Synthesis, conformational characteristics and anti-influenza virus A activity of some 2-adamantylsubstituted azacycles

Article abstract of DOI:10.1016/j.bioorg.2006.05.004

The broad-spectrum antiviral activity of 2-(2-adamantyl)piperidines 11, 13a,b, and 15, 3-(2-adamantyl)pyrrolidines 27, 21a-g and 2-(2-adamantylmethyl)piperidines 30, 32a-c, and 35a-d was examined. Several compounds in the new series were potent against influenza A H₃N₂ virus. When 1-aminoethyl pharmacophore group of 2-rimantadine 4 (2-isomer of rimantadine) is included into a saturated nitrogen heterocycle, see compound 11, potency was retained. The diamine derivatives 21e-g and particularly 35a-c possessing three pharmocophoric groups, that is, the adamantyl and the two amine groups, exhibited high potency. The new compounds did not afford specific activity at non-toxic concentrations against any of the other viruses tested. According to NMR spectroscopy and molecular mechanics calculations it is striking that the parent structures 11 and 27 adopt a fixed trans conformation around C2{single bond}C2′ bond. In the parent amines, which proved to be active compounds, the distance between nitrogen and adamantyl pharmacophoric groups was different; N{single bond}C2′ distance is 3.7, 3.8 A for 27, 30 and 2.5 A for 11 suggesting that M2 receptor site can accommodate different in size and orientation lipophilic cages.

Full text of DOI:10.1016/j.bioorg.2006.05.004

Bioorganic Chemistry 34 (2006) 248–273
www.elsevier.com/locate/bioorg
Synthesis, conformational characteristics and
anti-influenza virus A activity of some
2-adamantylsubstituted azacycles
a
a
a
Despina Setaki , Dimitris Tataridis , George Stamatiou ,
a
a,
a,
*
Antonios Kolocouris , George B. Foscolos *, George Fytas
,
a
b
b
Nicolas Kolocouris , Elizaveta Padalko , Johan Neyts ,
b
Erik De Clercq
a
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens,
Panepistimioupolis-Zografou, GR-15771 Athens, Greece
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
b
Received 5 April 2006
Available online 1 August 2006
Abstract
The broad-spectrum antiviral activity of 2-(2-adamantyl)piperidines 11, 13a,b, and 15, 3-(2-ada-
mantyl)pyrrolidines 27, 21a–g and 2-(2-adamantylmethyl)piperidines 30, 32a–c, and 35a–d was
examined. Several compounds in the new series were potent against influenza A H3N2 virus. When
1-aminoethyl pharmacophore group of 2-rimantadine 4 (2-isomer of rimantadine) is included into a
saturated nitrogen heterocycle, see compound 11, potency was retained. The diamine derivatives
21e–g and particularly 35a–c possessing three pharmocophoric groups, that is, the adamantyl and
the two amine groups, exhibited high potency. The new compounds did not afford specific activity
at non-toxic concentrations against any of the other viruses tested. According to NMR spectroscopy
and molecular mechanics calculations it is striking that the parent structures 11 and 27 adopt a fixed
trans conformation around C2AC20 bond. In the parent amines, which proved to be active com-
pounds, the distance between nitrogen and adamantyl pharmacophoric groups was different; NAC20
˚
˚
distance is 3.7, 3.8 A for 27, 30 and 2.5 A for 11 suggesting that M2 receptor site can accommodate
different in size and orientation lipophilic cages.
ꢀ 2006 Elsevier Inc. All rights reserved.
*
Corresponding authors. Fax: +301 210 7274747.
E-mail address: ankol@pharm.uoa.gr (A. Kolocouris).
0045-2068/$ - see front matter ꢀ 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.bioorg.2006.05.004

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
249
Keywords: Anti-influenza virus agent; H3N2; Aminoadamantanes; Adamantanamine; Rimantadine; Heterocy-
cles; Diamines; NOE; Conformation
1. Introduction
In the 20th century in Europe influenza A inflicted more casualties than any other infec-
tious disease. The Spanish flu pandemic of 1918 was the most lethal infectious epidemic in
the history of mankind, more than doubling the casualty total of the previous infamous
leader, the Black Death. Recent epidemics, while not as lethal, are still capable of infecting
significant portions of the population (up to at least 10%), resulting in a tremendous
amount of temporary debilitation, unsurpassed by any other human disease. In view of
the lethal effects of 1997 and the 2003 Asia influenza types, the danger of another major
pandemic, as occurred in 1957 and 1968, highlights the need to develop more effective ther-
apies [1].
Amantadine 1a and rimantadine 1b (Scheme 1) are anti-influenza A drugs that inhibit
virus replication at micromolar concentrations; their protonated form blocks the influenza
A M2 ion channel protein [2]. Many aminoadamantanes, potent against influenza virus A,
were synthesized in our laboratory during the past 10 years [3,4]. Some interesting results
are summarised in the next paragraph.
When the amino group is attached at C-2 of the adamantane nucleus biological potency is
retained (see structure 2, Scheme 1) [4a,4b,4i]. The 2-isomer of rimantadine (2-rimantadine,
CH3
(CH2)n
NH2
CH3
N
(CH2)n
n=1-3
NH2
H
R
n=1-2
NH2
N
1a
1b
2
3
4
R
4
4
5
3
5
6
3
2
N
1'
9'
1'
9'
R
2'
2'
8'
7'
8'
7'
1
1N
2
10'
H
10'
H
N
3'
3'
R
6'
6'
5'
5'
4'
R
4'
30: R = H
32a: R = CH3
32b: R = C2H5
32c: R = CH2
11: R = H
13a: R = CH3
13b: R = CH2CH3
27: R = H
21a: R = CH3
21b: R = CH2CH3
21c: R = n-C3H7
21d: R = n-C4H9
N
15: R = CH2CH2
35a: R = CH2CH2N(CH3)2
21e: R = CH2CH2N(CH3)2
21f: R = CH2CH2N(C2H5)2
35b: R = CH2CH2N(C2H5)2
35c: R = CH CH
2N
2
N
21g: R = CH2CH2
35d: R = CH2CH2N
O
Scheme 1. Structures of some aminoadamantane compounds.

250
D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
4) and some analogs proved to be more potent than rimantadine 1b [4g]. Recently, we dem-
onstrated that antiviral potency is increased if the 1-aminoethyl pharmacophoric group of
rimantadine drug 1b is included into a pyrrolidine or piperidine ring (compounds 3: n = 1,
2) [4h].
After short reports, [4d,4e] in this paper the antiviral potency of some new azacycles is
described. The 2-(2-adamantyl)piperidines 11, 13a,b, and 15, the 3-(2-adamantyl)pyrroli-
dines 27, 21a–g, and the 2-(2-adamantylmethyl)piperidines 30, 32a–c, and 35a–d, depicted
in Scheme 1, were synthesized and their activity was tested against many viruses. The con-
tribution of a second amine group to the anti-influenza A potency and the effect of includ-
ing the aminoethyl pharmacophore group of 2-rimantadine 4 into a piperidine ring, as
shown for the 2-(2-adamantyl)piperidine 11, were investigated. In the parent 3-(2-adaman-
tyl)pyrrolidine 27 and the 2-(2-adamantylmethyl)piperidine 30 nitrogen is one carbon fur-
ther remote from adamantane ring in comparison with compound 11.
2. Materials and methods
2.1. Chemical synthesis
2.1.1. Materials
Melting points were determined using a Buchi capillary apparatus and are uncorrected.
1
IR spectra were recorded on a Perkin-Elmer 833 spectrometer. H NMR spectra were
recorded on a Bruker AC 200 at 200 MHz, respectively, using CDCl3 as solvent and
TMS as internal standard. 13C NMR spectra were recorded on a Brucker AC 200 spec-
trometer at 50 MHz, using CDCl3 as solvent and TMS as internal standard. Carbon mul-
tiplicities were established by the DEPT experiments. The 2D NMR techniques
(XHCORR and COSY) were used for the elucidation of the structures of some derivatives.
All solvents were carefully dried before used. 1-Methyl-2-pyrrolidinone was commercially
available. Microanalyses were carried out by the Service Central de Microanalyse (CNRS)
France, and the results obtained had a maximum deviation of 0.4% from the theoretical
value.
2.1.1.1. 2-(2-Pyridinyl)tricyclo[3.3.1.1 3,7]decan-2-ol (6). To a stirred solution of 1.6 M
n-BuLi in hexanes (13.2 mL, 21.1 mmol), a solution of 2-bromopyridine (3.16 g, 20.0 mol)
in dry ether (25 mL) was added dropwise at ꢀ85 ꢁC under argon atmosphere. The mixture
was then warmed to ꢀ60 ꢁC and a solution of 2-adamantanone 5 (2.0 g, 13.3 mmol) in dry
THF (10 mL) was added dropwise over 30 min. The reaction mixture was allowed to reach
slowly room temperature and poured into HCl 10%. The organic layer was separated and
the aqueous layer was washed with ether and made alkaline with solid Na2CO3. The oily
residue was extracted with ether and the combined organic extracts were washed several
times with water, dried (Na2SO4), and evaporated in vacuo to give a dark coloured
solid product. After filtration through neutral aluminum oxide using ether as eluent the
solid base 6 was obtained (2.5 g, 82%); mp 105–107 ꢁC (ether–n-pentane); IR (Nujol):
m(OH) 3360 cmꢀ1 1H NMR (CDCl3, 200 MHz) d (ppm) 1.45–1.95 (complex m,
;
10H, 4eq,5,6,7,8,9eq,10-adamantane H), 2.20–2.51 (d, 2H, J ꢁ 12 Hz, 2H, 4ax,9ax-ada-
mantane H), 2.33 (br s, 1H, OH), 2.65 (s, 2H, 1,3-adamantane H), 7.11 (m, 1H, 5-pyridine
H), 7.46 (d, 1H, J ꢁ 8 Hz, 3-pyridine H), 7.65 (td, 1H, J = 2, 8 Hz, 4-pyridine H), 8.51
(d, 1H, J ꢁ 5 Hz, 6-pyridine H); 13C NMR (CDCl3, 50 MHz) d (ppm) 26.95, 27.28

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
251
(5,7-adamantane C), 32.79 (4,9-adamantane C), 34.74 (8,10-adamantane C), 34.90 (1,3-
adamantane C), 37.64 (6-adamantane C), 76.99 (2-adamantane C), 120.14 (3-pyridine
C), 122.02 (5-pyridine C), 136.58 (4-pyridine C), 149.05 (6-pyridine C), and 164.03 (2-pyr-
idine C). Anal. (C15H19NO) C, H. Hydrochloride: mp 197–199 ꢁC (EtOH–Et2O).
2.1.1.2. 2-(2-Piperidinyl)tricyclo[3.3.1.13,7]decan-2-ol (7). A solution of the hydrochlo-
ride of 2-(2-pyridinyl)-2-adamantanol 6 (1.0 g, 3.76 mmol) in absolute ethanol (20 mL)
was hydrogenated over PtO2 (60 mg) at 45 W for 8 h. The suspension was filtered to
remove the catalyst, and the filtrate was evaporated under reduced pressure. The crude sol-
id hydrochloride was triturated with dry ether and filtered off. The solid material was dis-
solved in water and the solution was made alkaline with solid Na2CO3. The mixture was
extracted with ether and the combined organic extracts were dried (Na2SO4) and evapo-
rated to give the solid piperidine 7: yield 860 mg (98%); mp 71–73 ꢁC (n-pentane); IR
1
(Nujol): m(NH), m(OH) 3480–3180 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 1.10–
1.95 (complex m, 18H, 3,4,5-piperidine H, 1,3,4eq,5,6,7,8,9eq,10-adamantane H), 2.12–
2.18 (m, 2H, 4ax,9ax-adamantane H), 2.67 (td, 1H, J = 12, 3 Hz, 6ax-piperidine H), 2.0
(br s, 2H, NH, OH), 2.98–3.15 (m, 2H, 2,6eq-piperidine H); 13C NMR (CDCl3,
50 MHz) d (ppm) 23.84 (4-piperidine C), 24.59 (5-piperidine C), 25.95 (3-piperidine C),
26.92, 27.19 (5,7-adamantane C), 33.13 (4,9-adamantane C), 34.04 (1,3-adamantane C),
34.14 (8,10-adamantane C), 38.07 (6-adamantane C), 46.91 (6-piperidine C), 59.96 (2-pi-
peridine C), and 74.26 (2- adamantane C). Anal. (C15H25NO) C, H. Hydrochloride: mp
>250 ꢁC (EtOH–Et2O).
2.1.1.3. 2-(Tricyclo[3.3.1.1 3,7]dec-2-yl)-3,4,5,6- tetrahydropyridine (10). Thionyl chlo-
ride (5 mL) in dichloromethane (15 mL) was added dropwise at 0 ꢁC to a stirred solution
of 2-(2-piperidinyl)-2-adamantanol 7 (5.35 g, 24.6 mmol) in dichloromethane (60 mL).
After stirring at room temperature for 2 h the reaction mixture was refluxed for 5 h.
The solvent was evaporated under vacuum to give crude 8. A solution of KOH (4.0 g,
71.3 mmol) in ethanol (50 mL) was added under ice cooling and the reaction mixture
was stirred for 24 h at room temperature under argon, and then refluxed for 3 h.
Solvent was evaporated, water was added to the residue and the mixture was extracted
with ether. The organic phase was washed with water and extracted with HCl 5%.
The acidic aqueous solution was washed with ether and made alkaline with solid
Na2CO3. The oil formed was extracted with ether and the combined organic extracts were
dried (Na2SO4) and evaporated in vacuo. The residue obtained was chromatographed on
neutral aluminum oxide with ether as eluent to give the oily imine 10: yield 3.04 g (61%);
1
IR (film): m(C@N) 1660 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 1.35–1.93 (complex
m, 16H, 4,5-piperidine H, 4,5,6,7,8,9eq,10-adamantane H), 2.04 (t, 2H, J = 7 Hz, 3-piper-
idine H), 2.25 (br s, 3H, 1,2,3-adamantane H), 3.49–3.68 (m, 2H, 6-piperidine H); 13C
NMR (CDCl3, 50 MHz) d (ppm) 19.67 (4-piperidine C), 22.16 (5-piperidine C), 27.31
(3-piperidine C), 27.81, 27.94 (5,7-adamantane C), 29.18 (1,3-adamantane C), 32.66,
37.69, 38.84 (4,6,8,9,10-adamantane C), 49.31 (6-piperidine C), 53.09 (2-adamantane C),
and 171.21 (2-piperidine C). Picrate: mp 159–161 ꢁC dec (MeOH). Anal. (C21H26N4O7)
C, H.
2.1.1.4. 2-(Tricyclo[3.3.1.13,7]dec-2-yl)piperidine (11). NaBH4 (1.10 g, 2.90 mmol) was
added portionwise to a solution of tetrahydropyridine 10 (2.12 g, 9.80 mmol) in methanol

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D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
(45 mL) at 0 ꢁC, and the reaction mixture was stirred for 5 h at this temperature. The
solvent was evaporated and the residue was treated with HCl 10%. The acidic aqueous
mixture was washed several times with ether and made alkaline with solid Na2CO3. The
oil separated was extracted with ether and the combined organic phase was dried
(Na2SO4) and evaporated under vacuum to afford the oily piperidine 11: yield 2.02 g
1
(94%); H NMR (CDCl3, 200 MHz) d (ppm) 0.80–1.0 (m, 1H, 3-piperidine H), 1.20–2.0
(complex m, 21H, 1,3,4,5-piperidine H, adamantane H), 2.48–2.73 (complex m, 2H, 2,6-
piperidine H), 2.98–3.16 (m, 1H, 6-piperidine H); 13C NMR (CDCl3, 50 MHz) d (ppm)
25.0 (4-piperidine C), 26.65 (5-piperidine C), 27.65, 27.75 (5,7-adamantane C), 27.94,
28.37 (1,3-adamantane C), 30.36 (3-piperidine C), 31.92, 32.16 (4,9-adamantane C),
38.13 (6-adamantane C), 38.82, 39.13 (8,10-adamantane C), 47.40 (6-piperidine C),
49.54 (2-adamantane C), and 55.72 (2-piperidine C). Hydrochloride: mp >300 ꢁC dec
(EtOH–Et2O). Picrate: mp 210–212 ꢁC dec (MeOH). Anal. (C21H28N4O7) C, H.
2.1.1.5. 1-Methyl-2-(tricyclo[3.3.1.13,7]dec-2-yl)piperidine (13a). A solution of ethyl
chloroformate (1.04 g, 9.30 mmol) in dry ether (15 mL) was added dropwise to a stir-
red solution of piperidine 11 (1.23 g, 5.62 mmol) and triethylamine (1.85 g, 18.3 mmol)
in dry ether (20 mL) under ice cooling. The reaction mixture was stirred at room tem-
perature for 24 h, and then treated with water. The organic phase was separated and
the aqueous phase was extracted with ether. The combined organic extracts were
washed with water, HCl 2%, water and dried (Na2SO4). After removal of the solvent
the carbamate 12a was obtained as an oil (1.37 g, 84%; IR film: m(C@O) 1695 cmꢀ1) and
was used without further purification for the preparation of derivative 13a as follows.
To a stirred suspension of LiAlH4 (1.60 g, 46.3 mmol) in THF (50 mL) was added drop-
wise to a solution of the carbamate 12a (1.35 g, 4.63 mmol) in dry THF (20 mL). The reac-
tion mixture was refluxed for 15 h and hydrolyzed with water and NaOH 10% under ice
cooling. The inorganic precipitate was filtered off and washed with THF, and the filtrate
was concentrated in vacuo. The residue was dissolved in ether and extracted with HCl 5%.
The acidic aqueous layer was made alkaline with solid Na2CO3 and extracted with ether.
The combined ether extracts were washed with water and dried (Na2SO4). After evapora-
tion of the solvent, the residue was chromatographed on silica gel with ether as eluent to
afford the amine 13a: yield 900 mg (83%); 1H NMR (CDCl3, 200 MHz) d (ppm) 1.20–1.97
(complex m, 20H, 3,4,5-piperidine H, 1,2,4,5,6,7,8,9,10-adamantane H), 2.03 (br s, 1H, 3-
adamantane H), 2.30 (s, 3H, NACH3), 2.73–3.09 (complex m, 3H, 2,6-piperidine H); 13C
NMR (CDCl3, 50 MHz) d (ppm) 19.07 (5-piperidine C), 20.19 (4-piperidine C), 24.89 (3-
piperidine C), 27.77 (1,3-adamantane C), 28.13, 28.74 (5,7-adamantane C), 31.93 (4,9-ada-
mantane C), 34.67 (NACH3), 38.33 (6-adamantane C), 39.03, 39.57 (8,10-adamantane C),
45.04 (2-adamantane C), 54.73 (6-piperidine C), and 59.05 (2-piperidine C). Fumarate: mp
195–197 ꢁC dec (EtOH–Et2O). Picrate: mp 180–182 ꢁC dec (MeOH). Anal. (C22H30N4O7)
C, H.
2.1.1.6. 1-Ethyl-2-(tricyclo[3.3.1.13,7]dec-2-yl)piperidine (13b). Amide 12b was pre-
pared by the procedure used for 12a, by the reaction of acetyl chloride with piperidine
11 in the presence of triethylamine. The oily residue thus obtained was chromatographed
on alkaline aluminum oxide with ether–n-hexane 1:1 as eluent to afford the solid com-
pound 12b: yield 94%; mp 90–92 ꢁC (ether–n-pentane); IR (Nujol): m(C@O) 1655,
1625 cmꢀ1. Anal. (C17H27NO) C, H.

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
253
The oily N-ethylpiperidine 13b was prepared by the LiAlH4 reduction of acetamide 12b
1
in THF, using the procedure followed for the preparation of 13a: yield 74%; H NMR
(CDCl3, 200 MHz) d (ppm) 0.98 (t, 3H, J = 6 Hz, NACH2CH3), 1.08–1.95 (complex m,
20 H, 3,4,5-piperidine H, 1,2,4,5,6,7,8,9,10-H), 2.03 (br s, 1H, 3-adamantane H), 2.38–
2.80 (complex m, 3H, 6-piperidine H, NACH2CH3), 2.81–2.94 (m, 1H, 2-piperidine H),
2.96–3.12 (m, 1H, 6-piperidine H); 13C NMR (CDCl3, 50 MHz) d (ppm) 14.17
(NACH2CH3), 19.11 (5-piperidine C), 20.06 (4-piperidine C), 22.91 (3-piperidine C),
27.52, 27.80 (1,3-adamantane C), 28.19, 29.02 (5,7-adamantane C), 31.88 (4,9-adamantane
C), 38.34 (6-adamantane C), 39.20, 39.64 (8,10-adamantane C), 41.92 (NACH2CH3),
43.28 (2-adamantane C), 48.03 (6-piperidine C), and 57.12 (2-piperidine C). Fumarate:
mp 169–171 ꢁC dec (EtOH–Et2O). Picrate: mp 164–166 ꢁC dec (MeOH). Anal.
(C23H32N4O7) C, H.
2.1.1.7. 1-[2-(1-Piperidinyl)ethyl]-2-(tricyclo[3.3.1.13,7]dec-2-yl)piperidine (15). To a
solution of the piperidine 11 (2.03 g, 9.25 mmol) in dichloromethane (40 mL) was added
a solution of K2CO3 (1.42 g, 10.3 mmol) in water (10 mL). To the vigorously stirred mix-
ture was added dropwise under ice cooling a solution of bromoacetyl chloride (1.61 g,
10.2 mmol) in dichloromethane (20 mL). After stirring for 3 h under ice cooling, the
organic phase was separated and the aqueous phase was extracted with dichloromethane.
The combined organic extracts were evaporated under vacuum, and the oily residue was
dissolved in ether. The ethereal solution was washed successively with Na2CO3 10%,
water, HCl 3%, water and dried (Na2SO4). After solvent evaporation the solid 2-(2-ada-
mantyl)-1-(brom0acetyl)piperidine 12c was obtained: yield 2.71 g (86%); mp 113–115 ꢁC
(ether); IR (Nujol): m(C@O) 1635 cmꢀ1; Anal. (C17H26BrNO) C, H.
To a stirred solution of bromoacetylpiperidine 12c (3.23 mmol) in dry benzene (10 mL)
was added dropwise under ice cooling a solution of piperidine (13.3 mmol) in dry benzene
(10 mL). The mixture was stirred for 30 min at 0 ꢁC, and 24 h at room temperature. The
solvent was evaporated in vacuo, and water was added to the residue. The aqueous mixture
was extracted with ether and the combined ether extracts were washed with water and
extracted with HCl 3%. The acidic aqueous solution was washed with ether and made
alkaline with solid Na2CO3. The mixture was extracted many times with ether and the
combined organic extracts were dried (Na2SO4). The solvent was evaporated and the res-
idue was chromatographed on silica gel with ether–n-hexane as eluent to afford the solid
amide 14: yield 60%; mp 94–96 ꢁC (ether–n-pentane); IR (Nujol): m(C@O) 1632 cmꢀ1
Anal. (C22H36N2O) C, H.
;
The oily N-piperidinoethyl derivative 15 was prepared by the LiAlH4 reduction of amide
14 in THF, using the procedure followed for the preparation of 13a: yield 78%; 1H NMR
(CDCl3, 200 MHz) d (ppm) 1.10–1.92 (complex m, 26H, 2 · 3,4,5-piperidine H,
1,2,4,5,6,7,8,9,10-adamantane H), 2.10 (br s, 1H, 3-adamantane H), 2.15–2.48 (complex
m, 6H, NCH2CH2N(CH2CH2)2C H2), 2.50–3.01 (complex m, 5H, 2,6-piperidine H,
NCH2CH2N(CH2CH2)2CH2); 13C NMR (CDCl3, 50 MHz) d (ppm) 19.47 (5-piperidine
C), 20.45 (4-piperidine C), 22.70 (3-piperidine C), 24.37 (N(CH2CH2)2CH2), 25.94
(N(CH2CH2)2C H2), 27.50, 27.738 (1,3-adamantane C), 28.15, 28.95 (5,7-adamantane C),
31.84, 31.90 (4,9-adamantane C), 38.36 (6-adamantane C), 39.14, 39.54 (8,10-adamantane
C), 43.31 (2-adamantane C), 46.47 (NCH2CH2N(CH2CH2)2CH2), 49.03 (6-piperidine C),
55.12 (N(CH2CH2)2C H2), 58.31 (2-piperidine C), and 59.29 (NCH2CH2N(CH2CH2)2CH2).
Monofumarate: 195–197 ꢁC dec (EtOH–Et2O). Anal. (C26H42N2O4) C, H.

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D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
2.1.1.8. General procedure for the preparation of 2-(2-oxopyrrolidin-3-yl)tricy-
clo[3.3.1.13,7]decan-2-ols (18a)–(18d) and (23). To a vigorously stirred solution of 2-
pyrrolidinone 16 (10.0 g, 0.12 mol) in dry DMF (40 mL) or dry benzene (80 mL), NaH
(3.10 g, 0.13 mol) was added in small portions, and the mixture was heated for 1 h at
60 ꢁC under nitrogen atmosphere. A solution of the suitable alkyliodide (0.13 mol) in
the same solvent (10 mL) was added dropwise and the resulting mixture was heated at
80 ꢁC for 3 h (benzene) or 15 h (DMF). When DMF was used as a solvent, brine was add-
ed to the reaction mixture; when benzene was used, solvent was first evaporated at ambient
temperature and then brine was added. The mixture was extracted many times with ether
and the combined organic extracts were dried (Na2SO4) and evaporated to dryness. Frac-
tional distillation of the oily residue gave pure 1-ethyl-2-pyrrolidinone 17b; yield 42%; bp
95–98 ꢁC (20 mmHg), 1-propyl-2-pyrrolidinone 17c; yield 36%; bp 102–104 ꢁC
(15 mmHg), 1-butyl-2-pyrrolidinone 17d; yield 33%; bp 126–127 ꢁC (20 mmHg).
1-Trimethylsilyl-2-pyrrolidinone 22 was prepared by refluxing for 4 h of a mixture of 2-
pyrrolidinone 16 (26.5 g, 0.311 mol), triethylamine (37.7 g, 0.373 mol), and trimethylchlo-
rosilane (40.5 g, 0.373 mol) in benzene (100 mL). After cooling at ambient temperature the
mixture was filtered off and the filtrate was evaporated under vacuum. Fractional distilla-
tion of the residue gave pure product; yield 67%; bp 102–104 ꢁC (25 mmHg).
To a stirred solution of dry diisopropylamine (5.05 g, 0.05 mol) in dry ether (30 mL)
was added, under an argon atmosphere at ꢀ80 ꢁC, a 1.6 M solution of n-BuLi in hexanes
(23.5 mL, 37.5 mmol). The solution was stirred for 15 min, and then a solution of 1-substi-
tuted-2-pyrrolidinone 17a–d or 22 (0.04 mol) in dry THF (10 mL) was added at ꢀ80 ꢁC.
After stirring for 20 min at the same temperature, a solution of 2-adamantanone 5
(3.76 g, 0.025 mol) in dry THF (45 mL) was added dropwise, and the mixture was allowed
to slowly reach room temperature. Stirring was continued for 18 h under argon atmo-
sphere, and the mixture was acidified with HCl 5% under ice cooling. In the case of trim-
ethylsilyl adduct 23, stirring for 1.5 h was needed in order to hydrolyze the NASi bond.
The organic phase was separated and the aqueous phase was extracted many times with
ether. The combined organic extracts were dried (Na2SO4) and evaporated to give 18a–
d, 23.
2.1.1.9. 2-(1-Methyl-2-oxopyrrolidin-3-yl)tricyclo[3.3.1.13,7]decan-2-ol (18a). Recrystal-
lization from ether afforded 5.70 g of pure lactam 18a: yield 91%; mp 134–135 ꢁC (ether);
IR (Nujol): m(OH) 3401, m(C@O) 1682 cmꢀ1; 1H NMR (CDCl3, 200 MHz) d (ppm) 1.43–
2.21 (complex m, 16H, 3,4,5,6,7,8,9,10-adamantane H, 4-H, OH), 2.78 (br s, 4H, CH3, 1-
adamantane H), 3.08 (ꢁt, 1H, J ꢂ 9.6 Hz, 3-H), 3.20–3.27 (m, 2H, 5-H); 13C NMR
(CDCl3, 50 MHz) d (ppm) 19.95 (4-C), 26.74, 26.91 (5,7-adamantane C), 29.64 (NACH3),
32.48, 32.67, 33.97, 34.94 (4,8,9,10-adamantane C), 34.41 (1,3-adamantane C), 38.13 (6-
adamantane C), 45.73 (3-C), 47.19 (5-C), 75.09 (2-adamantane C), and 175.20 (C@O).
Anal. (C15H23NO2) C, H.
2.1.1.10. 2-(1-Ethyl-2-oxopyrrolidin-3-yl)tricyclo[3.3.1.13,7]decan-2-ol (18b). Recrystal-
lization from ether-n-pentane afforded 5.52 g of pure lactam 18b: yield 84%; mp 117–
119 ꢁC (ether–n-pentane); IR (Nujol): m(OH) 3488, m(C@O) 1666 cmꢀ1; 1H NMR (CDCl3,
200 MHz) d (ppm) 1.04 (t, 3H, J = 7.2 Hz, CH3) 1.44–2.20 (complex m, 16H,
3,4,5,6,7,8,9,10-adamantane H, 4-H, OH), 2.78 (br s, 4H, CH3, 1-adamantane H), 3.07
(ꢁt, 1H, J ꢂ 9.6 Hz, 3-H), 3.20–3.27 (m, 4H, 5-H, CH2CH3); 13C NMR (CDCl3,

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
255
50 MHz) d (ppm) 12.40 (NACH2CH3), 20.0 (4-C), 26.70, 26.90 (5,7-adamantane C), 32.40,
32.60, 33.90, 34.90 (4,8,9,10-adamantane C), 34.30 (1-adamantane C), 34.40 (3-adaman-
tane C), 37.0 (NACH2CH3), 38.10 (6-adamantane C), 44.20 (5-C), 45.90 (3-C), 75.0 (2-
adamantane C), and 174.70 (C@O). Anal. (C16H25NO2) C, H.
2.1.1.11. 2-(2-Oxo-1-propylpyrrolidin-3-yl)tricyclo[3.3.1.13,7]decan-2-ol (18c). Recrys-
tallization from n-pentane afforded 6.58 g of pure lactam: yield 95%; mp 80–81 ꢁC (n-pen-
1
tane); H NMR (CDCl3, 200 MHz) d (ppm) 0.84 (t, J = 7.4 Hz, 3H, CH3), 1.43–2.21
(complex m, 18H, 3,4,5,6,7,8,9,10-adamantane H, 4-H, CH2CH3, OH), 2.79 (br s, 4H,
CH3, 1-adamantane H), 3.04–3.29 (m, 5H, 3,5-H, NACH2); 13C NMR (CDCl3,
50 MHz) d (ppm) 11.30 (CH3), 20.20 (4-C), 20.5 (NACH2CH2CH3), 26.70, 26.90 (5,7-ada-
mantane C), 32.50, 32.70, 34.0, 35.0 (4,8,9,10-adamantane C), 34.40 (1-adamantane C),
34.60 (3-adamantane C), 38.10 (6-adamantane C), 44.0 (NACH2), 44.80 (5-C), 46.0 (3-
C), 75.0 (2-adamantane C), 175.10 (C@O). Anal. (C17H27NO2) C, H.
2.1.1.12. 2-(1-Butyl-2-oxopyrrolidin-3-yl)tricyclo[3.3.1.13,7]decan-2-ol (18d). Chroma-
tography on silica gel afforded 5.53 g of pure lactam: yield 85%; mp 41 ꢁC (n-pentane);
1
IR (Nujol): m(OH) 3459, m(C@O) 1670 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 0.87
(ꢁt, J = 7.4 Hz, 3H, CH3), 1.16–1.34 (m, 2H, CH2CH3), 1.38–2.21 (complex m, 18H,
3,4,5,6,7,8,9,10-adamantane H, 4-H, NACH2CH2, OH), 2.78 (br s, 1H, 1-adamantane
H), 3.03–3.13 (m, 1H, 3-H), 3.18–3.28 (m, 4H, 5-H, NACH2); 13C NMR (CDCl3,
50 MHz) d (ppm) 13.70 (CH3), 20.0 (CH2CH3), 20.20 (4-C), 26.70, 26.90 (5,7-adamantane
C), 29.20 (NCH2CH2), 32.50, 32.70, 33.90, 35.0 (4,8,9,10-adamantane C), 34.30 (1-ada-
mantane C), 34.60 (3-adamantane C), 38.10 (6-adamantane C), 42.20 (NACH2), 44.80
(5-C), 45.90 (3-C), 75.0 (2-adamantane C), 175.0 (C@O). Anal. (C18H29NO2) C, H.
2.1.1.13. 2-(2-Oxopyrrolidin-3-yl)tricyclo[3.3.1.13,7] decan-2-ol (23). Chromatography
on silica gel with ether–ethyl acetate as an eluent afforded 5.60 g of pure lactam 23:
yield 95%; mp 169–171 ꢁC (acetone); IR (Nujol): m(NH), m(OH) 3220–3100, m(C@O)
;
1689 cmꢀ1 1H NMR (CDCl3, 200 MHz) d (ppm) 1.20–2.31 (complex m, 16H,
3,4,5,6,7,8,9,10-adamantane H, 4-H, OH), 2.75 (br s, 1H, 1-adamantane H), 3.06
(ꢁt, 1H, J ꢂ 9.6 Hz, 3-H), 3.27 (q, 2H, J = 8.8 Hz, 5-H), 6.11 (br s, 1H, NH); 13C NMR
(CDCl3, 50 MHz) d (ppm) 22.73 (4-C), 26.75, 26.87 (5,7-adamantane C), 32.51, 32.68, 33.96,
34.95 (4,8,9,10-adamantane C), 34.48 (1,3-adamantane C), 38.12 (6-adamantane C), 40.03
(5-C), 44.73 (3-C), 75.06 (2-adamantane C), and 175.40 (C@O). Anal. (C14H21NO2) C, H.
2.1.1.14. General procedure for the preparation of 2-[1-(2-dialkylaminoethyl)-2-oxopyrr-
olidin-3-yl]tricyclo[3.3.1.13,7]decan-2-ols 18e–g. To a stirred solution of 2-pyrrolidinone
16 (10.0 g, 0.12 mol) in dry DMF (40 mL) were added successively NaH (9.40 g, 0.39 mol)
and dialkylaminoethylchloride hydrochloride (18.7 g, 0.13 mol). The mixture was heated
at 70 ꢁC for 6 h under inert atmosphere, and then poured into an ice-water mixture and
extracted many times with ether. The combined organic extracts were washed with brine,
dried (Na2SO4) and evaporated to dryness. Fractional distillation of the resulted oily res-
idue gave pure 1-(2-dialkylaminoethyl)-2-pyrrolidinone 17e–g.
To a stirred solution of dry diisopropylamine (3.80 g, 37.5 mmol) in dry THF (20 mL)
was added, at ꢀ80 ꢁC under argon atmosphere, a 2.5 M solution of n-BuLi in hexanes
(11.2 mL). The solution was stirred for 10 min, and then a solution of 1-(2-dialkylamino-

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D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
ethyl)-2-pyrrolidinone 17e–g (28.0 mmol) in dry THF (20 mL) was rapidly added at
ꢀ80 ꢁC. After stirring for 20 min at the same temperature a solution of 2-adamantanone
5 (2.85 g, 19.0 mmol) in dry THF (50 mL) was added dropwise, and the mixture was
allowed to reach slowly room temperature. Stirring was continued for 12 h under an argon
atmosphere and the solvent was removed under vacuum. Water was added and the result-
ing mixture was extracted many times with ether. The ether phase was washed with water
and extracted with HCl 5%. The aqueous phase was made alkaline with solid Na2CO3 and
extracted with ether. The combined ether extracts were dried (Na2SO4) and evaporated to
give solid 18e–g.
2.1.1.15. 2-[1-(2-Dimethylaminoethyl)-2-oxopyrrolidin-3-yl]tricyclo[3.3.1. 13,7]decan-2-ol
(18e). Yield 91%; mp 110–112 ꢁC (ether–n-pentane); IR (Nujol): m(OH) 3216, m(C@O)
1
1655 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 1.41–2.33 (complex m, 24H, adaman-
tane H, 4-H, HCHN(CH3)2, OH), 2.52–2.66 (m, 1H, HCHN(CH3)2), 2.82–2.93 (m, 1H,
HCHCH2N(CH3)2), 3.04–3.14 (m, 2H, 5-H), 3.37–3.49 (m, 1H, 3-H), 3.86–4.01 (m, 1H,
HCHCH2N(CH3)2); 13C NMR (CDCl3, 50 MHz) d (ppm) 19.72 (4-C), 27.14 (5,7-adaman-
tane C), 32.76, 32.88, 34.14, 34.48 (4,8,9,10-adamantane C), 34.23 (1-adamantane C),
35.42 (3-adamantane C), 38.35 (6-adamantane C), 39.65 (CH2CH2N(CH3)2), 45.12
(CH3), 45.68 (5-C), 45.99 (3-C), 55.38 (N(CH3)2), 75.83 (2-C), and 175.60 (C@O). Anal.
(C18H30N2O2) C, H.
2.1.1.16. 2-[1-(2-Diethylaminoethyl)-2-oxopyrrolidin-3-yl]tricyclo[3.3.1. 13,7]decan-2-ol
(18f). Yield 91%; mp 79–81 ꢁC (ether–n-pentane); IR (Nujol): m(OH) 3490–3270,
1
m(C@O) 1655 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 0.97–1.01 (t, 6H, J = 7 Hz,
CH3), 1.50–2.67 (complex m, 23H, adamantane H, 4-H, HCHN(CH2CH3)2, OH), 2.96–
3.01 (m, 1H, HCHCH2N(CH2CH3)2), 3.11–3.21 (m, 2H, 5-H), 3.43–3.49 (m, 1H, 3-H),
3.82–3.89 (m, 1H, HCHCH2N(CH2CH3)2); 13C NMR (CDCl3, 50 MHz) d (ppm) 10.34
(CH3), 19.84 (4-C), 27.06, 27.12 (5,7-adamantane C), 32.70, 32.83, 34.08, 34.64
(4,8,9,10-adamantane C), 34.30 (1-adamantane C), 35.13 (3-adamantane C), 38.30
(6-adamantane C), 39.79 (CH2CH2N(CH3)2), 45.63, 47.71 (5-C, CH2CH3), 46.0 (3-C),
46.0 (3-C), 49.41 (CH2N(CH2CH3)2), 75.79 (2-C), and 175.30 (C@O). Anal.
(C20H34N2O2) C, H.
2.1.1.17. 2-[2-Oxo-1-[2-(1-piperidinylethyl)pyrrolidin-3-yl]tricyclo[3.3.1. 13,7]decan-2-ol
(18g). Yield 73%; mp 173–175 ꢁC (dichloromethane–ether); IR (Nujol): m(OH) 3293
1
m(C@O) 1660 cmꢀ1; H NMR (CDCl3, 200 MHz) d (ppm) 1.34–2.79 (complex m, 24H,
adamantane H, 4-H, CH2N(CH2)5, 3,4,5-piperidine H, OH), 2.45–2.79 (m, 6H, 3-adaman-
tane H,2,6-piperidine H, HCHCH2N(CH2)5), 3.0–3.12 (m, 2H, 5-H), 3.42–3.54 (m, 1H,
3-H), 4.04–4.26 (m, 1H, HCHCH2N(CH2)5; 13C NMR (CDCl3, 50 MHz) d (ppm) 19.43
(4-C), 24.16 (4-piperidine C), 25.21 (3,5-piperidine C), 27.15, 27.23 (5,7-adamantane C),
32.82, 32.92, 34.03, 34.55 (4,8,9,10-adamantane C), 34.24 (1-adamantane C), 35.23 (3-ada-
mantane C), 38.34 (6-adamantane C), 38.67 (CH2CH2N(CH2)5), 45.53 (5-C), 45.97 (3-C),
54.65 (2,6-piperidine C), 55.48 (CH2N(CH2)5), 76.65 (2-C), and 175.34 (C@O). Anal.
(C21H34N2O2) C, H.
2.1.1.18. General procedure for the preparation of 1-alkyl- and 1-[2-(dialkylamino)ethyl]-
3-(tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidinones 20a–g.
A solution of p-toluenesul-

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
257
phonic acid monohydrate (20.5 mmol) in dry benzene (80 mL) was heated to reflux
for 1 h using a Dean Stark receiver. To the refluxing solution adamantanol 18a–g
was added (8.2 mmol) and refluxing was continued for the appropriate time (12–
26 h for the different derivatives; TLC monitoring). The organic solution was washed
with water, NaOH 10%, dried (Na2SO4) and evaporated to dryness. The crude solid
material was chromatographed on alkaline aluminum oxide using ether as an eluent,
to afford pure lactam 19a–g.
A solution of the adamantyliden lactam 19a–g (9.90 mmol) in dry ethanol (35 mL) was
hydrogenated in the presence of Adams catalyst (100 mg), at ambient temperature, for 15–
24 h. The suspension was filtered off to remove the catalyst, and the filtrate was evaporated
to dryness to afford lactam 20a–g.
2.1.1.19. 1-Methyl-3-(tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidinone (20a). 1-Methyl-3-
(tricyclo [3.3.1.13,7]dec2-yliden)-2-pyrrolidinone 19a: yield 92%; mp 116–117 ꢁC (ether–n-
1
pentane); IR (Nujol): m(C@O), m(C@C) 1669–1644 cmꢀ1; H NMR (CDCl3, 200 MHz)
d (ppm) 1.71–1.91 (complex m, 12H, 4,5,6,7,8,9,10-adamantane H) 2.50 (br s, 1H, 1-ada-
mantane H), 2.59 (ꢁt, 2H, J ꢂ 7.0 Hz, 4-H), 2.85 (s, 3H, CH3), 3.31 (t, 2H, J ꢂ 7.0 Hz, 5-
H), 4.55 (br s, 1H, 3-adamantane H); 13C NMR (CDCl3, 50 MHz) d (ppm) 22.70 (4-C),
27.80 (5,7-adamantane C), 29.90 (CH3, 1-adamantane C), 35.90 (3-adamantane C),
36.90 (6-adamantane C), 39.0, 39.30 (4,8,9,10-adamantane C), 45.80 (5-C), 116.80,
157.10 (C@C), 169.60 (C@O). Anal. (C15H21NO) C, H.
1
(20a): yield 99%; mp 42–44 ꢁC (ether–n-pentane); IR (Nujol): m(C@O) 1672 cmꢀ1; H
NMR (CDCl3, 200 MHz) d (ppm) 1.48–2.18 (complex m, 16H, 1,3,4,5,6,7,8,9,10-adaman-
tane H, 4-H) 2.58–2.70 (m, 2H, 3-H, 2-adamantane H), 2.78 (s, 3H, CH3), 3.13–3.32 (m,
2H, 5-H), 4.55 (br s, 1H, 3-adamantane H); 13C NMR (CDCl3, 50 MHz) d (ppm) 23.99 (4-
C), 27.51, 27.86 (5,7-adamantane C), 28.80 (1-adamantane C), 29.59 (CH3), 30.04 (3-ada-
mantane C), 31.62, 31.73 (4,9-adamantane C), 38.21, 38.60 (8,10-adamantane C), 39.14 (6-
adamantane C), 41.08 (3-C), 46.19 (2-adamantane C), 47.17 (5-C), and 176.90 (C@O).
Anal. (C15H23NO) C, H.
2.1.1.20. 1-Ethyl-3-(tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidinone (20b). 1-Ethyl-3-(tricy-
clo[3.3.1.13,7] dec-2-yliden)-2-pyrrolidinone, 19b: yield 96%; mp 128–130 ꢁC (ether–n-pen-
tane); IR (Nujol): m(C@O), m(C@C)1667–1647 cmꢀ1; Anal. (C16H23NO) C, H.
1
(20b): yield 98%; mp 41–42 ꢁC (ether–n-pentane); IR (Nujol): m(C@O) 1693 cmꢀ1; H
NMR (CDCl3, 200 MHz) d (ppm) 1.10 (ꢁt, 3H, J = 7.1 Hz, CH3), 1.53–1.91 (complex
m, 14H, 1,3,4,5,6,7,8,9,10-adamantane H) 2.01–2.16 (m, 2H, 4-H), 2.64–2.71 (m, 2H, 3-
H, 2-adamantane H), 3.21–3.34 (m, 4H, 5-H, CH2CH3); 13C NMR (CDCl3, 50 MHz) d
(ppm) 12.49 (CH3), 24.14 (4-C), 27.56, 27.91 (5,7-adamantane C), 28.92 (1-adamantane
C), 30.07 (3-adamantane C), 31.69 31.79 (4,9-adamantane C), 36.98 (CH2CH3), 38.26,
38.66 (8,10-adamantane C), 39.18 (6-adamantane C), 41.55 (3-C), 44.22 (5-C), 46.16 (2-
C), and 176.53 (C@O). Anal. (C16H25NO) C, H.
2.1.1.21. 1-Propyl-3-(tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidinone (20c). 1-Propyl-3-(tri-
cyclo[3.3.1.13,7] dec-2-yliden)-2-pyrrolidinone, 19c: yield 93%; mp 57–58 ꢁC (ether–n-pen-
tane); IR (Nujol): m(C@O), m(CAC) 1669–1646 cmꢀ1; Anal. (C17H25NO) C, H.
(20c): Yield 98%; mp 45–46 ꢁC (ether–n-pentane); IR (Nujol): m(C@O) 1689 cmꢀ1
Anal. (C17H27NO) C, H.
;

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2.1.1.22. 1-Butyl-3-(tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidinone (20d). 1-Butyl-3-(tricy-
clo[3.3.1.13,7] dec-2-yliden)-2-pyrrolidinone, 19d: yield 80%; mp <25 ꢁC; IR (Nujol):
m(C@O), m(C@C) 1665–1640 cmꢀ1
.
(20d): Yield 99% (oil); IR (film): m(C@O) 1687 cmꢀ1
.
2.1.1.23. 1-[2-(Dimethylamino)ethyl]-3-(tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidinone (20.e).
1-[2-(Dimethylamino)ethyl]-3-(tricyclo[3.3.1.13,7]dec-2-yliden)-2-pyrrolidinone, 19e: yield
83%; mp 91–92 ꢁC (ether–n-pentane); IR (Nujol): m(C@O), m(C@C) 1668–1639 cmꢀ1; Anal.
(C18H28N2O) C, H.
1
(20e): yield quantitative (oil); IR (film): m(C@O) 1691–1675 cmꢀ1; H NMR (CDCl3,
200 MHz) d (ppm) 1.55–2.15 (complex m, 16H, 1,3,4,5,6,7,8,9,10-adamantane H), 4-H,
2.26 (s, 6H, 2 · CH3), 2.39–2.48 (m, 2H, 2-adamantane H, 3-H), 2.67–2.74 (m, 2H, 5-
H), 3.28–3.45 (m, 4H, NCH2CH2N); 13C NMR (CDCl3, 50 MHz) d (ppm) 24.27 (4-C),
27.57, 27.92 (5,7-adamantane C), 28.96 (1-adamantane C), 30.08 (3-adamantane C),
31.71 31.80 (4,9-adamantane C), 38.26, 38.67 (8,10-adamantane C), 39.20 (6-adamantane
C), 40.57 (NCH2CH2NMe2), 41.36 (3-C), 45.38 (5-C), 45.50 (CH2NMe2), 46.13 (2-ada-
mantane C), 56.69 (2 · CH3), and 179.30 (C@O). Picrate: mp 177–179 ꢁC (MeOH–ether).
Anal. (C24H33N5O8) C, H.
2.1.1.24. 1-[2-(Diethylamino)ethyl]-3-(tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidinone (20f).
1-[2-(Diethylamino)ethyl]-3-(tricyclo[3.3.1.13,7]dec-2-yliden)-2-pyrrolidinone, 19f: yield
87%; mp 60–62 ꢁC (ether–n-pentane); IR (Nujol): m(C@O), m(C@C) 1670–1640 cmꢀ1; Anal.
(C20H32N2O) C, H.
20f: yield quantitative (oil); IR (film): m(C@O) 1686 cmꢀ1; Fumarate: mp 109–111 ꢁC
(EtOH–Et2O). Anal. (C24H38N2O5) C, H.
2.1.1.25. 1-[2-(Piperidino)ethyl]-3-(tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidinone (20g). 1-[2-
(Piperidino) ethyl]-3-(tricyclo[3.3.1.13,7]dec-2-yliden)-2- pyrrolidinone 19g: yield 79%; mp
108–110 ꢁC (ether–n-pentane); IR (Nujol): m(C@O), m(C@C) 1666–1648 cmꢀ1; Picrate:
mp 162–164 ꢁC (MeOH–Et2O). Anal. (C27H35N5O8) C, H.
(20g): yield quantitative; IR (Nujol): m(C@O) 1675 cmꢀ1; mp 108–110 ꢁC (ether–n-pen-
tane). Anal. (C21H34N2O) C, H.
2.1.1.26. 3-(Tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidinone (26). To a stirred solution of
adamantanol 23 (2.50 g, 11.0 mmol) in chloroform (35 mL) was added dropwise SOCl2
(6.30 g, 53.0 mmol), distilled over quinoline and CaCO3 (300 mg, 3.0 mmol). The mixture
was stirred at room temperature for 2 h, refluxed for 3 h and then cooled at 0 ꢁC
and filtered off. The filtrate was evaporated under vacuum, and water was added
to the solid residue. The mixture was extracted with chloroform and the combined
organic extracts were washed with water, dried (Na2SO4) and evaporated. The result-
ed solid residue (1.47 g) was treated with MeONa/MeOH solution (1.26 g Na was
added to 60 mL of dry methanol). After treatment, solvent was removed under
reduced pressure, water was added and the mixture was extracted many times with
chloroform. The organic extracts were washed with water, dried and evaporated to
afford the solid unsaturated lactam 25 (1.26 g, 53%); mp 247–249 ꢁC (CH2Cl2–
Et2O); IR (Nujol): m(NH) 3200–3073, m(C@O) 1681, m(C@C)1652 cmꢀ1
;
1H NMR
(CDCl3, 200 MHz) d (ppm) 1.73–1.90 (complex m, 12H, 4,5,6,7,8,9,10-adamantane

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
259
H), 2.52 (s, 1H, 1-adamantane H), 2.69 (t, 2H, J = 7.0 Hz, 4-H), 3.33 (t, 2H,
J = 7.0 Hz, 5-H), 4.45 (s, 1H, 3-adamantane H), 6.61 (br s, 1H, NH); 13C NMR
(CDCl3, 50 MHz) d (ppm) 25.34 (4-C), 27.69 (5,7-adamantane C), 30.04 (1-adaman-
tane C), 36.06 (3-adamantane C), 36.82 (6-adamantane C), 38.63 (5-C), 38.96, 39.28
(4,8,9,10-adamantane C), 116.17, 158.28 (C@C), and 173.01 (C@O). Anal. (C14H19
NO) C, H.
Compound 25 was hydrogenated in the presence of Adams catalyst—using the same
procedure described for the preparation of lactams 20a–g—to afford pyrrolidinone 26:
yield quantitative; mp 200–201 ꢁC (CH2Cl2–Et2O); IR (Nujol): m(NH) 3190, m(C@O)
1677 cmꢀ1
;
1H NMR (CDCl3,400 MHz) d (ppm) 1.54–2.03 (complex m, 15H,
1,3,4,5,6,7,8,9,10-adamantane H, 4-H) 2.17–2.24 (m, 1H, 4-H), 2.59–2.66 (m, 2H, 3-H,
2-adamantane H), 3.24–3.35 (m, 2H, 5-H), 6.59 (br s, 1H, NH); 13C NMR (CDCl3,
50 MHz) d (ppm) 26.70 (4-C), 27.50, 27.80 (5,7-adamantane C), 28.92 (1-adamantane
C), 30.07 (3-adamantane C), 31.58, 31.74 (4,9-adamantane C), 38.18, 38.63 (8,10-adaman-
tane C), 39.11 (6-adamantane C), 40.03 (5-C), 40.47 (2-adamantane C), 45.58 (3-C), and
181.08 (C@O). Anal. (C14H21NO) C, H.
2.1.1.27. General procedure for the preparation of 1-alkyl- and 1-[2-(dialkylamino)ethyl]-3-
(tricyclo[3.3.1.13,7]dec-2-yl)pyrrolidines (21a–g) and (27). To a stirred suspension of
LiAlH4 (0.59 g, 15.0 mmol) in dry THF (25 mL) was added dropwise to a solution of
the lactam 20a–g or 26 (3.9 mmol) in dry THF (30 mL). The reaction mixture was refluxed
for 25 h, and then hydrolyzed with water and NaOH (10%) under ice cooling. The inor-
ganic precipitate was filtered off and washed with THF, and the filtrate was concentrated
in vacuo. The residue was dissolved in ether and extracted with HCl 5%. The aqueous layer
was made alkaline with solid Na2CO3 and extracted with ether. The combined ether
extracts were washed with water and dried (Na2SO4). After evaporation of the solvent,
the residue was chromatographed on silica gel with ether as an eluent to give the oily pyr-
rolidine 21a–g or 27.
2.1.1.28. 1-Methyl-3-(tricyclo[3.3.1.13,7]dec-2-yl)pyrrolidine (21a). Yield 89% (oil);
1H NMR (CDCl3, 200 MHz) d (ppm) 1.21–1.87 (complex m, 17H, adamantane H,
4-H), 1.91–2.01 (m, 1H, 2-H), 2.23–2.34 (m, 4H, 5-H, CH3), 2.42–2.59 (m, 1H, 3-H), 2.65–
2.85 (m, 2H, 2,5-H); 13C NMR (CDCl3, 50 MHz) d (ppm) 27.72, 28.10 (5,7-adamantane
C), 29.64 (4-C), 30.23, 31.03 (1,3-adamantane C), 31.60, 31.68 (4,9-adamantane C), 38.37
(6-adamantane C), 38.87 (3-C), 39.12 (8,10-adamantane C), 42.46 (CH3), 50.03 (2-adaman-
tane C), 56.04 (5-C), 61.25(2-C). Hydrochloride: mp 223–225 ꢁC (EtOH–Et2O); Picrate: mp
157–159 ꢁC (MeOH). Anal. (C21H28N4O7) C, H.
2.1.1.29. 1-Ethyl-3-(tricyclo[3.3.1.13,7]dec-2-yl)pyrrolidine (21b). Yield 86% (oil); 1H
NMR (CDCl3, 200 MHz) d (ppm) 1.06 (t, 3H, J = 7.0 Hz, CH3), 1.34–1.97 (complex
m, 18H, adamantane H, 2,4-H), 2.24–2.48 (m, 4H, 5-H, 3-H, CH2CH3), 2.75–2.91
(m, 2H, 2,5-H); 13C NMR (CDCl3, 50 MHz) d (ppm) 13.58 (CH3), 27.63, 28.0
(5,7-adamantane C), 28.80 (4-C), 30.23, 30.95 (1,3-adamantane C), 31.60 (4,9-ada-
mantane C), 38.12 (3-C), 38.26 (6-adamantane C), 39.0 (8,10-adamantane C),
49.93 (2-adamantane C), 50.40 (CH2CH3), 53.47 (5-C), 58.72 (2-C). Hydrochloride:
mp 210–211 ꢁC (EtOH–Et2O); Picrate: mp 163–165 ꢁC (MeOH). Anal.
(C22H30N4O7) C, H.

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D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
2.1.1.30. 1-Propyl-3-(tricyclo[3.3.1.13,7]dec-2-yl)pyrrolidine (21c). Yield 75% (oil);
Hydrochloride: mp 201–203 ꢁC (EtOH–Et2O); Picrate: mp 138–140 ꢁC (MeOH). Anal.
(C23H32N4O7) C, H.
2.1.1.31. 1-Butyl-3-(tricyclo[3.3.1.13,7]dec-2-yl)pyrrolidine (21d). Yield 72% (oil);
Hydrochloride: mp 218–220 ꢁC (EtOH–Et2O); Picrate: mp 106–108 ꢁC (MeOH). Anal.
(C24H34N4O7) C, H.
2.1.1.32.
1-[2-(Dimethylamino)ethyl]-3-(tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidine
1
(21e). Yield 83% (oil); H NMR (CDCl3, 400 MHz) d (ppm) 1.36–1.99 (complex
m, 18H, adamantane H, 2,4-H), 2.24 (br s, 6H, 2 · CH3), 2.30–2.38 (m, 1H, 5-H),
2.42–2.55 (m, 4H, NCH2CH2N), 2.57–2.64 (m, 1H, 3-H), 2.85–2.94 (m, 2H, 2,5-H);
13C NMR (CDCl3, 50 MHz) d (ppm) 27.72, 28.09 (5,7-adamantane C), 28.91 (4-C),
30.31 (1-adamantane C), 31.01 (3-adamantane C), 31.64 (4,9-adamantane C), 38.19
(3-C), 38.36 (6-adamantane C), 39.11 (8,10-adamantane C), 45.85 (CH3), 50.05 (2-ada-
mantane C), 54.24 (5-C), 54.87, 58.56 (NCH2CH2NMe2), 59.62 (2-C). Difumarate: mp
218–220 ꢁC (EtOH–Et2O). Anal. (C26H40N2O8) C, H.
2.1.1.33. 1-[2-(Diethylamino)ethyl]-3-(tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidine (21f). Yield
80% (oil); Difumarate: mp 142–144 ꢁC (EtOH–Et2O). Anal. (C28H44N2O8) C, H.
2.1.1.34.
1-[2-(1-Piperidinyl)ethyl]-3-(tricyclo[3.3.1.13,7]dec-2-yl)-2-pyrrolidine
1
(21g). Yield 86% (oil); H NMR (CDCl3, 400 MHz) d (ppm) 1.32–1.99 (complex
m, 24H, adamantane H, 2,4-H, 3,4,5-piperidine H), 2.31–2.93 (m, 12H, 2,5-H, 3-H,
NCH2CH2N, 2,6-piperidine H); 13C NMR (CDCl3, 50 MHz) d (ppm) 24.30 (4-piperi-
dine C), 25.89 (3,5-piperidine C), 27.73, 28.10 (5,7-adamantane C), 28.92 (4-C), 30.32 (1-
adamantane C), 31.02 (3-adamantane C), 31.64, 31.70 (4,9-adamantane C), 38.21 (3-C),
38.37 (6-adamantane C), 39.11 (8,10-adamantane C), 50.05 (2-adamantane C), 54.14 (5-
C), 54.31 (NCH2CH2NC5H10), 55.04 (2,6-piperidine C), 58.29 (NCH2CH2NC5H10),
59.61 (2-C). Difumarate: mp 212–214 ꢁC (EtOH–Et2O). Anal. (C29H44N2O8) C, H.
2.1.1.35. 3-(Tricyclo[3.3.1.13,7]dec-2-yl)pyrrolidine (27). Yield 68% (oil); 1H NMR
(CDCl3, 200 MHz) d (ppm) 1.16–1.97 (complex m, 17H, adamantane H, 4-H), 2.17–
2.46 (m, 2H, 2,3-H), 2.82–3.26 (m, 3H, 2,5-H), 4.65 (br s, 1H, NH); 13C NMR (CDCl3,
50 MHz) d (ppm) 27.73, 28.05 (5,7-adamantane C), 30.67 (4-C), 31.03, 31.30 (1,3-adaman-
tane C), 31.76 (4,9-adamantane C), 38.34 (6-adamantane C), 39.08, 39.13 (8,10-adaman-
tane C), 40.47 (3-C), 46.19 (5-C), 49.54 (2-adamantane C), 50.98 (2-C). Fumarate: mp
145–146 ꢁC (EtOH–Et2O); Anal. (C18H27NO4) C, H.
2.1.1.36. 2-(2-Pyridinylmethyl)tricyclo[3.3.1.13,7]decane-2-ol (28). To a stirred solution
of 2-picoline (3.1 g, 33.3 mmol) in dry THF (25 mL) cooled at ꢀ20 ꢁC was added dropwise
under argon atmosphere, a 2.5 M solution of n-BuLi in hexanes (13.4 mL, 33.3 mmol) dur-
ing a 45 min period. The reaction mixture was left to reach ambient temperature and a
solution of 2-adamantanone 5 (5 g, 33.3 mmol) in dry THF (18 mL) was added under vig-
orous stirring in 15 min. The reaction mixture was stirred for 2 h, and hydrolysed with
water. The organic layer was separated and the aqueous was extracted with ether. The
combined organic extracts were evaporated in vacuo and the oily residue was dissolved

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
261
in ether. The ether solution was washed with water and extracted with HCl (5%). The acid-
ic aqueous phase was made alkaline with solid Na2CO3 and extracted with ether. The com-
bined ether extracts were washed with water, dried (Na2SO4) and evaporated to give 5.5 g
of 28 as a yellow solid: yield 93%; mp 84–85 ꢁC (n-pentane); IR (Nujol): m(OH) 3380 cmꢀ1
;
1H NMR (CDCl3, 200 MHz) d (ppm) 1.40–1.93 (complex m, 12H, 4,5,6,7,8,9,10-adaman-
tane H), 2.30 (d, 2H, 1,3-adamantane H), 3.11 (s, 1H, CH2), 6.04 (br s, 1H, OH), 7.10–7.14
(m, 2H, 3,5-pyridine H), 7.54–7.63 (m, 1H, 4-pyridine H), 8.5 (ꢁt, 1H, 6-pyridine H); 13C
NMR (CDCl3, 50 MHz) d (ppm) 27.38, 27.42 (5,7-adamantane C), 32.77 (4,9-adamantane
C), 34.66 (8,10-adamantane C), 37.23 (1,3-adamantane C), 38.44 (6-adamantane C), 43.63
(CH2), 75.46 (2-adamantane C), 121.31, 124.43 (3,5-pyridine C), 136.70 (4-pyridine C),
148.41 (6-pyridine C), and 159.65 (2-pyridine C). Anal. (C16H21NO) C, H.
2.1.1.37. 2-(Tricyclo[3.3.1.13,7 ]dec-2-ylidenmethyl)pyridine (29). A mixture of alcohol
28 (1.78 g, 7.31 mmol) and p-TSA (3.36 g, 17.6 mmol) in dry benzene (50 mL) was refluxed
using a Dean-Stark receiver for 15 h. The solution was poured to NaOH (10%), the organ-
ic phase was separated and the aqueous phase was extracted with ether. The combined
organic phases were extracted with HCl (5%) and the aqueous solution was made alkaline
with solid Na2CO3. The mixture was extracted with ether, the ether solution was dried
(Na2SO4) and evaporated to dryness. The obtained residue was chromatographed on alka-
line aluminum oxide with ether–hexane (1:2) as the eluent to give pure 29 (1.52 g, 93%):
mp 43–44 ꢁC; 1H NMR (CDCl3, 200 MHz) d (ppm) 1.85–1.96 (m, 12H, 4,5,6,7,8,9,10-ada-
mantane H), 2.50 (br s, 1H, 1-adamantane H), 3.56 (br s, 1H, 3-adamantane H), 6.22 (br s,
1H, @CH), 7.0 (q, 1H, M region, AMXY, JAM = 4.8 Hz, JMX = JXY = 7.6 Hz, 5-pyridine
H), 7.10 (d, 1H, Y region, AMXY, JMX = JXY = 7.6 Hz, 3-pyridine H), 7.50 (t, 1H, X
region, AMXY, JMX = JXY = 7.6 Hz, 4-pyridine H), 8.50 (d, 1H), 7.10–7.14 (m, 2H,
3,5-pyridine H), 7.54–7.63 (m, 1H, 4-pyridine H), 8.50 (d, 1H, A region, AMXY,
JAM = 4.8 Hz, 6-pyridine H); 13C NMR (CDCl3, 50 MHz) d (ppm) 28.21 (5,7-adamantane
C), 32.33 (3-adamantane H), 37.08 (4,9-adamantane C), 38.95 (8,10-adamantane C), 39.89
(6-adamantane C), 41.24 (1-adamantane C), 117.49 (@CH), 120.34 (5-pyridine C), 123.56
(3-pyridine C), 135.75 (4-pyridine C), 149.18 (6-pyridine C), 156.01 (2-adamantane C),
157.38 (2-pyridine C). Hydrochloride: mp 173–175 ꢁC (EtOH–Et2O). Anal. (C16H20NCl)
C, H.
2.1.1.38. 2-(Tricyclo[3.3.1.13,7]dec-2-ylmethyl)piperidine (30). A solution of 2-(2-ada-
mantylidenemethyl)pyridine 29 hydrochloride (1.52 g, 5.8 mmol) in absolute ethanol
(60 mL) was hydrogenated over PtO2 (100 mg) under a pressure of 45 W for 8 h. The sus-
pension was filtered to remove the catalyst, and the filtrate was evaporated under reduced
pressure. The solid crude hydrochloride was treated with dry ether and filtered off. The
solid material was dissolved in water and the solution was made alkaline with solid
Na2CO3. The mixture was extracted with ether and the combined organic extracts were
dried (Na2SO4) and evaporated to give 1.53 g of piperidine 30: yield 98%; IR (film):
1
m(NH) 3280 cmꢀ1; H NMR (CDCl3, 400 MHz) d (ppm) 1.06–1.84 (complex m, 24H,
CH2, 1,3,4,5-piperidine H, adamantane H), 2.42–2.44 (m, 1H, 6-piperidine H), 2.58 (t,
1H, 2-piperidine H), 3.02 (d, 1H, 6-piperidine H); 13C NMR (CDCl3, 50 MHz) d (ppm)
24.97 (5-piperidine C), 26.68 (4-piperidine C), 28.03, 28.19 (1,3-adamantane C), 29.68
(7-adamantane C), 31.59 (5-adamantane C), 31.63 (3-piperidine C), 31.76 (CH2), 32.49,
33.50 (4,9-adamantane C), 38.35 (6-adamantane C), 39.22, 40.50 (8,10-adamantane C),

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D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
40.32 (2-adamantane C), 47.27 (6-piperidine C), and 54.28 (2-piperidine C). Hydrochlo-
ride: mp >250 ꢁC (EtOH–Et2O). Picrate: 161–164 ꢁC (MeOH–Et2O). Anal.
(C22H30N4O7) C, H.
2.1.1.39. 1-Methyl-2-(tricyclo[3.3.1.13,7]dec-2-ylmethyl)piperidine (32a). To a stirred
solution of piperidine 30 (750 mg, 3.21 mmol) and triethylamine (1.05 g, 10 mmol) in
dry ether (20 mL) was added dropwise under ice cooling a solution of ethyl chloroformate
(590 mg, 5.4 mmol) in dry ether (15 mL). The mixture was stirred at room temperature for
3 h and poured into water. The organic phase was separated and the aqueous phase was
extracted with ether. The combined organic extracts were washed with water, HCl (5%),
water and dried (Na2SO4). After removal of the solvent the carbamate 31a [IR (film):
m(C@O) 1695 cmꢀ1] was obtained as an oil (900 mg, 92%) which was used without further
purification for the preparation of derivative 32a as follows.
To a stirred suspension of LiAlH4 (0.60 g, 15.0 mmol) in dry THF (40 mL) was added
dropwise a solution of the carbamate 31a (3 mmol) in dry THF (10 mL). The reaction mix-
ture was refluxed for 15 h and then hydrolyzed with water and NaOH (10%) under ice
cooling. The inorganic precipitate was filtered off and washed with THF, and the filtrate
was concentrated in vacuo. The residue was dissolved in ether and extracted with HCl
(5%). The aqueous layer was made alkaline with solid Na2CO3 and extracted with ether.
The combined ether extracts were washed with water and dried (Na2SO4). After evapora-
tion of the solvent, the residue was chromatographed on silical gel with ether as an eluent
1
to give amine 32a as an oil: yield 75%; H NMR (CDCl3, 200 MHz) d (ppm) 1.04–2.15
(complex m, 25H, AdCH2, 2,3,4,5,6-piperidine H, adamantane H), 2.25 (s, 3H, CH3),
2.80 (m, 1H, 6-piperidine H); 13C NMR (CDCl3, 50 MHz) d (ppm) 24.22 (5-piperidine
C), 25.84 (4-piperidine C), 27.93, 28.15 (1,3-adamantane C), 30.95 (7-adamantane C),
31.39 (5-adamantane C), 31.44 (3-piperidine C), 31.85 (AdCH2), 33.46, 35.36 (4,9-ada-
mantane C), 38.35 (6-adamantane C), 39.11, 39.31 (8,10-adamantane C), 41.04 (NCH3),
43.11 (2-adamantane C), 57.02 (6-piperidine C), and 62.32 (2-piperidine C). Hydrochlo-
ride: 231–233 ꢁC (EtOH–Et2O). Anal. (C17H30NCl) C, H.
2.1.1.40. 1-Ethyl-2-(tricyclo[3.3.1.13,7]dec-2-ylmethyl)piperidine (32b). To a stirred
solution of piperidine 30 (730 mg, 3.13 mmol) and triethylamine (1.05 g, 10 mmol) in
dry ether (30 mL) was added dropwise under ice cooling a solution of acetyl chloride
(1.02 g, 18.0 mmol) in dry ether (20 mL). The mixture was stirred at room temperature
for 8 h and poured into water. The organic phase was separated and the aqueous phase
was extracted with ether. The combined organic extracts were washed with water, HCl
(5%), water and dried (Na2SO4). The solvent was evaporated and the residue was filtered
through alkaline alumina with ethyl acetate as an eluent. After removal of the solvent the
amide 31b (IR film: m(C@O) 1640 cmꢀ1) was obtained as an oil (770 mg, 89%) which was
used without further purification for the preparation of derivative 32b.
Compound 32b was prepared by the LiAlH4 reduction of the corresponding amide 31b
using the same procedure followed for the preparation of 32a: yield 80%;1H NMR
(CDCl3, 200 MHz) d (ppm) 0.98 (t, 3H, A3X2, JAX = 7 Hz, NCH2CH3), 1.07–1.95 (com-
plex m, 23 H, AdCH2, 3,4,5-piperidine H, adamantane H), 2.13–2.27 (m, 3H, 6-piperidine
H, NCH2CH3), 2.38–2.55 (m, 1H, 2-piperidine H), 2.62–2.80 (m, 1H, 6-piperidine H); 13
C
NMR (CDCl3, 50 MHz) d (ppm) 10.84 (CH3), 23.36 (5-piperidine C), 25.58 (4-piperidine
C), 27.95, 28.15 (1,3-adamantane C), 30.73 (7-adamantane C), 30.98 (5-adamantane C),

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
263
31.61 (3-piperidine C), 31.88 (AdCH2), 33.17, 33.54 (4,9-adamantane C), 38.33 (6-ada-
mantane C), 39.14, 39.36 (8,10-adamantane C), 41.26 (2-adamantane C), 47.12
(NCH2CH3), 51.03 (6-piperidine C), and 57.87 (2-piperidine C). Fumarate: 136–139 ꢁC
(EtOH–Et2O). Anal. (C22H35NO4) C, H.
2.1.1.41. 1-Cyclopropylmethyl-2-(Tricyclo[3.3.1.13,7]dec-2-ylmethyl)piperidine (32c). To
a stirred solution of piperidine 30 (850 mg, 3.64 mmol) and triethylamine (1.90 g,
18.8 mmol) in dry THF (20 mL) was added dropwise under ice cooling a solution of cyclo-
propanecarbonylchloride (1.26 g, 12.0 mmol) in dry THF (10 mL). The mixture was stir-
red at room temperature for 4 h and heated at 60 ꢁC for 30 min. The precipitated
triethylamine hydrochloride was filtered off, and the filtrate was evaporated to dryness.
The residue obtained was dissolved in ether and the organic solution was washed with
HCl (5%), water, NaOH (5%), water and dried (Na2SO4). The solvent was evaporated
and the residue was filtered through alkaline alumina with ether as an eluent. After remov-
al of the solvent the amide 31c [IR (film): m(C@O) 1635 cmꢀ1] was obtained as an oil
(900 mg, 82%) which was used without further purification for the preparation of deriva-
tive 32c.
Compound 32c was prepared by the LiAlH4 reduction of the corresponding amide 31c
using the same procedure followed for the preparation of 32a: yield 80%;1H NMR
(CDCl3, 400 MHz) d (ppm) 0.15–0.25 (m, 2H, 2,3-cyclopropane H), 0.55–0.65 (m, 2H,
2,3-cyclopropane H), 0.92–1.0 (m, 1H, 1-cyclopropane H), 1.30–2.0 (complex m, 23 H,
AdCH2, 3,4,5-piperidine H, adamantane H), 2.33–2.50 (m, 3H, 6-piperidine H,
CH2CH(CH2)2), 2.65 (q, 1H, 2-piperidine H), 3.12–3.20 (m, 1H, 6-piperidine H); 13C
NMR (CDCl3, 50 MHz) d (ppm) 4.01, 4.12 (2,3-cyclopropane C), 8.24 (1-cyclopropane
C), 23.51 (5-piperidine C), 25.28 (4-piperidine C), 27.95, 28.16 (1,3-adamantane C),
30.64 (7-adamantane C), 31.11 (5-adamantane C), 31.64 (3-piperidine C), 31.89 (AdCH2),
33.44, 34.02 (4,9-adamantane C), 38.35 (6-adamantane C), 39.14, 39.35 (8,10-adamantane
C), 41.28 (CH2CH(CH2)2), 52.14 (2-adamantane C), 58.49 (6-piperidine C), and 59.07 (2-
piperidine C). Fumarate: 158–160 ꢁC (EtOH–Et2O). Anal. (C24H37NO4) C, H.
2.1.1.42.
1-(2-Dimethylaminoethyl)-2-(tricyclo[3.3.1.13,7]dec-2-ylmethyl)piperidine
(35a). To a solution of piperidine 30 (3.2 g, 13.7 mmol) in dichloromethane
(50 mL) was added a solution of K2CO3 (1.99, 14.4 mmol) in water (15 mL). To the
vigorously stirred mixture was added dropwise under ice cooling a solution of bromo-
acetyl chloride (2.30 g, 14.4 mmol) in dichloromethane (20 mL). After stirring for 3 h
under ice cooling, the organic phase was separated and the aqueous was extracted with
dichloromethane. The combined organic extracts were evaporated under vacuum and
the oil residue was dissolved in ether. The ether solution was washed with Na2CO3
(10%), water, HCl (5%), water, brine and dried (Na2SO4). After removal of the solvent
the amide 33 [IR (film): m(C@O) 1650, 1660 cmꢀ1] was obtained as an oil (4.5 g, 93%)
which was used without further purification for the preparation of derivatives 34a–d.
To a stirred solution of N-bromoacetylpiperidine 33 (1.50 mg, 4.2 mmol) in dry benzene
(15 mL) was added dropwise under ice cooling a 15% solution of dimethylamine
(16.9 mmol) in benzene. The mixture was stirred under ice cooling for 30 min and 24 h
at room temperature. The solvent was evaporated in vacuo and water was added to the
residue. The aqueous mixture was extracted with ether and the combined ether extracts
were washed with water and extracted with HCl (5%). The resulted acidic aqueous solu-

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D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
tion was washed with ether and made alkaline with solid Na2CO3. The mixture was
extracted many times with ether and the combined organic extracts were dried (Na2SO4).
The solvent was evaporated and the residue was chromatographed on alkaline alumina
with ether as an eluent. After removal of the solvent amide 34a was obtained as an oil
(1.18 g, 89%), [IR (film): m(C@O) 1640 cmꢀ1]. Picrate: 158–160 ꢁC (MeOH–Et2O). Anal.
(C26H37N5O8) C, H.
To a stirred suspension of LiAlH4 (0.59 g, 15.0 mmol) in dry THF (25 mL) was added
dropwise a solution of the amide 34a (3 mmol) in dry THF (30 mL). The reaction mixture
was refluxed for 20 h and then hydrolyzed with water and NaOH (10%) under ice cooling.
The inorganic precipitate was filtered off and washed with THF, and the filtrate was con-
centrated in vacuo. The residue was dissolved in ether and extracted with HCl (5%). The
aqueous layer was made alkaline with solid Na2CO3 and extracted with ether. The com-
bined ether extracts were washed with water and dried (Na2SO4). After evaporation of
the solvent, the residue was chromatographed on silical gel with ether as an eluent to give
1
dimethylaminoethylpiperidine 35a as an oil: yield 80%; H NMR (CDCl3, 200 MHz) d
(ppm) 1.12–1.90 (complex m, 23H, AdCH2, 3,4,5-piperidine H, adamantane H), 2.22 (s,
6H, Me2N), 2.24–2.52 (m, 5H, NCH2CH2N, 6-piperidine H), 2.70–2.87 (m, 2H, 2,6-piper-
idine H); 13C NMR (CDCl3, 50 MHz) d (ppm) 23.02 (5-piperidine C), 25.11 (4-piperidine
C), 27.87, 28.10 (1,3-adamantane C), 30.30 (7-adamantane C), 30.98 (5-adamantane C),
31.58 (3-piperidine C), 31.81 (AdCH2), 33.37, 33.42 (4,9-adamantane C), 38.27 (6-ada-
mantane C), 39.07, 39.27 (8,10-adamantane C), 41.26 (2-adamantane C), 45.95
(2 · CH3), 51.61 (NCH2CH2NMe2), 52.04 (6-piperidine C), 57.12 (NCH2CH2NMe2),
59.91 (2-piperidine C). Difumarate: 128–131 ꢁC (EtOH–Et2O). Anal. (C28H44N2O8) C, H.
2.1.1.43.
1-(2-Diethylaminoethyl)-2-(tricyclo[3.3.1.13,7]dec-2-ylmethyl)piperidine
(35b). Amide 34b was obtained as an oil using the same procedure described for
the preparation of compound 34a: yield 87%; [IR (film): m(C@O) 1640 cmꢀ1]; Picrate:
178–180 ꢁC (MeOH–Et2O). Anal. (C28H41N5O8) C, H.
Compound 35b was prepared by the LiAlH4 reduction of the corresponding amide 34b
using the same procedure followed for the preparation of 35a: yield 80%; 1H NMR
(CDCl3, 400 MHz) d (ppm) 1.04 (t, 6H, N(CH2CH3)), 1.15–1.90 (complex m, 23H,
AdCH2, 3,4,5-piperidine H, adamantane H), 2.28–2.62 (complex m, 9H, NCH2CH2N,
N(CH2CH3)2, 6-piperidine H), 2.71–2.78 (m, 1H, 2-piperidine H), 2.80–2.88 (m, 1H, 6-pi-
peridine H); 13C NMR (CDCl3, 50 MHz) d (ppm) 11.74, 23.11, 25.19, 27.94, 28.16, 30.37,
31.12, 31.66, 31.86, 33.36, 33.61, 38.33, 39.13, 39.33, 41.33, 47.57, 50.65, 51.71, 52.22, and
59.0. Difumarate: 123–125 ꢁC (EtOH–Et2O). Anal. (C30H48N2O8) C, H.
2.1.1.44.
1-[2-(1-Piperidinyl)ethyl]-2-(tricyclo[3.3.1.
13,7]dec-2-ylmethyl)piperidine
(35c). Amide 34c was obtained as solid product using the same procedure described
for the preparation of compound 34a: yield 80%; mp 105–107 ꢁC (Et2O–n-pentane); IR
film: m(C@O) 1630, 1650 cmꢀ1; Anal. (C23H38N2O) C, H.
Compound 35c was prepared by the LiAlH4 reduction of the corresponding amide 34c
using the same procedure followed for the preparation of 35a: yield 75%; 1H NMR
(CDCl3, 400 MHz) d (ppm) 1.14–1.88 (complex m, 29H, CH2, 2 · 3,4,5-piperidine H, ada-
mantane H), 2.25–2.61 (complex m, 9H, NCH2CH2N, 2,6-piperidineethyl H, 6-adamant-
ylmethylpiperidine H), 2.70–2.83 (m, 2H, 2,6-adamantylmethylpiperidine H); 13C NMR
(CDCl3, 50 MHz) d (ppm) 15.25, 23.05, 24.37, 25.16, 25.95, 27.95, 28.19, 30.23, 31.08,

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
265
31.68, 31.88, 33.43, 38.35, 39.14, 39.36, 41.31, 50.70, 51.99, 55.20, 56.91, and 58.82. Difum-
arate: 160–162 ꢁC (EtOH–Et2O). Anal. (C31H48N2O8) C, H.
2.1.1.45. 1-[2-(1-Morpholinyl)ethyl]-2-(tricyclo[3.3.1.13,7]dec-2-ylmethyl)piperidine
(35d). Amide 34d was obtained as solid product using the same procedure described
for the preparation of compound 34a: yield 80%; mp 124–126 ꢁC (ether–n-pentane); IR
Film: m(C@O) 1630 cmꢀ1; Anal. (C22H36N2O2) C, H.
Compound 35d was prepared by the LiAlH4 reduction of the corresponding amide 34d
using the same procedure followed for the preparation of 35a: yield 89%; 1H NMR
(CDCl3, 400 MHz) d (ppm) 1.13–1.88 (complex m, 23H, AdCH2, 3,4,5-piperidine H, ada-
mantane H), 2.27–2.64 (complex m, 9H, NCH2CH2N, 3,5-morpholine H, 6-piperidine H),
2.70–2.85 (m, 2H, 2,6-piperidine H), 3.71 (t, 4H, 2,6-morpholine H); 13C NMR (CDCl3,
50 MHz) d (ppm) 23.05, 24.37, 25.16, 25.95, 27.95, 28.19, 30.23, 31.08, 31.68, 31.88,
33.43, 38.35, 39.14, 39.36, 41.31, 50.70, 51.99, 55.20, 56.91, and 58.82. Monofumarate:
163–165 ꢁC (EtOH–Et2O). Anal. (C26H42N2O5) C, H.
2.2. NMR spectroscopy—molecular mechanics calculations
NMR spectra for compounds 11, 27, and 30 and their protonated forms 11+ H, 27+H,
and 30+H were recorded on a Bruker DRX 400 MHz spectrometer. The COSY and phase
sensitive NOESY spectra were run using a recycling delay of 1.5–2 s; the mixing time for
the NOESY spectra was 1 s.
Molecular mechanics were performed using MM+[5] force field provided by the pro-
gram Hyperchem [6]. Molecular mechanics is the method of choice to reproduce confor-
mational energies consistent with the experimental results for saturated cyclic amines [7].
The minima were located using conjugate gradient and Newton–Raphson algorithms and
ꢀ1
an energy gradient tolerance of 0.001 kcal molꢀ1
A
.
˚
2.3. Virology
Cells and viruses
Influenza A and B viruses were kindly provided by Dr. K. Andries (Janssen Pharmaceu-
tica, Beerse, Belgium) and stocks were prepared on MDCK cells. Anti-influenza activity
and cytotoxicity assays—anti-influenza virus activity was assessed in 96-well plates in
one-day confluent MDCK cells. Cells were infected with 100 CCID50 virus/well. After
1 h of virus adsorption virus was removed and serial dilutions of the test compounds were
added, after which the cultures were further incubated at 35 ꢁC (5% CO2) for 4–5 days.
The cytopathic effect (and the cytotoxic effect in parallel) in non-infected cultures was read
using the MTS-method (Promega).
3. Results and Discussion
3.1. Chemistry
The synthetic route followed for the preparation of 2-(2-adamantyl)piperidine deriva-
tives 11, 13a, b, and 15 is illustrated in Scheme 2. Tertiary alcohol 6 was synthesized from
the reaction of adamantanone 5 and 2-pyridinyl lithium. Catalytic hydrogenation of the

266
D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
O
N
N
H
a
b, c
d
OH
OH
5
7
6
+
N
Cl-
N
H
f
N
e
Cl
H
H
8
10
9
N
H
N
N
j
g
COR
CH2R
11
12 a: R=OEt
13 a: R=H
b: R=CH3
b: R=CH3
h
N
N
N
i
j
COCH2Br
COCH2
N
CH2CH2 N
12c
14
15
Scheme 2. Reagents and Conditions: (a) 2-pyridinyl lithium, Et2O/THF, ꢀ60 ꢁC (82%); (b) gas HCl, EtOH; (c)
H2/PtO2, EtOH and then Na2CO3 10% (97%); (d) SOCl2, CH2Cl2, 6 h reflux; (e) KOH, EtOH, room temperature
for 24 h under argon and then gentle reflux for 3 h (61% from 7); (f) NaBH4, MeOH, 0–5 ꢁC and then RT for 5 h
(94%); (g) RCOCl, Et3N, Et2O or THF, 0–5 ꢁC and then room temperature for 24 h (84–94%); (h) BrCH2COCl,
K2CO3, CH2Cl2/H2O (86%); (i) piperidine, benzene, 0 ꢁC for 30 min and then room temperature for 24 h (60%);
(j) LiAlH4, THF, 15 h reflux (50–83%).
hydrochloride form of 6 over PtO2 catalyst led to the aminoalcohol 7. Reaction of the
alcohol 7 with SOCl2 gave the corresponding chloride 8 as hydrochloride. Elimination
reaction of the chloride 8, in refluxing KOH/EtOH solution, produced 2-piperideine 10,
possibly via the unstable enamine 9. Imine 10 was treated with sodium borohydride to give
the parent 2-(2-adamantyl)piperidine 11. The latter was N-alkylated to the piperidines
13a,b through LiAlH4 reduction of the compounds 12a,b. Diamine 15 was prepared
through LiAlH4 reduction of the piperidinoacetamide 14.
The synthetic routes followed for the preparation of the 3-(2-adamantyl)pyrrolidines
27, 21a–g are illustrated in Schemes 3, 4. N-Substituted pyrrolidines 21a–g were synthe-
sized according to Scheme 3, using N-alkyl-2-pyrrolidinones 17a–g as starting materials,
prepared through N-alkylation of the 2-pyrrolidinone 16. The N-alkyl-2-pyrrolidinones
17a–g were converted to the corresponding 2-oxo-3-pyrrolidinyl lithium form which react-
ed with 2-adamantanone 5 to produce the alcohols 18a–g. These alcohols were dehydrated
to form the methylene lactams 19a–g. Subsequent catalytic hydrogenation afforded the
3-(2-adamantyl)-2-pyrrolidinones 20a–g. Reduction of the lactams 20a–g with LiAlH4
yielded the compounds 21a–g.

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
267
R
N
N
O
R
O
b, c
a
d
e
OH
O
O
N
N
H
R
17a-g
18a-g
19a-g
16
N
O
R
N
R
17-21
a: R=CH3
b: R=C2H5
f
c: R=n-C3H7
d: R=n-C4H9
e: R=CH2CH2N(CH3)2
20a-g
21a-g
f: R=CH2CH2N(C2H5)2
N
g: R=CH2CH2
Scheme 3. Reagents and Conditions: (a) NaH, RI or HClÆNR2(CH2)2Cl, benzene, 3–6 h 60–70 ꢁC (23–58%); (b)
LDA, ꢀ70 ꢁC; (c) adamantanone, THF, ꢀ80 ꢁC and then HCl 5%, 0 ꢁC (73–95%); (d) TsOH, benzene, reflux (79–
96%); (e) H2, PtO2, ethanol, 40 lb/in2, room temperature 15–24 h (quant.); (f) LiAlH4, THF, 20–25 h reflux (72–
89%).
The parent NAH pyrrolidine 27 was synthesized using the N-trimethylsilyl-2-pyrrolid-
inone 22 as starting material (Scheme 4). Lithiation of the lactam 22 and subsequent reac-
tion with 2-adamantanone 5 afforded the alcohol 23. Compound 23 was treated with
thionyl chloride and the resulting mixture of 24 and 25 was treated with ethanolic potas-
sium hydroxide solution to afford methylenelactam 25. Catalytic hydrogenation of the
unsaturated compound 25 and subsequent LiAlH4 reduction of the pyrrolidinone 26
resulted in the pyrrolidine 27.
The preparation of the parent pyrrolidine 27 through demethylation of the N-methyl
derivative 21a failed to succeed. Although, the reaction of N-methylpyrrolidine 21a with
2,2,2-trichloroethyl chloroformate gave the corresponding carbamate, treatment of the lat-
ter with Zn/AcOH failed to produce the NAH derivative [8]; instead, the N-methyl deriv-
ative 21a was identified to be the reaction product.
Scheme 5 depicts the synthetic pathway followed for the synthesis of 2-(2-adamantylm-
ethyl)piperidine derivatives 30, 32a–c, and 35a–d. Tertiary alcohol 28 was synthesized by
the reaction of adamantanone 5 with 2-pyridinylmethyl lithium. Dehydration of the alco-
hol 28, by means of p-TSA, afforded alkene 29. Catalytic hydrogenation of the hydrochlo-
ride form of 29 over PtO2 catalyst led to the parent piperidine 30. This was N-alkylated to
the piperidines 32a–c through LiAlH4 reduction of the compounds 31a–c. Diamines 35a–d
were prepared via LiAlH4 reduction of dialkylaminoacetamides 34a–d.
The synthetic routes leading to 2-alkyl substitution of the biologically important piper-
idine ring have been recently the subject of intense research [9]. The procedures depicted in
Schemes 2, 5, and others published elsewhere [4h,4j], can be used to introduce bulky cyclo-
alkyl groups at C-2 piperidine ring position. The routes described in Schemes 3 and 4 can
be considered as general for the 3-substitution of c-lactam and pyrrolidine ring with cyclo-
alkyl groups.

268
D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
H
N
O
b, c
a
d
OH
O
O
N
N
H
SiMe3
22
23
16
H
N
N
O
H
N
O
H
O
e
f
Cl
+
24
25
25
N
H
N
O
H
g
26
27
Scheme 4. Reagents and Conditions: (a) NaH, Me3SiCl, benzene, 12 h room temperature (67%); (b) LDA,
ꢀ70 ꢁC; (c) adamantanone, THF, ꢀ80 ꢁC and then HCl 5%, 0 ꢁC (95%); (d) SOCl2, CHCl3, reflux 3 h (e)
CH3ONa/CH3OH, reflux (53% from 23); (f) H2, PtO2, EtOH, 40 lb/in2, 24 h room temperature (quant.); (g)
LiAlH4, THF, 15 h reflux (68%).
3.2. Conformational features
Some of our research aimed at the description of the conformational and dynamic
NMR properties of potent compounds in aminoadamantane series [4i,10]; the results
can be useful in the future understanding of SAR relationships.
The most interesting conformational feature in piperidine 11+H and pyrrolidine 27+H
is the conformation around C2AC20 or C3AC20 bond (Scheme 6). The molecular mechan-
ics calculations [5–7] suggest that the anti-conformation of the exocyclic CAC bond and
the equatorial adamantyl orientation are by far preferable. All the remaining conformers
are higher in energy by more than 2.2 or 3.3 kcal molꢀ1 and are considered unpopulated at
room temperature, according to equation DGo = ꢀRTlnK.
Experimental evidence for the above conformations could be extracted from the NMR
experiments. The chair conformation of the piperidine ring in compound 11+H is consis-
tent with the signal of H-6eq at 3.47 ppm which appears as a doublet, J = 12.3 Hz (one
large coupling with H-6ax), and the quartet assigned at H-6ax, J ꢁ 11.7 Hz, because of
its three large couplings with 6eq, 5ax, and N+H protons. The C2 proton signal appears
as a quartet with J = 10.2 Hz, because C2H has three large couplings with 20, 3ax, and
N+H protons, suggesting the predominance of a conformation in which that proton is axi-
al and the adamantyl group is equatorial and a trans conformation around C2AC20 bond.
The NOE spectroscopy gave also information consistent with the above observations; the

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
269
O
a
N
b
N
c,d
OH
5
28
29
e
f
N
N
N
C
H
R
RCH2
30
O
32 a: R=H
b: R=CH3
31 a: R=OEt
b: R=CH3
c: R=cyclopropyl
c: R=cyclopropyl
g
N
N
h
f
N
C
C
CH2
O
O
33
CH2Br
CH2NR2
CH2NR2
34a-d
35a-d
N
N
,
34a-d, 35a-d NR2=NMe2 , NEt2 ,
O
Scheme 5. Reagents and Conditions: (a) 2-pyridinylmethyl lithium, THF, ꢀ20 ꢁC, 2 h, (68%); (b) p-TSA,
benzene, reflux, 15 h, (93%); (c) gas HCl, EtOH; (d) H2, PtO2, EtOH, 40 lb/in2, and then Na2CO3 10% (98%); (e)
RCOCl, Et3N, ether, 0–5 ꢁC, and then room temperature, 3–8 h (82–92%); (f) LiAlH4, THF, 15 h reflux (71–
89%); (g) BrCH2COCl, K2CO3, CH2Cl2/H2O, 0–5 ꢁC, 3 h (93%); (h) R2NH, benzene, 0–5 ꢁC 30 min, and then
room temperature for 24 h (80–89%).
nOe
5'
9'ax
nOe
H
H
H
H
10'
6'
7'
5'
H
9'ax
H
H
3'
1'
H
H
1'
H
4'ax
8'
5
8'
H
1'
3
6'
7'
4
H
H
7'
6'
4'ax
8'
2
H
nOe
2'
4
9'ax
2'
H
3
2'
H
4'ax
5'
2
N
1
H
H
3'
2
4
H
H
H
3
H
1
N
H
3'
10'
nOe
H
H
5
6
6
H
H
C
H
5
+
H
H
+
H
H
10'
H
1N
H
H
H
H
H
27+H
H
H
nOe
30+H
11+H
Scheme 6. Most stable conformers for compounds 11+H, 27+H, and 30+H (the half arrow in 11+H indicated an
NOE observed in its base form).
dipolar correlation between H2 and H4ax0, H9ax0 protons confirms the anti relationship of
H2 and H20 protons, while the nOe between H20 and H6 protons—observed in 11—is in
agreement with the equatorial adamantyl group position.
In pyrrolidine 27+H the adamantane HA20 signal shape is informative for the confor-
mation around H3AC3AC20AH20 dihedral angle. However, this was not resolved for
27+H but appears as a doublet (J ꢁ 10 Hz) at 1.39 ppm in the proton NMR spectrum
of the free amine form 27. Thus, the conformation by rotation around C3AC20 bond must
be anti. In addition, the dipolar correlation between H20 and H4ax is consistent with the
equatorial adamantyl group position (Scheme 6).

270
D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
It is striking that despite 1,1,2,2-tetrasubstituted ethanes with large substituents prefer a
gauche over anti conformer to adopt [11], in compounds 11 and 27, which belong to this
class of compounds, the conformation by rotation around exocyclic carbon–carbon bond
is anti.
For piperidine 30+H molecular mechanics locate several low energy conformers that
differ in adamantyl orientation (equatorial or axial), heterocycle conformation and
C20ACH2 or C2ACH2 bond rotation. The chair conformation of the piperidine ring is
again consistent with the shape of H-6eq and H-6ax signals (3.47 ppm, d, J = 13 Hz
and 3.0 ppm, q, J = 12 Hz, respectively). The strong NOE between piperidine 2ax and
6ax protons provide evidence for the equatorial position of 2-adamantylmethyl group
1
(Scheme 6). The H 1D spectra or 2D NOESY experiments run for 30 or 30+H were
not informative for the conformation by rotation around C20ACH2 and C2ACH2 bonds
due to the complexity of the signal patterns or several signal overlapping, respectively.
However, molecular mechanics calculations locate the conformer having an a,gꢀ arrange-
ment of the two CHACH2 segments as the most stable, see Scheme 6 (the next more stable
was 1.2 kcal molꢀ1 higher in energy).
The parent molecules 11+H, 27+H, and 30+H acquire two pharmacophoric groups i.e.,
the amine and adamantyl groups. In this context, it is interesting to note that for 11+H,
+
+
0
˚
C2 AN1 distance is calculated to be 2.5 A, whereas for 27 H and 30 H, N1 is 3.7 and
0
˚
3.8 A, respectively, away from adamantyl C2 . N-Substituted derivatives of the parent
amines have, in general, the same heterocycle conformation, while adamantyl group
and N-substituent group prefer to adopt mainly an equatorial and axial orientation,
respectively [12].
3.3. Antiviral potency evaluation
3.3.1. Influenza virus
The potency of the new aminoadamantane heterocycles 11, 13a,b, 15, 20c,d, 27, 21a–f,
30, 32a–c, and 35a–d was examined in vitro against influenza A (H3N2) and B viruses, and
was compared to the activity of amantadine 1a, rimantadine 1b, and ribavirin 3. H3N2
strain is responsible for the current winter epidemics. The potency of 2-rimantadine 4
was also included for comparison (Table 1). The methods and antiviral assays used were
as previously reported [13].
Piperidine 11 was more potent than amantadine 1a and equipotent to the rimantadine
1b against influenza A. The effect of including the 1-aminoethyl pharmacophore group of
2-rimantadine 4 into a saturated nitrogen heterocycle was investigated; potency was
retained, as it is obvious by comparing the EC50 values of 2-(2-adamantyl)piperidine 11
and 2-rimantadine 4.
As regards the next series of compounds, it appears that the parent pyrrolidine 27 and
diamines 21e–g exhibited a good potency.
Whereas N-alkylation of the parent amine 27, resulting in 21a–d, caused a dramatic
reduction in antiviral potency, N-dialkylaminoethyl substitution led to the active analogs
21e–g. The specific activity of these diamines could be attributed to three pharmocophore
groups, the adamantyl and the two amine groups.
In the third series of compounds, 30, 32a–c, and 35a–d, the potency of the diamine
derivatives 35a–d was striking. Overall, of all the compounds tested, these derivatives were
the most potent.

D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
271
Table 1
Anti-influenza (H3N2) virus A activity and cytotoxicity of aminoadamantane derivatives 1–4, 11, 13a,b, 15, 20e,f,
27, 21a–g, 30, 32a–c, and 35a–da in MDCK cellsb
c
d
Compound
EC50 (lM)
MCC50 (lM)
11
13a
25
>100
>100
25.1
5.0
14.7
11.1
47.5
88.9
93.3
92.8
9.4
P977
977
143
13b
15
4.6
27
20e
124.4
122.4
92.0
P156.4
148.2
140.9
134.3
78.7
20f
21a
21b
21c
21d
21e
21f
21g
12.9
25.5
22.0
35.4
84.8
47.0
5.9
74.6
14.6
30
32a
185.3
176.1
132.4
123.9
93.2
32b
32c
35a
35b
7.2
88.5
35c
35d
3.6
86.7
81.4
49.1
19.1
31.1
122.9
111.9
1333
>1160
>1160
P1024.6
Amantadine, 1a
Rimantadine, 1b
2-Rimantadine, 4
Ribavirin
a
Aminoadamantanes 1a–b, 4, 11, 13a,b 15, 20c,d, 27, 21a–g, 30, 32a–c, and 35a–d were tested as hydrochlorides
or fumarate salts.
b
Abbreviations and strains used: MDCK, Madin-Darby canine kidney cells; influenza A H3N2 (X31).
Effective concentration or concentration required to reduce virus-induced cytopathogenicity by 50%.
Minimum cytotoxic concentration or concentration required to cause a microscopically detectable alteration
c
d
of normal cell morphology. All data represent mean values for at least two separate experiments.
All compounds tested were found to be inactive against influenza B virus, which is in
accordance with their putative mode of action, that is, an interaction with the influenza
A M2 protein which is absent from influenza B virion.
3.3.2. Broad-spectrum antiviral activity evaluation
All the new compounds were inactive against HIV-1 and -2; only a marginal activity
was exhibited by a diamine derivative of compound 11 against HIV-1. It is worth noting
that although the diamines 15 and 21e–g were inactive anti-HIV agents, the diamine deriv-
atives of 2-(1-adamantyl)piperidine (3, n = 1) showed some activity against HIV-1 [4c].
This result could trigger further research in this field.
The aminoadamantane derivatives prepared were also evaluated, according to previ-
ously reported methods [13,14], against the following viruses: parainfluenza type 3, herpes
simplex virus type 1 (HSV-1), thymidine kinase-deficient (TKꢀ) HSV-1, herpes simplex

272
D. Setaki et al. / Bioorganic Chemistry 34 (2006) 248–273
virus type 2 (HSV-2), vaccinia, vesicular stomatitis, polio 1, Coxsackie B4, Sindbis, Sem-
liki forest, Reo 1, varicella—zoster virus (VZV), TKꢀ VZV, human cytomegalovirus
(HCMV). The compounds did not afford specific activity against any of these viruses at
non-toxic concentrations.
4. Conclusion
The major aim of this study was to examine the anti-influenza A virus potency of some
series of 2-adamantyl substituted amines. All the parent amines 11, 27, and 30 were potent.
When 1-aminoethyl pharmacophore group of 2-rimantadine 4 (2-isomer of rimantadine) is
included into a saturated nitrogen heterocycle, see compound 11, potency was retained.
Diamine derivatives 21e–g and in particular 35a–d were found to be potent anti-influenza
A agents. It has been proposed by molecular modelling studies, that amantadine 1 blocks the
M2 channel activity because its two pharmacophoric groups, the adamantyl group and
amine groups, are complementary in shape, hydrophobicity, and polarity with the luminal
space of M2 protein [2]. The anti-influenza virus A potency of these diamines may be
determined by three pharmocophore groups, the adamantyl and the two amine groups.
In the parent amines, which proved to be active compounds, the distance between nitro-
0
˚
gen and adamantyl pharmacophoric groups was different; NAC2 distance is 3.7, 3.8 A for
+
+
+
˚
27 H, 30 H and 2.5 A for 11 H. Since the protonated amine functionalities interact with
the same H-acceptor group this suggest that M2 receptor site can accommodate different
in size and orientation lipophilic cages. The parent heterocycles 11 and 27 adopt a fixed
trans conformation around C2AC20 bond and an equatorial adamantyl group. These find-
ings and others previously reported will help future molecular modelling studies aiming to
understand how aminoadamantane compounds interact with their receptor protein.
Acknowledgment
This research activity was supported by a research grant from the Special Account for
Research Grants of National and Kapodistrian University of Athens, Greece.
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