6112 J . Org. Chem., Vol. 61, No. 18, 1996
Bhuniya et al.
of EtOAc. Water (100 µL) was added followed by the same
amount of 4 N NaOH. After 5 min, 300 µL of water was again
added and the mixture stirred for 15 min. A white precipitate
was filtered off, the filtrate was dried, and solvent was
evaporated. The diamines 6 or 12 were purified by distillation.
(R)-N-Meth yl-1-p h en yl-2-p yr r olid in oeth a n a m in e (6a ):
reaction with the base prepared from the (R)-6a gave (S)-
allylic alcohol in 51% ee. However, cyclopentene oxide
and acyclic substrates failed to give any required product.
In conclusion we have designed new chiral nonracemic
lithium amide bases which have been synthesized from
the easily available precursor, phenylglycine. Since both
enantiomers of the precursor are available at low cost,
the versatility of the ligands will be greater. We have
studied the deprotonation reaction of several epoxides.
We have achieved a maximum of 80% ee in the conver-
sion of cyclohexene oxide to 2-cyclohexen-1-ol. We have
also synthesized an enantiopure core unit in 97% ee
which is very useful for prostaglandin synthesis. The
latter enantioselectivity is the highest, to date, for this
kind of transformation.
yield 79%; bp 100-120 °C (bath) at 0.2 mmHg; [R]25 -64.0°
D
(c 1.4, EtOH); IR (film) 3380, 3060, 3030, 2960, 2880 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 1.77 (m, 4H), 2.25 (d, J ) 3.4Hz,
1H), 2.30 (s, 3H), 2.38, (s, NH, 1H), 2.45 (m, 2H), 2.62 (m, 2H),
2.84 (t, J ) 11.2 Hz, 1H), 3.58 (dd, J ) 9.6, 3.4 Hz, 1H), 7.18-
7.4 (aromatics, 5H); 13C NMR (CDCl3, 100 MHz) δ 23.6, 34.7,
54.14, 63.8, 64.3, 127.0, 127.4, 128.3, 142.8; MS (CI, m/z): 206
(M+ + 2), 205 (M+ + 1), 203, 174 (base peak), 175, 134, 120.
Anal. Calcd for C13H20N2: C, 76.47; H, 9.80; N, 13.72.
Found: C, 76.38; H, 9.86, N, 13.74.
(R)-N-Meth yl-1-isopr opyl-2-pyr r olidin oeth an am in e (6b):
yield 66%; bp 100 °C (bath) at 0.2 mmHg; [R]25 -51.5° (c 3.0,
D
EtOH); IR (film) 3320, 2960, 2940, 2880, 960 cm-1; H NMR
1
Exp er im en ta l Section
(CCl4, 60 MHz) δ 0.83 (two doublets, J ) 7 Hz, 6H), 1.0-2.7
(bm, 13H), 2.30 (s, 3H). Anal. Calcd for C10H22N2: C, 70.59;
H, 12.94; N, 16.47. Found: C, 70.46; H, 13.02; N, 16.48.
(R)-N-Meth yl-1-ter t-bu tyl-2-pyr r olidin oeth an am in e (6c):
Gen er a l. 1H NMR spectra were recorded on 60, 300, and
400 MHz spectrometers. Chemical shifts are expressed in ppm
downfield from TMS as internal standard, and coupling
constants are reported in hertz. Routine monitoring of reac-
tions was performed using silica gel-G obtained from Acme.
All the column chromatographic separations were done by
using silica gel (Acme’s, 60-120 mesh). Petroleum ether used
was of boiling range 60-80 °C. Reactions which needed
anhydrous conditions were run under an atmosphere of dry
nitrogen or argon using flame-dried glassware. The organic
extracts were dried over anhydrous sodium sulfate. Evapora-
tion of solvents was performed at reduced pressure. Tetrahy-
drofuran (THF) and diethyl ether were distilled from sodium
benzophenone ketyl under nitrogen. Benzene and dichlo-
romethane were distilled from CaH2. N,N-Dimethylformamide
(DMF) was distilled from CaH2 at reduced pressure. Amines
were distilled from CaH2 at atmospheric pressure.
Gen er al P r ocedu r e for Cou plin g of Acid 4 with Am in es.
To a stirred solution of (R)-N-CBZ-acid 4 (10 mmol), anhydrous
CuCl2 (12 mmol), and 1-hydroxybenzotriazole (12 mmol) in dry
DMF (50 mL) was added dropwise a solution of DCC (12 mmol)
in 10 mL of DMF at 0 °C, and the mixture was stirred for 20
min. Amines (20 mmol) was added and the stirring continued
for 20 h (0 °C to rt). The reaction mixture was diluted with
EtOAc (100 mL) and washed with cold 0.1 N HCl, water,
aqueous NaHCO3. The organic layer was dried, and the
solvent was evaporated in vacuo. Purification by column
chromatography over silica gel gave pure coupled product 5
or 11.
yield 70%; bp 100-120 °C (bath) at 0.2 mmHg; [R]25 -65.5°
D
(c 2.0, EtOH); 1H NMR (CDCl3, 60 MHz) δ 0.90 (s, 9H), 1.60-
2.80 (m, 12H), 2.50 (s, 3H); MS (CI, m/z): 184 (M+), 128, 100
(base peak), 84. Anal. Calcd for C11H24N2: C, 71.73; H, 13.04;
N, 15.21. Found: C, 71.70; H, 13.11, N, 15.33.
(R)-1-(P h en ylglycyl)p yr r olid in e (7). A solution of the
N-CBZ-amide 5a (821 mg, 2.4 mmol) in methanol (10 mL) was
hydrogenated (H2 balloon) in the presence of a small amount
of 10% Pd/C for 2 h. The solution was filtered, and the
methanol was removed in situ. The crude material was used
1
without further purification: yield 95%; H NMR (CDCl3, 60
MHz) δ 1.68-2.0 (m, 4H), 2.10 (bs, 2H, NH), 2.90-3.7 (m, 4H),
4.57 (bs, 1H), 7.43 (aromatics, 5H).
(R)-1-P h en yl-2-p yr r olid in oeth a n a m in e (8). The crude
(R)-7 (735 mg, 3.6 mmol) was taken in THF (15 mL) and
treated with LAH (140 mg, 3.6 mmol) under reflux for 6 h.
Excess of LAH was destroyed by addition of 2-3 drops of
EtOAc. Water (100 µL) was added followed by the same
amount of 4 N NaOH. After 5 min, 300 µL of water was again
added and the mixture stirred for 15 min. A white precipitate
was filtered off, the filtrate was dried, and solvent was
evaporated. The crude was distilled to afford 8 (527 mg, 77%
yield): bp 110-120 °C at 0.2 mmHg; [R]25 -50.8° (c 3.0,
D
EtOH); IR (film) 3300, 3080 cm-1; H NMR (CCl4, 60 MHz) δ
1
1.50-2.9 (bm, 12H), 3.96 (dd, J ) 10, 4 Hz, 1H), 7.2 (5H,
aromatics). Anal. Calcd for C12H18N2: C, 75.78; H, 9.47, N,
14.73. Found: C, 75.69; H, 9.49, N, 14.78.
( R ) -1 -[ N -( B e n z y l o x y c a r b o n y l ) p h e n y l g l y c y l ] -
p yr r olid in e (5a ). The amide 5a 13 is a viscous liquid; 90%
(R)-N-Ben zyl-1-p h en yl-2-p yr r olid in oet h a n a m in e (9).
A solution of (R)-7 (596 mg, 2.92 mmol) in benzene (3 mL) was
treated with freshly distilled benzaldehyde (328 µL, 3.21 mmol)
in the presence of 4 Å molecular sieves. The reaction mixture
was kept at rt for 7 h, and after that it was decanted. The
solvent was removed, and the crude was treated with LAH
(245 mg, 6.4 mmol) in THF (10 mL) under reflux for 8 h. After
usual workup as described earlier, 9 was obtained as a
yield; Rf 0.50 (1:2, EtOAc in petroleum ether); [R]25 -119.0°
D
(c 1.0, CHCl3) [lit.14 maximum [R]25 -123.0° (c 1.06, CHCl3)];
D
IR (film) 3410, 3300, 3040, 2980, 1700, 1630 cm-1; H NMR
1
(CCl4, 60 MHz) δ 1.5-1.95 (m, 4H), 2.8-3.7 (m, 4H), 4.95 (s,
2H), 5.23 (d, J ) 9 Hz, 1H), 6.43 (d, J ) 9 Hz, NH, 1H), 7.05-
7.5 (aromatics, 10H). Anal. Calcd for C20H22N2O3: C, 71.00;
H, 6.51; N, 8.28. Found: C, 70.72; H, 6.64; N, 8.32.
(R)-1-[N-(Ben zyloxyca r b on yl)va lyl]p yr r olid in e (5b ).
colorless liquid: yield 635 mg (77%); [R]25 -70.2° (c 1.2,
D
The amide 5b6b is a viscous liquid; 87% yield; Rf 0.65 (1:1,
EtOH); IR (film) 3300, 3080 cm-1; H NMR (CDCl3, 60 MHz)
1
EtOAc in petroleum ether); [R]25 -85.0° (c 1.6, EtOH); IR
δ 1.8 (m, 4H), 2.1-2.9 (m, 7H), 3.7 (m, 3H), 7.2 (aromatics,
10H). Anal. Calcd for C19H24N2: C, 81.42; H, 8.57, N, 10.0.
Found: C, 81.40; H, 8.61, N, 10.10.
D
(film) 3420, 3280, 3040, 2930, 1700, 1620 cm-1; 1H NMR (CCl4,
60 MHz) δ 0.93 (d, J ) 7 Hz, 6H), 1.5-2.2 (bm, 5H), 3.1-3.8
(m, 4H), 4.1 (dd, J ) 9, 3 Hz, 1H), 4.95 (s, 2H), 6.16 (d, J ) 9
Hz, NH, 1H), 7.2 (aromatics, 5H).
(R)-N-Isopr opyl-1-ph en yl-2-pyr r olidin oeth an am in e (10).
A solution of 8 (700 mg, 3.68 mmol) in acetone-methanol (1:
3, 5 mL) was treated with 5-6 drops of 35% aqueous HCl at
0 °C. To this solution was added sodium cyanoborohydride
(280 mg, 4.4 mmol), and the whole mixture was stirred at rt
for 24 h. Evaporation of the solvent gave a residue which was
mixed with 10 mL of ether. The mixture was extracted with
aqueous HCl. The aqueous layer was washed with ether and
basified with 4 N aqueous NaOH and extracted with CH2Cl2.
The organic layer was dried and condensed. The crude
material was distilled to give pure 1013 (682 mg, 80% yield)
(R)-1-[N-(Ben zyloxyca r bon yl)-ter t-leu cyl]p yr r olid in e
(5c). The amide 5c is a solid; 87% yield; mp 50 °C; [R]25
D
-87.0° (c 5, CHCl3); IR (KBr) 3420, 3280, 1760, 1630 cm-1; 1H
NMR (CDCl3, 60 MHz) δ 1.0 (s, 9H), 1.83 (m, 4H), 3.3-3.9 (m,
4H), 4.36 (d, J ) 10 Hz, 1H), 5.1 (s, 2H), 6.03 (d, J ) 10 Hz,
NH, 1H), 7.36 (aromatics, 5H). Anal. Calcd for C18H26N2O3:
C, 67.92; H, 8.16; N, 8.79. Found: C, 67.80; H, 8.19; N, 8.82.
Gen er a l P r oced u r e for LAH Red u ction of N-CBZ-
Am id es. The amide 5 or 11 (2 mmol) was dissolved in 30 mL
of THF, treated with LAH (4 mmol), and stirred under reflux
for 6 h. Excess of LAH was destroyed by addition of 2-3 drops
as a colourless liquid: bp 180 °C (bath) at 1 mmHg; [R]25
D
-66.0° (c 1.2, EtOH) [lit.13 [R]25D -72.0° (c 1.1, EtOH)]; IR (film)