1682
M. Amat et al. / Tetrahedron: Asymmetry 14 (2003) 1679–1683
was washed with 5% aqueous HCl, dried, and concen-
trated. The residue was chromatographed (9:1 AcOEt–
MeOH) to give pure 8 (75 mg, 82%): IR (NaCl) 3359,
3.5.1. With methylmagnesium bromide. Operating as
described in the general procedure, from trans-1 (300
mg, 1.38 mmol) and methylmagnesium bromide (3 M
in Et2O, 1.4 mL, 4.14 mmol) a residue was obtained.
Purification by column chromatography (AcOEt) gave
4a4b (36 mg, 11%) and 4b10b (199 mg, 62%). Compound
1
1619 cm−1; H NMR (CDCl3, 300 MHz) l 1.69 (m, 1H,
H-4), 1.79–1.97 (m, 3H, H-4, 2 H-5), 2.37–2.44 (m, 2H,
2 H-3), 3.51 (m, 1H, H-6), 3.61 (dd, J=12.0, 5.0 Hz,
1H, CH2OH), 3.75 (dd, J=12.0, 4.8 Hz, 1H, CH2OH),
3.99 (dd, J=10.0, 4.0 Hz, 1H, NCHjCH2O), 4.15 (br s,
2H, 2 OH), 4.63 (dd, J=10.0, 4.0 Hz, 1H, NCH), 4.70
(t, J=10.0 Hz, 1H, NCHCH2O), 7.27–7.31 (m, 5H,
Ar); 13C NMR (CDCl3, 75.4 MHz, HETCOR) l 17.2
(C-4), 26.2 (C-5), 32.5 (C-3), 60.2 (C-6), 62.8
(NCHCH2), 64.1 (CH2OH), 66.3 (NCH), 127.2 (2 CH),
128.5 (CH), 127.5 (2 CH), 137.5 (C), 172.7 (CO); [h]D22
−4.6 (c 1.5, EtOH); HRMS calcd for C14H19NO3 (M+−
H2O) m/z 231.1252, found 231.1259.
1
4b: H NMR (CDCl3, 300 MHz) l 1.17 (d, J=6.5 Hz,
3H), 1.58 (m, 1H), 1.69–1.80 (m, 2H), 1.93 (m, 1H),
2.48–2.54 (m, 2H), 3.45 (m, 1H), 4.16 (dd, J=11.5, 4.5
Hz), 4.25 (dd, J=11.5, 7.5 Hz, 1H), 5.22 (dd, J=7.5,
4.5 Hz, 1H), 7.26–7.34 (m, 5H, ArH); 13C NMR
(CDCl3, 50.4 MHz) l 16.6 (CH2), 21.2 (CH3), 30.3
(CH2), 32.1 (CH2), 52.3 (CH), 63.4 (CH), 64.3 (CH2),
127.4 (CH), 127.6 (2 CH), 128.5 (2 CH), 137.2 (C),
172.4 (CO); [h]2D2 −24.5 (c 1.0, EtOH); m/z 234 (1), 215
(26), 203 (31), 202 (100), 188 (7), 186 (6); HRMS calcd
for C14H19NO2 (M++H) m/z 233.1416, found 234.1485.
3.4. (6S)-6-Cyano-1-[(1R)-1-phenyl-2-hydroxyethyl]-2-
piperidone 9a and (6R)-6-cyano-1-[(1R)-1-phenyl-2-
hydroxyethyl]-2-piperidone 9b
3.5.2. With n-propylmagnesium chloride. Operating as
described in the general procedure, from trans-1 (500
mg, 2.30 mmol) and n-propylmagnesium chloride (2 M
in Et2O, 3.45 mL, 6.91 mmol) a residue was obtained.
Purification by column chromatography (97:3 AcOEt–
EtOH) gave 5a4b (36 mg, 6%) and 5b11 (397 mg, 66%)
as colorless oils. 5b: 1H NMR (CDCl3, 300 MHz,
COSY) l 0.82 (t, J=7.2 Hz, 3H, CH3), 1.09 (m, 1H,
CH2CH3), 1.25 (m, 1H, CH2CH3), 1.47–1.59 (m, 3H,
CH2CH2CH3, H-5), 1.65–1.75 (m, 2H, H-5, H-4), 1.84
(m, 1H, H-4), 2.45–2.50 (m, 2H, H-3), 3.22 (m, 1H,
H-6), 4.14 (dd, J=11.0, 5.5 Hz, 1H, CH2OH), 4.22 (dd,
J=11.0, 7.5 Hz, CH2OH), 5.25 (dd, J=7.5, 5.5 Hz,
NCH), 7.26–7.32 (m, 5H, Ar); 13C NMR (CDCl3, 75.5
MHz, HETCOR) l 13.7 (CH3), 16.0 (C-4), 19.3
(CH2CH3), 25.5 (C-5), 31.5 (C-3), 35.1 (CH2CH2CH3),
56.0 (C-6), 62.8 (NCH), 63.4 (CH2OH), 127.2 (CH),
127.5 (2 CH), 128.2 (2 CH), 137.2 (C), 172.1 (CO); [h]D22
+28 (c 1.0, CH2Cl2) {lit.11 [h]D20 +21 (c 1.0, CH2Cl2)};
HRMS calcd for C16H24NO2 (M++H) m/z 262.1807,
found 262.1796.
Trimethylsilyl cyanide (0.69 mL, 5.52 mmol) and tita-
nium tetrachloride (0.30 mL, 2.76 mmol) were added to
a solution of trans-1 (600 mg, 2.76 mmol) in CH2Cl2
(24 mL). The mixture was stirred for 18 h at room
temperature, poured into aqueous NaHCO3, and
extracted with CH2Cl2. The combined organic extracts
were dried and concentrated to give a residue, which
was chromatographed (AcOEt) to furnish 9a (470 mg,
70%) and 9b (30 mg, 4%). Compound 9a: IR (NaCl)
1
2247, 1619 cm−1; H NMR (CDCl3, 300 MHz) l 1.94–
2.19 (m, 4H), 2.55 (dt, J=18.3, 10.0 Hz, 1H), 2.72 (dm,
J=18.3 Hz, 1H), 2.80 (br s, 1H), 4.13 (dd, J=11.9, 4.9
Hz, 1H), 4.18 (dd, J=11.9, 7.0 Hz, 1H), 4.42 (dd,
J=4.3, 2.7 Hz, 1H), 5.46 (dd, J=7.0, 4.9 Hz, 1H),
7.37–7.30 (m, 5H); 13C NMR (CDCl3, 75.4 MHz) l
17.6 (CH2), 27.4 (CH2), 31.5 (CH2), 46.2 (CH), 60.3
(CH), 61.6 (CH2), 117.7 (C), 128.5, 128.6, 128.8 (5 CH),
135.4 (C), 170.6 (CO); [h]2D2 −121.6 (c 0.5, EtOH). Anal.
calcd for C14H16N2O2·1/4H2O: C, 67.58; H, 6.65; N,
11.26. Found: C, 67.70; H, 6.65; N, 11.01. Compound
3.5.3. With phenylmagnesium bromide. Operating as
described in the general procedure, from trans-1 (200
mg, 1.38 mmol) and phenylmagnesium bromide (1 M in
THF, 2.7 mL, 2.76 mmol) a residue was obtained.
Purification by column chromatography (AcOEt) gave
6b4b (196 mg, 72%).
1
9b: IR (NaCl) 2238, 1635 cm−1; H NMR (CDCl3, 300
MHz) l 1.73 (tdd, J=13.2, 5.0, 4.0 Hz, 1H), 1.93–2.21
(m, 3H), 2.52 (ddd, J=18.0, 10.1, 7.3 Hz, 1H), 2.73
(dddd, J=18.0, 7.0, 3.0, 1.4 Hz, 1H), 4.16 (ddd, J=5.1,
2.6, 1.4 Hz, 1H), 4.29 (dd, J=11.6, 6.0 Hz, 1H), 4.35
(dd, J=11.6, 7.5 Hz, 1H), 5.93 (t, J=6.6 Hz, 1H),
7.32–7.40 (m, 5H); 13C NMR (CDCl3, 75.4 MHz) l
17.9 (CH2), 27.5 (CH2), 31.3 (CH2), 44.6 (CH), 58.4
(CH), 61.0 (CH2), 118.9 (C), 128.1 (2 CH), 129.0 (CH),
128.5 (2 CH), 135.3 (C), 170.3 (CO).
3.5.4. With 2-methyl-1-propenylmagnesium bromide.
Operating as described in the general procedure, from
trans-1 (300 mg, 1.38 mmol) and 2-methyl-1-propenyl-
magnesium bromide (0.5 M in THF, 8.3 mL, 4.14
mmol) a residue was obtained. Purification by column
chromatography (AcOEt) gave starting material trans-1
3.5. General procedure for the reaction of lactam
trans-1 with Grignard reagents
1
(30 mg, 10%) and 7b (211 mg, 56%): H NMR (CDCl3,
300 MHz) l 1.37 (s, 3H), 1.56 (m, 1H), 1.68–1.75 (m,
2H), 1.65 (s, 3H), 1.87 (m, 1H), 2.42–2.62 (m, 2H), 3.40
(br s, 1H), 3.94 (dt, J=9.3, 4.5 Hz, 1H), 4.08–4.21 (m,
2H), 5.26 (dm, J=9.3 Hz, 1H), 5.50 (dd, J=8.0, 5.5
Hz, 1H), 7.21–7.36 (m, 5H); 13C NMR (CDCl3, 50.4
MHz) l 17.6 (CH3), 17.6 (CH2), 25.9 (CH3), 30.4
(CH2), 32.5 (CH2), 53.6 (CH), 60.7 (CH), 63.5 (CH2),
126.2 (CH), 127.5 (CH), 128.1 (2 CH), 128.4 (2 CH),
133.7 (C), 137.1 (C), 172.3 (CO); [h]2D2 −63 (c 1.0,
A solution of trans-1 (1 equiv.) in anhydrous THF (2
mL) was added via cannula to a solution of the Grig-
nard reagent (3 equiv.) in THF or Et2O at 0°C, and the
mixture was stirred at this temperature for 8 h. The
reaction was quenched by addition of saturated
aqueous NaCl, and the mixture was extracted with
AcOEt. The combined organic extracts were dried and
concentrated.