organic layers were washed with brine, dried over magnesium
sulfate, filtered, and concentrated. The brownish residue was
purified by flash column chromatography over silica gel (AcOEt/
EP: 8/2) to afford the desired compound (1.1 g, 61%).
alkylation with benzyl bromoacetate. After optimization
of this alkylation, we eventually found that subjection
of 6 to benzyl bromoacetate in the presence of sodium
iodide and sodium hydrogencarbonate in DMF minimized
the proportion of morpholinone formation and resulted
in the isolation of 13 in 74% yield. Chlorination and
cyclization went smoothly, and results obtained with this
route compare well with the those obtained with the
initial one. Finally, double debenzylation by hydrogenoly-
sis provided both enantiomers (-)-1 or (+)-1 starting
either from ester 15 or 16 in excellent yield (Scheme 3).
This modified route therefore allowed for a five-step
access to both enantiomers of azetidine-2-carboxylic acid
with a good overall yield. One extra purification step by
column chromatography is however required in this case
to obtain a clean alkylated product 13.
In summary, practical syntheses of both enantiomers
of azetidine-2-carboxylic acid were developed. Overall
yields over this enantiodivergent five- or six-step syn-
thesis range from 20% to 32% for each enantiomer. The
route starts from commercially available R-methylben-
zylamine, and a single purification by column chroma-
tography is required when a nitrile group is used for the
cyclization step. Reagents, reaction concentrations, and
conditions are easily amenable for large-scale synthesis.
(S)-[(2-Chloro-ethyl)-(1-phenyl-ethyl)-amino]-acetoni-
trile (8). To a solution of 7 (13.8 g, 67 mmol) in dichloromethane
(350 mL) was added dropwise thionyl chloride (9.9 mL, 135
mmol) at 0 °C. The resulting mixture was heated under gentle
reflux for 2 h, cooled to room temperature, and carefully
hydrolyzed with a saturated aqueous solution of NaHCO3. The
aqueous layer was then extracted with dichloromethane, and
the combined organic layers were washed with brine, dried over
magnesium sulfate, filtered, and concentrated to give the desired
chloride (13.9 g, 93%) as a yellow solid. Mp 49 °C; [R]20D -52 (c
1
0.9, CHCl3). H NMR (300 MHz, CDCl3): δ 7.36-7.38 (m, 5H),
3.85 (q, J ) 6.6 Hz, 1H), 3.50-3.57 (m, 4H), 2.99 (ddd app oct.,
J ) 7.0 Hz, 2H), 1.44 (d, J ) 6.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ ) 143.0, 128.8, 127.9, 127.4, 115.0, 61.8, 52.8, 42.0,
40.1, 20.5. MS (electrospray): 104.6. Anal. Calcd for C12H15
-
ClN2: C, 64.71; H, 6.79; N, 12.58. Found: C, 64.95; H, 6.88; N,
12.49.
[1(1S),2S]-1-(1-Phenyl-ethyl)-azetidine-2-carbonitrile (9)
and [1(1S),2R]-1-(1-Phenyl-ethyl)-azetidine-2-carbonitrile
(10). A solution of 8 (3.0 g, 13.4 mmol) in THF (255 mL) was
treated with potassium tert-butoxide (1.8 g, 16.2 mmol). The
resulting mixture was stirred at room temperature for 10
min, quenched by addition of a saturated aqueous solution of
NH4Cl, concentrated under vaccuum, and extracted with ethyl
acetate. Combined organic layers were washed with brine, dried
over magnesium sulfate, filtered, and concentrated. The brown-
ish residue was purified by flash column chromatography over
silica gel (AcOEt/PE: 2/8) to afford 9 (first eluting diastereoi-
somer, colorless crystals, 1.1 g, 44%) and 10 (second eluting
diastereoisomer, colorless crystals, 1.0 g, 40%). 9: mp 44 °C;
[R]20D -134 (c 0.9, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.25-
7.36 (m, 5H), 3.86 (t, J ) 7.1 Hz, 1H), 3.55 (q, J ) 6.5 Hz, 1H),
3.21 (qd, J ) 6.4 and 0.7 Hz, 1H), 3.05 (q, J ) 7.3 Hz, 1H), 2.38
(qd, J ) 6.9 and 1.4 Hz, 2H), 1.35 (d, J ) 6.4 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 141.8, 128.5, 127.6, 127.3, 119.6, 66.2, 51.5,
50.7, 21.9, 20.8. MS (electrospray): 209.2, 160.0, 104.6. Anal.
Experimental Section
(S)-2-(1-Phenylethylamino)-ethanol (6). To a solution of
L-(-)-R-methylbenzylamine (10.0 g, 82 mmol) in DMSO (50 mL)
was added bromoethanol (5.9 mL, 82 mmol). The resulting
solution was then stirred at 50 °C for 72 h, concentrated under
vacuum, treated with a saturated aqueous solution of NaHCO3,
and extracted with ether. The combined organic layers were
washed with brine, dried over magnesium sulfate, filtered, and
concentrated. The residue was purified by distillation under high
vacuum (Vigreux column, 4 mmHg, 134-135 °C) to give the
desired amino alcohol (10.6 g, 78%) as a colorless oil that
Calcd for C12H14N2: C, 77.38; H, 7.58; N, 15.04. Found: C, 77.25;
1
H, 7.77; N, 14.94. 10: mp 41 °C; [R]20 -18 (c 1.1, CHCl3). H
D
crystallized upon storage in a freezer. Mp 49 °C; [R]20 -57 (c
NMR (300 MHz, CDCl3): δ 7.27-7.37 (m, 5H), 3.87 (t, 1H, J )
7.3 Hz), 3.40-3.83 (m, 2H), 3.05 (q, J ) 7.3 Hz, 1H), 2.37 (qd, J
) 7.6 and 1.9 Hz, 2H), 1.35 (d, J ) 6.6 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 140.9, 128.6, 127.7, 127.3, 118.8, 66.5, 51.5, 50.7,
21.9, 20.4. MS (electrospray): 209.2, 160.0, 104.6. Anal. Calcd
for C12H14N2: C, 77.38; H, 7.58; N, 15.04. Found: C, 77.22; H,
7.79; N, 14.93.
D
1
0.9, CHCl3). H NMR (300 MHz, CDCl3): δ 7.18-7.30 (m, 5H),
3.74 (q, J ) 6.6 Hz, 1H), 3.44 (q, J ) 6.2 Hz, 2H), 2.92 (ddd app
oct., J ) 7.0 Hz, 2H), 1.36 (d, J ) 6.5 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 142.9, 128.8, 127.8, 127.3, 61.8, 52.7, 40.0, 20.4.
MS (electrospray): 166.1, 104.7. Anal. Calcd for C10H15NO: C,
72.69; H, 9.15; N, 8.48. Found: C, 72.67; H, 9.16; N, 8.50.
(S)-[(2-Hydroxy-ethyl)-(1-phenyl-ethyl)-amino]-acetoni-
trile (7). To a solution of 6 (12.1 g, 73 mmol) in acetonitrile (500
mL) were added bromoacetonitrile (6.1 mL, 86 mmol) and
potassium carbonate (14.2 g, 103 mmol). The resulting mixture
was then refluxed for 5 h, concentrated under vacuum, diluted
with water, and extracted with ether. Combined organic layers
were washed with brine, dried over magnesium sulfate, filtered,
and concentrated to afford the desired compound (14.8 g,
quantitative yield) as a yellow oil. [R]20D -93 (c 1.2, CHCl3). 1H
NMR (300 MHz, CDCl3): δ 7.23-7.39 (m, 5H), 3.82 (q, J ) 6.5
Hz, 1H), 3.52-3.72 (m, 4H), 2.75-2.92 (m, 2H), 2.14 (broad s,
1H), 1.46 (d, J ) 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
143.1, 129.0, 128.0, 127.4, 115.0, 62.0, 59.5, 52.4, 39.4, 20.4. MS
(electrospray): 215.1, 178.4, 176.1, 132.8, 118.7, 104.7, 100.5.
Anal. Calcd for C12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found:
C, 70.37; H, 7.97; N, 13.69.
(S)-Azetidine-2-carboxylic Acid [(-)-1]. A 50 mL flask was
charged with 9 (351 mg, 1.88 mmol) and 35% hydrochloric acid
(30 mL). After complete dissolution, the resulting mixture was
heated to 50 °C for 3 days, cooled to room temperature,
concentrated, and dried under high vacuum to yield the desired
1
amino acid as its hydrochloride salt. Mp 115 °C. H NMR (300
MHz, D2O): δ 7.36-7.40 (m, 5H), 5.04 (t, J ) 9.8 Hz, 1H), 4.43
(q, J ) 6.9 Hz, 1H), 3.86 (q, J ) 9.8 Hz, 1H), 3.45 (td, J ) 9.9
and 4.1 Hz, 1H), 2.38-2.62 (m, 2H), 1.51 (d, J ) 6.8 Hz, 3H).
13C NMR (75 MHz, D2O): δ 170.8, 133.6, 130.0, 129.2, 128.1, 65.2,
64.6, 49.0, 20.0, 15.9. MS (electrospray): 206.2, 104.6. HRMS
(CI, NH3) m/z calcd for C12H16ClNO2 [M]+ 241.087, found
241.089. The residue was dissolved in methanol (45 mL), and
Pd/C (10wt % Pd, 450 mg) was added. The resulting mixture
was then stirred under an atmosphere of hydrogen for 4 days,
filtered over a short plug of Celite, rinsed with methanol, and
concentrated to yield azetidine-2-carboxylic acid hydrochloride
as a white crystalline solid. This residue was dissolved in
distilled water and purified by ion exchange chromatography
(Dowex 50x8-200, 10 g, washed with water before use until pH
7 and first eluted with water until pH 7 and then with a 1%
aqueous ammonia solution) to give the desired zwitterionic
(S)-[(2-Hydroxy-ethyl)-(1-phenyl-ethyl)-amino]-acetoni-
trile (7). One-Pot Procedure from R-Methylbenzylamine.
To a solution of L-(-)-R-methylbenzylamine (1.0 g, 8.2 mmol) in
DMSO (5 mL) was added bromoethanol (1.07 g, 8.61 mmol). The
resulting solution was then stirred at 50 °C for 72 h, cooled to
room temperature, and successively treated with triethylamine
(3.4 mL, 24.6 mmol) and bromoacetonitrile (680 µL, 9.8 mmol).
The resulting mixture was next stirred at room temperature for
5 h, diluted with water, and extracted with ether. Combined
amino acid after lyophilization (175 mg, 92% over two steps).
1
Mp 212 °C (dec); [R]20 -118 (c 3.6, H2O). H NMR (300 MHz,
D
D2O): δ 4.51-4.74 (m, 1H), 3.86 (q, J ) 9.2 Hz, 1H), 3.45 (q, J
9030 J. Org. Chem., Vol. 70, No. 22, 2005