Mannich Reaction
2032±2043
7 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 3.31 (dd, J 16, 4 Hz, 1H), 3.19 (dd,
J 16 Hz, 11 Hz, 1H), 1.09 (s, 9H), 1.06 (ddd, J 12, 7, 7 Hz, 3H), 0.91 (s,
3H); 13C NMR (125.8 MHz, CDCl3): d 171.27 (q), 168.21 (q), 167.74 (q),
166.56 (q), 158.97 (q), 155.52 (q), 139.23 (q), 133.98 (CH), 133.70 (CH),
132.30 (q), 131.09 (CH), 130.92 (q), 130.09 (q), 128.98 (CH), 127.12 (q),
123.11 (CH), 122.93 (CH), 122.81 (CH), 112.85 (CH), 109.40 (CH), 60.18
(CH2), 59.52 (CH), 58.18 (CH), 55.18 (CH3), 55.08 (CH3), 38.23 (CH2),
37.06 (q), 27.73 (CH3), 17.15 (CH3), 14.04 (CH3); MS(70 eV, EI): m/z (%):
586 (86), 541 (14), 380 (74), 324 (35), 216 (80), 207 (100); C34H38N2O7
(586.68): calcd C 69.61, H 6.53, N 4.77; found: C 69.64, H 6.49, N 4.85; HR-
(400 MHz, CDCl3): d 8.11 (d, J 8 Hz, 1H), 7.62 (br, 4H), 7.47 (ddd, J
8, 8, 1 Hz, 1H), 7.13 (dd, J 8, 8 Hz, 1H), 6.92 (s, 1H), 6.81 (d, J 12 Hz,
1H), 6.40 (s, 1H), 6.35 (ddd, J 8, 8, 1 Hz, 1H), 5.42 (d, J 8 Hz, 1H), 4.50
(ddd, J 10, 9, 7 Hz, 1H), 4.59 (s, 1H), 4.32 (ddd, J 10, 9, 3 Hz, 1H), 3.30
(ddd, J 12, 9, 3 Hz, 1H), 2.59 (s, 3H), 2.30 (ddd, J 9, 10, 13 Hz, 1H), 2.17
(s, 3H), 1.70 (ddd, J 3, 7, 13 Hz, 1H), 1.12 (s, 12H); 13C NMR (100.6 MHz,
CDCl3): d 177.27 (q), 166.30 (q), 140.82 (q), 138.26 (q), 137.57 (q), 137.50
(q), 133.69 (CH), 130.94 (CH), 130.42 (CH), 130.25 (CH), 130.18 (CH),
130.08 (CH), 129.60 (q), 128.30 (CH), 128.13 (CH), 123.00 (CH), 66.34
(CH2), 57.49 (CH), 54.50 (CH), 39.34 (CH), 37.25 (q), 27.80 (CH3), 27.37
(CH2), 21.68 (CH3), 20.67 (CH3); MS(70 eV, EI): m/z (%): 552 (22), 496 (6),
336 (20), 308 (30), 280 (15), 216 (100); HR-MS(70 eV, EI): m/z: calcd for
MS(70 eV, EI): m/z: calcd for [M] : 586.2679, found: 586.2700.
Ethyl
(R)-3-(2'-methoxyphenyl)-3-[N-(2'-methoxy-6'-methylphenyl)-N-
[M] : 552.2624, found: 552.2626.
((S)-N',N'-phthaloyl-tert-leucyl)]-amino-propionate (8o): The product
was obtained from N-(2-methoxy-6-methylphenyl)-2'-methoxybenzylidene
amine (6k, 128 mg, 0.5 mmol). Colorless solid (51%); m.p.: 1728C; TLC:
Rf 0.12 (hexane/ethyl acetate 3:1); HPLC: tR 20'0'' (methanol/H2O
70:30); [a]2D2 À136.1 (c 0.5 in CHCl3); 1H NMR (400 MHz, CDCl3): d
7.81 (d, J 7 Hz, 1H), 7.68 (ddd, J 1, 7, 7 Hz, 1H), 7.64 (ddd, J 1, 7, 7 Hz,
1H), 7.57 (d, J 7 Hz, 1H), 7.06 (dd, J 8, 8 Hz, 1H), 7.06 (dd, J 8, 8 Hz,
1H), 6.98 (d, J 8, 8 Hz, 1H), 6.79 (d, J 8 Hz, 1H), 6.64 (d, J 8 Hz, 1H),
6.62 (dd, J 8, 8 Hz, 1H), 6.32 (dd, J 4, 11 Hz, 1H), 6.23 (d, J 8 Hz,
1H), 4.18 (s, 1H), 3.93 (dq, J 31, 7 Hz, 1H), 3.90 (dq, J 31, 7 Hz, 1H),
3.75 (s, 3H), 3.55 (s, 3H), 3.35 (dd, J 16, 4 Hz, 1H), 3.25 (dd, J 16, 11 Hz,
1H), 1.09 (s, 9H), 1.01 (dd, J 7, 7 Hz, 3H), 0.87 (s, 3H):13C NMR
(100.6 MHz, CDCl3): d 171.39 (q), 168.30 (q), 167.47 (q), 166.60 (q),
158.28 (q), 155.67 (q), 139.34 (q), 133.91 (CH), 133.62 (CH), 132.33 (q),
131.00 (q), 130.25 (CH), 128.65 (CH), 128.58 (CH), 127.44 (q), 125.97 (q),
122.94 (CH), 122.88 (CH), 122.51 (CH), 119.56 (CH), 109.75 (CH), 108.87
(CH), 59.94 (CH2), 58.03 (CH), 55.19 (CH3), 55.06 (CH3), 52.05 (CH), 37.10
(q), 37.01 (CH2), 27.75 (CH3),16.56 (CH3), 13.93 (CH3); MS(70 eV, EI): m/z
(%): 586 (99), 541 (16), 380 (80), 324 (41), 216 (100), 207 (19); C34H38N2O7
(586.68): calcd C 69.61, H 6.53, N 4.77; found: C 69.39, H 6.61, N 4.67; HR-
Methyl
(S)-3-[N-phenyl-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-3-
(2,4,6-trimethylphenyl)-(R)-2-methoxy-propionate (14syn): The product
was obtained from the same reaction mixture as 14anti after additional
chromatography with hexane/dichloromethane 1:6. Colorless solid (70%);
m.p.: 2358C; TLC: Rf 0.29 (hexane/ethyl acetate 3:1); HPLC: tR 18'58''
(methanol/H2O 75:25); [a]D22 À98 (c 0.5, CHCl3); H NMR (500 MHz,
1
CDCl3): d 7.86 (d, J 8 Hz, 1H), 7.61 (br, 4H), 7.45 (ddd, J 2, 8, 8 Hz,
1H), 7.12 (dd, J 8, 8 Hz, 1H), 6.85 (s, 1H), 6.67 (d, J 11 Hz, 1H), 6.37 (s,
1H), 6.32 (ddd, J 2, 8, 8 Hz, 1H), 5.37 (d, J 8 Hz, 1H), 4.46 (s, 1H), 4.36
(d, J 11 Hz, 1H), 3.93 (s, 3H), 3.24 (s, 3H), 2.51 (s, 3H), 2.15 (s, 3H), 1.13
(s, 3H), 1.09 (s, 9H); 13C NMR (125.8 MHz, CDCl3): d 172.58 (q), 166.13
(q), 140.51 (q), 139.14 (q), 137.77 (q), 137.06 (q), 133.71 (CH), 130.49 (CH),
130.46 (CH), 130.19 (CH), 129.88 (CH), 129.86 (CH), 129.28 (q), 128.30
(CH), 128.00 (CH), 123.06 (q), 79.52 (CH), 57.83 (CH3), 57.58 (CH), 56.62
(CH), 52.54 (CH3), 37.23 (q), 27.90 (CH3), 21.43 (CH3), 20.75 (CH3), 19.84
(CH3); MS(70 eV, EI): m/z (%): 570 (0.1), 539 (0.4), 511 (1), 467 (48), 244
(23), 216 (100); C34H38N2O6 (570.682): calcd C 71.56, H 6.71, N 4.91; found:
C 71.18, H 6.67, N 4.73; HR-MS(70 eV, EI): m/z: calcd for [M] : 570.2730,
found: 570.2755.
MS(70 eV, EI): m/z: calcd for [M] : 586.2679, found: 586.2664.
Methyl
(S)-3-[N-phenyl-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-3-
(2,4,6-trimethylphenyl)-(S)-2-methoxy-propionate (14anti): The product
was obtained from (Z)-1,2-dimethoxy-1-trimethyl siloxy-ethene 11
(132 mg, 0.75 mmol) after chromatography with hexane/ethyl acetate 4:1.
Colorless oil (7%); TLC: Rf 0.23 (hexane/ethyl acetate 3:1); HPLC: tR
18'2'' (methanol/H2O 75:25); [a]2D2 À21 (c 0.5 in CHCl3); 1H NMR
(500 MHz, CDCl3): d 7.62 (s, 4H), 7.45 (ddd, J 1, 8, 8 Hz, 1H), 7.29 (d,
J 8 Hz, 1H), 7.16 (dd, J 8, 8 Hz, 1H), 6.84 (d, J 10 Hz, 1H), 6.81 (s,
1H), 6.46 (ddd, J 1, 8, 8 Hz, 1H), 6.38 (s, 1H), 5.64 (d, J 8 Hz, 1H), 4.47
(d, J 10 Hz, 1H), 4.46 (s, 1H), 3.54 (s, 3H), 3.52 (s, 3H), 2.51 (s, 3H), 2.13
(s, 3H), 1.23 (s, 3H), 1.12 (s, 9H); 13C NMR (125.8 MHz, CDCl3): d
170.66 (q), 166.84 (q), 165.61 (q), 140.70 (q), 138.64 (q), 138.35 (q), 137.24
(q), 133.67 (CH), 131.52 (q), 130.63 (CH), 130.49 (CH), 130.07 (CH), 129.86
(CH), 129.62 (CH), 129.12 (q), 128.60 (CH), 128.35 (CH), 123.07 (CH),
80.99 (CH), 57.99 (CH), 57.85 (CH3), 51.86 (CH3), 37.11 (q), 27.60 (CH3),
21.79 (CH3), 20.77 (CH3); MS(70 eV, EI): m/z (%): 570 (0.1), 539 (0.5), 511
Mannich reaction with N,N-phthaloyl-tert-leucylchloride (2b), N-phenyl-
2,4,6-trimethylbenzylidene amine (6c), and the silylketene acetals 10, 11
and 12. General procedure: Acid chloride 2b (168 mg, 0.6 mmol) in dry
CH2Cl2 (3 mL) was added under argon at 08C to a solution of of Schiff base
6c (112 mg, 0.5 mmol) in dry CH2Cl2 (2 mL). The mixture was kept at 08C
for 10 min and then warmed to room temperature over 1 h. After cooling
the solution to 08C the silylketene acetal (0.75 mmol) was added over
5 min. The solution was then stirred at room temperature for 72 h. After
addition of CH2Cl2 (10 mL), the mixture was washed with 10% aq.
NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. After
evaporation to dryness, the residue was purified by chromatography on
silica gel.
(R)-2-{(R)-[N-Phenyl-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-(2',4',6'-
trimethylphenyl)-methyl}-butano-4-lactone (13syn): The product was ob-
tained from Schiff base 6c (223 mg, 1 mmol), acid chloride 2b (308 mg,
1.1 mmol) and 2-trimethylsiloxydihydrofuran (10, 237 mg, 0.75 mmol) after
chromatography with hexane/acetone 12:1). Colorless solid (47%);
m.p.: 1868C; TLC: Rf 0.06 (hexane/acetone 6:1); HPLC: tR 15'22''
(methanol/H2O 72:28); [a]2D2 À82.9 (c 0.5 in CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.63 (br, 4H), 7.42 (ddd, J 8, 8, 1 Hz, 1H), 7.23
(d, J 8 Hz, 1H), 7.15 (dd, J 8, 8 Hz, 1H), 6.81 (s, 1H), 6.65 (d, J 10 Hz,
1H), 6.39 (ddd, J 8, 8, 1 Hz, 1H), 6.38 (s, 1H), 4.45 (d, J 8 Hz, 1H), 4.58
(ddd, J 16, 8, 6 Hz, 1H), 4.46 (s, 1H), 4.30 (ddd, J 16, 8, 6 Hz, 1H), 3.46
(ddd, J 10, 16, 8 Hz, 1H), 2.60 ± 2.70 (m, 1H), 2.53 ± 2.59 (m, 1H), 2.50 (s,
3H), 2.12 (s, 3H), 1.27 (s, 3H), 1.11 (s, 9H); 13C NMR (100.6 MHz, CDCl3):
d 175.85 (q), 166.49 (q), 139.52 (q), 138.94 (q), 137.30 (q), 137.21 (q),
133.93 (CH), 130.67 (CH), 130.45 (CH), 130.13 (q), 129.77 (CH), 129.35
(CH), 128.62 (CH), 128.55 (CH), 123.16 (CH), 66.09 (CH2), 57.80 (CH),
55.66 (CH), 41.95 (CH), 37.13 (q), 27.78 (CH2), 27.67 (CH3), 21.62 (CH3),
21.28 (CH3), 20.76 (CH3); MS(70 eV, EI): m/z (%): 552 (18), 496 (6), 336
(20), 308 (27), 280 (14), 216 (100); C34H36N2O3 (552.67): calcd C 73.89, H
6.57, N 5.07; found: C 73.60, H 6.40, N 4.93; HR-MS(70 eV, EI): m/z: calcd
(1), 467 (48), 244 (21), 216 (100); HR-MS(70 eV, EI): m/z: calcd for [M] :
570.2730, found: 570.2748.
Methyl
(S)-3-[N-phenyl-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-3-
(2,4,6-trimethylphenyl)-(R)-2-(tert-butyl-dimethyl)-siloxy-propionate
(15syn): The product was obtained from (E)-1-(dimethyl-tert butylsiloxy)-
2-methoxy, 2-trimethylsiloxy-ethene 12 (207 mg, 0.75 mmol) after chroma-
tography with hexane/ethyl acetate 10:1. Colorless solid (66%);
m.p.: 1978C; TLC: Rf 0.17 (hexane/ethyl acetate 10:1); HPLC: tR
11'13'' (methanol/H2O 75:25); [a]2D2 À91.8 (c 0.5 in CHCl3); 1H NMR
(500 MHz, CDCl3): d 7.62 (s, 4H), 7.34 (d, J 8 Hz, 1H), 7.29 (ddd, J 1,
8, 8 Hz, 1H), 7.07 (dd, J 7, 7 Hz, 1H), 6.67 (s, 1H), 6.49 (s, 1H), 6.44 (ddd,
J 1, 8, 8 Hz, 1H), 6.08 (d, J 10 Hz, 1H), 6.00 (d, J 8 Hz, 1H), 5.12 (d,
J 10 Hz, 1H), 4.37 (s, 1H), 3.88 (s, 3H), 2.16 (s, 3H), 2.13 (s, 3H), 1.64 (s,
3H), 1.07 (s, 9H), 0.55 (s, 9H), À0.06 (s, 3H), À0.31 (s, 3H); 13C NMR
(125.8 MHz, CDCl3): d 172.54 (q), 166.72 (q), 165.87 (q), 140.41 (q),
139.52 (q), 138.15 (q), 136.74 (q), 133.68 (CH), 131.54 (q), 130.23 (CH),
130.19 (CH), 130.06 (q), 129.82 (CH), 129.61 (CH), 129.09 (CH), 128.29
(CH), 128.01 (CH), 123.05 (q), 72.31 (CH), 61.67 (CH), 57.94 (CH), 51.90
(CH3), 37.14 (q), 27.86 (CH3), 25.31 (CH3), 21.25 (CH3), 20.69 (CH3), 20.36
(CH3), 17.87 (q), À4.79 (CH3), À5.19 (CH3); MS(70 eV, EI): m/z (%): 670
(0.3), 613 (16), 585 (5), 467 (78), 244 (28), 216 (100); C39H50N2O6Si (670.92):
calcd C 69.82, H 7.51, N 4.18; found: C 69.83, H 7.42, N 4.05; HR-MS(70 eV,
for [M] : 552.2624, found: 552.2607.
(S)-2-{(R)-[N-Phenyl-N-((S)-N',N'-phthaloyl-tert-leucyl)]-amino-(2',4',6'-
trimethylphenyl)-methyl}-butano-4-lactone (13anti): colorless solid
(28%); m.p.: 1748C; TLC: Rf 0.11 (hexane/acetone 6:1); HPLC: tR
20'44'' (methanol/H2O 72:28); [a]2D2 À77.4 (c 0.5 in CHCl3); 1H NMR
EI): m/z: calcd for [M] : 670.3438, found: 670.3422.
Chem. Eur. J. 2000, 6, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
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