Investigation into the structure-activity relationship of novel concentration dependent, dual action T-type calcium channel agonists/antagonists

Article abstract of DOI:10.1016/j.bmc.2005.03.004

This paper describes the synthesis and biological evaluation of a series of straight chain analogs of a compound (1) that was previously synthesized in our research program. These compounds, which are T-type calcium channel antagonists, exhibits potent anti-proliferative activity against a variety of cancer cells. A structure-activity relationship of these analogs against a variety of cancer cells has provided insight into a logical pharmacophore for this series of compounds. Furthermore, this series of compounds has presented itself as a set of novel, concentration dependent, dual action agonists/antagonists for the T-type calcium channel.

Full text of DOI:10.1016/j.bmc.2005.03.004

Bioorganic & Medicinal Chemistry 13 (2005) 3821–3839
Investigation into the structure–activity relationship of
novel concentration dependent, dual action T-type calcium
channel agonists/antagonists
William F. McCalmont,a,* Jaclyn R. Patterson,a Michael A. Lindenmuth,a
Tiffany N. Heady,a Doris M. Haverstick,b Lloyd S. Grayb and Timothy L. Macdonalda
aDepartment of Chemistry, University of Virginia, Charlottesville, VA 22904-4319, USA
bDepartment of Pathology, University of Virginia, Charlottesville, VA 22904-4319, USA
Received 5 October 2004; revised 22 February 2005; accepted 1 March 2005
Available online 19 April 2005
Abstract—This paper describes the synthesis and biological evaluation of a series of straight chain analogs of a compound (1) that
was previously synthesized in our research program. These compounds, which are T-type calcium channel antagonists, exhibits
potent anti-proliferative activity against a variety of cancer cells. A structure–activity relationship of these analogs against a variety
of cancer cells has provided insight into a logical pharmacophore for this series of compounds. Furthermore, this series of com-
pounds has presented itself as a set of novel, concentration dependent, dual action agonists/antagonists for the T-type calcium
channel.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
cellular proliferation in certain types of cancer cells.11
A T-type calcium channel, which will be discussed in
more detail shortly, has recently been shown to be the
ion channel that is responsible for this link between cal-
cium influx and cellular proliferation.
The cell cycle and calcium influx have an intimate rela-
tionship.1–3 Calcium is known to regulate many pro-
cesses within the cell cycle via changes in the
intracellular calcium concentration.4–6 Therefore, regu-
lation of intracellular calcium concentrations directs cer-
tain aspects of the cell cycle which, in turn, lead to
inhibition of cellular proliferation. Thus, inhibition of
calcium influx could be an important tool in the fight
against a variety of disease states where the cell cycle
has become aberrant, such as cancer.
Of all the calcium channel subtypes, the T-type has been
the least studied and is the least understood.7 There is no
single reason for this lack of understanding. However,
the need for a selective antagonist for LVA channels
has definitely hampered investigations into this subtype
of ion channels. Most of what is known about LVA
channels has come from the over-expression of cloned
channels and the isolation of endogenous T-type currents
via pharmacological and electrophysiological methods.7
T-type calcium channels, also known as low voltage
activated (LVA) calcium channels, have been weakly
associated with cancer for some time.7 In fact, T-type
currents are recorded from a variety of cancer cell lines.7
They are also the only calcium current recorded from a
human medullary thyroid carcinoma cell line.8–10 Fur-
thermore, we have shown, in our laboratories that inhibi-
ting calcium influx into the cell leads to inhibition of
We have recently described the synthesis and biological
activity of a novel set of T-type calcium channel antag-
onists11 and provided a link between chemical blockade
of a T-type calcium channel and inhibition of cellular
proliferation. We have further described a brief SAR
of this series of compounds on inhibition of cellular pro-
liferation via calcium channel blockade. This study has
produced the lead compound (1) shown in Figure 1. Fig-
ure 2 shows the typical dose–response curve exhibited by
compound 1 on the inhibition of calcium influx.
Keywords: T-type calcium channels; Concentration dependent dual
antagonist/agonist; Cancer.
*
Corresponding author. Tel.: +1 434 9240595; fax: +1 434 9822302;
e-mail: wfm3s@virginia.edu
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.03.004

3822
W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
OMe
Williamson ether synthesis to afford the ether 2a from
the diol. Then the alcohol was treated with NaH, fol-
lowed by condensation with p-methoxybenzyl chloride
(PMB-Cl) affording the final diether product 2.
Cl
H
N
O
Compounds 3, 5, and 9 displayed in Table 1 were syn-
thesized as described in Scheme 2. Synthesis began with
an acid catalyzed reductive amination, which lead to the
aminoalcohols 3a, 5a, and 9a. Coupling of the aminoal-
cohols with 4-chlorobenzhydrol via Williamson ether
synthesis conditions afforded the final products 3, 5,
and 9.14
Figure 1. Structure of T-type calcium channel antagonist 1.
1200
Addition of Compound 1
OKT3 alone
1000
800
600
400
200
0
OKT3/30 µM1
OKT3/10 µM1
OKT3/3 µM1
OKT3/1 µM1
Compound 4 displayed in Table 1 was synthesized
according to Scheme 3. Synthesis began with the cou-
pling reaction of p-anisidine with succinic anhydride to
afford the amide acid 4a.15 Reduction of the amide acid
afforded the aminoalcohol 4b, which was then coupled
to 4-chlorobenzhydrol using the standard Williamson
ether synthesis conditions already mentioned to afford
the final product 4.
Addition of OKT3
0
50
150
100
time (sec)
Compounds 6 and 11 displayed in Table 1 were synthe-
sized as described in Scheme 4. Synthesis started with
the coupling of 4-methoxyphenyl acetic acid or 4-meth-
oxyphenyl propanoic acid to tert-butyl dimethyl silyl pro-
tected ethanolamine to afford the amides 6a and 11a.
Deprotection of the silyl ether afforded the amide alcohols
6b and 11b, which were reduced to the aminoalcohols 6c
and 11c.16 Coupling of the alcohols 6c and 11c to 4-chlo-
robenzhydrol afforded the final products 6 and 11.
Figure 2. Dose–response curve of compound 1 against intracellular
calcium concentration.
We have also recently shown that a T-type calcium
channel subtype is responsible for the biological activity
that is elicited by compound 1 and its structural ana-
logs.12 These subtypes include Cav3.2 and its variants.
In this study we were able to inhibit cellular prolifera-
tion of cancer cells that presented the Cav3.2 or one of
its variants, as well as cancer cell lines that were trans-
fected with the Cav3.2 subtype. However, a cancer cell
line that is known to utilize a different subtype of
LVA calcium channels shows resistance to the biological
effects of our compounds.
Compounds 7, 8, and 10 displayed in Table 1 were syn-
thesized according to Scheme 5. These syntheses began
with terminal alkynyl alcohols of varying chain lengths
between butynyl and hexynyl. The alkynyl alcohols were
coupled to 4-chlorobenzophenone to afford 7a, 8a, and
10a in good yields in all three cases. Dual hydrogena-
tion/hydrogenolysis of the alkynyl groups/benzylic alco-
hol afforded the corresponding reduced alcohols 7b, 8b,
and 10b. Oxidation of the primary alcohols afforded the
aldehydes 7c, 8c, and 10c.17 Finally compounds 7c and
8c were coupled to 4-methoxybenzyl amine and 4-meth-
oxyphenethyl amine, respectively, to afford the final
products 7 and 8 as shown. Reductive amination was at-
tempted at this point on 10c with p-anisidine, however in
our hands this could not be accomplished. Therefore,
the aldehyde was converted into the corresponding acid
10d.18 A PyBOP coupling reaction with p-anisidine en-
sued to form the amide 10e,19 which then underwent a
reduction to afford the amine 10.
In this paper we describe the synthesis and biological
evaluation of a variety of straight chain analogs of com-
pound 1 as well as two conformationally restricted ana-
logs. We provide further evidence that calcium channel
antagonism, via chemical means, is a viable way to cyto-
statically inhibit cellular proliferation. Representative
biological data is provided to establish a clearly defined
link between calcium channel antagonism and inhibition
of cellular proliferation. We will also provide a proposed
pharmacophore for the antagonist activity.
We will also provide proof of a concentration dependent
dual action agonism/antagonism of T-type calcium
channels exhibited by these compounds. There are sev-
eral examples of dual action agonist/antagonist for cal-
cium channels in the literature.13 However, none of
these examples have been shown to display this type of
activity on T-type calcium channels. Therefore, to the
best of our knowledge we believe this to be the first
example of such activity for T-type calcium channels.
Synthesis of compound 12 in Table 1 was accomplished
according to Scheme 6. Synthesis started with a Wittig
reaction to couple 4-chlorobenzophenone with (3-benz-
yloxypropyl)triphenylphosphonium bromide to form
the alkene 12a.20 A dual hydrogenation/hydrogenolysis
of the alkene/protected alcohol lead to the production
of the reduced, unprotected alcohol, which was oxidized
to the aldehyde 12b using Dess–Martin periodinane.21
2. Chemistry
Compound 2 displayed in Table 1 was synthesized
according to Scheme 1. Synthesis began with the typical
Next, 4-methoxycinnaminitrile was reduced to the corre-
sponding amine followed by hydrogenation of the

W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
Table 1. Antagonist data for all of the compounds
3823
Compound
Structure
IC50 (lM)
Jurkat
LNCaP
MDA-231
Cellular
proliferation
Calcium
influx
Cellular
proliferation
Calcium
influx
Cellular
proliferation
Calcium
influx
Cl
MeO
1
6
7
4
4
40
35
O
N
Cl
MeO
2
3
100
10
100
NE
>100
60
10
O
O
Cl
MeO
MeO
3.8
3
1.6
3
11.7
H
N
O
Cl
O
N
H
4
5
30
30
100
NE
NE
NE
10
Cl
MeO
H
N
O
4
7
4
5
11
H
N
6
7.6
10
3.5
10
8
10
O
MeO
MeO
Cl
7
8
>100
30
10
>100
30
10
NE
30
10
N
H
Cl
MeO
H
N
4
3.5
8
Cl
Cl
O
N
H
9
3
3
10
3
2
5
10
15
10
8
10
20
MeO
MeO
10
11
4
3
6
N
H
Cl
O
N
H
3.7
5.5
4
MeO
(continued on next page)
Cl

3824
W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
Table 1 (continued)
Compound
Structure
IC50 (lM)
Jurkat
LNCaP
MDA-231
Cellular
proliferation
Cellular
proliferation
Calcium
influx
Cellular
proliferation
Calcium
influx
Calcium
influx
N
H
12
70
60
42
NE
>100
100
MeO
Cl
H
N
13
14
30
13
30
7
9
NE
NE
15
25
30
10
MeO
Cl
N
H
3
MeO
Cl
H
N
15
16
30
NE
NE
100
NE
NE
NE
NE
NE
MeO
Cl
OMe
>300
>1 mM
1
NH
O
Cl
OMe
HN
17
5.4
3.3
3.3
NE
11.6
20
O
Cl
NE = no effect at the concentration tested; IC50 values are in lM concentrations.
Cl
Cl
O
O
i
ii
HO
O
OH
HO
MeO
2a
2
Scheme 1. Synthesis of diether 2. Reagents and conditions: (i) 4-chlorobenzhydrol, p-TsOH, toluene, reflux; (ii) NaH, DMF, then add PMB-Cl.
double bond leading to the corresponding reduced
amine 12c. Coupling of the amine to the previously
formed aldehyde 12b using reductive amination condi-
tions yielded the final product 12.
formed the a,b-unsaturated nitrile 13b.22 Reduction of
the nitrile resulted in the b,c-unsaturated amine 13c,
which was then coupled with the aldehyde 13a to form
the secondary amine 13d. Hydrogenation of the double
bond resulted in the reduced amine 13.
Synthesis of compound 13 in Table 1 was accomplished
as described in Scheme 7. The synthesis began with the
oxidation of 4-(4-methoxyphenyl)-1-butanol to the alde-
hyde 13a. Next, a Wittig reaction on 4-chlorobenzophe-
none using (triphenylphosphoranylidene) acetonitrile
Synthesis of compound 14 in Table 1 is described as
shown in Scheme 8. The reaction sequence started with
a Friedel–Crafts acylation of anisole with glutaric anhy-
dride to form the d-ketoacid 14a.23 Reduction of the

W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
3825
MeO
MeO
MeO
H
N
H
N
O
i
ii
OH
H
m
n
n
m
H N
OH
O
2
n
a
Cl
Compound
m
n
3
5
9
1
1
1
0
1
2
Scheme 2. Synthesis of several straight chain analogs 3, 5, and 9. Reagents and conditions: (i) AcOH or ZnCl2, MeOH, then add NaBH3CN; (ii) 4-
chloro-benzhydrol, p-TsOH, toluene, heat.
MeO
O
O
MeO
MeO
O
O
OH
ii
OH
N
H
NH2
N
H
i
O
4a
4b
MeO
O
iii
N
H
4
Cl
Scheme 3. Synthesis of straight chain analog 4. Reagents and conditions: (i) THF; (ii) LiAlH4, AlCl3, THF, 0 ꢁC; (iii) 4-chlorobenzhydrol, p-TsOH,
toluene, reflux.
OMe
Synthesis of compound 15 in Table 1 was accomplished
OMe
as described in Scheme 9. First, a Sonogashira coupling
of 4-iodoanisole with 5-hexyn-1-ol formed the aryl
alcohol 15a.26 Next, a hydrogenation produced the
reduced alcohol 15b, which was then oxidized to the
aldehyde 15c using typical Swern conditions. Reductive
amination of the aldehyde with 4-chlorobenz-
hydrylamine hydrochloride formed the final product 15.
Si
O
i
+
ii
O
O
O
N
H
Si
n
NH2
OH
n
OMe
6a n = 0
11a n = 1
n
OMe
OMe
HN
iv
iii
Synthesis of compound 16 in Table 1 was accomplished
according to Scheme 10. First, 2-cyanobenzaldehyde
was reduced to form the amino alcohol 16a. Then red-
uctive amination of 4-methoxybenzaldehyde and 16a
provided 16b. A condensation reaction between 16b
and 4-chlorobenzhydrol afforded 16.
O
O
H
OH
OH
N
H
N
H
n
n
6b n = 0
11c n = 1
6b n = 0
11b n = 1
Cl
6n = 0
11n = 1
Scheme 4. Synthesis of compounds 6 and 11. Reagents and conditions:
(i) DCC, TEA, CH2Cl2; (ii) TBAF, THF, 25 ꢁC, 1 h; (iii) LiAlH4,
THF; (iv) 4-chlorobenzhydrol, p-TsOH, toluene, 110 ꢁC.
Synthesis of compound 17 in Table 1 was accomplished
according to Scheme 11. First, the alcohol of 2-amino-
benzyl alcohol was protected with a tert-butyldimethylsi-
lyl group to form 17a27 then PyBOP mediated coupling
of 17a and 4-methoxyphenylacetic acid generated amide
17b. The silyl protecting group was then removed with
TBAF to provide the free alcohol 17c. Reduction of
the amide yielded amine 17d. The free alcohol of 17d
was then reacted with NaH and condensed with 4-
chloro bromobenzhydrol to afford the final product 17.
ketoacid resulted in the acid (not shown), which was
coupled to N,O-dimethylhydroxyamine to form the
Weinreb amide 14c. The Weinreb amide was then re-
duced to the aldehyde 14d.24 The aldehyde was coupled
to the b-aminoalcohol 14f to form the secondary amine.
The benzylic alcohol (not shown in scheme) was reduced
to yield the final product 14.
The b-aminoalcohol 14f was formed when 4-chlorobenzo-
phenone was reacted with trimethylsilylcyanide to form
the cyanohydrin 14e.25 Reduction of the cyanohydrin
was undertaken immediately, due to the instability of
the molecule, to the b-aminoalcohol, which was used
as previously mentioned.
3. Biological data
Table 1 illustrates the calcium influx and cellular prolif-
eration28 data exhibited by the compounds. Most of the
straight chain analogs of compound 1 that contain both
the nitrogen and the oxygen seem to display some degree

3826
W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
OH
n OH
n
HO
n
OH
ii
i
iii
Cl
n = 1 - 3
Cl
7b n=1
8b n=2
10b n=3
7a n=1
8a n=2
10a n=3
O
MeO
O
n
O
N
H
HO
n
vii
vii
Cl
7c n=1
8c n=2
10c n=3
Cl
Cl
10d For n = 3
10e
ix
iv, or v
then vi
H
N
MeO
Cl
H
N
10
MeO
n
m
7 n=2, m= 1
8 n=1, m=2
Cl
Scheme 5. Synthesis of compounds 7, 8, and 10. Reagents and conditions: (i) 2 equiv n-BuLi, THF, À78 ꢁC, then add 4-chlorobenzophenone; (ii) Pd/
C, H2, formic acid, EtOH; (iii) (ClCO)2, DMSO, DIEA, CH2Cl2; (iv) HCl, p-methoxybenzyl amine; (v) HCl, p-methoxyphenethyl amine; (vi)
NaCNBH3; (vii) NaClO, NaH2PO4, 2-methyl-2-butene, t-BuOH; (viii) PyBOP, DIEA, CH2Cl2, p-anisidine; (ix) LiAlH4, THF.
OMe
OMe
Br
O
i, ii
i
O
P
12a
O
OH
13a
Cl
O
H2N
iii
iii
iv
N
O
ii
iv
Cl
12b
Cl
13b
Cl
13c
Cl
OMe
OMe
OMe
OMe
OMe
H
N
H
N
v
vii
v
N
H
vi
N
NH2
12c
12
13d
13
Cl
Cl
Cl
Scheme 6. Synthesis of compound 12. Reagents and conditions: (i) K–
OtBu, THF, 67 ꢁC; (ii) 4-chlorobenzophenone; (iii) 10% Pd/C, H2,
formic acid; (iv) Dess–Martin periodinane, CH2Cl2; (v) LiAlH4, AlCl3,
THF; (vi) 10% Pd(OH)2/C, H2; (vii) HCl, 12b, followed by NaCNBH3.
Scheme 7. Synthesis of compound 13. Reagents and conditions: (i)
Dess–Martin periodinane, CH2Cl2; (ii) (triphenylphosphoranylid-
ene)acetonitrile, neat, 100 ꢁC; (iii) LiAlH4, AlCl3, THF; (iv) 13a,
HCl (cat), followed by NaCNBH3; (v) 10% Pd(OH)2/C, MeOH.
of biological activity (compounds 3, 5, 6, 9, and 11). The
importance of the nitrogen atom for the biological activ-
ity exhibited by the compounds seems to be very clear
and will be discussed shortly. However, the importance
of the oxygen atom seems to be slightly more convo-
luted. The importance of the oxygen atom, for biologi-
cal activity, seems to be conditional based on the
position of the nitrogen atom. For example, the omis-
sion of the oxygen atom is less important on the overall
biological activity exhibited in compounds 8 and 10, and
to some extent 14, compared to compounds 7, 12, 13,
and 15. The reason for this variance is still unclear.
However, when the nitrogen is omitted from the chain
an apparent loss in both inhibition of calcium influx
and cellular proliferation is realized (compound 2 com-
pared to compound 3).
Both location and basicity of the nitrogen play an
important role in whether an analog will exhibit biolog-
ical activity. Varying the location of the nitrogen, when
the oxygen is omitted, has a dramatic effect on the activ-

W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
3827
OMe
MeO
OMe
OMe
NH2
CN
O
O
O
O
i
ii
+
ii
i
H
O
OH
NH
O
iii
O
H
O
MeO
N
O
OH
OH
14a
16a
14c
OMe
MeO
16b
Cl
OMe
iv
NH
v, vi
iii
N
H
O
O
H
14d
14
16
Cl
N
H2N
Scheme 10. Synthesis of compound 16. Reagents and conditions: (i)
LiAlH4, THF, 0 ꢁC; (ii) HCl, MeOH, then add NaBH3CN; (iii) 4-
chlorobenzhydrol, p-TsOH, toluene, reflux.
O
vii, viii
ix
OH
OH
14f
Cl
Cl
Cl
14e
Scheme 8. Synthesis of compound 14. Reagents and conditions: (i)
neat, AlCl3; (ii) H2, 10% Pd/C, 3:1 EtOH–AcOH; (iii) N,O-dim-
ethylhydroxyamine hydrochloride, PyBOP, DIEA, CH2Cl2; (iv)
LiAlH4, THF, À78 ꢁC; (v) HCl (cat), 14f, followed by NaCNBH3;
(vi) H2, 10% Pd/C (cat), formic acid (cat), EtOH; (vii) TMS–Cl, KCN
(cat), 18-crown-6 (cat); (viii) 15% HCl, THF; (ix) LiAlH4, Et2O.
ity of the compound. There are several positions along
the chain that lead to an increase in biological activity
displayed by the compound. These locations are the 2,
3, and 6 positions of the chain (Fig. 3), relative to the
4-methoxyphenyl group, as opposed to all other loca-
tions (compounds 8, 10, and 14, respectively, compared
to compounds 12, 13, and 15). Basicity of the nitrogen
also plays an important role in whether the compound
will display biological activity. The best examples for
this are a comparison of the biological activity of com-
pounds 8 versus 17 and then compounds 10 versus 16.
In both comparisons the nitrogen atom resides in the
same position in the chain; but in the first example, 8
and 17, both compounds have nitrogen atoms that dis-
play comparable basicities. However, in the second
example the basicity of compound 16 is decreased, be-
cause of the inductive effect of the aromatic ring on
the nitrogen, in respect to the nitrogen atom of
compound 10. This reduction in basicity leads to a de-
crease in the biological activity exhibited by compound
16 when compared to compound 10, a decrease that is
not observed when comparing compounds 8 and 17.
OMe
OMe
OMe
I
OH
i
ii
+
OH
HO
15b
15a
OMe
H
N
iii
iv
MeO
Cl
15
15c
O
The length of the chain linking the two aryl regions to-
gether has little effect on biological activity. For exam-
ple, compounds 3, 5, and 9 are all analogs differing by
one carbon homologations in between the nitrogen
Scheme 9. Synthesis of compound 15. Reagents: (i) Pd(dba)2, PPh3,
CuI, THF, DIEA; (ii) H2, Pd/C, formic acid, EtOH; (iii) (ClCO)2,
DMSO, DIEA, CH2Cl2; (iv) TEA, TiCl4, CH2Cl2, 4-chlorobenzhyd-
rylamine hydrochloride, followed by NaBH3CN.
OMe
NH2
NH2
i
ii
iii
OH
OTBS
HO
O
NH
O
MeO
OTBS
17a
17b
OMe
OMe
OH
OMe
OH
v
iv
NH
O
NH
NH
Br
O
Cl
Cl
17c
17
17d
Scheme 11. Reagents and conditions: (i) TBSCl, DMF, imidazole; (ii) PyBOP, DiEA, CH2Cl2; (iii) TBAF, THF; (iv) LiAlH4, AlCl3, THF, 0 ꢁC, then
reflux; (v) NaH, DMF, 0 ꢁC, then add bromobenzhydryl.

3828
W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
5. Calcium channel agonism
MeO
2
4
6
During the course of this investigation it was discovered
that some of the straight chain analogs were observed to
cause an influx of extracellular calcium rather than pre-
vent it. At first, it was thought that this occurrence was
localized to a few compounds, however as new com-
pounds were made and subsequently submitted for bio-
logical activity the incidence of increased calcium influx
was observed repeatedly. It was not that these com-
pounds only displayed an ability to cause calcium influx
into the cell, they also effectively blocked calcium influx
at lower concentrations of the drug. Thus a concentra-
tion dependent dual action agonist/antagonist for T-
type calcium channels was discovered.
7
1
5
3
Cl
Figure 3. Possible locations for the nitrogen atom on the chain.
atom and the oxygen atom and all seem to exhibit rela-
tively similar biological activities. Also compounds 3, 6,
and 11 all maintain the two carbon ethanol–amine lin-
ker; however, they vary in the number of carbon atoms
in the chain between the nitrogen and the 4-methoxy-
phenyl group. In this case, as in the previous example,
there is no real difference in biological activity exhibited
by the compounds in all three of the chain lengths
shown.
Figure 2 displays the concentration dependent antago-
nist activity that was exhibited by the lead compound
up until this study. This is a typical dose–response curve
for many of the prolinol and piperidine type compounds
that were synthesized and provided in our previous
paper, albeit not as potent. Figure 5 displays the calcium
channel agonism data for one of the straight chain ana-
logs. As can be seen, there is no antagonism of calcium
influx exhibited at this concentration of the drug and the
relative agonistic effect is not affected by the addition of
OKT3.29,30 However, the intensity of the agonist effect is
affected, the reason for this occurrence is still unclear.
When compound 12 is added to the cells alone, without
any external stimulus to induce calcium influx, there is
still an increase in intracellular calcium concentrations
(red line). The delayed response of OKT3 on calcium in-
flux is typical for an entity that initiates calcium influx
via the calcium influx pathway (black line). We believe
that our compounds are acting on the calcium channels
directly to allow calcium influx. Thus there is no delayed
onset of calcium influx after the compound is adminis-
tered to the cell (red line).
Two conformationally restricted analogs (16 and 17)
were made. Compound 17 is a rigid analog of com-
pound 9 with an aniline heterocyclic core. Both com-
pound 16 and 17 contain aromatic functionality within
the carbon chain that links the 4-methoxyphenyl region
to the benzhydrol region. The ortho attachments to the
previously mentioned aromatic functionality positions
both ends of the chain in closer proximity to each other
than what is believed in the non-restricted analogs. Both
of these modifications limit the degrees of rotation and
conformations that these compounds can adopt. There
is no advantage in terms of additional biological activity
exhibited by these conformationally restricted analogs
to that of their unrestricted counterparts.
4. Updated pharmacophore
Based on all of the above information a pharmacophore
has been proposed (Fig. 4). It includes a straight chain
linking two regions of aromaticity together. X can either
be an oxygen atom or a carbon atom, however, if X is a
carbon atom then the nitrogen atom must be located in
the 2, 3, or 6 position from the 4-methoxyphenyl region
as designated in Figure 3. The chain can be either 6, 7, or
8 bonds long. The nitrogen atom is crucial for biological
activity of the compound. Not only does it have to be
present, but it must also be basic. The need for the aryl
rings and the positioning of their substituents has been
previously addressed11 and they are an absolute neces-
sity for biological activity.
The structural requirements needed to elicit this agon-
ism of calcium influx are yet to be optimized. However,
Table 2 displays the intensity of calcium channel agon-
ism that the compounds exhibit and the structures that
evoked this response. What appears to be clear as of
now is that placement of the nitrogen atom plays an
important role in whether the compound will exhibit
agonistic activity toward calcium channels. For exam-
ple, when the nitrogen atom is placed in the 2 and 3 po-
sition (compounds 8 and 10), as described in Figure 3,
1200
30 µM compound 12 alone
R1
R2
H
N
1000
OKT3 followed by 30µM
X
m
n
compound 12
800
OKT3 alone
Addition of
compound12
600
Addition of either
400
compound12 or OKT3
Figure 4. Proposed pharmacophore: (i) a basic nitrogen is required for
activity; (ii) X = O,CH2. If X = CH2 then nitrogen atom must be in the
2, 3, or 6 position of the chain as designated by Figure 3; (iii) R2
requires an electronegative group, which is comparable in size to that
of chlorine, or smaller. Larger groups are detrimental to activity; (iv)
the length of the chain is limited so that it should have 6–8 atoms total.
200
0
0
50
100
150
time (sec)
Figure 5. Agonist action of straight chain analogs.

W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
3829
Table 2. Calcium influx data
Compound Structure
Intracellular calcium Compound Structure
concentration (lM)
Intracellular calcium
concentration (lM)
taken at 100 lM
of druga
taken at 100 lM
of druga
Cl
Cl
MeO
1
30
9
1000
O
N
H
MeO
MeO
O
N
Cl
MeO
2
0
10
11
12
13
1500b
1300
0
N
H
O
O
Cl
Cl
O
N
H
MeO
MeO
3
4
5
6
400
MeO
H
N
O
Cl
Cl
N
H
O
N
H
N/T
MeO
Cl
Cl
H
N
MeO
H
N
O
N/T
1000
MeO
Cl
N
H
H
N
500
14
15
200
MeO
O
MeO
MeO
Cl
Cl
H
N
7
8
200
0
MeO
N
H
Cl
Cl
MeO
1400b
H
N
Cl
N/T = not tested for overall increase in intracellular calcium concentrations, but was tested to see if this effect is present.
a Intracellular calcium concentrations were obtained in the Jurkat cell line.
b Calcium influx data was obtained at 30 lM concentration of drug.
the compound elicits the greatest agonism that has been
seen in this lab to date. However, if the nitrogen atom is
moved down the chain to the 4 position (compound 12)
all activity is lost. Then if it is moved farther down to the
5 and 6 positions (compounds 13 and 14) the agonism
starts to rebound then drops off again as it is placed in
the 7 position (compound 15), including the oxygen
atom allows some variability to the agonism activity
elicited by the compounds compared to non-oxygenated
analogs. For example, compound 11 displays good
agonism data, compared to compound 12. However,
there is a reverse in this trend when comparing com-
pounds 10 and 11. Obviously, there are a lot of un-
known factors that need to be discovered in order to
fully map out the structural requirements needed to eli-
cit this biological effect. And there is a lot more work
that is needed in this area.
6. Conclusion
In summary, we have provided additional evidence link-
ing the inhibition of calcium influx to the cessation
of cellular proliferation. We have provided another

3830
W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
structural class of compounds to strengthen this conclu-
sion, as well as a proposed pharmacophore.
mained. The mixture was cooled to 0 ꢁC and the amide
(1 equiv), dissolved in a minimum amount of THF, was
added slowly via syringe. The reaction mixture was al-
lowed to stir overnight, then cooled to 0 ꢁC, and slowly
quenched with water. The reaction was diluted with
water (approximately twice the reaction volume) and
was allowed to stir until completely quenched. Then
the aqueous layer was extracted three times with ethyl
acetate. The combined organic layers were dried over
Na2SO4, concentrated under reduced pressure, and puri-
fied by flash chromatography.
We have also provided evidence of a concentration
dependent dual action agonist/antagonist to T-type cal-
cium channels. We believe this to be the first example in
the literature of such a concentration dependent dual ac-
tion agonist/antagonist.
7. Experimental
7.1. General procedure A: reductive amination
7.3. General procedure C: ether synthesis using p-tolu-
enesulfonic acid (p-TsOH)
7.1.1. Method 1: acetic acid catalyzed. A solution of
amine (4 equiv) in anhydrous MeOH (0.4 M aldehyde)
was acidified to pH 6 with glacial acetic acid. The alde-
hyde (1 equiv) was added slowly via syringe and this
mixture was allowed to stir for 2 h. (Note: If the alde-
hyde is a solid, dissolve it in a minimum amount of
MeOH to add it via syringe.) At this time, sodium
cyanoborohydride (0.6 equiv), dissolved in a minimum
amount of MeOH, was added slowly via syringe, and
the reaction was allowed to stir for 12–48 h. At its com-
pletion, methanol was removed under reduced pressure
and the crude oil was made basic (pH 8) with saturated
NaHCO3. The aqueous layer was extracted repeatedly
(five times or more) with ethyl acetate. The combined
organic layers were dried over Na2SO4, concentrated
under reduced pressure, and purified by flash
chromatography.
To a solution of alcohol (1 equiv) in toluene (0.1 M alco-
hol) was added the benzhydrol (1 equiv) and dry p-
TsOH (1 equiv). This mixture was refluxed using a
Dean–Stark trap for 6 h. The reaction was diluted with
ethyl acetate and extracted two times with saturated
NaHCO3. The organic layer was dried over Na2SO4,
concentrated under reduced pressure, and purified by
flash chromatography. Note: Dry p-TsOH was obtained
by refluxing p-TsOH monohydrate in toluene under
Dean–Stark conditions for 6 h. This mixture was then
concentrated under reduced pressure and placed under
vacuum to afford brown solid. Place under vacuum for
30 min before each use.
7.4. General procedure D: Swern oxidation
To a solution of oxalyl chloride (1.5 equiv) in dichloro-
methane was added a solution of dimethylsulfoxide
(3 equiv) in dichloromethane at À78 ꢁC. Reaction mix-
ture was allowed to stir for 10 min before addition of
the alcohol to be oxidized (1 equiv) in dichloromethane.
The reaction was stirred for an additional 30 min and
then diisopropylethylamine (6 equiv) was added, stirring
continued for 10 min before the mixture was allowed to
warm to room temperature. Cold 10% hydrochloric acid
was added until the reaction mixture was slightly acidic
and then the mixture was extracted with dichlorometh-
ane (3·). The organic layer was washed with saturated
sodium bicarbonate solution (3·) and then dried over
anhydrous magnesium sulfate, filtered, and then concen-
trated under reduced pressure.
7.1.2. Method 2: zinc chloride catalyzed. To a solution of
amine (2 equiv) and aldehyde (1 equiv) in anhydrous
MeOH (0.25 M aldehyde) was added dropwise a solu-
tion of sodium cyanoborohydride (1 equiv) and zinc
chloride (0.5 equiv) dissolved in a minimal amount of
MeOH. At the completion of the reaction (6 h), metha-
nol was removed under reduced pressure and enough
0.1 N NaOH was added to dissolve any inorganic salts.
The aqueous layer was extracted three times with ethyl
acetate. The combined organic layers were dried over
Na2SO4, concentrated under reduced pressure, and puri-
fied by flash chromatography.
7.1.3. Method 3: hydrochloric acid catalyzed. To a mix-
ture of amine (2 equiv) and aldehyde (1 equiv) in anhy-
drous MeOH (0.1 M aldehyde) was added one drop of
concentrated HCl (catalytic). After 2 h, sodium cyano-
borohydride (1 equiv) was added and the reaction was
allowed to stir for 6 h. Methanol was removed under re-
duced pressure and saturated NaHCO3 was added to the
resulting oil. This mixture was extracted three times with
ethyl acetate, and the combined organic layers were
dried over Na2SO4 and concentrated under reduced
pressure.
7.5. General procedure E: Pd/Creductions
To a solution of the substrate to be reduced in ethanol
under nitrogen was added a catalytic amount of 10%
palladium on carbon and formic acid. The reaction mix-
ture was then placed under a hydrogen atmosphere for
18 h. Reaction was then filtered through Celite to re-
move palladium and then concentrated under reduced
pressure.
7.2. General procedure B: reductions using lithium
aluminum hydride (LiAlH4)
7.6. General procedure F: coupling of alkynyl alcohols to
4-chlorobenzophenone
A solution of LiAlH4 (1.5 equiv) was prepared in THF
(0.5 M amide). This mixture was allowed to stir until
the reagents dissolved and a dark gray solution re-
To a solution of alkynyl alcohol (1 equiv) in THF at
À78 ꢁC was added n-butyl lithium (2.2 equiv), and the
reaction mixture was allowed to warm up to room tem-

W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
3831
perature and was stirred for 1 h. The reaction was then
cooled back down to À78 ꢁC then a solution of 4-chlo-
robenzophenone (1 equiv) in THF was carefully added.
The reaction was warmed up to 0 ꢁC and stirred for 3 h
and then carefully quenched with a saturated solution of
ammonium chloride. Next, the mixture was extracted
with ethyl acetate (3·), dried over anhydrous sodium
sulfate, filtered, and then concentrated under reduced
pressure.
(CDCl3): d 159.27, 132.48, 129.86, 114.37, 61.33, 55.78,
53.38, 50.96. MS (CI) m/z 181.9 (M+).
7.7.4. {2-[(4-Chloro-phenyl)-phenyl-methoxy]-ethyl}-(4-
methoxy-benzyl)-amine (3). This compound was pre-
pared from 3a and 4-chlorobenzhydrol according to
general procedure C. Flash chromatography (5%
MeOH/CHCl3) afforded an orange oil (0.188 g, 71%).
1H NMR (acetone-d6): d 7.36–7.07 (m, 11H), 6.75 (d,
J = 8.1 Hz, 2H), 5.36 (s, 1H), 3.65 (s, 3H), 3.60 (s,
2H), 3.45 (t, J = 5.4 Hz, 2H), 2.69 (t, J = 5.4 Hz, 2H).
13C NMR (acetone-d6): d 159.06, 142.93, 142.43,
133.47, 132.82, 129.49, 128.87, 128.77, 128.66, 127.83,
127.21, 113.89, 83.02, 69.02, 54.97, 53.15, 48.89. MS
(CI) m/z 382.1 (M+). Anal. Calcd for C23H24ClNO2:
C, 72.34; H, 6.33; N, 3.67. Found: C, 72.17; H, 6.56;
N, 3.62.
7.7. General procedure G: TBAF deprotection
To a solution of protected alcohol (1 equiv) in THF was
added tetra butyl ammonium fluoride (1.1 equiv). Reac-
tion was allowed to stir for 1 h at room temperature.
Then the reaction was quenched with water, and ex-
tracted three times with EtOAc. Solution was dried over
anhydrous sodium sulfate, and concentrated under re-
duced pressure.
7.7.5. 3-[N-(4-Methoxyphenyl)carbamoyl]propanoic acid
(4a). Succinic anhydride (0.081 g, 0.812 mmol) was dis-
solved in a minimum volume of THF (ꢀ1.5 mL) and
then was diluted to 3 mL with ether. To this solution,
p-anisidine (0.100 g, 0.812 mmol), dissolved in 6 mL of
ether, was added slowly via cannula. The white product
precipitate was filtered and washed with cold ethyl ace-
tate. The filtrate was concentrated under reduced pres-
sure and the resulting beige solid was dissolved in hot
ethyl acetate and stored in a cold room (4 ꢁC) to induce
crystallization. The crystals were collected by filtration
and rinsed with cold ethyl acetate. The initial precipitate
and the second batch of crystals were combined to af-
ford a white solid (0.164 g, 91%) as the desired product
7.7.1. 2-[(4-Chloro-phenyl)-phenyl-methoxy]-ethanol (2a).
To a solution of ethylene glycol (0.51 mL, 9.15 mmol) in
9 mL toluene was added 4-chlorobenzhydrol (0.20 g,
0.915 mmol) and p-TsOH (0.174 g, 0.915 mmol). This
mixture was refluxed under Dean–Stark conditions for
30 min. The reaction was diluted with ethyl acetate
and extracted two times with saturated NaHCO3. The
organic layer was dried over Na2SO4 and concentrated
under reduced pressure. Flash chromatography (80%
ether/hexanes, Rf = 0.2) afforded a yellow oil (0.218 g,
1
91%). H NMR (acetone-d6): d 7.39–7.07 (m, 9H), 5.40
(s, 1H), 3.72–3.55 (m, 2H), 3.42 (t, J = 5.0 Hz,
2H). 13C NMR (acetone-d6): d 142.90, 142.44, 132.78,
128.90, 128.71, 128.61, 127.78, 127.24, 83.00, 71.07,
61.61.
1
(Rf = 0.5 in 40% MeOH/CHCl3). H NMR (methanol-
d4): d 7.35 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz,
2H), 4.94–4.80 (br s, 1H), 3.69 (s, 3H), 2.61–2.55 (m,
5H). 13C NMR (methanol-d4): d 175.40, 171.64,
156.87, 131.90, 122.05, 113.96, 54.89, 31.24, 29.17. MS
(CI) m/z 224.1 (M+).
7.7.2. [(4-Chloro-phenyl)-phenyl-methyl]-(4-methoxy-benzyl)-
ethane-1,2-diether (2). To a slurry of NaH (60% disper-
sion in mineral oil, 0.015 g, 0.381 mmol) in 4 mL of
DMF at 0 ꢁC was added 2a, dissolved in a minimum
volume of DMF, slowly via syringe. After 30 min, 4-
methoxybenzyl chloride (0.06 mL, 0.419 mmol) was
added dropwise at 0 ꢁC. After 12 h, the reaction was di-
luted with ether and extracted twice with saturated LiBr.
The organic layer was dried over Na2SO4 and concen-
trated under reduced pressure. Flash chromatography
(25% ether/hexanes, Rf = 0.35) afforded a pale yellow
7.7.6. 4-[(4-Methoxyphenyl)amino]butan-1-ol (4b). This
compound was prepared from 4a according to general
procedure B. However, 3 equiv of LiAlH4 and 1 equiv
of AlCl3 were used. In addition, this reaction was con-
ducted at 0.1 M in THF with respect to the amide/acid
(due to its low solubility in THF). Flash chromatogra-
phy (100% ether, Rf = 0.3) afforded a dark orange oil
1
1
(0.079, 55%). H NMR (CDCl3): d 6.78 (d, J = 8.8 Hz,
oil (0.060 g, 41%). H NMR (acetone-d6): d 7.36–7.08
2H), 6.61 (d, J = 8.8 Hz, 2H), 3.75 (s, 3H), 3.67 (t,
J = 5.9 Hz, 2H), 3.10 (t, J = 6.6 Hz, 2H), 2.75–2.59 (br
s, 2H), 1.77–1.61 (m, 4H). 13C NMR (CDCl3): d
152.87, 142.93, 115.42, 115.12, 63.13, 56.33, 45.66,
31.06, 26.90. MS (CI) m/z 196.2 (M+).
(m, 11H), 6.79 (d, J = 8.9 Hz, 2H), 5.41 (s, 1H), 4.37
(s, 2H), 3.67 (s, 3H), 3.59–3.47 (m, 4H). 13C NMR (ace-
tone-d6): d 159.66, 142.83, 142.37, 132.81, 131.26,
129.43, 128.90, 128.72, 128.65, 127.81, 127.25, 113.95,
82.99, 72.65, 69.57, 68.75, 55.02. MS (CI) m/z 382.9
(M+). Anal. Calcd for C23H23ClO3: C, 72.15; H, 6.05.
Found: C, 72.21; H, 6.09.
7.7.7. {4-[(4-Chlorophenyl)phenylmethoxy]butyl}(4-meth-
oxyphenyl)amine (4). This compound was prepared from
4b and 4-chlorobenzhydrol according to general proce-
dure C. Flash chromatography afforded (50% ether/hex-
7.7.3. 2-(4-Methoxy-benzylamino)-ethanol (3a). This
compound was prepared according to general procedure
A (method 1). Flash chromatography (30% MeOH/
1
anes, Rf = 0.25) an orange oil (0.096 g, 83%). H NMR
1
(acetone-d6): d 7.35–7.09 (m, 9H), 6.61 (d, J = 8.9 Hz,
2H), 6.44 (d, J = 8.9 Hz, 2H), 5.34 (s, 1H), 4.38–4.23
(br s, 1H), 3.56 (s, 3H), 3.38 (t, J = 5.6 Hz, 2H), 2.96
(t, J = 6.4 Hz, 2H), 1.71–1.54 (m, 4H). 13C NMR
CHCl3) afforded a yellow oil (0.126 g, 38%). H NMR
(CDCl3): d 7.22 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz,
2H), 3.79 (s, 3H), 3.73 (s, 2H), 3.63 (t, J = 5.2 Hz, 2H),
2.77 (t, J = 5.0 Hz, 2H), 2.51–2.43 (br s, 2H). 13C NMR

3832
W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
(acetone-d6): d 151.92, 143.93, 143.03, 142.57, 132.77,
128.82, 128.74, 128.65, 127.78, 127.16, 115.00, 113.78,
82.84, 68.91, 55.35, 44.47, 27.72, 26.57. MS (CI) m/z
396.5 (M+). Anal. Calcd for C24H26ClNO2: C, 72.81;
H, 6.62; N, 3.54. Found: C, 72.63; H, 6.60; N, 3.55.
7.7.12. 2-[2-(4-Methoxy-phenyl)-ethylamino]-ethanol (6b).
This compound was prepared from 6a (217 mg,
0.98 mmol) according to general procedure G. Then this
compound was carried on according to general proce-
dure B. The product was purified by flash chromatogra-
phy using 20% MeOH in EtOAc. Yield: 80 mg (39%).
1H NMR (CDCl3): d 6.77–7.19 (m, 4H), 3.69 (s, 3H),
3.46–3.58 (t, J = 5.39 Hz, 2H), 2.72–3.06 (m, 6H). 13C
NMR (CDCl3): d 158.57, 132.32, 130.11, 114.44,
61.28, 55.75, 51.56, 51.40, 35.91; low-resolution MS
(CI) m/e 179 (MÀOH)+.
7.7.8. 3-{[(4-Methoxyphenyl)methyl]amino}propan-1-ol
(5a). This compound was prepared according to general
procedure A (method 1). Flash chromatography (30%
1
MeOH/CHCl3) afforded a yellow oil (1.03 g, 72%). H
NMR (CDCl3): d 7.22 (d, J = 8.5 Hz, 2H), 6.86 (d,
J = 8.9 Hz, 2H), 3.84–3.77 (m, 5H), 3.74 (s, 2H), 3.17–
2.97 (br s, 2H), 2.90 (t, J = 5.8 Hz, 2H), 1.73 (q,
J = 5.4 Hz, 2H). 13C NMR (CDCl3): d 159.28, 132.10,
129.86, 114.37, 64.75, 55.77, 53.82, 49.69, 31.24. MS
(ESI) m/z 196.0 (M+).
7.7.13. {2-[(4-Chloro-phenyl)-phenyl-methoxy]-ethyl}-[2-
(4-methoxy-phenyl)-ethyl]-amine (6). Reaction was
performed according to general procedure C. Flash
chromatography of the organic layer (40% MeOH/60%
1
ethyl acetate) afforded the product (0.208 g, 57%). H
7.7.9. {3-[(4-Chlorophenyl)phenylmethoxy]propyl}[(4-meth-
oxyphenyl)methyl]amine (5). This compound was pre-
pared from 3a and 4-chlorobenzhydrol according to
general procedure C. Flash chromatography (5%
MeOH/CHCl3) afforded an orange oil (0.321 g, 79%).
1H NMR (acetone-d6): d 7.31–7.07 (m, 11H), 6.74 (d,
J = 8.5 Hz, 2H), 5.32 (s, 1H), 3.65 (s, 3H), 3.58 (s, 2H),
3.42 (t, J = 6.2 Hz, 2H), 2.61 (t, J = 6.6 Hz, 2H), 2.53–
2.37 (br s, 1H), 1.70 (q, J = 6.6 Hz, 2H). 13C NMR (ace-
tone-d6): d 159.06, 143.00, 142.54, 133.24, 132.75, 129.59,
128.81, 128.72, 128.64, 127.76, 127.15, 113.83, 82.86,
67.56, 54.96, 53.30, 46.52, 30.36. MS (CI) m/z 396.3
(M+). Anal. Calcd for C24H26ClNO2: C, 72.81; H, 6.62;
N, 3.54. Found: C, 72.52; H, 6.60; N, 3.55.
NMR (CDCl3): d 6.75–7.57 (m, 13H), 5.31 (s, 1H),
3.79 (s, 3H), 2.58–3.64 (m, 8H). 13C NMR (CDCl3): d
158.60, 142.14, 141.29, 133.68, 132.38, 130.18, 129.03,
128.77, 128.23, 127.44, 114.44, 83.68, 68.76, 55.74,
51.58, 49.70, 35.81; low-resolution MS (CI) m/e 396
(MH+). Anal. Calcd for C24H26ClNO2: C, 72.81; H,
6.62; N, 3.54 Found: C, 72.61; H, 6.71; N, 3.53.
7.7.14. 1-(4-Chloro-phenyl)-1-phenyl-pent-2-yne-1,5-diol
(7a). This compound was prepared according to general
procedure F using 3-butyn-1-ol (500 mg, 7.13 mmol).
Flash chromatography (1:1 EtOAc/hexanes) yielded
the product in 26% (511 mg); Rf = 0.32. 1H NMR
(300 MHz, CDCl3): d 7.55 (m, 4H), 7.30 (m, 5H), 5.29
(s, 1H), 3.95 (s, 1H), 3.57 (m, 2H), 2.42 (m, 2H). 13C
NMR (300 MHz, CDCl3) ppm: 145.6, 144.7, 133.8,
128.8, 128.2, 128.1, 126.5, 85.6, 85.0, 74.4, 61.1, 23.3;
[MS] (ESI) m/z 269.1 [MÀOH]+.
7.7.10. 2-(1,1,2,2-Tetramethyl-1-silapropoxy)ethylamine.
Ethanolamine (1.0 mL, 16.6 mmol), tert-butyldimethyl-
silyl chloride (2.74 g, 18.2 mmol), and triethylamine
(1.31 mL, 18.2 mmol) were dissolved in CH2Cl2
(50 mL) and 4-dimethylaminopyridine was added
(cat.). The reaction mixture was allowed to stir for
18 h. The solution was then diluted with water
(50 mL) and the organic layer was washed with water
(25 mL) and brine (25 mL). The organic layer was then
dried (MgSO4) and concentrated. The protected etha-
nolamine was used without need for further purification.
7.7.15. 5-(4-Chloro-phenyl)-5-phenyl-pentan-1-ol (7b).
This compound was prepared from 7a (511 mg,
1.89 mmol) according to general procedure E. Flash
chromatography (3:1 hexanes/EtOAc, Rf = 0.26) affor-
1
ded the product in 100% yield. H NMR (300 MHz,
CDCl3): d 7.31 (m, 9H), 4.00 (m, 2H), 3.60 (t,
J = 6.6 Hz, 2H), 2.84 (s, 1H), 2.16 (m, 2H), 1.67 (m,
2H), 1.41 (m, 2H). 13C NMR (300 MHz, CDCl3) ppm:
145.2, 144.3, 132.4, 129.9, 129.2, 129.1, 128.5, 126.8,
63.0, 51.4, 36.1, 33.2, 24.9.
7.7.11. N-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-2-(4-
methoxy-phenyl)-acetamide (6a). TBDMS protected eth-
anol amine (389 mg, 2.2 mmol) was added to a solution
of 3-(4-methoxyphenyl)acetic acid (400 mg, 2.2 mmol) in
CH2Cl2 and TEA (289 mg, 2.2 mmol). Reaction mixture
was cooled to 0 ꢁC and DCC (458 mg, 2.2 mmol) was
added. Reaction mixture was warmed to room tempera-
ture and allowed to stir for 5 h. Reaction mixture was
then filtered to remove DCU, and solvent was removed
under reduced pressure. EtOAc was then added to crude
product and the mixture was cooled to 4 ꢁC. The mix-
ture was filtered at this temperature. Product was puri-
fied by flash chromatography using 25% EtOAc in
7.7.16. 5-(4-Chloro-phenyl)-5-phenyl-pentanal (7c). This
compound was prepared from 7b (250 mg, 0.910 mmol)
according to general procedure D. Flash chromatogra-
phy (3:1 hexanes/EtOAc, Rf = 0.52) yielded the product
in 82% (204 mg). 1H NMR (300 MHz, CDCl3): d 9.72 (s,
1H), 7.32 (m, 9H), 3.94 (q, J = 7.51, 10.78 Hz, 1H), 2.45
(t, J = 7.1 Hz, 2H), 2.09 (m, 2H), 1.63 (m, 2H). 13C
NMR (300 MHz, CDCl3) ppm: 202.8, 144.7, 143.8,
132.5, 129.8, 129.2, 129.1, 128.4, 51.2, 44.2, 35.5, 21.2.
1
hexanes (0.443 g, 48%). H NMR (CDCl3): d 7.09–7.22
7.7.17. [5-(4-Chloro-phenyl)-5-phenyl-pentyl]-[2-(4-meth-
oxy-phenyl)-ethyl]-amine (7). To a solution of 7c
(100 mg, 0.367 mmol) and 4-methoxyphenethylamine
(333 mg, 2.20 mmol) in dichloromethane was added tita-
nium tetrachloride (0.184 mL, 1 M in CH2Cl2) via syr-
inge. The reaction was stirred for 18 h and then
(m, 4H) 3.78 (s, 3H), 3.54–3.63 (m, 2H), 3.45–3.54 (s,
2H), 3.26–3.38 (m, 2H), 0.8 (s, 9H), 0.0 (s, 6H). 13C
NMR (CDCl3): d 171.86, 161.23, 131.13, 127.28,
114.99, 62.08, 55.72, 43.46, 42.10, 26.25, 18.57, À5.05;
low-resolution MS (CI) m/e 324 (MH+).

W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
3833
1
carefully quenched with a solution of methanolic sodium
cyanoborohydride (23 mg, 0.367 mmol) and stirred for
an additional 15 min. The reaction was then made basic
to a pH of 13 with 3 N sodium hydroxide, extracted with
ethyl acetate (3·), dried using magnesium sulfate, and
concentrated under reduced pressure. Flash chromatog-
raphy (1:9 MeOH/EtOAc, Rf = 0.13) yielded the product
in 19% (29 mg). 1H NMR (300 MHz, CDCl3): d 7.24 (m,
9H), 7.12 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H),
3.80 (s, 3H), 2.79 (dd, J = 6 Hz, 4H), 2.59 (t, J =
7.3 Hz, 2H). 13C NMR (300 MHz, CDCl3) ppm: 158.5,
145.6, 132.4, 130.1, 129.7, 129.0, 128.9, 128.3, 128.2,
126.8, 126.6, 114.4, 55.7, 51.8, 51.1, 50.1, 36.1, 35.8,
30.3, 26.3, 26.2; [MS] (APCI) m/z 408.2 [MH]+.
CHCl3) afforded a yellow oil (0.104 g, 39%). H NMR
(CDCl3): 7.21 (d, J = 8.5 Hz, 2H), 6.84 (d,
d
J = 8.5 Hz, 2H), 3.83 (br s, 2H), 3.77 (s, 3H), 3.70 (s,
2H), 3.56 (t, J = 5.0 Hz, 2H), 2.66 (t, J = 5.4 Hz, 2H),
1.73–1.49 (m, 4H). 13C NMR (CDCl3): d 159.34,
131.84, 130.04, 114.43, 63.07, 55.74, 53.70, 49.60,
32.92, 29.06. MS (ESI) m/z 210.1 (M+).
7.7.23. {4-[(4-Chloro-phenyl)-phenyl-methoxy]-butyl}-(4-
methoxy-benzyl)-amine (9). This compound was pre-
pared from 9a and 4-chlorobenzhydrol according to
general procedure C. Flash chromatography (5%
1
MeOH/CHCl3) afforded orange oil (0.168 g, 83%). H
NMR (acetone-d6): d 7.34–7.08 (m, 11H), 6.74 (d,
J = 8.5 Hz, 2H), 5.31 (s, 1H), 3.65 (s, 3H), 3.56 (s,
2H), 3.33 (t, J = 6.2 Hz, 2H), 2.46 (t, J = 6.9 Hz, 2H),
1.65–1.41 (m, 4H). 13C NMR (acetone-d6): d 158.99,
143.11, 142.63, 133.72, 132.74, 129.44, 128.81, 128.72,
128.64, 127.74, 127.15, 113.82, 82.81, 69.10, 54.96,
53.40, 49.17, 27.94, 27.14. MS (CI) m/z 410.3 (M+).
Anal. Calcd for C25H28ClNO2: C, 73.25; H, 6.88; N,
3.42. Found: C, 73.23; H, 6.84; N, 3.43.
7.7.18. 1-(4-Chloro-phenyl)-1-phenyl-hex-2-yne-1,6-diol
(8a). This compound was prepared according to general
procedure F using 4-pentyn-1-ol (500 mg, 5.94 mmol).
Flash chromatography (1:1 EtOAc/hexanes, Rf = 0.44)
yielded the product in 33% (562 mg). 1H NMR
(300 MHz, CDCl3): d 7.55 (m, 4H), 7.27 (m, 5H), 3.60
(t, J = 6.1, 2H), 2.36 (t, J = 6.9, 2H), 1.69 (t, J = 6.5,
2H). 13C NMR (300 MHz, CDCl3) ppm: 145.8, 144.9,
133.7, 128.1, 126.5, 87.9, 84.0, 74.3, 61.7, 31.4, 16.0;
[MS] (ESI) m/z 283.2 [MÀOH]+.
7.7.24. 1-(4-Chloro-phenyl)-1-phenyl-hept-2-yne-1,7-diol
(10a). This compound was prepared according to gen-
eral procedure F. 5-Hexyn-1-ol (500 mg, 5.09 mmol).
Flash chromatography (1:1 EtOAc/hexanes, Rf = 0.39)
yielded the product in 37% (559 mg). 1H NMR
(300 MHz, CDCl3): d 7.57 (m, 4H), 7.27 (m, 5H), 3.48
(m, 2H), 2.31 (m, 2H), 1.57 (m, 4H). 13C NMR
(300 MHz, CDCl3) ppm: 146.0, 145.1, 133.6, 128.7,
128.1, 126.5, 88.3, 83.9, 74.3, 62.3, 32.0, 25.4, 19.2;
[MS] (ESI) m/z 315.1 [MH]+; 297.2 [MÀOH]+.
7.7.19. 6-(4-Chloro-phenyl)-6-phenyl-hexan-1-ol (8b).
This compound was prepared from 8a (562 mg,
1.97 mmol) according to general procedure E. Flash
chromatography (3:1 hexanes/EtOAc, Rf = 0.31) affor-
1
ded the product in 100% yield. H NMR (300 MHz,
CDCl3): d 7.28 (m, 9H), 3.60 (t, J = 6.4 Hz, 2H), 2.09
(m, 2H), 1.54 (m, 2H). 13C NMR (300 MHz, CDCl3)
ppm: 145.2, 144.3, 132.3, 129.8, 129.1, 129.0, 128.4,
126.9, 126.6, 63.3, 51.9, 36.3, 33.1, 28.4, 26.3.
7.7.25. 7-(4-Chloro-phenyl)-7-phenyl-heptan-1-ol (10b).
This compound was prepared from 10a (559 mg,
1.87 mmol) according to general procedure D. Flash
chromatography (3:1 hexanes/EtOAc, Rf = 0.32) affor-
7.7.20. 6-(4-Chloro-phenyl)-6-phenyl-hexanal (8c). This
compound was prepared from 8b (250 mg, 0.866 mmol)
according to general procedure D. Flash chromatogra-
phy (3:1 hexanes/EtOAc, Rf = 0.58) yielded the product
in 73% (181 mg). 1H NMR (300 MHz, CDCl3): d 9.72 (s,
1H), 7.32 (m, 9H), 3.94 (m, 1H), 2.45 (t, J = 7.1 Hz, 2H),
2.09 (m, 2H), 1.65 (m, 2H). 13C NMR (CDCl3,
300 MHz) ppm: 202.6, 145.3, 143.8, 129.8, 129.2,
129.1, 128.4, 128.3, 127.1, 126.8, 51.2, 44.2, 35.5, 21.2.
1
ded the product in 100% yield. H NMR (300 MHz,
CDCl3): d 7.22 (m, 9H), 3.58 (m, 2H), 2.06 (m, 2H),
1.50 (m, 2H), 1.29 (m, 6H). 13C NMR (300 MHz,
CDCl3) ppm: 129.7, 129.0, 128.9, 128.4, 128.3, 63.4,
51.2, 36.1, 33.2. 29.9, 28.4, 26.1; [MS] (APCI) m/z
303.0 [MH]+.
7.7.26. 7-(4-Chloro-phenyl)-7-phenyl-heptanal (10c). This
compound was prepared from 10b (250 mg,
0.826 mmol) according to general procedure D. Flash
chromatography (3:1 hexanes/EtOAc, Rf = 0.57) yielded
the product in 65% (160 mg). 1H NMR (300 MHz,
CDCl3): d 9.74 (s, 1H), 7.24 (m, 9H), 3.90 (q, 1H),
2.37 (m, 2H), 2.03 (m, 2H), 1.60 (m, 2H), 1.25 (m,
4H). 13C NMR (300 MHz, CDCl3) ppm: 203.1, 145.1,
144.2, 132.3, 129.7, 129.2, 129.0, 128.4, 128.3, 51.1,
44.3, 36.0, 35.9, 29.9, 29.6, 28.2, 22.4; [MS] (APCI) m/z
301.0 [MH]+.
7.7.21. [6-(4-Chloro-phenyl)-6-phenyl-hexyl]-(4-methoxy-
benzyl)-amine (8). This compound was prepared from 8c
and 4-methoxybenzylamine according to general proce-
dure A (method 3). Flash chromatography (1:9 MeOH/
EtOAc, Rf = 0.33) yielded the product in 50% (50 mg).
1H NMR (300 MHz, CDCl3): d 7.15 (m, 9H), 7.07 (m,
2H), 6.80 (d, J = 8.7 Hz, 2H), 4.80 (s, 1H), 3.80 (t,
J = 7.9 Hz, 1H), 3.69 (s, 3H), 3.57 (s, 2H), 2.43 (t,
J = 7.4 Hz, 2H), 1.95 (m, 2H), 1.40 (m, 2H), 1.24 (m,
4H). 13C NMR (300 MHz, CDCl3) ppm: 159.5, 145.8,
131.3, 129.9, 128.5, 128.4, 127.9, 126.1, 113.9, 54.7,
52.8, 51.6, 50.9, 35.7, 29.1, 28.0, 27.3; [MS] (ESI) m/z
408.1 [MH]+.
7.7.27.
7-(4-Chloro-phenyl)-7-phenyl-heptanoic acid
(10d). An aqueous solution of sodium hypochlorite
(32 mg, 0.351 mmol) and phosphate monobasic buffer
(48 mg, 0.351 mmol) was added to a solution of 10c
(81 mg, 0.270 mmol) in t-butanol and 2-methyl-2-butene
7.7.22. 4-(4-Methoxy-benzylamino)-butan-1-ol (9a). This
compound was prepared according to general procedure
A (method 1). Flash chromatography (30% MeOH/

3834
W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
(solvent ratio 1:2, respectively). The reaction mixture
was allowed to stir at room temperature for 1 h, then
an additional equivalent of sodium hypochlorite and
monobasic phosphate buffer solution in water was
added. After an additional hour the solvent was re-
moved under reduced pressure and the residue was di-
luted with ether. Next the solution was acidified by the
dropwise addition of 10% hydrochloric acid. The organic
layer was washed with brine (2·), back extracted with
water (2·), dried over anhydrous sodium sulfate, fil-
tered, and concentrated under reduced pressure. Flash
chromatography (1:3 EtOAc/hexanes, Rf = 0.68) pro-
vided the product in 72% yield (62 mg). 1H NMR
(300 MHz, CDCl3): d 7.2 (m, 9H), 3.92 (s, 1H), 2.34
(t, J = 6 Hz, 2H), 2.08 (m, 2H), 1.64 (m, 2H), 1.41 (m,
4H). 13C NMR (300 MHz, CDCl3) ppm: 180.4, 145.5,
144.9, 132.9, 129.0, 128.8, 128.5, 128.2, 127.4, 50.5,
35.2, 34.5, 29.8, 25.1, 22.8; [MS] (APCI) m/z 282
[MÀCl]+.
152.5, 145.8, 143.3, 130.4, 129.7, 129.0, 128.9, 128.6,
128.4, 126.6, 115.4, 114.6, 56.4, 51.9, 45.5, 36.2, 30.1,
30.0, 28.5, 27.5; [MS] (ESI) m/z 408.3 [MÀH2O]+.
7.7.30. 3-(4-Methoxyphenyl)-N-[2-(1,1,2,2-tetramethyl-1-
silapropoxy)ethyl]propanamide (11a). TBDMS protected
ethanol amine (389 mg, 2.2 mmol) was added to a solu-
tion of 3-(4-methoxyphenyl)propionic acid (400 mg,
2.2 mmol) in CH2Cl2 and TEA (289 mg, 2.2 mmol).
Reaction mixture was cooled to 0 ꢁC and DCC
(458 mg, 2.2 mmol) was added at this temperature.
Reaction mixture was warmed to room temperature
and allowed to stir for 5 h. The solution was then filtered
to remove DCU, and solvent was removed under re-
duced pressure. EtOAc was then added to crude product
and mixture was cooled to 4 ꢁC. Then, mixture was fil-
tered at this temperature to remove any residual DCU.
Product was purified by flash chromatography (1:3
EtOAc/hexanes, Rf = 0.16). Yield: 314 mg (42%). 1H
NMR (300 MHz, CDCl3): d 7.11 (d, J = 8.9 Hz, 2H),
6.81 (d, J = 8.9 Hz, 2H), 3.77 (s, 3H), 3.62 (t,
J = 5.4 Hz, 2H), 3.34 (q, J = 5.4 Hz, 2H), 2.90 (t,
J = 7.3 Hz, 2H), 2.44 (t, J = 7.3 Hz, 2H), 0.88 (s, 9H),
0.04 (s, 6H). 13C NMR (CDCl3, 300 MHz) ppm:
172.5, 158.5, 133.4, 129.7, 114.4, 62.4, 55.7, 42.1, 39.3,
31.3, 26.4, 18.8, À4.9; MS (APCI) m/z 338.1 [MH]+.
7.7.28. 7-(4-Chloro-phenyl)-7-phenyl-heptanoic acid (4-
methoxy-phenyl)-amide (10e). To a solution of 10d
(62 mg, 0.196 mmol) in dichloromethane was added
diisopropylethylamine (51 mg, 0.391 mmol) followed
by PyBOP (102 mg, 0.196 mmol). The reaction mixture
was allowed to stir for 10 min at room temperature be-
fore a solution of 4-anisidine (24 mg, 0.196 mmol) in
dichloromethane was added. The reaction was then stir-
red for 30 min and then diluted with CH2Cl2, extracted
with a saturated solution of sodium bicarbonate in
water (3·), then 10% HCl (3·), and then washed with
brine (2·). The organic layer was then concentrated
under reduced pressure. Flash chromatography (1:1
EtOAc/hexanes, Rf = 0.73) yielded the product in 76%
7.7.31. N-(2-Hydroxyethyl)-3-(4-methoxyphenyl)propan-
amide (11b). This compound was prepared from 11a
(314 mg, 0.93 mmol) according to general procedure
G. Purification was not needed and product was yielded
in quantitative amounts. Yield: 217 mg (100%).
Rf = 0.47. 1H NMR (300 MHz, CDCl3): d 7.08 (d,
J = 8.8 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 3.74 (s, 3H),
3.61 (t, J = 4.6 Hz, 2H), 3.32 (q, J = 5.4 Hz, 2H), 3.17
(m, 1H), 2.86 (t, J = 7.3 Hz, 2H), 2.45 (t, J = 7.3 Hz,
2H). 13C NMR (CDCl3, 300 MHz) ppm: 174.0, 158.5,
133.4, 129.8, 114.4, 62.3, 55.8, 43.0, 39.0, 31.4; MS
(APCI) m/z 224.1 [MH]+.
1
yield (62 mg). H NMR (300 MHz, CDCl3): d 7.39 (d,
J = 8.9 Hz, 2H), 7.25 (m, 9H), 6.84 (d, J = 8.9 Hz,
2H), 3.78 (s, 3H), 2.26 (t, J = 7.4 Hz, 2H), 2.03 (m,
2H), 1.66 (p, J = 7.1, 7.5 Hz, 2H), 1.29 (m, 4H).
13C NMR (300 MHz, CDCl3) ppm: 171.7, 156.9,
145.1, 144.2, 131.6, 129.7, 129.0, 128.9, 128.4, 128.3,
127.3, 122.3, 114.6, 56.0, 51.2, 37.9, 36.0, 35.9, 29.7,
28.2, 26.0; [MS] (APCI) m/z 422.2 [MH]+.
7.7.32. 2-[3-(4-Methoxy-phenyl)-propylamino]-ethanol (11c).
This compound was prepared from 11b according to
General Procedure B. The product was purified by flash
chromatography (1:4 MeOH/EtOAc, Rf = 0.11). Yield:
7.7.29. [7-(4-Chloro-phenyl)-7-phenyl-heptyl]-(4-methoxy-
phenyl)-amine (10). LiAlH4 (17 mg, 0.441 mmol) was
added to THF. Reaction mixture was allowed to stir
until a homogenous slurry was formed. Reaction was
then cooled to 0 ꢁC and a solution of 10e (62 mg,
0.147 mmol) in tetrahydrofuran (THF) was added drop-
wise to reaction mixture. Reaction was allowed to warm
to room temperature and to stir overnight. Next, reac-
tion was quenched with sodium hydroxide (1.5 mL,
3 M solution). Mixture was filtered to remove any alu-
minum salts. Solid was washed with methanol to remove
any residual organics, and methanol was removed under
reduced pressure. The product was purified by flash
chromatography (1:3 EtOAc/hexanes, Rf = 0.61). Yield:
1
80 mg (39%). H NMR (300 MHz, CDCl3): d 7.08 (d,
J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H); 3.78 (s, 3H),
3.67 (t, 2H), 2.80 (t, 2H), 2.70 (t, 2H), 2.60 (t, 2H),
1.83 (p, 2H). 13C NMR (CDCl3, 300 MHz) ppm:
134.0, 129.7, 114.4, 60.4, 55.8, 51.3, 49.1, 32.9, 31.4;
MS (APCI) m/z 210.3 [MH]+.
7.7.33. {2-[(4-Chlorophenyl)phenylmethoxy]ethyl}[3-(4-
methoxyphenyl)propyl]amine (11). This compound was
prepared from 11c according to general procedure C.
The product was semi-purified by flash chromatography
using 10% MeOH in EtOAc. Product was totally puri-
fied with a Uniplate 1000 lm alumina prep plate using
25% EtOAc in hexanes (Rf = 0.40). Yield: 27 mg
1
30 mg, 50%. H NMR (300 MHz, CDCl3): d 7.23 (m,
1
9H), 6.80 (d, J = 8.9 Hz, 2H), 6.58 (d, J = 8.9 Hz, 2H),
3.88 (t, J = 8.9 Hz, 1H), 3.76 (s, 3H), 3.04 (t,
J = 6.9 Hz, 2H), 2.06 (q, J = 7.7, 7.3 Hz, 2H), 1.57 (m,
2H), 1.34 (m, 4H). 13C NMR (300 MHz, CDCl3) ppm:
(17%). H NMR (300 MHz, CD3OD): d 7.16–7.28 (m,
9H), 7.01 (d, 2H), 6.73 (d, 2H), 5.32 (s, 1H), 3.67 (s,
3H), 3.48 (t, J = 5.3 Hz, 2H), 2.72 (t, J = 5.3 Hz, 2H),
2.49–2.50 (m, 4H), 1.71 (p, J = 7.5 Hz, 2H). 13C NMR

W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
3835
(CDCl3, 300 MHz) ppm: 158.4, 142.3, 141.7, 134.1,
133.2, 129.3, 128.6, 128.5, 127.8, 127.1, 113.9,
83.5, 67.9, 54.7, 48.8, 32.6, 31.3; MS (ESI) m/z 410.2
[MH]+.
washed with methanol to remove any residual organics,
and methanol was removed under reduced pressure. The
product was purified by flash chromatography (40%
MeOH/CHlL3, Rf = 0.71). Yield: 760 mg (37%). 1H
NMR (300 MHz, CDCl3): d 7.27 (d, J = 8.7 Hz, 2H),
6.82 (d, J = 8.7 Hz, 2H), 6.4 (m, 1H), 6.16 (m, 1H),
3.76 (s, 3H), 3.41 (d, J = 5.8 Hz, 2H), 1.56 (m, 2H).
13C NMR (CDCl3, 300 MHz) ppm: 158.4, 134.4,
129.4, 113.9, 54.8, 41.2, 35.1, 32.4; MS (ESI) m/z 147.2
[MHÀNH3]+.
7.7.34.
1-(4-Benzyloxy-1-phenyl-but-1-enyl)-4-chloro-
benzene (12a). To a solution of (3-benzyloxypropyl)tri-
phenylphosphonium bromide (680 mg, 1.38 mmol) in
anhydrous THF under a nitrogen atmosphere was
added potassium t-butoxide (171 mg, 1.52 mmol). The
solution was heated to 70 ꢁC for 3 h and then cooled
to an ambient temperature. 4-Chlorobenzophenone
(300 mg, 1.38 mmol) was added to the reaction mixture
and the solution was then reheated to 70 ꢁC for 6 h.
After cooling to room temperature the reaction was
quenched by pouring into water (200 mL). The product
was extracted into EtOAc (3 · 60 mL). The organic
layer was washed with brine (2 · 50 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. Flash chromatography yielded
the product (1.388 g, 98%). 1H NMR (300 MHz, CDCl3):
d 7.7 (m, 4H), 7.4 (m, 5H), 7.3 (m, 5H), 4.4 (s, 3H), 3.5 (t,
2H), 2.3 (m, 2H), 1.9 (m, 2H). 13C NMR (CDCl3,
300 MHz) ppm: 138.8, 134.2, 132.9, 132.2, 131.3, 131.2,
129.2, 129.1, 128.9 128.1, 73.3, 70.6, 70.5, 27.5, 26.5,
22.6; MS (APCI) m/z 351.1 [MH3]+.
To a solution of 12c (198 mg, 1.21 mmol) in ethanol
under nitrogen was added a catalytic amount of 10%
palladium hydroxide on carbon. The reaction mixture
was then placed under a hydrogen atmosphere for
18 h. The reaction was then filtered through Celite to re-
move palladium and then concentrated under reduced
pressure. Residue was diluted with CHCl3 and extracted
with 10% HCl. The aqueous solution was back extracted
with CHCl3, then basified using solid NaOH to a pH of
13. Aqueous layer was then extracted with CHCl3. Or-
ganic layer was dried using anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. No
further purification was needed. Product was a pale yel-
1
low oil (200 mg 100%). Rf = 0.12. H NMR (300 MHz,
CDCl3): d 7.07 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz,
2H), 3.72 (s, 3H), 2.66 (t, J = 6.5 Hz, 2H), 2.55 (t,
J = 7.7 Hz, 2H), 1.69 (m, 2H). 13C NMR (CDCl3,
300 MHz) ppm: 158.2, 134.7, 129.7, 129.4, 114.2, 55.7,
42.2, 36.2, 32.8; MS (APCI) m/z 166.1 [MH]+.
7.7.35. 4-(4-Chloro-phenyl)-4-phenyl-butan-1-ol (12b).
This compound was prepared from 12a (484 mg,
1.39 mmol) according to general procedure E. Flash
chromatography (10% MeOH/EtOAc, Rf = 0.5) affor-
7.7.37. [4-(4-Chloro-phenyl)-4-phenyl-butyl]-[3-(4-meth-
oxy-phenyl)-propyl]-amine (12). This compound was pre-
pared from 12b (104 mg, 0.404 mmol) and 12c (200 mg,
1.21 mmol) according to general procedure A (method
3). Flash chromatography (10% MeOH in CHCl3,
Rf = 0.16) yielded the product. 13C NMR (CDCl3,
300 MHz) ppm: 158.3, 133.8, 133.3, 132.5, 132.0,
131.3, 131.2, 129.8, 129.4, 129.2, 114.3, 55.7, 50.1,
49.9, 49.0, 32.8, 30.8, 28.4, 27.4, 21.4; MS (APCI) m/z
408.2 [MH]+.
1
ded the product (318 mg, 88%). H NMR (300 MHz,
CDCl3): d 7.66 (m, 4H), 7.34 (m, 5H), 4.8 (s, 1H), 3.58
(t, J = 5.8 Hz, 2H), 2.34 (m, 2H), 1.77 (m, 2H). 13C
NMR (CDCl3, 300 MHz) ppm: 133.5, 132.3, 131.2,
131.1, 129.2, 129.1, 62.6, 62.4, 27.5, 26.5, 25.4; MS
(APCI) m/z 261.2 [MH]+.
To a solution of 12b (179 mg, 0.767 mmol) in CH2Cl2
was added the Dess–Martin periodinate (325 mg,
0.767 mmol). The reaction was allowed to stir for 1 h.
It was then quenched with sodium metabisulfate and ex-
tracted with dichloromethane (3 · 20 mL), dried with
anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. Flash chromatography yielded
the product (179 mg, 90%). 1H NMR (300 MHz, CDCl3):
d 9.65 (s, 1H), 7.7 (m, 4H), 7.4 (m, 5H), 2.85 (m, 2H), 2.5
(m, 2H).
7.7.38. 4-(4-Methoxy-phenyl)-butyraldehyde (13a). To a
solution of 1-[4-methoxyphenyl]-4-butanol (300 mg,
1.66 mmol) in CH2Cl2 was added Dess–Martin periodi-
nate (706 mg, 1.66 mmol). The reaction was allowed to
stir for 1 h. It was then quenched with sodium metabi-
sulfate and extracted with dichloromethane (3 · 20),
dried with anhydrous sodium sulfate, filtered, and con-
centrated under reduced pressure. Flash chromatogra-
phy yielded the product (257 mg, 87%). 1H NMR
(300 MHz, CDCl3): d 9.70 (s, 1H), 7.07 (d, J = 8.5 Hz,
2H), 6.83 (d, J = 8.5 Hz, 2H), 3.76 (s, 3H), 2.58 (t,
J = 7.5 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H), 1.90 (p,
J = 7.5 Hz, 2H).
7.7.36. 3-(4-Methoxy-phenyl)-propylamine (12c). LiAlH4
(262 mg, 6.91 mmol) was added to THF. Reaction mix-
ture was allowed to stir until a homogenous slurry was
formed. Aluminum chloride (921 mg, 6.91 mmol) was
then added to the slurry. Reaction was then cooled to
0 ꢁC and a solution of 4-methoxycinnamon nitrile (1 g,
6.28 mmol) in tetrahydrofuran was added dropwise to
the reaction mixture. Reaction was allowed to warm
to room temperature and to stir overnight. Next, reac-
tion was quenched with sodium hydroxide. The mixture
was filtered to remove any aluminum salts. Solid was
7.7.39. 3-(4-Chloro-phenyl)-3-phenyl-acrylonitrile (13b).
To 4-chlorobenzophenone (3.307 g, 15.3 mmol) at
100 ꢁC was added (triphenylphosphoranylidene)acetoni-
trile (4.6 g, 15.3 mmol) and the reaction was allowed to
stir for 60 h. The reaction was then quenched by adding

3836
W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
directly to 100 mL of water. The mixture was then ex-
tracted with EtOAc, the organic layer was extracted
with brine dried with anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure. Flash chro-
matography (10% EtOAc/hexanes, Rf = 0.35) yielded
the desired product (1.416 g, 39%). 1H NMR
ture was stirred at 0 ꢁC for 3 h and then was carefully
quenched by the dropwise addition of water. Reaction
mixture was then extracted with sodium bicarbonate
(3 · 20 mL). Aqueous layer was then acidified with con-
centrated HCl and extracted with EtOAc. Organic layer
was dried with anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. Product was
yielded in 50% (2.44 g, 50% yield); [MS] (APCI) m/z
223.0 [MH]+, 205/0 [MHÀOH]+.
(300 MHz, CDCl3):
d 7.35 (m, 10H), 5.72 (d,
J = 6.9 Hz, 1H); [MS] (APCI) m/z 240.3 [MH]+.
7.7.40. 3-(4-Chloro-phenyl)-3-phenyl-allylamine (13c).
LiAlH4 (87 mg, 2.29 mmol) was added to THF. Reac-
tion mixture was allowed to stir until a homogenous
slurry was formed. Aluminum chloride (306 mg,
2.29 mmol) was then added to the slurry. Reaction
was then cooled to 0 ꢁC and a solution of 13b
(500 mg, 2.09 mmol) in tetrahydrofuran was added
dropwise to reaction mixture. Reaction was allowed to
warm to room temperature, and to stir overnight. Next,
the reaction was quenched with sodium hydroxide. The
mixture was filtered to remove any aluminum salts.
Solid was washed with methanol to remove any residual
organics, and methanol was removed under reduced
pressure. The product was purified by flash chromatog-
raphy (10% MeOH in CHCl3, Rf = 0.32). Yield: 189 mg
(37%). 1H NMR (300 MHz, CDCl3): d 7.88 (s, 2H), 7.21
(m, 9H), 6.17 (q, J = 6.6 Hz, 1H), 3.51 (m, 2H).
7.7.44. 5-(4-Methoxy-phenyl)-pentanoic acid (14b). To a
solution of 14a (300 mg, 1.35 mmol) in 3:1 ethanol/ace-
tic acid was added 10% palladium on carbon and the
reaction was placed under a hydrogen atmosphere.
The reaction was allowed to stir for 4 h and then it
was filtered through a Celite plug to remove all palla-
dium. Next it was concentrated under reduced pressure
to produce a white grainular solid (yield 266 mg, 95%)
Rf = 0.77. 1H NMR (300 MHz, CD3OD): d 7.0 (d,
2H), 6.7 (d, 2H), 3.7 (s, 3H), 2.5 (m, 2H), 2.2 (m, 2H),
1.55 (m, 4H). 13C NMR (300 MHz, CDCl3) ppm:
176.7, 158.3, 134.5, 129.3, 113.8, 54.7, 34.7, 33.9, 31.4,
24.7; [MS] (APCI) m/z 191.0 [MHÀOH]+.
7.7.45. 5-(4-Methoxy-phenyl)-pentanoic acid methoxy-
methyl-amide (14c). To
a solution of 14b (1 g,
4.80 mmol) in dichloromethane was added diisopropyl-
ethylamine (1.862 g, 14.4 mmol) followed by PyBOP
(2.498 g, 4.80 mmol). The reaction mixture was allowed
to stir for 10 min at room temperature before a solution
of N,O-dimethylhydroxylamine hydrochloride (468 mg,
4.80 mmol) in dichloromethane was added. The reaction
was then stirred overnight. It was then diluted with
CH2Cl2, extracted with a saturated aqueous solution
of sodium bicarbonate (3 · 20 mL), 10% HCl
(3 · 20 mL) then washed with brine (2 · 20 mL). The or-
ganic layer was then concentrated under reduced pres-
sure. Flash chromatography (1:1 EtOAc/hexanes,
Rf = 0.72) yielded the product in 78% yield (940 mg).
1H NMR (300 MHz, CDCl3): d 7.1 (d, 2H), 6.8 (d,
2H), 3.76 (s, 3H), 3.65 (s, 3H), 3.15 (s, 3H), 2.56 (t,
2H), 2.43 (m, 2H), 1.65 (m, 4H). 13C NMR (300 MHz,
CDCl3) ppm: 175.8, 158.2, 134.9, 129.8, 114.2, 61.7,
55.7, 35.3, 32.7, 32.2, 31.9, 24.8.
7.7.41. [3-(4-Chloro-phenyl)-3-phenyl-allyl]-[4-(4-meth-
oxy-phenyl)-butyl]-amine (13d). This compound was pre-
pared from 13a (100 mg, 5.54 mmol) and 13c (405 mg,
1.66 mmol) according to general procedure A (method
3). Flash chromatography (10% MeOH in CHCl3,
Rf = 0.26) yielded the product in 18% (41 mg). 1H
NMR (300 MHz, CDCl3): d 7.21 (m, 11H), 6.82
(d, J = 7.5 Hz, 2H), 6.18 (q, J = 5.4 Hz, 1H), 3.31
(dd, J = 2.9, 3.9 Hz, 2H), 2.57 (m, 4H), 1.57 (m, 4H).
13C NMR (300 MHz, CDCl3) ppm: 158.2, 139.6,
134.9, 133.7, 133.7, 131.7, 130.2, 129.8, 129.2, 128.9,
128.8, 128.0, 114.2, 55.8, 49.8, 49.7, 48.9, 35.3; MS
(APCI) m/z 406.1 [MH]+, 408.3 [MH3]+.
7.7.42. [3-(4-Chloro-phenyl)-3-phenyl-propyl]-[4-(4-meth-
oxy-phenyl)-butyl]-amine (13). To a solution of 13d
(60 mg, 0.148 mmol) in ethanol under nitrogen was
added a catalytic amount of 10% palladium hydroxide
on carbon. The reaction mixture was then placed under
a hydrogen atmosphere for 18 h. The reaction was then
filtered through Celite to remove palladium and then
concentrated under reduced pressure. Flash chromato-
graphy (10% MeOH/CHCl3) afforded the product in
53% yield (32 mg). 1H NMR (300 MHz, CDCl3): d
7.21 (m, 9H), 7.01 (d, J = 8.3 Hz, 2H), 6.80 (d,
J = 8.5 Hz, 2H), 4.03 (t, J = 7.9 Hz, 1H), 3.77 (s, 3H),
2.75 (m, 2H), 2.44 (t, J = 7.6 Hz, 2H), 1.50 (m, 4H).
13C NMR (300 MHz, CDCl3) ppm: 158.4, 143.8,
134.2, 129.7, 129.2, 128.7, 128.2, 127.1, 127.0, 126.4,
114.3, 55.8, 49.2, 48.3, 47.1, 34.8, 32.5, 29.3, 26.5; MS
(APCI) m/z 374.4 [MHÀCl]+.
7.7.46. 5-(4-Methoxy-phenyl)-pentanal (14d). To a solu-
tion of 14c (400 mg, 1.59 mmol) in THF at À78 ꢁC
was added powdered lithium aluminum hydride
(72 mg, 1.91 mmol). Stirring was continued for 30 min
and then the reaction was poured into a 5% ethanolic
HCl solution at 0 ꢁC. Mixture was extracted with
EtOAc and then back extracted with brine. Organic
layer is then dried with anhydrous sodium sulfate, fil-
tered, and concentrated under reduced pressure. Flash
chromatography (10% EtOAc/hexane, Rf = 0.5) yielded
the product in 53% (161 mg).
7.7.47. 2-Amino-1-(4-chloro-phenyl)-1-phenyl-ethanol (14e).
To a solution of 4-chlorobenzophenone (1 g, 4.62 mmol)
in a minimal amount of CH2Cl2 was added trim-
ethylsilylcyanide (1.007 g, 10.2 mmol) dropwise. Reac-
tion mixture was stirred for 30 min and then cooled to
0 ꢁC and a catalytic amount of both 18-crown-6 and
7.7.43. 5-(4-Methoxy-phenyl)-5-oxo-pentanoic acid (14a).
To a solution of anisol (solvent) and gluteric anhydride
(2.5 g, 21.9 mmol) under neat conditions was added alu-
minum chloride (6.427 g, 48.2 mmol). The reaction mix-

W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
3837
potassium cyanide were added to the reaction mixture.
Reaction mixture was allowed to slowly warm to room
temperature over 2 h time, and it was allowed to stir
overnight. Next the CH2Cl2 was evaporated under re-
duced pressure, and the resulting residue was diluted
in THF (3 mL). The reaction mixture was cooled to
0 ꢁC and 10% HCl was added. Then the mixture was
warmed to room temperature and stirred for 2 h. Then
the mixture was combined with water and extracted with
EtOAc. The organic layer was then dried over anhy-
drous sodium sulfate, filtered, and concentrated under
reduced pressure. Product was carried on to the next
reaction without further purification.
7.7.49. 6-(4-Methoxy-phenyl)-hex-5-yn-1-ol (15a).
A
solution of iodoanisole (500 mg, 2.14 mmol), diisopro-
pyl ethyl amine (1.104 g, 8.55 mmol), and 5-hexyn-1-ol
(231 mg, 2.35 mmol) with catalytic amounts of triphen-
ylphosphine and copper iodide in tetrahydrofuran
(30 mL) was degassed with nitrogen for 1 h before a cata-
lytic amount of palladium bis(dibenzylideneacetone)
was added to the reaction mixture. The flask was then
sealed with parafilm and the reaction was stirred for
12 h before it was diluted with ethyl acetate and ex-
tracted with ammonium chloride (3 · 20 mL) and then
brine (2 · 20 mL). The organic layer was then dried over
anhydrous sodium sulfate, filtered, and then concen-
trated under reduced pressure. Flash chromatography
afforded the product in 100 percent yield. 1H NMR
(300 MHz, CDCl3): d 7.32 (d, J = 8.7 Hz, 2H), 6.80 (d,
J = 8.7 Hz, 2H), 3.77 (s, 3H), 3.68 (t, J = 6.0 Hz, 2H),
2.42 (t, J = 6.6 Hz, 2H), 1.69 (m, 4H). 13C NMR
(300 MHz, CDCl3) ppm: 159.5, 133.4, 116.6, 114.3,
88.8, 81.2, 62.9, 55.7, 32.4, 25.6, 19.7; MS (APCI) m/z
205.1 [MH]+.
LiAlH4 (210 mg, 5.54 mmol) was added to THF. Reac-
tion mixture was allowed to stir until a homogenous
slurry was formed. Reaction was then cooled to 0 ꢁC
and a solution of the nitrile in tetrahydrofuran was
added dropwise to the reaction mixture. Reaction was
allowed to warm to room temperature and to stir over-
night. Next, reaction was quenched with sodium
hydroxide. Mixture was filtered to remove any alumi-
num salts. Solid was washed with methanol to remove
any residual organics, and methanol was removed under
reduced pressure. The product was purified by flash
chromatography (10% MeOH in EtOAc, Rf = 0.43)
7.7.50. 6-(4-Methoxy-phenyl)-hexan-1-ol (15b). This
compound was prepared from 15a (437 mg, 2.14 mmol)
according to general procedure E. Flash chromatogra-
phy afforded the product in 100% yield. 1H NMR
(300 MHz, CDCl3): d 7.09 (d, J = 7.9 Hz, 2H), 6.83 (d,
J = 7.9 Hz, 2H), 3.79 (s, 3H), 3.62 (t, J = 6.2 Hz, 2H),
2.56 (t, J = 7.1 Hz, 2H), 1.85 (s, 1H), 1.57 (m, 4H),
1.37 (m, 4H). 13C (300 MHz, CDCl3) ppm: 158.1,
135.4, 129.7, 114.2, 63.4, 55.8, 35.4, 33.2, 33.1, 29.5,
26.1.
1
(169 mg, 15%). H NMR (300 MHz, CDCl3): d 7.3 (m,
9H), 3.4 (q, 2H), 2.5 (s, 2H). 13C NMR (300 MHz,
CDCl3) ppm: 145.4, 144.5, 133.4, 128.9, 128.2, 127.7,
126.6, 77.2, 51.3; [MS] (ESI) m/z 230.2 [MÀH2O]+.
7.7.48. [2-(4-Chloro-phenyl)-2-phenyl-ethyl]-[5-(4-methoxy-
phenyl)-pentyl]-amine (14). This compound was pre-
pared from 14d (161 mg, 0.837 mmol) and 14e
(601 mg, 2.51 mmol) according to general procedure A
(method 3). Flash chromatography (EtOAc, Rf = 0.72)
yielded the product in 64% (226 mg). 1H NMR
(300 MHz, CDCl3): d 7.46 (m, 4H), 7.35 (m, 5H), 7.12
(d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 3.81 (s,
3H), 3.30 (q, J = 11.9, 12.9 Hz, 2H), 2.65 (t,
J = 7.0 Hz, 2H), 2.57 (t, J = 7.5 Hz, 2H), 1.61 (m, 2H),
1.48 (m, 2H), 1.35 (m, 2H). 13C NMR (300 MHz,
CDCl3) ppm: 158.3, 145.9, 145.1, 135.1, 133.3, 129.8,
128.9, 128.1, 127.6, 126.5, 126.3, 114.3, 76.3, 59.1,
55.8, 50.3, 35.4, 32.0, 30.5, 27.2; [MS] (APCI) m/z
424.1 [MH]+, 406.3 [MHÀH2O]+.
7.7.51. 6-(4-Methoxy-phenyl)-hexanal (15c). This com-
pound was prepared from 15b (455 mg, 2.18 mmol)
according to general procedure D. Flash chromatogra-
phy yielded the product in 84%. Rf = 0.2. 1H NMR
(300 MHz, CDCl3): d 9.75 (s, 1H), 7.09 (d, J = 8.1 Hz,
2H), 6.82 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H), 2.56 (t,
J = 7.4 Hz, 2H), 2.42 (t, J = 6.9 Hz, 2H), 1.63 (m, 4H),
1.45 (m, 2H). 13C NMR (300 MHz, CDCl3) ppm:
203.2, 158.2, 135.0, 129.7, 114.2, 55.7, 44.3, 35.3, 31.9,
29.2, 22.4.
7.7.52. [(4-Chloro-phenyl)-phenyl-methyl]-[6-(4-methoxy-
phenyl)-hexyl]-amine (15). To a solution of 15c (200 mg,
0.97 mmol), 4-chlorobenzhydrylamine hydrochloride
(739 mg, 2.91 mmol), and triethylamine (392 mg,
3.88 mmol) in dichloromethane was added titanium tet-
rachloride (92 mg, 0.485 mmol) via syringe. The reaction
was stirred for 18 h and then carefully quenched with a
solution of methanolic sodium cyanoborohydride
(244 mg, 3.88 mmol) and stirred for an additional
15 min. The reaction was then made basic to a pH of
13 with 3 N sodium hydroxide, extracted with ethyl ace-
tate (3 · 20 mL), dried using magnesium sulfate, and
concentrated under reduced pressure. Flash chromato-
To a solution of the product of the prior reaction
(107 mg, 0.452 mmol) in ethanol under nitrogen was
added a catalytic amount of 10% palladium on carbon
and formic acid. The reaction mixture was then placed
under a hydrogen atmosphere for 18 h. Reaction was
then filtered through Celite to remove palladium and
then concentrated under reduced pressure. Flash chro-
matography (10% MeOH/EtOAc, Rf = 0.43) afforded
1
the product in 80% yield (82 mg). H NMR (300 MHz,
CDCl3): d 7.50 (m, 4H), 7.34 (m, 5H), 7.08, (d,
J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.13 (m,
1H), 3.80 (s, 3H), 3.40 (s, 2H), 2.65 (t, J = 7.2 Hz,
2H), 2.54 (t, J = 7.6 Hz, 2H), 1.55 (m, 4H), 1.28 (m,
2H). 13C NMR (300 MHz, CDCl3) ppm: 158.2, 145.9,
135.0, 129.8, 128.8, 127.6, 126.5, 126.2, 114.2, 76.5,
58.7, 55.7, 50.1, 35.4, 31.9, 29.6, 27.0.
1
graphy yielded the product in 75% (298 mg). H NMR
(300 MHz, CDCl3):
d
7.31 (m, 9H), 7.11 (d,
J = 7.9 Hz, 2H), 6.84 (d, J = 8.1 Hz, 2H), 4.80 (s, 1H),
3.80 (s, 3H), 2.56 (t, J = 7.0 Hz, 4H), 1.51 (m, 4H),
1.34 (m, 4H). 13C (300 MHz, CDCl3) ppm: 158.2,
144.5, 143.4, 135.4, 133.1, 129.8, 129.2, 129.1, 127.7,

3838
W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
114.2, 67.5, 55.7, 48.7, 35.3, 32.2, 30.7, 29.7, 27.7; [MS]
7.7.57. 2-(4-Methoxyphenyl)-N-{2-[(1,1,2,2-tetramethyl-
1-silapropoxy)methyl]phenyl}acetamide (17b). To a solu-
tion of 4-methoxyphenylacetic acid (0.255 g, 1.54 mmol)
in CH2Cl2 (15 mL) was added DiEA (0.32 mL,
1.84 mmol) and PyBOP (0.80 g, 1.54 mmol). This mix-
ture was allowed to stir for 15 min before 17a (0.365,
1.54 mmol) was added. After 1 h, the reaction was di-
luted with ethyl acetate and extracted with saturated
solutions of NH4Cl and NaHCO3. The organic layer
was dried over Na2SO4, concentrated under reduced
pressure, and purified by flash chromatography (50%
ether/hexanes, Rf = 0.3) to afford a pale yellow oil
(0.46 g, 78%). 1H NMR (CDCl3): d 8.67–8.52 (br s,
1H), 8.14 (d, J = 7.6 Hz, 1H), 7.34–7.23 (m, 3H), 7.13–
6.97 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.57 (s, 2H),
3.80 (s, 3H), 3.66 (s, 2H), 0.86 (s, 9H), 0.016 (s, 6H).
13C NMR (CDCl3): d 170.15, 159.37, 137.98, 130.82,
130.02, 129.11, 128.42, 127.32, 124.35, 122.60, 114.87,
65.33, 55.74, 44.86, 26.35, 18.71, À4.70. MS (CI) m/z
386.1 (M+).
(ESI) m/z 408.1 [MH]+.
7.7.53. [2-(Aminomethyl)phenyl]methan-1-ol (16a). To
7.6 mL of THF was added LiAlH4 (0.434 g, 11.4 mmol),
which was allowed to stir until the dark gray color per-
sisted. The slurry was cooled to 0 ꢁC, and 2-cyanobenz-
aldehyde (0.500 g, 3.81 mmol), dissolved in a minimum
volume of THF, was added dropwise via syringe. After
12 h, 10% HCl was added dropwise to quench. Enough
10% HCl was added to obtain a pH of 2–3. Then the
mixture was partitioned between ether and an aqueous
layer. Using 3 N NaOH, the acidic aqueous layer was
made basic (pH 9). The basic aqueous layer was ex-
tracted four times with ethyl acetate. The organic layer
was dried over Na2SO4 and concentrated under reduced
1
pressure to afford a dark brown oil (0.433 g, 83%). H
NMR (CDCl3): d 7.38–7.16 (m, 4H), 4.63 (s, 2H), 3.97
(s, 2H), 3.90–3.64 (br s, 3H). 13C NMR (CDCl3): d
141.97, 140.51, 130.63, 130.22, 128.78, 128.56, 65.09,
45.92. MS (CI) m/z 138.0 (M+).
7.7.58. N-[2-(Hydroxymethyl)phenyl]-2-(4-methoxyphen-
yl)acetamide (17c). This compound was prepared from
17b (0.46 g, 1.19 mmol) according to general procedure
G. The crude solid was recrystallized in methanol/hex-
anes (ꢀ95:5). The desired product (Rf = 0.30 in 50%
ethyl acetate/hexanes) was obtained (0.323 g, 100%) as
a white solid. 1H NMR (CDCl3): d 8.51–8.35 (br s,
1H), 8.00 (d, J = 8.1 Hz, 1H), 7.36–7.23 (m, 3H), 7.18–
7.00 (m, 2H), 6.92 (d, J = 8.5 Hz, 2H), 4.47 (d,
J = 5.0 Hz, 2H), 3.81 (s, 3H), 3.68 (s, 2H). 13C NMR
(CDCl3): d 170.80, 159.53, 137.76, 131.24, 130.17,
129.59, 129.37, 127.15, 124.92, 122.93, 114.97, 64.63,
55.85, 44.66. MS (ESI) m/z 272.0 (M+).
7.7.54. [2-({[(4-Methoxyphenyl)methyl]amino}methyl)phen-
yl]methan-1-ol (16b). This compound was prepared from
16a according to general procedure A (method 3). Flash
chromatography (2.5% MeOH/chloroform) afforded a
1
dark orange oil (0.062 g, 66%). H NMR (CDCl3): d
7.40–7.17 (m, 6H), 6.86 (d, J = 8.9 Hz, 2H), 4.63 (s,
2H), 4.09 (br s, 2H), 3.90 (s, 3H), 3.79 (s, 2H), 3.76 (s,
2H). 13C NMR (CDCl3): d 159.48, 142.35, 138.30,
131.09, 131.00, 130.61, 130.17, 128.98, 128.40, 114.53,
65.34, 55.78, 53.11, 52.92. MS (CI) m/z 258.2 (M+).
7.7.55. [(2-{[(4-Chlorophenyl)phenylmethoxy]methyl}phen-
yl)methyl][(4-methoxyphenyl)methyl]amine (16). This
compound was prepared from 16b and 4-chlorobenzhy-
drol according to general procedure C. Flash chroma-
tography (75% ethyl acetate/hexanes) afforded dark
orange oil (0.073 g, 66%). 1H NMR (acetone-d6): d
7.36–7.01 (m, 15H), 6.73 (d, J = 8.9 Hz, 2H), 5.41 (s,
1H), 4.52 (s, 2H), 3.66 (s, 3H), 3.63 (s, 2H), 3.53 (s,
2H). 13C NMR (acetone-d6): d 159.05, 142.65, 142.18,
139.73, 137.11, 133.29, 132.90, 129.60, 129.52, 129.29,
128.90, 128.83, 128.74, 127.96, 127.91, 127.27, 127.11,
113.87, 82.53, 68.90, 54.96, 53.02, 50.62. MS (CI) m/z
458.5 (M+). Anal. Calcd for C29H28ClNO2: C, 76.05;
H, 6.16; N, 3.06. Found: C, 75.90; H, 6.16; N, 3.05.
7.7.59.
(2-{[2-(4-Methoxyphenyl)ethyl]amino}phenyl)-
methan-1-ol (17d). This compound was prepared from
17c according to general procedure B, with the addition
of AlCl3 (0.5 equiv). However, this reaction was con-
ducted at 0.1 M in THF with respect to 17c, due to its
low solubility in THF, and the reaction was refluxed
for 53 h. Flash chromatography (20% ethyl acetate/hex-
anes, Rf = 0.15) afforded an orange oil (0.116 g, 38%).
1H NMR (CDCl3): d 7.28–7.10 (m, 3H), 7.06 (dd,
J = 7.3, 1.5 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 6.76–
6.60 (m, 2H), 4.59 (s, 2H), 3.80 (s, 3H), 3.39 (t,
J = 6.9 Hz, 2H), 2.91 (t, J = 7.1 Hz, 2H). 13C NMR
(CDCl3): d 158.73, 147.89, 131.99, 130.25, 130.16,
129.61, 124.90, 116.97, 114.49, 111.21, 65.23, 55.79,
45.59, 35.17. MS (ESI) m/z 258.1 (M+).
7.7.56. 2-[(1,1,2,2-Tetramethyl-1-silapropoxy)methyl]phen-
ylamine (17a). To 20 mL of DMF was added t-butyldim-
ethylsilyl chloride (0.581 g, 3.86 mmol), imidazole
(0.276 g, 4.06 mmol), and 2-aminobenzyl alcohol
(0.500 g, 4.06 mmol). This reaction was allowed to stir
12 h. Then the reaction was diluted with ethyl acetate
and extracted with saturated LiBr and brine. The organ-
ic layer was dried over Na2SO4 and concentrated under
reduced pressure. Flash chromatography (10% ether/
hexanes, Rf = 0.25) afforded a pale yellow liquid
(0.748 g, 78%). 1H NMR (CDCl3): d 7.18–6.98 (m,
2H), 6.78–6.62 (m, 2H), 4.71 (s, 2H), 4.34–4.05 (br s,
2H), 0.92 (s, 9H), 0.091 (s, 6H). 13C NMR (CDCl3): d
146.69, 129.21, 128.95, 125.73, 118.35, 116.22, 65.44,
26.39, 18.77, À4.74. MS (ESI) m/z 237.9 (M+).
7.7.60. (2-{[(4-Chlorophenyl)phenylmethoxy]methyl}phen-
yl)[2-(4-methoxyphenyl)ethyl]amine (17). Molecular
˚
sieves (4 A) were added to 2 mL of DMF before NaH
(60% dispersion in mineral oil, 7.8 mg, 0.194 mmol)
was added. After 10 min, this mixture was cooled to
0 ꢁC, and 17d (50 mg, 0.194 mmol), dissolved in a mini-
mum amount of DMF, was added slowly via syringe.
The reaction was allowed to stir for 30 min. Then, 4-
chloro-bromobenzhydrol dissolved in
a minimum
amount of DMF, was added slowly via syringe. The
reaction was allowed to stir overnight and then it was di-
luted with ethyl acetate and filtered to remove the

W. F. McCalmont et al. / Bioorg. Med. Chem. 13 (2005) 3821–3839
3839
12. Gray, L. S.; Perez-Reyes, E.; Gamorra, J. C.; Haverstick,
D. M.; Shattock, M.; McLatchie, L.; Harper, L.; Brooks,
G.; Heady, T. N.; Macdonald, T. L. Cell Calcium,
in press.
molecular sieves and NaBr. The organic layer was ex-
tracted with saturated solutions of LiBr and brine. Then
the organic layer was dried over Na2SO4, concentrated
under reduced pressure, and purification on a Analtech
1000 lm silica prep plate (10% ether/hexanes, Rf = 0.30)
afforded a yellow oil (16.1 mg, 18%). 1H NMR (acetone-
d6): d 7.33–6.93 (m, 12H), 6.89 (dd, J = 7.3, 1.2 Hz, 1H),
6.72 (d, J = 8.9 Hz, 2H), 6.63–6.43 (m, 2H), 5.37 (s, 1H),
4.35 (s, 2H), 3.63 (s, 3H), 3.26–3.14 (m, 2H), 2.65 (t,
J = 7.1 Hz, 2H). 13C NMR (acetone-d6): d 158.74,
148.02, 142.34, 141.86, 132.95, 131.93, 130.25, 130.00,
129.81, 128.95, 128.87, 128.75, 127.99, 127.36, 121.92,
116.30, 114.22, 110.66, 81.40, 69.95, 54.94, 45.20,
34.86. MS (CI) m/z 458.7 (M+).
13. Examples of concentration dependent, dual action ago-
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Acknowledgements
We would like to thank Dr. Mahendra Chordia and
Frank Foss for proof reading this manuscript.
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