Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites

Article abstract of DOI:10.1016/j.bmcl.2003.12.097

The rhodium(II)-catalyzed intermolecular C-H insertion of methyl aryldiazoacetates with either N-Boc-piperidine or N-Boc-pyrrolidine followed by deprotection with trifluoroacetic acid is a very direct method for the synthesis of methylphenidate analogues. By using either dirhodium tetraacetate or dirhodium tetraprolinate derivatives as catalyst, either the racemic or enantioenriched methylphenidate analogues can be prepared. The binding affinities of the methylphenidate analogues to both the dopamine and the serotonin transporters are described. The most notable compounds are the erythro-(2-naphthyl) analogues which display high binding affinity and selectivity for the serotonin transporter.

Full text of DOI:10.1016/j.bmcl.2003.12.097

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1799–1802
Synthesis of methylphenidate analogues and their binding affinities
at dopamine and serotonin transport sites
a,
a
a
b
Huw M. L. Davies, * Darrin W. Hopper, Tore Hansen, Quixu Liu
b,
and Steven R. Childers *
aDepartment of Chemistry, State University of New York at Buffalo, Buffalo, NY 14260-3000, USA
bDepartment of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Received 3October 200 3; accepted 23December 2003
Abstract—The rhodium(II)-catalyzed intermolecular C–H insertion of methyl aryldiazoacetates with either N-Boc-piperidine or
N-Boc-pyrrolidine followed by deprotection with trifluoroacetic acid is a very direct method for the synthesis of methylphenidate
analogues. By using either dirhodium tetraacetate or dirhodium tetraprolinate derivatives as catalyst, either the racemic or enan-
tioenriched methylphenidate analogues can be prepared. The binding affinities of the methylphenidate analogues to both the
dopamine and the serotonin transporters are described. The most notable compounds are the erythro-(2-naphthyl) analogues which
display high binding affinity and selectivity for the serotonin transporter.
#
2004 Elsevier Ltd. All rights reserved.
1
. Introduction
As most of the therapeutic activity of threo-methylphe-
0
14
nidate resides in the d-enantiomer (2R,2 R), while the
0
effects, effective methods for the asymmetric synthesis
Even though the dopamine reuptake inhibitor, methyl-
1
l-enantiomer (2S,2 S) may have undesirable side
15
phenidate has been known for over 50 years, its synth-
esis and biology continues to be of considerable interest.
Of the threo and erythro diastereomers (1a and 2a), for
methylphenidate, the threo form is most active and is
prescribed to patients as a racemate for the treatment of
Attention Deficit Hyperactivity Disorder (ADHD).
Additionally, threo-methylphenidate has undergone
of threo-methylphenidate have been explored. In the
late 1990s, two new but fairly lengthy asymmetric
1
6,17
syntheses of methylphenidate were reported.
shorter method was then reported using an asymmetric
A
2
18,19
Michael addition as the key step,
but this approach
required the use of a stoichiometric amount of an
expensive chiral auxiliary.
evaluation for its therapeutic potential for treatment of
cocaine (3) addiction,
3
ꢀ5
and shown promise in adults
who have been also diagnosed to have ADHD.3,5 Due
to this intense interest, new analogues of methylpheni-
date continue to be explored.
For some time, we have been designing new synthetic
methods for the asymmetric synthesis of classes of
compounds that inhibit monoamine transporters. The
ultimate goal of this work is to apply these enabling
synthetic technologies to the rapid synthesis of potential
therapeutic agents for the treatment of cocaine addic-
tion. Efficient asymmetric syntheses of many important
classes of monoamine re-uptake inhibitors such as 2b-
6ꢀ13
2
0,21
22
substituted 3b-aryl tropanes,
sertraline, and inda-
2
3
traline have been achieved. A hallmark of these syn-
thetic methodologies is that they are all based on
asymmetric carbenoid transformations induced by
chiral rhodium prolinate catalysts, such as Rh (S-
2
DOSP) (4) and Rh (S-biDOSP) (5a).
4 2 2
*
0
Corresponding author. Tel.: +1-716-645-6800x2186; fax: +1-716-
45-6547; e-mail: hdavies@acsu.buffalo.edu
2
4
6
960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.12.097

1800
H. M. L. Davies et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1799–1802
The C–H insertion reaction was also carried out with
N-Boc-pyrrolidine (8) to generate a new series of methyl-
phenidate analogues (Table 2). In contrast to the reac-
tion with N-Boc-piperidine, the reactions with N-Boc-
pyrrolidine are highly diastereoselective favoring the
8
erythro diastereomer. Indeed, when the reactions are
ꢁ
carried out with Rh (S-DOSP) at ꢀ50 C, both the de
2
4
0
and ee of the reactions are >90% favoring the (2R,2 S)
enantiomer. The first four entries describe reactions
with substituted phenyldiazoacetates to form 9a–c,f and
10a–c,f. The final four entries describe reactions with
substituted 2-naphthyldiazoacetates to form 9g–j and
10g–j. As the naphthyl analogues 10g–j displayed some
very promising biological activity, the pure enantiomers
of 10g–j were prepared by using either Rh (R-DOSP)
Recently, we described a very direct strategy for the
asymmetric synthesis of threo-methylphenidate by an
2
5ꢀ27
asymmetric C–H insertion N-Boc-piperidine (eq 1).
This new approach to threo-methylphenidate is unusual
because it is an example of a catalytic asymmetric C–H
activation process. This communication describes stud-
ies to exploit this C–H insertion for the synthesis of
methylphenidate analogues, which has led to the
discovery of analogues with novel binding selectivity
profiles.
2
4
or Rh (S-DOSP) catalyst at room temperature. This
2
4
resulted in the formation of 10g–j in 65–85% ee. A
single re-crystallization of products of 85% ee or above,
or two recrystallizations of products of 65–84% ee gave
enantiomerically pure 10g–j.
ð1Þ
3. Biology
Table 3 summarizes the binding affinities to the dopa-
mine and serotonin transporters (DAT and SERT) of
the methylphenidate analogues 1 and 2 containing a
Table 1. Reaction of aryldiazoacetates with N-Boc-piperidine
2. Chemistry
The general strategy for the synthesis of the methylphe-
nidate analogues is based on the C–H insertion that is
described in eq 1. Reaction of various aryldiazoacetates
7
with N-Boc-piperidine (6) resulted in the synthesis of a
series of methylphenidate analogues as illustrated in
Table 1. A major advantage of this strategy is that
either racemic analogues can be prepared by using
achiral catalysts or an asymmetric synthesis can be
achieved using chiral catalysts. In general these reac-
tions resulted in a slight preference for the threo dia-
stereomer 1. Rh (R-DOSP) and Rh (S-biTISP) generate
Compd
Ar
1&2
yield (%)
1:2
1 ee%
2 ee%
64a
2/1
1.8/1
—
68
—
89
a
b
44
2
4
2
2
0
preferentially (2R,2 R)-1, which is the biologically most
active enantiomer of threo-methylphenidate. The first
four entries are directed towards the synthesis of threo
and erythro methylphenidate (1a and 2a) and some of
the more interesting methylphenidate analogues (1b–d)
5a
0
5
5
2/1
1.4/1
—
57
—
92
b
b
a
67
68
1.4/1
1.5/1
—
77
—
94
1
0,11,28
c
a
that have been studied previously.
in entries 1–3, these reactions can be easily carried out
As can be seen
with good asymmetric induction using Rh (S-DOSP)
2
4
ꢁ
28c
as catalyst at ꢀ50 C. The biphenyl analogue 1e was
prepared because the biphenyl functionality at C-3in
the tropanes resulted in very potent monoamine reup-
d
1.5/1
1.6/1
—
—
—
—
2
9
take inhibitors. The 2-naphthyl analogue 1g and its
erythro diastereomer (2g) were prepared because (ꢂ)-1g
has been shown previously to be a potent methylpheni-
e
24a
9
date analogue and the 2-naphthyl functionality at C-3
in the tropanes generated extremely potent monoamine
2
9
reuptake inhibitors. The pure enantiomer of 1g was
readily prepared by carrying out the reaction with
Rh (S-biTISP) as catalyst at room temperature. This
0c
d
3
33
2/1
2/1
—
85
—
90
g
2
2
a
Rh
Rh
Rh
Rh
2
2
2
2
(OOct) , reflux.
4
resulted in the formation of 1g in 85% ee, which after a
single recrystallization gave enantiomerically pure (2R,
b
c
ꢁ
(S-DOSP)
(R,S-DOSP) , rt.
4
4
, ꢀ50 C.
0
d
2
R)-1g (>98% ee).
2
(S-biTISP) , rt.

H. M. L. Davies et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1799–1802
1801
piperidine ring. Several of these racemic piperidine ana-
logues are known and their binding affinities at the
stituted phenyl methylphendidate analogues 1a–e,
the naphthyl derivative 1g displays strong binding to the
SERT (71.6 nM). Considering the interesting activity of
1
0,11,28
DAT have been reported.
The binding data for
0
these compounds are in reasonable agreement with the
published results, especially considering that the radi-
oligand we use is different from those used in the earlier
studies. For all the compounds tested, the expected
trend was observed of enhanced binding of the threo
diastereomer 1 compared to the erythro diastereomer 2.
The threo 3,4-dichlorophenyl derivative 1d has the
highest binding affinity of a methylphenidate analogue
1g, its active (2R,2 R) enantiomer was prepared and
tested. The binding affinities of the erythro 2-naphthyl
derivative 2g was especially interesting because this
compound retained the binding affinity to the SERT,
even while there was the expected drop in binding affi-
nity to the DAT compared to 1g. Thus, 2g is the first
example of a methylphenidate analogue that binds
selectively to SERT.
8
to the DAT (2.67 nM, lit 5.03nM). Even the erythro
derivative 2d has an IC50 of 33.8 nM at the DAT. The
aryl functionality causes similar trends to the binding
affinities at DAT as was observed for the 3-aryltropanes
but there are some subtle differences. The 2-naphthyl
derivative 1g (33.9 nM) does not bind as effectively to
the DAT as the 3,4-dichlorophenyl derivative 1d, while
in the 3-aryltropanes, the 2-naphthyl group leads to one
Table 4 summarizes the binding affinities to the DAT
and SERT transporters of the methylphenidate analo-
gues 9 and 10 containing a pyrrolidine ring. Previous
studies had shown that replacement of the piperidine
ring in methylphenidate with a pyrrolidine ring results
8
,11
in a 10-fold decrease in binding affinity to the DAT.
A similar trend is seen with a range of substituted
phenyl derivatives, although certain compounds such as
the threo 4-chlorophenyl analogue 9c exhibit reasonable
binding affinity at the DAT (272 nM). The erythro sub-
stituted phenyl analogues 10a–c, 10f display limited
binding to the DAT and neither the threo or erythro
substituted phenyl analogues bind effectively to the
2
9
of the most potent tropanes known. Unlike the sub-
Table 2. Reaction of aryldiazoacetate with N-Boc-pyrrolidine
Table 3. Binding affinities of piperidine derivatives
Compd
a
Ar
1&2 yield (%)
1:2
1 ee%
4
7
9a
2
1/5
1/24
—
94
b
Compd
Ar
DA (IC50 nM)a
5-HT (K
i
nM)a
5
6
4a
7
1/11
>1/25
—
94
b
b
1
a (ꢂ)
164ꢂ40
>10,000
>10,000
b
(
lit 83.0ꢂ7.9 )
>1000
4
7
3a
0
1/4
>1/25
—
93
2a (ꢂ)
c
f
a
1
2
b (ꢂ)
b (ꢂ)
114ꢂ28
>10,000
>10,000
60c
1/21
—
b
(lit 33.0ꢂ1.2 )
7430ꢂ1520
4
40
4
3c
1/12
1/10
1/10
—
69
75
1
2
c (ꢂ)
c (ꢂ)
91.2ꢂ3.7
2220ꢂ220
>10,000
d
g
b
(
lit 20.6ꢂ3.4 )
2750ꢂ1200
0e
8c
8
1d (ꢂ)
d (ꢂ)
2.67ꢂ0.58
>10,000
>10,000
1
4
1/8
1/8
—
85
b
h
i
d
(lit 5.3ꢂ0.7 )
33.8ꢂ1.9
2
2
3
2c
1/18
1/14
—
72
1e (ꢂ)
2e (ꢂ)
1020ꢂ110
6470ꢂ820
>10,000
>10,000
d
2
2
3
1c
8
1/6
1/8
—
75
1g (ꢂ)
33.9ꢂ6.4
71.6ꢂ7.4
j
d
c
(lit 79.5 )
11.1ꢂ2.2
0
1
2
g (2R,2 R)
g (ꢂ)
94.8ꢂ23.7
105ꢂ12
2080ꢂ390
a
Rh
Rh
Rh
Rh
Rh
2
2
2
2
2
(OOct)
(S-DOSP)
(R,S-DOSP)
(R-DOSP) , rt.
(S-DOSP) , rt.
4
, reflux.
b
c
ꢁ
a
4
, ꢀ50 C.
i
K and IC50 values in binding assays were determined using the pro-
4
, rt.
cedures described in ref 21.
Ref 8.
Ref 9.
d
e
b
c
4
4

1802
H. M. L. Davies et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1799–1802
Table 4. Binding affinities of pyrrolidine derivatives
Acknowledgements
Financial support of this work by the National Institutes
of Health (DA06301 and DA15225) is gratefully acknowl-
edged. D.W.H. was supported by a National Institute of
Health postdoctoral fellowship grant (DA05886).
Compd
Ar
DAT
IC50 nM)a
SERT
(K nM)
i
a
(
References and notes
9
1
a (ꢂ)
3160ꢂ380
>10,000
>10,000
1. Perel, J.; Dayton, P. Methylphenidate; Marcel Decker:
New York, 1976.
b
(
lit 1336ꢂ108 )
>1000
2
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0a (ꢂ)
3
9
1
b (ꢂ)
1930ꢂ640
>1000
>10,000
>10,000
4. Gawin, F.; Riordan, C.; Kleber, H. Am. J. Drug Alcohol
Abuse 1985, 11, 193.
0b (ꢂ)
5
6
7
. Levin, F. R.; Evans, S. M.; McDowell, D. M.; Kleber,
H. D. J. Clin. Psychiatry 1998, 59, 300.
. Wayment, H. K.; Deutsch, H.; Schweri, M. M.; Schenk,
J. O. J. Neurochem. 1999, 72, 1266.
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Glaser, R.; Adin, I.; George, C.; Schweri, M. M. Bioorg.
Med. Chem. Lett. 1997, 7, 1213.
9
1
c (ꢂ)
272ꢂ37
>1000
1080ꢂ120
1900ꢂ690
0c (ꢂ)
1
0f (ꢂ)
637ꢂ100
>10,000
8
. Deutsch, H. M.; Shi, Q.; Gruszecka-Kowalik, E.; Schweri,
M. M. J. Med. Chem. 1996, 39, 1201.
1
1
1
0g (ꢂ)
805ꢂ102
465ꢂ65
4.0ꢂ1.3
2.5ꢂ0.9
0
9. Axten, J. M.; Krim, L.; Kung, H. F.; Winkler, J. D.
J. Org. Chem. 1998, 63, 9628.
0g (2R,2 S)
0g (2S,2 R)
0
1750ꢂ270
2020ꢂ290
1
0. Gatley, S. J.; Pan, D. F.; Chen, R. Y.; Chaturvedi, G.;
Ding, Y. S. Life Sci. 1996, 58, L231.
11. Deutsch, H. M. Med. Chem. Res. 1998, 8, 91.
1
1
0h (ꢂ)
195ꢂ54
446ꢂ6
11.4ꢂ2.2
5.5ꢂ1.2
0
0h (2R,2 S)
1
2. Deutsch, H. M.; Collard, D. M.; Zhang, L. A.; Burnham,
K. S.; Deshpande, A. K.; Holtzman, S. G.; Schweri,
M. M. J. Med. Chem. 1999, 42, 882.
10i
1410ꢂ490
850ꢂ178
3.2ꢂ0.5
2.3ꢂ0.6
0
13. Meltzer, P. C.; Wang, P.; Blundell, P.; Madras, P. K.
J. Med. Chem. 2003, 46, 1538.
12i (2R,2 S)
1
4. Patrick, K. S.; Caldwell, R. W.; Ferris, R. M.; Breese,
G. R. J. Pharmacol. Exp. Ther. 1987, 241, 152.
15. Szporny, K.; Gorog, P. Biochem. Pharmacol. 1961, 8, 263.
1
1
0j (ꢂ)
2050ꢂ540
945ꢂ114
245ꢂ63
0
0j (2R,2 S)
54.6ꢂ16.7
1
1
1
6. Prashad, M.; Liu, Y. G.; Kim, H. Y.; Repic, O.; Black-
lock, T. J. Tetrahedron: Asymmetry 1999, 10, 3479.
7. Thai, D. L.; Sapko, M. T.; Reiter, C. T.; Bierer, D. E.;
Perel, J. M. J. Med. Chem. 1998, 41, 591.
8. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.;
Maki, T. Org. Lett. 1999, 1, 175.
a
i
K and IC50 values in binding assays were determined using the pro-
cedures described in ref 21.
Ref 9.
b
SERT. In contrast, a very interesting trend was found
for the erythro substituted 2-naphthyl derivatives 10g–j.
The 2-naphthyl analogue 10g, has decreased binding to
the DAT compared to the piperidine analogue 2g, but
enhanced binding at the SERT, leading to nearly a 200-
fold selectivity for the SERT (K =2.5 nM). Similar
i
behavior was found for the 2-(6-bromonaphthyl) 10h
(5.5 nM) and 2-(6-methylnaphthyl) 10i (2.3nM) deriv-
atives, while the 2-(6-methoxynaphthyl) derivative 10j
was not as potent (54.6 nM).
19. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.;
Maki, T. Tetrahedron 2000, 56, 7411.
20. Davies, H. M. L.; Matasi, J. J.; Hodges, L. M.; Huby,
N. J. S.; Thornley, C.; Kong, N.; Houser, J. H. J. Org.
Chem. 1997, 62, 1095.
2
1. Davies, H. M. L.; Gilliatt, V.; Kuhn, L. A.; Saikali, E.;
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Med. Chem. 2001, 44, 1509.
2
2. Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett.
999, 1, 233.
1
2
3. Davies, H. M. L.; Gregg, T. M. Tetrahedron Lett. 2002,
43, 4951.
In conclusion, these studies describe new methylpheni-
date analogues with a greater range of binding selectiv-
ity than had been previously available. Considering that
recent studies indicate that threo-methylphenidate may
not be sufficiently potent to have significant therapeutic
effect on cocaine abusers other than those diagnosed
24. Davies, H. M. L. Eur. J. Org. Chem. 1999, 10, 2459.
25. Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hop-
per, D. W. J. Am. Chem. Soc. 2003, 125, 6462.
2
6. Davies, H. M. L.; Hansen, T.; Hopper, D. W.; Panaro,
S. A. J. Am. Chem. Soc. 1999, 121, 6509.
3ꢀ5
27. Axten, J. M.; Ivy, R.; Krim, L.; Winkler, J. D. J. Am.
Chem. Soc. 1999, 121, 6511.
with ADHD, a compound such as the threo-analogue
g, which is 15 times more potent than threo-methyl-
1
2
8. Deutsch, H. M.; Dunn, T.; Ye, X. C.; Schweri, M. M.
Med. Chem. Res. 1999, 9, 213.
phenidate will be worth further evaluation. Further-
more, the new erythro-naphthyl analogues such as 2g
and 10g–j are strongly SERT selective and merit further
study.
2
9. Bennett, B. A.; Wichems, C. H.; Hollingsworth, C. K.;
Davies, H. M. L.; Thornley, C.; Sexton, T.; Childers, S. R.
J. Pharmacol. Exp. Ther. 1995, 272, 1176.