18 h, the product was quenched with anhydrous sodium sulfite and
extracted with ethyl acetate three times. The combined organic
phases were washed with brine, dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by chromatography (1:1
ethyl acetate/hexane) to furnish 11 (10.9 g, 73.8%) as an amorphous
diastereoselective additions of Grignard reagent to bis(1,3-
oxazolidine) and was a highly effective means for preparing
C2-asymmetrical chiral diamines.
1
white solid: H NMR (CDCl3) δ 2.00 (dd, J ) 5.3, 5.8 Hz, 4H),
Experimental Section
2.96 (br, 2H), 4.14-4.22 (m, 3H), 4.42 (s, 2H), 7.25-7.33 (m,
5H); 13C NMR (CDCl3) δ 37.6, 70.2, 71.9, 76.2, 126.9, 127.0, 127.7,
137.7; IR (film) cm-1; 3400, 3000, 2940, 1600, 1500, 1460, 1350,
1240, 1200, 1170, 1070, 1020, 700; MS (EI) 208 (M+); HRMS
calcd for C12H16O3 208.1099, found 208.1105.
(2R,2′R)-[1,9-Bis(1,3-dioxan-2-yl)nonane-(3S,7S)-diamino]bis-
(2-phenylethanol) (4a). A solution of 5a (21.30 g, 30.52 mmol) in
THF (150 mL) was treated with a freshly prepared Grignard reagent
6, derived from 2-(2-bromoethyl)-1,3-dioxane (30.37 mL, 183.12
mmol) and magnesium (7.27 g, 244.16 mmol) in THF (150 mL),
heated at 60 °C for 2 d, and allowed to cool to rt. The reaction
mixture was quenched with saturated aqueous NH4Cl solution (200
mL) and extracted with ethyl acetate three times. The combined
organic extracts were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by chromatography
(200:10:1 CH2Cl2/CH3OH/NH4OH) to furnish 4a (16.52 g, 95%)
(2R,2′R)-[5-Benzyloxy-1,9-bis(1,3-dioxan-2-yl)nonane-(3S,7S)-di-
amino]bis(2-phenylethanol) (4b). A solution of 11 (4.41 g, 21.2
mmol) in CH2Cl2 (110 mL) and H2O (22 mL) was treated with
sodium periodate (4.53 g, 21.2 mmol) and stirred for 10 min, and
N-2,4,6-trimethoxybenzylphenylglycinol (12.1 g, 38.16 mmol) was
added. The reaction mixture was stirred for 16 h before being
separated, dried, and concentrated. The crude product 5b was
1
as a dark yellow gum: [R]26D -55.2 (c 3.06, CHCl3); H NMR
1
unstable and used without further purification: H NMR (CDCl3)
(CDCl3) δ 1.28-1.71 (m, 18H), 1.95-2.13 (m, 2H), 2.44 (m, 2H),
3.01 (br, 2H), 3.40-3.47 (dd, J ) 9.0, 10.5 Hz, 2H), 3.62-3.68
(dd, J ) 4.4, 10.5 Hz, 2H), 3.69-3.74 (dt, J ) 2.1, 11.0 Hz, 4H),
3.78-3.83 (dd, J ) 4.4, 9.0 Hz, 2H), 4.03-4.09 (dd, J ) 4.8, 11.0
δ 1.83-2.05 (m, 4H), 3.54 (s, 6H), 3.66 (s, 6H), 3.74 (s, 3H), 3.76
(s, 3H), 3.50-3.83 (m, 6H), 3.92-4.07 (m, 5H), 4.40-4.51 (m,
2H), 4.58-4.73 (m, 2H), 5.95 (s, 2H), 6.00 (s, 2H), 7.18-7.44
(m, 15H). A solution of crude 5b (16.08 g) in THF (90 mL) and
Grignard reagent [2-(2-bromoethyl)-1,3-dioxane (27.3 mL, 20.0
mmol) and magnesium (4.86 g, 20.0 mmol) in THF (90 mL)] were
reacted at 60 °C for 3 d and worked up as described for 4b to give
4b (8.60 g, 60%) as a dark yellow oil: [R]26D -55.4 (c 3.10, CHCl3);
1H NMR (CDCl3) δ 1.26-1.62 (m, 14H), 1.99-2.04 (m, 2H),
2.54-2.69 (m, 2H), 3.45 (dd, J ) 8.4, 10.7 Hz, 2H), 3.61-3.83
(m, 12H), 4.01-4.09 (m, 5H), 4.24 (t, J ) 4.8 Hz, 1H), 4.29 (t, J
) 4.8 Hz, 1H), 4.38 (d, J ) 11.2 Hz, 1H), 4.44 (d, J ) 11.2 Hz,
1H), 7.20-7.34 (m, 15H); 13C NMR (CDCl3) δ 25.7, 29.4, 29.7,
31.1, 31.1, 39.2, 39.4, 51.6, 51.9, 61.8, 62.3, 66.7, 70.2, 74.3, 102.0,
102.1, 127.1, 127.3, 127.4, 127.8, 128.2, 128.4, 138.4, 141.5, 141.8;
IR (film) cm-1 3440, 3020, 2960, 2940, 2860, 1600, 1500, 1450,
1220, 1140, 750; MS (EI) 676 (M+); HRMS calcd for C40H56N2O7
676.4072, found 676.4087.
3-Benzyloxy-(1S,3S)-bis[(2-hydroxy-(1R)-phenethyl)pyrrolidin-
2-yl]propane (3b). A solution of 4b (7.04 g, 10.4 mmol) in CH3OH
(165 mL), 15% HCl (55 mL), and sodium cyanoborohydride (2.62
g, 41.6 mmol) were reacted and worked up as described for 3a to
give 3b (4.66 g, 85%) as a colorless crystal: mp 122-123 °C (ether/
ethyl acetate); [R]26D -155.1 (c 0.63, EtOH); 1H NMR (CDCl3) δ
1.28-1.78 (m, 10H), 2.05-2.29 (m, 4H), 2.63 (m, 1H), 2.84-2.94
(m, 3H), 3.26 (br, 2H), 3.44 (m, 1H), 3.63-3.70 (m, 2H), 3.94-4.08
(m, 4H), 4.38 (d, J ) 11.4 Hz, 1H), 4.67 (d, J ) 11.4 Hz, 1H),
7.16-7.39 (m, 15H,); 13C NMR (CDCl3) δ 22.1, 30.3, 30.6, 39.2,
40.4, 45.1, 45.4, 55.6, 56.1, 60.9, 61.2, 62.0, 62.4, 70.8, 75.7, 127.5,
127.6, 127.8, 128.0, 128.2, 128.3, 129.3, 129.4, 135.1, 138.5; IR
(film) cm-1 3100, 2920, 2880, 1600, 1450, 1100, 1060, 740, 700;
MS (EI) 528 (M+). Anal. Calcd for C34H44N2O3: C, 77.23; H, 8.89;
N, 5.30. Found: C, 77.01; H, 8.27; N, 5.27. X-ray crystal data:
C34H44N2O3, M ) 528.73; monoclinic, space group P21(#4), a )
16.481(4) Å, b ) 7.997(3) Å, c ) 11.861(3) Å, ꢀ ) 105.21(2)°, V
) 1508.6(7) A3, Z ) 2, and Dcalc ) 1.16 g/cm3; R ) 0.050 and Rw
) 0.057 for 2726 reflections with I > 3.00σ(I). A crystal of 0.20
× 0.30 × 0.30 mm was used.
Hz, 4H), 4.35-4.38 (t, J ) 4.8 Hz, 2H), 7.23-7.36 (m, 10H); 13
C
NMR (CDCl3) δ 19.2, 25.7, 29.0, 31.6, 33.5, 53.4, 61.8, 66.8, 66.9,
102.2, 127.3, 127.4, 128.5, 141.3; IR (film) cm-1; 3440, 2930, 2850,
1455, 1140, 700; MS (EI) 570 (M+); HRMS calcd for C33H50N2O6
570.3668, found 570.3675.
(1S,3S)-Bis[(2-hydroxy-(1R)-phenethyl)pyrrolidin-2-yl]pro-
pane (3a). A solution of 4a (3.90 g, 6.84 mmol) in CH3OH (30
mL) was treated with 10% HCl (10 mL), heated to reflux for 3 h,
and allowed to cool to rt. The reaction mixture was treated with
sodium cyanoborohydride (1.29 g, 20.53 mmol) and stirred for an
additional 2.5 h before concentration of CH3OH. The product was
alkalized with 1 M NaOH and extracted with CH2Cl2 three times.
The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The residue was purified by chromatography
(150:10:1 CH2Cl2/CH3OH/NH4OH) to furnish 3a (1.88 g, 65%) as
a light yellow oil: [R]23D -136.1 (c 2.62, EtOH); 1H NMR (CDCl3)
δ 1.38-1.88 (m, 14H), 2.16-2.25 (dd, J ) 8.5, 16.0 Hz, 2H),
2.60-2.63 (m, 2H), 2.87-2.94 (dt, J ) 2.6, 9.0 Hz, 2H), 3.25 (br,
2H), 3.63-3.68 (dd, J ) 4.5, 9.4 Hz, 2H), 3.93-4.00 (dd, J )
9.4, 10.6 Hz, 2H), 4.03-4.09 (dd, J ) 4.5, 10.6 Hz, 2H), 7.16-7.39
(m, 10H); 13C NMR (CDCl3) δ 21.9, 22.2, 29.5, 34.2, 45.3, 58.7,
60.9, 62.2, 127.5, 127.9, 129.0, 135.1; IR (film) cm-1 3410, 3020,
2940, 2880, 1240, 1030, 910; MS (EI) 422 (M+); HRMS calcd for
C27H37N2O2 421.2855, found 421.2853.
(-)-Deoxocuscohygrine (2) Dihydrochloride. A solution of 3a
(357 mg, 0.846 mmol) in CH3OH (5 mL) was treated with Raney
Ni (W-2) (ca. 4 g), heated for refluxing for 16 h, allowed to cool
to rt, and concentrated. The product was diluted with 10% HCl (5
mL), washed with ether (10 mL), alkalized with 1 M NaOH,
extracted with CH2Cl2 for three times. The combined organic layers
were dried over Na2SO4, a few drops of saturated hydrogen chloride
ethanol solution was added, and the mixture was concentrated in
vacuo. The residue was purified by recrystalization with ethyl
acetate to furnish 2 dihydrochloride (134 mg, 56%) as a colorless
solid: [R]22D -14.4 (c 0.56, EtOH); 1H NMR (CDCl3) δ 1.52-1.70
(m, 2H), 1.86-2.11 (m, 12H), 2.23-2.32 (m, 2H), 2.84 (m, 6H),
2.91-3.10 (dt, J ) 8.4, 11.5 Hz, 2H), 3.21-3.40 (m, 2H),
3.66-3.71 (m, 2H); 13C NMR (CDCl3) δ 21.3, 23.2, 29.6, 31.0,
39.2, 56.2, 67.2; IR (film) cm-1 3390, 2960, 2560, 1460, 1240;
MS (EI) 210 (M+); HRMS (CI) calcd for C13H29N2Cl2 283.1708,
found 283.1685.
Dihydrocuscohygrine (1). A solution of 3b (115 mg, 0.218
mmol) in CH3OH (5 mL) was treated with 20% palladium
hydroxide on carbon under hydrogen atmosphere for 3 d. The
reaction mixture was filtrated with celite pad, and concentrated in
vacuo. The residue was diluted with CH3OH (2 mL), formaldehyde
(0.5 mL), and 10% HCl (0.5 mL) before being stirred for 1 h and
treated with sodium cyanoborohydride (200 mg, 3.18 mmol) for
an additional 30 min. The product was diluted with water, washed
with ether at twice, alkalized with 1 M NaOH, and extracted with
CH2Cl2 at 5 times. The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
chromatography (10:4:1 hexane/CH2Cl2/Et2NH) to furnish 33 mg
4-Benzyloxycyclopentane-1,2-diol (11). A solution of 10 (12.2
g, 71 mmol) in t-BuOH (700 mL) was treated with H2O (700 mL),
K3Fe(CN)6 (70.0 g, 212 mmol), K2CO3 (29.4 g, 212 mmol), 1,4-
diazabicyclo[2.2.2]octane (2.10 g, 17.8 mmol), and 5% aqueous
OsO4 (17.6 mL) at rt. After the reaction mixture was stirred for
9786 J. Org. Chem. Vol. 73, No. 24, 2008