New Chiral 2,2′-Bipyridine Ligands
gel (20 g) with a petroleum ether/ethyl acetate mixture (10:1)
to give the pure bipyridine (+)-47 as white crystals (666 mg,
51%): mp 170-172 °C (ethyl acetate/hexane); [R]D + 91.0 (c,
solution was extracted with brine (3 × 15 mL). The organic
layers were dried over Na2SO4, and the solvent was removed
in vacuo. The residue was purified by flash chromatography
on a silica gel column (15 × 3 cm) with petroleum ether,
followed by a petroleum ether/ethyl acetate mixture (97:3) to
afford pure oxime 4963 (1.40 g, 90%) as a white solid: 1H NMR
δ 0.86 (s, 3 H, 18-H), 1.02 (s, 3 H, 19-H), 1.50-1.10 (m, 4 H),
1.74-1.56 (m, 6 H), 2.00-1.87 (m, 4 H), 2.03 (s, 3 H, AcO),
2.05 (s, 3 H, 21-H), 2.41-2.21 (m, 4 H), 4.63 (m, 1 H, 3R-H),
5.41 (bd, J ) 4.8 Hz, 1 H, 6-H), 6.08 (m, 1 H) in accordance
with the literature.63
2′-Ch lor op yr id o[17,16-b ]a n d r ost -5-en e-3â-ol Acet a t e
(51). A solution of oxime 49 (600 mg, 1.6 mmol) and POCl3
(2.5 g, 16 mmol) in DMF (1.50 mL) was heated at 65 °C for 2
h while stirring. The solution was then cooled to 0 °C and
quenched with ice (5 g) and aqueous saturated NaHCO3 (4
mL). The mixture was extracted by CH2Cl2 (3 × 50 mL), the
combined organic layers were washed with brine (3 × 10 mL)
and dried over Na2SO4, and the solvent was evaporated in
vacuo. The residue was purified by flash chromatography on
a silica gel column (15 × 3 cm) with a petroleum ether/ethyl
acetate mixture (98:2) to afford the 51 as a pale yellow solid
(430 mg, 70%): mp 198-199 °C (lit.45b 200 °C); 1H NMR δ 0.92
(s, 3H, 18-H), 1.03 (s, 3H, 19-H), 1.04-1.15 (m, 2H), 1.49-
1.85 (m, 8H), 1.97 (s, 3H, AcO), 2.01 (m, 1H), 2.20-2.29 (m,
4H), 2.40 (dd, J ) 14.7 and 12.3 Hz, 1H), 2.64 (dd, J ) 15.0
and 6.4 Hz, 1H), 4.53 (m, 1H, 3R-H), 5.34 (bd, J ) 5.2 Hz, 1H,
6-H), 6.96 (d, J ) 8.0 Hz, 1H), 7.36 (d, J ) 8.0 Hz, 1H); 13C
NMR δ 17.5 (CH3), 19.7 (CH3), 20.9 (CH2), 21.8 (CH3), 28.1
(CH2), 30.2 (CH2), 31.1 (CH), 31.6 (CH2), 33.7 (CH2), 37.2 (CH2),
37.3 (CH2), 38.5 (CH2), 46.1 (C), 50.8 (CH), 56.5 (CH), 74.1
(CH), 121.4 (CH), 122.2 (CH), 135.3 (CH), 135.4 (C), 140.6 (C),
149.4 (C), 170.8 (C), 174.3 (C) in accordance with the
literature.45b
1
1.05, CH2Cl2); H NMR δ 0.62 (s, 6 H), 1.32 (d, J ) 9.4 Hz, 2
H), 1.41 (s, 6 H), 2.39 (m, 2 H), 2.70 (m, 2 H), 2.79 (t, J ) 5.8
Hz, 2 H), 3.19 (s, 4 H), 7.31 (m, 2 H), 7.98 (d, J ) 7.7 Hz, 2 H);
13C NMR δ 21.7 (CH3), 26.5 (CH3), 32.9 (CH2), 38.1 (CH2), 39.9
(C), 43.6 (CH), 46.9 (CH), 118.4 (CH), 134.1 (CH), 141.9 (C),
154.8 (C), 156.7 (C) in accordance with the literature.5e-g
Alk yla tion of iso-P INDY (+)-47. n-Butyllithium (1.6 M,
hexane, 5.4 mL, 8.70 mmol) was added dropwise to a solution
of iso-PINDY (+)-47 (1.0 g, 2.90 mmol) in THF (30 mL) at -35
°C, turning the color from pale yellow to deep blue.62 The
solution was stirred for 1 h at that temperature, then the neat
alkyl halide (8.70 mmol) was added dropwise at -35 °C, and
the mixture was then stirred at room temperature overnight.
Aqueous 1 M NaOH was added, and the mixture was extracted
with CH2Cl2 (3 × 30 mL). The organic layers were combined,
washed with brine (30 mL), and dried (MgSO4), and the solvent
was evaporated under vacuum. The crude product was purified
using flash chromatography on silica gel (40 g) with
a
petroleum ether/ethyl acetate mixture (10:1) to give pure
a lk yl-iso-P INDY as a white solid.
Me-iso-P INDY (-)-6 (99%): mp 58-60 °C (ethyl acetate/
1
hexane); [R]D -5.6 (c, 1.1, CH2Cl2); H NMR δ 0.64 (s, 6 H),
1.33 (d, J ) 9.4 Hz, 2 H), 1.42 (s, 6 H), 1.47 (d, J ) 7.2 Hz, 6
H), 2.16 (m, 2 H), 2.57 (dt, J ) 9.6 and 5.8 Hz, 2 H), 2.79 (t, J
) 5.8 Hz, 2 H), 3.26 (dq, J ) 7.2 and 2.4 Hz, 2 H), 7.30 (d, J
) 7.6 and 2.3 Hz, 2 H), 7.98 (d, J ) 7.7 and 2.4 Hz, 2 H);13C
NMR δ 18.6 (CH3), 21.2 (CH3), 26.7 (CH3), 29.0 (CH2), 39.3
(CH), 41.8 (C), 47.2 (CH), 47.5 (CH) in accordance with the
data reported for the opposite enantiomer (except optical
rotation, which has not been reported);5e-g MS (EI) m/z (%)
372 (M•+, 62%), 357 (M•+ - Me, 100%); HRMS (EI) 372.2565
(C26H32N2 requires 372. 2566).
Gen er a l P r oced u r e for Asym m etr ic Allylic Oxid a tion
Ca ta lyzed by Cu (I) Com p lexes. Meth od A. The ligand (0.06
mmol) and (TfO)2Cu (18 mg, 0.05 mmol) were dissolved in
acetone (4 mL), and the green solution was stirred under a
nitrogen atmosphere at 20 °C for 1 h. Phenylhydrazine (5.9
µL, 0.06 mmol) was then added, and the color of the solution
changed to red. After 10 min, olefin 52 (5 mmol) was added at
the temperature indicated in Table 1, followed by a dropwise
addition of tert-butyl peroxybenzoate (0.2 mL, 1.0 mmol). The
progress of the reaction (at the temperature indicated in Table
1) was monitored by TLC (hexanes/ethyl acetate, 9:1). Disap-
pearance of the peroxyester indicated the completion of the
reaction. The solvent was evaporated in a vacuum, and the
residue was dissolved in CH2Cl2 (15 mL), washed successively
with an aqueous KHCO3 solution, brine, and water, and dried
over MgSO4. Concentration and chromatography on a silica
gel column (15 × 2.5 cm) with a hexanes/ethyl acetate mixture
(20:1) afforded pure allylic benzoate 53. The yields and ee are
given in Table 1. Enantiomeric purity of the products was
determined by chiral HPLC as follows. 53a : Chiralcel OD-H,
hexane/isopropyl alcohol (99.8:0.2), flow rate 0.5 mL/min, tS
) 30.2 min (major), tR ) 38.3 min (minor), UV detection at
220 nm. 53b: Chiralpak AD, hexane/isopropyl alcohol (99.6:
0.4), flow rate 1 mL/min, tR ) 12.6 min (minor), tS ) 13.8 min
(major), UV detection at 220 nm. 53c: Chiralcel OJ , hexane/
isopropyl alcohol (99.7:0.3), flow rate 0.5 mL/min, tR ) 23.7
min (minor), tS ) 25.7 min (major), UV detection at 220 nm.
Bu -iso-P INDY (-)-7 (93%): mp 43-45 °C (ethyl acetate/
hexane); [R]D -30.4 (c, 1.05, CH2Cl2); 1H NMR δ 0.62 (s, 6 H),
0.88 (t, J ) 7.0 Hz, 6 H), 1.25 (d, J ) 9.6 Hz, 2 H), 1.32 (s, 6
H), 1.40-1.49 (m, 10 H), 2.22-2.25 (m, 4 H), 2.28-2.33 (m, 2
H), 2.45 (dt, J ) 9.7 and 5.8 Hz, 2 H), 2.66 (t, J ) 5.8 Hz, 2
H), 2.97 (s, 2 H), 7.20 (d, J ) 8.0 Hz, 2 H), 7.93 (d, J ) 8.0 Hz,
2 H); 13C NMR δ 14.6 (CH3), 21.3 (CH3), 23.5 (CH2), 26.9 (CH3),
28.9 (CH2), 30.6 (CH2), 32.7 (CH2), 41.5 (C), 43.9 (CH), 44.7
(CH), 47.3 (CH), 117.7 (CH), 133.8 (CH), 141.6 (C), 154.6 (C),
160.1 (C) in accordance with the literature data reported for
the opposite enantiomer (except optical rotation, which has
not been reported);5e-g MS (EI) m/z 456 (M, 53%), 399 (M -
Bu, 100%); HRMS (EI) 456.3508 (C32H44N2 requires 456.3505).
i-P r -iso-P INDY (-)-8 (56%): mp 50-53 °C (ethyl acetate/
1
hexane); [R]D -17.1 (c 1.0, CH2Cl2); H NMR δ 0.54 (s, 6 H),
0.81 (d, J ) 6.8 Hz, 6 H), 1.17 (d, J ) 6.8 Hz, 6 H), 1.35 (s,
6H), 1.35 (d, J ) 9.6 Hz, 2 H), 2.29-2.32 (m, 2 H), 2.51 (dt, J
) 9.7 and 5.8 Hz, 2 H), 2.68 (t, J ) 5.8 Hz, 2 H), 2.76-2.84
(m, 2 H), 2.90-2.91 (m, 2 H), 7.22 (d, J ) 8.0 Hz, 2 H), 7.93
(d, J ) 8.0 Hz, 2 H); 13C NMR δ 20.6 (CH3), 21.3 (CH3), 22.7
(CH3), 26.7 (CH3), 29.7 (CH2), 30.8 (CH3), 41.9 (CH), 42.4 (C),
47.2 (CH), 49.6 (CH), 117.9 (CH), 133.9 (CH), 142.3 (C), 154.4
(C), 159.0 (C) in accordance with the literature data reported
for the opposite enantiomer (except optical rotation, which has
not been reported);5e-g MS (EI) m/z 428 (M•+, 13%), 385 (M•+
- i-Pr, 100%); HRMS (EI) 428.3191 (C30H40N2 requires
428.31915).
20-Oxim in o-p r egn a n e-5,16-d ien -3â-ol Aceta te (49).
NH2OH‚HCl (3.80 g, 5.5 mmol) was added to a solution of
dehydropregnenolone acetate 48 (1.50 g, 4.2 mmol) in a
mixture of EtOH (10 mL), CH2Cl2 (5 mL) and pyridine (0.57
mL), and the mixture was set aside at room temperature for
24 h. Dichloromethane (100 mL) was then added, and the
Meth od B. The oxidation was performed analogously with
the catalyst prepared from the ligand (0.06 mmol) and (OTf)-
Cu‚0.5C6H6 (12 mg, 0.05 mmol) without the use of phenylhy-
drazine.
Gen er a l P r oced u r e for Asym m etr ic Cyclop r op a n a tion
Ca ta lyzed by Cu (I) Com p lexes. A solution of the ligand
(0.06 mmol) and (TfO)2Cu (18 mg, 0.05 mmol) in dichlo-
(62) (a) Lo¨tscher, D.; Rupprecht, S.; Stoeckli-Evans, H.; Zelewsky,
A. Tetrahedron: Asymmetry 2000, 11, 4143. (b) Doerner, M. P. Chem.
Abstr. 1958, 52, 9198i. (c) Maria, P. D.; Fontana, A.; Arlotta, M.;
Chimichi, S.; Spinelli, D. J . Chem. Soc., Perkin Trans. 2 1994, 415.
(63) (a) Suvorov, N. N.; Morozovskaya, L. M. J . Gen. Chem. USSR
(Engl. Transl.) 1960, 30, 2042; Zh. Obshch. Khim. 1960, 30, 2062;
Chem. Abstr. 1961, 7472. (b) Gandhi; C. Indian J . Chem. 1969, 7, 633.
J . Org. Chem, Vol. 68, No. 12, 2003 4741