A. Armstrong et al. / Tetrahedron 61 (2005) 8423–8442
8439
(185 mg, 100%) as an off-white solid, dH (250 MHz,
CDCl3) 8.87 (2H, br s, NH2), 4.37–4.19 (2H, m,
CH3CH2O), 3.90 (1H, d, JZ4.8 Hz, NCH), 2.49 (1H, m,
(CH3)2CH), 1.31 (3H, t, JZ7.0 Hz, CH3CH2O), 1.20–1.09
(6H, m, (CH3)2CH). Further reaction of (R)-(K)-valine
ethyl ester hydrochloride (180 mg, 0.97 mmol) afforded the
title compound (R)-27 (420 mg, 78%) as a colourless
viscous oil, [a]D20 C37.3 (c 3.8, CHCl3); nmax/cmK1 3438,
3071, 2963, 2858, 2242, 1731, 1650, 1503, 1372, 1311,
1262, 1195, 1111, 921, 823, 735, 703, 612; dH (250 MHz,
CDCl3) 7.65–7.10 (15H, m, Ar-H), 4.88 (1H, d, JZ7.7 Hz,
NH), 4.72–4.55 (1H, br m, PhCHCH), 4.50 (1H, d, JZ
removed under reduced pressure to afford 30 as a colourless
viscous oil (10 mg, 44%), [a]2D7 C40.0 (c 0.2, CHCl3); nmax
/
cmK1 3377, 2966, 2606, 2248, 1723, 1611, 1525, 1396,
1203, 732; dH (250 MHz, CDCl3) 7.36–7.26 (5H, m, Ar-H),
5.61 (1H, br d, JZ8.6 Hz, NH), 4.52 (1H, d, JZ9.1 Hz,
PhCH), 4.29 (1H, dd, JZ8.6, 5.2 Hz, iPrCH), 4.13 (1H, m,
PhCHCH), 2.84 (3H, s, NCH3), 2.22 (1H, m, (CH3)2CH),
1.08–0.90 (9H, m, NCHCH3 and (CH3)2CH); dC (62.9 MHz,
CDCl3) 175.6 (C), 161.0 (C), 141.6 (C), 128.5 (CH), 127.9
(CH), 126.7 (CH), 76.3 (CH), 59.1 (CH), 58.7 (CH), 30.4
(CH), 29.6 (CH3), 19.4 (CH3), 18.0 (CH3), 15.3 (CH3); m/z
(CI, NH3) 309 ([MCH]C, 10%). Found: [MCH]C,
309.1812. C16H25N2O4 requires 309.1814.
i
7.9 Hz, PhCHCH), 4.43 (1H, dd, JZ7.7, 4.7 Hz, PrCH),
4.22–4.10 (2H, m, CH3CH2O), 2.34 (3H, s, NCH3), 2.15–
1.95 (1H, m, (CH3)2CH), 1.25 (3H, t, JZ7.0 Hz,
CH3CH2O), 0.93 (9H, s, C(CH3)3), 0.89 (3H, d, JZ
6.9 Hz, (CH3)2CH), 0.86 (3H, d, JZ6.9 Hz, (CH3)2CH),
0.77 (3H, d, JZ6.6 Hz, NCHCH3); dC (62.9 MHz, CDCl3, 3
aromatic CH not found) 172.8 (C), 157.7 (C), 141.6 (C),
135.7 (CH), 133.4 (C), 133.0 (C), 129.3 (CH), 129.1 (CH),
127.7 (CH), 127.2 (CH), 126.8 (CH), 77.0 (CH), 60.5 (CH2),
58.1 (CH), 55.8 (CH), 31.4 (CH), 28.1 (CH3), 26.6 (CH3),
18.9 (C), 18.5 (CH3), 17.7 (CH3), 14.2 (CH3), 14.0 (CH3);
m/z (CI, NH3) 575 ([MCH]C, 100%). Found: [MCH]C,
575.3312. C34H47N2O4Si requires 575.3305.
Method B. To a solution of free-hydroxy carboxamido
valinate 29 (30 mg, 0.09 mmol) in THF (0.5 ml) at 0 8C
under nitrogen was added sodium hydride (60% w/w in
mineral oil, 4 mg, 0.1 mmol). After stirring at room
temperature for 20 h the reaction mixture was evaporated
and partitioned between water (2 ml) and CH2Cl2 (4 ml).
TLC analysis of the organic layer showed unreacted starting
material 29. The aqueous layer was acidified to pHw2 with
2 M HCl and re-extracted with CH2Cl2 (4 ml). This organic
layer was dried over MgSO4, filtered, and the solvent
removed under reduced pressure to afford 30 as a colourless
viscous oil (12 mg, 44%), analytically identical to that
derived from method A.
4.3.2.3. Attempted cleavage of the pseudoephedrine
auxiliary. Ethyl N-(N-methyl-N-((10S,20S)-10-hydroxy-10-
phenyl-20-propyl)carboxamido)-(S)-valinate 29. To a sol-
ution of TBDPS protected carboxamido valinate (S)-27
(98 mg, 0.17 mmol) in THF (1.5 ml) was added 1 M TBAF
in THF (0.3 ml, 0.3 mmol). After stirring at room
temperature for 90 min, water (4 ml) was added and
extracted with ether (2!5 ml). The organics were dried
over MgSO4, evaporated and purified by flash chromato-
graphy (2–5% MeOH in CH2Cl2) to afford the free-hydroxy
carboxamido valinate 29 (55 mg, 96%) as a colourless
viscous oil, [a]D24 C56.0 (c 0.50, CHCl3); nmax/cmK1 3323,
2966, 1733, 1632, 1518, 1454, 1394, 1314, 1260, 1191,
1028, 759, 702; dH (300 MHz, CDCl3) 7.36–7.27 (5H, m,
Ar-H), 5.24 (1H, d, JZ8.2 Hz, NH), 4.52 (1H, dd, JZ8.5,
Ethyl N-(((10S,20S)-20-methylamino-10-phenyl-10-propyl)
alkoxycarbonyl)-(S)-valinate hydrochloride 31. To a sample
of crude free-hydroxy carboxamido valinate 29, derived
from TBDPS protected carboxamido valinate 27 (166 mg,
0.29 mmol) without chromatographic purification, was
added 1 M HCl in ether (2 ml, 2 mmol). After stirring
under nitrogen at room temperature for 20 h, a white
precipitate had formed which was removed by filtration and
recrystallised from ethyl acetate to afford 31 (18 mg, 17%)
as white needles, mp 145 8C (decomp.), [a]2D9 C31.6 (c
0.095, CHCl3); nmax/cmK1 3372, 2967, 2736, 2459, 1729,
1529, 1467, 1375, 1270, 1233, 1209, 1095, 1028, 702; dH
(250 MHz, CDCl3) 9.94 and 9.72 (2H, 2!br, NH2), 7.46–
7.30 (5H, m, Ar-H), 6.39 (1H, d, JZ9.2 Hz, NH), 5.47 (1H,
d, JZ9.7 Hz, PhCH), 4.20–4.00 (3H, m, iPrCH, CH3CH2O),
3.85–3.65 (1H, br m, PhCHCH), 2.67 (3H, br s, NCH3),
2.30–2.10 (1H, m, (CH3)2CH), 1.24 (3H, d, JZ6.8 Hz,
NCHCH3), 1.16 (3H, t, JZ7.0 Hz, CH3CH2O), 1.02 (3H, d,
JZ6.7 Hz, (CH3)2CH), 1.00 (3H, d, JZ6.7 Hz, (CH3)2CH);
dC (62.9 MHz, CDCl3) 171.4 (C), 154.6 (C), 136.3 (C),
129.2 (CH), 128.9 (CH), 127.1 (CH), 75.3 (CH), 60.9 (CH2),
59.5 (CH), 57.1 (CH), 31.1 (CH), 27.1 (CH3), 19.1 (CH3),
17.8 (CH3), 14.1 (CH3), 12.3 (CH3); m/z (CI, NH3) 337
([MCH]C, 58%). Found: [MCH]C, 337.2116.
C18H29N2O4 requires 337.2127. The structure was con-
firmed by X-ray crystallography.31
i
5.1 Hz, PhCHCH), 4.40 (1H, dd, JZ8.4, 4.8 Hz, PrCH),
4.29–4.15 (4H, m, PhCHCH, OH, CH3CH2O), 2.82 (3H, s,
NCH3), 2.15 (1H, m, (CH3)2CH), 1.29 (3H, t, JZ7.1 Hz,
CH3CH2O), 1.00–0.92 (9H, m, (CH3)2CH and NCHCH3);
dC (75.4 MHz, CDCl3) 173.2 (C), 159.9 (C), 142.3 (C),
128.3 (CH), 127.6 (CH), 126.6 (CH), 76.8 (CH), 61.0 (CH2),
58.5 (CH), 58.2 (CH), 31.2 (CH), 30.0 (CH3), 19.0 (CH3),
17.9 (CH3), 15.1 (CH3), 14.2 (CH3); m/z (CI, NH3) 337
([MCH]C, 100%). Found: [MCH]C, 337.2123.
C18H29N2O4 requires 337.2127.
N-(N-Methyl-N-((10S,20S)-10-hydroxy-10-phenyl-20-propyl)
carboxamido)-(S)-valine 30. Method A. To a solution of
free-hydroxy carboxamido valinate 29 (25 mg, 0.07 mmol)
in THF (0.5 ml) and water (3 drops) was added lithium
hydroxide monohydrate (3 mg, 0.07 mmol). After stirring at
room temperature for 20 h the reaction mixture was
partitioned between water (2 ml) and ether (4 ml). TLC
analysis of the organic layer showed unreacted starting
material 29. The aqueous layer was acidified to pHw2 with
2 M HCl and re-extracted with ether (4 ml). This organic
layer was dried over MgSO4, filtered, and the solvent
1
The filtrate was shown by H NMR to be predominantly
unreacted free-hydroxy carboxamido valinate 27.
4.3.3. Aminations using oxaziridine 4 (Tables 3–5).
4.3.3.1. General procedure. To a stirred solution of
LiHMDS (1.0 M in hexanes, 0.22 ml, 0.22 mmol) in THF
(1 ml) at K78 8C was added substrate (0.22 mmol)
dropwise. After 30 min oxaziridine (65 mg, 0.22 mmol) in