1734 J . Org. Chem., Vol. 63, No. 5, 1998
Notes
N,S-Keten e Aceta l 9. To a stirred solution of thiolactam 8
(1.59 g, 5.77 mmol) in 30 mL of CH2Cl2 was added triethyloxo-
nium tetrafluoroborate6 (1.4 M solution in CH2Cl2, 5.36 mL, 7.51
mmol). The solution was heated at reflux for 1 h, cooled, poured
into saturated NaHCO3 (aq, 50 mL), and shaken. The phases
were separated, and the aqueous phase was extracted with CH2-
Cl2 (30 mL). The combined organic phases were dried (K2CO3)
and concentrated to yield 1.75 g (100%) of N,S-ketene acetal 9
as a colorless cloudy oil: 1H NMR (CDCl3) δ 0.81 (d, J ) 6.7 Hz,
3H), 1.04 (t, J ) 7.4 Hz, 3H), 1.22 (t, J ) 7.3 Hz, 3H), 1.68 (q, J
) 7.5 Hz, 2H), 1.78 (m, 2H), 2.06-2.23 (m, 2H), 2.54 (m, 1H),
2.80 (m, 1H), 4.00 (quint, J ) 6.6 Hz, 1H), 4.92 (m, 1H), 5.28 (d,
J ) 5.4 Hz, 1H), 7.28 (m, 5H).
Cya n o En a m in e 5. To a stirred solution of N,S-ketene acetal
9 (1.75 g, 5.77 mmol) in 40 mL of THF were added potassium
cyanide (0.56 g, 8.66 mmol), copper(I) iodide (1.65 g, 8.66 mmol),
and iodine (73 mg, 0.29 mmol). The mixture was heated to reflux
for 12 h, cooled to ambient temperature, and concentrated to
ca. 5 mL. The residue was diluted with 5 mL of hexanes-ethyl
acetate (8:1) and loaded onto a 5 × 4 cm plug of basic alumina.
Elution with hexanes-ethyl acetate (8:1) provided 1.41 g (91%
from thiolactam 8) of cyano enamine 5 as a pale yellow oil. The
crude cyano enamine was suitable for alkylation. Analytically
likelihood was no less than 95% optically pure. It is
indeed possible that the naturally occurring enone 1
isolated from iris rhizomes exists as a mixture of enan-
tiomers, thus accounting for the smaller magnitude of
optical rotation.
Exp er im en ta l Section
Thin-layer chromatography (TLC) and flash chromatography
were performed with E. Merck or Amicon Matrix silica gel
(230-400 mesh). All reagents were purchased from Aldrich. All
nonaqueous reactions were conducted under an argon atmo-
sphere in flame-dried apparatus. Tetrahydrofuran was distilled
from sodium-benzophenone ketyl under argon atmosphere prior
to use. HMPA was distilled from calcium hydride under reduced
pressure prior to use. Methyl iodide was passed through a plug
of basic Al2O3 prior to use.
Meth yl 5-Oxoh ep ta n oa te. To 25.0 mL of stirred THF was
added ethylmagnesium bromide (1.0 M solution in THF, 15.2
mL, 15.2 mmol). The solution was cooled to -78 °C, and
4-carbomethoxybutanoyl chloride (Aldrich, 2.10 mL, 15.2 mmol)
was added dropwise at such a rate that the temperature of the
mixture did not exceed -70 °C. The mixture was allowed to
warm slowly to ambient temperature over 12 h and then
quenched with saturated NH4Cl (aq, 15 mL). Water (10 mL)
was added to dissolve the solids, and the phases were separated.
The aqueous phase was extracted with ether (2 × 30 mL), and
the combined organic phases dried (MgSO4) and concentrated
to yield 2.35 g (98%) of keto ester as a pale yellow oil: 1H NMR
(CDCl3) δ 0.99 (t, J ) 7.3 Hz, 3H), 1.84 (quint, J ) 7.2 Hz, 2H),
2.26-2.45 (m, 4H), 3.61 (s, 3H); 13C NMR (CDCl3) δ 7.60, 18.77,
32.90, 35.73, 40.89, 51.34, 173.44, 210.45; IR (neat) 1736, 1715
pure material was obtained by flash chromatography (8:1
1
hexanes-ethyl acetate): [R]23 +79.3 (c 1.63, CHCl3); H NMR
D
(CDCl3) δ 0.85 (d, J ) 6.7 Hz, 3H), 1.04 (t, J ) 7.5 Hz, 3H), 1.65
(m, 3H), 1.91 (m, 1H), 2.13 (m, 1H), 2.30 (m, 1H), 3.85 (quint, J
) 6.6 Hz, 1H), 5.27 (d, J ) 6.2 Hz, 1H), 5.47 (m, 1H), 7.31 (m,
5H); 13C NMR (CDCl3) δ 7.36, 18.25, 21.98, 26.21, 30.00, 60.52,
78.59, 94.13, 115.00, 116.35, 118.93, 126.29, 127.71, 128.26,
136.74; IR (neat) 2223, 1617 cm-1. Anal. Calcd for C17H20N2O:
C, 76.08; H, 7.51. Found: C, 75.95; H, 7.58.
â-Meth yl La cta m 10. To a stirred solution of 2,2,6,6-
tetramethylpiperidine (1.33 mL, 7.88 mmol) in 20.0 mL of THF
at -78 °C was added n-butyllithium (1.89 M solution in hexanes,
4.17 mL, 7.88 mmol) followed by HMPA (1.37 mL, 7.88 mmol).
The solution was stirred for 5 min at -78 °C, warmed to 0 °C,
stirred for 15 min, anhd then cooled to -78 °C, at which time
cyano enamine 5 (1.41 g, 5.25 mmol) in 7.0 mL of THF was added
dropwise over 5 min. The solution was stirred at -78 °C for 20
min, and methyl iodide (0.65 mL, 10.5 mmol) was added
dropwise over 5 min, stirred for 1 h at -78 °C, and quenched
with saturated NaHCO3 (aqueous 15 mL). The mixture was
diluted with ether (15 mL), water was added to dissolve the
solids (15 mL), and the phases were separated. The aqueous
phase was extracted with ether (2 × 25 mL), and the combined
organic phases were dried (K2CO3) and concentrated to a red
oil. To the crude cyano enamine were added THF (50 mL) and
1 N HCl (aq, 50 mL) and the mixture stirred at ambient
temperature for 6 h. The THF was evaporated, the residue was
extracted with ether (3 × 50 mL), and the combined organic
phases were dried (MgSO4) and concentrated. Flash chroma-
tography of the residue (1:1 hexanes-ethyl acetate) provided
cm-1
.
5-Oxoh ep ta n oic Acid 6. To the crude keto ester (2.35 g,
14.9 mmol) were added methanol (50 mL) and 20% KOH (aq,
50 mL). The mixture was stirred at ambient temperature for 4
h, poured into a separatory funnel, and washed with ether (100
mL). The phases were separated, and the aqueous phase was
acidified to pH 2 with concentrated HCl (exotherm). The
solution was allowed to cool to ambient temperature and
extracted with ether (2 × 100 mL). The combined organic phases
were dried (MgSO4) and concentrated to yield 1.98 g (92%) of 6
as a yellow oil that solidified upon standing: mp 42-44 °C (lit.8
1
mp 39.1-41.4 °C); H NMR (CDCl3) δ 1.01 (t, J ) 7.3 Hz, 3H),
1.86 (quint, J ) 7.2 Hz, 1H), 2.32-2.49 (m, 7H), 11.3 (br s, 1H);
13C NMR (CDCl3) δ 7.62, 18.48, 32.91, 35.80, 40.79, 179.15,
210.92; IR (neat) 1734, 1709 cm-1
. Physical and spectral
properties matched well with those described previously.8
Bicyclic La cta m 7. The crude keto acid 6 (1.98 g, 13.7 mmol)
and (-)-(1R,2S)-nor-ephedrine (2.30 g, 15.2 mmol) were taken
up in toluene (76 mL) and heated at reflux with azeotropic
removal of water for 12 h, cooled, and concentrated. Flash
chromatography (twice) of the residue (1:1 hexanes-ethyl
0.84 g (59%) of â-methyl lactam 10 as a pale yellow oil: [R]23
D
1
acetate) provided 2.29 g (64%) of the lactam 7 as a pale yellow
-72.8 (c 1.93, CHCl3); H NMR (CDCl3) δ 0.85 (d, J ) 7.0 Hz,
1
oil: [R]23 -49.5 (c 1.60, CHCl3); H NMR (CDCl3) δ 0.84 (d, J
D
3H), 1.06 (d, J ) 5.9 Hz, 3H), 1.09 (t, J ) 7.6 Hz, 3H), 1.27 (app
t, J ) 12.1 Hz, 1H), 1.75-2.07 (m, 4H), 2.25 (dd, J ) 4.5, 12.7
Hz, 1H), 2.67 (app q, J ) 10.8 Hz, 1H), 4.70 (quint, J ) 6.8 Hz,
1H), 5.09 (d, J ) 5.9 Hz, 1H), 7.30 (m, 5H); 13C NMR (CDCl3) δ
8.80, 16.26, 22.78, 22.96, 32.94, 37.96, 38.42, 54.79, 79.28, 94.89,
126.08, 127.67, 128.28, 136.77, 169.06; IR (neat) 1652 cm-1. Anal.
Calcd for C17H23NO2: C, 74.69; H, 8.48. Found: C, 74.80; H,
8.57.
) 7.0 Hz, 3H), 1.09 (t, J ) 7.5 Hz, 3H), 1.52-1.98 (m, 5H), 2.21
(ddd, J ) 2.4, 5.4, 8.0 Hz, 1H), 2.44 (m, 2H), 4.70 (quint, J ) 6.7
Hz, 1H), 5.09 (d, J ) 5.8 Hz, 1H), 7.30 (m, 5H); 13C NMR (CDCl3)
δ 8.75, 14.97, 16.14, 28.53, 29.31, 32.05, 54.67, 78.99, 94.94,
126.08, 127.69, 128.28, 136.64, 169.02; IR (neat) 1649 cm-1. Anal.
Calcd for C16H21NO2: C, 74.10; H, 8.16. Found: C, 73.99; H,
8.21.
Th iola cta m 8. To a stirred solution of lactam 7 (1.67 g, 6.44
mmol) in 32.0 mL of toluene was added Belleau’s reagent5 (1.79
g, 3.86 mmol). The mixture was heated to reflux for 1 h, cooled,
and concentrated onto silica gel. Flash chromatography of the
residue (4:1, hexanes: ethyl acetate) afforded 1.48 g (84%) of
thiolactam 8 as a colorless crystalline solid: mp 173-175 °C;
r,r,â-Tr im eth yl La cta m 4. To a stirred solution of diiso-
propylamine (0.53 mL, 3.79 mmol) in 6.0 mL of THF at 0 °C
was added n-butyllithium (2.15 M solution in hexanes, 1.72 mL,
3.70 mmol). The solution was stirred for 15 min at 0 °C and
then cooled to -78 °C, at which time lactam 10 (0.51 g, 1.85
mmol) in 3.5 mL of THF was added dropwise over 3 min.
Stirring was continued at -78 °C for 30 min, and methyl iodide
(0.35 mL, 5.54 mmol) was added in one portion. After being
stirred for 15 min at -78 °C, the solution was warmed to
ambient temperature and stirred for 15 min. The mixture was
quenched with saturated NH4Cl (aq, 10 mL), and the phases
were separated. The aqueous phase was extracted with ether
(15 mL), and the combined organic phases were dried (MgSO4)
and concentrated to 0.58 g of an orange oil containing a mixture
[R]23 +45.9 (c 1.64, CHCl3); 1H NMR (CDCl3) δ 0.97 (d, J ) 6.0
D
Hz, 3H), 1.11 (t, J ) 7.5 Hz, 3H), 1.71-2.02 (m, 5H), 2.21 (m,
1H), 2.80 (m, 1H), 3.20 (m, 1H), 5.21 (m, 2H), 7.33 (m, 5H); 13
C
NMR (CDCl3) δ 8.62, 13.72, 15.21, 28.40, 30.91, 37.95, 61.42,
77.78, 96.76, 126.05, 127.97, 128.38, 135.64, 197.37; IR (neat)
1466 cm-1
.
(8) Utaka, M.; Watabu, H.; Takeda, A. J . Org. Chem. 1987, 52, 4363.