New aporphinoid 5-HT2A and α1A antagonists via structural manipulations of nantenine

Article abstract of DOI:10.1016/j.bmc.2011.08.019

A series of C1, C2, C3 and N6 analogs of nantenine (2) was synthesized and evaluated in 5-HT_2A and α_1A receptor functional assays. Alkyl substitution of the C1 and N6 methyl groups of nantenine provided selective 5-HT_2A an

Full text of DOI:10.1016/j.bmc.2011.08.019

Bioorganic & Medicinal Chemistry 19 (2011) 5861–5868
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
New aporphinoid 5-HT2A and a1A antagonists via structural
manipulations of nantenine
Sandeep Chaudhary a, , Shashikanth Ponnala a, , Onica LeGendre a, Junior A. Gonzales a,
Hernán A. Navarro b, Wayne W. Harding a,
⇑
a Department of Chemistry, Hunter College, CUNY, New York, NY 10065, USA
b Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of C1, C2, C3 and N6 analogs of nantenine (2) was synthesized and evaluated in 5-HT2A and a1A
receptor functional assays. Alkyl substitution of the C1 and N6 methyl groups of nantenine provided
Received 2 June 2011
Revised 4 August 2011
Accepted 9 August 2011
Available online 6 September 2011
selective 5-HT2A and
tive for 1A versus 5-HT2A. The C3 bromo analog 15 is one of the most potent aporphinoid 5-HT2A antag-
onists known presently.
a1A antagonists, respectively. The C2 alkyloxy analogs studied were generally selec-
a
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aporphine
Nantenine
MDMA
5-HT2A
a1A
1. Introduction
H
N
3
MeO
MeO
2
Aporphines are a group of tetracyclic alkaloids that are a subset of
the ubiquitous tetrahydroisoquinoline family. The aporphine tem-
plate is known to be associated with a range of biological activities.
For example, aporphines have been explored as antituberculosis and
cytotoxic agents.1,2 In the realm of central nervous system (CNS)
activity, members of the aporphine class are known to inhibit the
enzyme acetylcholinesterase—an important therapeutic target in
current treatment modalities for Alzheimers disease.3–5 Behavioral
and physiological effects of the designer drug MDMA aka ‘Ecstasy’
(1, Fig. 1) are antagonized by nantenine (2), an isolate of a number
of Lauraceous plants. With regards to clinically available aporphine
drugs, apomorphine (3, Fig. 1) is a potent dopamine D1/D2 agonist
that is used to treat symptoms of Parkinson’s disease.6
Naturally occurring aporphines and their synthetic derivatives
are known to have affinity for dopaminergic, adrenergic and seroto-
nergic receptors.7–14 The aporphine chemotype may be regarded as
a ‘privileged’ CNS receptor template. Indeed, this scaffold represents
an attractive opportunity to identify and develop selective mono-
potent as well as multi-potent CNS receptor ligands for dopaminer-
gic, adrenergic and serotonergic receptors. Such molecules will be
useful as interrogative chemical tools and potential therapeutic
A
B
N
H
N
1
6
O
C
HO
HO
O
D
MDMA (1)
10
O
O9
Apomorphine (3)
(
)-Nantenine (2)
Figure 1. Structures of MDMA (1), ( )-Nantenine (2) and Apomorphine (3).
interventions for a variety of neuropsychiatric conditions such as
stress, depression, anxiety, psychosis and psychostimulant abuse.
As indicated earlier, a number of groups have investigated the
structure–activity properties of aporphines (particularly apomor-
phine derivatives) as dopamine D1 and D2 receptor ligands. In
contrast, the structure–activity relationships (SAR) of aporphines
as 5-HT2A receptor ligands have been little explored. We are partic-
ularly interested in ‘tooling’ aporphines as 5-HT2A and a1A dual
antagonists and as probes to study antagonism of MDMA’s behav-
ioral and physiological effects. Our interest is propelled by abun-
dant literature studies that implicate 5-HT2A and a1 adrenergic
receptors in mediating physiological and psychobehavioral effects
of MDMA in animals and humans.15–21 Currently, no medications
are specifically approved to treat adverse effects of ‘Ecstasy’ over
⇑
Corresponding author. Tel.: +1 212 772 5359: fax: +1 212 772 5332.
E-mail address: whardi@hunter.cuny.edu (W.W. Harding).
These authors contributed equally on this paper.
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.08.019

5862
S. Chaudhary et al. / Bioorg. Med. Chem. 19 (2011) 5861–5868
dose although the muscle relaxant, dantrolene, has been effectively
used as an antidote in cases of hospitalization due to ‘Ecstasy’—in-
duced hyperthermia.22
was subsequently reduced to secondary racemic amine 930 (without
purification of the imine). Reaction of 9 with Boc anhydride gave the
carbamate 10, which was then cyclized via a palladium-mediated
microwave-assisted procedure to afford the aporphine 11. Removal
of the benzyl protecting group of 11 then gave phenol 12. Alkylation
of 12 with respective alkyl bromides afforded the boc protected
aporphines 13a–13f. Removal of the Boc group with ZnBr2 and stan-
dard reductive amination gave the target C2 derivatives 14a–14f.
(We attempted to reduce the Boc group directly to the N-methyl
group with lithium aluminum hydride but found that this gave
competing cleavage of the Boc group).
Bromination of ( )-nantenine with bromine/acetic acid (Fig. 3)
gave the C3-bromo analog 15. This reaction also produced a
substantial amount of tribromo derivative 16.
The preparation of N6 analogs was achieved by N-alklyation of
secondary ( )-amine 17 (see Ref. 4) under reductive amination
conditions (Fig. 4).
Prior to our forays in this area, only one SAR study on
aporphines at the 5-HT2A receptor was reported. In that study,
conducted with ( )-nantenine (2) as the lead, it was revealed that
replacement of the C1 methoxy group with a hydroxyl group gave
decreased 5-HT2A affinity.23 Replacement of the N6 methyl group
with a hydrogen or ethyl group also gave reduced affinity. We have
recently reported further investigations at the C1 position and have
identified new 5-HT2A antagonists up to 12 times more potent than
nantenine.24,25
In addition, we have screened ( )-nantenine in a CNS panel of
over 30 receptors, ion-channels and transporters and determined
that the molecule is a potent and selective a1A ligand.26 Others
have documented the affinity trends of aporphines at the a1A
receptor, but no study has done so with nantenine as the lead.12
One prior study has investigated the structure-affinity relation-
ships of nantenine at a1 receptors.27 Here it was reported that
replacement of the C1 methoxy group with a hydroxyl group gave
2.2. Pharmacology
improved
a1 affinity. Substitution of the N6 methyl group of nant-
All analogs were screened at 10 lM in multi-well format for
enine with a hydrogen or ethyl group gave reduced affinities
however.
Taken together, the results of previous investigations of
( )-nantenine suggest that the substituents on the aporphine core
are important determinants of its 5-HT2A and a1A activity. While
intrinsic (agonist) and antagonist activity at the human 5-HT2A
receptor using FLIPR Tetra (Molecular Devices, Sunnydale, CA)
functional assays that detect receptor-mediated mobilization of
internal calcium with a calcium sensitive fluorescent dye. Com-
pounds that showed no intrinsic activity in the functional assay
and inhibited the increase in basal fluorescence elicited by the
EC80 of 5-HT by at least 50%, had their Ke (apparent affinity in a
functional assay) determined. Ke values were determined by run-
ning an 8-point half-log 5-HT concentration response curve in
the presence and absence of a single concentration of antagonist.
EC50 values were calculated for 5-HT (A) and 5-HT + test compound
(A’), and these used to calculate the test compound Ke using the
formula: Ke = [L]/(DR-1), where [L] equals the concentration of test
compound in the assay and DR equals the dose ratio or A0/A. A sim-
the ultimate goal of optimizing aporphines as 5-HT2A/a1A dual
antagonist probes seems achievable, more extensive SAR studies
are necessary. In this manuscript, we describe an SAR study to
further probe the effects of structural manipulations in the ring A
and N6 regions of the molecule on antagonism of 5-HT2A and a1A
receptors. For comparison to our prior work, all evaluations in
the following discussion were conducted with racemic aporphine
derivatives.
ilar set of assays was performed for the a1A-adrenergic receptor.
2. Results and discussion
2.1. Chemistry
In our previous SAR study, we found that successive alkyl
homologation of the C1 methyl group of nantenine resulted in a
progressive increase in 5-HT2A antagonist activity (ethyl to n-pentyl:
890–171 nM).24 Additionally, the C1 cyclopropylmethyloxy analog
was the most potent 5-HT2A antagonist (68 nM) identified in that
study. Therefore, we continued our exploration of this position by
investigating other alkyloxy, and cycloalkyloxy analogs. n-Hexyloxy
analog 6a (Ke = 71 nM, Table 1), showed activity comparable to the
cyclopropylmethyloxy compound and two fold improved activity
as compared to the previously reported n-pentyloxy analog.
Compound 6b was prepared as a ring-opened analog for comparison
to the cyclopropylmethyloxy compound but this had five fold lower
The ring A C1 modified racemic analogs were prepared using
methods analogous to that previously described via the key phenolic
precursor 5.24,28 Standard Williamson ether O-alkylation of 5
followed by reduction of the carbamate group gave the C1 analogs
6a–i (Fig. 2). Synthesis of the ring A C2 analogs is shown in Scheme
1. The key intermediate 12 was synthesized from readily available 7
and used to prepare C2 analogs as shown. Thus, coupling of 7 with
readily available bromomethylenedioxyphenylacetic acid gave
amide 8.29 Bischler–Napieralski cyclization of 8 gave an imine which
MeO
HO
MeO
MeO
BnO
NCO2Et
N
ref. 25
NH2
R1O
4
5
6
O
O
O
O
6a: R1=n-hexyl
6b: R1=isobutyl
6c
: R1=isopentyl
6d
: R1=2-ethyl-butyl
6e
: R1=cyclobutylmethyl
: R1=cyclopentylmethyl
6f
6g
6h
: R1=cyclohexylmethyl
: R1=allyl
6i
: R1=hydroxypropyl
Figure 2. Preparation of C1 analogs.

S. Chaudhary et al. / Bioorg. Med. Chem. 19 (2011) 5861–5868
5863
BnO
BnO
BnO
MeO
BnO
b, c
a
d
NH
NH2
NH
NBoc
MeO
MeO
MeO
O
O
7
O
O
O
Br
O
O
Br
Br
8
9
10
e
R2O
R2O
HO
BnO
MeO
g
h, i
70-80%
f
N
NBoc
NBoc
NBoc
MeO
MeO
MeO
O
O
O
O
13
12
14
11
O
O
O
O
14a
14b
14c
14d
14e
: R2=ethyl
13a
: R2=ethyl
: R2=n-propyl
13b
13c
13d
13e
: R2=n-propyl
: R2=n-butyl
: R2=n-pentyl
: R2=n-butyl
: R2=n-pentyl
: R2=cyclopropylmethyl
: R2=cyclopropylmethyl
: R2=benzyl
14f: R2=benzyl
13f
Scheme 1. Synthesis of C2 ring A analogs. Reagents and conditions: (a) bromomethylenedioxyphenylacetic acid, CDI, THF, 0 °C-rt. (b) PCl5, DCM, 0 °C-rt. (c) NaBH4, MeOH,
0 °C. (d) (Boc)2O, DMAP, iPr2EtN, DCM, rt. (e) Pd(OAc)2, Cs2CO3, PPh3, 175 °C, DMF, microwaves. (f) H2/Pd, rt. (g) alkyl bromide, KI, K2CO3, acetone, 70 °C. (h) ZnBr2, DCM, rt. (i)
HCHO, Na(OAc)3BH, DCM, rt.
Br
Br
MeO
MeO
MeO
MeO
MeO
Br2, AcOH
N
N
N
+
MeO
Br
Br
16
O
O
O
2
15
O
O
O
Figure 3. Bromination of nantenine.
functionality of 6h is electronically similar to a cyclopropyloxy
group, this may account for the similar activities seen; this is in need
of further investigation. We then decided to test the tolerance for a
polar group in this region. Addition of a hydroxypropyloxy moiety
(6i) was associated with a reduction in 5-HT2A antagonist activity.
Compounds 6a–6i were evaluated in a1A assays but were devoid
of activity.
We then progressed to examine C2 nantenine analogs. With
regards to 5-HT2A activity, the ethyloxy and n-propyloxy analogs
(14a and 14b, respectively) were equipotent. Further extension of
the alkyl chain resulted in decreased antagonist activity with a
plummet in activity in going from the n-butyloxy analog to the
n-pentyloxy homolog (14c to 14d). The C2 cyclopropylmethyloxy
analog was found to have moderate activity that was comparable
to 14a and 14b. Benzyloxy analog (14f) was the most potent C2 ana-
MeO
MeO
MeO
MeO
aldehyde
NaBH(OAc)3
DCM
NR3
NH
O
O
17
O
O
18
18a
: R3=ethyl
18b: R3=n-propyl
18c: R3=n-butyl
18d: R3=n-pentyl
18e
: R3=cyclopropylmethyl
Figure 4. Synthesis of N-alkyl analogs.
5-HT2A antagonist activity. Nevertheless, we anticipated that
homologation of 6b would cause a rebound in antagonist activity
as seen with the C1 n-alkyloxy series and so we prepared and
evaluated isopentyloxy analog 6c and 2-ethylbutyloxy analog 6d.
However, homologation did not improve the antagonist activity. In
fact in the case of 6c, this compound had weak agonist activity
(19% of 5-HT Emax). Next we decided to investigate other cycloalkyl-
oxy analogs. The cyclohexylmethyloxy analog (6g) showed moder-
ate activity, albeit 25-fold lower than the cyclopropyloxy analog.
Other cycloalkyloxyderivatives testedshowed weak agonist activity
(25% and 35% of 5-HT Emax for 6e and 6f, respectively). However, we
were pleased to observe that the allyloxy analog (6h) had activity
comparable to the cyclopropylmethyloxy analog. Since the alkene
log tested. In the a1A assay a clear SAR trend was observed. The C2
ethyloxy analog had the highest activity though this was slightly
lower than that obtained for nantenine in this assay. Increasing
the alkyl chain length at this position led to a progressive decrease
in a1A antagonist activity. The C2 alkyloxy analogs (14a–14d) are
generally more selective for a1A versus 5-HT2A. Interestingly, this
selectivity is reversed with the benzyloxy analog 14e.
The C3 bromo analog (15) had high 5-HT2A antagonist activity
(Ke = 53 nM). Polybromination of ring D (16) did not affect this
activity. Compounds 15 and 16 are the most potent 5-HT2A apor-
phine antagonists identified up to now. Both of these halogenated
analogs were found to be highly selective for the 5-HT2A receptor
versus the a1A receptor.

5864
S. Chaudhary et al. / Bioorg. Med. Chem. 19 (2011) 5861–5868
Table 1
Ke values for ring A and N6 analogs at 5-HT2A and a1A receptors
X1
R2O
NR3
R1O
X2
X2
O
O
Compd
R1
R2
R3
X1
X2
Ke SEMa (nM)
5-HT2A
a1A
6a
6b
6c
6d
6e
6f
6g
6h
n-Hex
Isobu
Isopen
2-EthylBu
CyclobutylMe
CyclopentylMe
CyclohexylMe
Allyl
HydroxyPr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
71 19
367 82
NDb
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
52 13
133 45
234 52
449 169
195 86
1917 226
>10,000
>10,000
806 152
NDb
NDb
1722 258
70 15
708 316
378 92
389 93
943 283
>10,000
484 123
154 76
53 14
43 11
>10,000
>10,000
>10,000
>10,000
>10,000
850 6c
6i
Me
Et
14a
14b
14c
14d
14e
14f
15
n-Pr
n-Bu
n-Pen
CyclopropylMe
Benzyl
Me
Me
Me
Me
Me
16
18a
18b
18c
18d
18e
2
26
38
6
3
n-Pr
n-Bu
n-Pen
CyclopropylMe
Me
210 50
720 204
319 60
Me
Me
Me
36
7
Prazosin
Ketanserin
1.1 0.4
32c,d
a
b
c
Values represent mean SEM for three independent experiments.
ND = Ke not determined (compounds were weak agonists).
Data from Ref. 25.
d
IC50 determined in the presence of 5-HT EC80
.
None of the N6 analogs tested had activity at the 5-HT2A recep-
tor. The N6 ethyl (18a) and N6 n-propyl (18b) congeners had activ-
ities that were comparable to nantenine in the a1A assay. Further
lengthening of the alkyl chain gave reduced a1A antagonist activity.
most potent aporphine 5-HT2A antagonists known. It is clear that
the aporphine skeleton is sensitive to structural changes and that
this template is amenable to the development of selective 5-HT2A
versus a1A and selective a1A versus 5-HT2A antagonists.
The preceding evaluations were conducted with the compounds
in racemic form. It will be interesting to evaluate enantiomers of
these molecules to ascertain whether there is any enantio-prefer-
ence with respect to selectivity and activity. This is especially nec-
essary in light of the fact that series of aporphine enantiomers have
been shown to have opposing effects (agonism and antagonism) at
the related 5-HT1A receptor.11,31,32
Altogether, these results suggest that it is possible to synthesize
potent dual-acting 5-HT2A/a1A aporphine ligands because the
receptor selectivity can be directed through modifications of differ-
ent substituents. Evaluation of the aporphine enantiomers is an
important direction for future work. Our research team is actively
investigating these avenues.
4. Experimental section
3. Conclusions
4.1. General experimental procedures
In summary, we have identified a number of new aporphine 5-
HT2A and a1A antagonists via manipulation of the ring A and N6
substituents of nantenine. The results of our SAR study suggest that
C1 and C3 substituents may be modified to develop potent 5-HT2A
antagonists that are highly selective versus the a1A receptor. In
contrast, the C2 alkyloxy analogs are generally more selective for
the a1A receptor versus. 5-HT2A. However, it would appear that
only relatively small alkyl groups are tolerated at this position
for optimal activity at either receptor. Similarly, at N6 the relatively
small methyl group is best tolerated. Compounds 15 and 16 are the
Reagent grade chemicals and solvents were purchased from Sig-
ma–Aldrich Inc. or Fisher Scientific Inc. Reactions were monitored
by TLC with Analtech Uniplate silica gel G/UV 254 precoated plates
(0.2 mm). TLC plates were visualized by UV (254 nm), by iodine
vapor or by staining with phosphomolybdic acid reagent followed
by heating. Microwave reactions were conducted on a CEM
Discover microwave reactor. Flash column chromatography was
performed with Silicagel 60 (EMD Chemicals, 230–400 mesh,
0.04–0.063 lm particle size). High Resolution Electrospray Mass

S. Chaudhary et al. / Bioorg. Med. Chem. 19 (2011) 5861–5868
5865
Spectra (HRESIMS) were obtained using an Agilent 6520 Q-TOF
instrument. NMR data were collected on a Bruker 500 MHz ma-
chine with TMS as internal standard. Chemical shift (d) values
are reported in ppm and coupling constants in Hertz (Hz). Melting
points were obtained on a Mel-Temp capillary electrothermal
melting point apparatus.
d 152.1, 146.4, 146.7, 143.7, 130.7, 128.4, 127.5, 127.2, 125.9,
110.7, 109.7, 108.2, 101.0, 62.6, 56.1, 53.3, 44.0, 35.5, 35.2, 29.8,
29.1, 25.5, 25.0, 18.6; HRMS (ESI) m/z calcd for
C24H27NO4
([M+H]+), 394.2013, found 394.2017.
4.2.6. 1-(Cyclopentylmethoxy)domesticine (6f)
Brown oil; 1H NMR (500 MHz, CDCl3) d 7.97 (s, 1H), 6.74 (s, 1H),
6.57 (s, 1H), 5.97 (d, J = 1.3 Hz, 1H), 5.94 (d, J = 1.3 Hz, 1H), 3.85 (s,
3H), 3.73 (dd, J = 7.0, 7.0 Hz, 1H), 3.47 (dd, J = 7.6, 7.6 Hz, 1H), 3.16–
3.10 (m, 1H), 3.03 (dd, J = 11.6, 5.5 Hz, 1H), 2.98–2.94 (m, 2H), 2.66
(br d, J = 16.1 Hz, 1H), 2.54–2.47 (m, 4H), 2.31–2.25 (m, 1H), 1.92–
1.85 (m, 1H), 1.80–1.71 (m, 2H), 1.55–1.49 (m, 4H), 1.33–1.22 (m,
2H); 13C NMR (125 MHz, CDCl3) d 152.1, 146.4, 146.3, 144.0, 130.7,
128.4, 127.4, 127.2, 125.9, 110.8, 109.7, 108.2, 101.0, 62.7, 56.0,
53.4, 44.1, 40.2, 35.2, 29.9, 29.4, 29.3, 25.6, 25.0, 25.5; HRMS
(ESI) m/z calcd for C25H29NO4 ([M+H]+), 408.2169, found 408.2172.
4.2. Synthesis of C1 analogs (6)
C1 analogs were prepared from 4 using methods as described in
Ref. 25.
4.2.1. 1-(Hexyloxy)domesticine (6a)
Off white solid; mp: 68–70 °C; 1H NMR (500 MHz, CDCl3) d 7.95
(s, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 5.97 (d, J = 1.5 Hz, 1H), 5.95 (d,
J = 1.5 Hz, 1H), 3.84 (s, 3H), 3.83.3.81 (m, 1H), 3.61-3.59 (m, 1H),
3.16–3.11 (m, 1H), 3.03 (dd, J = 11.3, 6.0 Hz, 1H), 2.98–2.95 (m,
2H), 2.68–2.64 (br d, J = 16 Hz, 1H), 2.54–2.49 (m, 5H), 1.74–1.60
(m, 2H), 1.45–1.26 (m, 6H), 0.88–0.85 (m, 3H); 13C NMR
(125 MHz, CDCl3) d 152.2, 146.48, 143.9, 130.8, 129.9, 128.8,
128.5, 127.5, 126.0, 110.8, 109.5, 108.3, 101.0, 73.4, 64.5, 56.0,
53.4, 44.1, 35.3, 31.8, 30.3, 29.3, 26.0, 22.8, 14.2; HRMS (ESI) m/z
calcd for C25H31NO4 ([M+H]+), 410.2326, found 410.2330.
4.2.7. 1-(Cyclohexylmethoxy)domesticine (6g)
Yellow oil; 1H NMR (500 MHz, CDCl3) d 7.94 (s, 1H), 6.74 (s, 1H),
6.57 (s, 1H), 5.97 (s, 1H), 5.94 (s, 1H), 3.84 (s, 3H), 3.60 (dd, J = 8.7,
6.1 Hz, 1H), 3.40 (t, J = 7.6 Hz, 1H), 3.17–3.10 (m, 1H), 3.05–2.94
(m, 3H), 2.66 (br d. J = 16.0 Hz, 1H), 2.53–2.49 (m, 5H), 1.90–1.63
(m, 10H), 1.17–1.10 (m,1H); 13C NMR (125 MHz, CDCl3) d 152.2,
146.49, 146.45, 144.2, 130.7, 128.4, 127.4 (ꢀ2), 125.8, 110.9,
109.7, 108.2, 101.0, 78.7, 62.7, 56.1, 53.4, 44.1, 38.7, 35.2, 30.2,
29.9, 29.1, 26.7, 26.1, 26.0; HRMS (ESI) m/z calcd for C26H31NO4
([M+H]+), 422.2326, found 422.2329.
4.2.2. 1-(Isobutyloxy)domesticine (6b)
Brown oil; 1H NMR (500 MHz, CDCl3) d 7.95 (s, 1H), 6.74 (s, 1H),
6.57 (s, 1H), 5.97 (s, 1H), 5.94 (s, 1H), 3.84 (s, 3H), 3.61 (t, J = 7.6 Hz,
1H), 3.36 (t, J = 7.6 Hz, 1H), 3.16–3.10 (m, 1H), 3.04–2.95 (m, 2H),
2.67–2.64 (br d, J = 15.7 Hz, 1H), 2.54–2.48 (m, 5H), 2.04–1.99
(m, 1H), 1.01–0.95 (m, 6H); 13C NMR (125 MHz, CDCl3) d 152.2,
146.4 (ꢀ2), 144.1, 130.7, 128.4, 127.4, 125.8, 110.9, 109.6, 108.2,
101.0, 100.84, 79.8, 62.8, 56.1, 53.5, 44.2, 35.3, 29.3, 29.2, 19.7,
19.5; HRMS (ESI) m/z calcd for C23H27NO4 ([M+H]+), 382.2013,
found 382.2017.
4.2.8. 1-(Allyloxy)domesticine (6h)
Brown solid; mp: 63–65 °C; 1H NMR (500 MHz, CDCl3) d 7.95 (s,
1H), 6.74 (s, 1H), 6.58 (s, 1H), 6.01–5.93 (m, 3H), 5.27 (ddd, J = 17.3,
3.0, 1.4 Hz, 1H), 5.14 (dd, J = 10.4, 1.4 Hz, 1H), 4.37–4.33 (m, 1H),
4.22–4.21 (m, 1H), 3.86 (s, 3H), 3.17–3.10 (m, 1H), 3.04–2.94 (m,
3H), 2.66 (dd, J = 16.3, 3.35 Hz, 1H), 2.54–2.48 (m, 2H), 2.53 (s,
3H); 13C NMR (125 MHz, CDCl3) d 152.2, 146.5, 146.4, 143.1,
134.4, 130.8, 128.8, 127.6, 127.3,125.8, 117.6, 110.7, 109.4, 108.3,
101.0, 73.8, 62.6, 56.0, 53.3, 44.1, 35.2, 29.3; HRMS (ESI) m/z calcd
for C22H23NO4 ([M+Na]+), 388.1519, found 388.1520.
4.2.3. 1-(Isopentyloxy)domesticine (6c)
Brown oil; 1H NMR (500 MHz, CDCl3) d 7.95 (s, 1H), 6.74 (s, 1H),
6.57 (s, 1H), 5.96 (s, 1H), 5.95 (s, 1H), 3.86–3.82 (m, 4H), 3.66–3.61
(m, 1H), 3.17–3.10 (m, 1H), 3.04–3.01 (m, 1H), 2.98–2.94 (m, 2H),
2.68–2.64 (m, 1H), 2.55–2.48 (m, 5H), 1.84–1.76 (m, 1H), 1.63–1.52
(m, 2H), 0.88–0.87 (m, 6H); 13C NMR (125 MHz, CDCl3) d 152.1,
146.4, 144.1, 143.7, 130.7, 129.7, 128.5, 127.3, 125.7, 110.5,
109.2, 108.1, 100.8, 71.5, 62.5, 55.8, 53.2, 40.3, 39.1, 35.1, 24.7,
4.2.9. 1-(3-Hydroxy-propanyloxy)domesticine (6i)
Brown Oil; 1H NMR (500 MHz, CDCl3) d 7.95 (s, 1H), 6.74 (s, 1H),
6.59 (s, 1H), 5.98 (s, 1H), 5.96 (s, 1H), 3.97–3.92 (m, 2H), 3.90–3.84
(m, 5H), 3.82–3.77 (m, 1H), 3.19–3.13 (m, 1H), 3.07–2.95 (m, 3H),
2.68 (dd, J = 16.2, 2.8 Hz, 1H), 2.54 (m, 5H), 2.05–1.97 (s, 1H), 1.85–
1.78 (m, 1H); 13C NMR (125 MHz, CDCl3) d 151.8, 146.7, 146.6,
143.4, 130.8, 128.9, 127.4, 125.6, 110.6, 108.7, 108.5, 101.1, 71.0,
62.6, 61.2, 56.0, 53.3, 44.1, 44.0, 35.1, 29.9; HRMS (ESI) m/z calcd
for C22H25NO5 ([M+H]+), 384.4376, found 384.4376.
22.6, 22.4; HRMS (ESI) m/z calcd for
C
24H29NO4 ([M+H]+),
396.4914, found 396.4914.
4.2.4. 1-(2-Ethylbutyloxy)domesticine (6d)
Brown solid; mp: 62–64 °C; 1H NMR (500 MHz, CDCl3) d 7.91 (s,
1H), 6.74 (s, 1H), 6.57 (s, 1H), 5.95 (d, J = 1.4 Hz, 1H), 5.94 (d,
J = 1.4 Hz, 1H), 3.84 (s, 3H), 3.74 (dd, J = 9.1, 5.3 Hz, 1H), 3.49 (dd,
J = 9.0, 5.3 Hz, 1H), 3.17–3.10 (m, 1H), 3.03 (dd, J = 11.3, 5.1 Hz,
1H), 2.98–2.94 (m, 2H), 2.66 (dd, J = 16.3, 3.4 Hz, 1H), 2.54–2.48
(m, 5H), 1.56–1.34 (m, 5H), 0.86 (d, J = 7.2 Hz, 3H), 0.83 (d,
J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 152.1, 146.4, 146.3,
144.1, 130.6, 128.3, 127.5, 127.4, 125.8, 110.8, 109.6, 108.2,
100.9, 75.2, 62.7, 55.9, 53.4, 44.1, 42.1, 35.2, 29.3, 23.4, 23.2,
4.3. 3-(6-Bromobenzo[d][1,3] dioxol-5-yl)-N-(3,4-dimethoxyphe
nethyl) ethanamide (8)
A solution of bromomethylenedioxyphenylacetic acid (4.76 g,
17.5 mmol) and 1,10-carbonyldiimidazole (2.84 g, 17.5 mmol) in
anhydrous THF (40 mL) was stirred at 0 °C for 1.5 h and then at
room temperature for 1 h. The mixture was cooled in an ice-bath
and stirred for 1 h. Then 3-benzyloxy-4-methoxyphenethylamine
(7) (4.50 g, 17.5 mmol) was added and the solution was stirred at
0 °C for 4 h and left to stir overnight at room temperature. The
reaction mixture was evaporated under reduced pressure and the
residue was dissolved in EtOAc and washed sequentially with
1 N HCl (25 mL), water (50 mL), satd NaHCO3 solution (25 mL)
and finally with brine (50 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was crystallized from EtOAc/diethylether to furnish
amide 8 (6.65 g, 76.5%).
11.3, 11.1; HRMS (ESI) m/z calcd for
C
25H31NO4 ([M+H]+),
410.2326, found 410.2329.
4.2.5. 1-(Cyclobutylmethoxy)domesticine (6e)
Brown oil; 1H NMR (500 MHz, CDCl3) d 7.93 (s, 1H), 6.74 (s, 1H),
6.56 (s, 1H), 5.98 (d, J = 1.5 Hz 1H), 5.94 (d, J = 1.5 Hz, 1H), 3.85 (s,
3H), 3.83 (dd, J = 9.4, 6.7 Hz, 1H), 3.59 (dd, J = 9.4, 7.4 Hz, 1H),
3.18–3.11 (m, 1H), 3.05 (dd, J = 6.0, 5.5 Hz, 1H), 3.0–2.95 (m, 2H),
2.69–2.64 (m, 2H), 2.56–2.50 (m, 5H), 2.06–1.95 (m, 2H),
1.92–1.85 (m, 1H), 1.83–1.66 (m, 3H); 13C NMR (125 MHz, CDCl3)

5866
S. Chaudhary et al. / Bioorg. Med. Chem. 19 (2011) 5861–5868
White solid; mp: 163–165 °C; 1H NMR (500 MHz, CDCl3) d 7.45
4.6. 2-(Benzyloxy)N-boc-nor-isodomesticine (11)
(m, 2H), 7.39 (m, 2H), 7.30 (m, 1H), 7.00 (s, 1H), 6.80 (d, J = 8.2 Hz,
1H), 6.75 (s, 1H), 6.70 (br s., 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.00 (s, 2H),
5.38 (br s, 1H), 5.12 (s, 2H), 3.89 (s, 3H), 3.55 (s, 2H), 3.44 (dd,
J = 13.0, 6.5 Hz, 2H), 2.69 (dd, J = 6.9, 6.9 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 169.5, 148.4, 148.3, 147.9, 147.7, 137.1, 131.0,
128.5, 127.9, 127.5, 127.4, 121.4, 115.3, 114.6, 112.9, 112.0, 110.9,
102.0, 71.1, 56.1, 43.8, 40.6, 34.9; HRMS (ESI) m/z calcd for
In a microwave reaction vial, compound 10 (0.12 g, 0.21 mmol),
Pd(OAc)2 (0.009 g, 0.04 mmol), triphenylphosphine (0.02 g,
0.08 mmol) and Cs2CO3 (0.13 g, 0.4 mmol),) were added and
dissolved in degassed DMF (2 mL). The mixture was irradiated in
the CEM microwave reactor for 15 min at 175 °C with the power
level at 300 W. After cooling to room temperature, the reaction
mixture was loaded directly onto a deactivated silica gel column
and eluted in gradient fashion with 15–30% EtOAc/hexanes to
furnish compound 11 (0.05 g, 52%).
C
25H24BrNO5 ([M+H]+), 498.0838, found 498.0840.
4.4. 6-(Benzyloxy)-1-((6-bromobenzo[d][1,3]dioxol-5-yl)
methyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (9)
Off-white solid; mp: 170–172 °C; 1H NMR (500 MHz, CDCl3) d
8.07 (s, 1H), 7.52–7.29 (m, 5H), 6.76 (s, 1H), 6.68 (s, 1H), 6.01 (s,
2H), 5.15 (m, 2H), 4.65 (m, 1H), 4.42 (m, 1H), 3.75 (s, 3H),
2.86–2.64 (m, 5H), 1.52 (s, 9H); 13C NMR (125 MHz, CDCl3) d
151.1, 146.6, 146.5, 145.5, 137.1, 129.7, 128.6, 127.9, 127.3,
125.2, 112.8, 109.1, 100.9, 79.9, 71.0, 60.1, 51.8, 30.3, 28.6; HRMS
(ESI) m/z calcd for C30H31NO6 ([M]+), 501.2151, found 501.2154.
To a magnetically stirred ice-cooled solution of 8 (5.00 g,
10.05 mmol) in dry DCM (40 mL) was added solid phosphorus
pentachloride (4.19 g, 20.1 mmol) in portions over 10 min. The
reaction mixture was stirred at 0 °C for 1 h and then left to stir at
room temperature for 20 h. The reaction mixture was then poured
onto a saturated solution of aqueous NaHCO3 (100 mL) and the
contents of the flask were stirred for 1 h. The aqueous layer was
extracted with dichloromethane (3 ꢀ 20 mL). The combined
organic layer was washed with saturated NaHCO3 solution
(100 mL) and brine (40 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure. To a magnetically stirred
ice-cooled solution of the crude imine thus obtained in a mixture
of dry MeOH (40 mL) and dry DCM (20 mL), was added powdered
NaBH4 (3.60 g, 98 mmol) in three portions over 10 min. The
reaction mixture was stirred at 0 °C for 2 h. The reaction mixture
was diluted with water and extracted with dichloromethane
(3 ꢀ 10 mL). The combined organic layer was washed with brine
(30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
The crude product was purified by flash column chromatography
over deactivated silica gel using 0.7% MeOH/DCM as eluant to
furnish pure 9 (3.92 g, 81% yield from 8).
4.7. N-boc-nor-isodomesticine (12)
To a solution of 11 (0.50 g, 1 mmol) in dry methanol (10 mL)
was added 10% Pd/C (25 mg) under inert atmosphere. The reaction
was purged with H2 and stirred under a balloon of H2 for 6 h. Pd/C
was filtered through a Celite pad and the filtrate was evaporated to
give the corresponding phenol 12 (0.38 g, 92%).
White solid; mp: 218–220 °C; 1H NMR (500 MHz, CDCl3) d 7.90
(s, 1H), 6.79 (s, 1H), 6.73 (s, 1H), 6.02 (s, 2H), 5.86 (s, 1H), 4.70–4.68
(m, 1H), 4.61 (m, 1H), 4.40 (m, 1H), 3.61 (s, 3H), 2.92–2.76 (m, 4H),
2.66–2.62 (m, 1H), 1.57–1.52 (s, 9H); 13C NMR (125 MHz, CDCl3) d
148.1, 146.9, 146.8, 142.6, 131.5, 131.1, 126.5, 125.4, 124.9, 124.8,
113.4, 108.6, 107.8, 101.0, 79.9, 60.2, 51.8, 30.2, 28.6; HRMS (ESI)
m/z calcd for C23H25NO6 ([M]+), 411.1682, found 411.1684.
White solid; mp: 115–117 °C; 1H NMR (500 MHz, CDCl3) d 7.44
(m, 2H), 7.36 (m, 2H), 7.30 (m, 1H), 7.05 (s, 1H), 6.79 (s, 1H), 6.76 (s,
1H), 6.63 (s, 1H), 6.00 (s, 2H), 5.12 (s, 2H), 4.21 (t, J=6.5 Hz, 1H),
3.84 (s, 3H), 3.28–3.20 (m, 2H), 2.99–2.89 (m, 2H), 2.71 (m, 2H);
13C NMR (125 MHz, CDCl3) d 147.9, 147.3, 147.2, 147.0, 137.3,
131.6, 130.8, 128.5, 127.8, 127.3, 127.1, 115.0, 114.5, 112.9,
111.4, 110.4, 101.7, 71.1, 56.2, 55.2, 42.8, 40.0, 29.1; HRMS (ESI)
m/z calcd for C25H24BrNO4 ([M+H]+), 482.0889, found 482.0886.
4.8. General procedure for preparation of C2 analogs (14)
O-methylation of 12: To a stirred solution of phenol (1 equiv)
in acetone (10 mL) was added solid K2CO3 (2 equiv) and potas-
sium iodide (2 equiv) at rt The resulting mixture was stirred for
5 min and then alkyl halide (1.5 equiv) was added and refluxed
for 7 h. The solvent was evaporated and the resulting solid dis-
solved in water and extracted with dichloromethane twice
(20 mL each). The organic layer was dried over sodium sulfate
and concentrated under reduced pressure. The crude product
was purified by flash column chromatography using 12.5%
EtOAc/hexanes.
4.5. tert-butyl-6-(benzyloxy)-1-((6-bromobenzo[d][1,3]dioxol-
5-yl)methyl)-7-methoxy-3,4-dihydroisoquinoline-2(1H)-
carboxylate (10)
N-Boc deprotection and reductive amination of 13: To a solution
of the boc-protected amine (1 equiv) in dichloromethane (15 mL)
was added dry ZnBr2 (2 equiv) and the reaction allowed to stir at
rt overnight under N2. The mixture was diluted with dichlorometh-
ane (20 mL) and washed with saturated aqueous NaHCO3 twice
(10 mL each). The organic layer was dried (Na2SO4), filtered and
concentrated in vacuo. The crude amine product was purified by
column chromatography on water-deactivated silica gel in 5%
methanol/dichloromethane. To a solution of this amine (1 equiv)
in dichloromethane (10 mL) was added the aldehyde (3 equiv)
and sodium triacetoxyborohydride (3 equiv) under N2. The reac-
tion mixture was allowed to stir at rt overnight. The reaction was
quenched with water and extracted with dichloromethane twice
(20 mL each). The combined organic layer was washed with 10%
aq NaHCO3, then with brine, dried over anhydrous Na2SO4, and
concentrated to give crude product. The crude product was sub-
jected to column chromatography over water-deactivated silica
gel using methanol/dichloromethane (2:98) as eluant, to furnish
N-alkylated final product.
To a stirred solution of 9 (3.67 g, 7.63 mmol) in DCM (30 mL)
was added DIPEA (2.66 mL, 15.3 mmol), a catalytic amount of
DMAP (0.01 g) followed by BOC anhydride (3.26 mL, 15.3 mmol)
at room temperature and the solution stirred under inert atmo-
sphere for 18 h. The reaction mixture was washed with saturated
NH4Cl solution and water, dried over anhydrous Na2SO4, and con-
centrated under reduced pressure. The crude product was purified
by flash column chromatography on silica gel using 30% EtOAc/
hexanes as eluant to furnish pure 10 (5.10 g, 65%).
Off-white solid; mp: 128–130 °C; 1H NMR (500 MHz, CDCl3) d
7.43 (m, 2H), 7.36 (m, 2H), 7.29 (m, 1H), 7.02 (s, 1H), 6.96 (s,1H),
6.63 (s, 1H), 6.65 (s, 1H), 5.97 (s, 1H), 5.93 (s, 1H), 5.27 (m, 1H),
5.10–5.09 (s, 2H), 4.35 (dd, J = 13.2, 5.3 Hz, 1H), 3.85 (s, 3H), 3.21
(m, 2H), 2.89 (m, 2H), 1.40–1.23 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 154.9, 148.3, 147.2, 137.8, 131.3, 128.6, 127.9, 127.8, 127.3,
126.6, 115.3, 114.2, 112.5, 111.4, 111.0, 110.6, 101.6, 79.5, 71.1,
56.2, 54.0, 42.6, 36.4, 28.1; HRMS (ESI) m/z calcd for C30H32BrNO6
([M]+), 581.1413, found 581.1415.

S. Chaudhary et al. / Bioorg. Med. Chem. 19 (2011) 5861–5868
5867
4.8.1. 2-(Ethoxy)isodomesticine (14a)
62.5, 60.3, 53.2, 44.0, 35.1, 29.1; HRMS (ESI) m/z calcd for
26H25NO4 ([M+H]+), 416.1784, found 416.1788.
Yellow solid; mp: 101–104 °C; 1H NMR (500 MHz, CDCl3) d 7.92
(s, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 5.96 (d, J = 1.4 Hz, 1H), 5.95 (d,
J = 1.4 Hz, 1H), 4.12–4.02 (m, 2H), 3.67 (s, 3H), 3.15–3.08 (m, 1H),
3.02–2.94 (m, 3H), 2.66–2.62 (m, 1H), 2.54–2.45 (m, 5H), 1.47 (t,
J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 151.5, 146.5, 146.4,
144.7, 130.5, 128.9, 127.3, 127.1, 125.6, 111.6, 109.1, 108.4,
100.9, 64.2, 62.4, 60.2, 53.4, 44.2, 35.3, 29.3, 15.1; HRMS (ESI) m/
z calcd for C21H23NO4 ([M+H]+), 354.4116, found 354.4120.
C
4.9. Synthesis of 3-bromonantenine (15) and 3,8,11-
tribromonantenine (16)
To a solution of nantenine (2) (25 mg, 1 equiv) in acetic acid
(5 mL) was slowly added a solution of bromine (3 equiv) dissolved
in acetic acid (2 mL) at room temperature. The mixture was stirred
overnight at room temperature and the solvent evaporated in va-
cuo. The residue was dissolved in toluene and the solvent again re-
moved by rotary evaporation. The residue was purified by column
chromatography with elution in 2% MeOH/DCM to give com-
pounds 15 (5 mg, 16%) and 16 (22 mg, 52%).
4.8.2. 2-(Propyloxy)isodomesticine (14b)
Yellow solid; mp: 76–77 °C; 1H NMR (500 MHz, CDCl3) d 7.95 (s,
1H), 6.76 (s, 1H), 6.59 (s, 1H), 5.98 (d, J = 1.4 Hz, 1H) 5.95 (d,
J = 1.4 Hz, 1H), 4.04–3.90 (m, 2H), 3.69 (s, 3H), 3.17–3.10 (m, 1H),
3.04–2.96 (m, 3H), 2.65 (m, 1H), 2.55–2.48 (m, 5H), 1.93–1.85
(m, 3H), 1.09 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) d
151.6, 146.5, 146.4, 144.7, 131.0, 128.6, 127.3, 127.1, 125.8,
111.8, 109.1, 108.4, 101.0, 70.3, 62.6, 60.3, 53.4, 44.2, 35.3, 29.4,
4.9.1. 3-Bromonantenine (15)
Off white solid; mp: 142–144 °C; 1H NMR (500 MHz, CDCl3) d
7.80 (s, 1H), 6.75 (s, 1H), 5.98 (d, J = 1.2 Hz, 1H), 5.97 (d,
J = 1.2 Hz, 1H), 3.93 (s, 3H), 3.73 (s, 3H), 3.10-3.07 (dd, J = 10.7,
5.2 Hz, 1H), 2.98–2.89 (m, 3H), 2.83–2.79 (m, 1H), 2.52 (s, 3H),
2.49–2.41 (m, 2H); 13C NMR (125 MHz, CDCl3) d 150.1, 149.3,
146.77, 146.76, 132.6, 130.7, 129.4, 127.0, 124.9, 118.5, 108.8,
108.3, 101.1, 62.9, 60.8, 60.6, 53.2, 44.0, 34.8, 30.5; HRMS (ESI)
m/z calcd for C20H20BrNO4 ([M+H]+), 418.0648, found 418.0651.
22.9, 10.9; HRMS (ESI) m/z calcd for
368.1882, found 368.1888.
C
22H25NO4 ([M+H]+),
4.8.3. 2-(Butyloxy)isodomesticine (14c)
Yellow solid; mp: 95–97 °C; 1H NMR (500 MHz, CDCl3) d 7.95 (s,
1H), 6.76 (s, 1H), 6.60 (s, 1H), 5.98 (d, J = 1.4 Hz, 1H), 5.97 (d,
J = 1.4 Hz, 1H), 4.05–3.94 (m, 2H), 3.68 (s, 3H), 3.17–3.10 (m, 1H),
3.04–2.95 (m, 3H), 2.68–2.64 (m, 1H), 2.55–2.46 (m, 5H), 1.92–
1.78 (m, 2H), 1.63–1.47 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 151.6, 146.5, 146.4, 144.7, 130.9, 128.6,
127.3, 127.0, 125.8, 111.7, 109.1, 108.3, 100.9, 68.4, 62.6, 60.3,
53.4, 44.2, 35.3, 31.6, 27.4, 19.5, 14.0; HRMS (ESI) m/z calcd for
4.9.2. 3,8,11-Tribromonantenine (16)
White solid; mp: 193–195 °C; 1H NMR (500 MHz, CDCl3) d 6.18
(s, 1H), 6.14 (s, 1H), 3.95 (s, 3H), 3.54 (s, 3H), 3.08 (dd, J = 11.5,
5.2 Hz, 1H), 2.96–2.90 (m, 1H), 2.85–2.77 (m, 2H), 2.54 (s, 3H),
2.49 (dt, J = 11.8, 4.1 Hz, 1H), 2.18 (dd, J = 14.5, 12.9 Hz, 1H); 13C
NMR (125 MHz, CDCl3) d 149.6, 145.9, 145.0, 133.8, 132.6, 128.7,
127.5, 127.1, 125.7, 119.7, 101.7, 101.5, 101.4, 63.0, 61.5, 61.1,
53.0, 44.1, 34.9, 30.3; HRMS (ESI) m/z calcd for C20H18 Br3NO4
([M+H]+), 572.8859, found 572.8859.
C
23H27NO4 ([M+H]+), 382.2016 found 382.2013.
4.8.4. 2-(Pentyloxy)isodomesticine (14d)
Yellow oil; 1H NMR (500 MHz, CDCl3) d 7.94 (s, 1H), 6.75 (s, 1H),
6.59 (s, 1H), 5.97 (d, J = 1.4 Hz, 1H), 5.95 (d, J = 1.4 Hz, 1H), 4.05–
3.94 (m, 2H), 3.68 (s, 3H), 3.15–3.09 (m, 1H), 3.03–2.95 (m, 3H),
2.67–2.63 (m, 1H), 2.54–2.46 (m, 5H), 1.92–1.81 (m, 2H), 1.55–
1.37 (m, 4H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) d
151.6, 146.5, 146.4, 144.7, 130.9, 128.6, 127.3, 127.1, 125.8,
111.8, 109.1, 108.4, 100.9, 68.7, 62.6, 60.3, 53.4, 44.2, 35.3, 29.4,
4.10. Synthesis of N6 analogs (18)
These compounds were prepared by reductive amination on
amine 17 using the procedure as described above for synthesis of
the C2 analogs.
29.2, 28.4, 22.6, 14.2; HRMS (ESI) m/z calcd for
C24H29NO4
([M+H]+), 396.2194, found 396.2192.
4.10.1. N-Ethyl-nornantenine (18a)
Brown solid; mp: 220–222 °C; 1H NMR (500 MHz, CDCl3) d 7.92
(s, 1H), 6.76 (s, 1H), 6.60 (s, 1H), 5.98 (d, J = 1.4 Hz, 1H), 5.95 (d,
J = 1.4 Hz, 1H), 3.88 (s, 3H), 3.65 (s, 3H), 3.27 (d, J = 8 Hz, 1H),
3.19–3.17 (m, 1H), 3.12–3.08 (m, 2H), 2.99–2.96 (m, 1H),
2.71–2.48 (m, 4H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 152.0, 146.6, 146.4, 144.6, 131.0, 129.0, 127.3, 125.7,
110.7, 109.1, 109.0, 108.4, 101.0, 60.4, 59.2, 55.9, 48.4, 47.9, 35.0,
4.8.5. 2-(Cyclopropylmethyloxy)isodomesticine (14e)
Yellow solid; mp: 91–92 °C; 1H NMR (500 MHz, CDCl3) d 7.93 (s,
1H), 6.74 (s, 1H), 6.56 (s, 1H), 5.97 (d, J = 1.4 Hz, 1H), 5.95 (d,
J = 1.4 Hz, 1H), 3.94–3.90 (m, 1H), 3.79–3.75 (m, 1H), 3.70 (s, 3H),
3.14–3.07 (m, 1H), 3.02–2.94 (m, 3H), 2.65–2.61 (m, 1H), 2.54–
2.45 (m, 5H), 1.37–1.24 (m, 1H), 0.64 (m, 2H), 0.37 (m, 2H); 13C
NMR (125 MHz, CDCl3) d 151.6, 146.5, 146.4, 144.7, 130.9, 128.6,
127.3, 127.1, 125.8, 111.8, 109.1, 108.4, 100.9, 68.7, 62.6, 60.3,
53.4, 44.2, 35.3, 29.4, 29.2, 28.4, 22.6, 14.2; HRMS (ESI) m/z calcd
for C23H25NO4 ([M+H]+), 380.1872 found 380.1874.
29.3, 10.8; HRMS (ESI) m/z calcd for
354.4116, found, 354.4115.
C
21H23NO4 ([M+H]+),
4.10.2. N-Propyl-nornantenine (18b)
Yellow oil; 1H NMR (500 MHz, CDCl3) d 7.91 (s, 1H), 6.76 (s, 1H),
6.59 (s, 1H), 5.98 (d, J = 1.1 Hz, 1H), 5.97 (d, J = 1.1 Hz, 1H), 3.90 (s,
3H), 3.87 (s, 3H), 3.23–3.20 (d, 1H), 3.17–3.14 (m, 2H), 2.98–2.95
(m, 1H), 2.69–2.66 (d, 1H), 2.51–2.41 (m, 4H), 1.60–1.57 (m, 2H),
0.97 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) d; 151.9,
146.5, 146.4, 144.5, 131.2, 129.2, 128.2, 128.1, 127.3, 125.7,
110.8, 109.0, 108.3, 101.0, 60.3, 60.0, 56.4, 55.9, 49.3, 35.3, 29.8,
29.5, 19.7,12.2; HRMS (ESI) m/z calcd for C22H25NO4 ([M+H]+),
368.4382, found, 368.4380.
4.8.6. 2-(Benzyloxy)isodomesticine (14f)
Brown solid; mp: 112–114 °C; 1H NMR (500 MHz, CDCl3) d 7.95
(s, 1H), 7.50–7.32 (m, 5H), 6.77 (s, 1H), 6.67 (s, 1H), 5.98 (d,
J = 1.4 Hz, 1H), 5.97 (d, J = 1.4 Hz, 1H), 5.12 (d, J = 11.8 Hz, 1H),
5.11 (d, J = 11.8 Hz, 1H), 3.72 (s, 3H), 3.11 (m, 1H), 3.09–2.97 (m,
3H), 2.64 (m, 1H), 2.56–2.46 (m, 5H); 13C NMR (125 MHz, CDCl3)
d 151.2, 146.5, 146.4, 145.0, 137.2, 130.8, 128.6, 128.5, 127.9,
127.8, 127.4, 127.3, 127.2, 125.6, 112.7, 109.0, 108.3, 100.9, 70.9,

5868
S. Chaudhary et al. / Bioorg. Med. Chem. 19 (2011) 5861–5868
4.10.3. N-butyl-nornantenine (18c)
References and notes
Yellow oil; 1H NMR (500 MHz, CDCl3) d 7.92 (s, 1H), 6.77 (s, 1H),
6.60 (s, 1H), 5.99 (d, J = 1.5 Hz, 1H), 5.97 (d, J = 1.5 Hz, 1H), 3.88 (s,
3H), 3.65 (s, 3H), 3.17–3.15 (m, 2H), 2.99–2.95 (m, 3H), 2.70 (m,
1H), 2.54–2.43 (m, 3H), 1.59–1.54 (m, 2H), 1.41–1.37 (m, 2H),
0.97 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 151.9, 146.6,
146.4, 144.5, 131.3, 129.3, 128.6, 127.3, 125.8, 110.7, 109.0,
108.4, 101.0, 60.4, 60.0, 56.0, 54.2, 49.3, 35.3, 29.6, 28.7, 21.0,
14.3; HRMS (ESI) m/z calcd for C23H27NO4 ([M+H]+), 382.4648,
found 382.4645.
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Yellow Oil; 1H NMR (500 MHz, CDCl3) d 7.91 (s, 1H), 6.77 (s, 1H),
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4.10.5. N-Cyclopropylmethyl-nornantenine (18e)
Yellow Oil; 1H NMR (500 MHz, CDCl3) d 7.92 (s, 1H), 6.76 (s, 1H),
6.60 (s, 1H), 5.98 (d, 1.5 Hz, 1H), 5.97 (d, 1.5 Hz, 1H), 3.88 (s, 3H), 3.65
(s, 3H) 3.38–3.37 (m, 1H), 2.99–2.92 (m, 4H), 2.72–2.71 (m, 1H),
2.57–2.56 (m, 1H), 2.53–2.47 (m, 1H), 2.40–2.36 (m, 1H), 0.96 (m,
1H), 0.59 (dd, J = 8.0, 8.0 Hz, 1H), 0.54 (dd, J = 8.0, 8.0 Hz, 1H), 0.19
(d, J = 4.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 151.9, 146.6, 146.4,
144.5, 131.2, 129.2, 128.0, 127.2, 125.8, 110.7, 109.0, 108.3, 101.0,
60.4, 59.5, 59.2, 56.0, 49.5, 35.2, 29.5, 7.7, 5.2, 3.1; HRMS (ESI) m/z
calcd for C23H25NO4 ([M+H]+), 380.4489, found 380.4490.
Acknowledgments
This publication was made possible by Grant Number RR03037
and R03DA025910 from the National Center for Research Re-
sources (NCRR) and National Institute of Drug Abuse (NIDA)
respectively, components of the National Institutes of Health. Its
contents are solely the responsibility of the authors and do not
necessarily represent the official views of the NIH or its divisions.
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2011.08.019.