A. Avenoza et al. / Tetrahedron 57 (2001) 545±548
547
1
gel 60 (230±400 mesh). H and 13C NMR spectra were
C6); 53.4 (CH3O); 58.5 (C1); 127.1, 128.6, 130.5, 132.2 (C3,
Arom.); 133.0 (Arom.); 146.9 (C2); 167.0, 171.2 (COO,
CON); 197.2 (CO).
recorded on a Bruker ARX-300 spectrometer at 300 MHz
(1H) and at 75 MHz (13C), at 208C, and are reported in ppm
down®eld from TMS (chemical shifts are reported in ppm
on the d scale, coupling constants in Hz). Melting points
were determined on a BuÈchi SMP-20 melting point appara-
tus and are uncorrected. Optical rotations were measured on
a Perkin±Elmer 341 polarimeter in an 1 dm cell of 1 mL
capacity. Microanalyses were carried out on a CE Instru-
ments EA-1110 analyser and were in good agreement with
the calculated values. IR spectra were recorded on a Perkin±
Elmer FT-IR Spectrum 1000 spectrometer.
4.1.3. Methyl 1-benzamido-4-oxocyclohexane-1-carboxyl-
ate (6). Method A: A solution of enone 5 (4 g, 14.63 mmol)
in dry CH2Cl2 (200 mL) was hydrogenated at atmospheric
pressure for 24 h at room temperature, using 10%
palladium±carbon (1 g) as a catalyst. After the removal of
the catalyst and the solvent, the residue was chromato-
graphed on silica gel eluting with hexane±ethyl acetate
(6:4), to yield 3.8 g of compound 6 as a white solid.
(95%). Method B: 2-Trimethylsilyloxy-1,3-butadiene
(8.3 g, 58.5 mmol) was added to a solution of methyl
2-benzamidoacrylate 4 (4.0 g, 19.5 mmol) and ZnI2 (6.3 g,
19.5 mmol) in dry CH2Cl2 (90 mL) kept under an inert
atmosphere. After stirring for 24 h, at re¯ux, the solution
was ®ltered and washed with water (1£20 mL), the organic
phase was dried over anhydrous Na2SO4 and ®ltered. Then,
a solution of 0.005N HCl±THF (1:4) (40 mL) was added to
the residue and the reaction mixture was stirred for 5 h at
room temperature. The solvent was evaporated and the
mixture was diluted with CH2Cl2 (75 mL) and washed
with brine (2£20 mL). The combined organic phases were
dried over anhydrous Na2SO4, ®ltered, and evaporated. The
residue was chromatographed on silica gel eluting with
hexane±ethyl acetate (6:4) to yield 5.0 g of compound 6
as a white solid. (94%). Mp: 133±48C; Anal. calcd for
C15H17NO4; C, 65.44; H, 6.22; N, 5.09; found C, 65.67;
H, 6.27; N, 5.25; IR (CH2Cl2, cm21): 3430 (NH), 1743
4.1.1. Methyl 2-benzamidoacrylate (4). To a solution of
d,l-serine methyl ester hydrochloride (4.5 g, 28.9 mmol) in
CH2Cl2 were added in portions Et3N (9.6 g, 98.2 mmol) and
BzCl (9.3 g, 66.7 mmol) kept under an inert atmosphere.
The mixture was stirred for 7 h at room temperature and
then was washed with a saturated solution of NaHCO3
(2£50 mL), dried over anhydrous Na2SO4, ®ltered and
evaporated. The white solid was dissolved in CH2Cl2, kept
under inert atmosphere, at 58C and then DBU (5.2 g,
33.9 mmol) was added. After 3 h stirring at the same
temperature, the reaction was washed with water (50 mL)
and a saturated solution of NaHCO3 (2£50 mL). The
organic layer was dried over anhydrous Na2SO4, ®ltered
and evaporated to obtain 5.5 g of compound 4 as an oil
(93%). Anal. calcd for C11H11NO3; C, 64.38; H, 5.40; N,
6.83.; found C, 64.46; H, 5.32; N, 6.74; IR (CH2Cl2, cm21):
1
3410 (NH), 1720 (CO), 1678 (CON); H NMR (CDCl3): d
1
3.85 (s, 3H, CH3O); 5.95±6.02 (m, 1H); 6.79 (s, 1H), 7.43±
7.58 (m, 3H, Arom.); 7.79±7.88 (m, 2H, Arom.); 8.55 (br s,
1H, NH); 13C NMR (CDCl3): d 52.9 (CH3O); 108.6 (C3);
126.7, 128.6 (Arom.); 130.8 (C2); 131.8, 134.0, (Arom.);
164.5, 165.5 (COO, CON).
(COO), 1716 (CO), 1673 (CON); H NMR (CDCl3): d
2.40±2.58 (m, 8H); 3.77 (s, 3H, CH3O); 6.67 (br s, 1H,
NH); 7.24±7.54 (m, 3H, Arom.); 7.60±7.81 (m, 2H,
Arom.); 13C NMR (CDCl3): d 32.3, 36.7 (C2, C3, C5, C6);
52.8 (CH3O); 58.0 (C1); 127.1, 128.6, 132.0, 133.6 (Arom.);
167.9, 173.2 (COO, CON); 209.1 (CO).
4.1.2. Methyl 1-benzamido-4-oxo-2-cyclohexene-1-car-
boxylate (5). Danishefsky's diene (6.5 mL, 33.4 mmol)
was added to a solution of methyl 2-benzamidoacrylate 4
(1.7 g, 8.3 mmol) in dry toluene (80 mL) under an inert
atmosphere. After stirring for 24 h, at re¯ux, another
8.3 mmol of 4 was added. After two days stirring at the
same temperature, the solvent was evaporated in vacuo
and a solution of 0.005N HCl±THF (1:4) (40 mL) was
added to the residue. The reaction mixture was stirred for
15 h at 208C, the solvent was evaporated and the residue was
chromatographed on silica gel, eluting with hexane±ethyl
acetate (2:8). The mixture was dissolved in CH2Cl2 (75 mL)
and DBU (2.7 mL, 18.2 mmol) was added. The reaction
mixture was stirred for 24 h at 28C and the solution was
washed with 0.5N HCl (60 mL). The aqueous phase was
extracted with CH2Cl2 (5£30 mL) and the combined
organic phases were dried over anhydrous Na2SO4, ®ltered
and evaporated. The residue was chromatographed on silica
gel eluting with hexane±ethyl acetate (1:1), to yield 2.5 g of
enone 5 as a white solid (55%). Mp: 126±78C; Anal. calcd
for C15H15NO4; C, 65.92; H, 5.53; N, 5.13.; found C, 65.84;
H, 5.59; N, 5.05; IR (CH2Cl2, cm21): 3433 (NH), 1743
4.1.4. Methyl 1-benzamido-c-4-methanesulfonyloxycyclo-
hexane-r-1-carboxylate (7). Compound
6
(4.0 g,
14.5 mmol) was dissolved in dry THF (80 mL) and l-selec-
tridew (17.3 mL of 1 M sol. in THF, 17.3 mmol) was added
dropwise at 2788C under an inert atmosphere. After 20 h
stirring at the same temperature, the reaction was quenched
by the addition of a saturated NH4Cl solution (20 mL). The
resulting mixture was allowed to warm up to room tempera-
ture, the solvent evaporated and the residue washed with
ethyl acetate (1£50 mL) and CHCl3/2-propanol (3:1)
(2£30 mL). Evaporation of the solvent gave a residue that
was chromatographed on silica gel eluting with hexane±
ethyl acetate (1:9), obtaining 3.63 g as a mixture of alcohols
trans/cis, in a 10:90 ratio (determined by the integration of
1H NMR signals). The mixture of alcohols was dissolved in
dry CH2Cl2 (70 mL) under an inert atmosphere and
diisopropylethylamine (4.5 mL, 26.2 mmol) and methane-
sulfonyl chloride (2.0 mL, 26.2 mmol) were then added to
this solution at 08C. The solution was left to reach room
temperature and, after 36 h stirring at room temperature,
the mixture was washed with an aqueous solution of 5%
NaHCO3, dried over anhydrous Na2SO4 and ®ltered. After
the evaporation of the solvent, the residue was chromato-
graphed on a silica gel column, eluting with hexane±ethyl
acetate (1:1), to obtain 3.5 g of compound 7 (68% from
ketone 6). Mp: 140±28C; Anal. calcd for C16H21NO6S; C,
1
(CO), 1685 (CON); H NMR (CDCl3): d 2.50±2.65 (m,
4H, 2H512H6); 3.82 (s, 3H, CH3O); 6.14 (d, 1H,
J3±210.0 Hz, H3); 7.10±7.20 (m, 2H, NH1H2); 7.41±
7.48 (m, 2H, Arom.); 7.50±7.58 (m, 1H, Arom.); 7.76±
7.82 (m, 2H, Arom.); 13C NMR (CDCl3): d 31.6, 33.7 (C5,