2388 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 12
Portevin et al.
layer was extracted with ether. The organic layers were
combined, washed with water and brine, and dried over
Na2SO4. Concentration under reduced pressure gave a crude
mixture, which was purified by column chromatography
(CH2Cl2-EtOAc, 95:5) to give 340 mg (13%) of the desired
thienyl ketone; 1 g of the starting nitrile was recovered and
recycled: 1H NMR (CDCl3) δ 1.5-2.0 (11H, m), 2.6-2.8 (4H,
m), 3.5 (1H, broad s), 4.3 (1H, broad s), 6.9 (3H, t), 7.0-7.3
(5H, m).
(2S,3aS,7aS)-1-[3-P h en yl-3-(tr iflu or om eth yl)pr opan oyl]-
2-(p yr r olid in -1-ylca r b on yl)p er h yd r oin d ole (isom er r)
(39): IR (Nujol) 1645, 1340 cm-1; 1H NMR (CDCl3) δ 1.0-2.1
(14H, m), 2.3-2.5 (1H, m), 2.6-2.7 (1H, dd), 3.0-3.2 (1H, dd),
3.3-3.7 (3H, m), 3.7-4.0 (2H, m), 4.1-4.3 (1H, m), 4.55 (1H,
t), 7.3-7.4 (5H, broad s).
(2S,3aS,7aS)-1-[3-P h en yl-3-(tr iflu or om eth yl)pr opan oyl]-
2-(p yr r olid in -1-ylca r b on yl)p er h yd r oin d ole (isom er â)
(40): IR (Nujol) 1651, 1342 cm-1; 1H NMR (CDCl3) δ 1.0-2.1
(15H, m), 2.9-3.0 (2H, m), 3.2-3.4 (2H, m), 3.5-3.7 (3H, m),
3.9-4.2 (1H, m), 4.4 (1H, t), 7.3 (5H, broad s).
Gr ou p 3. Syn th esis of 32: Gen er a l P r oced u r e. Step
A: (2S,3a S,7a S)-2-(P yr r olid in -1-ylca r bon yl)p er h yd r oin -
d ole. This compound is prepared from compound 14 according
(2S,3a S,7a S)-1-[3-(Tr iflu or om eth yl)cin n a m oyl]-2-(p yr -
r olidin -1-ylcar bon yl)per h ydr oin dole (41): IR (Nujol) 1655,
1
to Scheme 2: IR (Nujol) 3288, 1631 cm-1; H NMR (CDCl3) δ
1
1645, 1630 cm-1; H NMR (CDCl3) δ 1.0-2.4 (15H, m), 3.2-
1.1-2.3 (15H, m), 2.8 (1H, broad s), 3.1 (1H, m), 3.3-3.7 (4H,
m), 3.85 (1H, q).
3.65 (4H, m), 3.65-3.90 (1H, m), 3.97, 4.03, 4.34 (1H, tt), 6.57,
6.82 (1H, 2s), 703-705 (5H, m).
Step B: (2S,3a S,7a S)-1-(5,5-Dicyclop r op ylp en ta n oyl)-
2-(p yr r olid in -1-ylca r bon yl)p er h yd r oin d ole (32). To the
intermediate obtained above (2.22 g, 0.01 mol) in DMF (40 mL)
was added 1.82 g (0.01 mol) of 5,5-dicyclopropylvaleric acid in
60 mL of DMF followed by 1.55 g (0.01 mol) of HOBT in 40
mL of DMF and 2.06 g (0.01 mol) of DCC in 40 mL of DMF.
The reaction was stirred at room temperature overnight, DCU
was filtered, and the solvent was evaporated. After washing
with aqueous saturated NaHCO3 solution, 10% aqueous citric
acid solution, water, and brine, the organic phase was dried
over CaSO4 and evaporated. Silica gel chromatography (EtOAc)
gave 1.5 g (39%) of the title compound: IR (KBr) 3700-3100,
(2S,3a S,7a S)-1-[(R,S)-4-P h en yl-4-(tr iflu or om eth yl)bu -
t a n o y l]-2-(p y r r o lid in -1-y lc a r b o n y l)p e r h y d r o in d o le
(42): IR (Nujol) 1649, 1635 cm-1; 1H NMR (CDCl3) δ 0.9-2.3
(18H, m), 2.45 (1H, m), 3.4 (4H, m), 3.65 (1H, m), 3.85 (1H,
m), 4.5 (1H, m), 7.3 (5H, m).
(2S,3a S,7a S)-1-[(R,S)-5-P h en yl-5-(tr iflu or om eth yl)p en -
t a n o y l]-2-(p y r r o lid in -1-y lc a r b o n y l)p e r h y d r o in d o le
1
(43): IR (KBr) 1655 cm-1; H NMR (CDCl3) δ 0.8-2.4 (19H,
m), 2.3 (2H, m), 3.1-3.9 (6H, m), 4.5 (1H, m), 7.3 (5H, m).
(2S,3a S,7a S)-1-[(R,S)-5-Cyclop en tyl-5-(tr iflu or om eth -
yl)p en t a n oyl]-2-(p yr r olid in -1-ylca r b on yl)p er h yd r oin -
1
1649 cm-1; H NMR (CDCl3) δ 0.0-0.3 (5H, m), 0.3-0.5 (4H,
1
d ole (44): IR (KBr) 1655 cm-1; H NMR (CDCl3) δ 1.0-2.5
m), 0.5-0.7 (2H, m), 1.1-2.2 (15H, m), 2.2-2.5 (6H, m), 3.3-
3.5 (2H, m), 3.5-4.0 (3H, m), 4.55 (1H, t).
(31H, m), 3.2-4.0 (5H, m), 4.5 (1H, t).
(2S,3a S,7a S)-1-[(tr a n s-2-P h en ylcyclop r op a n -1-yl)ca r -
bon yl]-2-(p yr r olid in -1-ylca r bon yl)p er h yd r oin d oles (51
a n d 52) (Scheme 2). To 2.2 g (0.01 mol) of PHI-pyrrolidine
(obtained from 14 as described in Scheme 2) in 20 mL of CH2-
Cl2 was added at 5 °C 1.7 mL (0.012 mol) of triethylamine,
followed by 1.8 g (0.01 mol) of 2-phenylcyclopropanecarbonyl
chloride in 10 mL of CH2Cl2. After 15 h at room temperature,
the reaction mixture was washed with water, aqueous NaH-
CO3 solution, and brine. Drying over Na2SO4 and concentra-
tion under reduced pressure afforded 4.1 g of a brown oil.
Purification on silica gel (CH2Cl2-EtOAc, 50:50) gave the two
diastereomers 51 and 52.
(3S)-2-Aza -(6,6-d icyclop r op ylh exa n oyl)-3-(p yr r olid in -
1-ylca r bon yl)bicyclo[2.2.2]octa n e (29): IR (KBr) 1650
cm-1; 1H NMR (CDCl3) δ 0.0-0.7 (10H, m), 1.4-2.1 (19H, m),
2.3 (3H, m), 3.3 (2H, m), 3.7 (2H, m), 3.9 (1H, m), 4.5 (1H, m).
(3S)-2-Aza -(5,5-d icyclop r op ylp en ta n oyl)-3-(p yr r olid in -
1-ylca r bon yl)bicyclo[2.2.2]octa n e (30): IR (Nujol) 1651,
1
1633 cm-1; H NMR (CDCl3) δ 0.0-0.5 (9H, m), 0.5-0.7 (2H,
m), 1.4-1.5 (19H, 2m), 3.3-3.5 (2H, m), 3.5-3.85 (2H, m), 3.9
(1H, m), 4.45 (1H, m).
(1S,3S,4R)-2-Aza -(5,5-d icyclop r op ylp en ta n oyl)-3-(p yr -
r olid in -1-ylca r bon yl)bicyclo[2.2.2]h ep ta n e (31): IR (KBr)
1645 cm-1; 1H NMR (CDCl3) δ 0.0-0.7 (10H, m), 1.2-2.1 (15H,
m), 2.3 (2H, t), 2.7 (1H, m), 3.3-3.8 (4H, m), 4.2 (1H, m), 4.5
(1H, m).
(2S,3a S,7a S)-1-(4,4-Dicyclop r op ylbu ta n oyl)-2-(p yr r oli-
d in -1-ylca r bon yl)p er h yd r oin d ole (33): IR (KBr) 1653
cm-1; 1H NMR (CDCl3) δ 0.0-0.7 (11H, m), 1.0-2.2 (16H, m),
2.3 (1H, m), 2.5 (2H, m), 3.3-4.0 (5H, m), 4.5 (1H, t).
(2S,3a S,7a S)-1-(3,3-Dicyclop r op ylp r op ion yl)-2-(p yr r o-
lid in -1-ylca r bon yl)p er h yd r oin d ole (34): IR (Nujol) 1655,
1618 cm-1; 1H NMR (CDCl3) δ 0.0-0.5 (8H, m), 0.55-1.0 (3H,
m), 1.0-2.4 (15H, m), 2.4 (2H, m), 3.3-3.65 (3H, m), 3.9 (2H,
m), 4.5 (1H, t).
51 (isomer S,S): 1.2 g (32%); crystallization from iPr2O; IR
(Nujol) 1657, 1633 cm-1; 1H NMR (DMSO-d6) δ 1.0-2.5 (19H,
m), 3.1-3.7 (4H, m), 4.0-4.1 (1H, m), 4.45 (1H, dt), 7.0-7.3
(5H, m).
52 (isomer R,R): 900 mg (24%); crystallization from pen-
1
tane; IR (Nujol) 1643 cm-1; H NMR (DMSO-d6) δ 0.95-2.4
(19H, m), 3.1-3.7 (4H, m), 3.8-4.0 (1H, m), 4.45-4.8 (1H, 2t),
7.0-7.3 (5H, m).
(4R)-3-[(tr a n s-(S,S)-2-P h en ylcyclopr opan -1-yl)car bon yl]-
4-(p yr r olid in -1-ylca r bon yl)th ia zolid in e (45): IR (Nujol)
1660, 1635 cm-1; 1H NMR (DMSO-d6) δ 1.2-1.4 (2H, 2m), 1.7
(3H, m), 1.9 (2H, m), 2.3 (2H, t), 2.9-3.6 (3H, m), 4.3, 4.9 (2H,
dd), 4.6, 5.2 (2H, dd), 5.0 (1H, t), 7.1-7.4 (5H, m).
(4R)-3-[(tr a n s-(R,R)-2-P h en ylcyclop r op a n -1-yl)ca r bo-
n yl]-4-(p yr r olid in -1-ylca r bon yl)th ia zolid in e (46): IR (Nu-
(2S,3a S,7a S)-1-[3-[(Dicyclop r op ylm et h yl)t h io]p r op i-
on yl]-2-(p yr r olid in -1-ylca r bon yl)p er h yd r oin d ole (35): IR
1
(KBr) 1651 cm-1; H NMR (CDCl3) δ 0.25-0.4 (4H, m), 0.5-
1
jol) 1641 cm-1; H NMR (DMSO-d6) δ 1.2-1.4 (2H, 2m), 1.7
0.7 (4H, m), 0.8-1.0 (2H, m), 1.1-2.4 (16H, m), 2.6 (2H, t),
3.0 (2H, t), 3.3-3.5 (2H, m), 3.5-3.95 (3H, m), 4.55 (1H, t).
(3S)-2-Aza-2-[3-[[(dicyclopr opylm eth yl)am in o]car bon yl]-
p r op ion yl]-3-(p yr r olid in -1-ylca r b on yl)b icyclo[2.2.2]-
(3H, m), 1.9 (2H, m), 2.3 (2H, t), 2.9-3.6 (3H, m), 4.4, 4.8 (2H,
dd), 4.7, 5.0 (2H, dd), 5.25 (1H, t), 7.0-7.3 (5H, m).
(3S)-2-Aza -2-[(tr a n s-(S,S)-2-p h en ylcyclop r op a n -1-yl)-
c a r b o n y l]-3-(p yr r o lid in -1-y lc a r b on y l)b ic yc lo [2.2.2]-
octa n e (47): IR (Nujol) 1647, 1622 cm-1; 1H NMR (CDCl3) δ
1.1-2.0 (15H, m), 2.1-2.4 (1H, m), 2.4-2.6 (1H, m), 3.35 (2H,
m), 3.7 (2H, m), 4.1 (1H, m), 4.45 (1H, m), 7.0-7.3 (5H, m).
(3S)-2-Aza -2-[(tr a n s-(R,R)-2-p h en ylcyclop r op a n -1-yl)-
c a r b o n yl]-3-(p y r r olid in -1-ylc a r b o n yl)b ic y c lo [2.2.2]-
1
octa n e (36): IR (Nujol) 1645 cm-1; H NMR (CDCl3) δ 0.2-
0.6 (8H, m), 0.8-1.0 (2H, m), 1.35-2.6 (15H, m), 2.6-2.8 (2H,
m), 3.0-3.2 (1H, t), 3.3-3.5 (2H, m), 3.55-3.8 (2H, m), 2H,
m), 3.9 (1H, m), 4.45 (1H, m), 6.1 (1H, broad s).
(3S)-2-Aza -2-(6,6-d icyclop r op ylh ex-5-en oyl)-3-(p yr r oli-
d in -1-ylca r bon yl)bicyclo[2.2.2]octa n e (37): IR (KBr) 1653,
1
1630 cm-1; H NMR (CDCl3) δ 0.3-0.8 (8H, m), 0.9 (1H, m),
; 1H NMR (DMSO-d6) δ 1.1-
octa n e (48): IR (Nujol) 1643 cm-1
1.3-2.5 (20H, m), 3.4 (2H, m), 3.7 (2H, m), 3.9 (1H, m), 4.4
(1H, m), 5.1 (1H, t).
2.1 (15H, m), 2.3-2.5 (2H, m), 3.2-3.4 (2H, m), 3.6-3.85 (2H,
m), 4.1 (1H, m), 4.5-4.7 (1H, 2m), 7.1-7.4 (5H, m).
(1S,3S,4R)-2-Aza -2-[(tr a n s-(S,S)-2-p h en ylcyclop r op a n -
1-yl)ca r bon yl]-3-(p yr r olid in -1-ylca r bon yl)bicyclo[2.2.1]-
h ep ta n e (49): IR (Nujol) 1660, 1640 cm-1; 1H NMR (DMSO-
d6) δ 1.0-1.9 (12H, m), 2.1 (1H, m), 2.25 (1H, m), 2.7-2.9 (1H,
m), 3.2-3.6 (4H, m), 4.35, 4.5, 4.65 (2H, 3 broad s), 7.0-7.4
(5H, m).
(3S)-2-Aza -2-(6,6-d icyclop r op ylh ex-4-en oyl)-3-(p yr r oli-
d in -1-ylca r bon yl)bicyclo[2.2.2]octa n e (38): IR (KBr) 1639
1
cm-1; H NMR (CDCl3) δ 0-0.55 (8H, m), 0.65-0.85 (2H, m),
1.2-2.1 (13H, m), 2.1-2.5 (5H, m), 3.3-3.45 (2H, m), 3.6-3.8
(2H, m), 3.85 (1H, broad s), 4.45 (1H, broad s), 5.2-5.5 (2H,
m).