NMR (400 MHz, CDCl3) δ 1.19 (3H, d, J ) 6.7), 2.25 (1H, dd,
J ) 13.8, J ) 6.8), 2.41-2.50 (1H, m), 2.51 (1H, bdd, J ) 14.7,
J ) 4.0), 2.53-2.63 (1H, m), 2.64 (1H, bdd, J ) 13.8, J ) 4.5),
2.86-2.94 (1H, m), 3.06-3.12 (1H, m), 3.61 (1H, dd, J ) 10.8,
J ) 7.0), 3.83-3.89 (2H, m), 3.99 (1H, q, J ) 6.7), 4.45 (1H, d,
J ) 12.1), 4.49 (1H, d, J ) 12.1), 4.57 (1H, d, J ) 11.9), 4.71
(1H, d, J ) 11.9), 6.58 (1H, bs), 7.08-7.40 (15H, m), 7.40-7.47
(2H, m), 7.50-7.55 (1H, m), 7.77-7.82 (2H, m); 13C NMR (100
MHz, CDCl3) δ 13.6 (CH3), 30.4 (CH2), 36.4 (CH2), 43.5 (CH2),
57.1 (CH), 58.9 (CH), 71.1 (CH2), 72.8 (CH2), 73.5 (CH2), 78.9
(CH), 119.4 (CH), 126.6 (CH), 127.4 (CH), 127.5 (CH), 127.6 (CH),
127.7 (CH), 127.7 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 128.4
(CH), 128.4 (CH), 132.3 (CH), 138.2 (C), 138.8 (C), 139.1 (C),
144.6 (C), 160.6 (C), 191.4 (C); HRMS (FAB+) calcd for C37H40-
NO3 (MH+) 546.3008, found 546.3019.
Representative Procedures for the Synthesis of (E/Z)-(S)-2-
Substituted-4-alkylidenepiperidines 4. Method A (Wadsworth-
Emmons Reaction). To a suspension of anhydrous lithium chloride
[148 mg, 3.5 mmol for the synthesis of (E/Z)-4a,c,d or 210 mg,
5.0 mmol for the synthesis of (E/Z)-4b] in anhydrous CH3CN (10
mL) at room temperature under argon was added the corresponding
diethylphosphonate [3.5 mmol for the synthesis of (E/Z)-4a,c,d or
5.0 mmol for the synthesis of (E/Z)-4b] and DBU (1.52 g, 10
mmol). The mixture was stirred for 10 min at room temperature.
A solution of compound 2 (443 mg, 1.0 mmol) in anhydrous CH3-
CN (20 mL) was added, and the resulting mixture was stirred at
room temperature for 7 days. The reaction was quenched with water
(30 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined
organic extracts were dried over anhydrous MgSO4, filtered,
evaporated under reduced pressure, and subsequently chromato-
graphed to yield the corresponding alkenes 4a-d as E/Z mixtures
of diastereoisomers.
(E)-(S)-2-[(S)-1,2-Dibenzyloxyethyl]-4-[(N-methoxy-N-meth-
yl)carbamoylmethylene]-1-[(S)-1-phenylethyl]piperidine [(E)-
4d]. From a 73:27 E/Z mixture isolated in 78% yield after
purification by column chromatography (first eluent, Et2O/hexanes
2:1; second eluent, Et2O) of crude obtained according to method
A: oil; IR absorptions (pure) νmax 1665; 1H NMR (400 MHz,
CDCl3) δ 1.20 (3H, d, J ) 6.7), 1.76-1.96 (2H, m), 2.58-2.70
(2H, m), 2.87-2.94 (1H, m), 2.96-3.04 (1H, m), 3.08 (3H, s),
3.35-3.40 (1H, m), 3.51 (1H, dd, J ) 10.7, J ) 7.6), 3.56 (3H, s),
3.70 (1H, dd, J ) 10.7, J ) 2.0), 3.77 (1H, ddd, J ) 7.6, J ) 4.3,
J ) 2.0), 3.88 (1H, q, J ) 6.7), 4.38 (1H, d, J ) 12.1), 4.43 (1H,
d, J ) 12.1), 4.56 (1H, d, J ) 12.0), 4.65 (1H, d, J ) 12.0), 5.53
(1H, bs), 7.06-7.35 (15H, m); 13C NMR (100 MHz, CDCl3) δ
14.5 (CH3), 26.9 (CH2), 30.2 (CH3), 40.9 (CH2), 45.4 (CH2), 56.9
(CH), 57.8 (CH), 60.4 (CH3), 72.3 (CH2), 72.8 (CH2), 73.2 (CH2),
79.7 (CH), 123.8 (CH), 126.4 (CH), 127.2 (CH), 127.3 (CH), 127.4
(CH), 127.5 (CH), 127.7 (CH), 127.9 (CH), 128.1 (CH), 128.2 (CH),
132.4 (C), 138.7 (C), 139.0 (C), 144.8 (C), 164.4 (C); HRMS
(FAB+) calcd for C33H41N2O4 (MH+) 529.3066, found 529.3081.
Method B (from Olefins of 2R Configuration). To a suspension
of anhydrous lithium chloride (148 mg, 3.5 mmol) in anhydrous
CH3CN (10 mL) at room temperature under argon were added
successively DBU (1.52 g, 10 mmol) and a solution of the
corresponding compound (E/Z)-3a-g (1.0 mmol) in anhydrous CH3-
CN (20 mL). The mixture was stirred at room temperature for 7
days. The reaction was quenched with water (30 mL) and extracted
with CH2Cl2 (3 × 50 mL). The combined organic extracts were
dried over anhydrous MgSO4, filtered, evaporated under reduced
pressure, and subsequently chromatographed to yield the corre-
sponding alkenes 4a-g as E/Z mixtures of diastereoisomers.
(E)-(S)-2-[(S)-1,2-Dibenzyloxyethyl]-4-(2-oxo)propylidene-1-
[(S)-1-phenylethyl]piperidine [(E)-4e]. Purification by column
chromatography (first eluent, Et2O/hexanes 2:1, second eluent, Et2O/
hexanes 4:1; third eluent, Et2O) of crude obtained according to
method B yielded 260 mg (54%) of a 94:6 mixture of (E)-4e/(Z)-
4e from which an analytically pure sample of the E isomer was
isolated by column chromatography using the same system of
eluents: oil; IR absorptions (pure) νmax 1716, 1655; [R]25D ) +50.4
1
(c 0.81, CHCl3); H NMR (400 MHz, CDCl3) δ 1.21 (3H, d, J )
6.6), 1.73-1.78 (2H, m), 2.20 (3H, s), 2.53-2.67 (2H, m), 2.92-
3.04 (2H, m), 3.36-3.42 (1H, m), 3.50 (1H, dd, J ) 10.6, J )
7.4), 3.71 (1H, dd, J ) 10.6, J ) 2.0), 3.80 (1H, ddd, J ) 7.4,
J ) 4.3, J ) 2.0), 3.88 (1H, q, J ) 6.6), 4.40 (1H, d, J ) 12.1),
4.45 (1H, d, J ) 12.1), 4.57 (1H, d, J ) 11.9), 4.68 (1H, d, J )
11.9), 5.57 (1H, bs), 7.10-7.34 (15H, m); 13C NMR (100 MHz,
CDCl3) δ 14.2 (CH3), 27.0 (CH2), 29.1 (CH3), 40.9 (CH2), 52.7
(CH2), 56.9 (CH), 58.0 (CH), 72.2 (CH2), 73.0 (CH2), 73.3 (CH2),
79.6 (CH), 125.1 (CH), 126.6 (CH), 127.4 (CH), 127.4 (CH), 127.5
(CH), 127.6 (CH), 127.7 (CH), 128.0 (CH), 128.2 (CH), 128.3 (CH),
132.2 (C), 138.5 (C), 139.0 (C), 144.6 (C), 207.0 (C); HRMS
(FAB+) calcd for C32H38NO3 (MH+) 484.2851, found 484.2840.
Acknowledgment. This work was supported by the Spanish
MCYT and FEDER (Project CTQ2004-05358) and the Gobierno
de Arago´n. P.E. was supported by a Spanish MCYT Predoctoral
Fellowship.
Supporting Information Available: General statement describ-
ing materials and methods, spectroscopic data, and full experimental
procedure for compound 2, physical and spectral data for com-
pounds (E)-3a-c, (E)-3f, (E)-4a, (Z)-4a, (E)-4b, (E)-4c, (Z)-4c,
1
(E)-4f, and (E)-4g, as well as copies of H NMR and 13C NMR
spectra for all compounds. This material is available free of charge
JO062075C
1008 J. Org. Chem., Vol. 72, No. 3, 2007