4092
H.-K. Kim, K.-J. J. Park / Tetrahedron Letters 53 (2012) 4090–4092
11. Procedures and selected data
at the same time and compound 9 was easily isolated from the
impurity by a simple filtration after the reaction. Next, one-pot
operation was employed to perform the cyclization step of the
(a) Synthesis of compound 3. Et3N (2.97 mL, 21.29 mmol) was added to a
solution of serine methyl ester hydrochloride (1.1 g, 7.09 mmol) in CH2Cl2
(20 mL). After the mixture solution was cooled to 0 °C, trifluoroacetic
anhydride (2.17 ml, 15.62 mmol) was added over 10 min. The mixture was
stirred for 6 h at room temperature and then concentrated under reduced
pressure. The residue was extracted with ethyl acetate and washed with
aqueous NaHCO3, 0.1 M HCl and brine, followed by the drying step under
MgSO4. The residue was purified by flash chromatography on silica gel (eluent:
compound 9 for the completion of D-cycloserine. The one-pot cycli-
zation in Scheme 3 consisted of three steps: formation of hydroxa-
mic acids, cyclization through nucleophilic reaction, and removal
of HCl from nitrogen. After the treatment of hydroxylamine hydro-
chloride with sodium methoxide in MeOH, transformation of acid
chloride of the compound 9 into hydroxamine acids was achieved
by addition of hydroxylamine. Then, the cyclization reaction be-
tween alcohol and chlorine was carried out in the presence of LiOH
in methanol and H2O. Meanwhile, deprotection of the HCl synchro-
AcOEt/hexane, 1:1) to give compound
3 (1.49 g, 98%) as a colorless oil.
½
a 2D0
ꢀ
= ꢁ34.7 (c = 4.4, MeOH); 1H NMR (CDCl3, 300 MHz) d 7.52 (s, 1H), 4.45–
4.56 (m, 1H), 3.95 (dd, J = 6.8 Hz, J = 18.8 Hz, 1H), 3.89 (dd, J = 5.2 Hz,
J = 17.8 Hz, 1H), 3.77 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 171.4, 156.1, 115.5,
62.6, 55.5, 52.2; HRMS (ESI) m/z (M+H)+ calcd for C6H8F3NO4 = 215.1272, found
215.1263.
(b) Synthesis of compound 6 from compound 3 (method A). Et3N (0.79 mL,
5.65 mmol) was added to a solution of compound 3 (0.9 g, 4.19 mmol) in
CH2Cl2 (20 mL) and stirred at 0 °C for 10 min. Methanesulfonyl chloride (0.55 g,
4.81 mmol) was added and the mixture was stirred at 0 °C for 1 h and warmed
to room temperature with stirring for 1 h. After stirring the solution of DBU
(0.94 mL, 6.28 mmol) and trifluoroacetohydroxamic acid (0.76 g, 5.86 mmol) in
CH2Cl2 (30 mL) to 0 °C for 30 min, the mixture of DBU and
trifluoroacetohydroxamic acid was added to crude mesylate solution at 0 °C.
The mixture was stirred at 0 °C for 1 h and warmed to room temperature with
stirring for 2 d. After the addition of NaOH (1.12 g, 27 mmol) in water (40 mL)
and MeOH (40 mL), the mixture was stirred at room temperature for 6 h. 50 mL
of ethanol/isopropyl alcohol was added. The precipitated salts were filtered,
and the filtrate was cooled to 0 °C in an ice bath. Glacial acetic acid was added
dropwise to the well-stirred mixture to reach pH of 6.0 and then gave a
colorless solid. The crystalline precipitates were filtered and washed twice
nously took place to produce
In summary, three simple and practical processes for the syn-
thesis of -cycloserine from -serine were developed. In our syn-
D-cycloserine.
D
D
thesis, cyclization reaction was the key step for each synthetic
route, and multi-step one-pot operations provided novel efficient
and short synthetic methods for the completion of synthesis of tar-
get molecule. The main advantages of the present synthesis are the
mild reaction conditions, easy treatment, and fair yields. These effi-
cient synthetic routes can be amenable to the synthesis of
serine for the industrial process.
D-cyclo-
with 1:1 ethanol/isopropyl alcohol and diethyl ether to give
D
-4-amino-3-
Acknowledgments
isoxazolidone (233 mg, 55%). m.p. 146–148 °C; ½a D25
ꢀ
= +110 (c 1.0, H2O); 1H
NMR (DMSO-d6, 300 MHz) d 4.38 (t, 1H), 3.51 (m, 2H); 13C NMR (DMSO-d6,
174.5, 75.1, 53.6; HRMS (ESI) m/z (M+H)+ calcd for
H.K. is thankful to Professor P.L. Fuchs (Purdue University) for
useful discussions and use of laboratory space. Financial support
was provided by the Purdue Research Foundation.
75 MHz)
d
C3H6N2O2 = 102.0919, found 102.0927.
(c) Synthesis of compound 6 from compound 3 (method B). Chlorosulfonic acid
(0.72 g, 6.14 mmol) was added to a solution of compound 3 (1.1 g, 5.12 mmol)
in Et2O (40 mL) at 0 °C. The mixture was stirred at 0 °C for 4 h. After sodium
hydroxide (1.02 g, 25.57 mmol) was added to hydroxylamine hydrochloride
(0.49 g, 7.16 mmol) in H2O (50 mL) and MeOH (50 mL) and stirred at room
temperature for 5 min, the mixture of hydroxylamine was added to the
solution of sulfonic acid compound. The mixture was stirred at 0 °C for 2 h and
then stirred at 60 °C for 8 h. The reaction mixture was neutralized with AcOH
and concentrated under reduced pressure. 60 mL of ethanol/isopropyl alcohol
was added. The precipitated salts were filtered, and the filtrate was cooled to
0 °C in an ice bath. Glacial acetic acid was added dropwise to the well-stirred
mixture to reach pH of 6.0, giving a colorless solid. The crystalline precipitates
were filtered and washed twice with 1:1 ethanol/isopropyl alcohol and diethyl
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ether to give D-4-amino-3-isoxazolidone 341 mg, 65%).
(d) Synthesis of compound 6 from compound 9 (method C). Sodium methoxide
(0.806 g, 14.92 mmol) was added to hydroxylamine hydrochloride (0.57 g,
8.14 mmol) in H2O (50 mL) and MeOH (50 mL) and stirred for 5 min. The
solution of hydroxylamine was added to the compound 9 (1.2 g, 6.78 mmol)
and stirred at room temperature for 10 min. Lithium hydroxide (0.65 g,
27.13 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 5 h. The
reaction mixture was neutralized with AcOH and then concentrated under
reduced pressure. 60 mL of ethanol/isopropyl alcohol was added. The
precipitated salts were filtered, and the filtrate was cooled to 0 °C in an ice
bath. Glacial acetic acid was added dropwise to the well-stirred mixture to
reach pH of 6.0 and gave a colorless solid. The crystalline precipitates were
filtered and washed twice with 1:1 ethanol/isopropyl alcohol and diethyl ether
to give D-4-amino-3-isoxazolidone (494 mg, 71%).
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