2296 J . Org. Chem., Vol. 62, No. 7, 1997
Notes
solution was diluted with ethyl acetate (100 mL), washed with
aqueous NH4Cl (2 × 50 mL), H2O (100 mL), and brine (100 mL),
and then dried (MgSO4), filtered, and concentrated to afford 7a
(535 mg, 86%), which was virtually pure by NMR analysis.
Using KOH (560 mg, 10.0 mmol), the saponification took a total
of 6 days (yield 79%).
Other N,N-dibenzylamino esters (5b-d ,h ) gave similar re-
sults; however, this procedure failed to give hydrolysis products
7e-g from 5e-g, which are â-branched.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-m et h ylh ex-
a n oa te (3f): yield 75% (based on 7f) and >97% ee as a colorless
oil after purification by flash chromatography (hexane:ethyl
acetate ) 95:5 to 90:10); [R]25 +201.7 (c 0.60, CHCl3); 1H NMR
D
(CDCl3) δ 0.80 (enol) (d, 3H, J ) 6.4 Hz), 0.82 (d, 3H, J ) 6.5
Hz), 1.08 (enol) (d, 3H, J ) 6.5 Hz), 1.12 (d, 3H, J ) 6.6 Hz),
1.46 (s, 9H), 1.54 (enol) (s, 9H), 2.28 (m, 1H), 3.07 (d, 1H, J )
10.4 Hz), 3.21 (d, 1H, J ) 15.0 Hz), 3.30 (d, 1H, J ) 15.0 Hz),
3.38 (enol) (d, 2H, J ) 14.0 Hz), 3.60 (d, 2H, J ) 13.9 Hz), 3.94
(d, 2H, J ) 13.9 Hz), 3.98 (enol) (d, 2H, J ) 14.0 Hz), 4.73 (enol)
(s, 1H), 7.31 (m, 10H); 13 C NMR (CDCl3) (keto and enol) δ 20.4,
20.7, 26.5, 27.6, 28.4, 28.9, 52.4, 54.7, 68.6, 71.4, 81.4, 82.0, 94.7,
127.2, 127.6, 128.6, 129.3, 139.8, 140.7, 174.2, 204.8; FTIR (neat)
2977, 1751, 1721, 1646 (br) cm-1. Anal. Calcd for C25H33O3N:
C, 75.91; H, 8.41; N, 3.54. Found: C, 76.07; H, 8.18; N, 3.56.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-m et h ylh ep -
ta n oa te (3g): yield 74% (based on7g) and > 97% ee as a
colorless oil after purification by flash chromatography (hexane:
ter t-Bu t yl 4-(N,N-Dib en zyla m in o)-3-oxo-6-m et h ylh ep -
ta n oa te (3a ). Gen er a l P r oced u r e. To a stirred solution of
N,N-dibenzylamino acid 7a (1.34 g, 4.30 mmol) in THF (20 mL)
was added CDI (767 mg, 4.70 mmol) at room temperature under
a N2 atmosphere. The resulting solution was stirred at room
temperture for 1 h. Meanwhile, a solution of lithium (tert-
butoxycarbonyl)methanide was made from BuLi (2.50 M, 3.60
mL, 9.00 mmol), diisopropylamine (1.30 mL, 9.00 mmol), and
tert-butyl acetate (1.22 mL, 9.00 mmol). The imidazole solution
was added dropwise to the pale yellow solution of the lithium
enloate at -78 °C under a N2 atmosphere. The resulting
mixture was stirred at -78 °C for 50 min, quenched with 1 N
HCl (50 mL), and extracted with ethyl acetate (3 × 50 mL). The
organic extracts were combined, washed with brine (100 mL),
dried (MgSO4), passed through a short pad of silica gel, and
concentrated to provide 3a as a colorless oil (1.32 g, 80% based
on 7a ) after purification by flash chromatography (hexane:ether
) 95:5 to 85:10): 97% ee by a chiral LIS study using Eu(hfc)3 in
comparison with a racemic sample); [R]25D +93.8 (c 0.45, CHCl3);
1H NMR (CDCl3) δ 0.79 (d, 3H, J ) 5.8 Hz), 0.88 (d, 3H, J ) 6.0
Hz), 1.37 (s, 9H), 1.38 (m, 2H), 1.81 (m, 1H), 3.34 (dd, 1H, J )
3.3, 9.5 Hz), 3.44 (d, 2H, J ) 13.7 Hz), 3.70 (d, 2H, J ) 13.7 Hz),
3.53 (s, 2H), 7.32 (m, 10H); 13C NMR (CDCl3) δ 22.7, 23.5, 25.8,
31.3, 48.1, 54.9, 64.8, 82.0, 127.2, 127.7, 128.9, 129.5, 139.7,
ethyl acetate ) 95:5 to 90:10); [R]25 +197.3 (c 0.55, CHCl3); 1H
D
NMR (CDCl3) δ 0.83 (t, 3H, J ) 6.9 Hz), 1.08 (d, 3H, J ) 6.8
Hz), 1.25 (m, 1H), 1.46 (s, 9H), 1.54 (enol) (s, 9H), 2.08 (m, 2H),
3.17 (d, 1H, J ) 6.4 Hz), 3.19 (d, 1H, J ) 15.6 Hz), 3.31 (d, 1H,
J ) 15.6 Hz), 3.37 (enol) (d, 2H, J ) 14.0 Hz), 3.59 (d, 2H, J )
13.9 Hz), 3.93 (d, 2H, J ) 13.9 Hz), 3.99 (enol) (d, 2H, J ) 14.0
Hz), 4.70 (enol) (s, 1H), 7.31 (m, 10H), 12.16 (enol) (s, 1H); 13C
NMR (CDCl3) (keto and enol) δ 11.8, 16.2, 16.6, 27.1, 28.5, 28.8,
32.8, 34.2, 52.4, 54.6, 67.2, 70.1, 82.0, 94.8, 127.2, 127.6, 128.6,
128.9, 139.8, 140.7, 166.8, 173.0, 174.2, 204.7; FTIR (neat) 2957,
1751, 1711, 1646 (enol) (br) cm-1. Anal. Calcd for C26H35O3N:
C, 76.25; H, 8.61; N, 3.42. Found: C, 76.48; H, 8.42; N, 3.50.
ter t-Bu tyl 4-(N,N-d iben zyla m in o)-3-oxo-p en ta n oa te (3h ):
yield 78% (based on 7h ) and 70% ee as a colorless oil after
purification by flash chromatography (hexane: ether ) 85:5 to
80:10); 1H NMR (CDCl3) δ 1.18 (d, 3H, J ) 6.7 Hz), 1.37 (s, 9H),
3.41 (d, 2H, J ) 13.6 Hz), 3.46 (q, 1H, J ) 6.7 Hz), 3.54 (d, 1H,
J ) 15.6 Hz), 3.68 (d, 1H, J ) 15.6 Hz), 3.72 (d, 2H, J ) 13.6
Hz), 7.34 (m, 10H); 13C NMR (CDCl3) 6.9, 28.4, 47.3, 55.0, 62.6,
81.9, 127.9, 129.0, 129.3, 139.4, 167.6, 205.7; FTIR (neat) 2996,
167.4, 204.3; FTIR (neat) 2955, 1730, 1710 cm-1
.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-p h en ylp en -
ta n oa te (3b): yield 76% (based on 7b) and >97% ee as a
colorless oil after purification by flash chromatography (hexane:
ether ) 95:5 to 85:10); [R]25 -69.4 (c 0.85, CHCl3); 1H NMR
D
1741, 1716 cm-1
.
(CDCl3) δ 1.24 (s, 9H), 3.02 (m, 2H), 3.37 (d, 1H, J ) 15.4 Hz),
3.54 (d, 2H, J ) 13.2 Hz), 3.57 (d, 1H, J ) 15.4 Hz), 3.60 (dd,
1H, J ) 3.7, 7.5 Hz), 3.82 (d, 2H, J ) 13.2 Hz), 7.30 (m, 15H);
13C NMR (CDCl3) δ 28.2, 28.9, 48.2, 55.1, 68.8, 82.0, 126.6, 127.9,
129.0, 129.5, 130.1, 139.2, 140.0, 166.9, 203.0; FTIR (neat) 2976,
P r ep a r a tion of 3-Oxo Ester s Dir ectly fr om Ester s 5a -
d ,h . ter t-Bu tyl 4-(N,N-Diben zyla m in o)-3-oxo-6-m eth ylh ep -
ta n oa te (3a ). Gen er a l P r oced u r e. A solution of lithium (tert-
butylcarbonyl)methanide was prepared using BuLi (2.50 M, 2.10
mL, 5.25 mmol), diisopropylamine (531 mg, 5.25 mmol), and tert-
butyl acetate (609 mg, 5.25 mmol). To this pale yellow solution
at -78 °C was added dropwise (S)-methyl 2-(N,N-dibenzyl-
amino)-4-methylpentanoate (5a ) (812 mg, 2.50 mmol). The
resulting mixture was stirred at -78 °C for 5 min and then
warmed to room temperature. The reaction was monitord by
TLC. Six hours later, the yellow solution was quenched with 1
N HCl (50 mL) and extracted with ethyl acetate (3 × 50 mL).
The organic extracts were combined, washed with brine (100
mL), dried (MgSO4), passed through a short pad of silica gel,
and concentrated by evaporation in vacuum to provide 3a as a
colorless oil (870 mg, 85% based on 5a ; 87% ee by chiral LIS
study using Eu(hfc)3 in comparison with a racemic sample).
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-p h en ylp en -
ta n oa te (3b): yield 84% (based on 5b) and 92% ee as a colorless
oil after purification by radial chromatography (hexane:ether )
85:10).
1745, 1730 cm-1
.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-6-p h en ylh ex-
a n oa te (3c): yield 78% (based on 7c) and 94% ee as a colorless
oil after purification by radial chromatography (hexane:ethyl
acetate ) 95:5); [R]25 -35.9 (c 1.0, CHCl3); 1H NMR (CDCl3) δ
D
1.38 (s, 9H), 1.88 (m, 1H), 2.19 (m, 1H), 2.33 (m, 1H), 2.70 (m,
1H), 3.28 (dd, 1H, J ) 2.8, 9.6 Hz), 3.35 (d, 2H, J ) 13.4 Hz),
3.44 (d, 1H, J ) 15.8 Hz), 3.54 (d, 1H, J ) 15.8 Hz), 3.67 (d, 2H,
J ) 13.4 Hz), 7.28 (m, 15H); 13C NMR (CDCl3) δ 24.6, 28.4, 28.8,
33.5, 47.9, 55.0, 65.7, 82.0, 126.5, 127.8, 128.1, 129.6, 139.4,
142.4, 167.5, 203.5; FTIR (neat) 2987, 1741, 1716 cm-1
.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-cycloh exyl-
p en ta n oa te (3d ): yield 77% (based on 7d ) and > 97% ee as a
colorless oil after purification by flash chromatography (hexane:
1
ether ) 85:10); [R]25 +113.0 (c 0.50, CHCl3); H NMR (CDCl3)
D
δ 1.37 (s, 9H), 0.70-1.85 (set of m, 13H), 1.53 (enol) (s, 9H), 3.38
(dd, 1H, J ) 4.5, 9.4 Hz), 3.44 (d, 2H, J ) 13.5 Hz), 3.47 (d, 1H,
J ) 15.5 Hz), 3.58 (d, 1H, J ) 15.5 Hz), 3.69 (d, 2H, J ) 13.5
Hz), 4.80 (enol) (s, 1H), 7.31 (m, 10H); 13C NMR (CDCl3) δ 26.7,
28.4, 30.0, 33.5, 34.4, 35.3, 48.2, 54.9, 64.2, 82.0, 127.7, 128.9,
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-6-p h en ylh ex-
a n oa te (3c): yield 88% (based on 5c) and 88% ee as a colorless
oil after purification by radial chromatography (hexane:ether )
95:5).
129.5, 140.0, 167.4, 204.5; FTIR (neat) 2937, 1745, 1720 cm-1
.
ter t-Bu t yl 4-(N,N-d ib en zyla m in o)-3-oxo-5-cycloh exyl-
p en ta n oa te (3d ): yield 85% (based on 5d ) and 90% ee as a
colorless oil after purification by radial chromatography (hexane:
ethyl acetate ) 95:5).
ter t-Bu tyl 4-(N,N-d iben zyla m in o)-3-oxop en ta n oa te (3h ):
yield 80% (based on 5h ) and 78% ee as a colorless oil after
purification by radial chromatography (hexane:ether ) 85:5 to
80:10).
This procedure failed for the synthesis of 3e-g from 5e-g,
which are â-branched.
(3R,4R)-ter t-Bu tyl 4-(N,N-Diben zyla m in o)-3-h yd r oxy-6-
m eth ylh ep ta n oa te, (8a ). Gen er a l P r oced u r e. 3-Oxo ester
3a (372 mg, 0.910 mmol) was dissolved in methanol (17.0 mL),
which was dried using Mg turnings and iodine. The resulting
ter t-Bu tyl 4-(N,N-d iben zyla m in o)-3-oxo-4-cycloh exylbu -
ta n oa te (3e): yield 73% (based on 7e) and >97% ee as a colorless
oil after purification by flash chromatography (hexane:ethyl
acetate ) 95:5 to 90:10); [R]25 -200.5 (c 0.40, CHCl3); 1H NMR
D
(CDCl3) δ 0.70-2.24 (set of m, 11H), 1.46 (s, 9H), 1.53 (enol) (s,
9H), 3.17 (d, 1H, J ) 10.4 Hz), 3.18 (d, 1H, J ) 15.8 Hz), 3.28
(d, 1H, J ) 15.8 Hz), 3.39 (enol) (d, 2H, J ) 14.1 Hz), 3.59 (d,
2H, J )14.0 Hz), 3.96 (d, 2H, J ) 14.0 Hz), 3.99 (enol) (d, 2H, J
) 14.1 Hz), 4.70 (enol) (s, 1H),7.31 (m, 10H); 13C NMR (CDCl3)
(keto and enol) δ 26.2, 26.5, 27.1, 28.4, 28.8, 30.5, 30.9, 35.7,
37.3, 52.7, 54.7, 67.3, 70.2, 81.4, 82.0, 94.8, 127.2, 127.6, 128.6,
129.0, 140.0, 140.7, 172.9, 174.0, 205.1; FTIR (neat) 2937, 1745,
1715, 1646 (br) cm-1. Anal. Calcd for C28H37O3N: C, 77.20; H,
8.56; N, 3.22. Found: C, 77.30; H, 8.33; N, 3.15.