376 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Ornstein et al.
methylphenyl)ethyl)imidazolidine-2,4-dione and 2.7 g (8.5
mmol) of barium hydroxide in 10 mL of water was heated to
200 °C for 24 h in a stainless steel high-pressure reactor. The
mixture was cooled and acidified to pH 7 with 0.5 mL (8.5
mmol) of concentrated sulfuric acid. The resulting solution
was heated at 100 °C for 1 h, and then the solid was filtered
and washed three times with 10 mL each of water. Cation-
exchange chromatography of the filtrate afforded a solid that
was suspended in water and filtered, washed, water, acetone,
and ether, and dried in vacuo at 60 °C to afford 0.21 g (44%)
of 179.
(2S)-2-Am in o-2-((1S,2S)-2-ca r boxycyclop r op -1-yl)-4-(3-
m eth ylp h en yl)bu ta n oic Acid (180). A solution of 7.3 g
(13.4 mmol) of 178 in 100 mL of 1 N sodium hydroxide was
heated to 200 °C for 24 h in a stainless steel high-pressure
reactor. The mixture was cooled, washed three times with 30
mL each of ether, and then acidified to pH 7 with concentrated
hydrochloric acid. Cation-exchange chromatography of this
solution afforded a solid that was suspended in water, filtered,
washed with water, acetone, and ether, and dried in vacuo at
60 °C to afford 1.9 g (50%) of 180.
(1R,2R)-2-((1S,2R,5S)-Ca r b om e n t h yloxy)cyclop r op -
1-yl 2-(3-Meth ylp h en yl)eth yl Keton e (181). As for 163, 5.7
g (23.0 mmol) of 1-iodo-2-(3-methylphenyl)ethane and 2.9 g
(44.2 mmol) of zinc/copper couple then with 0.44 g (0.38 mmol)
of tetrakis(triphenylphosphine)palladium(0) and 5.5 g (19.2
mmol) of 162b in 65 mL of benzene and 6.5 mL of N,N-
dimethylacetamide afforded 4.7 g (65%) of 181.
(1R,2R)-2-(Ca r boxycyclop r op -1-yl) 2-(3-Meth ylp h en yl)-
eth yl Keton e. A solution of 4.4 g (11.8 mmol) of 181 in 35
mL of ethanol and 14.3 mL of 1 N sodium hydroxide was
stirred 18 h at 65 °C and then concentrated in vacuo. The
residue was dissolved in 30 mL of water, extracted three times
with 10 mL each of ether, and then brought to pH 2 with 10%
aqueous sodium bisulfate. The resulting solution was ex-
tracted four times with 15 mL each of ethyl acetate, and then
the combined organics were dried (MgSO4), filtered, and
concentrated in vacuo at 60 °C to afford 2.3 g (95%) of (1R,2R)-
2-carboxycycloprop-1-yl 2-(3-methylphenyl)ethyl ketone.
(5SR)-5-((1R,2R)-2-Ca r boxycyclop r op -1-yl)-5-(2-(3-m e-
th ylp h en yl)eth yl)im id a zolid in e-2,4-d ion e (182). A solu-
tion of 2.4 g (10.3 mmol) of (1R,2R)-2-carboxycycloprop-1-yl
2-(3-methylphenyl)ethyl ketone in 16 mL of ethanol was added
to a solution of 3.4 g (51.7 mmol) of potassium cyanide and
8.9 g (93.0 mmol) of ammonium carbonate in 16 mL of water,
and then this mixture was heated to 55 °C for 24 h. The
mixture was cooled and added to 200 mL of 10% aqueous
sodium bisulfate. The resulting mixture was allowed to stand
at room temperature, the solid thus obtained was filtered, and
recrystallization from acetone and water afforded 2.0 g (63%)
of 182.
(5S)-5-((1R,2R)-2-(((4-Meth oxyben zyl)oxy)ca r bon yl)cy-
clop r op -1-yl)-3-(4-m eth oxyben zyl)-5-(2-(3-m eth ylp h en yl)-
eth yl)im id a zolid in e-2,4-d ion e (183) a n d (5R)-5-((1R,2R)-
2-(((4-Meth oxyben zyl)oxy)ca r bon yl)cyclop r op -1-yl)-3-(4-
m et h oxyb en zyl)-5-(2-(3-m et h ylp h en yl)et h yl)im id a zoli-
d in e-2,4-d ion e (184). As for 165/166, 2.0 g (6.5 mmol) of 182,
1.8 g (18.3 mmol) of potassium bicarbonate, and 2.4 g (15.0
mmol) of 4-methoxybenzyl chloride in 25 mL of DMF afforded
1.7 g (48%) of 183 (higher Rf material) and 1.2 g (34%) of 184
(lower Rf material).
(5S)-5-((1R,2R)-2-Ca r boxycyclop r op -1-yl)-5-(2-(3-m eth -
ylp h en yl)eth yl)im id a zolid in e-2,4-d ion e. A solution of 1.6
g (2.9 mmol) of 183 in 90 mL of acetonitrile was added to a
solution of 12.5 g (22.9 mmol) of ceric ammonium nitrate in
30 mL of water, and then this mixture was stirred at room
temperature for 2.5 h. The mixture was diluted with 60 mL
of brine and extracted four times with 40 mL each of ethyl
acetate, and then the combined organics were dried (MgSO4),
filtered, and concentrated in vacuo. Chromatography (200 g
of silica gel, 2% glacial acetic acid/50% ethyl acetate/48%
hexane) of the residue afforded a solid which was recrystallized
from water/acetone. The crystals were filtered, rinsed with
water, and dried in vacuo at 60 °C to afford 0.44 g (50%) of
(5S)-5-((1R,2R)-2-carboxycycloprop-1-yl)-5-(2-(3-methylphenyl)-
ethyl)imidazolidine-2,4-dione.
(2S)-2-Am in o-2-((1R,2R)-2-ca r boxycyclop r op -1-yl)-4-(3-
m eth ylp h en yl)bu ta n oic Acid (185). A solution of 0.44 g
(1.4 mmol) of (5S)-5-((1R,2R)-2-carboxycycloprop-1-yl)-5-(2-(3-
methylphenyl)ethyl)imidazolidine-2,4-dione and 2.3 g (7.2
mmol) of barium hydroxide in 12 mL of water was heated to
250 °C for 16 h in a stainless steel high-pressure reactor. The
mixture was cooled and acidified to pH 2 with concentrated
sulfuric acid. The resulting solution was heated at 90 °C for
1 h, and then the solid was filtered and washed three times
with 10 mL each of water. The filtrate was concentrated in
vacuo to a volume of 10 mL. Cation-exchange chromatography
of the filtrate afforded a solid that was dissolved in water and
concentrated in vacuo. The resulting solid was suspended in
acetone, filtered, washed with acetone and ether, and then
dried in vacuo at 60 °C to afford 21 mg (5%) of 185.
(5R)-5-((1R,2R)-2-Ca r boxycyclop r op -1-yl)-5-(2-(3-m eth -
ylp h en yl)eth yl)im id a zolid in e-2,4-d ion e. A solution of 1.0
g (1.9 mmol) of 184 in 60 mL of acetonitrile was added to a
solution of 8.3 g (15.2 mmol) of ceric ammonium nitrate in 20
mL of water, and then this mixture was stirred at room
temperature for 2.5 h. The mixture was diluted with 60 mL
of brine and extracted four times with 20 mL each of ethyl
acetate, and then the combined organics were dried (MgSO4),
filtered, and concentrated in vacuo. Chromatography (50 g of
silica gel, 2% glacial acetic acid/50% ethyl acetate/48% hexane)
of the residue afforded a solid which was recrystallized from
water/acetone. The crystals were filtered, rinsed with water,
and dried in vacuo at 60 °C to afford 0.25 g (42%) of (5R)-5-
((1R,2R)-2-carboxycycloprop-1-yl)-5-(2-(3-methylphenyl)ethyl)-
imidazolidine-2,4-dione.
(2R)-2-Am in o-2-((1R,2R)-2-ca r boxycyclop r op -1-yl)-4-(3-
m eth ylp h en yl)bu ta n oic Acid (186). A solution of 0.53 g
(1.75 mmol) of (5R)-5-((1R,2R)-2-carboxycycloprop-1-yl)-5-(2-
(3-methylphenyl)ethyl)imidazolidine-2,4-dione and 2.8 g (8.8
mmol) of barium hydroxide in 15 mL of water was heated to
250 °C for 16 h in a stainless steel high-pressure reactor. The
mixture was cooled and acidified to pH 2 with concentrated
sulfuric acid. The resulting solution was heated at 90 °C for
1 h, and then the solid was filtered through Celite, washed
three times with 10 mL each of water and three times with
10 mL each of 0.33 N sodium hydroxide, and concentrated in
vacuo to about 10 mL. Cation-exchange chromatography of
the filtrate afforded a solid that was suspended in water,
filtered, washed with water, acetone, and ether, and dried in
vacuo at 60 °C to afford 0.09 g (19%) of 186.
(1S ,2S )-2-((1R ,2S ,5R )-Ca r b om e n t h yloxy)cyclop r op -
1-yl 2,2-Dip h en yleth yl Keton e (187). As for 163, 5.5 g (18
mmol) of 2,2-diphenyl-1-iodoethane and 2.8 g (42.9 mmol) of
zinc/copper couple and then 0.8 g (0.7 mmol) of tetrakis-
(triphenylphosphine)palladium(0) and 4.7 g (16.4 mmol) of
162a in 60 mL of benzene and 8 mL of N,N-dimethylacetamide
afforded 5.2 g (73%) of 187.
(5SR)-5-((1S,2S)-2-Car boxycyclopr op-1-yl)-5-(2,2-diph e-
n yleth yl)im id a zolid in e-2,4-d ion e (188). As for 164, 9.4 g
(21.7 mmol) of 187 and 24 mL of 1 N sodium hydroxide in 50
mL of ethanol and then 7.7 g (119.0 mmol) of potassium
cyanide, 19.5 g (195.0 mmol) of ammonium carbonate, and 24
mL of water afforded 4.0 g (50%) of 188.
(5R)-5-((1S,2S)-2-(((4-Meth oxyben zyl)oxy)ca r bon yl)cy-
clop r op -1-yl)-5-(2,2-d ip h en yleth yl)-3-(4-m eth oxyben zyl)-
im id a zolid in e-2,4-d ion e (189) a n d (5S)-5-((1S,2S)-2-((4-
Meth oxy)ben zyloxy)cyclopr op-1-yl)-5-(2,2-diph en yleth yl)-
3-(4-m eth oxyben zyl)im id a zolid in e-2,4-d ion e (190). As for
165/166, 4.0 g (11.0 mmol) of 187, 3.1 g (30.7 mmol) of
potassium bicarbonate, and 3.9 g (25.2 mmol) of 4-methoxy-
benzyl chloride in 40 mL of DMF afforded 2.0 g (30%) of 189
(higher Rf material) and 2.7 g (41%) of 190 (lower Rf material).
(5R)-5-((1S,2S)-2-Ca r boxycyclop r op -1-yl)-5-(2,2-d ip h e-
n yleth yl)im id a zolid in e-2,4-d ion e. A solution of 1.0 g (1.6
mmol) of 189 in 50 mL of acetonitrile was added to a solution
of 7.2 g (13.2 mmol) of ceric ammonium nitrate in 15 mL of
water, and then this mixture was stirred at room temperature