Direct Access to -Azetidine-2-carboxylic Acid
lite, and the filtrate was concentrated under reduced pressure to
give an intermediate amine as a colorless oil (832 mg, 98%).To this
amine (200 mg, 1.14 mmol, 1 equiv.) dissolved in anhydrous DMF
2 4
was extracted with ethyl acetate (3ϫ1 mL) dried with Na SO , and
concentrated in vacuo to afford 6 (15.8 mg, 99%) as a colorless oil.
Method C: A ball-mill vessel was charged with sulfonamide 7
(
1
4.5 mL) was directly added triethylamine (204 µL, 1.48 mmol,
.3 equiv.), and the mixture was cooled to –40 °C in an immersion-
cooler cold bath. A solution of SESCl (228 mg, 1.14 mmol,
equiv.) in anhydrous DMF (1.5 mL) was added dropwise. The
(90 mg, 0.18 mmol, 1 equiv.) and Cs
2 3
CO (235 mg, 0.72 mmol,
4
equiv.). Stirring was started in a grinding bowl by using the ball
–1
mill with a vibration speed of 30 vibs . After 3 h, the crude prod-
uct was washed off the reaction vessel with EtOAc (4ϫ2 mL) and
the combined organic fractions were washed with water (3ϫ2 mL)
1
mixture was stirred overnight at –40 °C. DMF was removed by
evaporation under low pressure. The residue was taken up in water
and dried with Na
2
SO
= –90.4 (c = 6.7, CH
): δ = 4.72 (m, 1 H), 4.12 (dd, J = 8.56, 16.18 Hz, 1 H),
.42–3.71 (m, 1 H), 2.89–3.10 (m, 2 H), 2.23–2.44 (m, 2 H), 1.45
4
and concentrated in vacuo to give 6 (56 mg,
(
20 mL) and ethyl acetate (20 mL). The organic layer was washed
with brine (15 mL), dried with Na SO , and concentrated in vacuo
to give 5, which was purified by column chromatography (silica gel;
petroleum ether/Et O, 3:7) to afford sulfonamide 5 (254 mg, 66%)
as a white solid. M.p. 65 °C. [α]2
NMR (300 MHz, CDCl ): δ = 5.6 (d, J = 9.16 Hz, 1 H), 4.08 (dt,
24
1
9
7%). [α]
D
2 2
Cl ). H NMR (300 MHz,
2
4
CDCl
3
3
2
13
(
s, 9 H), 0.92–1.12 (m, 2 H), 0.00 (s, 9 H) ppm. C NMR (75 MHz,
CDCl ): δ = 171.9, 84.2, 62.8, 51.7, 48.6, 30.0, 21.5, 16.1, 11.7,
0.3 ppm. MS (ESI): m/z = 344.0, 322.1, 266.1, 202.1, 174.2.
HRMS (FAB+): calcd. for SSi 322.1464; found
22.1516.
4
1
D
2 2
= –75.4 (c = 1.2, CH Cl ). H
3
3
–
J = 4.32, 9.33, 9.35 Hz, 1 H), 3.68–3.84 (m, 2 H), 2.82–2.99 (m, 2
H), 2.35 (s, 1 H),1.98–2.12 (m, 1 H), 1.62–1.78 (m, 1 H), 1.42 (s, 9
13 4
C H27NO
3
H), 1.04 (m, 2 H), 0.00 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl
):
δ = 173.7, 85.0, 60.1, 55.8, 51.3, 37.9, 30.0, 12.4, 0.00 ppm. MS
ESI): m/z = 362.1, 340.1, 284.1, 220.2, 192.1.
3
H-Aze-OH (1): SES-Aze-OtBu (6; 150 mg, 0.5 mmol, 1 equiv.) was
treated with anhydrous HF (2 mL) at 0 °C for 1.5 h in a Teflon
apparatus. HF was removed by distillation. The residue was washed
(
SES-Hse(OSES)-OtBu (7): To a solution of Z-Hse-OtBu (4;
2
with Et O and then dissolved in water, which was removed by ly-
00 mg, 2.58 mmol) in EtOAc (9 mL) was added 10% Pd/C ophilization to afford product 1 as its hydrofluoride salt (49 mg,
8
2
4
[19]
(c = 3.1, H
2
O). 1H NMR
(200 mg), and the mixture was stirred for 3 h under a hydrogen
97%). M.p. 210 °C. [α]
(300 MHz, D O): δ = 4.07 (dd, J = 9.46, 18.73 Hz, 1 H), 3.89 (dt,
J = 6.11, 10.16, 10.24 Hz, 1 H), 2.65–2.85 (m, 1 H), 2.37–2.61 (m, 1
D
= –107.6
atmosphere at room temperature. The reaction mixture was filtered
through Celite, and the filtrate was concentrated under reduced
pressure to give an intermediate amine as a colorless oil (448 mg,
2
O peak at 4.7 ppm. 1 C NMR
3
H), remaining signal obscured by H
(75 MHz, D O): δ = 173.8, 42.2, 58.9, 23.2 ppm. MS (ESI): m/z =
225.1, 130.2, 103.1. HRMS (FAB+): calcd. for C
2
9
9%). To this intermediate amine (200 mg, 1.14 mmol, 1 equiv.)
dissolved in anhydrous DMF (5 mL) was added triethylamine
637 µL, 4.58 mmol, 4 equiv.), and the mixture was cooled to 0 °C
in an immersion-cooler cold bath. A solution of SESCl (456 mg,
.28 mmol, 2 equiv.) in anhydrous DMF (2 mL) was added drop-
2
4 8 2
H NO 102.0555;
(
found 102.0561.
SES-Aze-OH (8): A solution of SES-Aze-OtBu (6; (50 mg,
.15 mmol) in CH Cl /trifluoroacetic acid (TFA; 7:3, 0.5 mL) was
stirred for 3 h at room temperature. The CH Cl /TFA mixture was
removed by evaporation under reduced pressure, and the resulting
residue was taken up in ethyl acetate (1 mL) and 1 HCl (2 mL).
The mixture was extracted with ethyl acetate (3ϫ1 mL), dried with
2
0
2
2
wise. The mixture was stirred overnight at 0 °C. The reaction mix-
ture was poured into water (10 mL) and extracted with ethyl acetate
2
2
(
(
3ϫ10 mL). The combined organic layer was washed with brine
15 mL), dried with Na SO , and concentrated in vacuo to give 7,
2
4
which was purified by column chromatography (silica gel; petro-
leum ether/Et O, 8:2) to afford sulfonamide 7 (327 mg, 65%) as
slightly yellow crystals. M.p. 75 °C. [α]
Na
a colorless oil. [α]
CDCl ): δ = 8.25 (s, 1 H), 4.92 (t, J = 9.02 Hz, 1 H), 4.12 (m, 1
H), 3.42–3.71 (m, 1 H), 2.90–3.12 (m, 2 H), 2.23–2.44 (m, 2 H),
2 4
SO , and concentrated in vacuo to afford 8 (39.5 mg, 99%) as
2
24
2 2
= –70.4 (c = 4.3, CH Cl ). H NMR (300 MHz,
1
D
2
4
D
= –108.0 (c = 6.5,
2 2 3
CH Cl ). H NMR (300 MHz, CDCl ): δ = 5.09 (d, J = 9.18 Hz,
3
1
1
3
H), 4.27 (m, 2 H), 4.06 (dt, J = 4.45, 8.93, 9.97 Hz, 1 H), 2.97–
.10 (m, 2 H), 2.80–2.92 (m, 2 H), 2.18–2.32 (m, 1 H), 1.90–2.03
13
0
.92–1.12 (m, 2 H), 0.00 (s, 9 H) ppm. C NMR (75 MHz, CDCl
δ = 177.9, 61.7, 51.7, 48.6, 31.5, 21.4, 11.7, 0.3, –0.0, –0.3 ppm. MS
ESI): m/z = 294.9, 283.1, 268.0, 267.0, 266.0.
3
):
(m, 1 H), 1.45 (s, 9 H), 0.95–1.1 (m, 4 H), 0.05 (s, 9 H), 0.00 (s, 9
(
13
H) ppm. C NMR (75 MHz, CDCl
3
): δ = 172.8, 85.6, 67.5, 51.6,
9.0, 35.4, 29.9, 12.3, 12.1, 0.0, –0.05 ppm. MS (ESI): m/z = 526.26,
21.2, 448.1, 384.2, 356.1.
H-Aze-OtBu (9): To solution of sulfonamide
.15 mmol, 1 equiv.) in anhydrous THF (5 mL) was added tetrabu-
tylammonium fluoride (TBAF; 1 in THF, 0.45 mL, 0.45 mmol,
equiv.). The resulting mixture was stirred for 24 h at room tem-
perature. The solution was concentrated in vacuo, and the residue
was purified by chromatography (silica gel; EtOAc/MeOH, 90:10)
a
6 (50 mg,
4
5
0
3
SES-Aze-OtBu (6)
3
Method A: To a solution of PPh (62 mg, 0.24 mmol, 2 equiv.) in
THF (2 mL) under an argon atmosphere was added dropwise di-
ethyl azodicarboxylate (DEAD; 47 µL, 0.24 mmol, 2 equiv.) at
0
2
4
to afford 9 (17.55 mg, 75%) as a pale-yellow oil. [α]
D
= –57.4 (c =
): δ = 5.22 (s, 1 H), 4.45
m, 1 H), 3.52–3.81 (m, 2 H), 2.65 (m, 1 H), 2.29 (m, 1 H), 1.42 (s,
1
2
2 2 3
.1, CH Cl ). H NMR (300 MHz, CDCl
(
9
°C. The mixture was stirred at 0 °C for 30 min. Compound 5
1
3
H) ppm. C NMR (75 MHz, CDCl
8.0, 23.7 ppm. MS (ESI): m/z = 179.6, 157.8, 101.4.
3
): δ = 172.9, 81.2, 58.8, 44.7,
(40 mg, 0.118 mmol, 1 equiv.) in THF (3.5 mL) was added drop-
2
wise at 0 °C over 30 min. The mixture was stirred at 20 °C for 12 h.
The solution was concentrated in vacuo, and the residue was puri-
fied by column chromatography (silica gel; petroleum ether/EtOAc,
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of compounds 1, 3–9.
20:1) to afford 6 as a colorless oil (32.6 mg, 86%).
Method B: To a solution of sulfonamide 7 (25 mg, 0.05 mmol, Acknowledgments
equiv.) in anhydrous acetonitrile (1.2 mL) was added Cs CO
60 mg, 0.2 mmol, 4 equiv.). The resulting mixture was irradiated This work was supported by the program Toxicologie Nucléaire
1
2
3
(
by microwave-assisted heating (20 min, 90 °C). The mixture was
taken up in water (2 mL) and ethyl acetate (1 mL). The mixture
Environnementale (CEA, CNRS, INRA, INSERM; www.toxnuc-e.
org).
Eur. J. Org. Chem. 2009, 2729–2732
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2731