Ligands for Asymmetric Synthesis
diborane to provide (3R,5S)-3-hydroxy-5-(hydroxymethyl)-N-tosyl-
pyrrolidine (1.6 g, 85% yield) as a white solid, m.p. 128–130 °C,
[α]2D0 = –47.1 (c = 2, EtOH) [ref.[15c] m.p. 132–133 °C, [α]2D0 = –43.3
(c = 1.85, EtOH)]. ii) This intermediate was treated with additional
p-toluenesulfonyl chloride to provide tritosylate 1 (3.65 g, 95%
yield) as a white solid, m.p. 135–136 °C, [α]2D0 = –57.0 (c = 1.9,
acetone) [ref.[15c] m.p. 134–136 °C, [α]2D0 = –56.0 (c = 1.16, acetone)].
1H NMR (CDCl3, 400 MHz): δ = 2.05 (m, 2 H), 2.42 (s, 3 H), 2.45
(s, 6 H), 3.51 (m, 2 H), 3.80 (m, 1 H), 4.10 (dd, JH,H = 6.2, 10.2 Hz,
(1S,4S)-5-Butyl-2-tosyl-2,5-diazabicyclo[2.2.1]heptane (4): GP 1 was
followed with 1 (10.0 g, 17.3 mmol) and butylamine (22.2 g,
303.6 mmol, 30 mL). The reaction time was 2 h, and the product
was purified by recrystallization from propan-2-ol to provide 4
(4.5 g, 85% yield), white solid, m.p. 69–70 °C, [α]2D0 = +26.8 (c = 1,
3
CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 0.84 [t, JH,H = 7.3 Hz,
3 H, NCH2(CH2)2CH3], 1.02 (d, 2JH,H = 9.8 Hz, 1 H, CHCH2CH),
2
1.29 [m, 4 H, NCH2(CH2)2CH3], 1.62 (d, JH,H = 9.8 Hz, 1 H,
CHCH2CH), 2.39 [m, 5 H, NCH2(CH2)2CH3, ArCH3], 2.54 [d,
2
1 H), 4.30 (dd, JH,H = 3.2, 10.2 Hz, 1 H), 4.77 (m, 1 H) 7.27–7.78 3JH,H = 8.8 Hz, 1 H, NCH2(endo)CH], 2.86–2.89 [dd, JH,H = 9.5,
(m, 12 H) ppm. 13C NMR (CDCl3, 100.5 MHz): δ = 21.6, 21.7, 3JH,H = 2.5 Hz, 1 H, NCH2(exo)CH], 2.94–2.97 [dd, JH,H = 9.5,
21.7, 35.8, 54.7, 56.8, 71.6, 78.1, 127.7, 127.8, 128.0, 129.9, 130.0,
130.1, 132.7, 133.2, 133.3, 144.5, 145.3, 145.4 ppm. MS (EI): m/z
(%) = 580 [M + 1]+ (0.2), 394 (32), 222 (100), 155 (24), 80 (22).
2
3JH,H = 2.2 Hz, 1 H, NCH2(exo)CH], 3.38 (s, 1 H, NCHCH2), 3.53
2
[d, JH,H = 9.5 Hz, 1 H, NCH2(endo)CH], 4.21 (s, 1 H, NCHCH2),
3
7.28 (d, 3JH,H = 8.0 Hz, 2 H, CHAr), 7.69 (d, JH,H = 8.0 Hz, 2 H,
CHAr) ppm. 13C NMR (CDCl3, 100.5 MHz): δ = 14.1, 20.5, 21.6,
(1S,4S)-5-Benzyl-2-tosyl-2,5-diazabicyclo[2.2.1]heptane (2): This
compound was produced as described in GP 1, with tritosylate 1
(10 g, 17.3 mmol) and benzylamine (22 g, 20.6 mmol, 22.5 mL).
The reaction time was 2 h, and the product was purified by
recrystallization from ethanol (5.5 g, 93% yield). White solid, m.p.
122–124 °C, [α]2D0 = +14.3 (c = 1.6, acetone) [ref.[29] m.p. 124 °C,
[α]2D0 = –15.7 (c = 1.6, acetone) for the (R,R) enantiomer].
31.4, 35.3, 49.9, 53.2, 59.7, 60.7, 61.4, 127.5, 129.8, 135.6,
143.5 ppm. IR (KBr): ν
= 3446, 2935, 2407, 1595, 1465, 1337,
˜
max
1222, 818 cm–1. MS (EI): m/z (%) = 309 [M + 1]+ (1), 265 (11), 153
(100), 124 (82), 68 (14), 44 (4). C16H24N2O2S (308.44): calcd. C
62.30, H 7.84, N 9.08; found C 62.20, H 7.86, N 9.28.
(1S,4S)-5-Octyl-2-tosyl-2,5-diazabicyclo[2.2.1]heptane·HCl
(5):
Microwave Modification: Tritosylate 1 (0.5 g, 0.86 mmol) and tolu-
ene (1 mL) were placed in a 10 mL reactor tube contaiing a mag-
netic stirrer and the resulting solution was treated with benzyl-
amine (0.37 g, 3.45 mmol, 0.37 mL). The reaction mixture was
heated with microwave irradiation (50 W) for 30 min at 130 °C, co-
oled to room temp., diluted with EtOAc and water, extracted with
EtOAc, washed with HCl solution (1 ) and brine, and dried with
anhyd. Na2SO4. The product was concentrated in a rotary evapora-
tor, and the residue was crystallized from ethanol to afford 2
(0.28 g, 95% yield), white solid, m.p. 120–122 °C, [α]2D0 = +13.8 (c
GP 1 was followed with 1 (10.0 g, 17.3 mmol) and octylamine
(19.6 g, 151.7 mmol, 25 mL). The reaction time was 3 h, and the
product was purified by recrystallization of the hydrochloride salt
from EtOAc, to provide 5 (5.3 g, 77% yield), white solid, m.p. 197–
199 °C, [α]2D0 = +8.5 (c = 1, MeOH). H NMR (CDCl3, 400 MHz):
1
3
2
δ = 0.86 [t, JH,H = 6.6 Hz, 3 H, NCH2(CH2)6CH3], 1.03 (d, JH,H
= 10.2 Hz, 1 H, CHCH2CH), 1.23–1.36 [m, 12 H, NCH2(CH2)6-
2
CH3], 1.65 (d, JH,H = 9.8 Hz, 1 H, CHCH2CH), 2.42 [m, 5 H,
NCH2(CH2)6CH3, ArCH3], 2.56 [d, JH,H
NCH2(endo)CH], 2.89–2.92 [dd, JH,H = 9.8, JH,H = 2.2 Hz, 1 H,
NCH2(exo)CH], 2.95–2.98 [dd, JH,H = 9.8, JH,H = 2.2 Hz, 1 H,
NCH2(exo)CH], 3.40 (s, 1 H, NCHCH2), 3.55 [d, JH,H = 9.5 Hz, 1
H, NCH2(endo)CH], 4.23 (s, 1 H, NCHCH2), 7.31 (d, JH,H
8.0 Hz, 2 H, CHAr), 7.71 (d, JH,H = 8.0 Hz, 2 H, CHAr) ppm.
13C NMR (CDCl3, 100.5 MHz): δ = 14.2, 21.6, 22.7, 27.5, 29.2,
29.3, 29.7, 31.9, 35.4, 49.8, 53.5, 59.7, 60.7, 61.3, 127.5, 129.8,
2
= 9.9 Hz, 1 H,
2
3
1
2
= 1.6, acetone). H NMR (CDCl3, 400 MHz): δ = 1.09 (d, JH,H
=
2
3
2
9.8 Hz,
1 H, CHCH2CH), 1.70 (d, JH,H = 9.8 Hz, 1 H,
2
2
CHCH2CH), 2.44 (s, 3 H, ArCH3), 2.66 [d, JH,H = 9.9 Hz, 1 H,
NCH2(endo)CH], 2.82 [dd, JH,H = 9.9, JH,H = 2.2 Hz, 1 H,
3
=
2
3
3
2
3
NCH2(exo)CH], 3.03 [dd, JH,H = 9.9, JH,H = 2.2 Hz, 1 H,
NCH2(exo)CH], 3.40 (s, 1 H, NCHCH2), 3.64 [m, 3 H, NCH2(endo)
-
CH, CH2Ph], 4.28 (s, 1 H, NCHCH2), 7.21–7.28 (m, 5 H, CHAr),
135.5, 143.5 ppm. IR (KBr): ν
= 3401, 2925, 2422, 1597, 1460,
˜
max
3
7.32 (d, 3JH,H = 8.0 Hz, 2 H, CHAr), 7.73 (d, JH,H = 8.0 Hz, 2 H,
1338, 1215, 823 cm–1. MS (EI): m/z (%) = 364 [M + 1]+ (0.1), 265
(5), 209 (100), 180 (5), 111 (8), 68 (9). C20H32N2O2S·HCl (401.01):
calcd. C 59.90, H 8.29, N 6.99; found C 60.01, H 8.51, N 7.00.
CHAr) ppm. 13C NMR (CDCl3, 100.5 MHz): δ = 21.6 (ArCH3),
35.2 (CH2), 50.8 (CH2), 57.6 (CH2), 59.6 (CH2Ph), 60.9 (CH), 61.1
(CH), 127.1, 127.6, 128.4, 128.5, 129.8, 137.3, 139.2, 143.5 ppm.
MS (EI): m/z (%) = 343 [M + 1]+ (5), 265 (1), 187 (100), 158 (84),
91 (97).
(1S,4S)-5-[(S)-1-Phenylethyl]-2-tosyl-2,5-diazabicyclo[2.2.1]-
heptane·HCl (6): GP 1 was followed with 1 (20.0 g, 34.5 mmol) and
(S)-phenylethylamine (46.0 g, 379.5 mmol, 48.5 mL). The reaction
time was 5.5 h, and the product was purified by recrystallization of
the hydrochloride salt from EtOAc, to provide 6·HCl (9.5 g, 70%
yield), white solid, m.p. 232–236 °C, [α]2D0 = –18.9 (c = 1, MeOH).
(1S,4S)-5-Isopropyl-2-tosyl-2,5-diazabicyclo[2.2.1]heptane (3): GP 1
was followed with tritosylate 1 (4.0 g, 6.9 mmol) and isopro-
pylamine (5.6 g, 94.7 mmol, 8.0 mL) in acetonitrile (8 mL). The re-
action time was 5 h, and the product was purified by recrystalli-
zation from ethanol (1.9 g, 95% yield). White solid, m.p. 88–89 °C,
[α]2D0 = +27.2 (c = 1, CHCl3). 1H NMR (CDCl3, 400 MHz): δ =
2
1H NMR (CDCl3, 400 MHz): δ = 1.12 (d, JH,H = 11.4 Hz, 1 H,
3
CHCH2CH), 1.75 (d, JH,H = 6.6 Hz, 3 H, CHCH3), 2.38 (s, 3 H,
0.97 [d, JH,H = 5.9 Hz, 6 H, CH(CH3)2], 1.03 (d, JH,H = 9.5 Hz,
ArCH3), 2.57 (d, 2JH,H = 11.4 Hz, 1 H, CHCH2CH), 2.91 [d, 2JH,H
3
2
2
2
1 H, CHCH2CH), 1.65 (d, JH,H = 9.8 Hz, 1 H, CHCH2CH), 2.41
= 11.8 Hz, 1 H, NCH2(endo)CH], 3.30 [d, JH,H = 11.0 Hz, 1 H,
(s, 3 H, ArCH3), 2.58 [m, 2 H, CH(CH3)2, NCH2(endo)CH], 2.93–
NCH2(endo)CH], 3.69–3.73 [m, 2 H, NCH2(exo)CH, NCHCH2], 4.0–
2
3
2.96 [dd, JH,H = 9.5, JH,H = 1.8 Hz, 1 H, NCH2(exo)CH], 3.02–
4.08 [m, 1 H, NCH2(exo)CH], 4.25 (m, 1 H, CHCH3), 4.43 (s, 1 H,
2
3
3
3.05 [dd, JH,H = 9.8, JH,H = 2.2 Hz, 1 H, NCH2(exo)CH], 3.56 [d, NCHCH2), 7.30–7.40 (m, 5 H, CHAr), 7.65 (d, JH,H = 8.3 Hz, 2
2JH,H = 9.8 Hz, 1 H, NCH2(endo)CH], 3.58 (s, 1 H, NCHCH2), 4.22 H, CHAr), 7.71 (d, JH,H = 8.3 Hz, 2 H, CHAr) ppm. 13C NMR
3
3
(s, 1 H, NCHCH2), 7.30 (d, JH,H = 8.4 Hz, 2 H, CHAr), 7.70 (d, (CDCl3, 100.5 MHz): δ = 20.4 (CHCH3), 21.7 (ArCH3), 35.2
3JH,H = 8.0 Hz, 2 H, CHAr) ppm. 13C NMR (CDCl3, 100.5 MHz):
δ = 21.6, 21.9, 22.6, 36.0, 48.9, 50.6, 58.6, 58.9, 60.6, 127.5, 129.8,
(CHCH2CH), 46.9, 59.0, 59.9, 62.7, 63.8, 127.5, 127.9, 129.6, 129.9,
130.7, 133.7, 136.3, 145.1 ppm. IR (KBr): νmax = 3447, 2987, 2880,
˜
135.7, 143.6 ppm. IR (KBr): ν
= 3437, 2977, 2855, 1596, 1343,
2451, 1596, 1348, 1158, 684 cm–1. MS (EI): m/z (%) = 357 [M +
1]+ (1), 341 (2), 201 (100), 105 (71), 97 (73), 68 (28). C20H24N2O2S
(356.48): calcd. C 67.38, H 6.79, N 7.86; found C 67.29, H 6.81, N
7.94.
˜
max
1158, 673 cm–1. MS (EI): m/z (%) = 293 [M + 1]+ (1), 279 (5), 139
(100), 110 (42), 68 (25). C15H22N2O2S (294.41): calcd. C 61.19, H
7.53, N 9.52; found C 60.94, H 7.91, N 9.58.
Eur. J. Org. Chem. 2008, 655–672
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
665