Diaminoimidazopyrimidines: Access via the Groebke–Blackburn–Bienaymé Reaction and Structural Data Mining

Article abstract of DOI:10.1002/ejoc.202000933

Imidazopyrimidines with diverse substitution patterns are a prime class of heterocycles, present in many commercially available or late-stage clinical trials drugs. Here, we describe a fast access to diaminoimidazopyrimidines by means of a powerful multicomponent reaction; the Groebke–Blackburn–Bienaymé reaction. We provide the design of such libraries of compounds, identifying all the structural motifs, and subsequently their synthesis. Scope and limitations are discussed, in addition to data mining in the Cambridge Structural Database and pharmacophore search with Crossminer. The presented approach highlights the vast amount of data available in the databases and provides potential future scaffold hopping alternatives for compounds with similar binding patterns. Further studies are ongoing to introduce more “drug-like” properties into this scaffold and to investigate cellular mechanism-based anti-cancer behaviours.

Full text of DOI:10.1002/ejoc.202000933

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Diaminoimidazopyrimidines: Access via the Groebke – Blackburn
–
Bienaymé reaction and structural data mining
Authors: Markella Konstantinidou, Zlata Boiarska, Roberto Butera,
Constantinos G. Neochoritis, Katarzyna Kurpiewska, Justyna
Kalinowska-Tłuscik, and Alexander Doemling
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000933
Link to VoR: https://doi.org/10.1002/ejoc.202000933
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000933
COMMUNICATION
Diaminoimidazopyrimidines: Access via the Groebke – Blackburn
Bienaymé reaction and structural data mining
–
[a]
[a]
[a]
[b]
Markella Konstantinidou, Zlata Boiarska, Roberto Butera, Constantinos G. Neochoritis, Katarzyna
[c]
[c]
[a]
Kurpiewska, Justyna Kalinowska-Tłuscik, and Alexander Dömling*
[a]
Dr. M. Konstantinidou, Z. Boiarska, R. Butera,Prof. A. Dömling
Department of Pharmacy
Group of Drug Design
Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands
E-mail: a.s.s.domling@rug.nl, homepage http://www.drugdesign.nl/
Ass. Prof. C.G. Neochoritis
Department of Chemistry
University of Crete
[
[
b]
c]
70013, Heraklion, Greece
Dr.K. Kurpiewska, Dr. J. Kalinowska-Tłuscik
Department of Crystal Chemistry and Crystal Physics
Faculty of Pharmacy
Jagiellonian University, ul. Gronostajowa 2
30-387, Krakow, Poland
Supporting information for this article is given via a link at the end of the document.
Abstract: Imidazopyrimidines with diverse substitution patterns are
more diversity and functional groups on the flat fused bis-
heterocyclic ring system.1
2–14
As a result, certain potential ligand-
a
prime class of heterocycles, present in many commercially
available or late-stage clinical trials drugs. Here, we describe a fast
access to diaminoimidazopyrimidines by means of powerful
protein binding interactions can be incorporated in the design of
the GBB reaction, including hydrogen bonds, electrostatic
interactions, as well as hydrophobic interactions.
a
multicomponent reaction; the Groebke-Blackburn-Bienaymé reaction.
We provide the design of such libraries of compounds, identifying all
the structural motifs, and subsequently their synthesis. Scope and
limitations are discussed, in addition to data mining in the Cambridge
Structural Database and pharmacophore search with Crossminer.
The presented approach highlights the vast amount of data available
in the databases and provides potential future scaffold hopping
alternatives for compounds with similar binding patterns. Further
studies are ongoing to introduce more ‘drug-like’ properties into this
scaffold and to investigate cellular mechanism-based anti-cancer
behaviours.
In medicinal chemistry, one of the most explored targets with
clear structural understanding are kinases.15 Type I - active site
kinase inhibitors bear the characteristic binding motif of a
hydrogen bond donor in close proximity to a hydrogen bond
acceptor. This common motif can be observed for instance in
dabrafenib (a reversible ATP-competitive kinase inhibitor
1
6
targeting the BRAF, PDB ID 5CSW), lorlatinib (a macrocylic
17
kinase inhibitor targeting ALK, PDB ID 5A9U),
an
18
aminopyridine inhibitor targeting GLK kinase (PDB ID 5J5T)
and ibrutinib (a covalent inhibitor of Bruton’s tyrosine kinase,
PDB ID 5P9J).19 A similar motif of hydrogen bond donor in
adjacent position to a hydrogen bond acceptor is also observed
in ganciclovir (a guanine analogue targeting thymidine kinase,
PDB ID 1KI2)20 and trimethoprim (an antifolate antibacterial
inhibiting bacterial dihydrofolate reductase, PDB ID 1DG5)21
(Figure 1). We are very interested to access the binding motifs
of those marketed drugs (the specific combination of hydrogen
bond donors-hydrogen bond acceptors in a relatively flat system,
figure 1), utilizing suitably substituted aminopyrimidines as
starting materials in a GBB reaction.
Multicomponent reactions (MCR) combining at least three
starting materials in
a single reaction step are powerful
convergent chemical transformations to access complex
1–4
scaffolds.
Among the many advantages are the diversity of
building blocks that can be utilized and the functional group
tolerance allowing for plenty of post-MCR modifications.5,6 One
of the youngest MCR reactions, the three component Groebke-
Blackburn-Bienaymé reaction (GBB-3CR) was first described in
7
–9
1998
and a detailed overview of the chemistry, as well as
1
0
applications of the GBB reaction was recently published. The
GBB reaction, typically occurring between an aldehyde, an
isocyanide and 2-aminopyridine, leads to fused imidazo[1,2-
a]pyridines, a privileged scaffold,11 present in many commercial
and clinical trials drugs, such as the zolpidem, miroprofen,
minondronic acid and olprinone. It is noteworthy, that the choice
of the starting materials in GBB reactions, in particular the
aminopyridine component variation can be used to introduce
1
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European Journal of Organic Chemistry
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Figure 1. The common binding motif of H-B donor (blue) and H-B acceptor (red) on heterocyclic ring systems in marketed drugs and in a cocrystal structure of
GLK kinase with aminopyridine inhibitor (PDB ID 5J5T).
Therefore, we wish to explore the scope and limitations of
accessing polysubstituted aminopyrimidines and in particular
diaminoimidazopyrimidines via the GBB-3CR. Despite the
usefulness of this MCR reaction in providing in a single step
drug-like heterocycles, diaminoimidazopyrimidines have not
been previously thoroughly studied. One exception includes the
work of LaVilla et al.22 where the 2,4-diaminopyrimidine 1 is
used without protection in a GBB-3CR, leading selectively to the
partially dearomatize the imidazopyrimidine ring. For that
reason, 2,4-dimethoxybenzylamine appeared as an attractive
alternative.
substituted imidazo[1,2-a]pyrimidin-7-amine derivatives
2
(
Scheme 1). That work served as inspiration for us since the use
of this diamine 1 could potentially lead also to the scaffold of
imidazo[1,2-c]pyrimidin-5-amine 3, which is our targeted scaffold
(
Scheme 1). This scaffold which is comprised of a flat
substituted 2-aminopyrimidine ring fused with a substituted
imidazole ring with distinct hydrogen donors (blue) and
acceptors (red) bears exactly the desired hydrogen donor-
acceptor structural motif (Figure 1). Moreover, the two
possibilities of an intramolecular hydrogen bond (the 5-amino
group could serve both as hydrogen bond acceptor and donor),
in a pseudo peri position enhancing the conformational rigidity of
the scaffold and potentially increasing the permeability of the
molecule, made the whole design quite attractive. The structural
motif of the scaffold could potentially be of interest not only for
kinase inhibitors, but also for protein-protein interactions due to
the flatness of the bicyclic ring system and the specific polar
interactions that can be rationally introduced by choosing
appropriate starting materials. Establishing a suitable synthetic
route would facilitate future biological applications of the
scaffold. The retrosynthetic analysis led us to two possible
strategies based on one common moiety; the protected
diaminopyrimidine 4, which could be accessed either by a
simple monoamine protection, followed by the GBB-3CR and
finally a deprotection (Scheme 1, strategy I) or by employing the
Scheme 1. The targeted scaffold, which consists of the flat (green circle),
fused 2-aminopyrimidine ring with distinct hydrogen donors (blue) and
acceptors (red) and the proposed retrosynthetic pathways towards it.
2-chloropyrimidin-4-amine 5 (Scheme 1, strategy II). The latter
could be directly employed in the GBB-3CR, followed by a
nucleophilic aromatic substitution with ammonia or be used first
in the synthesis of the protected diaminopyrimidines 4 via an
aromatic nucleophilic substitution and then in GBB-3CR,
followed by deprotection (Scheme 1, strategy II).
Scheme
diaminoimidazopyrimidines.
2.
Syntheses
pursued
in
this
work
towards
Trials using 2-chloropyrimidin-4-amine 5 in the GBB-3CR as
the amine component led to the desired product 6 but with low
yields in both the GBB step and the nucleophilic aromatic
substitution with ammonia, even after thorough investigation of
the reaction conditions (Scheme 2, strategy II). It is noteworthy,
that with 2,6-dichloropyrimidin-4-amine in the GBB-3CR, only
starting materials were obtained even by using harsh conditions
and large amounts of catalyst (data not shown). The hypothesis
is that the presence of the chlorine substituents significantly
2
Initially, 2,4-diaminopyrimidine 1 was protected with Boc O as
described previously23 and the obtained product 4a was used in
the GBB-3CR. However, the Boc group turned out to be
unstable in this step (data not shown), leading to the formation
of a mixture of products (Scheme 2, strategy I). The trityl group
was not included in the study due to unfavorable atom economy.
The -Cbz group was also excluded, since utilizing
a
hydrogenation reaction as the deprotecting step would probably
2
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European Journal of Organic Chemistry
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COMMUNICATION
inactivated the ring in the GBB reaction. For this reason, we
turned our focus on accessing the protected 2,4-
diaminopyrimidine 4a in a different way. Therefore, an aromatic
nucleophilic substitution of the 2-chloropyrimidin-4-amine 5 with
the (2,4-dimethoxyphenyl)methanamine proved to be the best
strategy (Scheme 2, strategy II). The protected aminopyrimidine
step: aldehyde (1.5 equiv), aminopyrimidine (1.0 equiv), isocyanide (1.5
equiv), scandium triflate (20 mol%), acetonitrile (0.5 M), MW 1 h 120 C.
Reaction conditions in the deprotection step: TFA (0.1 M), reflux overnight.
o
A single crystal X-ray structure was solved for compound 3f
(Figure 2). To our delight, the anticipated intramolecular
hydrogen bond of 2.1 Å between the exocyclic amine groups
was observed in which the 5-amino group serves as hydrogen
5
a proved to be stable under the GBB-3CR reaction conditions
and successfully gave rise to compounds 7 and finally the
desired adducts 3. Via this route, series of protected
.
..
bond donor (H-N-H N-H). In addition, the designed structural
motif was achieved as intermolecular hydrogen bonding of 2.0 Å
between the pyridine type nitrogen and the exocyclic amino
group was observed. Finally, as expected, the fused heterocyclic
system is relatively rigid.
a
aminopyrimidines 5a-j were prepared under microwave
irradiation (Supporting Information, SI, Scheme S1).
After selecting the protecting group, the optimization of the
GBB reactions was performed (SI, Table S1). It was found out
o
that microwave irradiation at 120 C for 1 h with catalytic amount
of Sc(OTf)
3
(20 mol%) was beneficial. The protected
aminopyrimidines were stable in the GBB reaction, although
significant variations in the reactivity were noted (see SI for
details). Regarding the final deprotection step, trials with
hydrochloric acid or mixtures of DCM/TFA resulted in slow and
incomplete transformations. Performing the deprotection with
refluxing TFA overnight led to the desired products, which were
isolated as free amines after column chromatography.
Next, we turned our focus on aminopyrimidines 5a and 5b and
further explored the scope and limitations of the aldehyde and
isocyanide components. Regarding the aldehyde component,
aromatic aldehydes with electron withdrawing and electron
donating groups, as well as heterocyclic aldehydes were well
tolerated in the GBB reaction. On the other hand, aliphatic
aldehydes reacted with lower yields and led to more complex
reaction mixtures. The main issue with aliphatic aldehydes was
the instability of the deprotected GBB products. Regarding the
isocyanide component, both aliphatic and aromatic variations
were well tolerated and no instability was observed in those
cases. An overview of the obtained products and isolated yields
is provided in the next scheme (Scheme 3).
Figure 2. X-ray structure of compound 3f (CCDC 1986084).
At that point, it would be very interesting to check similar
structural motifs and extract useful insights that would potentially
be utilized in drug discovery. One of the best tools to get those
insights is the Cambridge Structural Database (CSD). The
CSD provides the ultimate reference for evaluating the geometry
24
and interactions of a putative drug design bound to its protein
TM
target. Thus, data mining in CSD-ConQuest
showed 824
derivatives of 2-aminopyrimidines (Figure 3, A). We are highly
interested in the features of the hydrogen bond that forms the N-
H with any atoms such as O,N (QA). Interestingly, it was
revealed that the mean value of such hydrogen bond is 2.2 Å
o
(
dist1, red color) with the angle (ang1, blue color) at 162 (Figure
3
, B). As the distance of the hydrogen bond gets to the value of
o
o 25
2.0 Å, the angle becomes linear (~170 -180 ).
Figure 3. Geometrical features of the intermolecular hydrogen bond of the 2-
aminopyrimidines (824 hits in CSD) between the amino group and
a
heteroatom (O or N, QA). The angle N-H-QA (ang1) is depicted with blue color
and the distance H-QA (dist1) with red color.
Next, we wanted to query both CSD and the Protein Data Bank
(
PDB)26 utilizing the aforementioned structural motif of our
2
7
compounds. CSD-Crossminer is a tool that allows such types
of pharmacophore investigations giving us the opportunity to
identify patterns and ideas for lead optimization and scaffold
hopping. Matching crystal structures are overlaid onto the
pharmacophore query and visualized as soon as they are
available. Consequently, we employed two crystal structures,
both from the CSD and PDB with the representative binding
pattern (as it is seen both in our obtained crystal structure and
the literature). Firstly, we used as pharmacophore query the
CSD x-ray structure UFOJEF28 (the structure was mined from
the 824 different crystal structures of the CSD, Figure 3). Thus,
we wanted to search for similar structures in PDB with the
Scheme 3. Obtained products 3a-n and isolated yields (the yield of the
second step is noted in the parenthesis); Reaction conditions in the GBB
3
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European Journal of Organic Chemistry
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COMMUNICATION
following characteristics (Figure 4, A); flat, fused (green sphere)
data
can
be
obtained
free
of
charge
via
2-aminopyrimidine structures with the NH
2
as hydrogen donor
www.ccdc.cam.ac.uk/data_requist/cif
or
by emailing
(
blue sphere) and a N as donor acceptor (red sphere). The
data_request/cif@ccdc.cac.ac or by contacting the Cambridge
Crystallographic Data Center, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +441223336033.
query revealed 28 different cocrystal structures of 2-
aminopyrimidines with a very similar binding mode as shown
from the alignment (SI). As a second pharmacophore query, we
employed
as
“pharmacophore
template”
the
8-
aminoimidazo[1,2-a]pyrazine with Hsp90 inhibitory activity from
a cocrystal structure (PDB ID 4R3M) with very similar binding
pattern to our GBB scaffold 3. Noteworthy, this pyrazine is also
synthesized by a GBB reaction.29 The pharmacophore query is
depicted in Figure 4, B and consists of a flat, fused (green
Acknowledgements
This research has been supported (to AD) through ITN
“Accelerated Early stage drug dIScovery” (AEGIS, grant
agreement No 675555). Moreover, funding was received by the
National Institute of Health (NIH) (2R01GM097082-05), the
European Lead Factory (IMI) (grant agreement number 115489),
the Qatar National Research Foundation (NPRP6-065-3-
012)and COFUNDs ALERT (grant agreement No 665250),
Prominent (grant agreement No 754425) and KWF
Kankerbestrijding grant (grant agreement No 10504).K.K and
J.K-T. acknowledge the financial support of the European
Regional Development Fund in the framework of the Polish
Innovation Economy Operational Program (contract no.
POIG.02.01.00-12-023/08) for equipment purchase.
2
sphere) heterocycle with the -NH as hydrogen donor (blue
sphere) and a N as hydrogen acceptor (red sphere). Moreover,
we searched a –NH group adjacent to the pyridine ring (blue
sphere), a similar motif with our scaffold with the exocyclic NH
(
derived from the isocyanide moiety). The query revealed 37
different cocrystal structures of fused aminopyridines which are
nicely aligned (SI). By this exercise, we implement the binding
pattern to various scaffolds not only demonstrating the
usefulness of our synthesized library but also offering alternative
type of pharmacophores for future scaffold hopping against
3
0
similar targets.
Keywords: diaminoimidazopyrimidines• heterocycles•
multicomponent reactions • GBB • data mining
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Entry for the Table of Contents
Key topic: diaminoimidazopyrimidines, MCR chemistry
Here we present a multi-component-based strategy towards the synthesis of diaminoimidazopyrimidines, a heterocyclic scaffold of
interest in medicinal chemistry. Scope and limitations of the synthetic approach are discussed. A data mining analysis was performed
in the Cambridge Structural Database, in addition to a pharmacophore search in Crossminer.
6
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