1100 J . Org. Chem., Vol. 67, No. 4, 2002
Maligres et al.
× 4.6 mm HP Eclipse XDB-C8 5 µm column, gradient elution
with 60 f 80% MeCN in 0.025% aq H3PO4 over 7 min then
isocratic elution with 80% MeCN in 0.025% aq H3PO4 for 5
min at 1 mL/min, 25 °C with detection at 220 nm. 16: Rf )
20 min, maintaining the temperature <16 °C and using DMF
(2 mL) to complete the transfer. The mixture was aged at 15
°C for 1 h, diluted with water, saturated aq NH4Cl, MTBE,
and hexanes (15 mL each), and filtered from any remaining
zinc through a cotton plug. The organic phase was separated
from the filtrate and was washed with a mixture of water (15
mL) and saturated aq NH4Cl (15 mL) and then with water
(40 mL). The aqueous phases were extracted with 1:1 MTBE-
hexanes (20 mL). The combined organic phases were dried
(MgSO4) and evaporated. The residue (97 area% purity by
HPLC and NMR analysis) was purified by flash column
chromatography (silica, 25% MTBE in hexanes) to provide
homoallylic alcohol 24a as a white crystalline solid (7.84 g,
99%, >99 area% purity by HPLC and NMR analysis). Crystals
suitable for X-ray diffraction analysis was prepared by recrys-
tallization of a sample of 24a from hexane. HPLC retention
times: 24a ) 9.7 min, (R)-Boc-2-phenyl-3-piperidone (3) ) 4.7
min. HPLC conditions: 150 × 4.6 mm HP Eclipse XDB-C8 5
µm column, gradient elution with 60 f 80% MeCN in 0.025%
aq H3PO4 over 7 min then isocratic elution with 80% MeCN
in 0.025% aq H3PO4 for 5 min at 1 mL/min, 25 °C with
detection at 220 nm. Chiral supercritical phase chromatogra-
phy (SFC) indicated 24a (after chromatography but not
crystallized) to be >96%ee. SFC conditions: Chiralpak AD 250
× 4.6 mm column, isocratic elution, 2% MeOH in supercritical
CO2 for 2 min then gradient elution with 2 f 10% MeOH in
supercritical CO2 over 8 min at 250 bar, 1.5 mL/min flow at
50 °C with detection at 220 nm. SFC Retention times: (2R,3S)-
24a ) 8.3 min, (2S,3R)-24a ) 9.4 min. 24a : mp 78-80 °C; Rf
) 0.23 (4:1 hexane-MTBE); 1H NMR (250 MHz, CDCl3) δ
7.41-7.07 (m, 8 H), 5.32 (d, J ) 1.7, 1 H), 5.24 (d, J ) 1.7, 1
H), 4.62 (s, 1 H), 4.03 (dt, J ) 12.9, 3.3, 1 H), 3.72 (m, 1 H),
3.08 (m, 1 H), 2.94 (dd, J ) 17.5, 14.1, 2 H), 1.81 (m, 1 H),
1.59 (m, 3 H), 1.37 (s, 9 H), 0.74 (m, 4H); 13C NMR (62.9 MHz,
CDCl3) δ 155.4, 154.1, 142.9, 142.7, 139.3, 133.8, 129.3, 128.1,
127.2, 122.9, 121.6, 120.9, 120.6 (q, J ) 254, OCF3), 113.5, 79.9,
72.7, 63.3, 51.5, 45.1, 39.0, 31.2, 28.4, 21.6, 6.4; FTIR (thin
film) νmax 3455, 1688, 1492, 1416, 1245, 1214, 1162 cm-1. Anal.
Calcd for C29H34F3NO5: C, 65.28; H, 6.42; N, 2.63. Found: C,
65.11; H, 6.36; N, 2.51.
1
0.53 (1:1 hexane-MTBE); H NMR (250 MHz, CDCl3) δ 7.24
(d, J ) 9.9, 1 H), 7.11 (m, 2 H), 5.43 (dd, J ) 2.7, 1.3, 1 H),
5.23 (d, J ) 1.3, 1 H), 4.36 (s, 2 H), 3.74 (m, 1 H), 2.18 (br s,
1 H), 0.80 (m, 4H); 13C NMR (62.9 MHz, CDCl3) δ 154.4, 146.8,
142.9, 130.5, 123.2, 121.2, 120.5 (q, J ) 256, OCF3), 116.2,
113.4, 65.2, 51.5, 6.3; FTIR (thin film) νmax 3375, 1492, 1246,
1220, 1185, 1160 cm-1
.
Allylic Meth a n esu lfon a te 22. Methanesulfonyl chloride
(2.41 g, 21.0 mmol) was added over 15 min to a mixture of
allylic alcohol 16 (5.48 g, 20.0 mmol) and DIEA (2.84 g, 22.0
mmol) in CH2Cl2 (20 mL), maintaining the temperature below
-40 °C. The mixture was warmed to 0 °C over 15 min, and
water (35 mL), pentane (30 mL), and ether (30 mL) were
added. The organic phase was washed with 5% aq HBr (2 ×
25 mL), water (25 mL), and saturated aq Na2SO4 (25 mL). The
organic phase was dried (MgSO4), treated with Darco G60 (200
mg, 15 min), and filtered through a plug composed of silica (5
g) layered over neutral alumina (5 g). The plug was washed
with 1:1 pentane-ether (50 mL), and the combined filtrates
were evaporated to provide the crude allylic methanesulfonate
22 (7.05 g). HPLC retention time: 22 ) 5.9 min. HPLC
conditions: 150 × 4.6 mm HP Eclipse XDB-C8 5 µm column,
gradient elution with 60 f 80% MeCN in 0.025% aq H3PO4
over 7 min and then isocratic elution with 80% MeCN in
0.025% aq H3PO4 for 5 min at 1 mL/min, 25 °C with detection
1
at 220 nm. 22: Rf ) 0.50 (1:1 hexane-MTBE); H NMR (400
MHz, CDCl3) δ 7.27-7.17 (m, 2 H), 7.09 (m, 1 H), 5.55 (d, J )
0.6, 1 H), 5.40 (s, 1 H), 5.06 (s, 2 H), 3.76 (m, 1 H), 2.90 (s, 3
H), 0.82 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 154.7, 142.9,
140.6, 128.3, 123.5, 122.1, 120.6 (q, J ) 256, OCF3), 120.0,
113.6, 71.1, 51.7, 37.9, 6.4; FTIR (thin film) νmax 1492, 1358,
1248, 1218, 1176, 971 cm-1
.
Allylic Br om id e 23. A mixture of crude allylic methane-
sulfonate 22 (7.05 g, 20.0 mmol) and LiBr (3.47 g, 40.0 mmol)
in DMF (20 mL) was stirred for 16 h at 10 °C and was diluted
with water (50 mL), pentane (49 mL), and ether (1 mL). The
organic phase was separated and washed with 0.5% aq Na2-
SO4 (2 × 50 mL) and saturated aq Na2SO4 (25 mL). The
organic phase was dried (MgSO4), treated with Darco G60 (200
mg, 15 min), and filtered through a plug composed of silica (5
g) layered over neutral alumina (5 g). The plug was washed
with 29:1 pentane-ether (50 mL), and the combined filtrates
were evaporated to provide the crude allylic bromide 23 (6.47
g, 96% from 16). HPLC retention times: 23 ) 7.7 min. HPLC
conditions: 150 × 4.6 mm HP Eclipse XDB-C8 5 µm column,
gradient elution with 60 f 80% MeCN in 0.025% aq H3PO4
over 7 min and then isocratic elution with 80% MeCN in
0.025% aq H3PO4 for 5 min at 1 mL/min, 25 °C with detection
at 220 nm. 23: Rf ) 0.40 (19:1 hexane-MTBE); 1H NMR (250
MHz, CDCl3) δ 7.24 (d, J ) 9.0, 1 H), 7.16 (m, 2 H), 5.50 (d, J
) 1.0, 1 H), 5.24 (d, J ) 1.0, 1 H), 4.37 (s, 2 H), 3.75 (m, 1 H),
0.80 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 154.6, 143.7, 142.8,
129.4, 123.8, 121.7, 120.6 (q, J ) 256, OCF3), 120.1, 113.4, 51.6,
35.2, 6.4; FTIR (thin film) νmax 1492, 1245, 1221, 1190, 1160
TMS Eth er 26a . Chlorotrimethylsilane (TMSCl, 1.01 mL,
0.869 g, 8.00 mmol) and a 1 M solution of LiHMDS (8.0 mL,
8.0 mmol) in THF were added simultaneously over 30 min to
a solution of 24a (2.13 g, 4.00 mmol) in THF (8 mL) maintained
at 20 °C, and the mixture was aged for 1 h. The mixture was
evaporated to half its volume, diluted with water (40 mL), and
extracted with hexanes (40 mL). The organic extract was
washed with aq NaH2PO4 (2 × 40 mL) and filtered through a
plug of 2:1 by wt silica gel-MgSO4 (5 g). The plug was washed
with 2:1 hexanes-MTBE (20 mL), and the combined filtrates
were evaporated to provide TMS ether 26a (2.30 g, 95%).
HPLC retention time: 26a ) 11.3 min, HPLC conditions: 150
× 4.6 mm ACE 3 C18 column, isocratic elution with 90%
MeCN in 0.025% aq H3PO4 at 1 mL/min, 25 °C with detection
at 220 nm. 26a : Rf ) 0.31 (4:1 hexane-MTBE); 1H NMR (400
MHz, CDCl3) δ 7.27-7.11 (m, 8 H), 5.29 (d, J ) 2.0, 1 H), 5.25
(d, J ) 2.0, 1 H), 5.10 (s, 1 H), 4.13 (dd, J ) 13.4, 3.6, 1 H),
3.73 (m, 1 H), 3.39 (m, 1 H), 3.04 (d, J ) 13.7, 1 H), 2.80 (d, J
) 13.7, 1 H), 1.89-1.74 (m, 3 H), 1.63 (m, 1 H), 1.27 (s, 9 H),
0.80 (m, 4 H), -0.44 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ
155.8, 154.2, 143.9, 142.8, 141.2, 134.8, 129.4, 127.1, 126.3,
123.1, 121.5, 120.6 (q, J ) 256, OCF3), 120.2, 113.1, 79.5, 76.4,
61.4, 51.3, 44.9, 40.0, 32.1, 28.2, 21.4, 6.4, 6.2, 1.7; FTIR (thin
cm-1
.
Meth od 2. Bromine (352 mg, 2.20 mmol) was added to a
mixture of PPh3 (629 mg, 2.40 mmol) and CH2Cl2 (3 mL) over
10 min, maintaining the temperature below -10 °C. Allylic
alcohol 16 (548 mg, 2.00 mmol) in CH2Cl2 (1 mL) was added,
and the mixture was allowed to warm to 10 °C over 20 min.
The mixture was diluted with pentane (25 mL) and filtered
through a plug composed of silica (5 g) layered over neutral
alumina (5 g). The plug was washed with 29:1 pentane-ether
(30 mL), and the combined filtrates were evaporated to provide
the crude allylic bromide 23 (641 mg, 95% from 16).
Hom oa llylic Alcoh ol 24a . TMSCl (0.050 mL) was added
to a mixture of (R)-piperidine 3 (4.08 g, 14.83 mmol), zinc dust
(1.16 g, 17.8 mmol), and DMF (13 mL), the mixture was aged
for 10 min at 40 °C, dibromoethane (0.050 mL) was added,
and the mixture was again aged for 10 min at 40 °C. Allylic
bromide 23 (5.10 g, 15.1 mmol) was added to the mixture over
film) νmax 1693, 1362, 1245, 1164, 978, 837 cm-1
.
Diol 25a . A solution of 26a (1.82 g, 3.00 mmol) in THF (6
mL) was added over 15 min to a 1 M solution of borane in
THF (15.0 mL, 15.0 mmol) maintained at -10 °C. The mixture
was allowed to gradually warm to 20 °C over 16 h and
evaporated to dryness. The residue was dissolved in THF (6
mL), and a mixture of 2 M aq NaOH (10 mL) and 30% H2O2
(5 mL) was added over 10 min, maintaining the temperature
at 10 °C. The mixture was aged 1 h at 20 °C and 15 min at 45
°C. The mixture was cooled to 20 °C, diluted with water (15
mL), and extracted with MTBE (2 × 20 mL). The combined
organic extracts were washed with water (10 mL), 10% aq Na2-