C-10 Analogues of Huperzine A
J. Am. Chem. Soc., Vol. 118, No. 46, 1996 11361
dioxane (2 mL) was added dropwise. After stirring at room temperature
for 20 min, the mixture was refluxed for 3 h. Concentration and flash
chromatography (10% EtOAc in hexanes) gave 0.66 g (89%) of 4 as
a mixture of two diastereoisomers (70/30). Major diastereoisomer (ax-
H, J ) 8.8 Hz), 5.42 (m, 1 H), 5.18 (q, 1 H, J ) 6.6 Hz), 3.89 (s, 3 H),
3.73 (s, 3 H), 3.31 (d, 1 H, J ) 4.6 Hz), 3.10 (m, 2 H), 2.18 (d, 1 H,
J ) 16.9 Hz), 1.68 (d, 3 H, J ) 6.8 Hz), 1.51 (s, 3 H), 1.27 (d, 3 H,
J ) 6.9 Hz).
C(10)Me, less polar): mp 112-113 °C (from hexanes); R
f
0.18 (10%
(11E)-(()-11-Ethylidene-9,10-dihydro-2-methoxy-7,10-dimethyl-
5,9-methanocycloocta[b]pyridine-5(6H)-carboxylic Acid (6). Ester
5 (237 mg, 0.76 mmol, E/Z ) 95/5) was dissolved in 1.8 mL of MeOH/
THF 2:1, and 20% NaOH (0.6 mL) was added. The mixture was heated
under reflux for 26 h. After cooling, the solution was adjusted to pH
5-6 with 5% HCl, and MeOH and THF were evaporated. The aqueous
residue was extracted with EtOAc. The organic layers were washed
with brine, dried, and concentrated. The crude product was purified
by flash chromatography (EtOAc) to give 211 mg (83%) of the acid 6
as colorless prisms. Crystallization from acetone/hexanes afforded 83
mg of the pure major ax-C(10)Me diastereoisomer: mp 220 °C (dec)
f
-1
EtOAc in hexanes); IR (neat) 1741, 1728, 1589, 1479, 1116, 738 cm
;
1
H NMR (CDCl
3
) δ 6.97 (d, 1 H, J ) 8.7 Hz), 6.57 (d, 1 H, J ) 8.7
Hz), 4.76 (m, 1 H), 4.43 (m, 1 H), 3.89 (s, 3 H), 3.79 (s, 3 H), 3.21 (q,
1
2
2
5
H, J ) 7.3 Hz), 3.12 (d, 1 H, J ) 12.2 Hz), 2.72 (m, 2 H), 2.58 (d,
13
H, J ) 13.6 Hz), 1.30 (d, 3 H, J ) 7.0 Hz); C NMR (CDCl
08.3, 171.4, 163.0, 156.1, 138.9, 137.5, 123.5, 115.8, 109.8, 62.3,
4
3.3, 53.1, 52.6, 47.8, 46.8, 43.0, 23.1. Anal. Calcd for C17 19NO :
3
) δ
H
C, 67.77; H, 6.31; N, 4.65. Found: C, 67.90; H, 6.34; N, 4.59. Minor
diastereoisomer (eq-C(10)Me, more polar): R 0.15 (10% EtOAc in
) δ 6.94 (d, 1 H, J ) 7.9 Hz), 6.57 (d, 1 H,
J ) 8.5 Hz), 4.75 (m, 1 H), 4.45 (m, 1 H), 3.89 (s, 3 H), 3.79 (s, 3 H),
.44 (m, 1 H), 3.17 (d, 1 H, J ) 14.2 Hz), 2.84 (m, 2 H), 2.59 (dd, 2
f
1
hexanes); H NMR (CDCl
3
(from EtOAc); R 0.58 (EtOAc); IR (KBr) 2941, 1706, 1599, 1425,
-
1 1
3
746 cm ; H NMR (CDCl ) δ 7.22 (d, 1 H, J ) 8.8 Hz), 6.55 (d, 1 H,
3
1
3
H, J ) 13.8, 2.8 Hz), 1.51 (d, 3 H, J ) 7.6 Hz); C NMR (CDCl
3
) δ
08.1, 171.3, 162.6, 154.9, 139.1, 137.1, 124.4, 115.7, 109.6, 63.1,
3.1, 52.5, 51.1, 48.2, 40.7, 36.5, 15.2.
11Z)-(()-11-Ethylidene-7,8,9,10-tetrahydro-10-methyl-7-meth-
ylene-2-methoxy-5,9-methanocycloocta[b]pyridine-5(6H)-carbox-
ylic Acid Methyl Ester. To a suspension of EtPPh Br (574 mg, 1.55
mmol) in dry THF (5.6 mL) was added n-BuLi (0.72 mL, 1.32 mmol,
.5 M in hexane) within 10 min. The resulting orange-colored
J ) 8.8 Hz), 5.47 (m, 2 H), 3.90 (s, 3 H), 3.34 (d, 1 H, J ) 5.2 Hz),
3.00 (m, 2 H), 2.13 (d, 1 H, J ) 16.9 Hz), 1.72 (d, 3 H, J ) 6.3 Hz),
1.52 (s, 3 H), 1.29 (d, 3 H, J ) 7.0 Hz); 13C NMR δ 179.2, 162.8,
157.4, 137.8, 134.7, 132.2, 126.5, 124.9, 116.6, 108.5, 54.8, 53.3, 45.2,
2
5
(
44.0, 39.3, 22.7, 20.3, 13.2. Anal. Calcd for C18
3
H21NO : C, 72.24;
3
H, 7.02; N, 4.68. Found: C, 72.47; H, 7.19; N, 4.46.
(11E)-(()-[11-Ethylidene-9,10-dihydro-2-methoxy-7,10-dimethyl-
5,9-methanocycloocta[b]pyridin-5(6H)-yl]carbamic Acid Methyl
Ester, Axial Isomer (7a). A mixture of ax-C(10)Me acid 6 (30 mg,
0.1 mmol), dry Et N (13.7 µL, 0.1 mmol), (PhO) P(O)N (21.3 µL,
2
suspension was stirred at room temperature for 70 min. After cooling
to 0 °C, a solution of â-ketoester 4 (100 mg, 0.33 mmol) in dry THF
3
2
3
(1.5 mL) was slowly added over a period of 15 min. The resulting
0.1 mmol), and dry toluene (0.36 mL) was heated at 85 °C for 3 h.
After cooling, the solvent was removed, and the residue was dissolved
in dry MeOH (0.36 mL). The resulting solution was heated under reflux
for 18 h. Evaporation and flash chromatography (10% EtOAc in
CH Cl ) gave the urethane 7a (27 mg, 82%) as a colorless solid: mp
mixture was allowed to warm to room temperature and stirred at room
temperature for 2 h. The reaction was quenched with water, the THF
was removed by rotary evaporation, and the aqueous residue was
extracted with EtOAc. The organic layers were washed with brine,
dried, and concentrated. Flash chromatography of the residue (20%
EtOAc in hexanes) gave 245 mg (79%) of the olefin as a colorless oil
which was a mixture of diastereoisomers (E/Z ) 10/90). Major
2
2
173-174 °C (from hexanes); R 0.29 (10% EtOAc in CH Cl ); IR (KBr)
f
2
2
-
1 1
3325, 1712, 1599, 1531, 1475, 1041 cm ; H NMR (CDCl ) δ 7.51
3
(d, 1 H, J ) 8.6 Hz), 6.52 (d, 1 H, J ) 8.8 Hz), 5.53 (q, 1 H, J ) 6.8
Hz), 5.48 (m, 1 H), 4.99 (s, 1 H), 3.88 (s, 3 H), 3.61 (s, 3 H), 3.38 (d,
1 H, J ) 4.8 Hz), 2.94 (dq, 1 H, J ) 5.4, 1.4 Hz), 2.49 (d, 1 H, J )
13.4 Hz), 2.15 (d, 1 H, J ) 15.5 Hz), 1.71 (d, 3 H, J ) 6.8 Hz), 1.49
diastereoisomer (less polar): R
f
0.49 (20% EtOAc in hexanes); IR (neat)
-
1 1
2
6
)
2
945, 1730, 1661, 1601, 1578 cm ; H NMR ((Z)-olefin, CDCl
.83 (d, 1 H, J ) 8.8 Hz), 6.41 (d, 1 H, J ) 7.9 Hz), 5.49 (q, 1 H, J
7.6 Hz), 4.47 (m, 1 H), 4.19 (m, 1 H), 3.83 (s, 3 H), 3.67 (s, 3 H),
3
) δ
+
(s, 3 H), 1.27 (d, 3 H, J ) 6.9 Hz); MS m/z 328 (48%, M ), 313, 281,
.73 (d, 1 H, J ) 7.3 Hz), 2.53 (m, 1 H), 2.38 (m, 2 H), 2.10 (s, 2 H),
.51 (d, 3 H, J ) 7.0 Hz), 1.31 (d, 3 H, J ) 7.1 Hz). Anal. Calcd for
C H23NO : C, 72.84; H, 7.35; N, 4.47. Found: C, 73.03; H, 7.41; N,
19 3
253, 238 (100%), 224. Anal. Calcd for C H N O : C, 69.49; H,
19
24
2
3
1
7.37; N, 8.53. Found: C, 69.77; H, 7.52; N, 8.66.
11E)-(()-5-Amino-11-ethylidene-5,6,9,10-tetrahydro-7,10-di-
methyl-5,9-methanocycloocta[b]pyridin-2(1H)-one, Axial Isomer
(8a). Me SiI (94 µL, 0.67 mmol) was added to a solution of carbamate
7a (22 mg, 0.067 mmol) in dry CHCl (2.4 mL) at room temperature,
(
4
.59.
11Z)-(()-11-Ethylidene-9,10-dihydro-2-methoxy-7,10-dimethyl-
,9-methanocycloocta[b]pyridine-5(6H)-carboxylic Acid Methyl Es-
SO
46 µL, 0.055 mmol), and dry dioxane (0.3 mL) was heated at 93 °C
in a resealable tube for 12 h. The solvent was removed, and the residue
was partitioned between aqueous NaHCO and EtOAc. The organic
(
3
5
3
ter. A mixture of the above olefin (11 mg, 0.035 mmol), CF
(
3
3
H
and the solution was refluxed for 6 h. After cooling and evaporation,
the residue was dissolved in MeOH (2.4 mL), and the solution refluxed
for 18 h. Evaporation of the solvent afforded a residue which was
3
partitioned between 10% NaHCO
layers were washed with brine, dried, and concentrated. Flash
chromatography (15% MeOH in CHCl ) gave 15 mg (88%) of 8a as
colorless prisms: mp 289-290 °C (EtOAc); R 0.22 (15% MeOH in
); IR (KBr) 3420, 1656, 1618 cm ; H NMR (CDCl ) δ 7.87
3 3
solution and CHCl . The organic
phase was washed with brine, dried, and filtered. Concentration and
flash chromatography (20% EtOAc in hexanes) gave 10 mg (91%) of
the title compound as a colorless oil which was a mixture of
3
f
-
1 1
diastereoisomers. Major diastereoisomer: R
hexanes); IR (neat) 1730, 1661, 1601, 1578 cm ; H NMR ((Z)-olefin,
f
-
0.46 (20% EtOAc in
CHCl
3
3
1 1
(d, 1 H, J ) 9.0 Hz), 6.42 (d, 1 H, J ) 9.7 Hz), 5.66 (q, 1 H, J ) 6.8
Hz), 5.43 (d, 1 H, J ) 5.1 Hz), 3.30 (d, 1 H, J ) 5.1 Hz), 2.93 (br q,
1 H, J ) 6.4 Hz), 2.08 (s, 2 H), 1.70 (d, 3 H, J ) 6.7 Hz), 1.52 (s, 3
H), 1.26 (d, 3 H, J ) 7.1 Hz); a better resolved signal for 10-H was
CDC l
3
) δ 7.02 (d, 1 H, J ) 8.7 Hz), 6.44 (d, 1 H, J ) 8.3 Hz), 5.28
(m, 2 H), 3.83 (s, 3 H), 3.62 (s, 3 H), 3.03 (m, 1 H), 2.85 (m, 1 H),
2
)
C
.63 (d, 1 H, J ) 4.7 Hz), 2.16 (d, 1 H, J ) 11.3 Hz), 1.46 (d, 3 H, J
6.8 Hz), 1.41 (s, 3 H), 1.22 (d, 3 H, J ) 6.9 Hz). Anal. Calcd for
: C, 72.84; H, 7.35; N, 4.47. Found: C, 72.87; H, 7.29; N,
1
3
obtained in CDCl
NMR (CDCl ) δ 165.5, 147.6, 140.4, 140.3, 133.7, 124.7, 121.4, 117.4,
113.1, 54.6, 49.7, 40.5, 40.1, 22.5, 20.0, 13.0; C NMR (CD
3 3
/CD OD 1:1: δ 2.70 (dq, 1 H, J ) 6.8, 1.3 Hz); C
19
H23NO
3
3
13
4
.41.
11E)-(()-11-Ethylidene-9,10-dihydro-2-methoxy-7,10-dimethyl-
,9-methanocycloocta[b]pyridine-5(6H)-carboxylic Acid Methyl Es-
3
OD) δ
(
165.9, 148.8, 141.9, 139.7, 135.0, 125.6, 123.7, 118.1, 115.0, 55.5,
+
5
41.8, 40.9, 22.6, 20.2, 13.2; MS m/z 256 (82%, M ), 241 (100%), 227,
ter (5). To a solution of the above olefin mixture (E/Z ) 10/90, 270
mg, 0.86 mmol) in dry toluene (1.9 mL) were added AIBN (105 mg,
226, 211, 201, 174, 161. Anal. Calcd for C16
20 2
H N O: C, 74.97; H,
7.86; N, 10.93. Found: C, 75.22; H, 8.00; N, 10.92.
0
.62 mmol) and PhSH (134 µL, 1.29 mmol). The resulting solution
was heated at 85 °C for 21.5 h. Evaporation of the solvent afforded a
residue which was dissolved in CH
Cl , washed with brine, and dried.
(11E)-(()-[11-Ethylidene-9,10-dihydro-2-methoxy-7,10-dimethyl-
5,9-methanocycloocta[b]pyridin-5(6H)-yl]carbamic Acid Methyl
Ester, Equatorial Isomer (7b). Starting from the stereoisomeric
mixture of carboxylic acids 6, a stereoisomeric mixture of methyl
carbamates was obtained following the same procedure as above. From
this mixture, 7b was isolated in 28% yield by crystallization from
2
2
After concentration, the crude product was chromatographed (15%
EtOAc in hexanes) to afford 237 mg (88%) of 5 as a colorless oil,
which by H NMR analysis consisted of a 95/5 mixture of the (E)- and
1
(
Z)-alkenes. Major diastereoisomer: R
f
0.42 (15% EtOAc in hexanes);
hexane: colorless prisms, mp 189-190 °C (hexane); R
f
0.31 (10%
1
-1 1
H NMR ((E)-olefin, CDCl
3
) δ 7.05 (d, 1 H, J ) 8.1 Hz), 6.50 (d, 1
2 2
EtOAc in CH Cl ); IR (KBr) 1715, 1601, 1531, 1028 cm ; H NMR