The Journal of Organic Chemistry
Article
hydroxypyrrolidine-2-carboxylic acid (4) (0.500 g, 2.16 mmol) in dry
tetrahydrofuran (2.5 mL), under argon at 0 °C was added tert-butyl
N,N′-diisopropylcarbamimidate (0.500 mL, 2.16 mmol). The reaction
mixture was heated to 70 °C for 3 h, followed by further addition of
tert-butyl N,N′-diisopropylcarbamimidate (0.500 mL, 2.16 mmol).
The reaction mixture was heated for a further 18 h. The reaction
mixture was filtered through Celite and then concentrated in vacuo.
Purification by flash column chromatography eluting with 50% ethyl
acetate in hexane gave di-tert-butyl (2S,4R)-4-hydroxypyrrolidine-1,2-
dicarboxylate (5) as a white solid (0.420 g, 68%): [α]D14 −55.3 (c 0.2,
concentrated in vacuo. Purification by column chromatography eluting
with 80% diethyl ether in hexane gave tert-butyl (1S,4S)-2-oxa-3-oxo-
5-azabicyclo[2.2.1]heptane-5-carboxylate (8) as a white solid (4.30 g,
77%): [α]D +43.8 (c 1.0, CHCl3) [lit.20 [α]D +46.3 (c 1.0,
CHCl3)]. Spectroscopic data matched the literature.20
19
20
N-(tert-Butoxycarbonyl)-(2S,4S)-4-hydroxypyrrolidine-2-
carboxylic Acid (9).21 To a solution of tert-butyl (1S,4S)-2-oxa-3-
oxo-5-azabicyclo[2.2.1]heptane-5-carboxylate (8) (4.00 g, 18.8
mmol) in a mixture of water (60 mL), tetrahydrofuran (40 mL),
and methanol (40 mL) was added lithium hydroxide monohydrate
(2.36 g, 56.3 mmol). The reaction mixture was stirred at room
temperature for 18 h and concentrated in vacuo, and ethyl acetate
(100 mL) was added to the oily residue. The solution was acidified
using a saturated aqueous solution of potassium hydrogen sulfate, and
the aqueous layer extracted with ethyl acetate (3 × 150 mL). The
combined extracts were dried over MgSO4 and concentrated in vacuo
to give N-(tert-butoxycarbonyl)-(2S,4S)-4-hydroxypyrrolidine-2-car-
CHCl3) [lit.18 [α]D −51.3 (c 1.3, CHCl3)]. Spectroscopic data
25
matched the literature.18
Di-tert-butyl (2S,4R)-4-(Tosyloxy)pyrrolidine-1,2-dicarboxy-
late (6).19 To a solution of di-tert-butyl (2S,4R)-4-hydroxypyrroli-
dine-1,2-dicarboxylate (5) (1.50 g, 5.22 mmol) in dichloromethane
(30 mL) at 0 °C were added pyridine (0.840 mL, 10.4 mmol), 4-
dimethylaminopyridine (0.0640 g, 0.520 mmol), and p-toluenesul-
fonyl chloride (1.99 g, 10.4 mmol). The reaction mixture was heated
to 40 °C for 96 h and then concentrated in vacuo. Purification by flash
column chromatography eluting with 20% ethyl acetate in hexane
gave di-tert-butyl (2S,4R)-4-(tosyloxy)pyrrolidine-1,2-dicarboxylate
21
boxylic acid (9) as a white solid (4.00 g, 92%): [α]D −38.5 (c 0.3,
MeOH) [lit.21 [α]D −39.0 (c 0.7, MeOH)]. Spectroscopic data
matched the literature.21
Di-tert-butyl (2S,4S)-4-Hydroxypyrrolidine-1,2-dicarboxy-
late (10).22 Di-tert-butyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarbox-
ylate (10) was prepared as described for di-tert-butyl (2S,4R)-4-
hydroxypyrrolidine-1,2-dicarboxylate (5) using N-(tert-butoxycarbon-
yl)-(2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (9) (1.00 g, 4.32
mmol), dry tetrahydrofuran (5.0 mL), and tert-butyl N,N′-
diisopropylcarbamimidate (0.965 mL, 4.33 mmol), followed by
further addition of tert-butyl N,N′-diisopropylcarbamimidate (0.965
mL, 4.33 mmol) after 3 h. Purification by column chromatography
eluting with 40% ethyl acetate in hexane gave di-tert-butyl (2S,4S)-4-
hydroxypyrrolidine-1,2-dicarboxylate (10) as a white solid (0.650 g,
17
(6) as a white solid (1.90 g, 81%): [α]D −27.0 (c 0.1, CHCl3).
Spectroscopic data matched the literature.19
Di-tert-butyl (2S,4S)-4-Fluoropyrrolidine-1,2-dicarboxylate
(7). To a solution of di-tert-butyl (2S,4R)-4-hydroxypyrrolidine-1,2-
dicarboxylate (5) (0.150 g, 0.522 mmol) in dry dichloromethane (3
mL), under argon, was added dropwise morpholinosulfur trifluoride
(0.330 mL, 2.61 mmol). The reaction mixture was stirred at room
temperature for 48 h and concentrated in vacuo, and water (20 mL)
was added to the resulting residue. The aqueous layer was extracted
with ethyl acetate (3 × 10 mL), and the combined extracts were then
washed with water (3 × 10 mL) and sodium bicarbonate (3 × 10
mL), dried over MgSO4, filtered, and concentrated in vacuo.
Purification by flash column chromatography eluting with 30% ethyl
acetate in hexane gave di-tert-butyl (2S,4S)-4-fluoropyrrolidine-1,2-
dicarboxylate (7) as a colorless oil (0.092 g, 63%): IR (neat) 2976,
1736, 1701, 1395, 1366, 1151, 1117, 1070, 769 cm−1; [α]D15 −33.3 (c
0.2, CHCl3); NMR spectra showed a 2:1 mixture of rotamers. Only
data for the major rotamer were recorded: 1H NMR (500 MHz,
CDCl3) δ 5.18 (dt, J = 53.0, 4.2 Hz, 1H), 4.29 (d, J = 9.3 Hz, 1H),
3.79 (dt, J = 27.0, 13.0 Hz, 1H), 3.73−3.57 (m, 1H), 2.51−2.20 (m,
2H), 1.48 (s, 9H), 1.45 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ
170.8 (C), 153.8 (C), 91.2 (d, 1JC−F = 177.3 Hz, CH), 81.4 (C), 80.1
(C), 58.4 (CH), 53.0 (d, 2JC−F = 24.6 Hz, CH2), 37.7 (d, 2JC−F = 22.0
Hz, CH2), 28.3 (3 × CH3), 27.9 (3 × CH3); MS (ESI) m/z 312 (M +
Na+, 100); HRMS (ESI) m/z [M + Na]+ calcd for C14H24FNNaO4
312.1582, found 312.1579.
20
87%): [α]D −7.0 (c 0.1, CHCl3). Spectroscopic data matched the
literature.22
Di-tert-butyl (2S,4S)-4-(Tosyloxy)pyrrolidine-1,2-dicarboxy-
late (11).22 Di-tert-butyl (2S,4S)-4-(tosyloxy)pyrrolidine-1,2-dicar-
boxylate (11) was prepared as described for di-tert-butyl (2S,4R)-4-
(tosyloxy)pyrrolidine-1,2-dicarboxylate (6) using di-tert-butyl
(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (10) (0.500 g, 1.74
mmol), dry dichloromethane (10 mL), pyridine (0.280 mL, 3.48
mmol), 4-dimethylaminopyridine (0.0210 g, 0.174 mmol), and p-
toluenesulfonyl chloride (0.663 g, 3.48 mmol). The reaction mixture
was heated for 48 h. Purification by column chromatography eluting
with 20% ethyl acetate in hexane gave di-tert-butyl (2S,4S)-4-
(tosyloxy)pyrrolidine-1,2-dicarboxylate (11) as a white solid (0.500
g, 66%): [α]D −25.4 (c 0.5, CHCl3) [lit.22 [α]D −28.3 (c 0.5,
20
34
CHCl3)]. Spectroscopic data matched the literature.22
Di-tert-butyl (2S,4R)-4-Fluoropyrrolidine-1,2-dicarboxylate
(12). Di-tert-butyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate
(12) was prepared as described for di-tert-butyl (2S,4S)-4-
fluoropyrrolidine-1,2-dicarboxylate (7) using di-tert-butyl (2S,4S)-4-
hydroxypyrrolidine-1,2-dicarboxylate (10) (0.150 g, 0.522 mmol), dry
dichloromethane (3 mL), and morpholinosulfur trifluoride (0.330
mL, 2.61 mmol). Purification by column chromatography eluting with
20% ethyl acetate in hexane gave di-tert-butyl (2S,4R)-4-fluoropyrro-
lidine-1,2-dicarboxylate (12) as a colorless oil (0.084 g, 57%): IR
(neat) 2978, 1744, 1703, 1398, 1368, 1152 cm−1; [α]D20 −8.8 (c 0.2,
CHCl3). NMR spectra showed a 2:1 mixture of rotamers; only data
for the major rotamer were recorded: 1H NMR (400 MHz, CDCl3) δ
5.16 (dt, J = 52.6, 3.0 Hz, 1H), 4.26 (t, J = 8.3 Hz, 1H), 3.89 (ddd, J =
21.8, 13.0, 3.0 Hz, 1H), 3.55 (ddd, J = 36.1, 13.0, 3.0 Hz, 1H), 2.64−
2.44 (m, 1H), 2.14−1.92 (m, 1H), 1.44 (s, 9H), 1.42 (s, 9H);
13C{1H} NMR (101 MHz, CDCl3) δ 171.7 (C), 153.8 (C), 91.0 (d,
(2S,4S)-4-Fluoropyrrolidine-2-carboxylic Acid Hydrochlor-
ide (1). To a solution of di-tert-butyl (2S,4S)-4-fluoropyrrolidine-1,2-
dicarboxylate (7) (0.0500 g, 0.170 mmol) in acetonitrile (0.2 mL)
was added 2 M hydrochloric acid (2 mL). The reaction mixture was
stirred at room temperature for 5 h and then concentrated in vacuo.
Purification by trituration with chloroform yielded (2S,4S)-4-
fluoropyrrolidine-2-carboxylic acid hydrochloride (1) as a white
solid (0.0180 g, 64%): mp 130−136 °C dec; IR (neat) 3358, 2947,
15
1742, 1717, 1603, 1499, 1263, 1246, 1179, 1026 cm−1; [α]D −13.9
1
(c 0.1, MeOH); H NMR (500 MHz, CD3OD) δ 5.44 (dt, J = 52.1,
3.6 Hz, 1H), 4.65−4.59 (m, 1H), 3.74 (ddd, J = 20.0, 13.5, 1.5 Hz,
1H), 3.56 (ddd, J = 35.7, 13.5, 3.6 Hz, 1H), 2.78−2.58 (m, 2H);
1
13C{1H} NMR (126 MHz, CD3OD) δ 169.5 (C), 91.5 (d, JC−F
=
2
177.2 Hz, CH), 58.2 (CH), 52.0 (d, JC−F = 24.0 Hz, CH2), 35.4 (d,
2JC−F = 22.0 Hz, CH2); MS (ESI) m/z 134 (M + H+, 100); HRMS
1JC−F = 178.7 Hz, CH), 81.4 (C), 80.4 (C), 58.2 (CH), 53.0 (d, 2JC−F
(ESI) m/z [M + H]+ calcd for C5H9FNO2 134.0612, found 134.0611.
tert-Butyl (1S,4S)-2-Oxa-3-oxo-5-azabicyclo[2.2.1]heptane-
5-carboxylate (8).20 To a solution of N-(tert-butoxycarbonyl)-
(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (4) (6.00 g, 26.0
mmol) in dry tetrahydrofuran (200 mL) under argon at 0 °C was
added triphenylphosphine (8.17 g, 31.1 mmol), followed by dropwise
addition of diisopropyl azodicarboxylate (6.13 mL, 31.1 mmol). The
reaction mixture was stirred at room temperature for 18 h and
2
= 22.8 Hz, CH2), 37.6 (d, JC−F = 22.8 Hz, CH2), 28.3 (3 × CH3),
28.0 (3 × CH3); MS (ESI) m/z 312 (M + Na+, 100); HRMS (ESI)
m/z [M + Na]+ calcd for C14H24FNNaO4 312.1582, found 312.1580.
(2S,4R)-4-Fluoropyrrolidine-2-carboxylic Acid Hydrochlor-
ide (2). (2S,4R)-4-Fluoropyrrolidine-2-carboxylic acid hydrochloride
(2) was prepared as described for (2S,4S)-4-fluoropyrrolidine-2-
carboxylic acid hydrochloride (1) using di-tert-butyl (2S,4R)-4-
E
J. Org. Chem. XXXX, XXX, XXX−XXX