Banerjee et al.
filtered through Celite (washed with MeOH) to afford the crude
amino alcohol, which was used directly in the next step.
aq sodium potassium tartrate solution (5 mL), then extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. Fifty percent of the crude
amine mixture was subjected to flash chromatography (SiO2, 1-4%
MeOH in CH2Cl2 gradient elution) to afford samples of the pure
syn and anti diastereomers suitable for chiral HPLC analysis after
further derivatization (either N-Cbz or N-Ac protection; see below).
The remaining 50% of the crude amine mixture was treated with
benzyl chloroformate (15 µL, 18.1 mg, 0.098 mmol), Na2CO3 (12.0
mg, 0.11 mmol), and THF (1 mL). The resulting mixture was stirred
at rt for 18 h, concentrated in vacuo, and purified by flash
chromatography (90:10 SiO2-KF,17 0-30% EtOAc in hexanes
gradient elution), affording carbamates 15 or 17 as white solids
that were mixtures of diastereomers. Spectral data for 15a-c and
17a-c were consistent with previously reported data.2
N-Benzyl 2-Benzyloxycarbonylamino-3-(4-methoxyphenyl)-4-
methylpentanamide (15a). syn-15a was obtained in 97% ee, as
analyzed by HPLC (Chiralcel OD-H, 98:2 hexane:i-PrOH, 0.7 mL/
min; tR ) 20.6 min (major), 28.6 min). anti-15a was obtained in
92% ee, as analyzed by HPLC (Chiralcel OD-H, 98:2 hexane:i-
PrOH, 1 mL/min; tR ) 25.0 min (major), 31.6 min).
N-Benzyl 2-Benzyloxycarbonylamino-4-methyl-3-phenylpen-
tanamide (15b). syn-15b was obtained in 74% ee, as analyzed by
HPLC of the derivative in which the N-Cbz group is replaced by
an acetate2 (Chiralcel OD-H, 98:2 hexane:i-PrOH, 1 mL/min; tR
) 6.2 min (major), 8.8 min). anti-15b was obtained in 87% ee, as
analyzed by HPLC under identical conditions (tR ) 18.1 min
(major), 22.9 min).
N-Benzyl 2-Benzyloxycarbonylamino-3-(4-fluorophenyl)-4-me-
thylpentamide (15c). syn-15c was obtained in 70% ee, as analyzed
by HPLC of the derivative in which the N-Cbz group is replaced
by an acetate2 (Chiralcel OD-H, 98:2 hexane:i-PrOH, 1 mL/min;
tR ) 5.9 min (major), 9.2 min). anti-15c was obtained in 63% ee,
as analyzed by HPLC under identical conditions (tR ) 16.2 min
(major), 21.2 min).
A solution of 41c (73.8 mg, 0.25 mmol) in anhydrous CHCl3
(2.0 mL) was stirred at 0 °C under Ar for 5 min, then treated
dropwise with a solution of the crude amino alcohol and Et3N (80
µL, 58.2 mg, 0.58 mmol) in anhydrous CHCl3 (1.0 mL). The
resulting mixture was stirred at 35 °C under Ar for 24 h, then treated
with solid NH4Cl (50 mg), stirred at rt for 30 min, and filtered.
The solid was stirred in THF (10 mL) for 30 min, and the mixture
was filtered. The combined organic solutions were concentrated in
vacuo. Flash chromatography (SiO2, 1.5 × 20 cm, 50-100% EtOAc
in hexanes gradient elution) afforded 5a (133.9 mg, 0.23 mmol,
91%) as a yellow oil: [R]25D +131 (c 0.10, EtOH); 1H NMR (CDCl3,
500 MHz) δ 8.10 (d, J ) 7.5 Hz, 2H), 8.03 (d, J ) 7.0 Hz, 4H),
7.86 (s, 2H), 7.80-7.72 (m, 8H), 7.50-7.47 (m, 4H), 7.42-7.39
(m, 2H), 5.45 (dd, J ) 10.0, 6.5 Hz, 2H), 4.07 (dd, J ) 12, 3.5 Hz,
2H), 3.99 (dd, J ) 11.5, 6.5 Hz, 2H), 3.51 (br s, 2H); 13C NMR
(CDCl3, 125 MHz) δ 164.5 (2C), 153.4 (2C), 136.5 (2C), 133.3
(2C), 132.9 (2C), 128.6 (2C), 127.9 (2C), 127.6 (2C), 127.5 (2C),
126.2 (2C), 125.9 (2C), 125.6 (2C), 124.8 (2C), 124.3 (2C), 124.2
(2C), 123.6 (2C), 118.9 (2C), 66.0 (2C), 56.6 (2C); IR (film) νmax
3325, 2920, 2850, 1731, 1695, 1682, 1658, 1641, 1592, 1547, 1539,
1531, 1462, 1060 cm-1; HRMS (ESI) m/z 595.2226 (MH+,
C38H30N2O5H requires 595.2228).
4,6-Bis((R)-4-(naphthalen-2-yl)-4,5-dihydrooxazol-2-yl)diben-
zo[b,d]furan (6a). A solution of 5a (59.2 mg, 0.10 mmol) in
anhydrous CH2Cl2 (1.5 mL) was treated with Et3N (40 µL, 29.1
mg, 0.29 mmol) and 4-pyrrolidinopyridine (4.8 mg, 0.032 mmol).
The mixture was stirred at 0 °C for 10 min, then treated dropwise
with a solution of TsCl (45.9 mg, 0.23 mmol) in anhydrous CH2Cl2
(1.5 mL). The resulting mixture was vigorously stirred at rt for
19 h, then treated with saturated aq NH4Cl (7 mL) and extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. Flash chromatography (SiO2,
1.5 × 19 cm, 20-100% EtOAc in hexanes gradient elution)
Methyl 2-Benzyloxycarbonylamino-3-(4-methoxyphenyl)-4-me-
thylpentanoate (17a). syn-17a was obtained in 10% ee, as analyzed
by HPLC (Chiralcel OD-H, 98:2 hexane:i-PrOH, 1 mL/min; tR )
17.4 min (major), 23.9 min). anti-17a was obtained in 7% ee, as
analyzed by HPLC under identical conditions (tR ) 11.8 min
(major), 23.0 min).
Methyl 2-Benzyloxycarbonylamino-4-methyl-3-phenylpentanoate
(17b). syn-17b was obtained in 7% ee, as analyzed by HPLC
(Chiralcel OD-H, 98:2 hexane:i-PrOH, 1 mL/min; tR ) 11.7 min
(major), 18.3 min). anti-17b was obtained in 5% ee, as analyzed
by HPLC under identical conditions (tR ) 7.3 min (major), 21.8
min).
afforded 6a (49.1 mg, 0.088 mmol, 88%) as an off-white solid:
1
[R]25 -28 (c 0.13, EtOH); H NMR (CDCl3, 500 MHz) δ 8.24
D
(d, J ) 8.0 Hz, 2H), 8.17 (d, J ) 7.5 Hz, 2H), 7.87 (s, 2H), 7.80
(d, J ) 8.0 Hz, 4H), 7.77 (d, J ) 8.5 Hz, 2H), 7.53-7.48 (m, 4H),
7.44-7.36 (m, 4H), 5.68 (t, J ) 9.0 Hz, 2H), 4.96 (t, J ) 9.0 Hz,
2H), 4.40 (t, J ) 8.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ
162.5 (2C), 154.4 (2C), 145.3 (2C), 139.8 (2C), 133.4 (2C), 132.8
(2C), 128.8 (2C), 128.6 (2C), 127.9 (2C), 127.7 (2C), 126.2 (2C),
125.8 (2C), 125.5 (2C), 124.9 (2C), 124.8 (2C), 123.9 (2C), 123.1
(2C), 74.8 (2C), 70.1 (2C); IR (film) νmax 2928, 1650, 1494, 1427,
1185, 1124, 984 cm-1; HRMS (ESI) m/z 559.2026 (MH+,
C38H26N2O3H requires 559.2016).
Methyl 2-Benzyloxycarbonylamino-3-(4-fluorophenyl)-4-meth-
ylpentanoate (17c). syn-17c was obtained in 3% ee, as analyzed
by HPLC (Chiralcel OD-H, 98:2 hexane:i-PrOH, 1 mL/min; tR )
11.5 min (major), 16.7 min). anti-17c was obtained in 3% ee, as
analyzed by HPLC under identical conditions (tR ) 7.6 min (major),
14.9 min).
General Procedure for Enantioselective Radical Conjugate
Additions Promoted by Mg(NTf2)2 and 6a. A solution of Mg(NTf2)2
(64.0 mg, 0.11 mmol) and ligand 6a (50.0 mg, 0.11 mmol) in
anhydrous CH2Cl2 (1.5 mL) was stirred at rt for 16 h, then treated
with 14 or 16 (0.11 mmol). The walls of the reaction vessel were
washed with CH2Cl2 (0.5 mL), and the mixture was stirred at -78
°C for 30 min. Isopropyl iodide (60 µL, 100 mg, 0.60 mmol),
Bu3SnH (72 µL, 78 mg, 0.27 mmol), Et3B (3.45 M solution in
CH2Cl2, 157 µL, 0.55 mmol), and O2 (5 mL) were added
sequentially, and identical quantities of these reagents were added
twice more at 1.5 h intervals. The mixture was stirred at -78 °C
for an additional 1 h (4 h total since initiation of radical reaction),
treated with 2 N HCl (5 mL), and extracted with CH2Cl2 (2 × 5
mL). The combined organic layers were concentrated in vacuo.
The crude adducts were treated with concd HCl (0.30 mL, 3.6
mmol), H2O (1 mL), THF (1 mL), and indium powder (101.0 mg,
0.88 mmol). The resulting mixture was stirred at rt for 15 h, the
solids were removed, and the volatiles were removed in vacuo.
The residue was diluted with 1 N HCl (5 mL), and tin byproducts
were removed by extraction with hexanes (5 × 5 mL). The aqueous
layer was treated with Na2CO3 (added until pH ∼8) and saturated
Acknowledgment. We thank Brigham Young University
(Cancer Research Center Fellowship to SGC) and the National
Institutes of Health (GM70483) for financial support.
Supporting Information Available: General experimental
details, synthetic procedures, spectral data, and 1H and 13C NMR
spectra for all new compounds, as well as HPLC traces for
enantioselective radical conjugate additions. This material is
org.
JO801721Z
(17) Harrowven, D. C.; Guy, I. L. Chem. Commun. 2004, 1968.
8978 J. Org. Chem. Vol. 73, No. 22, 2008