Chiral resolution and serendipitous fluorination reaction for the selective dopamine d3 receptor antagonist BAK2-66

Article abstract of DOI:10.1021/ml500006v

The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)1H- indole-2-carboxamide ((R)-PG648) is described. The same chiral secondary alcohol intermediate was used to prepare the enantiomers of a 3-F-benzofuranyl analogue, BAK 2-66. The absolute configurations of the 3-F enantiomers were assigned from their X-ray crystal structures that confirmed retention of configuration during fluorination with N,N-diethylaminosulfur trifluoride (DAST). (R)-BAK2-66 showed higher D3R affinity and selectivity than its (S)-enantiomer; however, it had lower D3R affinity and enantioselectivity than (R)-PG648. Further, importance of the 4-atom linker length between the aryl amide and 4-phenylpiperazine was demonstrated with the 4-fluorobutyl-product (8). This article not subject to U.S. Copyright. Published 2014 by the American Chemical Society.

Full text of DOI:10.1021/ml500006v

Letter
pubs.acs.org/acsmedchemlett
Chiral Resolution and Serendipitous Fluorination Reaction for the
Selective Dopamine D3 Receptor Antagonist BAK2-66
Vivek Kumar,† Ashwini K. Banala,† Erick G. Garcia,† Jianjing Cao,† Thomas M. Keck,†
Alessandro Bonifazi,† Jeffery R. Deschamps,‡ and Amy Hauck Newman*,†
†Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural
Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States
‡Naval Research Laboratory, Code 6030, 4555 Overlook Avenue, Washington, D.C. 20375, United States
S
* Supporting Information
ABSTRACT: The improved chiral synthesis of the selective
dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-
dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)1H-indole-2-
carboxamide ((R)-PG648) is described. The same chiral
secondary alcohol intermediate was used to prepare the
enantiomers of a 3-F-benzofuranyl analogue, BAK 2-66. The
absolute configurations of the 3-F enantiomers were assigned from their X-ray crystal structures that confirmed retention of
configuration during fluorination with N,N-diethylaminosulfur trifluoride (DAST). (R)-BAK2-66 showed higher D3R affinity
and selectivity than its (S)-enantiomer; however, it had lower D3R affinity and enantioselectivity than (R)-PG648. Further,
importance of the 4-atom linker length between the aryl amide and 4-phenylpiperazine was demonstrated with the 4-fluorobutyl-
product (8).
KEYWORDS: DAST, asymmetric catalysis, enantioselectivity, dopamine
he neurotransmitter dopamine is synthesized in dop-
aminergic neurons and released to stimulate G protein-
with 15-fold higher affinity at D3Rs than its (S) enantiomer; in
contrast there was <2-fold enantioselectivity at D2R.12 The
recently reported D3R crystal structure provided the
coordinates for molecular dynamics studies that suggested an
interaction between a tyrosine residue in the seventh
transmembrane domain (Y7.43) that may have polar
interactions with the 3-OH group on the linking chain of
(R)-PG648.13 Note: (R)-PG648 was referred to as R-22
previously.12,13 Using these models and a deconstruction
strategy, the molecular determinants of both D3R-selectivity
and efficacy were derived that underscored the roles of the
primary pharmacophore (2,3-dichloropiperazine) and the
secondary pharmacophore (exemplified in (R)-PG648 by the
indolylamide function), which binds uniquely to a second
binding pocket in D3R.14 Moreover, the length and
composition of the linker between these pharmacophoric
moieties has also been determined to play a critical role in the
affinity and selectivity of these ligands.15 To further explore the
linking chain composition and determine if the 3-OH group
could be substituted with other functional groups, a highly
selective D3R antagonist (BAK2-66) was discovered.16 Note:
BAK2-66 was previously referred to as compound 8d.16
T
coupled receptors, affecting movement, cognition, and emotion.
The five known dopamine receptors (DRs) are divided into
two subfamilies, D1-like receptors (D1R and D5R) and D2-like
receptors (D2R, D3R, and D4R), on the basis of signaling
properties and sequence similarity.1 Dysfunction within the
dopamine system can lead to a variety of pathological
conditions, including Parkinson’s disease, schizophrenia,
ADHD, and drug addiction.1,2
Addictive drugs, such as the psychostimulants cocaine and
methamphetamine, enhance dopamine release in mesolimbic
pathways. The D3R subtype is expressed primarily in the
ventral striatum, particularly in the nucleus accumbens,3 regions
in which high levels of dopamine neurotransmission are
induced by drug exposure.4 D3R expression is known to be
elevated in laboratory animals and humans following exposure
to cocaine and methamphetamine.5−7 A significant effort to
target the D3R for therapeutics to treat drug abuse and other
neuropsychiatric disorders has identified templates for the
design of many high-affinity and selective D3R antagonists and
partial agonists, which have been studied in numerous animal
models of addiction.5,8−11
Because (R)- and (S)-PG648 showed enantioselectivity at
D3R, it was of interest to resolve the enantiomers of BAK2-66
and evaluate these in vitro. Furthermore, in order to complete
Extensive investigation of the 4-phenylpiperazine class of
D3R antagonists has revealed that a terminal heteroaryl amide
attached by a functionalized 4-carbon linking chain can result in
highly selective D3R antagonists that have appropriate
physicochemical properties to be used as in vivo tools.8−11
The first enantioselective D3R antagonist, (R)-PG648, was
discovered to be ∼400-fold more selective for D3R over D2R,
Received: January 6, 2014
Accepted: March 24, 2014
Published: March 24, 2014
This article not subject to U.S. Copyright.
Published 2014 by the American Chemical
Society
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ACS Medicinal Chemistry Letters
Letter
behavioral studies in rat and nonhuman primate models of
addiction, multigram quantities of enantiopure (R)- and (S)-
PG648 had to be prepared. Hence in the present study we (1)
improved the enantiopure synthesis of (R)- and (S)-PG648 for
behavioral studies, (2) used this chiral resolution to synthesize
(R)- and (S)-BAK2-66, by converting a 3-OH intermediate to
a 3-F analogue using N,N-diethylaminosulfur trifluoride
(DAST), wherein retention of stereochemistry resulted, and
(3) evaluated the enantiomeric pairs for binding affinities (Ki
values) using [3H]N-methylspiperone radioligand binding
competition in membranes prepared from HEK293 cells
expressing human dopamine D2R, D3R, and D4R (hD2R,
hD3R, and hD4R, respectively).
Scheme 1 outlines the synthetic strategy used for the chiral
intermediate (R)-4, used for both (R)-BAK2-66 and (R)-
a
Scheme 1. Synthesis of (R)-BAK2-66
Figure 1. X-ray crystal structures of (S)-4, (S)-5, and (S)-BAK2-66.
In Scheme 2, a side reaction of our synthetic strategy is
described. Fluorination of the alcohol intermediate (4) gave the
a
Scheme 2. Synthesis of Compound 8
a
Reagents and conditions: (a) potassium phthalimide, DMF, RT, 12 h;
(b) (Salen)Co(III)(OAc) complex, H2O, THF, 72 h; (c) 1-(2,3-
dichlorophenyl)piperazine, isopropanol, reflux, 12 h; (d) DAST,
CH2Cl2, −78 °C to RT, 12 h; (e) hydrazine, EtOH, reflux, 3 h; (f)
benzofuran-2-carboxylic acid, SOCl2, 3 h.
PG648. As previously described, compound (R)-3 was
synthesized by asymmetric hydrolysis of the terminal epoxide
2 using Jacobsen’s catalyst.12,17 This hydrolytic kinetic
resolution provided the terminal epoxide with ≥99% ee. (S)-
2-(Bromoethyl) oxirane ((S)-1) is commercially available, and
thus, chiral resolution to obtain (S)-3 was not required. The
rest of the synthetic strategy to obtain (S)-BAK2-66 was
identical and is not depicted. The purity and ee of both (R)-
and (S)-enantiomers of compounds 3, 5, and BAK2-66 were
determined using chiral HPLC analysis (experimental details
and HPLC spectra in Supporting Information).
Interestingly, when the alcohol intermediate 4 was converted
to its fluoro analogue 5 using DAST, no change in the
configuration at C-3 was observed, where inversion of
stereochemistry was expected.18 Typically DAST reactions
undergo an SN2 nucleophilic displacement of the OH group
with F, leading to an inversion of stereochemistry; however,
inversion was not observed. This was confirmed via extensive
HPLC and X-ray analysis of (S)-4, (S)-5, and (S)-BAK2-66
that established the absolute configuration (S) at C-14 as
shown in Figure 1. (Note: C-14 as depicted in the X-ray
structures corresponds to C3, based on IUPAC nomenclature.)
To our knowledge, there has only been one report of
stereochemistry retention in a DAST-mediated fluorination
reaction, with a double inversion mechanism suggested.19
a
Reagents and conditions: (a) DAST, CH2Cl2, −78 °C to RT, 12 h;
(b) hydrazine, EtOH, reflux, 3 h; (c) benzofuran-2-carboxylic acid,
SOCl2, 3 h.
expected intermediate 5a and an additional intermediate 5b in a
ratio of ∼2.5:1, which were separated by column chromatog-
raphy. Deprotection of 5b using hydrazine gave the free amine
7, which was reacted with benzofuran-2-carboxylic acid to
afford compound 8, a structural isomer of BAK2-66.
A proposed mechanism is shown in Figure 2 for the
retention of configuration in Scheme 1 and the formation of the
additional minor intermediate in Scheme 2, during the
fluorination reactions. We propose that an aziridinium ion
intermediate is formed via neighboring group participation to
give the resulting products.20 The liberated F− can attack the
aziridinium ion either at C-1 or C-2 to produce (S)-5 or (S)-5b
(via ( )-4), respectively. To our knowledge this is the first
time this mechanism has been suggested for a fluorination
reaction using DAST and reflects the unique juxtaposition of
the piperazine nitrogen to the 3-position −OH group to enable
ultimate retention of configuration.
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ACS Medicinal Chemistry Letters
Letter
commercially available starting material (S)-2-(bromoethyl)
oxirane to give (S)-4 (not shown) using the same procedure as
described for the (R)-enantiomer (experimental details in
Supporting Information). We have previously reported the X-
ray analysis of (S)-PG648.12
Evaluation of the analogues described herein for binding at
hD2R, hD3R, and hD4R revealed enantioselectivity similar to
previously results for (R)- and (S)-PG648, although the
absolute Ki values are not identical, due to different binding
assay conditions and radioligands used (Table 1 and
Supporting Information).12 ( )-BAK2-66 showed a similar
affinity for D3R (10 vs 5.4 nM) as previously reported, but a
significantly higher affinity for D2R than previously reported
(960 vs 9160 nM), resulting in a 96-fold selectivity for D3R
over D2R, in contrast to our previously published selectivity
ratio of >1000.16 (R)-BAK2-66 (Ki = 6.9 nM) was similarly
D3R-selective (∼115-fold) compared to its racemate (∼86-
fold). This contrasts to the more dramatic D3R enantiose-
lectivity observed with the (R)- and (S)-enantiomers of PG648
(Table 1). These data suggest that the polar interaction
between the Y7.43 residue of the D3R and the 3-OH group in
(R)-PG648 is more prominent than with the 3-F group of (R)-
BAK2-66, although enantioselectivity was retained. It must also
be noted that PG648 is an indolylamide, whereas BAK2-66 is a
benzofuranylamide. Therefore, the structure of this secondary
pharmacophore likely affects the binding pocket interactions of
these molecules.15 Of note, (R)-PG648 has ∼13-fold higher
affinity for D3R than (R)-BAK2-66; in contrast, (R)-BAK2-66
has only 3-fold lower affinity at D2R than (R)-PG648.
As noted above, a minor product (5b) with a shorter tether
was obtained in the fluorination reaction (Scheme 2).
Decreasing the length of the linking chain between the primary
pharmacophore (4-phenylpiperazine) and the secondary
pharmacophore (benzofuranylamide), from the optimum 4-
carbon linker to a 3-carbon linker, and increasing the steric bulk
on the linker with the fluoromethylene group significantly
decreased the binding affinities of compound 8 for both D3R
and D2R. This was not unexpected, as previous structure−
activity relationships (SAR) have exemplified the importance of
the 4-carbon linker length and the lack of tolerance for
functional groups that are larger than OH.12,21,22 Recently,
molecular dynamic studies demonstrated that a 3-carbon linker
prevents optimal placement of the secondary pharmacophore in
the ptm 23 subpocket of both D3R and D2R, which is likely
responsible for the lower binding affinity.15 In the D3R, the
shorter linker results in the secondary pharmacophore being
positioned away from the critical Gly94 in the EL1 loop.
In summary, we report herein an improved chiral synthesis of
(R)- and (S)-PG648, for in vivo studies, and the chiral
Figure 2. Proposed mechanism for fluorination reactions. Step 1: The
3-OH is converted to the leaving group −O−SF2−NEt2 with DAST.
Step 2: The piperazine N attacks from the backside via neighboring
group participation (SN2). Step 3: F− attacks the vulnerable
aziridinium ion intermediate at C-1 by SN2 nucleophilic displacement
resulting in double inversion with overall retention of stereochemistry.
Step 4: In the case of ( )4, nucleophilic attack by F− occurs at the C-2
giving intermediate 5b.
The synthesis of (R)-PG648, presented in Scheme 3, has
previously been reported on a small scale.12 However,
a
Scheme 3. Synthesis of (R)-PG648
a
Reagents and conditions: (a) hydazine, EtOH, reflux, 3 h; (b) indole-
2-carboxylic acid, CDI, 3 h.
modification of the original method resulted in the synthesis
of multigram quantities of this compound as the pure single
enantiomer in ≥99% ee in comparison to the earlier reported
method (>90% ee).12 (S)-PG648 was also synthesized from the
Table 1. Human D2-Like Family Receptor Subtype Binding Results
a
a
a
compd
Ki D3R (nM)
Ki D2R (nM)
D2/D3
Ki D4R (nM)
(
)-PG648
1.9 0.11
0.53 0.091
3.9 0.36
10 2.0
750 120
300 65
395
566
233
96
2600 660
4000 880
1900 490
NT
(R)-PG648
(S)-PG648
790 160
960 270
800 100
2500 790
(
)-BAK2-66
(R)-BAK2-66
(S)-BAK2-66
8
6.9 1.5
29 8.6
116
86
>9000
>14000
560 80
7400 1400
13
>3000
a
Ki values determined by competitive inhibition of [3H]N-methylpsiperone binding in membranes harvested from HEK 293 cells stably expressing
hD2R, hD3R, or hD4R. NT, not tested. Further details in the Supporting Information.
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ACS Medicinal Chemistry Letters
Letter
resolution of its analogue BAK2-66. In the DAST-mediated
fluorination reaction, retention of configuration was confirmed
by both HPLC and X-ray analysis. In addition, we report the
product of a side reaction during fluorination that yielded a
structural isomer of BAK2-66. Binding experiments at hD2R,
hD3R, and hD4R confirmed enantioselectivity at D3R for (R)-
and (S)-PG648 as well as for the enantiomers of BAK2-66.
However, less significant enantioselectivity was noted between
the (R)- and (S)-BAK2-66 pair, likely due to less pronounced
polar interactions with a Y7.43 residue previously reported to
interact with the 3-OH group of (R)-PG648.13−15 On the basis
of the previously reported off-target binding profiles for both
PG64812 and BAK2-6616 and the lower enantioselectivity for
the (R)- and (S)-enantiomers of BAK2-66, only PG648 and its
enantiomers have been selected for further evaluation in vivo
and will be reported in due course. The present findings serve
to extend SAR in the 4-phenylpiperazine class of D3R ligands,
especially highlighting the critical role of the length and
functionalization of the linker between the primary and
secondary pharmacophores in producing high D3R affinity
and favorable D2R-like subtype selectivity of these compounds.
We also highlight serendipitous reactions with DAST, likely via
neighboring group participation to form an aziridinium
intermediate with the piperazine N, that led to the final
products described.
ABBREVIATIONS
■
SAR, structure−activity relationship; CDI, 1,1′-carbonyldiimi-
dazole; DAST, N,N-diethylaminosulfur trifluoride; D2R,
dopamine D2 receptor; D3R, dopamine D3 receptor; D4R,
dopamine D4 receptor; ee, enantiomeric excess; RT, room
temperature; PTSA, para-toluenesulfonic acid; EL, extracellular
loop; ptm 23, pocket between the second and third
transmembrane segments
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details for the synthesis and purification and the
in vitro pharmacological characterizations of the compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*(A.H.N.) Tel: +1-443-740-2887. Fax: +1-443-740-2111. E-
mail: anewman@intra.nida.nih.gov.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
This research was funded by the NIDA Intramural Research
Program, National Institutes of Health, Department of Health
and Human Services. V.K. was supported by an NIH Visiting
Fellowship, and T.M.K. was supported by an NIH Postdoctoral
Intramural Research Training Award (IRTA) Fellowship. The
X-ray crystallographic studies were supported by NIDA
through Interagency Agreement #Y1-DA1101 with the Naval
Research Laboratory (NRL).
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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HEK cells expressing hD2R, hD3R, or hD4R were provided by
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