Nonproteinogenic R-Amino Acid Derivatives
J . Org. Chem., Vol. 64, No. 7, 1999 2279
prepared using a literature procedure.7 (S)-1-Phenylethyl-
amine (10 mL, 79 mmol) was added to a solution of ethylgly-
oxylate (10 g, 75 mmol) in dry CH2Cl2 (100 mL) containing
activated molecular sieves (30 g) at 0 °C, and the mixture was
stirred for 1 h. The reaction mixture was cooled to -78 °C,
and trifluoroacetic acid (6.0 mL, 79 mmol), BF3-OEt2 (9.9 mL,
79 mmol), and cyclohexadiene (6.3 g, 79 mmol) were added.
The reaction mixture was allowed to slowly reach room
temperature and was stirred for 48 h. The reaction was
quenched by addition of saturated aqueous NaHCO3. After
filtration and extraction with CH2Cl2, the organic phase was
dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash chromatography (deactivated silica, pentane/
EtOAc, 20:1) to afford 8 (6.9 g, 31%) as a colorless oil. All the
physical and spectroscopic data were in complete agreement
with the reported data.7
a stirred suspension of LiAlH4 (0.91 g, 24 mmol) in dry THF
at 0 °C, and the mixture was stirred for 10 min under N2. The
ice bath was removed, and the reaction mixture was stirred
for 3 h at room temperature and then quenched following a
literature procedure,15 affording 12 as white crystals in 98%
yield (1.0 g). An analytical amount was recrystallized (tert-
butyl methyl ether) for characterization: Rf 0.40 (pentane/
acetone, 4:1); mp 61-62 °C; [R]25 -12.0 (c 0.15, EtOH); IR
D
(KBr, cm-1) 3352, 3251, 1622; 1H NMR (400 MHz) δ 1.05-
1.35 (2 H, m), 1.45-1.92 (10 H, m), 2.60 (1 H, m), 3.25 (1 H,
app. t, J ) 9.4 Hz), 3.64 (1 H, dd, J ) 6.8, 3.6 Hz); 13C NMR
(100.4 MHz) δ 25.1, 25.5, 29.4, 29.8, 44.4, 57.9, 66.0; MS (GC)
m/z (rel intensity) 130 (M + H+, 1), 98 (89), 81 (100), 79 (56).
Anal. Calcd for C7H15NO: C, 65.07; H, 11.78; N, 10.84.
Found: C, 65.20; H, 11.85; N, 10.97. The S-enantiomer has
the same experimental data, except for the sign of the optical
rotation.
(2R)-Cycloh exyl Glycin e Eth yl Ester (9).14 The product
was prepared following the same procedure as described above
for 3 to afford 9 (0.4 g, 93%) as a colorless oil. An analytical
(4R)-Cyclop en tyl-oxa zolid in -2-on e (13). Triethylamine
(3.1 mL, 22 mmol) and a 1.9 M solution of phosgene in toluene
(5.1 mL, 9.8 mmol) were added to a solution of 12 (0.63 g, 4.9
mmol) in dry CH2Cl2 (30 mL), and the mixture was stirred
under N2 for 1 h. The reaction was quenched with 1 M NaOH
(10 mL). The aqueous phase was extracted with CH2Cl2 (3 ×
50 mL), and the combined organic layers were washed with 1
M HCl (40 mL) and saturated aqueous NaCl (40 mL) and dried
(MgSO4). Concentration in vacuo afforded 13 (0.73 g, 96%) as
white crystals, pure by 1H NMR. An analytical amount was
purified by flash chromatography (deactivated silica, pentane/
EtOAc, 2:3): Rf 0.30 (pentane/EtOAc, 2:5); mp 115-116 °C;
amount was purified by flash chromatography (deactivated
24
silica, pentane/ether, 1:1): Rf 0.25 (pentane/Et2O, 1:1); ηD
)
25
1.4641; [R ]D ) -31.0 (c 0.50, CHCl3); IR (film, cm-1) 3450-
3200, 1732; 1H NMR (200 MHz) δ 0.90-1.18 (5 H, m), 1.22 (3
H, t, J ) 7.0 Hz) 1.40-1.78 (8 H, m), 3.19 (1 H, d, J ) 4.8 Hz),
4.12 (2 H, q, J ) 7.0); 13C NMR (50.2 MHz) δ 14.1, 25.9, 26.0,
26.1, 27.6, 29.5, 42.0, 59.5, 60.4, 175.6; MS (GC) m/z (rel
intensity) 186 (M + H+, 13), 112 (100), 95 (84), 67 (30).
(1R,3R,4S)-3-Ben zoyl-2-[(1S)-ph en yleth yl]-2-azabicyclo-
[2.2.1]h ep t-5-en e (10). Compound 10 was prepared using a
literature procedure.7 (S)-1-Phenylethylamine (2.0 mL, 16
mmol) was added to a solution of phenylglyoxal monohydrate-
(2.0 g, 15 mmol) in dry CH2Cl2 (15 mL) containing activated
molecular sieves (10 g) at 0 °C, and the mixture was stirred
for 1 h. The reaction mixture was cooled to -78 °C, and
trifluoroacetic acid (1.2 mL, 16 mmol), BF3-OEt2 (2.0 mL, 16
mmol) and cyclopentadiene (1.3 mL, 16 mmol) were added. The
reaction mixture was allowed to slowly warm to room tem-
perature overnight. The reaction was quenched by addition of
saturated aqueous NaHCO3. After filtration and extraction
with CH2Cl2 (3 × 50 mL), the combined organic phases were
dried (MgSO4)and concentrated in vacuo. The residue was
purified by flash chromatography (deactivated silica, pentane/
Et2O, 99:1 to 4:1) to afford 10 as the major diastereomer (2.0
g, 42%, 6:1 diastereomeric ratio of exo isomers): Rf 0.45 (Et2O/
[R]25 +22.4 (c 0.25, EtOH); IR (KBr, cm-1) 3281, 1750, 1722;
D
1H NMR (200 MHz) δ 1.05-1.30 (2 H, m), 1.55-1.90 (6 H, m),
2.01 (1 H, m), 3.71 (1 H, m), 4.08 (1 H, dd, J ) 8.4, 6.4 Hz),
4.46 (1 H, t, J ) 8.4 Hz), 5.41 (1 H, s); 13C NMR (100.4 MHz)
δ 25.1, 25.2, 28.1, 29.0, 44.5, 56.9, 69.4, 160.5; MS (GC) m/z
(rel intensity) 156 (M + H+, 7), 97 (18), 85 (100), 58 (30). Anal.
Calcd for C8H13NO2: C, 61.91; H, 8.44; N, 9.02. Found: C,
62.04; H, 8.23; N, 8.79.
(4R)-Cyclopen tyl-2-m eth yl-4,5-dih ydr o-oxazole (14). The
oxazoline was prepared using a method developed by A. I.
Meyers et al.16 To a solution of acetimidoethyl ether hydro-
chloride17 (0.21 g, 1.7 mmol) in dry CH2Cl2 (4 mL) was added
the amino alcohol 12 (0.20 g, 1.6 mmol) dissolved in CH2Cl2
(1 mL) at 0 °C. The reaction mixture was stirred for 3 h at 0
°C and then allowed to slowly reach room temperature. After
7 h, the reaction was quenched by pouring the solution into
ice water (10 mL). The organic layer was separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with saturated aqueous
NaCl (10 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure to afford 14 (0.17 g, 70% yield) as a colorless
oil. An analytical sample was purified by flash chromatography
(pentane/EtOAc, 8:2), using deactivated silica: Rf 0.36 (pen-
pentane, 1:4); mp 111-112 °C; [R]25 + 10.1 (c 1.00, CH2Cl2);
D
IR (CDCl3, cm-1) 3680, 3601, 1711, 1691; 1H NMR (400 MHz)
δ 1.40 (1 H, d, J ) 8.0 Hz), 1.46 (3 H, d, J ) 6.8 Hz), 2.19 (1
H, d, J ) 8.4 Hz), 2.84 (1 H, s), 3.15 (1 H, q, J ) 6.4 Hz), 3.19
(1 H, s), 4.40 (1 H, s), 6.36 (1 H, dd, J ) 5.6 Hz, J ) 2.0 Hz),
6.5 (1 H, m), 6.94 (1 H, m), 7.05 (2 H, t, J ) 7.6 Hz), 7.20-
7.40 (7 H, m); 13C NMR (75.3 MHz) δ 22.7, 44.6, 49.3, 62.7,
64.2, 66.9, 127.0, 127.4, 127.9, 128.0, 128.1, 132.1, 133.6, 136.1,
137.2, 145.1, 201.1; MS (EI) m/z (rel intensity) 304 (M + H+,
4), 198 (66), 105 (100), 94 (49). Anal. Calcd for C21H21NO: C,
83.13; H, 6.98; N, 4.62. Found: C, 83.21; H, 6.87; N, 4.78.
tane/EtOAc, 3:2); [R]21 ) + 19.9 (c 0.89, CH2Cl2); IR (film,
D
cm-1) 3401, 2361, 1677, 1386; 1H NMR (400 MHz) δ 1.12-
1.25 (1 H, m), 1.27-1.41 (1 H, m), 1.46-1.73 (5 H, m), 1.77-
1.93 (2 H, m), 1.94 (3 H, d, J ) 1.3 Hz), 3.85 (1 H, t, J ) 7.9
Hz), 3.92 (1 H, ddq, J ) 9.1, 7.9, 1.3 Hz), 4.24 (1 H, dd, J )
9.1, 7.8 Hz); 13C NMR (100.4 MHz) δ 13.9, 25.3, 25.4, 29.0,
29.5, 45.1, 71.0, 71.5, 164.4; MS (EI) m/z (rel intensity) 153
(M+, <1), 121 (22), 105 (100), 103 (10), 77 (25); HRMS calcd
for C9H15NO 153.1154, found 153.1155.
(2R)-Cyclop en tyl-1-p h en yl-2-[(1S)-p h en yleth yla m in o]-
eth a n on e (11). The product was prepared following the same
procedure as described above for 2, to afford 11 (0.5 g, 97%)
as white crystals. An analytical amount was purified by flash
chromatography (deactivated silica, pentane/Et2O, 99:1): Rf
25
0.30 (pentane/ether, 99:1); [R ]D ) -36.5 (c 0.60, EtOAc); IR
2,2-Isop r op ylid en ebis-[((4R)-cycloh exyl)-4,5-d ih yd r o-
oxa zole] (15).The ligand was prepared using a three-step
literature procedure.18 To a solution of cyclopentylglycinol (0.50
g, 3.9 mmol) and Et3N (1.4 mL, 9.7 mmol) in CH2Cl2 (10 mL)
(film, cm-1) 3300, 1676; 1H NMR (200 MHz) δ 1.15-1.70 (7 H,
m), 1.36 (3 H, d, J ) 6.4 Hz), 1.95-2.20 (3 H, m), 3.72 (1 H, q,
J ) 6.4 Hz,), 4.18 (1 H, d, J ) 5.8 Hz), 7.05-7.60 (8 H, m),
7.77 (2 H, app. d, J ) 8.6 Hz); 13C NMR (50.2 MHz) δ 23.0,
25.0, 25.3, 27.9, 29.5, 43.9, 57.3, 62.8, 126.8, 126.9, 128.1, 128.3,
128.6, 132.9, 137.0, 146.1, 204.6; MS (GC) m/z (rel intensity)
(15) Mi′covi′c, V. M.; Mihailovi′c, M. L. J . Org. Chem. 1953, 18, 1190.
(16) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J . Am. Chem.
Soc. 1976, 98, 567.
(17) Dox, A. W. Organic Synthesis; Wiley: New York, 1941, Collect.
Vol. I, p 5.
308 (M + H+, 3), 105 (100), 79 (53); HRMS calcd for C21H25
NO 307.1936, found 307.1935.
-
2-Am in o-(2R)-cyclop en tyl-eth a n ol (12). A solution of 3
(1.4 g, 8.0 mmol) in dry THF (10 mL) was added dropwise to
(18) (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M.
J . Am. Chem. Soc. 1991, 113, 726. (b) After completion of this work, a
new improved method for synthesis of bisoxazoline ligands was
published: Evans, D. A.; Peterson, G. S.; J ohnson, J . S.; Barnes, D.
M.; Campos, K. R.; Woerpel, K. A. J . Org. Chem. 1998, 63, 4541.
(14) Klyne, W.; Scopes, P. M.; Thomas, R. N.; Dahn, H. Helv. Chim.
Acta 1971, 54, 2420.