Synthesis of Optically Active N-Protected ꢀ-Aminoketones and ꢀ-Amino Alcohols 605
(s, 3H, CH3O), 3.98 (m, 2H, CH2), 4.86 (br, 1H, NH),
5.21 (m, 1H, CH), 7.07–7.10 (m, 5Harom).
6.99–7.23 (m, 5Harom), 7.81 (d, 2Harom, JAB = 15.6 Hz).
Anal. Calcd for C21H25NO3: C, 74.32; H, 7.37; N, 4.13.
Found: C, 74.37; H, 7.46; N, 4.23.
Nꢀ-(tert-Butoxycarbonyl)-L-proline N-Methoxy-N-
7: White solid, m.p. 85–86◦C, 63.3% yield, [ꢀ]20
D
methylamide (6). Thick liquid, 98.2% yield, [ꢀ]20
−22.9 (c 0.96, CHCl3). H NMR (δ, CDCl3): 1.24 (s,
1
D
1
+15.6 (c 1.55, CHCl3). H NMR (δ, CDCl3): 1.31 (s,
5H, five protons of t-Bu), 1.43 (s, 4H, four protons of
t-Bu), 1.90 (m, 4H, 2CH2), 2.39 (s, 3H, CH3), 3.64 (m,
5H, five protons of t-Bu), 1.35 (s, 4H, four protons of
t-Bu), 1.69 (m, 2H, CH2), 2.01 (m, 2H, CH2), 3.09 (s,
3H, NCH3), 3.48 (m, 2H, NCH2), 3.65 (s, 3H, CH3O),
4.58 (m, 1H, CH).
2H, NCH2), 5.18 (m, 1H, CH), 7.24 (d, 2Harom, JAB
=
7.84 Hz), 7.83 (d, 2Harom, JAB = 7.84 Hz). Anal. Calcd
for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C,
70.64; H, 8.02; N, 5.00.
Preparation of the ꢀ-Aminoketones 3
(General Procedure)
Preparation of the 1,2-Amino Alcohols 4 and 8
(General Procedure)
To an ice-cold solution of the Weinreb amides
(4 mmol) in 10 ml anhydrous THF was added
dropwise a solution of arylmagnesium bromide
[10 mmol, prepared from Mg (4.48 g, 20 mmol) and
aryl bromide (10 mmol) in THF] . The resulting mix-
ture was stirred at the same temperature for 4 h.
The reaction was quenched by addition of aqueous
10% HCl solution (10 ml) and stirred for 5 min. The
resulting solution was extracted with ethyl acetate
(3 × 25 ml). The combined extract was washed se-
quentially with water and brine, and dried over an-
hydrous Na2SO4. After removal of the solvent the
crude product was purified by column chromatogra-
phy [silica gel 200–300 mesh, petroleum ether/ethyl
acetate (1:10) as the eluent] to afford the pure ꢀ-
aminoketones 3.
To a stirred solution of the aminoketones 3 (2 mmol)
in dry methanol (25 ml) at −20◦C was added sodium
borohydride (0.15 g, 4 mmol) in one lot and stir-
ring was continued at the same temperature for 5 h.
The reaction was then quenched by addition of water
(5 ml). The resulting mixture was concentrated un-
der reduced pressure. The residue was dissolved in
ethyl acetate (50 ml) and washed successively with
water and brine. After drying over anhydrous Na2SO4
and removal of the solvent the crude product was
purified by column chromatography [silica gel 200–
300 mesh, petroleum ether/ethyl acetate (1:5) as the
eluent] to provide the syn-amino alcohols 4.
4a: White solid, m.p. 86–87◦C, 82.3% yield, [ꢀ]20
D
1
+9.8 (c 1, CHCl3). H NMR (δ, CDCl3): 1.37 (d, 3H,
3a: Thick liquid, 47.5% yield, [ꢀ]20 0 (c 0.9,
CH3, 3 JHH = 6.98 Hz), 1.44 (s, 9H, t-Bu), 3.09 (br, 1H,
D
CHCl3). 1H NMR (δ, CDCl3): 1.37 (d, 3H, CH3, 3 JHH
6.98 Hz), 1.44 (s, 9H, t-Bu), 5.21 (q, 1H, CH, JHH
=
OH), 3.96 (m, 1H, CHCH3), 4.61 (br, 1H, NH), 4.82 (d,
3
3
=
1H, CHOH, JHH = 2.76 Hz), 7.28–7.32 (m, 5Harom).
6.98 Hz), 5.56 (br, 1H, NH), 7.20–7.48 (m, 5Harom).
Anal. Calcd for C14H19NO3: C, 67.44; H, 7.68; N, 5.62.
Found: C, 67.36; H, 7.65; N, 5.57.
Anal. Calcd for C14H21NO3: C, 66.90; H, 8.84; N, 5.57.
Found: C, 66.81; H, 9.02; N, 5.55.
4b: White solid, m.p. 128–129◦C, 97.6% yield,
3b: White solid, m.p. 99–100◦C, 59.6% yield,
[ꢀ]20D −66.0 (c 0.94, CHCl3). 1H NMR (δ, CDCl3): 1.36
(d, 3H, CH3, 3 JHH = 7.10 Hz), 1.43 (s, 9H, t-Bu), 2.39
[ꢀ]20 −70.4 (c 1.02, CHCl3). H NMR (δ, CDCl3):
1
D
3
0.96 (d, 3H, CH3, JHH = 6.74 Hz), 1.44 (s, 9H, t-
Bu), 2.32 (s, 3H, CH3), 3.92 (m, 1H, CHCH3), 4.86 (d,
3
3
(s, 3H, CH3), 5.16 (q, 1H, CH, JHH = 7.10 Hz), 5.60
1H, CHOH, JHH = 2.92 Hz), 7.15–7.23 (m, 9Harom).
(br, 1H, NH), 7.25 (d, 2Harom, JAB = 16.1 Hz), 7.83 (d,
2Harom, JAB = 16.1 Hz). Anal. Calcd for C15H21NO3: C,
68.41; H, 8.04; N, 5.32. Found: C, 68.27; H, 8.01; N,
5.38.
Anal. Calcd for C15H23NO3: C, 67.89; H, 8.74; N, 5.28.
Found: C, 67.71; H, 8.84; N, 5.20.
4c: White solid, m.p. 136–137◦C, 77.1% yield,
[ꢀ]20 −24.8 (c 0.71, CHCl3). H NMR (δ, CDCl3):
1
D
3c: White solid, m.p. 94–96◦C, 58.1% yield, [ꢀ]20
1.31 (s, 9H, t-Bu), 2.68–2.94 (m, 2H, CHOH and
CHNH), 3.16 (br, 1H, OH), 4.05 (br, 1H, NH), 4.91
(m, 2H, CH2), 7.11–7.38 (m, 10Harom). Anal. Calcd
for C20H25NO3: C, 73.37; H, 7.70; N, 4.28. Found: C,
73.26; H, 7.74; N, 4.35.
D
1
+52.3 (c 1, CHCl3). H NMR (δ, CDCl3): 1.41 (s, 9H,
t-Bu), 2.96 (m, 1H, NH), 3.16 (m, 1H, CH), 5.45
(m, 2H, CH2), 7.18–7.94 (m, 10Harom). Anal. Calcd
for C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C,
73.62; H, 7.24; N, 4.35.
4d: White solid, m.p. 131–134, 92.3% yield, [ꢀ]20
D
3d: White solid, m.p. 89–91◦C, 47.3% yield, [ꢀ]20
−25.3 (c 0.3, CHCl3). H NMR (δ, CDCl3): 1.31 (s,
1
D
+51.2 (c 0.5, CHCl3). 1H NMR (δ, CDCl3): 1.31 (s, 9H,
t-Bu), 2.35 (s, 1H, one proton of CH3), 2.41 (s, 2H, two
protons of CH3), 4.08 (m, 1H, CH), 4.65 (br, 1H, NH),
5.52 (m, 2H, CH2), 6.68 (d, 2Harom, JAB = 15.6 Hz),
9H, t-Bu), 2.31 (s, 1H, one proton of CH3), 2.35 (s,
2H, two protons of CH3), 2.71–2.98 (m, 2H, CHOH
and CHNH), 3.56 (br, 1H, OH), 4.01 (br, 1H, NH),
4.86 (m, 2H, CH2), 7.13–7.24 (m, 9Harom). Anal. Calcd