320
V.-T. Pham et al. / Tetrahedron: Asymmetry 19 (2008) 318–321
room temperature. The solvents were evaporated under
reduced pressure. The crude aldehyde was immediately
employed in the next step without further purification.
To a stirred solution of LiCl (164 mg, 3.78 mmol) in
CH3CN (20 mL) were added trimethyl-phosphonoacetate
(0.54 mL, 3.78 mmol), diisopropyl-ethylamine (0.61 mL,
3.78 mmol) and stirring was allowed to continue for 1 h.
The crude aldehyde in CH3CN (10 mL) was added and
the reaction mixture was stirred for 2 h. The reaction mix-
ture was poured into H2O (20 mL), extracted with EtOAc
(50 mL). The organic extract was washed with brine, dried
over MgSO4 and evaporated in vacuo. Purification by silica
gel chromatography (ethyl acetate/hexane = 1/6) gave 6
was vigorously shaken under 70 psi H2 for 3 days at ambi-
ent temperature. The mixture was then filtered through a
pad of silica and concentrated in vacuo. Then the reduced
mixture was diluted with ethyl acetate (30 mL). A saturated
solution of NaHCO3 was added slowly, stirred for 30 min.
The aqueous layer was then separated and extracted with
ethyl acetate (30 mL ꢃ 3).The combined organic layer
was washed twice with water and brine, dried over anhy-
drous MgSO4, filtered and concentrated under reduced
pressure. Purification by column chromatography over sil-
ica gel (CHCl3/MeOH = 9/1) gave 3 (330 mg, 80%) as a
25
white solid; Rf = 0.5 (CHCl3/MeOH = 9/1); ½aꢂD ¼ þ10:0
(c 1.0, CHCl3); mp 85 °C; IR (neat) 838, 1095, 1648,
(1.13 g, 95% for 2 steps) as a colorless oil; Rf = 0.3 (ethyl
2941, 3394 cmꢀ1 1H NMR (500 MHz, CDCl3) d 0.06–
;
25
acetate/hexane = 1/6); ½aꢂD ¼ ꢀ75:2 (c 1.0, CHCl3); IR
0.07 (m, 6H), 0.88–0.92 (m, 9H), 1.80–1.86 (m, 1H),
2.00–2.06 (m, 1H), 2.26–2.33 (m, 1H), 2.57–2.64 (m, 1H),
3.44–3.46 (m, 1H), 3.79–3.81 (m, 2H), 4.13–4.14 (m, 1H),
6.32 (s, 1H); 13C NMR (125MHz, CDCl3) d ꢀ5.30,
ꢀ5.29, 18.35, 26.01, 26.52, 27.77, 57.78, 64.20, 64.37,
172.66; HRMS (M++H) m/z calcd for C12H26NO3Si:
260.1682; found, 260.1678.
1
(neat) 839, 1174, 1264, 1653, 1727, 2859, 2943 cmꢀ1; H
NMR (500 MHz, CDCl3) d 0.05 (s, 3H), 0.09 (s, 3H), 0.87
(s, 9H), 3.69 (dd, J = 3.5, 10.5 Hz, 1H), 3.75 (s, 3H), 3.98
(dd, J = 3.5, 10.5 Hz, 1H) 4.14–4.16 (m, 1H), 5.18–5.19
(m, 1H), 6.11 (dd, J = 1.5, 15.5 Hz, 1H), 7.00 (dd, J = 5.0,
16.0 Hz, 1H) 7.40–7.43 (m, 2H), 7.48–7.49 (m, 1H), 7.95–
7.97 (m, 2H); 13C NMR (125 MHz, CDCl3) d ꢀ5.12,
18.42, 26.01, 51.98, 64.87, 74.44, 80.90, 120.84, 127.53,
128.56, 131.84, 145.90, 163.97, 166.57; HRMS (M++H)
m/z calcd for C20H30NO4Si: 376.1944; found, 376.1948.
4.5. (2R,3R)-2-((tert-Butyldimethylsilyloxy)methyl)-piperi-
din-3-ol 7
To a 0 °C solution of 3 (200 mg, 0.77 mmol) in dry THF
(8 mL) was added BH3ꢁSMe2 (1.93 mL, 2 M solution in
THF, 3.86 mmol) dropwise under argon, and the reaction
mixture was kept at room temperature for 4 h. The excess
of reducing agent was quenched by slow addition of EtOH
(8 mL). After evaporation of the solvent, the residue was
dissolved in EtOH (20 mL) and heated at reflux for 2 h.
The cooled mixture was then evaporated and purified by
column chromatography (CHCl3/MeOH = 4/1) to afford
4.3. Methyl 3-((4R,5R)-4-((tert-butyldimethylsilyloxy)-
methyl)-2-phenyl-4,5-dihydrooxazol-5-yl)propanoate 4
A solution of 6 (1.0 g, 2.66 mmol) and tert-butyl alcohol
(0.51 mL, 5.33 mmol) in dry THF (5 mL) was added over
5 min to L-Selectride (2.93 mL, 1 M solution in THF,
2.93 mmol) at ꢀ78 °C. After 20 min, the reaction was
quenched with methanol (2 mL). The reaction mixture
was then warmed to room temperature and solvent was
removed under reduced pressure. Then the reaction mixture
was diluted with hexanes (30 mL), cooled to 0 °C, followed
by addition of 10% NaOH (3.5 mL) and 30% H2O2
(2.5 mL) and the reaction mixture was stirred for 4 h at
room temperature. The aqueous layer was then separated
and extracted with hexanes (30 mL ꢃ 3). The combined
organic layer was washed twice with water and brine, dried
over anhydrous MgSO4, filtered and concentrated under
reduced pressure. Purification by silica gel chromatography
7 (157 mg, 83%) as a white solid; mp 265 °C; Rf = 0.3
25
(CHCl3/MeOH = 4/1); ½aꢂD ¼ þ3:0 (c 1.0, CHCl3); IR
(neat) 838, 1093, 1620, 2352, 2937 cmꢀ1
;
1H NMR
(500 MHz, CD3OD) d 0.011–0.014 (m, 6H), 0.92–0.96 (m,
9H), 1.48–1.52 (m, 1H), 1.60–1.66 (m, 1H), 1.86–1.93 (m,
2H), 2.72 (td, J = 3.15, 12.35 Hz, 1H), 2.81 (td, J = 1.8,
8.1 Hz, 1H), 3.10 (dt, J = 1.88, 10.48 Hz, 1H), 3.17–3.33
(m, 1H), 3.73–3.75 (m, 2H), 3.91–3.93 (m, 1H); 13C
NMR (125 MHz, CD3OD) d ꢀ6.57, ꢀ6.50, 18.00, 19.55,
25.21, 30.78, 45.33, 60.90, 63.40, 64.07; HRMS (M++H)
m/z calcd for C12H28NO2Si: 246.1889; found, 246.1891.
(ethyl acetate/hexane = 1/4) gave 4 (865 mg, 86%) as a col-
25
orless oil; Rf = 0.3 (ethyl acetate/hexane = 1/4); ½aꢂD
¼
þ47:6 (c 1.0, CHCl3); IR (neat) 841, 1173, 1252, 1649,
4.6. (2R,3R)-tert-Butyl 2-((tert-butyldimethylsilyloxy)-
methyl)-3-hydroxypiperidine-1-carboxylate 8
1740, 2860, 2943 cmꢀ1 1H NMR (500 MHz, CDCl3) d
;
0.04 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 2.01–2.05 (m, 2H),
2.52–2.56 (m, 2H), 3.59 (dd, J = 7.0, 10.0 Hz, 1H), 3.67 (s,
3H), 3.92–3.98 (m, 2H), 3.98–4.64 (m, 1H), 7.38–7.42 (m,
2H), 7.46–7.49 (m, 1H), 7.19–7.94 (m, 2H); 13C NMR
(125 MHz, CDCl3) d ꢀ5.15, ꢀ5.13, 18.45, 26.05, 30.06,
30.85, 51.87, 65.28, 73.54, 82.23, 128.08, 128.47, 128.49,
131.56, 164.07, 173.54. HRMS (M++H) m/z calcd for
C20H32NO4Si: 378.2101; found, 378.2102.
To a solution of 7 (100 mg, 0.41 mmol) in CH2Cl2 (4.0 mL)
was added triethylamine (0.23 mL, 1.63 mmol) via syringe
followed by di(tert-butyl)dicarbonate (107 mg, 0.49 mmol)
in one portion. The reaction mixture was stirred for 4 h
after which the resulting yellow solution was poured into
5 mL of water. The layer was separated, and the organic
layer was washed with 5 mL of water. The organic layer
was dried over MgSO4, filtered, and the solvent was
removed in vacuo. The crude compound was purified by
flash column chromatography to afford 8 (128 mg, 91 %)
4.4. (5R,6R)-6-((tert-Butyldimethylsilyloxy)methyl)-5-
hydroxypiperidin-2-one 3
as a colorless oil; Rf = 0.3 (ethyl acetate/hexane = 1/2);
25
A solution of 4 (600 mg, 1.59 mmol) in AcOH/MeOH (1:9,
½aꢂD ¼ þ29:25 (c 0.5, CHCl3); IR (neat) 842, 1152, 1423,
10 mL), to which was added 300 mg of 20% Pd(OH)2/C,
1670, 2938, 3436 cmꢀ1 1H NMR (500 MHz, CDCl3) d
;