SYNTHESIS
October 1998
1495
layer was adjusted to pH = 11 with K2CO3, extracted with CHCl3 (4
× 4 mL) and the organic layer was dried (MgSO4). The residue was
evaporated and purified by flash chromatography (light petroleum/
EtOAc/Et2NMe 50:15:1 to 7:3:0) to give 15a (0.341 g, 84%) as a col-
orless oil.
Determination of the Enantiomeric Purity of 15b:
A stirred solution of 15b (0.0472 g, 0.215 mmol) and N-methylmor-
pholine (NMM) (0.0237 mL, 0.215 mmol) in THF (3 mL) was cooled
to –15°C and isobutyl chloroformate (0.029 mL, 0.23 mmol) was
added. After 1 min, a solution of (S)-alanine hydrochloride (0.033 g,
0.24 mmol) and NMM (0.026 mL, 0.24 mmol) in DMF (1 mL) was
added. After 5 min the mixture was warmed to 5°C, stirred for 2 h,
filtered and evaporated (r.t/10–3 mbar).The residue was dissolved in
anhyd EtOAc, filtered (Celite) and evaporated to give the dipeptide
16 (0.0246 g, 38%). Coupling was also carried out with (R)-alanine
hydrochloride to give the appropriate (2'R)-diastereomer.
Ent-15a was prepared under the same reaction conditions starting
from ent-14a.
15a: [α]D21 +0.5 (c = 10, CHCl3); ent-15a: [α]D21 –0.2 (c = 10, CHCl3).
1H NMR (400 MHz): δ = 1.16 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.59
(dddd, J = 13.0, 7.7, 6.5, 6.1 Hz, 1H, H4), 2.01 (dddd, J = 13.0, 9.1,
7.9, 5.8 Hz, 1H, H4), 2.12 (dd, J = 9.3, 6.7 Hz, 1H, H2), 2.32 (d, J =
7.5 Hz, 2H, CH2COO), 2.45 (ddd, J = 8.7, 9.1, 6.1 Hz, 1H, H5), 2.46–
2.57 (m, 2H, H5, H3), 2.74 (dd, J = 9.3, 7.5 Hz, 1H, H2), 3.51 (d, J =
12.6 Hz, 1H, NCH2Ph), 3.55 (d, J = 12.6 Hz, 1H, NCH2Ph), 4.04 (q,
J = 7.1 Hz, 2H, OCH2CH3), 7.14–7.26 (m, 5H,H-arom).
IR (NaCl): ν = 3090, 3070, 3030, 2960, 2930, 2880, 2795, 1735,
1605, 1495, 1480, 1455, 745, 700 cm–1.
Diagnostic signals: 1H NMR (400 MHz): 16: δ = 3.73; (2'R)-diastere-
omer: δ = 3.72.
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie.
CI-MS: m/z = 247 (M+).
HRMS: m/z C15H21NO2: calcd: 247.1572, found: 247.1568.
(1) For examples, see:
(a) Hart, D. J.; Ha, D.-C. Chem. Rev. 1989, 89, 1447 and ref-
erences cited therein.
(3R)-2-(1-Benzylpyrrolidin-3-yl)acetic Acid (15b):
(b) Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouf-
fard, F. A. J. Am. Chem. Soc. 1980, 102, 6161.
(2) (a) Drey, C. N. C. In Chemistry and Biochemistry of Amino
Acids; Barret, G. C. Ed.; Chapman and Hall: London, 1985; pp
25–54.
(b) Amblard, M.; Rodriguez, M.; Lignon, M.-F.; Galas, M.-C.;
Bernard, N.; Artis.-Noel, A.-M.; Hauad, L.; Laur, J.; Califano,
J.-C.; Aumelas, A.; Martinez, J. J. Med. Chem. 1993, 36, 3021.
(3) For a review, see: Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. An-
gew. Chem. 1994, 106, 38.
A stirred solution of 15a (0.3606 g, 1.458 mmol) in 1 M HCl (4.0 mL)
was heated at 40°C for 24 h and lyophilized. The residue was dis-
solved in sat. Ba(OH)2 (30.0 mL) and a stream of CO2 was bubbled
through the suspension. Afterwards the residue was filtered (Celite)
and the filtrate lyophilized. The crude product was purified by column
chromatography (XAD 2, H2O/MeOH 1:0 to 1:1) to give 15b
(0.3091 g, 97%) as an amorphous powder; mp 198–200°C.
Ent-15b was prepared under the same reaction conditions starting
from ent-15a.
15b: [α]D23 –0.4 (c = 5.0, CHCl3); ent-15b: [α]D20 +1.2 (c = 1.0,
(4) For reviews on the synthesis of nonracemic β-amino acids, see:
(a) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichimica Acta
1994, 27, 3
(b) Enantioselective Synthesis of β-Amino Acids; Juaristi, E.
Ed.; Wiley-VCH: New York, 1997.
(5) Johnson, G.; Drummond, J. T.; Boxer, P. A.; Bruns, R. F.
J. Med. Chem. 1992, 35, 233.
(6) Ma, Z.; Wang, S.; Cooper, C. S.; Fung, A. K. L.; Lynch, J. K.;
Plagge, F.; Chu, D. T. W. Tetrahedron: Asymmetry 1997, 8,
883.
CHCl3).
1
•
H NMR (15b HOAc, 400 MHz): δ = 1.72 (dddd, J = 13.2, 8.4, 8.0,
7.8 Hz, 1H, H4), 2.04 (s, 3H, CH3COO–), 2.21 (dddd, J = 13.2, 8.7,
8.4, 4.2 Hz, 1H, H4), 2.44 (dd, J = 16.2, 7.5 Hz, 1H, CH2COOH), 2.50
(dd, J = 16.2, 5.9 Hz, 1H, CH2COOH), 2.72 (dddddd, J = 8.4, 7.8, 7.5,
7.3, 6.5, 5.9 Hz, 1H, H3), 2.95 (ddd, J = 10.5, 8.7, 8.4 Hz, 1H, H5),
3.00 (dd, J = 10.9, 6.5 Hz, 1H, H2), 3.20–3.25 (m, 1H, H2), 3.22–3.27
(m, 1H, H5), 4.10 (s, 2H, NCH2Ph), 6.84–7.07 (br. s, 2H, NH/OH),
7.35–7.42 (m, 5H, H-arom).
CI-MS: m/z = 219 (M+).
(7) Klein, I. S.; Czekaj, M.; Molino, B. F.; Chu, V. Bioorg. Med.
Chem. Lett. 1997, 7, 1773.
HRMS: m/z C13H17NO2: calcd: 219.1259, found: 219.1259.
(8) (a) Nielsen, L.; Brehm, L., Krogsgaard-Larsen, P. J. Med.
Chem. 1990, 33, 71.
(3R)-Pyrrolidine-3-acetic Acid (15c):
(b) Galeazzi, R.; Geremia, S.; Mobbili, G.; Orena, M. Tetrahe-
dron: Asymmetry 1996, 7, 79.
(9) (a) Schousboe, A.; Thorbek, P.; Hertz, L.; Krogsgaard-Larsen,
P. J. Neurochem. 1979, 33, 181.
(b) Larsson, O. M.; Thorbek, P.; Krogsgaard-Larsen, P.;
Schousboe, A. J. Neurochem. 1981, 37, 1509.
(10) (a) Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1994, 116,
1054.
A solution of 15b (0.085 g, 0.39 mmol) in EtOH (5 mL) was hydro-
genated in a Parr hydrogenation apparatus (16 h, r.t., 1013 mbar H2)
using 20% Pd(OH)2/C (0.010 g) as a catalyst. The mixture was fil-
tered (Celite), evaporated, and dried to give pure 15c (0.029 g, 58%)
as an amorphous powder; mp 163–165°C (Lit.8a mp 160–165°C;
Lit.8b mp 163°C).
Ent-15c was prepared under the same reaction conditions starting
from ent-15b.
15c: [α]D23 –10.1 (c = 1.0, H2O) (Lit.8a [α]D25 –9.3 (c = 1.0, H2O), Lit.8b
[α]D –9.1 (c = 1.0, H2O)); ent-15c: [α]D20 +8.6 (c = 1.0, H2O) (Lit.8a
[α]D27 +9.6 (c = 1.0, H2O), Lit.8b [α]D +9.2 (c = 1.0, H2O)).
1H NMR (D2O, 400 MHz): δ = 1.46 (dddd, J = 13.4, 8.9, 8.4, 7.2 Hz,
1H, H4), 2.01 (dddd, J = 13.4, 9.1, 7.2, 4.1 Hz, 1H, H4), 2.14 (dd, J =
14.6, 8.4 Hz, 1H, CH2COO), 2.15 (dd, J = 14.6, 8.5 Hz, 1H,
CH2COO), 2.42 (dddddd, J = 8.9, 8.9, 8.5, 8.4, 7.6, 7.2 Hz, 1H, H3),
2.70 (dd, J = 11.7, 8.9 Hz, 1H, H2), 3.04 (ddd, J = 11.9, 9.1, 7.2 Hz,
1H, H5), 3.21 (ddd, J = 11.9, 8.4, 4.1 Hz, 1H, H5), 3.29 (dd, J = 11.7,
7.6 Hz, 1H, H2).
(b) Seebach, D.; Overhand, M.; Kühnle, F. N. M.; Martinoni,
B.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta
1996, 79, 913.
(c) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D.
R.; Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 13071.
(d) Hintermann, T.; Seebach, D. Synlett 1997, 437.
(e) Karle, I. L.; Pramanik, A.; Banerjee, A.; Bhattacharjya, S.;
Balaram, P. J. Am. Chem. Soc. 1997, 119, 9087.
(f) Krauthäuser, S.; Christianson, L. A.; Powell, D. R.; Gellman,
S. H. J. Am. Chem. Soc. 1997, 119, 11719.
(11) Matthews, J. L.; Overhand, M.; Kühnle, F. N. M.; Ciceri, P. E.;
Seebach, D. Liebigs Ann. Chem. 1997, 1371.
IR (KBr): ν = 3400, 2940, 2910, 2840, 2680, 2470, 1565, 1390, 920,
740, 700 cm–1.