PAPER
Synthesis of Optically Active a-Amino Acids Containing Pyrazolyl Ring as Substituent
1297
(EtOAc/petroleum ether, 0.2:1) to yield 3a as a pale yellow oil
(8.7 g, 80%).
1H NMR: d = 0.22 (s, 9 H), 1.43 (br s, 9 H), 4.05-4.55 (m, 3 H),
4.90 (br s,1 H), 5.01 (br s,1 H).
13C NMR: d = -0.9, 23.7, 70.6, 72.0, 73.7, 79.0, 80.4, 81.4, 153.6,
182.5.
1H NMR: d = 1.43 (br s, 9 H), 1.82-2.27 (m, 3 H), 2.26-2.13 (m, 1
H), 3.34-3.61 (m, 2 H, CH2), 4. 95 (br dd, 0.4 H, CH), 5.02 (br dd,
0.7 H, CH), 6.07 (dd, 1 H, J = 1.9 Hz), 7.44 (dd, 1 H, J = 1.9 Hz).
13C NMR: d =: 28.7, 63.5, 69.8, 80.2, 80.9, 106.8, 135.8, 145.3,
154.5.
Anal. calcd for C11H17N3O3: C, 55.22; H, 7.16; N, 17.56. Found C,
55.19; H, 7.19; N, 17.56.
Anal. calcd for C14H23NO4Si: C, 56.54; H, 7.79; N, 4.71. Found C,
56.59; H, 7.74; N, 4.70.
(R)-tert-Butoxycarbonylamino[1H-pyrazol-3(5)-yl]acetic Acid
(7)
(S)-4-[3-(Trimethylsilanyl)propynoyl]oxazolidine-3-carboxylic
Acid Benzyl Ester (3b)
p-Toluenesulfonic acid (0.35 g) was added to a solution of 5a
(0.4 g, 1.8 mmol) in anhyd MeOH (60 mL). The mixture was stirred
at r.t. for 24 h, then treated with aq sat. NaHCO3 and concentrated
in vacuo to eliminate MeOH. The residue was saturated with brine
and extracted with EtOAc. The extracts were then washed with
brine and dried (Na2SO4). Removal of the solvent under vacuum
and purification by flash chromatography (SiO2, EtOAc/petroleum
ether, 4:1) gave 6 (61 mg, 15%) as an oil, along with 0.32 g of un-
reacted 5a. Compound 6 was characterized by 1H NMR: d = 1.39 (s,
9 H), 3.15 (br s, 1 H), 3.81-3.99 (dd, 2 H, J = 1.9 Hz), 4.89 (br s, 1
H), 5.57-5.60 (br s, 1 H), 6.07 (dd, 1 H, J = 1.9 Hz), 7.48 (dd, 1 H,
J = 1.9 Hz)]. Jones’ reagent (45 mL) was added dropwise at 0 °C to
a solution of 6 (61 mg) in acetone (20 mL). The mixture was stirred
at r.t. for additional 2 h, then diluted with MeOH to destroy excess
Jones’ reagent. The organic phase was extracted with CH2Cl2, the
CH2Cl2 layer was washed with H2O and brine and extracted with aq
sat. NaHCO3. The organic phase was discarded and the aq NaHCO3
solution was treated with 10% HCl and extracted with EtOAc. The
EtOAc layer was dried (Na2SO4) and evaporated to give the pure
acid 7 (59 mg, 90%).
Compound 3b was prepared accordingly, starting from 2b (5.5 g,
18.7 mmol). The crude product obtained was purified by flash chro-
matography (SiO2, EtOAc/hexane, 6:4) to give pure 3b (4.9 g,
80%).
1H NMR (mixture of two conformers): d = 0.29 (s, 9 H), 4,22 (br s,
2 H), 4.44 (s, 0.6 H), 4.60 (s, 0.4 H), 5.00 (br s, 1 H), 5.07 (br s, 1
H), 5.16 (m, 2 H), 7.34 (m, 5 H).
13C NMR: d = -0.9, 69.6, 72.0, 73.7, 79.0, 80.4, 81.4, 127.2, 127.5,
128,8, 141.0, 153.6, 182.5
Anal. calcd for C17H21NO4Si: C, 61.60; H, 6.39; N, 4.23. Found C,
61.59; H, 6.34; N, 4.23.
(S)-4-[(E)-3-(N,N-Diethylamino)propenoyl]oxazolidine-3-car-
boxylic Acid tert-Butyl Ester (4a); Typical Procedure
A solution of 3a (1.8 g, 6.1 mmol) was added at 0 °C to a 40% aq
solution of Et2NH (12 mmol). The mixture was stirred at r.t. for 3 h,
then extracted with Et2O. After drying the Et2O layer (Na2SO4) and
removal of the solvent gave the pure enamino ketone 4a (1.6 g,
86%) as a colorless oil.
1H NMR: d = 1.14 (br t, 6 H), 1.43 (br s, 9 H), 3.23 (br q, 4 H), 3.97
(br m, 1 H), 4.09-4.40 (br m, 2 H), 4.72-5.05 (m, 2 H), 5.16 (d, 1
H, J = 12.6 Hz), 7.66 (d, 1 H, J = 12.6 Hz).
1H NMR: d = 1.35 (s, 9 H), 5.95 (s, 1 H), 6.05 (dd, 1 H, J = 1.8 Hz),
7.44 (dd, 1 H, J = 1.8 Hz), 11.4 (s, 1 H).
13C NMR: d = 28.8, 62.5, 70.6, 106.3,135.8, 144.8, 154.5, 176.0.
Anal. calcd for C10H15N3O4: C, 49.79; H, 6.27; N, 17.42. Found C,
49.81; H, 6.30; N, 17.41.
13C NMR: d = 13.8, 28.6, 46.0, 70.6, 71.9, 74.5, 80.3, 107.4, 144.0,
157.0, 191.8.
Anal. calcd for C15H26N2O4: C, 60.38; H, 8.78; N, 9.39. Found C,
60.31; H, 8.74; N, 9.35.
(S)-4-(1-Phenyl-1H-pyrazol-3-yl)oxazolidine-3-carboxylic Acid
Benzyl Ester (8); Typical Procedure
To a refluxing solution of compound 3b (2.0 g, 6.1 mmol) and phe-
nylhydrazine hydrochloride (1.2 g, 8 mmol) in EtOH was added
slowly sat. aq of Na2CO3 (1.2 g, 11 mmol). The mixture was stirred
for additional 20 h, then diluted with H2O and extracted with Et2O.
After drying the Et2O layer (Na2SO4) and removal of the solvent un-
der vacuum a viscous oil (2.2 g) was obtained. Purification by flash
chromatography (EtOAc/CH2Cl2/petroleum ether, 0.2.:0.5:1) gave
pure 8 (1.1 g, 52%).
1H NMR: d = 4.24 (br s, 1 H), 4.33 (m, 1 H), 5.08 (br m, 2 H), 5.18
(br m, 3 H), 6.41 (br d, 1 H), 7.10-7.52 (m, 8 H), 7.61-7.66 m, 2
H), 7.84 (d, 1 H, J = 1.9 Hz).
(S)-4-[(E)-3-(N,N-Diethylamino)propenoyl]oxazolidine-3-car-
boxylic Acid Benzyl Ester (4b)
Compound 4b was prepared accordingly, starting from 3b (2.0 g,
6.0 mmol). The crude product obtained was purified by flash chro-
matography (SiO2, EtOAc/EtOH, 10:1) to give pure 4b as an oil
(1.8 g, 89%).
1H NMR: d = 1.03 (br t, 3 H), 1.14 (t, 3 H, J = 7.1 Hz), 3.07 (br s, 2
H), 3.22 (q, 2 H, J = 7.1 Hz), 4.00 (m, 1 H), 4.16 (br m, 1 H), 4.40
(br m, 1 H), 4.88 (br m, 1 H), 5.10 (m, 4 H), 7.26 (br s, 5 H), 7.61
(br d, 1 H).
13C NMR: d = 13.8, 46.1, 70.0, 71.8, 74.5, 80.3, 107.2, 127.2, 127.5,
128,8, 141.0, 144.0, 157.0, 191.8.
13C NMR: d = 63.8, 69.7, 80.2, 80.9, 108.0, 118.8, 126.0, 127.2,
127.5, 128.6, 128.8, 140.0, 141.0, 151.4, 156.0.
Anal. calcd for C18H24N2O4: C, 65.04; H, 7.28; N, 8.43. Found C,
65.00; H, 7.32; N, 8.40.
Anal. calcd for C20H23N3O3: C, 68.75; H, 5.48; N, 12.03. Found C,
68.73; H, 5.48; N, 12.06.
(S)-4-[1H-Pyrazol-3(5)-yl]oxazolidine-3-carboxylic Acid tert-
Butyl Ester (5a)
(S)-4-(1-Phenyl-1H-pyrazol-5-yl)oxazolidine-3-carboxylic Acid
Benzyl Ester (9)
Compound 9 was prepared accordingly, starting from 4b (2.0 g,
6.1 mmol) in MeOH. A viscous oil (2.5 g) was obtained, which was
purified by flash chromatography (SiO2, EtOAc/CH2Cl2/petroleum
ether, 0.5:1:1) to give pure 9 (1.5 g, 72%) as an oil.
1H NMR: d = 3.87 (br s, 1H), 4.11 (br s, 1 H) 5.01-5.09 (br m, 5 H)
6.34 (d, 1H, J = 1.9 Hz), 6.98-7.55 (m, 10 H) 7.52 (d, 1 H, J = 1.9
Hz).
To a solution of 3a (1.8 g, 6 mmol) and hydrazine sulfate (1.1 g,
8 mmol) in refluxing EtOH was added slowly sat. aq Na2CO3 (1.0
g, 9 mmol). The mixture was stirred under reflux for additional 20
h, then diluted with H2O and extracted with Et2O. After drying the
Et2O layer (Na2SO4) and elimination of the solvent under vacuum a
crude product (1 g) was obtained. Purification by flash chromatog-
raphy (EtOAc/petroleum ether, 7:3) gave pure 5a (0.8 g, 54%) as an
oil.
Synthesis 2000, No. 9, 1295–1298 ISSN 0039-7881 © Thieme Stuttgart · New York