Cyclopentane Derivatives
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25 4389
tection and catalytic reduction as described for 25 provided
Met h yl (3a S*,5S*,6a S*)-3-Bu t yl-4,5,6,6a -t et r a h yd r o-
3a H-cyclop en ta [d ]isoxa zole-5-ca r boxyla te (31). Further
elution of the reaction mixture from 31 gave 2.0 g (11%) of 32
2
6a and 27a .
1
2
6a . H NMR (DMSO-d
6
): δ 7.8-7.0 (m, 5H), 3.84 (m, 1H),
1
3
3
.6 (s, 3H), 2.9 (m, 1H), 2.12-1.95 (m, 3H), 1.86 and 1.85 (s,
as a yellow oil. H NMR (CDCl
3
): δ 5.00 (m, 1H), 3.62 (s, 3 H),
H), 1.79-1.48 (m, 2H), 1.32-1.20 (m, 5H), 0.86-0.82 (m, 3H).
3.55 (m, 1H), 2.84 (m, 1H), 2.13-2.45 (m, 5H), 2.02 (m, 1H),
-1
IR (NaCl): 3338, 3186, 2958, 1675, 1202, 1137, 1032 cm . MS
1.41-1.63 (m, 2H), 1.27-1.40 (m, 2H), 0.90 (t, J ) 7.0 Hz, 3H).
+
13
(
ES ), m/z: 313.2. Anal. (C15
H
28
N
4
O
3
‚1.5CF
): δ 7.55-6.96 (m, 5H), 3.71 (m,
H), 3.6 (s, 3H), 2.92-2.76 (m, 2H), 2.29-1.90 (m, 3H), 1.80
3
CO
2
H) C, H, N.
C NMR: δ 13.67, 22.40, 25.98, 28.11, 31.93, 38.21, 42.76,
1
51.88, 54.10, 84.94, 160.49, 173.88. IR (neat): 1729, 1216 cm-1
.
2
7a : H NMR (DMSO-d
6
+
1
(
3
MS (ES ), m/z: 225.8. Anal. (C12
H
19NO
3
) C, H, N.
s, 3H), 1.77-1.44 (m, 3H), 1.40-1.18 (m, 5H), 0.86-0.83 (m,
H). IR (NaCl): 3370, 2947, 2833, 1679, 1448, 1203, 1140, 1031
Meth yl (1R*,3S*,4S*)-3-[(1R*)-1-(Acetyla m in o)p en tyl]-
4-h yd r oxycyclop en ta n eca r boxyla te (33a ). To 31 (1.5 g, 6.7
mmol) in methanol (50 mL) were added concentrated HCl (0.6
-1
+
cm . MS (ES ), m/z: 313.3. Anal. (C15
H
28
N
4
O
3
3 2
‚1.75CF CO H)
C, H, N.
mL, 7.2 mmol) and PtO (0.2 g). The mixture was stirred very
2
(
3R*,4R*)-3-[(1R*)-1-(Acet yla m in o)p en t yl]-4-{[a m in o-
im in o)m eth yl]am in o}cyclopen tan ecar boxylic Acid (26b)
a n d (3R*,4R*)-3-[(1S*)-1-(Acetyla m in o)p en tyl]-4-{[a m in o-
im in o)m eth yl]am in o}cyclopen tan ecar boxylic Acid (27b).
The saponification of the esters 26a and 27a provided 26b and
vigorously at 100 psi hydrogen pressure for 4 h. The catalyst
was removed by filtration, and the filtrate was concentrated
to give (()-methyl 3â-(1-aminopentyl)-4â-hydroxycyclopentane-
1R-carboxylate hydrochloride, which was used for acetylation.
To this amine hydrochloride in dichloromethane (20 mL) were
added triethylamine (0.93 mL, 6.7 mmol) and acetic anhydride
(0.67 g, 6.7 mmol) at room temperature. The mixture was
stirred for 2 h, then was washed with water. The water layer
was back-extracted with dichloromethane (20 mL). The com-
bined organic layers were washed with water and brine and
were dried. The filtered solution was then concentrated, and
the residue was purified by flash column chromatography
using hexane/ethyl acetate (1:1) as the eluent. The appropriate
(
(
2
7b.
2
2
+
6b. MS (ES ), m/z: 299.2.
+
7b. MS (ES ), m/z: 299.2.
Ben zyl (1S*,3R*,4R*)-3-[(1S*)-1-(Acetyla m in o)p en tyl]-
-({-[(ter t-bu toxyca r bon yl)a m in o][(ter t-bu toxyca r bon yl)-
im in o]m eth yl}am in o)cyclopen tan ecar boxylate (28a) an d
Ben zyl (1S*,3R*,4R*)-3-[(1R*)-1-(Acetyla m in o)p en tyl]-4-
4
(
{-[(ter t-bu toxyca r bon yl)a m in o][(ter t-bu toxyca r bon yl)-
fractions were pooled together and concentrated to give 1.1 g
im in o]m et h yl}a m in o)cyclop en t a n eca r b oxyla t e (29a ).
These compounds were obtained from 23 by chromatographic
separation of isomers at C-1′, further reducing the alkene of
the isomer A (active) to alkane, converting methyl ester to
benzyl ester through acid, and again separating the isomers
by chromatography at C-1.
2
H),), 8.2 (d, J ) 9.0 Hz, 1H), 7.47-7.26 (m, 5H), 5.1 (q, J )
2 Hz, 2H), 4.12 (m, 1H), 3.91 (m, 1H), 2.99 (m, 1H), 2.27 (m,
H), 2.20 (m, 1H), 2.14 (m, 1H), 1.86 (m, 1H), 1.80 (m, 1H),
.63-1.51 (m, 24H), 0.93-0.83 (m, 6H). IR (KBr): 3437, 3317,
283, 2931, 1736, 1727, 1654, 1616, 1411, 1369, 1061 cm
MS (ES ), m/z: 589.7. Anal. (C31
1
(
(
1
7
)
N.
61%) of 33a as a white solid, mp 137-139 °C. H NMR
CDCl
3
): δ 5.40 (d, J ) 9.4 Hz, 1H), 4.29 (m, 1H), 4.15 (m,
H), 3.68 (s, 3H), 3.15 (m, 1H), 2.90 (m, 1H), 1.90-2.10 (m,
H), 1.80 (m, 1H), 1.70 (m, 1H), 1.45-1.20 (m, 5H), 0.80 (t, J
+
4
6.0 Hz, 3H). MS (ES ), m/z: 272.1. Anal. (C14H25NO ) C, H,
1
8a . H NMR (CDCl
3
): δ 11.4 (s, 1H), 8.4 (d, J ) 9.0 Hz,
1
1
1
1
3
Meth yl (1R*,3S*,4S*)-3-[(1R*)-1-(Acetyla m in o)p en tyl]-
4-m et h a n esu lfon yloxycyclop en t a n eca r b oxyla t e (33b ).
Methanesulfonyl chloride (1.0 mL, 12.9 mmol) and Et N (2.7
3
mL, 19.4 mmol) were added to a mixture of 33a (2.13 g, 7.85
mmol) and 4-(dimethylamino)pyridine (106 mg, 0.87 mmol) in
-
1
.
+
H
48
N
4
O
7
) C, H, N.
dry CH
2 2
Cl (38 mL) at 4 °C. The mixture was stirred at 4 °C
1
for 16 h, then treated with H O (50 mL). The organic layer
2
9a . H NMR (CDCl
3
): δ 11.41 (s, 1H), 8.49 (d, J ) 6.7 Hz,
2
1
1
1
H), 7.95 (d, J ) 9.3 Hz, 1H), 7.33-7.36 (m, 5H), 5.13 (q, J )
0 Hz, 1H), 4.13 (m, 1H), 3.96 (m, 1H), 2.87 (m, 1H), 2.30 (m,
H), 2.05-2.14 (m, 4H), 1.94 (m, 1H), 1.77 (m, 1H), 1.44-1.56
m, 20H), 1.23-1.35 (m, 4H), 0.84-0.86 (m, 4H).
(
b u t oxyca r b on yl)a m in o][(ter t-b u t oxyca r b on yl)im in o]-
m eth yl}a m in o)cyclop en ta n eca r boxylic Acid (28b) a n d
1S*,3R*,4R*)-3-[(1R*)-1-(Acetyla m in o)p en tyl]-4-({-[(ter t-
b u t oxyca r b on yl)a m in o][(ter t-b u t oxyca r b on yl)im in o]-
m eth yl}a m in o)cyclop en ta n eca r boxylic Acid (29b). Hy-
drogenolysis and trifluoroacetic acid treatment of 28a and 29a
was separated, and the aqueous layer was extracted with CH
Cl
(3 × 50 mL). The combined organic extracts were washed
with brine (50 mL), dried, filtered, and concentrated. The
residue was crystallized from Et O/hexane to give 1.1 g (41%)
of 33b as a white solid, mp 128-129 °C. H NMR (CDCl
2
-
2
(
2
1
3
): δ
1S*,3R*,4R*)-3-[(1S*)-1-(Acetylam in o)pen tyl]-4-({-[(ter t-
5
3
4
.15-5.25 (m, 1 H), 4.00-4.15 (m, 1H), 3.65 (s, 3H), 3.04-
.10 (m, 1H), 3.02 (s, 3H), 2.48-2.51 (m, 1H), 2.01-2.21 (m,
H), 1.98 (s, 3H), 1.53-1.80 (m, 2H), 1.20-1.45 (m, 5H), 0.91
t, J ) 6 Hz, 3H). IR (KBr): 3303, 1722, 1649, 1556 cm . MS
(
-
1
(
+
(ES ), m/z: 350.4. Anal. (C15
6
H27NO S) C, H, N.
Meth yl (1R*,3S*,4R*)-3-[(1R*)-1-(Acetyla m in o)p en tyl]-
gave 28b and 29b, respectively.
4-a zid ocyclop en ta n eca r boxyla te (34a ). Sodium azide (2.3
g, 35.4 mmol) was added to a solution of 33b (2.4 g, 6.8 mmol)
in dry DMF (75 mL), and the resulting mixture was heated at
+
2
2
8b. MS (ES ), m/z: 299.4.
9b. MS (ES ), m/z: 299.3.
+
8
0 °C for 3 h. Water (100 mL) was added to the cooled mixture,
Met h yl (3a S*,5R*,6a S*)-3-Bu t yl-4,5,6,6a -t et r a h yd r o-
a H-cyclop en ta [d ]isoxa zole-5-ca r boxyla te (31). A solution
and extraction with EtOAc (3 × 50 mL) followed. The combined
extracts were washed with water (2 × 50 mL) and brine (50
mL) and were dried. After filtration, the filtrate was concen-
trated and the residue was purified by flash column chroma-
tography using 20% CMA-80 in methylene chloride to give 1.74
3
3
of nitropentane (10.8 mL, 87.8 mmol) and Et N (20 drops) in
dry benzene (30 mL) was added to a refluxing solution of
methyl 3-cyclopentenecarboxylate 30 (10.21 g, 80.9 mmol) and
phenyl isocyanate (17.5 mL, 161.0 mmol) in dry benzene (50
mL) over a period of 1 h. The mixture was boiled under reflux
for an additional hour, the diphenylurea was filtered off and
1
g (86%) of 34a as a white solid, mp 67-68 °C. H NMR
(
3
2
3
CDCl ): δ 5.20 (d, J ) 6 Hz, 1 H), 4.05-4.10 (m, 1H), 3.65 (s,
H), 3.50-3.61 (m, 1H), 2.75-2.80 (m, 1H), 2.29-2.39 (m, 1H),
.01 (s, 3H), 1.95-2.13 (m, 3H), 1.58-1.69 (m, 2H), 1.20-1.40
2
washed with Et O (20 mL), and the combined filtrates were
concentrated to yield an orange oil. This crude product was
distilled (Kugelrohr) to remove unreacted phenyl isocyanate.
The remaining mixture was purified by flash chromatography
(
1
m, 5H), 0.90 (t, J ) 6 Hz, 3H). IR (KBr): 3200, 3085, 2091,
-
1
+
24 4 3
737, 1645 cm . MS (ES ), m/z: 297.4. Anal. (C14H N O )
C, H, N.
using a gradient of Et
2
O/hexane to provide fractions homoge-
1
neous in 31 (8.1 g, 45%) as a yellow oil. H NMR (CDCl
3
): δ
.02 (m, 1H), 3.65 (m, 1H), 3.63 (s, 3H), 2.74 (m, 1H), 2.32 (m,
H), 1.98 (m, 1H), 1.85-2.20 (m, 4H), 1.39-1.58 (m, 2H), 1.24-
.38 (m, 2H), 0.83 (t, J ) 7.2 Hz, 3H). C NMR: δ 13.61, 22.31,
5.95, 28.14, 33.53, 39.24, 41.30, 51.78, 53.71, 84.39, 159.50,
74.54. IR (neat): 1729, 1215 cm-1. MS (ES ), m/z: 225.9.
Meth yl (1R*,3R*,4R*)-3-[(1R*)-1-(Acetyla m in o)p en tyl]-
4-a m in ocyclop en ta n eca r boxyla te (34b). Compound 34a
(95 mg, 0.32 mmol) was hydrogenated in methanol (10 mL) in
5
1
1
2
1
1
3
2
the presence of PtO (25 mg) at 48 psi for 2 h. The catalyst
was removed by filtration, and the filtrate was concentrated
to give a crude oil, which was purified by flash column
chromatography using ethyl acetate (50 mL) followed by CMA-
+
3
Anal. (C12H19NO ) C, H, N.