Synthesis of novel spirocyclic cocaine analogs using the Suzuki coupling

Article abstract of DOI:10.1016/S0040-4039(00)00113-1

Novel spirocyclic cocaine analogs were synthesized by employing the Suzuki coupling of ortho-substituted arylboronic acids and an enol triflate derived from cocaine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00113-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2055–2058
Synthesis of novel spirocyclic cocaine analogs using the Suzuki
coupling
Sukumar Sakamuri,a Clifford George,b Judith Flippen-Anderson b and Alan P. Kozikowski a,∗
aDrug Discovery Program, Institute for Cognitive and Computational Sciences, Georgetown University Medical Center,
3900 Reservoir Road N.W., Washington, DC 20007-2197, USA
bLaboratory for the Structure of Matter, Naval Research Laboratory, 4555 Overlook Ave, SW, Washington, DC 20375-5341,
USA
Received 30 November 1999; accepted 5 January 2000
Abstract
Novel spirocyclic cocaine analogs were synthesized by employing the Suzuki coupling of ortho-substituted
arylboronic acids and an enol triflate derived from cocaine. © 2000 Elsevier Science Ltd. All rights reserved.
Cocaine (1) is a major drug of abuse whose devastating effects have captured the attention of health
officials and policy makers. Its reinforcing and stimulant properties have been associated with its ability
to bind to monoamine transporter systems, particularly the dopamine transporter (DAT).1 A number of
highly potent cocaine analogs together with information concerning their structure–activity relationships
(SAR) at the DAT have been reported.2 However, the precise details of the binding interactions between
these analogs and the DAT are still a matter of much discussion.2–4
Previously it has been shown that replacement of the C-3 benzoate by phenyl leads to higher potency
cocaine analogs referred to as the ‘WIN series’. With respect to the 3-position of these WIN analogs,
SAR studies have focused primarily on the steric and electronic effects of substituents located at the
para position of the phenyl ring, replacement of the phenyl group by other aromatic moieties, and
additionally on the orientation (α versus β) of the aryl substituent.3a,4 In continuation of our efforts
to identify ligands of possible use in the treatment of cocaine abuse, we chose to explore the effects
of rigidifying the orientation of the 3-aryl substituent by making it part of a spirocyclic system with or
∗
Corresponding author. E-mail: kozikowa@giccs.georgetown.edu (A. P. Kozikowski)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00113-1
tetl 16393

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without a heteroatom. To our knowledge, the synthesis of such spiro compounds has not been reported
previously.
The synthetic route employed in the present study (Scheme 1) exploits the Pd-catalyzed Suzuki
coupling of ortho-substituted arylboronic acids and an enol triflate prepared from cocaine, and the
subsequent formation of the spiro compound using a radical cyclization or intramolecular Michael addi-
tion. The synthesis commences with the preparation of (R)-2-(methoxycarbonyl)-3-tropinone from (−)-
cocaine by benzoate hydrolysis5 followed by Swern oxidation of the resulting alcohol. The ketone was
then converted to the enol triflate 2 in 75% yield by reaction with N-phenyltrifluoromethanesulfonimide
and sodium bis(trimethylsilyl)amide in THF as previously described by Carroll et al.6 The enol triflate
2 was then coupled with the arylboronic acid 3 (prepared by treatment of the aryl bromide with n-BuLi
and triisopropyl borate in THF, followed by hydrolysis of the resulting alkoxyborane with 1N HCl)
using Suzuki’s method.7 The reaction of ortho-substituted arylboronic acids with enol triflates proved
troublesome in some cases and the low yields of these reactions can be attributed to the steric hindrance
exerted by the ortho-substituent.7 After careful experimentation with the known literature variants of the
Suzuki coupling, we found that treatment of arylboronic acid 3 with the enol triflate 2 in diethoxymethane
in the presence of lithium bromide, tris(dibenzylideneacetone)dipalladium(0) catalyst, and 2M aqueous
sodium carbonate under reflux conditions followed by chromatographic purification gave the desired
product 4 in 72% yield.6
Scheme 1. Reagents and conditions: (a) Pd2dba3, LiBr, aq. Na2CO3, diethoxymethane, reflux; (b) TBAF, THF, rt; (c) PPh3,
CBr4, CH2Cl2, rt; (d) AlBN, Bu3SnH, benzene, 80°C
The t-butyldiphenylsilyl group was removed using n-Bu4NF in THF at room temperature to give
the alcohol 5 in 81% yield. The alcohol was converted to the bromo compound 6 by reaction with
triphenylphosphine and carbon tetrabromide in CH2Cl2 at room temperature in 87% yield. The radical
cyclization was carried out in 74% yield with an excess of tributyltin hydride and an equimolar amount
of AIBN in benzene at 80°C using a syringe pump for slow addition. Two isomers 7 and 8 were formed
in a 3:2 ratio, and these were separated by careful flash chromatography.8 The orientation of the ester
group was established by X-ray analysis (Fig. 1)9 as α in both compounds, a consequence of trapping
the radical formed after the cyclization step from the sterically less hindered exo face of the tropane ring.
The C-3 spirocyclic cocaine analog containing sulfur as a heteroatom was synthesized as described
in Scheme 2. Suzuki coupling of the enol triflate 2 with the boronic acid 9 gave compound 10 in 82%
yield. The oxidation of the sulfide 10 was carried out using Oxone® in a 2:1 mixture of MeOH and H2O
at room temperature for 4 h to give the sulfone 11 in 91% yield.10 The presence of the sulfone function

2057
Fig. 1. ORTEP drawings of compounds 7, 8, 12 and 13
was confirmed by a strong IR absorption at 1310 cm−1. Sulfone 11 was subjected to an intramolecular
Michael addition by employing LDA as a base at −78°C for 2 h, then quenching with aq. NH4Cl solution
at the same temperature to obtain a 3:1 mixture of two spiro sulfones 12 and 13 in 72% yield. X-Ray
crystal structure analysis demonstrated again that the C-2 ester groups possess the α-orientation in both
products (Fig. 1).9 Reduction of sulfones 12 and 13 to sulfides 14 and 158 was carried out with SmI2 in
THF/HMPA at 65°C in good yield.11
Scheme 2. Reagents and conditions: (e) Pd2dba3, LiBr, aq. Na2CO3, diethoxymethane, reflux; (f) Oxone®, MeOH/H2O, rt; (g)
LDA, THF, −78°C; (h) SmI2, THF, HMPA, 65°C
In conclusion, the synthesis of a novel class of spirocyclic cocaine analogs has been accomplished
by means of the Suzuki coupling in combination with a radical cyclization or intramolecular Michael
addition. To our surprise, pharmacological studies show that compound 8 has reasonable potency at the
NET (Ki=143±29 nM) while it is relatively inactive at the DAT (Ki=2.09±0.38 µM).12 Some of the
present compounds are being investigated for their effects in animal behavioral models, and these results
will be reported elsewhere.

2058
Acknowledgements
We are indebted to NIH/NIDA for support of this work (DA10458).
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8. Compound 7: 1H NMR (CDCl3, 300 MHz) δ 7.33 (d, J=7.3 Hz, 1H), 7.25–7.15 (m, 3H), 3.46–3.34 (m, 5H), 3.25 (narrow
m, 1H), 3.00–2.76 (m, 2H), 2.42–2.20 (m, 5H), 2.17–2.07 (m, 2H), 1.98–1.88 (m, 1H), 1.80–1.71 (m, 3H). Compound 8: 1H
NMR (CDCl3, 300 MHz) δ 7.37 (d, J=5.9 Hz, 1H), 7.19–7.09 (m, 3H), 3.47 (t, J=4.7 Hz, 1H), 3.33 (s, 3H), 3.31 (d, J=3.9
Hz, 1H), 3.21 (narrow m, 1H), 2.92–2.71 (m, 3H), 2.68–2.58 (m, 1H), 2.41 (s, 3H), 2.34–2.18 (m, 2H), 2.11–1.99 (m, 2H),
1.88 (dd, J=1.7 Hz, 13.9 Hz, 1H), 1.82–1.72 (m, 1H). Compound 14: 1H NMR (CDCl3, 300 MHz) δ 7.40 (dd, J=2.4 Hz, 6.1
Hz, 1H), 7.16–7.08 (m, 3H), 3.68 (d, J=11.4 Hz, 1H), 3.49–3.40 (m, 6H), 3.28–3.20 (m, 1H), 2.40 (s, 3H), 2.33–2.13 (m,
4H), 2.07–1.98 (m, 1H), 1.92–1.89 (m, 1H). Compound 15: 1H NMR (CDCl3, 300 MHz) δ 7.40–7.32 (m, 1H), 7.16–7.08
(m, 3H), 3.66 (d, J=11.5 Hz, 1H), 3.58–3.41 (m, 6H), 3.35 (narrow m, 1H), 2.46 (s, 3H), 2.38 (narrow m, 1H), 2.26–2.14
(m, 3H), 1.96–1.63 (m, 2H).
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12. We thank Dr. Kenneth M. Johnson for providing the uptake data.