Radical cyclization strategies for the formation of ring constrained tricyclic tropane analogues

Article abstract of DOI:10.1016/S0040-4039(00)01288-0

A concise and efficient method for the construction of N,C3-constrained tropane derivatives has been developed. The key step of the reaction sequence involves either a 6- or a 7-trig radical cyclization. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01288-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7427–7432
Radical cyclization strategies for the formation of ring
constrained tricyclic tropane analogues
a
b
b
Alexander Hoepping, Clifford George, Judith Flippen-Anderson and
a,
Alan P. Kozikowski *
a
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center,
3
900 Reservoir Road, NW, Washington, DC 20007-2197, USA
b
Laboratory for the Structure of Matter, Code 6030, Naval Research Laboratory, 4555 Overlook Ave., SW,
Washington, DC 20375-5000, USA
Received 13 June 2000; accepted 30 June 2000
Abstract
A concise and efficient method for the construction of N,C3-constrained tropane derivatives has been
developed. The key step of the reaction sequence involves either a 6- or a 7-trig radical cyclization.
©
2000 Published by Elsevier Science Ltd.
It is well known that cocaine not only displays strong anesthetic effects, but that is also a
strong reinforcing drug that leads to addiction. According to the dopamine theory of addiction,
cocaine is believed to elicit its behavioral and pharmacological effects primarily by binding to
the dopamine transporter (DAT), thereby elevating extracellular dopamine levels in some areas
1
,2
in the midbrain. Cocaine also binds with high affinity to the serotonin (SERT) and nore-
3
pinephrine transporters (NET). We have postulated that drugs lacking the ability to inhibit
transport at all three monoamine transporters may exhibit only partial cocaine-like properties,
4
–6
and thus possibly serve as medications. Recently we demonstrated that it is possible to tune
the selectivity of aryl-substituted tropanes for the SERT or the NET by introduction of a ring
6
constraint between the nitrogen atom and carbon 3 of the tropane ring. However, as we have
shown, not only is the ring constraint an important feature for binding and selectivity, but
additionally the phenyl substituent at the terminus of the alkylidene group contributes to the
activity and selectivity as well. Thus compounds with high activity for either the SERT or the
NET, or both have been obtained (Fig. 1).
*
Corresponding author. E-mail: kozikowa@giccs.georgetown.edu
0
040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01288-0

7428
Figure 1.
Our present aim was to further investigate the role of the additional carbon bridge and the
influence of the phenyl substituent on binding activity and transporter selectivity. A compound
lacking the phenyl substituent should substantiate the requirement for this structural feature,
while compounds with either two phenyl substituents or one containing a phenyl ring con-
strained by incorporating it into the bridge would be useful in further elucidating the steric and
geometric requirements for transporter binding and selectivity. In this letter we describe
cyclization strategies that provide access to tropanes bearing these substituents or that have been
rigidified through an aryl ring. This chemistry allows for a more comprehensive SAR, and hence
provides further insights into the design of selective monoamine reuptake inhibitors.
Radical cyclization reactions have become a very powerful tool in organic synthesis, in
7,8
particular in carbonꢀcarbon bond forming reactions that lead to constrained compounds.
Thus we envisioned a synthesis strategy that involves a radical mediated ring closure as a key
step. Our approach to the synthesis of the constrained tropanes is illustrated in Scheme 1. This
chemistry is based on the 6- or 7-trig radical cyclization of an intermediate vinyl or aryl radical,
generated by tri-n-butyltin hydride mediated carbonꢀhalogen bond cleavage, followed by
addition to the activated double bond in anhydroecgonine methyl ester.
Scheme 1. E=COOMe
The synthetic pathway started with cocaine (1), which was converted to anhydroecgonine
9
methyl ester by acid hydrolysis, dehydration, and reesterification. Demethylation with a-
10
chloroethyl chloroformate afforded noranhydroecgonine methyl ester (2). The secondary
amino group was in turn alkylated with a variety of substituents required for the radical
cyclization step (Scheme 2).

7429
Scheme 2. Reagents and conditions: (i) 1N HCl, reflux, 16 h; (ii) POCl , reflux, 4 h; (iii) MeOH, −40°C ꢀ rt, 20 min;
3
(
iv) CH CH(Cl)OCOCl, 1,2-dichloroethane, K CO ; MeOH, 92%; (v) K CO , RBr, DMF, 77–85%; a, R=2-bromo-
3 2 3 2 3
propenyl; b, R=2-bromobenzyl; c, R=2-bromo-1,1-diphenylprop-1-enyl; d, R=propargyl
As our previously published series of compounds bears an aryl substituent at the terminus of
6
the alkylidene group (Fig. 1), we wished to probe the role of this aryl group by preparing
compound 4a which lacks this substituent as noted above. Thus, N-(2-bromo-
propenyl)noranhydroecgonine methyl ester (3a) was cyclized using tributyltin hydride and AIBN
to afford a 1:1 mixture of diastereoisomers which we were unable to separate under various
chromatographic conditions. However, one epimer could be enriched by basic epimerization in
methanol (Scheme 3).
Scheme 3. Reagents and conditions: (i) n-Bu SnH, AIBN, benzene, reflux; (ii) NaOMe, MeOH, reflux; (iii) TFA, CH Cl
2
3
2
To confirm the structure of the major diastereoisomer, we prepared compound 4a according
6
to our previously published vinylstannane route. This route utilizes the cyclization of a
propargyl substituent which is converted into a stannylvinyl radical under the cyclization
conditions. A Z/E mixture of the tricyclic vinylstannanes 5 and 6 with the ester group in the
b-orientation was obtained in about 75% combined yield. Subsequent protodestannylation of
this mixture was carried out to furnish diastereoisomerically pure 4a. The reported procedure for
protodestannylation that makes use of dry silica gel in dichloromethane proved to be ineffi-
1
1
cient. However, the use of trifluoroacetic acid in dichloromethane led to the pure product in
about 80% yield in 12 hours. Comparison of the NMR spectra and the optical rotation of the
sample obtained in this way with that obtained using the epimerization protocol proved that the
diastereoisomer 4a, bearing the b-oriented ester, was the major diastereomer after epimerization.
With compound 4a in hand and with the effect of compounds with one terminal aryl
substituent already investigated, an interesting question was how a second phenyl substituent at
the double bond terminus would influence the biological activity (Scheme 4).

7430
Scheme 4. Reagents and conditions: (i) n-Bu SnH, AIBN, benzene, reflux
3
The requisite starting material, N-(2-bromo-3,3-diphenylprop-2-enyl)anhydroecgonine methyl
ester (3c) was obtained by alkylation of 2 with 2,3-dibromo-1,1-diphenylpropene which in turn
12,13
was prepared following an established literature procedure.
Radical cyclization mediated by
n-Bu SnH/AIBN furnished a variable mixture of diastereoisomers (b/a 4:1–6:1) in about 30%
3
yield which we were unable to separate by standard chromatographic methods. The enhanced
diastereoselectivity in comparison to the cyclization employing an unsubstituted vinyl radical is
a consequence of the enhanced steric demand exerted by the voluminous substituent.
Finally, we reasoned that it would be of interest to investigate the activity of a benzoannelated
tricyclic tropane system. In this system the phenyl ring is constrained by annelation with the
newly formed bridge and adopts a position perpendicular to the basal plane of the tropane
nucleus.
The orientation of this phenyl ring together with the strong restriction of conformational
freedom was postulated to lead to enhanced selectivity at the monoamine reuptake sites. For the
construction of the ring system we had to make use of a 7-trig radical cyclization. The formation
14
of 7-membered rings through radical cyclization is usually difficult. However, the radical
stabilizing effect of the ester group in 3d was anticipated to work in favor of the desired
regiochemistry. In the event, simple refluxing of the reactants in benzene or toluene resulted only
in the radical-mediated reduction of the aryl bromide. Only when tributyltin hydride and AIBN
were added under kinetic conditions using a syringe pump, was the desired product obtained in
3
3% yield. Tris(trimethylsilyl)silane, a less reactive radical chain mediator, gave the same
product but only in 4% yield (Scheme 5).
Scheme 5. Reagents and conditions: (i) n-Bu SnH, AIBN, benzene, reflux
3
By virtue of the bulky nature of the newly formed bridge, the final hydride delivery step leads
predominantly to the product possessing a b-oriented ester group (b/a=9:1). By crystallization
with (−)-camphorsulfonic acid we were able to obtain crystals of the major diastereoisomer
15
suitable for X-ray crystallography which confirmed the structure of this compound (Fig. 2).

7431
Figure 2. ORTEP drawing of the (−)-camphorsulfonate of 8a (anion omitted). The figure is drawn from the
experimentally determined coordinates with thermal parameters at the 20% probability level
In summary, we have developed a concise route to novel tricyclic tropanes based on radical
1
6
cyclization technology. The syntheses feature a 6-trig radical ring closure of a vinyl radical and
a 7-trig ring closure of an aryl radical. The biological testing of the described compounds and
the application of this method to the preparation of other modified tropanes with the aim of
probing the SAR for the inhibition of monoamine reuptake are underway.
Acknowledgements
We are indebted to NIH/NIDA for support of this work (DA10458).
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5. Atomic coordinates for 8a have been deposited with the Cambridge Crystallographic Data Base, 12 Union Road,
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1
6. Compound 4a: H NMR (CDCl , 300 MHz) l 1.46 (m, 3H), 1.99 (ddd, J=2.7, 9.6, 22.8 Hz, 1H), 2.13 (m, 2H),
3
2
.34 (t, J=3.3 Hz, 1H), 2.62 (dd, J=6.1, 3.4 Hz, 1H), 3.26 (m, 1H), 3.28–3.66 (m, 2H), 3.66 (s, 3H), 4.68 (m, 1H),
1
4
.72 (m, 1H). 7: H NMR (CDCl , 300 MHz) l 1.46 (m, 3H), 2.18 (m, 3H), 2.26 (t, J=2.7 Hz, 1H), 2.93 (dd,
3
J=6.1, 3.6 Hz, 1H), 3.18 (m, 1H, minor isomer) 3.27 (m, 1H), 3.44 (A part of ABq, J=18.3 Hz, 1H), 3.54 (s,
1
3
H), 3.55 (s, 3H, minor isomer), 3.77 (m, 1H), 3.97 (B part of ABq, J=18.3 Hz, 1H), 7.0–7.4 (m, 10H). 8a: H
NMR (CDCl , 300 MHz) l 1.53 (m, 2H), 1.86 (ddd, J=14.2, 7.1, 1.8 Hz, 1H), 2.13 (m, 2H), 2.42 (dd, J=14.4,
3
8
.9 Hz, 1H), 2.78 (dd, J=6.5, 2.2 Hz, 1H) 3.09 (t, J=6.6 Hz, 1H), 3.38 (s, 3H), 3.61 (m, 1H), 4.12 (m, 1H), 4.48
and 4.69 (ABq, J=18.1 Hz, 2H), 6.9–7.1 (m, 4H).
.