mGluR Agonist Effects of (2R,4R)-APDC
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15 2997
stirred at room temperature overnight; 1 N NaOH (200 mL)
was added to the reaction mixture and the product extracted
with Et2O (3 × 300 mL). All of the organic phases were
combined, washed with brine, dried over K2CO3, and concen-
trated under reduced pressure to afford the crude product,
which was purified by HPLC (10% EtOAc/hexanes to 50%
EtOAc/hexanes) affording 4 (47.20 g, 189 mmol) in 83% yield:
1H NMR (CDCl3) δ 1.20 (t, J ) 7 Hz, 3H), 1.90-2.0 (m, 1H),
2.3-2.42 (m, 1H), 2.65 (dd, J ) 3.7, 10 Hz, 1H), 3.02 (d, J )
10 Hz, 1H), 3.20 (br s, 1H), 3.35 (dd, J ) 3.3, 10 Hz, 1H), 3.73
(d, J ) 13.2 Hz, 1H), 3.90 (d, J ) 13.2 Hz, 1H), 4.00-4.20 (m,
2H), 4.20-4.30 (m, 1H), 7.20-7.50 (m, 5H); FDMS M+ ) 249.
Anal. (C14H19NO3) C, H, N. [R]D ) +70.3° (c ) 0.05, CH2Cl2)
[lit. +76.2° (CH3OH)11].
M+ ) 320. Anal. (C17H24N2O4‚0.3EtOAc) C, H, N. [R]D
+38.8° (c ) 0.102, CH2Cl2).
)
(2R,4R)-Dieth yl N1-Ben zyl-4-[(ter t-bu tyloxyca r bon yl)-
a m in o]p yr r olid in e-2,4-d ica r boxyla te (9). Di-tert-butyl di-
carbonate (12.26 g, 56.2 mmol) was added in one portion to a
solution of 7 (12.0 g, 37.5 mmol) in CH2Cl2 (400 mL), and the
resulting reaction mixture was stirred at room temperature
overnight; 0.5 N NaOH (100 mL) was added to the reaction
mixture, and the product was extracted with Et2O. All the
organic phases were combined, washed with brine, dried over
K2CO3, and concentrated in vacuo to yield the crude product,
which was purified by HPLC (10% EtOAc/hexanes to 50%
EtOAc/hexanes) affording 9 (15.92 g, 37.5 mmol) in 100%
yield: 1H NMR (CDCl3) δ 1.20-1.30 (m, 6H), 1.40 (s, 9H), 2.26
(dd, J ) 5.9, 13.6 Hz, 1H), 2.86 (dd, J ) 2.7, 9.6 Hz, 1H), 2.91
(d, J ) 9.6 Hz, 1H), 3.07 (d, J ) 9.6 Hz, 1H), 3.48 (dd, J ) 5.9,
9.6 Hz, 1H), 3.57 (d, J ) 12.9 Hz, 1H), 4.03 (d, J ) 13.2 Hz,
1H), 4.10-4.25 (m, 4H), 5.40 (br s, 1H), 7.25-7.40 (m, 5H);
FDMS M+ ) 420. Anal. (C22H32N2O6) C, N; H: calcd, 6.93;
found, 6.52. [R]D ) +30.7° (c ) 0.01, CH2Cl2).
(2R,4R)-Dieth yl 4-[(ter t-Bu tyloxyca r bon yl)a m in o]p y-
r r olid in e-2,4-d ica r boxyla te (10). The amine 9 (15.80 g, 37.5
mmol) was added to an ethanolic suspension (100 mL) of 5%
Pd/C (4.0 g) and exposed to H2 (60 psi) for 4 h at room
temperature. The reaction mixture was filtered through Celite
and concentrated in vacuo to yield the crude product which
was purified by HPLC (20% EtOAc/hexanes to 80% EtOAc/
hexanes) affording 10 (10.48 g, 31.7 mmol) in 85% yield: mp
(2R)-Eth yl N1-Ben zyl-4-oxop yr r olid in e-2-ca r boxyla te
(5). Oxalyl chloride (16.0 g, 126 mmol, 11 mL) was added
dropwise to a solution of anhydrous CH2Cl2 (300 mL) and
DMSO (13.12 g, 168 mmol) at -78 °C. The reaction mixture
was allowed to equilibrate for 10 min, after which time a
solution of 4 (20.90 g, 84 mmol) in CH2Cl2 (100 mL) was added
dropwise at a rate to keep the reaction temperature below -60
°C. Upon complete addition the reaction mixture was allowed
to stir at -78 °C for 2 h; then triethylamine (25.50 g, 252
mmol) was added dropwise. After complete addition, the
reaction mixture was allowed to warm to room temperature.
H2O (50 mL) was added to the reaction mixture, the pH was
adjusted to 10 with saturated aqueous NaHCO3, and the
product was extracted with Et2O (3 × 500 mL). All organic
phases were combined, washed with brine, dried over K2CO3,
and concentrated in vacuo to yield crude product which was
purified by HPLC (10% EtOAc/hexanes to 50% EtOAc/hex-
anes) affording 5 (20.44 g, 82.7 mmol) in 98% yield: 1H NMR
(CDCl3) δ 1.30 (t, J ) 7 Hz, 3H), 2.55 (dd, J ) 7.7, 18.4 Hz,
1H), 2.70 (dd, J ) 7.7, 18.4 Hz, 1H), 3.00 (d, J ) 17.3 Hz, 1H),
3.35 (d, J ) 17.3 Hz, 1H), 3.75 (d, J ) 13.2 Hz, 1H), 3.85 (dd,
J ) 5.5, 7.7 Hz, 1H), 3.95 (d, J ) 13.2 Hz, 1H), 4.22 (q, J ) 7.7
1
) 58-60 °C; H NMR (CDCl3) δ 1.25-1.30 (m, 6H), 1.42 (s,
9H), 2.28-2.38 (m, 1H), 2.77 (dd, J ) 9.2, 14.2 Hz, 1H), 3.25-
3.40 (m, 2H), 3.95 (dd, J ) 5.1, 9.2 Hz, 1H), 4.20 (q, J ) 7.2
Hz, 2H), 4.22 (q, J ) 7.2 Hz, 2H), 5.00 (br s, 1H); FDMS M+
+
1 ) 331. Anal. (C15H26N2O6) C, H, N. [R]D ) +4.94° (c )
0.053, CH2Cl2).
(2R,4R)-4-Am in op yr r olid in e-2,4-d ica r boxyla te (2a ). A
solution of 10 (1.00 g, 3.00 mmol) in Et2O (35 mL) was chilled
to 0 °C, purged with anhydrous HCl gas, and allowed to warm
to room temperature as it stirred for 1 h. The reaction mixture
was concentrated to dryness and stirred in a 1:1 mixture of
THF/1 N NaOH (20 mL total volume) at room temperature
overnight. The reaction mixture was neutralized, concentrated
to dryness, reconstituted in H2O, and adjusted to pH 2 with 1
N HCl. The title compound was purified by cation-exchange
chromatography (5% pyridine/H2O) affording 2a (0.40 g, 2.30
mmol) in 77% yield: mp > 250 °C; 1H NMR (D2O/KOD) δ 2.22
(dd, J ) 7.7, 14.0 Hz, 1H), 2.82 (dd, J ) 9.2, 14.0 Hz, 1H),
3.47 (d, J ) 12.5 Hz, 1H), 3.69 (d, J ) 12.5 Hz, 1H), 4.29 (dd,
J ) 7, 9 Hz, 1H); FDMS M+ + 1 ) 175. Anal. (C6H10N2O4) C,
H, N. [R]D ) +26.6° (c ) 0.10, 1 N HCl), [R]D ) +46.3° (c )
0.10, H2O) [lit. -24.8° (H2O)11,37].
Hz, 2H), 7.25-7.40 (m, 5H); FDMS M+ ) 247. Anal. (C14H17
-
NO3) C, H, N. [R]D ) +46.6° (c ) 0.10, CH2Cl2) [lit. +48.8°
(CH3OH)11].
(2R,4R)-Dieth yl N1-Ben zyl-4-a m in op yr r olid in e-2,4-d i-
ca r boxyla te (7) a n d (2R,4S)-Dieth yl N1-Ben zyl-4-a m i-
n op yr r olid in e-2,4-d ica r boxyla te (8). KCN (13.36 g, 205
mmol) was added in one portion to a solution of 5 (20.30 g, 82
mmol) and ammonium carbamate (19.21 g, 246 mmol) in EtOH
(500 mL) and H2O (500 mL). The resulting reaction mixture
was heated at 55 °C for 2 days. NaOH (90.0 g, 2.25 mol) was
added, and the reaction mixture was warmed under reflux
overnight. The reaction mixture was chilled to 0 °C, acidified
to pH 1 with concentrated HCl (∼200 mL), and concentrated
in vacuo. EtOH (500 mL) was added to the crude amino diacid
mixture and then concentrated to dryness (5×) so as to remove
residual H2O. The resulting anhydrous amino diacid was then
reconstituted in EtOH (1 L), cooled to 0 °C, and treated with
SOCl2 (39.02 g, 328 mmol). Upon complete addition the
reaction mixture was refluxed for 3 days. The solids were
filtered, and the filtrate was concentrated in vacuo. The crude
product was partitioned between 3 N NaOH, NaCl, and EtOAc.
The EtOAc was removed and the aqueous phase extracted with
EtOAc (3 × 1 L). All the organic phases were combined,
washed with brine, dried over K2CO3, and concentrated in
vacuo to yield a dark red oil which was purified by HPLC (10%
EtOAc/hexanes to 90% EtOAc/hexanes) affording 7 (12.14 g,
38 mmol) in 46% yield and 8 (3.05 g, 10 mmol) in 12% yield.
(2R,4S)-Dieth yl N1-Ben zyl-4-[(ter t-bu tyloxyca r bon yl)-
a m in o]p yr r olid in e-2,4-d ica r boxyla te (11). Di-tert-butyl
dicarbonate (0.91 g, 4.17 mmol) was added in one portion to a
solution of 8 (0.89 g, 2.78 mmol) in CH2Cl2 (35 mL), and the
resulting reaction mixture was stirred at room temperature
overnight; 0.5 N NaOH (100 mL) was added to the reaction
mixture and the product extracted with Et2O. All the organic
phases were combined, washed with brine, dried over K2CO3,
and concentrated in vacuo to yield the crude product which
was purified by PC-TLC (10% EtOAc/hexanes to 20% EtOAc/
hexanes) affording 11 (0.95 g, 2.26 mmol) in 81% yield: 1H
NMR (CDCl3) δ 1.26 (t, J ) 8 Hz, 3H), 1.28 (t, J ) 7 Hz, 3H),
1.42 (s, 9H), 2.40 (dd, J ) 8.5, 13.6 Hz, 1H), 2.71 (d, J ) 10.3
Hz, 1H), 2.83 (dd, J ) 7.7, 13.6 Hz, 1H), 3.48 (d, J ) 10.3 Hz,
1H), 3.71 (d, J ) 12.9 Hz, 1H), 3.72 (d, J ) 7.7 Hz, 1H), 4.03
(d, J ) 13.2 Hz, 1H), 4.15-4.25 (m, 4H), 4.92 (br s, 1H), 7.25-
7.40 (m, 5H); FDMS M+ ) 420. Anal. (C22H32N2O6) C, H, N.
[R]D ) +41.04° (c ) 0.10, CH2Cl2).
Compound 7: 1H NMR (CDCl3) δ 1.20-1.30 (m, 6H), 2.04
(dd, J ) 5.9, 13.6 Hz, 1H), 2.25 (br s, 2H), 2.78 (dd, J ) 9.9,
13.6 Hz, 1H), 2.82 (d, J ) 9.6 Hz, 1H), 2.92 (d, J ) 9.6 Hz,
1H), 3.45 (dd, J ) 5.9, 9.9 Hz, 1H), 3.58 (d, J ) 12.9 Hz, 1H),
3.98 (d, J ) 12.9 Hz, 1H), 4.10-4.22 (m, 4H), 7.22-7.38 (m,
(2R,4S)-Dieth yl N1-(ter t-Bu tyloxyca r bon yl)-4-[(ter t-bu -
tyloxycar bon yl)am in o]pyr r olidin e-2,4-dicar boxylate (12).
The amine 11 (0.85 g, 2.02 mmol) and di-tert-butyl dicarbonate
(0.88 g, 4.04 mmol) were consecutively added to an ethanolic
suspension (30 mL) of 5% Pd/C (0.25 g) and exposed to H2 (40
psi) for 4 h at room temperature. The reaction mixture was
filtered through Celite and concentrated in vacuo to yield the
crude product which was purified by PC-TLC (10% EtOAc/
5H); FDMS M+ ) 320. Anal. (C17H24N2O4) C, H, N. [R]D
+60.6° (c ) 0.10, CH2Cl2).
)
Compound 8: 1H NMR (CDCl3) δ 1.20-1.30 (m, 6H), 1.75
(br s, 2H), 2.07 (dd, J ) 7.4, 12.5 Hz, 1H), 2.47 (d, J ) 9.9 Hz,
1H), 2.60 (dd, J ) 8.1, 12.5 Hz, 1H), 3.51 (d, J ) 9.9 Hz, 1H),
3.68 (d, J ) 12.9 Hz, 1H), 3.76 (t, J ) 7.9 Hz, 1H), 4.05 (d, J
) 12.9 Hz, 1H), 4.10-4.20 (m, 4H), 7.20-7.40 (m, 5H); FDMS