, 84%) as a light-brown oil. H NMR
.21 Hz, 3 H, OCH
2
CH
3
3
): δ ϭ
00.2 (t, 1
1JC-C ϭ 39.55 Hz, CϭO), 177.2 (d,
1
3
(200 MHz, CDCl ): δ ϭ 10.50 (br., COOH), 7.56 (br., NH), 5.27
J
C-C
ϭ
J
C-C
ϭ
3
3
1
2
(d, JH-NH ϭ 6.86 Hz, CH-NH), 4.21 (q, JH-H ϭ 7.20 Hz,
OCH CH ), 3.02 (t, 2 H, CH ), 2.75 (m, 2 H, CH ), 2.06 (s, 3 H,
7.13 Hz, CϭO), 48.39 (dd, JC-C ϭ 52.74, JC-C ϭ 13.19 Hz, CH
2
),
1
2
1
6.66 (td, JC-C ϭ 39.55, JC-C ϭ 13.18 Hz, CH
2
), 27.32 (dd, JC-C
2
3
2
2
1
3
1
3 3 3
CH ), 1.29 (t, 3 H, CH ) ppm. C NMR (50 MHz, CDCl ): δ ϭ
ϭ 55.66, JC-C ϭ 38.08 Hz, CH
2
) ppm.
72.33 (dd, JC-C ϭ JC-C ϭ 45.41, 2JC-C ϭ 4.3 Hz, CϭO), 160.0
1
1
1
13
1
2
1
[
(
(
5- C]-α-Ethoxycarbonyl-β-oxoadipic Acid (10B): Similarly, 9B
(dd, J
ϭ 36.63 Hz, J
ϭ 4.3 Hz, CϭO), 101.58 (d, J
ϭ
C-C
C-C
C-C
1
1
1
0.87 g, 4 mmol) yielded 10B (0.57 g, 3 mmol, 75%). H NMR 43.94 Hz), 25.28 (dm, JC-C ϭ 43.41 Hz), 25.01 (dm, JC-C
ϭ
3
300 MHz, CDCl
.51 (s, CH
), 2.88 (t, 3
C-H ϭ 128.6 Hz, 2 H, CH
3
): δ ϭ 4.22 (q, JH-H ϭ 6.86 Hz, 2 H, OCH
2
CH
), 2.66 (m,
H-H ϭ 7.21 Hz, 3 H,
): δ ϭ 27.12 ppm.
3
),
44.31 Hz) ppm.
3
J
2
JH-H ϭ 6.18 Hz, 2 H, CH
2
1
3
1
), 1.28 (t, 3
J
[2- C]-5-(Acetylamino)-6-ethoxy-4,6-dioxohexanoic Acid (11B):
2
1
3
) ppm. 1 C NMR (75 MHz, CDCl
3
Similarly, 10B (0.57 g, 3 mmol) yielded [2- C]-6-ethoxy-5-oximino-
OCH
2
CH
3
3
1
4,6-dioxohexanoic acid (0.54 g, 2.5 mmol, 83%).
H NMR
13
[
4- C]-α-Ethoxycarbonyl-β-oxoadipic Acid (10C): Similarly, 9C
(300 MHz, CDCl ): δ ϭ 11.05 (br., COOH), 4.39 (q, 2 H, CH ,
3
2
1
3
1
(2.17 g, 10 mmol) yielded 10C (1.49 g, 7.88 mmol, 79%). H NMR
JH-H ϭ 6.8 Hz), 3.13 (m, 2 H, CH
2
), 2.72 (dm, JC-H ϭ 131.5 Hz,
Eur. J. Org. Chem. 2003, 4654Ϫ4663
www.eurjoc.org
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4661