Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine analogues from terpenic cyclanones

Article abstract of DOI:10.1016/j.ejmech.2009.10.039

This work describes the enantioselective synthesis of a new series of terpenic chiral 9-aminotetrahydroacridine analogues. Several chiral ketones were synthesized from natural monoterpenes in an optically active form and subjected to the cyclodehydration reactions with anthranilonitrile in the presence of BF₃·Et₂O as catalyst. The 9-aminotetrahydroacridine analogues were tested as acetylcholinesterase (AChE) inhibitors. Based on qualitative structure-activity relationship some trends are suggested.

Full text of DOI:10.1016/j.ejmech.2009.10.039

European Journal of Medicinal Chemistry 45 (2010) 526–535
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine
analogues from terpenic cyclanones
a
a
a
a
´
Diego dos Santos Pisoni , Jesse Sobieski da Costa , Douglas Gamba , Cesar Liberato Petzhold ,
a
a,
b
*
´
Antonio Cesar de Amorim Borges , Marco Antonio Ceschi , Paula Lunardi ,
Carlos Alberto Saraiva Gonçalves b
a
´
Instituto de Quımica, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500, Campus do Vale, 91501-970 Porto Alegre, RS, Brazil
Departamento de Bioquımica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Predio Anexo, 90035-003, Brazil
b
´
´
a r t i c l e i n f o
a b s t r a c t
Article history:
This work describes the enantioselective synthesis of a new series of terpenic chiral 9-amino-
tetrahydroacridine analogues. Several chiral ketones were synthesized from natural monoterpenes in an
optically active form and subjected to the cyclodehydration reactions with anthranilonitrile in the
presence of BF3$Et2O as catalyst. The 9-aminotetrahydroacridine analogues were tested as acetylcho-
linesterase (AChE) inhibitors. Based on qualitative structure–activity relationship some trends are
suggested.
Received 4 June 2009
Received in revised form
14 October 2009
Accepted 27 October 2009
Available online 10 November 2009
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
Acridines
Tacrine
AChE inhibitory activity
1. Introduction
metabolite of tacrine, has been chosen for clinical trial. 6-Fluoro-
tacrin-1-ol (1c) has been reported to be slightly more potent than
Alzheimer’s disease (AD) is a neurodegenerative disorder that
results in the progressive and irreversible loss of higher brain
functions, including memory, cognition and reason [1–4]. Current
treatment approaches for this disease remain primarily symp-
tomatic, with the major therapeutic strategy being based on the
cholinergic hypothesis [1,5–7] and specifically on acetylcholines-
terase inhibition [8–10]. Under this hypothesis, the first approved
drug for the management of AD was tacrine (1a, 9-amino-1,2,3,4-
tetrahydroacridine or THA, Fig. 1), a potent inhibitor of both
acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).
However, the use of tacrine in AD has been limited by serious side
effects such as hepatotoxicity, which often forces patients to dis-
continue treatment [11–14]. Tacrine has also been shown to possess
a much broader pharmacological profile than cholinesterase inhi-
bition: blockage of potassium channels [15,16], inhibition of the
neuronal monoamine uptake processes [17,18], and inhibition of
monoamine oxidase [19], have all been reported.
tacrine, and 6-chlorotacrin-1-ol (1d) 30 times more potent [21]. In
particular 6-chlorotacrine (1e) has been found to be more potent
than other substituted analogues [22,23].
(ꢀ)-Huperzine A (HA, 2), an alkaloid first isolated from Huperzia
serrata [24], is another AChE inhibitor. (ꢀ)-HA (2) is currently in the
phase IV clinical trial for AD treatment in China and in clinical trials
for the treatment of age-related memory deficiency in the United
States [25,26].
Despite achievements in synthesis and pharmacomodulation,
huprines 3, a series of tacrine-huperzine A hybrids designed by the
combination of the 4-aminoquinoline moiety of tacrine with the
carbobicyclic substructure of (ꢀ)-HA (2), have recently emerged as
a new class of very potent and selective AChE inhibitors of interest
for the treatment of AD [27]. At present, the most powerful
huprines are the so-called huprine X (3a) and huprine Y (3b) [28].
Indeed, huprines can be regarded as tacrine analogues modified at
the cyclohexene ring, namely at positions C1 and C3 of the tacrine
system, also in enantiopure forms [29–32].
In this regard, few reports exist in the literature dealing with
enantioselective modification of tacrine structure in the saturated C-
Ring (C1–C4 positions) [33,34]. In 1997 McKenna and co-workers, in
their reported results on the synthesis of novel THA analogues,
described the first example of a chiral THA analogue, which was
An important contribution to the development of tacrine related
agents showed that tacrin-1-ol (1b, velnacrine) [20], an active
* Corresponding author. Tel.: þ55 51 33087205; fax: þ55 51 33087304.
E-mail address: mceschi@iq.ufrgs.br (M.A. Ceschi).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.10.039

D.dos Santos Pisoni et al. / European Journal of Medicinal Chemistry 45 (2010) 526–535
527
R
Me
NH2
R
1
N
H
N
Cl
2
3
O
X
N
Me
NH2
NH2
(-)-huperzine A
2
4
1a, X = R = H
1b, X = H, R = OH
1c, X = F, R = OH
3a (-)-huprine X R = Et
3b (-)-huprine Y R = Me
1d, X = Cl, R = OH
1e, X = Cl, R = H
Fig. 1. AChE inhibitors of interest for the treatment of Alzheimer’s disease.
obtained by the condensation reaction of anthranilonitrile and (R)-
(þ)-camphor in the presence of BF3$Et2O as catalyst, in 18% yield [16].
Recently, Frideling and co-workers described the synthesis of a series
of chiral tetrahydroacridin-9-ones, derived from chiral cyclanones
such as (R)-(þ)-3-methylcyclohexanone, (2S,5R)-(ꢀ)-menthone, (R)-
(þ)-pulegone, (R)-(ꢀ)-carvone and (5R)-(þ)-dihydrocarvone by the
reaction of anthranilic acid under classical heating or under micro-
wave irradiation [33]. Also in this work, Frideling and co-workers
described the synthesis of 9-aminotetrahydroacridines derived from
the cyclodehydratation reaction between cyclohexanones (men-
thone, 3-methylcyclohexanone) and anthranilonitrile using micro-
wave irradiation, but in this case yields were between 12% and 18%,
even using solid supports (silica, basic alumina, montmorillonite K10
and KSF).
Terpenes as chirons have an intrinsic advantage over other
natural products in the ‘chiral pool’, as they are amenable to
restructuring into cyclic and acyclic fragments that can be directly
incorporated into the carbocyclic framework of complex target
structures.
As part of our studies directed towards the enantioselective
synthesis of building blocks from terpenes [35,36], we describe
herein the enantioselective synthesis of a new series of chiral tetra-
hydroacridine analogues 7 (Scheme 1).
yield by a synthetic route previously reported by our group
(Scheme 2) [35]. The key strategic feature is the thiophenoxide
opening of the a,b-epoxy ketones 31 with concomitant retro-aldol
expulsion of acetone and subsequent desulfenylation of 32 by thi-
ophenoxide to afford (S)-12. Hydrogenation of the isopropenyl
double bond in (S)-12 using PtO2 as the catalyst in methanol at
1 atm of hydrogen furnished the (S)-(ꢀ)-3-isopropylcyclohexanone
(8) in 94% yield, which was used directly in the cyclocondensation
reaction.
As an extension of this synthetic route, the a,b-epoxy ketones 31
were subjected to deoxygenation with the use of an equimolar
amount of Mo(CO)6 under toluene reflux to afford a mixture of
enone 33 and the expanded 1,3-diketone 34, which were separated
by column chromatography in a ratio of 5 : 1 (Scheme 3). The
selective hydrogenation of 33 in the presence of Rh(PPh)3Cl affor-
ded 20 in high yield (94% after purification by column chroma-
tography). Hydrogenation of 34 using PtO2 as the catalyst led to 19
in 85% yield. The reduction of the enone 33 using sodium tellurium
hydride led to a mixture of ketones 35a and 35b in 87% yield, in
a ratio of 2:1, which were separated by column chromatography
(Scheme 4). Hydrogenation of the isopropenyl double bond in 35a
using PtO2 as the catalyst afforded trans-diisopropylcyclohexanone
(24). In the case of cis-isomer 35b, isomerization of the isopropyl
The construction of terpenic chiral THA analogues from
synthetic ketones relies on availability for specific reactions to
elaborate and couple them.
group in a-position to the carbonyl group was observed, when
subjected to hydrogenation under a variety of conditions in the
presence of several catalysts.
For this purpose, several chiral ketones 5 were synthesized from
natural monoterpenes in an optically active form and subjected to
the cyclodehydration reactions with anthranilonitrile (4) in the
presence of BF3$Et2O as catalyst. The new series of chiral tetrahy-
droacridine analogues thus obtained were assayed for their ability
to inhibit AChE.
The acid-catalyzed retro-aldol reaction of (R)-pulegone (36)
(HClaq, reflux, 8 h), using standard conditions [37] led in 70% yield
to (R)-3-methylcyclohexanone (10), obtained without loss of
optical activity. (R)-3-methylcyclopentanone (15) was also
prepared from (R)-pulegone (36) in 66% yield in two reaction steps.
Oxidative cleavage of (R)-pulegone using RuCl3/NaIO4 afforded the
(R)-3-methyladipic acid 37 [38]. Next, 37 was subjected to ketonic
decarboxylation and cyclization processes in the presence of cata-
lytic Na2CO3 under thermal conditions (Scheme 5) [39]. Mecha-
nistic considerations, for the later reaction, involve an initial
ketonic decarboxylation, followed by the attack of an unstable
carbanion to the second carboxyl group, leading to the cyclo-
pentanone 15. (R)-2,2,5-trimethylcycloheptane-1,3-dione (17) was
2. Results and discussion
2.1. Chemistry
Regarding the synthesis of the terpenic chiral ketones used in
this work (Table 1), the (S)-(ꢀ)-3-isopropenylcyclohexanone (12)
was prepared from (S)-perillaldehyde (30) in approximately 45%
obtained in high yield (90%) by
a
BF3$Et2O-catalyzed
NH2
N
N
C
C
BF3.Et2O
(CH2)n
+
(CH2)n
(CH2)n
*
R
O
NH2
R
*
R
*
N
N
H
n = 1,2,3
4
5
6
7
Scheme 1. Cyclocondensation reaction between anthranilonitrile and chiral cyclanones.

528
D.dos Santos Pisoni et al. / European Journal of Medicinal Chemistry 45 (2010) 526–535
Table 1
9-Aminotetrahydroacridines synthesized from chiral terpenic cyclanones.
Entry
Substrate
Product
[a
]
D
(conc.)a
Yield (%)b
1
ꢀ52 (1.64)
84
2
þ38 (1.50)
82
3
Complex Mixture
4
ꢀ18 (0.29) for 14a
68
5
ꢀ2 (1.10) for 16a
75
6
þ17(1.5)
78
7
No Reaction
8
ꢀ52 (1.64)
57

D.dos Santos Pisoni et al. / European Journal of Medicinal Chemistry 45 (2010) 526–535
529
Table 1 (continued )
Entry
Substrate
Product
[a
]
D
(conc.)a
Yield (%)b
9
þ38 (1.50)
65
10
þ38 (1.50)
52
11
ꢀ111 (0.45)
58
12
ꢀ111 (0.45)
35
13
ꢀ45 (0.72)
48
(continued on next page)

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D.dos Santos Pisoni et al. / European Journal of Medicinal Chemistry 45 (2010) 526–535
Table 1 (continued)
Entry
Substrate
Product
[a
]
D
(conc.)a
Yield (%)b
14
ꢀ32 (1.70)
57
15
þ15 (1.42)
63
a
Optical rotations were measured in CHCl3 at 20 ꢁC.
All yields refer to purified product.
b
rearrangement from pulegone oxide [40]. Also, the cis and trans
stereomers of methyl and phenyl (R)-pulegone derivatives 22a,
22b, 21a and 22b were easily prepared by conjugated addition of
Me2CuLi and PhMgBr/CuI respectively, as previously described in
the literature [41,42].
(S)-3-isopropylcyclopentanone (13) was prepared as depicted in
Scheme 6. The synthetic route includes the initial conversion of (S)-
perillaldehyde (30) in allylic alcohol 38. Subsequent epoxidation of
38 to 39 followed by oxidative cleavage afforded (S)-3-iso-
propylhexanedioic acid (40) [43,44]. In the next step, diacid 40 was
heated at 350 ꢁC in the presence of a catalytic amount of Na2CO3 to
give 13 in 35% general yield from (S)-perillaldehyde (30).
(þ)-Nopinone (26) was prepared from
b-pinene using RuCl3
(0.023 equiv) and NaIO4 (2.1 equiv) in 81% yield [45,46]. It is
noteworthy that this method offers advantages over the traditional
ozonolysis used to effect this operation, which is known to be quite
hazardous due to occurrence of explosions. The optically active cis-
verbanone (28) was prepared from the (S)-verbenone in high
selectivity and good yield (78%), employing catalytic transfer
hydrogenation in the presence of limonene and 10% Pd/C, according
to the method described by Holleben et al. [47].
The cyclodehydratation reactions between the ketones and
anthranilonitrile were performed according to the standard
methodology for the synthesis of tacrines, by the Lewis acid
promoted Friedla¨nder reaction. It is noteworthy from a mechanistic
viewpoint that an intermediate, probably enamine 6, was first
formed, which then converted to tetrahydroacridine (Scheme 1).
Among several catalysts reported in the literature, such as ZnCl2
[48], AlCl3 [49], P2O5 [50], and BF3$Et2O [16], the catalyst of choice
for this work was BF3$Et2O. As described in the literature, also in
O
H
SPh
O
PhSH
NaH
O
O
Ref. 28
50
90
31
32
30
O
O
Mo(CO)6
O
PhMe, reflux
O
31
+
83%
34
33
H2, PtO2
85%
12
H2, Rh(PPh3)3Cl
94%
H2, PtO2
94
O
O
O
O
19
8
20
Scheme 2. Synthetic pathway for the preparation of compound 8.
Scheme 3. Synthetic pathway for the preparation of compounds 19 and 20.

D.dos Santos Pisoni et al. / European Journal of Medicinal Chemistry 45 (2010) 526–535
531
The
cyclocondensation
reaction
using
(S)-(ꢀ)-3-iso-
propylcyclohexanone (8) and (R)-(þ)-3-methylcyclohexanone (10)
occurred in a completely regioselective manner giving, respectively,
optically active 9 and 11 in good yields (entries 1 and 2). Not all the
substrates tested proved as susceptible to the cyclocondensation
reaction. In the case of (S)-(ꢀ)-3-isopropenylcyclohexanone (12)
(entry 3), the acidic reaction conditions brought about isomeriza-
tion to a substantial extent and a complex mixture was observed by
NMR analysis.
O
O
O
NaTeH
87%
+
35a
35b
33
2 : 1
As can be seen from entries 4 and 5, both cyclopentanones 13
and 15 afforded a mixture of the corresponding isomers (14a, 14b in
a ratio of 3.5:1 and 16a, 16b in a ratio of 3:1), which proved to be
difficult to separate by column chromatography. In both cases,
a small amount of the major isomers 14a and 16a could be isolated.
(R)-2,2,5-trimethylcycloheptane-1,3-dione (17, entry 6) and (S)-5-
isopropyl-2,2 dimethylcycloheptane-1,3-dione (19, entry 7) were
subjected to the cyclocondensation reaction. In the case of 17 as
substrate, the reaction led to the chemoselective formation of the
tacrine analogue 18 in 78% yield. However, isopropyl-substituted
1,3-dione 19 was not reactive under similar reaction conditions and
starting material was recovered unchanged. Next, we performed the
reaction with enone 20 (entry 8). Under the reaction conditions
employed, the cyclocondensation reaction led only to 9 (identical to
that obtained from (S)-(ꢀ)-3-isopropylcyclohexanone). The
cleavage of the methylethylidene group observed has precedence in
the reaction of cyclocondensation between pulegone and anthra-
nilic acid, under thermal or microwave irradiation conditions, to
afford the corresponding 3-methyltetrahydroacridinone [33].
Fragmentation was also observed in the case of both stereo-
mers 21a and 21b (entries 9 and 10), with the elimination of the
methyl-1-phenylethyl group, yielding the product 11. Using
(2S,5R)-2-tert-butyl-5-methylcyclohexanone (22a, trans isomer),
the formation of the trans isomer 23 was observed. Also, 23 was
observed as the product performing the reaction with the cis-
isomer 22b, which underwent isomerization to the most stable
form.
H2, PtO2
90%
O
24
Scheme 4. Synthetic pathway for the preparation of compound 24.
O
Na2CO3
350 oC
O
NaIO4/RuCl3
92%
OH
HO
72%
O
O
15
37
36
Scheme 5. Synthetic pathway for the preparation of compound 15.
When the reaction was performed using (2R,5S)-2,5-diisopro-
pylcyclohexanone (24) as starting material, the cyclocondensation
reaction led to the corresponding product 25 and no fragmentation
or isomerization products were observed in this case.
The bicyclic ketones (þ)-nopinone (26) and cis-verbanone (28)
afforded the respective tetracyclic chiral tacrine analogues 27 and
29 (entries 14 and 15). It is noteworthy that no side product from
our hands, BF3$Et2O proved to be an effective catalyst for the
cyclodehydratation reactions, giving the best overall yield and
highest purity, using cyclohexanone and anthranilonitrile as the
model substrate [16,34]. Next, we examined the reactivity and
product selectivity of the cyclocondensation reaction with several
chiral terpenic cyclanones synthesized for this purpose, as depicted
in Table 1.
HO
O
H
HO
1. LiAlH4, THF
O
2. H2, PtO2, MeOH
mCPBA, CH2Cl2
84%
83% (for two steps)
30
38
39
O
O
Na2CO3
1. H5IO6,
H2O : THF
350 oC
OH
HO
39
75%
O
2. NaClO2, NaH2PO4
H2O2
40
13
68% (for two steps)
Scheme 6. Synthetic pathway for the preparation of compound 13.

532
D.dos Santos Pisoni et al. / European Journal of Medicinal Chemistry 45 (2010) 526–535
Table 2
molecular targets such as butyrylcholinesterase or biochemical
pathways, such as glutamate neurotransmission or amyloid
precursor protein processing, pointed out as involved in the
symptomatology of Alzheimer’s disease [52,53].
Structures and ChE inhibitory activities of tacrine analogues.
Compound
AChE inhibition (IC50) (m
M)a
Tacrine (1a)
9
0.088
0.816
1.384
2.446
0.061
0.288
1.352
7.217
1.931
2.616
11
14a
16a
18
23
25
27
29
3. Conclusion
Several synthetic routes were used to access specific chiral
ketones in an optically active form. These ketones were subjected to
the cyclodehydration reactions with anthranilonitrile in the pres-
ence of BF3$Et2O as catalyst to afford the chiral 9-amino-
tetrahydroacridine analogues in good yields. The products were
obtained in high selectivity except in the cases of substituted five-
membered ketones 13 and 15. Compound 16a was an effective
inhibitor of AChE and slightly more potent than prototype tacrine. It
is noteworthy that the decrease of inhibitory activity is a conse-
quence of the increasing bulk of alkyl group at C-1 position.
a
ꢂ95% Confidence limits.
ring opening of the bicyclic ketones 26 and 28 was observed under
the reaction conditions employed.
The new 9-aminotetrahydroacridines synthesized in this work
were identified by the usual spectroscopic and analytical methods,
and also by comparison with the 1H and 13C NMR assignment of the
9-aminotetrahydroacridines and tetrahydroacridin-9-ones previ-
ously synthesized by Frideling [33].
4. Experimental protocols
Melting points were measured on an Electrothermal IA 9100
digital melting point apparatus. IR spectra were measured on
a Mattson Galaxy Series FT-IR 3000 (model 3020). 1H and 13C NMR
spectra were recorded on a Varian Gemini 300 MHz spectrometer.
2.2. AChE inhibition evaluation
The chemical shifts are expressed as
d (ppm) relative to TMS as an
To determine the potential interest of the chiral terpenic THA
analogues synthesized, AChE (rat cortex) inhibitory potency was
measured by the principle of the Ellman method (Table 2) [51]. To
allow comparison of the results, tacrine (1a) was used as the
reference compound. Analogue 16a was effective inhibitor of AChE
and slightly more potent than prototype tacrine, and the most
active in the assayed series. All the other analogues examined were
of lower activity than 1a, the least active being 25.
Structure–activity relationship analysis regarding variations
around the cyclohexene ring of tacrine and their five and seven-
membered analogues still have limited information. Also, not all
synthesized analogues reported in the literature have been sub-
jected to AChE activity evaluation [33,34].
The potency against AChE has been presumed to result from the
increased bulk and flexibility of the saturated ring [34]. Some
qualitative structure–activity relationship emerges from the above
results. The analogue 25 having a trans configuration of isopropyl
groups at the C-1 and C-4 positions in the cyclohexene ring strongly
decreases the inhibitory potency in comparison to tacrine, while, in
the analogue 23 having a trans configuration of methyl and tert-
butyl groups, the decrease of inhibitory potency is less drastic. This
result can be a consequence of steric increase caused by isopropyl
substituent at C-1 in 25, while the sterically larger tert-butyl group
at C-4 leads to a lower decrease of inhibitory potency. This is an
evidence that the bulk of alkyl substituent at C-1 plays an impor-
tant role in the inhibitory activity, rather than C-4. Further support
of this evidence comes from the comparison of the inhibitory
potency for tetracyclic chiral tacrine analogues 27 and 29. The
presence of the methyl group at C-1 in 29 leads to a significant
decrease of inhibitory potency.
In the cases of five-membered analogues 16a and 14a, a similar
loss of activity was observed by replacing the methyl group by the
isopropyl group. In the cases of 11 and 9 an inverse effect, however
less substantial, was observed by replacing the C-3 methyl group by
isopropyl. The seven-membered analogue 18 was found to be
a significantly potent inhibitor as compared with other compound
screened. In this particular case the polar carbonyl group should
account to the observed inhibitory potency. Although our results
indicate an effect of these tacrine analogs on AChE activity,
particularly compound 16a. Further studies should include other
internal standard and J standard values are given in Hz. Optical
rotations were measured in a Perkin–Elmer 341 polarimeter with
a 0.1 dm cell at a temperature of 20 ꢁC. ESI-HRMS data on the
positive mode were collected on a WatersÒ MicromassÒ Q-Tof
micro mass spectrometer YB320 with Z-spray electrospray source.
Samples were infused from a 100 mL gas-tight syringe at 30 mL/min.
The instrument settings were the following: capillary voltage
3000 V, cone voltage 40 V, source temperature 100 ꢁC, desolvation
gas temperature 100 ꢁC. Nitrogen was used as the desolvation gas.
The samples were dissolved in an acetonitrile/milliQ water 1:1
solution (TEDIA) HPLC grade, made lightly acid with five drops of
formic acid 0.1% solution. Purification by column chromatography
was carried out on silica gel 60 (70–230 mesh). Analytical thin-
layer chromatography (TLC) was conducted on Merck aluminum
plates with 0.2 mm of silica gel 60F-254.
4.1. Synthesis
4.1.1. General procedure for the preparation of tetrahydroacridines
To a solution of the ketone (1.1 equiv) in anhydrous toluene was
added anthranilonitrile (1.0 equiv) followed by addition of BF3$Et2O
(1.2 equiv) under argon. The reaction mixture was heated under
reflux during 24 h. On cooling, the toluene was decanted and, to
liberate the product, the remaining solids were treated with NaOH
2 mol Lꢀ1 solution and heated at reflux for 24 h. After cooling, the
reaction mixture was extracted with CHCl3, the organic layers were
combined and dried over Na2SO4, filtrated and the solvent was
evaporated under reduced pressure to give the desired product. The
resultant solid was purified by silica gel flash chromatography
using MeOH/CH2Cl2 or alumina chromatography using hexane/
AcOEt as eluent to give pure compounds.
4.1.1.1. (3S)-9-amino-3-isopropyl-1,2,3,4-tetrahydroacridine(9). Follo-
wing the general procedure, ketone 8 (200 mg, 1.43 mmol), toluene
(4 mL), anthranilonitrile (154 mg, 1.30 mmol) and BF3$Et2O (0.20 mL,
1.57 mmol) afforded amine 9 (264 mg, 1.10 mmol, 84%): [
a
]D ¼ ꢀ52
(c ¼ 1.64, CHCl3); m.p. 119–123 ꢁC; IR (KBr) nmax/cmꢀ1: 3489, 3330,
3170, 2954, 1637, 1577, 1500, 1427, 1377, 754; 1H NMR (CDCl3)
d 7.90
(d, 1H, J ¼ 8.4 Hz), 7.73 (d, 1H, J ¼ 8.4 Hz), 7.55 (t, 1H, J ¼ 8.3 Hz), 7.34
(t, 1H, J ¼ 8.3 Hz), 4.83 (br s, 2H, NH2), 3.10 (ddd, 1H, J ¼ 16.8, 7.8,

D.dos Santos Pisoni et al. / European Journal of Medicinal Chemistry 45 (2010) 526–535
533
2.1 Hz), 2.72 (dd, 1H, J ¼ 16.8, 10.8 Hz), 2.70 (m, 1H), 2.52 (m, 1H), 2.08
(m, 1H), 1.61 (m, 2H), 1.49 (m, 1H), 0.99 (d, 6H, J ¼ 6.3 Hz); 13C NMR
4.1.1.6. (1S,4R)-9-amino-4-tert-butyl-1-methyl-1,2,3,4-tetrahy-
droacridine (23). Following the general procedure, ketone 22a
(200 mg, 1.19 mmol), toluene (4 mL), anthranilonitrile (128 mg,
1.08 mmol) and BF3$Et2O (0.17 mL, 1.30 mmol) afforded amine 23
(CDCl3)
d 158.5, 146.6, 146.2, 128.5, 128.2, 123.8, 119.8, 116.9, 110.1,
40.2, 37.2, 32.0, 26.1, 23.8, 19.9, 19.4; MS (ESIþ) calc. 240.1626, found
240.1618.
(168 mg, 0.63 mmol, 58%): [
123 ꢁC; IR (KBr) nmax/cmꢀ1: 3489, 3350, 3235, 2958, 1621, 1572,
1496, 1428, 1375; 1H NMR (CDCl3)
a]
¼ ꢀ111 (c ¼ 0.45, CHCl3); m.p. 121–
D
4.1.1.2. (3R)-9-amino-3-methyl-1,2,3,4-tetrahydroacridine(11). Follo-
wing the general procedure, ketone 10 (200 mg, 1.78 mmol), toluene
(5 mL), anthranilonitrile (191 mg, 1.62 mmol) and BF3$Et2O
(0.25 mL, 1.94 mmol) afforded amine 11 (282 mg, 1.33 mmol, 82%):
d
7.94 (d, 1H, J ¼ 8.4 Hz), 7.74 (d,
1H, J ¼ 8.4 Hz), 7.56 (t,1H, J ¼ 8.3 Hz), 7.37 (t,1H, J ¼ 8.3 Hz), 4.80 (br
s, 2H, NH2), 3.07 (q, 1H, J ¼ 6.6 Hz), 2.85 (dd, 1H, J ¼ 5.4 Hz), 2.27
(tdd, 1H, J ¼ 13.8, 6.6, 3.3), 2.11 (ddd, 1H, J ¼ 14.1, 6.3, 3.0), 2.04 (ddd,
1H, J ¼ 14.2, 5.4, 3.3), 1.58 (dt, 1H, J ¼ 13.5, 3.3 Hz), 1.18 (d, 3H,
[
a
]D ¼ þ38 (c ¼ 1.5, CHCl3); m.p. 196–198 ꢁC; IR (KBr) nmax/cmꢀ1
:
3484, 3293, 3055, 2919, 1643, 1565, 1498, 1437, 1376, 1279.
J ¼ 6.9 Hz), 0.98 (s, 9H); 13C NMR (CDCl3)
d 159.8, 145.7, 145.1, 129.0,
1H NMR and 13C NMR spectra gave the same absorptions as
reported earlier [33].
128.3, 123.9, 119.7, 117.5, 116.3, 48.7, 35.6, 30.4 (3Me, tBu), 27.3, 26.7,
21.1, 19.9; MS (ESIþ) calc. 268.1939 found 268.1938.
4.1.1.3. (2R)-9-amino-2-methyl-2,3-dihydro-1H-cyclopenta[b]quinoline
(16a) and (1R)-9-amino-1-methyl-2,3-dihydro-1H-cyclopenta[b]quino-
line (16b). Following the general procedure, ketone 15 (200 mg,
2.04 mmol), toluene (6 mL), anthranilonitrile (219 mg, 1.85 mmol)
and BF3$Et2O (0.28 mL, 2.22 mmol) afforded amines 16a (206 mg,
1.04 mmol, 56%) and 16b (70 mg, 0.35 mmol, 19%).
4.1.1.7. (1R,4R)-9-amino-1,4-diisopropyl-1,2,3,4-tetrahydroacridine
(25). Following the general procedure, ketone 24 (200 mg,
1.10 mmol), toluene (3 mL), anthranilonitrile (118 mg, 1.00 mmol)
and BF3$Et2O (0.15 mL, 1.20 mmol) afforded amine 25 (137 mg,
0.48 mmol, 48%): [
a
]
¼ ꢀ45 (c ¼ 0.72, CHCl3); m.p. 137–139 ꢁC; IR
D
(KBr) nmax/cmꢀ1: 3488, 3349, 3146, 2956, 1622, 1572, 1495, 1382; 1H
Data for 16a: [
a
]D ¼ ꢀ2 (c ¼ 1.1, CHCl3); m.p. 154–156 ꢁC; IR (KBr)
NMR (CDCl3)
d
7.95 (d, 1H, J ¼ 8.4 Hz), 7.73 (d, 1H, J ¼ 8.4 Hz), 7.58
nmax/cmꢀ1: 3411, 3352, 3234, 2950, 1660, 1570, 1514, 1440, 1384; 1H
(t, 1H, J ¼ 8.3 Hz), 7.39 (t, 1H, J ¼ 8.3 Hz), 4.66 (s, 2H, NH2), 3.09 (m,
1H), 2.90–2,70 (m, 2H), 2.21 (m, 1H), 2.02 (m, 1H), 1.89 (m, 2H), 1.56
(m, 1H), 1.10 (d, 3H, J ¼ 6.6 Hz), 0.99 (d, 3H, J ¼ 6.6 Hz), 0.79 (d, 3H,
NMR (CDCl3)
d
7.95 (d, 1H, J ¼ 8.1 Hz), 7.75 (d, 1H, J ¼ 8.1 Hz), 7.56 (t,
1H, J ¼ 8.1 Hz), 7.36 (t, 1H, J ¼ 8.1 Hz), 4.82 (br s, 2H, NH2), 3.24 (dd,
1H, J ¼ 16.0, 7.5 Hz), 3.00 (dd, 1H, J ¼ 15.0, 7.8 Hz), 2.74 (dd, 1H,
J ¼ 16.0, 7.2 Hz), 2.67 (m, 1H), 2.42 (dd, 1H, J ¼ 15.0, 6.3 Hz), 1.20 (d,
J ¼ 6.6 Hz), 0.69 (d, 3H, J ¼ 6.6 Hz); 13C NMR (CDCl3)
d 161.8, 145.9,
145.6, 129.2, 128.1, 123.9, 119.8, 117.4, 115.5, 45.9, 39.2, 30.0, 29.8,
3H, J ¼ 6.6 Hz); 13C NMR (CDCl3)
d
166.9, 147.7, 145.1, 128.8, 128.2,
21.4, 21.1, 18.7, 17.2; MS (ESIþ) calc. 282.2096, found 282.2089.
123.7, 119.9, 117.7, 114.7, 43.3, 35.5, 31.9, 21.2; MS (ESIþ) calc.
198.1157, found 198.1158.
4.1.1.8. (2R,4R)-9-amino-2,4-methano-3,3-dimethyl-1,2,3,4-tetrahy-
droacridine (27). Following the general procedure, ketone 26
(200 mg, 1.45 mmol), toluene (4 mL), anthranilonitrile (156 mg,
1.32 mmol) and BF3$Et2O (0.20 mL, 1.59 mmol) afforded amine 27
Data for 16b: 13C NMR (CDCl3)
d 166.8, 148.8, 144.4, 128.3, 128.2,
123.7, 119.9, 119.7, 114.7, 34.8, 33.1, 31.5, 18.4.
(179 mg, 0.75 mmol, 57%): [
133 ꢁC; IR (KBr) nmax/cmꢀ1: 3363, 3240, 2959, 2933, 1638, 1567,
1502, 1433, 1376; 1H NMR (CDCl3)
a
]D ¼ ꢀ32 (c ¼ 1.7, CHCl3); m.p. 131–
4.1.1.4. (2S)-9-Amino-2-isopropyl-2,3-dihydro-1H-cyclopenta[b]quino-
line (14a) and (1R)-9-amino-1-isopropyl-2,3-dihydro-1H-cyclopenta[b]
quinoline (14b). Following the general procedure, ketone 13
(200 mg, 1.59 mmol), toluene (5 mL), anthranilonitrile (170 mg,
1.44 mmol) and BF3$Et2O (0.22 mL,1.73 mmol) afforded amines 14a
(172 mg, 0.76 mmol, 53%) and 14b (49 mg, 0.22 mmol, 15%):
d
7.93 (d, 1H, J ¼ 8.4 Hz), 7.75 (d,
1H, J ¼ 8.4 Hz), 7.57 (t, 1H, J ¼ 8.3 Hz), 7.38 (t, 1H, J ¼ 8.3 Hz), 4.69 (s
br, 2H, NH2), 3.10 (t, 1H, J ¼ 5.7 Hz), 2.85 (m, 2H,), 2.77 (dd, 1H,
J ¼ 7.2, 3.0, Hz), 2.45 (m,1H),1.43 (s, 3H),1.40 (d,1H, J ¼ 9.9 Hz), 0.72
(s, 3H); 13C NMR (CDCl3)
d 166.8, 146.1, 145.7, 128.7, 128.4, 124.1,
Data. for 14a: [
a
]D ¼ ꢀ18 (c ¼ 0.29, CHCl3); m.p. 167–169 ꢁC; IR
119.6, 118.5, 107.8, 50.4, 39.7, 39.5, 30.9, 27.7, 26.1, 21.2; MS (ESIþ)
(KBr) nmax/cmꢀ1: 3444, 3359, 3243, 2956,1650, 1569, 1438,1384; 1H
calc. 238.1470, found 238.1475
NMR (CDCl3)
d
7.93 (d, 1H, J ¼ 8.1 Hz), 7.72 (d, 1H, J ¼ 8.1 Hz), 7.57
(t, 1H, J ¼ 8.1 Hz), 7.38 (t, 1H, J ¼ 8.1 Hz), 4.67 (br s, 2H, NH2), 3.18
(dd, 1H, J ¼ 16.6, 8.4 Hz), 2.96 (dd, 1H, J ¼ 15.2, 8.5 Hz), 2.84 (dd, 1H,
J ¼ 16.7, 9.6 Hz), 2.52 (dd,1H,15.1, 8.6 Hz), 2.28 (m,1H),1,73 (m,1H),
1.03 (d, 3H, J ¼ 6.6 Hz), 1.01 (d, 3H, J ¼ 6.6 Hz); 13C NMR (CDCl3)
4.1.1.9. (1S,2S,4S)-9-Amino-2,4-methano-1,3,3-trimethyl-1,2,3,4-tet-
rahydroacridine (29). Following the general procedure, ketone 28
(200 mg, 1.31 mmol), toluene (4 mL), anthranilonitrile (140 mg,
1.19 mmol) and BF3$Et2O (0.18 mL, 1.43 mmol) afforded amine 29
d
166.8, 148.1, 144.4, 128.7, 128.4, 123.9, 119.9, 117.7, 115.1, 45.1, 39.8,
(189 mg, 0.75 mmol, 63%): [
136 ꢁC; IR (KBr) nmax/cmꢀ1: 3378, 3254, 2959, 2933, 1644, 1554,
1502, 1453, 1388; 1H NMR (CDCl3)
a
]D ¼ þ15 (c ¼ 1.42, CHCl3); m.p. 133–
33.6, 32.0, 21.1, 20.8; MS (ESIþ) calc. 226.1470, found 226.1468.
Data. for 14b: (from crude product) 13C NMR (CDCl3)
d
167.6,
d
7.92 (d, 1H, J ¼ 8.3 Hz), 7,76 (d,
148.4, 145.0, 128.6, 128.2, 123.6, 120.1, 117.8, 117.5, 46.8, 34.4, 30.2,
23.9, 21.4, 17.5.
1H, J ¼ 8.3 Hz), 7.56 (t, 1H, J ¼ 8.2 Hz), 7.38 (t, 1H, J ¼ 8.2 Hz), 4.72 (s
br, 2H, NH2), 3.19 (qd,1H, J ¼ 7.2, 3.0 Hz), 3.04 (t,1H, J ¼ 5.4 Hz), 2.71
(dt, 1H, J ¼ 9.9, 5.8 Hz), 2.34 (td, 1H, J ¼ 6.0, 3.0 Hz), 1.48 (d, 3H,
J ¼ 7.2 Hz), 1.45 (s, 3H), 1.34 (d, 1H, J ¼ 9.9 Hz), 0.88 (s, 3H); 13C NMR
4.1.1.5. (9R)-11-amino-6,6,9-trimethyl-9,10-dihydro-6H-cyclo-
hepta[b]quinolin-7(8H)-one (18). Following the general procedure,
ketone 17 (200 mg, 1.19 mmol), toluene (3.5 mL), anthranilonitrile
(128 mg, 1.08 mmol) and BF3$Et2O (0.17 mL, 1.30 mmol) afforded
(CDCl3)
d 166.9, 146.2, 145.8, 128.6, 128.5, 124.1, 119.6, 119.1, 112.4,
51.8, 39.7, 48.3, 39.3, 35.1, 32.7, 27.1, 24.2, 17.4; MS (ESIþ) calc.
252.1626, found 252.1629.
amine 18 (226 mg, 0.84 mmol, 78%): [
m.p. 121–123 ꢁC; IR (KBr) nmax/cmꢀ1: 3463, 3388, 3254, 2963, 1699,
1641, 1579, 1498, 1426, 1374; 1H NMR (CDCl3)
7.96 (d, 1H,
a
]
¼ þ17 (c ¼ 1.5, CHCl3);
D
4.1.2. Preparation of chiral cyclanones
4.1.2.1. Synthesis of (S)-3-isopropylcyclopentanone (13)
d
J ¼ 8.4 Hz), 7.74 (d, 1H, J ¼ 8.4 Hz), 7.60 (t, 1H, J ¼ 8.3 Hz), 7.42
4.1.2.1.1. (1RS,2RS,4S)-4-isopropyl-7-oxabicyclo[4.1.0]heptan-1-yl)
methanol (39). To a stirred solution of allylic alcohol 38 (1.34 g,
8.7 mmol) in CH2Cl2 (60 mL) was added, slowly and at 0 ꢁC,
a solution of mCPBA 65% (2.24 g, 13.0 mmol) in CH2Cl2 (100 mL).
The reaction mixture was stirred during 3 h while the temperature
(t, J ¼ 8.3 Hz), 4.79 (br s, 2H, NH2), 2.78–2.18 (m, 5H), 1.59 (s, 3H),
1.52 (s, 3H), 1.06 (d, 3H, J ¼ 4.8 Hz); 13C NMR (CDCl3)
d 215.4, 163.0,
146.7, 146.6, 129.8, 128.5, 124.8, 120.0, 117.8, 108.8, 56.3, 43.9, 32.8,
30.0, 24.5, 24.4, 20.4; MS (ESIþ) calc. 268.1576, found 268.1570.

534
D.dos Santos Pisoni et al. / European Journal of Medicinal Chemistry 45 (2010) 526–535
was maintained at 0 ꢁC. Next, sodium bisulfite 10% solution
(100 mL) was added and the resulting mixture was stirred for
30 min at room temperature. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3 ꢃ 100 mL). The
combined extracts were washed with NaHCO3 saturated solution
(2 ꢃ100 mL) and brine (2 ꢃ 100 mL). The organic layer was dried
over Na2SO4 and concentrated in vacuo. The crude product 39
(1.37 g) was used without any further purification in the next step.
Data for 39 (diastereomeric mixture): IR (film) nmax/cmꢀ1: 3423,
2957, 2872, 1466, 1433, 1368, 1038, 1021, 842; 1H NMR (CDCl3)
4.1.2.2. (S)-2-(isopropylidene)-5-(2-propenyl)-cyclohexanone
(33)
and (S)-2,2-dimethyl-5-(2-propenyl)-cycloheptane-1,3-dione (34). To
a stirred solution of epoxiketones 31 (505 mg, 2.56 mmol) in
anhydrous toluene (6 mL) was added Mo(CO)6 (676 mg, 2.56 mmol).
The reaction mixture was heated at reflux for 4 h, allowed to cool,
and filtered through celite. The filtrate was concentrated in vacuo
and the residue was purified by silica gel column chromatography
(eluting with hexane-EtOAc, 99:1) to give enone 33 (332 mg,
1.86 mmol, 73%) and diketone 34 (52 mg, 0.27 mmol, 10%).
Data for 33: [
a
]D ¼ ꢀ28 (c ¼ 1.3, CHCl3); IR (film) nmax/cmꢀ1
:
d
3.72–3.51 (m, 2H), 3.32–3.22 (m, 1H), 2.12–1.70 (m, 4H), 1.69–1.02
3082, 2858, 1681, 1644, 1602, 1439, 1372, 1127, 1073; 1H NMR
(m, 5H), 0.86–0.80 (m, 6H); 13C NMR (CDCl3)
d
64.5, 64.2, 60.6, 60.3,
(CDCl3)
d
4.76 (s, 1H), 4.72 (s, 1H), 2.73 (dt, 1H, J ¼ 15.3, 4.2 Hz), 2.55
57.1, 56.0, 39.4, 35.8, 32.1, 31.7, 28.5, 27.3, 26.1, 25.2, 24.6, 21.9, 19.6,
19.5, 19.3.
(m, 1H), 2.45 (dt, 1H, J ¼ 11.4, 3.6 Hz), 2.37–2.22 (m, 2H), 2.00
(s, 3H), 1.99–1.91 (m, 1H), 1.79 (s, 3H), 1.74 (s, 3H), 1.58 (m, 1H); 13C
4.1.2.1.2. (S)-3-isopropylhexanedioic acid (40). To a stirred solu-
tion of epoxide 39 (1.3 g, 7.5 mmol) in 37 mL of THF-H2O (10:1) at
0 ꢁC was added H5IO6 (3.65 g, 16 mmol) in one portion. After 3 h,
Et2O (100 mL) and water (100 mL) were added. The aqueous layer
was separated and extracted with Et2O (3 ꢃ 100 mL). The combined
organic layer was washed with brine (2 ꢃ 200 mL) and dried over
Na2SO4. The solvent was removed under reduced pressure to afford
an aldehyde-acid (1.1 g), which was used without any further
purification in the next step.
NMR (CDCl3) d 203.5, 147.5, 142.8, 131.4, 109.7, 47.3, 43.0, 29.3, 28.3,
23.0, 22.2, 20.5; MS (ESIþ) calc. 178.1357, found 178.1363.
Data for 34: [
a
]D ¼ þ79 (c ¼ 1.4, CHCl3); IR (film) nmax/cmꢀ1
:
3079, 2975, 2935, 2866, 1696, 1645, 1446, 1381, 1328, 1289, 1114,
1072, 987, 894; 1H NMR (CDCl3)
d 4.77 (s,1H), 4.73 (s,1H), 2.66–2.54
(m, 2H), 2.45 (dd, 1H, J ¼ 6.9, 2.7 Hz), 2.44–2.36 (m, 2H), 2.09–1.98
(m, 1H), 1.84–1.65 (m, 1H), 1.72 (s, 3H), 1.26 (s, 3H), 1.25 (s, 3H,); 13C
NMR (CDCl3)
20.4, 20.3.
d 212.2, 211.4, 147.6, 110.5, 61.4, 47.0, 45.7, 39.9, 33.1,
A solution of NaClO2 (0.93 g, 8.13 mmol) in H2O (8.1 mL) was
added at 0 ꢁC to a mixture of aldehyde-acid (1.0 g, 5.81 mmol) in
MeCN (5.8 mL), NaH2PO4 (185 mg) in H2O (2.3 mL) and 0.58 mL
(0.61 mmol) of 35% H2O2 solution. After being stirred for further 2 h
at same temperature, 60 mg of Na2S2O3 were added and the
mixture was acidified to pH 1 by the dropwise addition of 37% HCl
and extracted with EtOAc (2 ꢃ 20 mL). The combined organic layers
were extracted with saturated NaHCO3 solution and brine. The
aqueous extracts were combined, acidified to pH 1 by the dropwise
addition of 37% HCl and extracted with EtOAc (2 ꢃ 20 mL). The
combined organic extracts were washed with brine and dried over
Na2SO4. The solvent was removed under reduced pressure to afford
the diacid 40 (0.82 g) which was used without any further purifi-
cation in the next step.
4.1.2.3. (2R,5S)-2-isopropyl-5-(2-propenyl)-cyclohexanone
(35a)
and (2S,5S)-2-isopropyl-5-(2-propenyl)-cyclohexanone (35b). A
suspension of Te (861 mg, 6.73 mmol) and NaBH4 (618 mg,
16.27 mmol) in anhydrous ethanol (18 mL) was heated at reflux for
2 h. The solution was allowed to cool at room temperature and
a solution of the enone (300 mg, 1.68 mmol) in anhydrous ethanol
(5 mL) was added. The resulting mixture was heated at reflux for
24 h under argon. Next, the reaction mixture was allowed to cool at
room temperature and filtered through celite. The filtrate was
concentrated in vacuo and the residue was purified by silica gel
column chromatography (eluting with hexane-EtOAc, 99:1) to give
ketone 35a (176 mg, 0.98 mmol, 58%) and ketone 35b (88 mg,
0.49 mmol, 29%).
Data for aldehyde-acid: [
cmꢀ1: 2959, 2874, 1723, 1466, 1412, 1368, 1180, 1035; 1H NMR
(CDCl3)
a]
¼ ꢀ6 (c ¼ 1.30, CHCl3); IR (film) nmax
/
Data for 35a: [
a
]D ¼ þ16 (c ¼ 1.33, CHCl3); IR (film) nmax/cmꢀ1
:
D
2956, 2937, 1709, 1645, 1179, 1082, 891; 1H NMR (CDCl3)
d 4.75
d
9.77 (t, 1H, J ¼ 1.8 Hz), 2.50–2.25 (m, 1H), 2.35 (t, 2H,
(s, 1H), 4.73 (s, 1H), 2.48–2.24 (m, 3H), 2.20–2.05 (m, 3H), 2.04–1.93
(m, 1H), 1.74 (s, 3H), 1.69–1.53 (m, 1H), 1.40 (dq, 1H, J ¼ 13.8, 3.3,
1.30), 0.93 (d, 3H, J ¼ 6.6 Hz), 0.87 (d, 3H, J ¼ 6.6 Hz); 13C NMR
J ¼ 7.8 Hz), 1.99–1.88 (m, 1H), 1.81–1.68 (m, 2H), 1.62–1.50 (m, 2H),
0.89 (d, 3H, J ¼ 6.9 Hz), 0.86 (d, 3H, J ¼ 6.9 Hz); 13C NMR (CDCl3)
d
202.9, 178.6, 45.1, 37.6, 31.9, 29.8, 26.4, 19.5, 18.2.
(CDCl3) d 211.8, 147.5, 109.5, 56.0; 47.5, 46.9, 30.6, 27.7, 25.8, 21.1;
Data for diacid 40: [
cmꢀ1: 3044, 2962, 1708, 1413, 1371, 1285, 1219, 1163; 1H NMR
(CDCl3)
a
]
¼ ꢀ8 (c ¼ 1.30, CHCl3); IR (film) nmax
/
20.4; 18.6; MS (ESIþ) calc. 180.1514, found 180.1506.
D
Data for 35b: [
a]
¼ ꢀ88 (c ¼ 1.33, CHCl3); IR (film) nmax/cmꢀ1
:
D
d
10.10 (br, 1H), 2.42–2.34 (m, 1H,), 2.39 (t, 2H, J ¼ 7.5 Hz),
2958, 2869, 1708, 1644, 1369, 1246, 893; 1H NMR (CDCl3)
d 4.79
(s, 1H), 4.71 (s, 1H), 2.49–2.28 (m, 3H), 2.15–1.91 (m, 3H), 1.80–1.64
2.18 (dd, 1H, J ¼ 16.5, 7.5 Hz), 1.88–1.69 (m, 2H), 1.68–1.55 (m, 2H),
0.91 (d, 3H, J ¼ 6.6 Hz), 0.87 (d, 3H, J ¼ 6.6 Hz); 13C NMR (CDCl3)
(m, 3H), 1.74 (s, 3H), 0.94 (d, 3H, J ¼ 6.6 Hz), 0.85 (d, 3H, J ¼ 6.6 Hz);
d
180.2, 180.1, 40.0, 35.6, 32.1, 29.8, 26.1, 19.3, 18.3.
13C NMR (CDCl3)
d 214.2, 147.4, 110.3, 57.2, 45.7, 44.5, 26.9, 26.4,
4.1.2.1.3. (S)-3-isopropylcyclopentanone
(13). The
crude
25.8, 20.9, 20.7, 19.8.
mixture containing diacid 40 (0.82 g) and Na2CO3 (100 mg,
0.94 mmol) was heated at 350 ꢁC during 30 min. The mixture
was diluted with CH2Cl2 and filtered through celite. The filtrate
was concentrated in vacuo and the residue was purified by
silica gel column chromatography (eluting with hexane–Et2O,
8:2) to give (S)-3-isopropylcyclopentanone 13 in 35% of yield
4.1.2.4. (2R,5S)-2,5-diisopropylcyclohexanone (24). The ketone 35a
(134 mg, 0.74 mmol) was dissolved in MeOH (2 mL) and treated
with catalytic PtO2 (1.0 mg, 0.004 mmol). The mixture was stirred
vigorously for 1 h under hydrogen atmosphere. The reaction
mixture was filtered through a pad of silica gel. The filtrate was
evaporated and the residue was purified by silica gel column
chromatography (eluting with hexane-EtOAc, 99:1) to give 24
from (S)-perillaldehyde (30). [
(film) nmax/cmꢀ1: 2962, 2874, 1746, 1406, 1386, 1160; 1H NMR
(CDCl3) 2.52–2.27 (m, 2H), 2.25–2.07 (m, 2H), 1.94–1.76
a
]
¼ ꢀ84 (c ¼ 0.28, CHCl3); IR
D
d
(122 mg, 0.67 mmol) in 90% of yield. [
(film) nmax/cmꢀ1: 2958, 2872, 1711, 1467, 1387, 1369, 1238, 1196; 1H
NMR (CDCl3)
2.36 (ddd, 1H, J ¼ 12.9, 3.3, 2.1 Hz), 2.22–1.98 (m,
a
]D ¼ þ14 (1.51, CHCl3); IR
(m, 2H), 1.62–1.54 (m, 2H), 0.96 (d, 3H, J ¼ 6.6 Hz), 0.93 (d, 3H,
J ¼ 6.6 Hz) 13C NMR (CDCl3)
d
220.2, 44.6, 43.7, 39.1, 33.5, 27.7,
d
21.2, 20.3.
4H), 1.95–1.82 (m, 1H), 1.65–1.44 (m, 2H), 1.43–1.22 (m, 2H), 0.96–
Specific rotation, IR data [54]1H and 13C NMR data [54,55], were
consistent with previously reported data for this compound.
0.82 (m, 12H) 13C NMR (CDCl3)
27.9, 25.9, 21.2, 19.6, 19.3, 18.6.
d 213.0, 56.2, 46.5, 46.1, 32.6, 28.8,

D.dos Santos Pisoni et al. / European Journal of Medicinal Chemistry 45 (2010) 526–535
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1H NMR (CDCl3)
2.56–2.26 (m, 4H), 1.98–1.86 (m, 1H), 1.78–1.58
a
]D ¼ þ85 (c ¼ 1.4, CHCl3);
d
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13C NMR (CDCl3)
20.4, 19.2, 18.9.
d 212.8, 212.6, 61.4, 46.0, 43.9, 39.9, 33.2, 20.5,
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Appendix. Supplementary data
Supplementary data associated with this article can be found in
the online version at, doi:10.1016/j.ejmech.2009.10.039.
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