4070
A. Iza et al.
SPECIAL TOPIC
sponding aldehyde and 4-methoxyphenylamine under standard con-
ditions and the preparation of pseudoephedrine amides 1a–h is
described in the literature.10a All other reagents were used as pur-
chased. Diastereomeric excesses and enantiomeric excesses were
determined by HPLC under conditions specified in each case. The
characterization of amides 3a and 3g–m, b-amino esters 4a and
4g–m, and b-lactams 8a and 8k–m was reported in our previous
preliminary reports.18
(+)-(2R,3S)-2-Butyl-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenyl-
ethyl]-3-[(4-methoxyphenyl)amino]-N-methyl-3-phenylpro-
panamide (3d)
[a]D20 +35.5 (c 1.0, CH2Cl2).
IR (CHCl3): 3357 (OH, NH), 1615 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d (8:1 rotamer ratio) = 0.61 (d, J = 6.8
Hz, 3 H), 0.68* (t, J = 7.1 Hz, 3 H), 0.92 (t, J = 7.1 Hz, 3 H), 1.43
(m, 5 H), 1.78 (m, 1 H), 2.42 (s, 3 H), 2.57* (s, 3 H), 3.11 (m, 1 H),
3.65* (s, 3 H), 3.81 (s, 3 H), 4.02* (m, 1 H), 4.49 (m, 1 H), 4.60 (m,
1 H), 4.68 (m, 1 H), 6.39 (d, J = 6.7 Hz, 2 H), 6.46* (d, J = 6.5 Hz,
2 H), 6.61 (d, J = 6.5 Hz, 2 H), 6.75* (d, J = 6.7 Hz, 2 H), 7.21–7.86
(m, 10 H).
13C NMR (75 MHz, CDCl3): d (4:1 rotamer ratio) = 14.2, 14.3,
14.9*, 20.1, 22.0, 29.1, 30.5, 33.2*, 48.6, 48.8*, 55.7, 55.8*, 58.5*,
60.1, 63.6, 75.1*, 75.4, 113.6*, 114.2, 114.8, 116.5, 126.3, 126.5*,
127.0, 127.1*, 127.3, 127.5*, 127.9, 128.2*, 128.5, 128.7*, 128.8*,
129.0, 132.3*, 132.6, 141.5, 141.8*, 142.7, 143.2*, 151.5, 151.7*,
175.6*, 175.8.
Asymmetric Mannich Reaction Using Nonenolizable Imines;
General Procedure
Propanamide 1a–h (1 mmol) was slowly added to a suspension of
LDA (2 mmol) and LiCl (5 mmol) in THF at –78 °C. After stirring
for 1 h at this temperature the mixture was allowed to reach r.t. and
stirred for another 15 min. The reaction was then cooled to 0 °C and
a soln of the corresponding nonenolizable imine 2a–e (4 mmol) was
slowly added. The mixture was stirred until TLC analysis of ali-
quots indicated full conversion (6–24 h). The reaction was
quenched with H2O and extracted with CH2Cl2. The combined or-
ganic extracts were dried (Na2SO4) and filtered and the solvent was
removed in vacuo. The residue was purified by flash column chro-
matography (hexanes–EtOAc, 2:8).
HRMS: m/z [M+] calcd for C30H38N2O3: 474.2882; found:
474.2888.
(+)-(2R,3S)-2-Benzyl-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenyl-
ethyl]-3-[(4-methoxyphenyl)amino]-N-methyl-3-phenyl-
propanamide (3e)
(+)-(2R,3S)-2-Ethyl-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenyl-
ethyl]-3-[(4-methoxyphenyl)amino]-N-methyl-3-phenyl-
propanamide (3b)
[a]D20 +41.6 (c 1.0, CH2Cl2).
[a]D20 +33.8 (c 1.0, CH2Cl2).
IR (CHCl3): 3354 (OH, NH), 1613 (C=O) cm–1.
IR (CHCl3): 3361 (OH, NH), 1613 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d (3:1 rotamer ratio) = 0.51* (d,
J = 6.5 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 2.51 (s, 3 H), 3.06* (s, 3
H), 3.54 (m, 1 H), 3.66 (m, 1 H), 3.97 (m, 1 H), 4.06 (s, 3 H), 4.12*
(s, 3 H), 4.57 (m, 1 H), 5.06 (m, 2 H), 6.45 (d, J = 6.6 Hz, 2 H),
6.52* (d, J = 6.5 Hz, 2 H), 6.61* (d, J = 6.5 Hz, 2 H), 6.73 (d,
J = 6.5 Hz, 2 H), 7.38–7.93 (m, 15 H).
13C NMR (75 MHz, CDCl3): d (4:1 rotamer ratio) = 13.6, 14.4*,
27.0*, 30.5, 37.8, 38.0*, 50.8*, 55.8, 56.3*, 58.6, 59.6, 62.2*,
75.5*, 76.7, 113.9, 114.4*, 114.8*, 114.9, 126.4*, 126.5, 126.6*,
127.0, 127.3, 127.4, 127.6*, 127.9, 128.4, 128.5*, 128.6, 128.7,
128.9*, 129.0*, 129.1, 131.2*, 131.3, 139.9*, 141.2, 141.3, 141.6*,
142.5, 142.8*, 151.3, 151.7*, 174.5*, 175.4.
1H NMR (300 MHz, CDCl3): d (6:1 rotamer ratio) = 0.63 (d, J = 6.7
Hz, 3 H), 0.79* (t, J = 7.1 Hz, 3 H), 0.95 (t, J = 7.3 Hz, 3 H), 1.76
(m, 1 H), 2.08 (m, 1 H), 2.47 (s, 3 H), 2.92* (s, 3 H), 3.12 (m, 1 H),
3.68* (s, 3 H), 3.86 (s, 3 H), 4.05* (m, 1 H), 4.51 (d, J = 3.6 Hz, 1
H), 4.62 (d, J = 2.8 Hz, 1 H), 4.68 (m, 1 H), 6.48 (d, J = 6.7 Hz, 2
H), 6.54* (d, J = 6.5 Hz, 2 H), 6.63* (d, J = 6.5 Hz, 2 H), 6.78 (d,
J = 6.7 Hz, 2 H), 7.23–7.89 (m, 10 H).
13C NMR (75 MHz, CDCl3): d (6:1 rotamer ratio) = 12.5*, 12.7,
15.8, 23.6, 31.2, 31.6*, 37.0, 37.4*, 49.8*, 50.6, 56.5, 56.9*, 61.2,
61.7*, 75.4*, 76.1, 112.6*, 114.5, 114.8*, 115.4, 127.3, 127.4,*,
127.6*, 127.9, 128.1*, 128.3, 128.6, 129.0*, 129.8, 130.1, 136.4*,
136.6, 141.8, 142.0*, 144.1*, 144.3, 151.2*, 151.5, 177.1*, 178.4.
HRMS: m/z [M+] calcd for C33H36N2O3: 508.2726; found:
508.2722.
HRMS: m/z [M+] calcd for C28H34N2O3: 446.2569; found:
446.2554.
(–)-(2R,3S)-N-[(1S,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-2-
isopropyl-3-[(4-methoxyphenyl)amino]-N-methyl-3-phenyl-
propanamide (3f)
(+)-(2R,3S)-N-[(1S,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-3-
[(4-methoxyphenyl)amino]-N-methyl-3-phenyl-2-propyl-
propanamide (3c)
[a]D20 –32.7 (c 1.0, CH2Cl2).
[a]D20 +40.7 (c 2.0, CH2Cl2).
IR (CHCl3): 3369 (OH, NH), 1612 (C=O) cm–1.
IR (CHCl3): 3366 (OH, NH), 1614 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d (4:1 rotamer ratio) = 0.52 (d, J = 6.9
Hz, 3 H), 0.78* (d, J = 7.0 Hz, 3 H), 0.85* (d, J = 5.1 Hz, 3 H), 0.94
(d, J = 5.2 Hz, 3 H), 1.09* (d, J = 5.1 Hz, 3 H), 1.12 (d, J = 5.2 Hz,
3 H), 2.34 (s, 3 H), 2.36* (s, 3 H), 2.45 (m, 1 H), 2.79 (dd, J = 3.8,
9.6 Hz, 1 H), 3.69* (s, 3 H), 3.76 (s, 3 H), 4.29* (d, J = 9.0 Hz, 1
H), 4.38 (d, J = 9.1 Hz, 1 H), 4.52* (m, 1 H), 4.73 (m, 2 H), 6.37*
(d, J = 6.4 Hz, 2 H), 6.47 (d, J = 6.5 Hz, 2 H), 6.75 (d, J = 6.4 Hz, 2
H), 6.79* (d, J = 6.5 Hz, 2 H), 7.16–7.95 (m, 10 H).
13C NMR (75 MHz, CDCl3): d (4:1 rotamer ratio) = 11.6*, 12.3,
20.0, 20.4*, 20.5*, 20.7, 24.2, 31.1, 31.4*, 37.2, 37.6*, 51.4*, 51.5,
52.3, 52.7*, 61.4, 61.7*, 75.2*, 76.5, 112.0*, 112.4, 112.6*, 113.5,
125.3, 125.4,*, 126.1, 126.7*, 127.3*, 127.6, 128.0, 128.1*, 128.4*,
129.6, 129.7*, 130.2, 136.1*, 136.4, 141.8, 142.3*, 144.0*, 144.5,
151.2*, 151.7, 177.0*, 177.9.
1H NMR (300 MHz, CDCl3): d (8:1 rotamer ratio) = 0.61 (d, J = 6.8
Hz, 3 H), 0.75* (t, J = 7.0 Hz, 3 H), 0.93 (t, J = 7.1 Hz, 3 H), 1.18
(m, 2 H), 1.62 (m, 1 H), 2.03 (m, 1 H), 2.39 (s, 3 H), 2.43* (s, 3 H),
3.21 (m, 1 H), 3.66* (s, 3 H), 3.81 (s, 3 H), 4.02* (m, 1 H), 4.54 (d,
J = 3.9 Hz, 1 H), 4.58 (m, 1 H), 4.71 (m, 1 H), 6.47 (d, J = 6.7 Hz,
2 H), 6.51* (d, J = 6.5 Hz, 2 H), 6.70* (d, J = 6.5 Hz, 2 H), 6.75 (d,
J = 6.7 Hz, 2 H), 7.20–7.90 (m, 10 H).
13C NMR (75 MHz, CDCl3): d (4:1 rotamer ratio) = 14.0, 14.4,
15.7*, 20.7, 20.9*, 27.2, 30.6, 33.7*, 47.6, 47.9*, 55.7, 55.8*,
58.6*, 60.2, 62.2, 75.1*, 75.9, 113.7, 114.5*, 114.9, 116.6*, 126.5,
126.7*, 127.1*, 127.2, 127.3, 127.6*, 127.8*, 128.4, 128.6, 128.8*,
128.9*, 129.1, 132.1*, 132.4, 141.7, 142.0*, 142.9, 143.1*, 151.2,
151.4*, 175.5*, 175.9.
HRMS: m/z [M+] calcd for C29H36N2O3: 460.2726; found:
460.2729.
HRMS: m/z [M – H]+ calcd for C29H35N2O3: 459.2648; found:
459.2642.
Synthesis 2006, No. 23, 4065–4074 © Thieme Stuttgart · New York