Easy access to 4-substituted (±)-huperzine a analogues

Article abstract of DOI:10.1081/SCC-100106212

Condensation of the readily available 7-methylbicyclo[3.3.1]-non-6-en-3-one with dimethyl acetylenedicarboxylate and ammonia or with acetylenedicarboxamide gave a 4-carboxamido (±)-huperzine A analogue, from which other analogues were easily prepared.

Full text of DOI:10.1081/SCC-100106212

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EASY ACCESS TO 4-SUBSTITUTED (±)-HUPERZINE A
ANALOGUES
Pelayo Camps a , Diego Muñoz-Torrero a & Montserrat Simon a
a Universitat de Barcelona, Laboratori de Química Farmacèutica, Facultat de Farmàcia,
Av. Diagonal 643, Barcelona, E-08028, Spain
Published online: 22 Aug 2006.
To cite this article: Pelayo Camps , Diego Muñoz-Torrero & Montserrat Simon (2001): EASY ACCESS TO 4-SUBSTITUTED (±)-
HUPERZINE A ANALOGUES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:22, 3507-3516
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SYNTHETIC COMMUNICATIONS, 31(22), 3507–3516 (2001)
EASY ACCESS TO 4-SUBSTITUTED
(S)-HUPERZINE A ANALOGUES
Pelayo Camps,* Diego Munoz-Torrero,
and Montserrat Simon
Laboratori de Quımica Farmaceutica,
Facultat de Farmacia, Universitat de Barcelona,
Av. Diagonal 643, E-08028, Barcelona, Spain
ABSTRACT
Condensation of the readily available 7-methylbicyclo[3.3.1]-
non-6-en-3-one with dimethyl acetylenedicarboxylate and
ammonia or with acetylenedicarboxamide gave a 4-carboxa-
mido (ꢀ)-huperzine A analogue, from which other analogues
were easily prepared.
(ꢀ)-Huperzine A, 1, a lycopodium alkaloid isolated from the club
moss Huperzia serrata (Thunb.) Trev. ¼ Lycopodium serratum Thunb. and
a Chinese traditional medicine,1,2 is a potent and selective reversible inhibi-
tor of acetylcholinesterase (AChE) which appears to be superior to other
AChE inhibitors such as tacrine, physostigmine or galanthamine, because of
its comparatively longer duration of action and higher therapeutic index.3–5
The scarcity of huperzine A from natural sources induced several groups
to develop synthetic routes to this compound and to prepare numerous
*Corresponding author. E-mail: camps@farmacia.far.ub.es
3507
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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CAMPS, MUNOZ-TORRERO, AND SIMON
huperzine A analogues.3–5 To the best of our knowledge, the sole analogues
which can rival the activity of the parent compound are the C-10 axial
methylated, the 10,10-dimethylated, and the 10-spirocyclopropyl deriva-
tives.3 We have recently published the synthesis of an 11-unsubstituted6
and a 7-ethyl7 (ꢀ)-huperzine A analogues (7 and 2, respectively) which
showed to be less active than the lead compound. Although, the 5-amino
substituent in huperzine A analogues seems to be an essential feature for a
high AChE inhibitory activity, the synthesis of huperzine A derivatives in
which the 5-amino substituent has been replaced by polar groups, such as
OH, F or OAc (3–5) has been recently described (Figure 1).8 These huper-
zine A analogues may retain part of the polar interactions with the active
site of AChE in which the amino group of huperzine A is involved. In
fact, all of them showed to be AChE inhibitors although their activities
are low. More recently, a multi-step synthesis of a (ꢀ)-5-desamino-huper-
zine A analogue, 6, has been described,9 although its activity was not
reported (Figure 1).
To the best of our knowledge, no huperzine A analogues substituted
at the pyridone ring have been described yet. Compounds substituted at
position 4 with polar groups could also retain part of the interactions of
the amino group of huperzine A with the active site of the enzyme, thus
showing AChE inhibitory activity.
Herein we describe a straightforward synthesis of a 5-desamino-11-
desethylidene-4-carbamoyl (ꢀ)-huperzine A analogue, 13, and the related
derivatives 15–17, as well as the 4-unsubstituted model compound 9
(Schemes 1 and 2).
The synthesis of the model compound 9 was envisaged by conden-
sation of the readily available 7-methylbicyclo[3.3.1]non-6-en-3-one,10 8,
with ethyl propiolate and ammonia in methanol as described by
Kozikowski et al.11 in a related case starting from the symmetrical 4,4-ethy-
lidenedioxycyclohexanone. We have recently applied this procedure for the
synthesis of the (ꢀ)-huperzine A analogues 2 and 7. However, in both cases,
the reaction of the corresponding non-symmetrical starting ketone [methyl
Figure 1. Structure of (À)-huperzine A, 1, and several analogues.

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4-SUBSTITUTED (S)-HUPERZINE A ANALOGUES
3509
Scheme 1.
Scheme 2.

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CAMPS, MUNOZ-TORRERO, AND SIMON
N-{3-methyl-7-oxobicyclo[3.3.1]non-3-en-l-yl}carbamate and methyl (E )-N-
{3-ethyl-9-ethylidene-7-oxobicyclo[3.3.1]non-3-en-l-yl}carbamate] with ethyl
propiolate and ammonia was not regioselective. Moreover, the separation of
the resulting regioisomeric pyridones turned out to be a difficult task. The
lack of regioselectivity in the above cases was ascribed to the steric
hindrance of the bridgehead substituent which difficults the approach of
the Michael acceptor (ethyl propiolate or propiolamide) to the intermediate
enamine (Michael donor).
When ketone 8 was reacted with ethyl propiolate and ammonia in
methanol at 100ꢁC in a pressure flask for 16 h, 9 was obtained in 27%
yield. From this reaction, methyl 1,4-dihydro-4-oxopyridine-3-carboxy-
late,12 10, was isolated as a by-product (15% yield from ethyl propiolate).
The formation of this by-product might be explained by a double Michael
addition of ammonia to ethyl propiolate followed by Dieckmann condensa-
tion, and transesterification. Worthy of note, only the anti-pyridone 9 was
isolated. In the key-step of the formation of 9, the enamine derived from 8
and ammonia would react with ethyl propiolate or propiolamide, the
lactame function being formed later from the Michael adduct. The regiose-
lective formation of 9 might be due to the greater stability of the intermedi-
ate anti-enamine that directs the subsequent Michael addition at the
unhindered position 2. Mulzer et al.9 described the failure of the attempted
condensation of 9,9-ethylenedioxy-7-methylenebicyclo[3.3.1]nonan-3-one
with methyl propiolate and ammonia to give the corresponding pyridone
under Kozikowski’s conditions. This failure must be related to the 1,3-dia-
xial steric interaction between the methyl propiolate and one of the ketal
oxygen atoms in the transition state of the Michael reaction, a kind of
interaction that is absent in the conversion of 8 to 9.
In a modification of the above procedure, ketone 8 was transformed
into the corresponding pyrrolidine enamine, 11, whose NMR data were
consistent for the anti-stereoisomer. Condensation of this enamine with
propiolamide13 in refluxing benzene gave 9 in 26% yield (33% yield,
taking into account the recovered starting 8). Also a significant amount of
the (E )-3-pyrrolidinoacrylamide,14 12, (50% yield from the starting pyrro-
lidine) was isolated.
In order to prepare huperzine A analogues substituted at the 4
position, ketone 8 was reacted with dimethyl acetylenedicarboxylate and
ammonia in methanol under similar conditions to those used to prepare
9, pyridone carboxamide 13 being obtained in 27% yield. A substantial
amount of methyl (Z )-2-amino-3-carbamoylacrylate,15 14, (55% yield
from dimethyl acetylenedicarboxylate) was isolated from this reaction. To
preclude formation of this by-product, freshly prepared pyrrolidine enamine
11 was reacted with acetylenedicarboxamide, obtaining compound 13 in

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4-SUBSTITUTED (S)-HUPERZINE A ANALOGUES
3511
17% yield. Although the yields of these transformations are low, they allow
a direct access to a new kind of huperzine A analogues, substituted at
position 4 with polar groups from readily available starting materials. In
fact, compound 13 could be easily transformed into other 4-substituted
huperzine A analogues, such as compounds 15–17 by standard procedures.
Thus, reaction of 13 with P2O5 in refluxing xylene afforded nitrile 15 in 74%
yield (92% yield based on reacted 13). Also, reaction of 13 with ethanol and
HCl (g) gave ester 16 in 72% yield (85% yield based on reacted 13). Finally,
ester 16 was transformed into methyl amide 17 on reaction with aqueous
methylamine (80% yield).
In conclusion, the Kozikowski0s pyridone synthesis has been success-
fully applied to the regioselective preparation of the 5-desamino-11-desethy-
lidene (ꢀ)-huperzine A analogue 9. An extension of the above procedure
using dimethyl acetylenedicarboxylate and ammonia or acetylenedicarbox-
amide has allowed for the first time the regioselective synthesis of the
(ꢀ)-4-carbamoyl-huperzine A analogue 13, from which other huperzine A
analogues substituted at position 4 with polar groups such as 15–17 have
been prepared. The polar groups at position 4 of these compounds could
mimic part of the interactions of the amino group of huperzine A with the
active site of AChE. Consequently, compounds 13 and 15–17 could show
AChE inhibitory activity, a matter which is under study.
EXPERIMENTAL
General. Melting points were determined with a MFB 595010 M
1
Gallenkamp melting point apparatus. 500 MHz H NMR spectra were per-
formed on a Varian VXR 500 spectrometer, 300 MHz 1H NMR and
75.4 MHz 13C NMR spectra were taken on a Varian Gemini 300, and
1
200 MHz H NMR and 50.3MHz 13C NMR spectra were carried out on a
Varian Gemini 200. Chemical shifts (d) are reported in ppm related to
internal tetramethylsilane (TMS). Assignments given for the NMR spectra
are based on DEPT, 1H/1H and 1H/13C COSY experiments (HMQC
sequence). IR spectra were recorded on a FT/IR Perkin–Elmer spectro-
meter, model 1600. Silica gel SDS 60 (60–200 mm) was utilized for the
column chromatography. Elemental analyses were carried out at the
´
Microanalysis Service of the Centro de Investigacion y Desarrollo (C.I.D.),
C.S.I.C., Barcelona, Spain. All new compounds herein described are race-
mic, although this is not indicated neither in their names nor in their
numbering.
5,6,9,10-Tetrahydro-7-methyl-1H-5,9-methanocycloocta[e]pyridin-2-one
(9). Method A: A mixture of enone 8 (300 mg, 2.00 mmol), ethyl propiolate

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CAMPS, MUNOZ-TORRERO, AND SIMON
(0.60 mL, 0.58 g, 5.92 mmol) and a 3M methanolic NH3 solution (25 mL)
was heated at 100ꢁC in a pressure flask overnight. The mixture was cooled to
room temperature and evaporated at reduced pressure. The resulting black
solid residue (1.29 g) was submitted to column chromatography through
silica gel using hexane/AcOEt mixtures as eluent. On elution with hexane/
AcOEt in the ratio of 50 : 50, methyl 1,4-dihydro-4-oxopyridine-3-carboxy-
late,12 10, (140 mg, 15% yield from ethyl propiolate) was obtained. On
elution with AcOEt, impure 9 (390 mg) was obtained. After a second chro-
matographic purification of the above product, pure 9 (109 mg, 27% yield)
was obtained.
Spectroscopic and analytical data of 9: Mp 252–256ꢁC (AcOEt). IR
(KBr) n: 1660 (C¼O st), 1622 (C¼C st) cmꢂ1. 1H NMR (500 MHz, CD3OD)
d: 1.57 (s, 3H, 7-CH3), 1.77–1.90 (complex signal, 3H, 6-Hendo, 11-Hanti
and 11-Hsyn), 2.43(complex signal, 2H, 6-H exo and 10-Hendo), 2.61 (m,
1H, 9-H), 2.78 (dd, J ¼ 17.0 Hz, J0 ¼ 5.0 Hz, 1H, 10-Hexo), 2.94 (m, 1H, 5-
H), 4.88 (H2O and NH), 5.49 (d, J ¼ 4.0 Hz, 1H, 8-H), 6.33 (d, J ¼ 9.0 Hz,
1H, 3-H), 7.41 (d, J ¼ 9.0 Hz, 1H, 4-H). 13C NMR (50.3MHz, CDCl 3) d:
23.4 (CH3, 7-CH3), 27.2 (CH, C9), 28.4 (CH2, C11), 30.3 (CH, C5), 33.4
(CH2, C10), 38.0 (CH2, C6), 116.7 (CH, C3), 119.5 (C, C4a), 124.8 (CH,
C8), 132.2 (C, C7), 142.8 (C, C10a), 143.4 (CH, C4), 165.3 (C, C2). Anal.
calcd. for C13H15NO: C 77.58; H 7.51; N 6.96. Found: C 77.42; H 7.51; N
6.93.
1H NMR (200 MHz, CDCl3) data of 10, d: 3.90 (s, 3H, COOCH3),
6.61 (d, J ¼ 9.5 Hz, 1H, 5-H), 8.04 (dd, J ¼ 9.5 Hz, J 0 ¼ 2.5 Hz, 1H, 6-H),
8.25 (d, J ¼ 2.5 Hz, 1H, 2-H).
Method B: A mixture of enone 8 (430 mg, 2.87 mmol), 4 A molecular
sieves (1.00 g), pyrrolidine (0.30 mL, 0.26 g, 3.59 mmol) and anhydrous ben-
zene (30 mL) was heated under reflux for 5 h. The mixture was allowed to
cool to room temperature and was filtered under argon. The filtrate contain-
ing the enamine 11 was treated with propiolamide (430 mg, 6.23 mmol), and
the reaction mixture was heated under reflux for 1.5 h. The resulting suspen-
sion was allowed to cool to room temperature and was filtered. The filtrate
was evaporated in vacuo to give a residue which was submitted to column
chromatography through silica gel under the above described conditions,
obtaining starting enone 8 (90 mg) and pure 9 (150 mg, 26% yield, 33% yield
from reacted 8). The solid separated in the filtration was extracted with
MeOH. Evaporation of the solvent from the organic extract in vacuo
afforded (E)-3-pyrrolidinoacrylamide,14 12 (250 mg, 50% yield from pyrro-
lidine).
In another operation of method B, the dried benzene solution of the
enamine was concentrated in vacuo obtaining 11 as a yellow oil (79% yield),
which was analyzed without further purification. IR (KBr) n: 1634

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4-SUBSTITUTED (S)-HUPERZINE A ANALOGUES
3513
(C¼C st) cmꢂ1. 1H NMR (300 MHz, CDCl3) d: 1.62 (complex signal, 5H, 7-
CH3, 9-Hanti and 9-Hsyn), 1.69 (d, J ¼ 17.1 Hz, 1H, 8-Hendo), 1.83[m, 4H,
pyrrolidine 3(4)-H2], 2.05 (d, J ¼ 16.1 Hz, 1H, 4-Hendo), 2.20 (broad d,
J ¼ 17.1 Hz, 1H, 8-Hexo), 2.37 (dd, J ¼ 16.1 Hz, J 0 ¼ 4.8 Hz, 1H, 4-Hexo),
2.47 (m, 1H) and 2.55 (m, 1H) (1-H and 5-H), 2.97 [m, 4H, pyrrolidine 2(5)-
H2], 4.29 (d, J ¼ 5.8 Hz, 1H, 2-H), 5.45 (m, 1H, 6-H). 13C NMR (75.4 MHz,
CDCl3) d: 24.4 (CH3, 7-CH3), 25.1 [CH2, pyrrolidine C3(4)], 28.5 (CH) and
29.1 (CH) (C1 and C5), 30.0 (CH2, C9), 34.0 (CH2, C4), 38.7 (CH2, C8), 48.0
[CH2, pyrrolidine C2(5)], 99.0 (CH, C2), 125.8 (CH, C6), 133.2 (C, C7),
142.4 (C, C3).
1,2,5,6,9,10-Hexahydro-7-methyl-2-oxo-5,9-methanocycloocta[e]pyri-
dine-4-carboxamide (13). Method A: It was prepared as described above
under method A, starting from enone 8 (500 mg, 3.33 mmol), dimethyl
acetylenedicarboxylate (0.81 mL, 0.94 g, 6.59 mmol) and a 3M methanolic
NH3 solution (20 mL). The mixture was cooled to room temperature and
evaporated at reduced pressure. The resulting black solid residue (1.53g)
was submitted to column chromatography through silica gel using hexane/
AcOEt/MeOH mixtures as eluent. In order of elution, methyl (Z)-2-amino-
3-carbamoylacrylate,15 14, (520 mg, 55% yield based on dimethyl acetylene-
dicarboxylate) and compound 13 (220 mg, 27% yield) were obtained.
Spectroscopic and analytical data of 13: Mp 288–292ꢁC (dec., AcOEt/
MeOH). IR (KBr) n: 3293 and 3103 (NH st), 1661 and 1644 (C¼O st),
1
1607 (C¼C st) cmꢂ1. H NMR (500 MHz, DMSO-d6) d: 1.51 (s, 3H, 7-
CH3), 1.61 (broad d, J ¼ 12.0 Hz, 1H) and 1.66 (broad d, J ¼ 12.0 Hz, 1H)
(11-Hanti and 11-Hsyn), 1.88 (d, J ¼ 17.5 Hz, 1H, 6-Hendo), 2.19 (dd,
J ¼ 17.5 Hz, J 0 ¼ 4.5 Hz, 1H, 6-Hexo), 2.32 (d, J ¼ 17.5 Hz, 1H, 10-
Hendo), 2.49 (m, 1H, 9-H), 2.66 (dd, J ¼ 17.5 Hz, J 0 ¼ 5.5 Hz, 1H, 10-
Hexo), 3.15 (m, 1H, 5-H), 5.44 (d, J ¼ 5.0 Hz, 1H, 8-H), 6.00 (s, 1H, 3-H),
7.52 (s, 1H) and 7.90 (s, 1H) (CONH2), 11.44 (s, 1H, 1-H). 13C NMR
(50.3MHz, DMSO-d 6) d: 23.5 (CH3, 7-CH3), 26.3(CH, C5), 26.7 (CH,
C9), 28.3(CH , C11), 33.6 (CH2, C10), 37.5 (CH2, C6), 113.6 (C, C4a),
2
114.6 (CH, C3), 124.9 (CH, C8), 132.3 (C, C7), 143.4 (C, C10a), 150.4 (C,
C4), 162.2 (C, C2), 169.3(C, CONH 2). Anal. calcd. for
C14H16N2O2 ꢃ 1=5H2O: C 67.83; H 6.67; N 11.30. Found: C 67.98; H 6.51;
N 11.30.
Method B: The same procedure described above under method B
was followed, starting from enone 8 (500 mg, 3.33 mmol), 4 A molecular
sieves (1.60 g), pyrrolidine (0.40 mL, 0.34 g, 4.79 mmol) and anhydrous
benzene (30 mL). The mixture was allowed to cool to room temperature
and was filtered under argon. The filtrate containing the enamine 11 was
treated with acetylenedicarboxamide (910 mg, 8.12 mmol), and the reaction
mixture was heated under reflux for 2 h. The resulting suspension was

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CAMPS, MUNOZ-TORRERO, AND SIMON
allowed to cool to room temperature and was filtered. The filtrate was
evaporated in vacuo to give a residue (0.62 g) which was submitted to
column chromatography through silica gel under the above described con-
ditions, affording 13 (20 mg). The solid separated in the filtration was con-
tinuously extracted with AcOEt (70 mL) for 18 h. Evaporation of the solvent
from the organic phase at reduced pressure afforded pure 13 (120 mg, 17%
total yield).
1,2,5,6,9,10-Hexahydro-7-methyl-2-oxo-5,9-methanocycloocta[e]pyri-
dine-4-carbonitrile (15). A suspension of compound 13 (250 mg, 1.02 mmol)
and P2O5 (600 mg, 4.22 mmol) in xylene (40 mL) was heated under reflux for
2 h. The mixture was cooled to room temperature and evaporated at reduced
pressure. The resulting residue was treated with CH2Cl2 (50 mL) and
neutralized with aqueous saturated Na2CO3. The organic phase was
separated and the aqueous one was extracted with CH2Cl2 (5 ꢄ 50 mL).
The combined organic extracts were dried with anhydrous Na2SO4 and
evaporated at reduced pressure to afford pure nitrile 15 (170 mg, 74%
yield). On extraction of the aqueous layer with AcOEt, starting amide 13
(50 mg) was recovered. Spectroscopic and analytical data of 15: Mp
224–226ꢁC (dec., AcOEt). IR (KBr) n: 2234 (CN st), 1665 (C¼O st), 1621
1
(C¼C st) cmꢂ1. H NMR (300 MHz, CDCl3) d: 1.59 (s, 3H, 7-CH3), 1.76
(dm, J ¼ 12.6 Hz, 1H) and 1.93(complex signal, 2H) (6-H endo, 11-Hanti and
11-Hsyn), 2.50 (dd, J ¼ 17.6 Hz, J 0 ¼ 4.5 Hz, 1H, 6-Hexo), 2.61 (d,
J ¼ 17.8 Hz, 1H, 10-Hendo), 2.67 (m, 1H, 9-H), 2.86 (dd, J ¼ 17.8 Hz,
J 0 ¼ 5.4 Hz, 1H, 10-Hexo), 3.24 (m, 1H, 5-H), 5.47 (broad d, J ¼ 4.6 Hz,
1H, 8-H), 6.75 (s, 1H, 3-H), 1-H was not observed. 13C NMR (75.4 MHz,
CDCl3) d: 23.3 (CH3, 7-CH3), 26.8 (CH, C5), 28.0 (CH2, C11), 28.9 (CH,
C9), 33.7 (CH2, C10), 37.1 (CH2, C6), 115.1 (C, CN), 118.8 (C, C4a), 122.7
(CH, C3), 124.3 (CH, C8), 126.8 (C, C4), 132.7 (C, C7), 146.0 (C, C10a),
163.5 (C, C2). Anal. calcd. for C14H14N2O: C 74.31; H 6.24; N 12.38.
Found: C 74.21; H 6.31; N 12.23.
Ethyl 1,2,5,6,9,10-Hexahydro-7-methyl-2-oxo-5,9-methanocycloocta[e]-
pyridine-4-carboxylate (16). HCl (g) was bubbled through a refluxing
solution of amide 13 (310 mg, 1.27 mmol) in absolute EtOH for 1 h, and
the reaction mixture was heated under reflux for 48 h. The mixture
was allowed to cool to room temperature and was evaporated at reduced
pressure. The resulting residue was diluted with water and neutralized
with aqueous saturated Na2CO3. The aqueous solution was extracted with
CH2Cl2 (5 ꢄ 25 mL), and the combined organic extracts were dried with
anhydrous Na2SO4 and evaporated at reduced pressure to afford pure
ester 16 (250 mg, 72% yield). On extraction of the aqueous layer with
AcOEt (5 ꢄ 25 mL), starting amide 13 (50 mg) was recovered.
Spectroscopic and analytical data of 16: Mp 180–185ꢁC (hexane/AcOEt).

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4-SUBSTITUTED (S)-HUPERZINE A ANALOGUES
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IR (KBr) n: 1708 and 1655 (C¼O st), 1595 (C¼C st) cmꢂ1
.
1H NMR
(200 MHz, CDCl3) d: 1.39 (t, J ¼ 7.2 Hz, 3H, OCH2CH3), 1.58 (s, 3H,
7-CH3), 1.60–1.90 (complex signal, 2H, 11-Hanti and 11-Hsyn), 1.93(d,
J ¼ 17.7 Hz, 1H, 6-Hendo), 2.40 (dd, J ¼ 17.7 Hz, J 0 ¼ 4.7 Hz, 1H, 6-
Hexo), 2.63(m, 1H, 9-H), 2.64 (d, J ¼ 17.6 Hz, 1H, 10-Hendo), 2.90 (dd,
J ¼ 17.6 Hz, J 0 ¼ 5.5 Hz, 1H, 10-Hexo), 3.48 (m, 1H, 5-H), 4.37 (q,
J ¼ 7.2 Hz, 2H, OCH2CH3), 5.48 (broad d, J ¼ 4.7 Hz, 1H, 8-H), 6.80 (s,
1H, 3-H), 12.8–13.8 (broad signal, 1H, 1-H). 13C NMR (50.3MHz, CDCl 3)
d: 14.1 (CH3, OCH2CH3), 23.4 (CH3, 7-CH3), 26.8 (CH, C5), 27.1 (CH, C9),
28.5 (CH2, C11), 34.1 (CH2, C10), 37.8 (CH2, C6), 61.7 (CH2, OCH2CH3),
117.6 (C, C4a), 118.3(CH, C 3), 124.4 (CH, C8), 132.9 (C, C7), 144.6 (2C, C4
and C10a), 164.5 (C, C2), 166.2 (C, 4-COO). Anal. calcd. for C16H19NO3: C
70.31; H 7.01; N 5.12. Found: C 70.16; H 7.08; N 5.22.
1,2,5,6,9,10-Hexahydro-7,N-dimethyl-2-oxo-5,9-methanocycloocta[e]
pyridine-4-carboxamide (17). A mixture of ester 16 (80 mg, 0.29 mmol) and
40% aqueous methylamine (10 mL) was stirred at room temperature for 4
days. The mixture was evaporated at reduced pressure to give a solid residue
(120 mg), which was submitted to column chromatography through silica
gel, by using AcOEt/MeOH mixtures as eluent. On elution with AcOEt/
MeOH in the ratio of 99:1 pure amide 17 (60 mg, 80% yield) was obtained.
Spectroscopic and analytical data of 17: Mp 191–197ꢁC (AcOEt). IR (KBr)
n: 3263 (NH st), 1650 (C¼O st) cmꢂ1. 1H NMR (500 MHz, CD3OD) d: 1.57
(s, 3H, 7-CH3), 1.78 (m, 1H) and 1.83(m, 1H) (11-H anti and 11-Hsyn), 1.94
(d, J ¼ 18.0 Hz, main rotamer 6-Hendo), 2.02 (d, J ¼ 18.0 Hz, minor rotamer
6-Hendo), 2.28–2.38 (complex signal, 1H, 6-Hexo), 2.46 (d, J ¼ 17.5 Hz, 1H,
10-Hendo), 2.60 (m, 1H, 9-H), 2.81 (dd, J ¼ 17.5 Hz, J 0 ¼ 5.0 Hz, 1H,
10-Hexo), 2.86 (s, 3H, NCH3), 3.22 (m, main rotamer 5-H), 3.30 (m,
minor rotamer 5-H), 4.87 (s, H2O and NH), 5.50 (m, 1H, 8-H), 6.26
(s, main rotamer 3-H), 6.32 (s, minor rotamer 3-H). 13C NMR (50.3MHz,
CD3OD) d: 23.5 (CH3, 7-CH3), 26.4 (CH3, N-CH3), 28.4 (2 CH, C5 and C9),
29.3(CH , C11), 34.8 (CH2, C10), 38.5 (CH2, C6), 115.4 (CH, minor rota-
2
mer C3), 115.6 (CH, main rotamer C3), 117.9 (C, minor rotamer C4a), 118.0
(C, main rotamer C4a), 125.6 (CH, C8), 133.9 (C, C7), 145.6 (C, C10a),
152.6 (C, C4), 165.1 (C, C2), 170.3(C, main rotamer CONHCH3), 172.3
(C, minor rotamer CONHCH3). Anal. calcd. for C15H18N2O2 ꢃ 1=2H2O:
C 67.39; H 7.17; N 10.48. Found: C 67.10; H 6.92; N 10.51.
ACKNOWLEDGMENTS
´
A fellowship from Comissio Interdepartamental de Recerca i Innovacio
Tecnologica (CIRIT) of the Generalitat de Catalunya to M. Simon and
´
`

ORDER
REPRINTS
3516
CAMPS, MUNOZ-TORRERO, AND SIMON
´
financial support from Fundacio ‘‘La Marato de TV3’’ (project 3004/97) is
gratefully acknowledged. We also thank the Serveis Cientıfico-Tecnics of the
´
´
`
University of Barcelona and particularly Dr. M. Feliz and Dr. A. Linares for
´
recording the NMR spectra and Ms. P. Domenech from the Centro de
Investigacion y Desarrollo (C.I.D.) (Barcelona, Spain) for carrying out the
´
elemental analyses.
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Received in the Netherlands January 25, 2001

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