Asymmetric Michael Reactions on Polymeric Support
FULL PAPER
IR (ATR): ν = 3302 (w), 2931 (m), 2861 (m), 1705 (vs), 1634 (vs),
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2
1 H; CHNH), 4.54 [A-part of an AB system, J = (–)14.5 Hz, 1 H;
2
Ph-CH2], 4.57 [B-part of an AB system, J = (–)14.5 Hz, 1 H; Ph- 1497 (m), 1451 (s), 1390 (w), 1366 (m), 1251 (m), 1169 (s), 1092
3
CH2], 5.35 (br. d, J = 8.9 Hz, 1 H; NH), 7.28–7.38 (m, 5 H, Ar-
H) ppm. 13C{1H} NMR (CDCl3, 126 MHz): δ = 14.2 (CH3), 17.0
(CH3), 28.4 (CH3; Boc), 30.6 (CH2; C-3), 31.6 (CH2; C-3), 31.63
(CH3–CH), 39.1 (CH2; C-2), 42.9 (CH2; C-2), 54.7 (CHNH), 70.1
(m), 1017 (w) cm–1. MS (EI, 70 eV), m/z (%): 490 (15) [M+], 434
(3) [M+ – C4H8], 417 (5), 389 (3), 373 (3) [M+ – NH3 – CO2
–
C4H8], 347 (2), 320 (3), 290 (4) [M+ – C10H18NO3+], 172 (33)
[C9H18NO2+], 128 (3), 116 (100) [NHBoc+], 91 (49) [C7H7+], 84
(CH2; Ph-CH2), 73.1 (CH; C-4), 79.4 (C; Boc), 127.5 (CH; o-CH), (11), 72 (86), 57 (33) [C4H9+]. C28H46N2O5 (490.68): calcd. C 68.54,
127.6 (CH; p-CH), 128.5 (CH; m-CH), 138.4 (C; i-C), 155.9 (C; H 9.45, N 5.71; found C 68.47, H 9.45, N 5.66. [α]2D0 = +21 (c =
OCON), 170.4 (C; CON) ppm. IR (ATR): ν = 3302 (w), 2964 (m),
5.2 in CHCl3).
˜
2930 (m), 2871 (w), 1707 (s), 1636 (vs), 1797 (m), 1452 (s), 1366 (m),
1171 (s), 1090 (m), 734 (m) cm–1. MS (FAB; matrix: 4-nitrobenzyl
alcohol), m/z (%): 391 (100) [MH+], 335 (31) [MH+ – C4H8], 317
(7) [MH+ – C4H8], 291 (48) [MH+ – C4H8 – CO2], 190 (18)
[C12H16NO+], 116 (16) [C5H10NO2+], 91 (49) [C7H7+], 72 (23)
[C4H8O+], 57 (27) [C4H9+]. C22H34N2O4 (390.52): calcd. C 67.66,
H 8.78, N 7.17; found C 67.60, H 8.75, N 7.04. HRMS (FAB):
calcd. for C22H34N2O4 391.2597; found 391.2591 (M+). [α]2D0 = +25
(c = 7.3 in CHCl3).
N-tert-Butyloxycarbonyl-L-valine 4-Hydroxypiperidide (16a): Benzyl
ether 15a (7.88 g, 20.2 mmol) and Pd/C (5%, 2.50 g) were dissolved
in a mixture of ethanol (18 mL) and EtOAc (2 mL) in a Schlenk
flask. After removal of air (freeze, pump, thaw), hydrogen was
added from a balloon. The mixture was stirred for 18 h at 23 °C,
then two drops of conc. hydrochloric acid were added. After stir-
ring for a further 2 d, the mixture was filtered through a short pad
of SiO2 and the residue washed with MeOH. Evaporation of the
combined filtrates afforded 16a (5.69 g, 18.9 mmol, 94%) as a col-
orless solid, m.p. 111–112 °C. 1H NMR (CDCl3, 300 MHz): δ =
PS-Supported N-tert-Butyloxycarbonyl-L-valine 4-Hydroxypiperi-
dide (15b): DCC (2.37 g, 11.5 mmol), 14 (2.50 g, 11.5 mmol) in
CH2Cl2 (15 mL) and 13b (1.00 g) were allowed to react according
to General Procedure E. Shaking at 500 rpm for 16 h, purification
with MeOH and CH2Cl2 (General Procedure B) and drying gave
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3
0.87 (d, J = 6.7 Hz, 3 H; CH3), 0.96 (d, J = 6.7 Hz, 3 H; CH3),
1.43 (s, 9 H, Boc-CH3), 1.46–1.64 (m, 2 H, 3-Hax), 1.86–1.95 (m, 3
H, 2-Hax and CH3–CH), 2.22 (s, br. signal; OH), 3.18–3.37 (m, 2
3
3
H, 3-Heq), 3.82 (tt, J = 12.1, J = 4.7 Hz, 1 H; OCH), 3.88–4.11
15b (1.06 g, 52% over two steps). IR (ATR): ν = 3316 (w, br), 3024
(m, 2 H, 2-Heq), 4.48 (dd, 3J = 9.1, 3J = 5.6 Hz, 1 H; CHNH),
˜
(w), 2922 (w), 2188 (w), 1962 (m), 1684 (s), 1643 (s), 1493 (s), 1450 5.39 (br. d, J = 9.0 Hz, 1 H; NH) ppm. 13C{1H} NMR (CDCl3,
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(vs), 1365 (s), 1250 (m), 1219 (m), 1160 (s), 1088 (s), 1019 (m) cm–1. 126 MHz): δ = 17.5 (CH3), 20.0 (CH3), 28.7 (CH3; Boc), 31.9 (CH;
Found C 80.13, H 8.02, N 3.59.
OCH), 34.1 (CH2; C-3), 35.0 (CH2; C-3), 39.6 (CH2; C-2), 43.2
(CH2; C-2), 55.1 (CHNH), 66.8 (OCH), 79.8 (C; Boc), 156.3 (C;
PEG-Supported N-tert-Butyloxycarbonyl-L-valine 4-Hydroxypiperi-
dide (15c): DCC (8.67 g, 42.0 mmol), 14 (9.12 g, 42.0 mmol) in
CH2Cl2 (30 mL) and 13c (4.20 g) were allowed to react according
to General Procedure E. The mixture was filtered off and the fil-
trate was purified (General Procedure A) to give a colorless poly-
mer 15c (3.81 g, 91%). Load according to 1H NMR: 72%. 1H
NMR (CDCl3, 300 MHz): δ = 0.87 (d, 3J = 6.5 Hz, 3 H; CH3),
OCON), 170.9 (C; CON) ppm. IR (ATR): ν = 3345 (w), 3264 (m),
˜
2963 (m), 2926 (m), 2874 (m), 2204 (w), 1976 (m), 1680 (s), 1632
(vs), 1536 (s), 1440 (s), 1364 (s), 1269 (s), 1252 (s), 1217 (s), 1159
(vs), 1115 (m), 1012 (vs), 940 (s), 869 (m) cm–1. MS (EI, 70 eV),
m/z (%): 300 (11) [M+], 227 (9), 172 (27), 128 (12), 116 (73), 72 (100)
[NEt2+], 57 (60). C15H28N2O4 (300.41): calcd. C 59.97, H 9.40, N
9.33; found C 59.91, H 9.35, N 9.11. [α]2D0 = +29.9 (c = 10.2 in
CHCl3).
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0.96 (d, J = 6.9 Hz, 3 H; CH3), 1.43 (s, 9 H, Boc-CH3), 1.55–1.68
(m, 2 H, 3Ј-Hax), 1.78–1.94 (m, 3 H, 2Ј-Hax and CH3–CH), 3.26–
3.38 (m, 2 H, 3Ј-Heq), 3.58–3.71 (m, 123 H, PEG–H and 4Ј-H), N-tert-Butyloxycarbonyl-L-valine 4-(6-Hydroxyhexyloxy)piperidide
4.48 (dd, 3J = 8.8, 3J = 5.3 Hz, 1 H; CHNH), 5.35 (br. d, 3J = (16b): According to the procedure for 16a, benzyl ether 15d (13.9 g,
9.2 Hz, 1 H; NH) ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 16.7
28.3 mmol) and Pd/C (5%, 1.5 g) were converted in a mixture of
(CH3), 19.7 (CH3), 28.4 (CH3; CCH3), 30.7 (CH2; C-3Ј), 31.56 ethanol (18 mL) and EtOAc (2.5 mL) to give 16b (11.3 g,
(CH2; C-3Ј), 31.6 (CH3–CH), 39.2 (CH2; C-2Ј), 42.9 (CH2; C-2Ј),
54.5 (CHNH), 70.0–71.3 (m, CH2; PEG-CH2), 74.1 (CH; C-4Ј), 300 MHz): δ = 0.87 (d, J = 6.7 Hz, 3 H; CHCH3), 0.96 (d, J =
28.3 mmol, quant.) as
a
colorless solid. 1H NMR (CDCl3,
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79.3 (C; CCH3), 155.9 (C; OCON), 170.4 (C; CON) ppm. Found
C 55.43, H 9.39, N 1.93.
6.7 Hz, 3 H; CHCH3), 1.26 (s, 1 H, OH), 1.24–1.41 (m, 3 H), 1.43
(s, 9 H, CH3), 1.50–1.65 (m, 7 H), 1.74–1.96 (m, 3 H), 3.24–3.57
3
(m, 5 H), 3.64 (t, J = 6.5 Hz, 2 H), 3.69–3.81 (m, 1 H), 3.83–3.94
N-tert-Butyloxycarbonyl-L-valine 4-[(6-Benzyloxy)hexyloxy]piperi-
dide (15d): DCC (8.00 g, 38.8 mmol), 14 (7.00 g, 32.3 mmol) and
13d (9.40 g, 32.3 mmol) were allowed to react according to General
Procedure E. Chromatography (Rf = 0.16) gave 15d (14.81 g,
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(m, 1 H), 4.48 (dd, J = 8.6, J = 5.3 Hz, 1 H; CHNH), 5.37 (br.
d, J = 8.9 Hz, 1 H; NH) ppm. 13C{1H} NMR (CDCl3, 75 MHz):
3
δ = 17.0 (CH3), 19.7 (CH3), 25.6 (CH2), 26.1 (CH2), 28.4 (CH3;
Boc-CH3), 30.0 (CH2), 30.8 (CH2), 31.64 (CH2), 31.6 (CH;
CHCH3), 32.7 (CH2), 39.3 (CH2), 43.0 (CH2), 54.7 (CH; CHNH),
62.9 (CH2), 68.0 (CH; OCH), 73.6 (CH2), 79.4 (C; CCH3), 155.9
1
30.2 mmol, 93%) as a colorless oil. H NMR (CDCl3, 300 MHz):
δ = 0.87 (d, 3J = 6.7 Hz, 3 H; CH3), 0.96 (d, 3J = 6.8 Hz, 3 H;
CH3), 1.37–1.39 (m, 4 H), 1.43 (s, 9 H, Boc-CH3), 1.55–1.65 (m, 6
H), 1.72–1.96 (m, 3 H, 2-Hax and CH3–CH), 3.23–3.52 (m, 5 H),
3.47 (t, 3J = 6.5 Hz, 2 H), 3.17–3.29 (m, 1 H), 3.32– 3.42 (m, 1 H),
4.46–4.50 (m, 1 H), 4.50 (s, 2 H, Ph-CH2), 5.36 (br. d, 3J = 8.9 Hz,
1 H; NH), 7.27–7.34 (m, 5 H, Ar-H) ppm. 13C{1H}NMR (CDCl3,
75 MHz): δ = 14.2 (CH3), 17.0 (CH3), 26.07 (CH2), 26.1 (CH2),
28.4 (CH3; Boc), 29.7 (CH2), 30.0 (CH2), 30.6 (CH2; C-3), 31.6
(CH3–CH), 31.7 (CH2; C-3), 39.3 (CH2; C-2), 42.9 (CH2; C-2), 54.7
(CHNH), 68.2 (CH2), 70.4 (CH2; Ph-CH2), 73.0 (CH2), 73.6 (CH;
C-4), 79.3 (C; Boc), 127.5 (CH; o-CH), 127.6 (CH; p-CH), 128.3
(CH; m-CH), 138.7 (C; i-C), 155.9 (C; OCON), 170.3 (C; CON)
ppm. A shoulder at δ = 31.7 ppm indicates the missing CH signal.
(C; OCON), 170.4 (CON) ppm. IR (ATR): ν = 3409 (w), 3299 (w),
˜
2930 (s), 2860 (m), 1703 (s), 1633 (vs), 1522 (m), 1500 (m), 1451
(s), 1390 (w), 1365 (m), 1328 (w), 1251 (w), 1221 (w), 1171 (s), 1107
(m), 1089 (m), 1043 (m), 1017 (w), 969 (w) cm–1. MS (EI, 70 eV),
m/z (%): 400 (9) [M+], 327 (6), 283 (5), 200 (5) [C10H18NO3+], 172
(32) [C9H18NO2+], 128 (7), 116 (99) [C5H10NO2+], 101 (10)
[C5H9O2+], 84 (17), 72 (100) [C4H8O+], 57 (51) [C4H9+], 43 (54)
[C3H7+]. C21H40N2O5 (400.55): calcd. C 62.97, H 10.07, N 7.00;
found C 62.77, H 9.98, N 6.79. [α]2D0 = +26 (c = 9.2 in CDCl3).
Attempts of Enamine Formation Using Polystyrene-Supported 1c:
To a suspension of 1c (100 mg) and molecular sieves (4 Å, 1.00 g)
Eur. J. Org. Chem. 2005, 5339–5348
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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