Synthesis of 2-alkyl-3-aryl-substituted quinuclidines as novel dopamine transporter inhibitors

Article abstract of DOI:10.1016/S0040-4039(00)01810-4

The synthesis of 2-alkyl-3-aryl-substituted quinuclidines was accomplished in a simple synthetic sequence. The separation of enantiomers was carried out using chiral HPLC. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01810-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9949–9952
Synthesis of 2-alkyl-3-aryl-substituted quinuclidines as novel
dopamine transporter inhibitors
Sukumar Sakamuri,†,‡ Istvan J. Enyedy,†,§,ꢀꢀ Alan P. Kozikowski†,‡ and Shaomeng Wang†,§,ꢀꢀ
Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, DC 20007-2197, USA
Received 10 August 2000; accepted 15 September 2000
*
Abstract
The synthesis of 2-alkyl-3-aryl-substituted quinuclidines was accomplished in a simple synthetic
sequence. The separation of enantiomers was carried out using chiral HPLC. © 2000 Elsevier Science Ltd.
All rights reserved.
Cocaine abuse remains a serious health and social problem in the United States and
worldwide, with an estimated 1.5 million cocaine users in the United States alone. As a
consequence, it is obvious that immediate strategies are needed for the treatment of cocaine
addiction to combat the destructive effects of this reinforcing drug on individuals and on society
at large. The reinforcing and stimulant properties of cocaine have been associated with its ability
to bind to monoamine transporter systems, particularly the dopamine transporter (DAT).1 To
date, most structure–activity studies of DAT inhibitors have been focused on a limited number
of compounds, including cocaine/tropane analogs, GBR compounds, methylphenidate analogs,
mazindol analogs, and piperidine analogs.2 In view of the urgency and complexity of the
development of an effective cocaine therapy, we believe that the discovery of DAT inhibitors
that have truly novel chemical scaffolds may have considerable value. Lead compounds with
novel chemical scaffolds will provide new chemical insights into DAT inhibitor design. DAT
inhibitors with novel chemical scaffolds may also have pharmacological and behavioral profiles
different from known DAT inhibitors.
R1
Me
Me
N
N
R2
COOMe
COOMe
3
3
2
O
Ph
N
R
2
O
(±)
Quinuclidine (3)
Me
(R)-(-)-Cocaine (1)
WIN series (2)
* Corresponding author. Tel: (202) 687-2028; fax: (202) 687-0617; e-mail: wangs@giccs.georgetown.edu
†
§
ꢀꢀ
Drug Discovery Program; ‡Department of Neurology; Department of Oncology; Department of Neuroscience.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01810-4

9950
Previously, we have reported the discovery of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-pipe-
ridyl 4-methylphenyl ketones as a novel class of dopamine transporter inhibitors through
3D-database pharmacophore searching.3 In continuation of our efforts to identify ligands of
possible use in the treatment of cocaine abuse, we discovered quinuclidines as another novel
class of dopamine transporter inhibitors employing the same method.4 With the aid of molecular
modeling based on the structure activity relationships (SAR) of the ‘WIN series’, we predicted
that alkyl substitution at C2 and aryl substitution at C3 of such quinuclidines should yield new
analogs as potent DAT inhibitors (Fig. 1). An extensive literature search revealed that no
synthetic method has been reported to prepare compounds of general structure 3, i.e. C2-alkyl-
and C3-aryl-substituted quinuclidines. Herein, we report a simple route for the synthesis of
compound 3.
Figure 1. Superposition of the lowest energy conformations of compound 2 (yellow) and quinuclidine ( )-3b (green)
Thus, starting from 3-quinuclidinone (4), 2-methylene-3-quinuclidinone (5) was prepared by a
Mannich reaction (Scheme 1).5 Our earlier attempts to directly alkylate 3-quinuclidinone (4)
under various reaction conditions using different bases like LDA, NaHMDS and NaNH2 with
1-iodopropane or allyl bromide proved unsuccessful. Reaction of 4 with aq. dimethylamine and
aq. formaldehyde in an ethanol/water mixture at 70°C gave the Mannich base, which on
distillation gave compound 5 in 86% yield. Reaction of 5 with allylmagnesium bromide in the
presence of CuI·Me2S and Me3SiCl at −78°C furnished the conjugate addition product 6 in 47%
yield along with the 1,2-addition product 7 in 12% yield, which were isolated by column
chromatography. Addition of arylmagnesium bromide to compound 6 was carried out in THF
at 0°C to give compounds 8, 9 or 10, which were subsequently treated with a 1:1 mixture of

9951
EtOH and 6N HCl under reflux conditions to give the dehydrated compounds 11, 12 or 13,
respectively. Reduction of the double bonds was carried out using standard hydrogenation
conditions (60 psi H2, Pd/C, EtOH) to provide compounds 3a, 3b and 3c in near quantitative
yields.6
OH
1. Me2NH, HCHO
EtOH/H2O, reflux
MgBr
O
O
O
+
N
N
N
N
2. vacuum distillation
86%
CuI•Me2S, HMPA
TMS-Cl, ether
-78 °C
CH2
7 (12%)
CH2
6 (47%)
4
5
R1
R1
R2
R2
60 psi H2, Pd/C
ArMgBr
THF, 0 °C
6N HCl, EtOH
reflux
N
6
N
OH
EtOH, (quantitative)
8 R1 = R2 = H (70%)
9 R1 = H, R2 = Me (74%)
10 R1 = R2 = Me (68%)
11 R1 = R2 = H (61%)
12 R1 = H, R2 = Me (66%)
13 R1 = R2 = Me (64%)
R1
R2
Chiral HPLC
separation
(-)-3b
(+)-3b
+
N
Me
(±)
R1 = H, R2 = Me
R1 = H, R2 = Me
3a R1 = R2 = H
3b R1 = H, R2 = Me
3c R1 = R2 = Me
Scheme 1.
The hydrogen addition took place with syn stereochemistry as expected, and the structure of
compound ( )-3b was confirmed by X-ray crystallography. The enantiomers (+)-3b and (−)-3b
were separated on a 250×10 mm Chirex 3018 HPLC column, in which the chiral stationary
phase (CPS) consists of (S)-proline covalently bound to g-aminopropyl silinized silica gel (5 mm
particle size) and derivatized via an urea linkage with (R)-1-(a-naphthyl)ethylamine.7 The optical
rotation of (+)-3b (tR=19.5 min) was found to be [h]D=+104 (c 0.5, acetone) and that of (−)-3b
(tR=23.0 min) was [h]D=−104 (c 0.5, acetone).
In summary, the synthesis and chiral separation of a novel class of 2-alkyl-3-aryl-substituted
quinuclidines has been accomplished in a five step sequence. This synthesis will provide access
to a new class of dopamine transporter inhibitors which may be useful in the development of
medications for the treatment of cocaine abuse. Preliminary biological testing showed that some
of these compounds are potent DAT inhibitors, thus confirming our design strategy. The details
of this work will be reported elsewhere.4

9952
Acknowledgements
We are indebted to the National Institute on Drug Abuse (NIDA), National Institute of
Health for their financial support of this work (DA-11545).
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1
6. (a) Compound 3a: H NMR (300 MHz, CDCl3) l 0.79 (3H, t, J=6.8 Hz), 1.07–1.36 (6H, m), 1.45–1.56 (1H, m),
1.70–1.76 (2H, m), 2.01–2.12 (2H, m), 2.67–2.78 (1H, m), 2.96–3.29 (5H, m), 7.19–7.34 (5H, m); 13C NMR
(CDCl3) l 14.0, 22.3, 22.7, 26.8, 29.7, 30.2, 30.3, 40.7, 45.4, 49.4, 60.2, 125.5, 127.8, 128.9, 142.9; MS m/z (%) 243
1
(25), 42 (100); compound 3b: H NMR (300 MHz, CDCl3) l 0.77 (3H, t, J=6.8 Hz), 1.02–1.32 (6H, m), 1.40–1.49
(1H, m), 1.65–1.72 (2H, m), 1.96–2.06 (2H, m), 2.32 (3H, s), 2.64–2.74 (1H, m), 2.89–3.00 (1H, m), 3.05–3.23 (4H,
m), 7.06–7.14 (4H, m); 13C NMR (CDCl3) l 14.2, 21.1, 22.5, 22.9, 27.2, 29.9, 30.4, 30.6, 40.9, 45.3, 49.7, 60.4,
1
128.8, 129.0, 135.1, 140.0; MS m/z (%) 257 (29), 42 (100); compound 3c: H NMR (300 MHz, CDCl3) l 0.78 (3H,
t, J=6.9 Hz), 1.07–1.33 (6H, m), 1.41–1.49 (1H, m), 1.64–1.70 (2H, m), 2.00–2.08 (2H, m), 2.24 (3H, s), 2.52 (3H,
s), 2.64–2.74 (1H, m), 2.90–3.23 (5H, m), 6.99–7.06 (3H, m); 13C NMR (CDCl3) l 14.3, 19.4, 20.1, 22.5, 22.9, 27.3,
29.9, 30.4, 30.6, 41.0, 45.4, 49.7, 60.4, 126.4, 129.3, 130.7, 133.8, 136.1, 140.5; MS m/z (%) 271 (36), 42 (100). (b)
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.
.