Oxalyl Boronates Enable Modular Synthesis of Bioactive Imidazoles

Article abstract of DOI:10.1002/anie.201611006

Described herein is the preparation of oxalyl boronate building blocks and their application for the construction of heterocycles. The oxalyl unit, readily accessible through commercially available starting materials, enables a modular approach for the synthesis of imidazoles. A variety of aromatic, heteroaromatic, and alkyl carboxaldehydes were condensed with oxalyl boronates to afford substituted boryl imidazoles in a regiocontrolled fashion. Subsequent palladium-catalyzed cross-coupling with haloarenes furnished the desired trisubstituted imidazole scaffolds. To demonstrate the utility of these scaffolds, potent inhibitors of the serine/threonine-protein kinase STK10 were synthesized.

Full text of DOI:10.1002/anie.201611006

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611006
German Edition: DOI: 10.1002/ange.201611006
Heterocycles
Oxalyl Boronates Enable Modular Synthesis of Bioactive Imidazoles
C. Frank Lee, Aleksandra Holownia, James M. Bennett, Jonathan M. Elkins, Jeffrey D. St. Denis,
Shinya Adachi, and Andrei K. Yudin*
Abstract: Described herein is the preparation of oxalyl
boronate building blocks and their application for the con-
struction of heterocycles. The oxalyl unit, readily accessible
through commercially available starting materials, enables
a modular approach for the synthesis of imidazoles. A variety
of aromatic, heteroaromatic, and alkyl carboxaldehydes were
condensed with oxalyl boronates to afford substituted boryl
imidazoles in a regiocontrolled fashion. Subsequent palla-
dium-catalyzed cross-coupling with haloarenes furnished the
desired trisubstituted imidazole scaffolds. To demonstrate the
utility of these scaffolds, potent inhibitors of the serine/
threonine-protein kinase STK10 were synthesized.
R
apid access to small organic molecules continues to attract
the attention of synthetic chemists and chemical biologists.[1]
Approaches that utilize readily accessible reagents are
deemed particularly useful. In this regard, cross-coupling
reactions offer a versatile path to generate collections of
diverse compounds[2] in which rotatable bonds serve as
connectors between variously substituted building blocks.
The ultimate goal of these endeavors is to deliver molecules
capable of productive interactions with the binding pockets
on protein surfaces. The nature of small molecule/protein
interactions ranges from hydrophobic contacts to hydrogen
bonds.[3] The most useful molecules are often based on either
linear (e.g. Gleevec, Figure 1) or “hub” scaffolds (e.g.
Celebrex, Figure 1). The hub systems are especially attractive
because rotatable bonds emanating from the central ring offer
different vectors to interact with the grooves on protein
surfaces and in binding sites. However, the construction of
hub scaffolds, particularly azacycles, in a regiochemically
controlled fashion continues to be a challenge, one that often
requires elaborate precursors and harsh reaction conditions.[4]
We became interested in creating a flexible approach to the
synthesis of hub architectures. Herein, we highlight oxalyl
MIDA (N-methyliminodiacetic acid) boronates in the syn-
thesis of hub-based scaffolds, and demonstrate their utility for
the design of orphan kinase inhibitors.
Figure 1. Select therapeutic agents with linear and “hub” topologies.[5]
Imidazoles have found widespread application in medic-
inal chemistry as a central heterocyclic unit for biologically
active small molecules, pharmaceuticals, natural products,
and application in materials chemistry.[6] A wide variety of
classical methods for constructing the imidazole scaffold have
been reported.[4e,7] Given the role of 1,2-dicarbonyl com-
pounds in synthesis, we became interested in merging the
boronate and diketone functionalities in the same molecule.
Treatment of vinyl MIDA boronates (2a–h) with catalytic
OsO4 and N-methylmorpholine N-oxide (NMO) afforded
dihydroxylated MIDA boronates (3a–h) in high yields
(Table 1).[8] 1,2-Boryl alcohols are typically unstable motifs
because of the facile borono-Peterson-type elimination that is
commonly observed.[9] However, the stability of 3 is attrib-
uted to the MIDA ligand on the boron atom, thus shielding
the empty p-orbital from the elimination pathway.
The oxidation of 3 with Dess–Martin periodinane (DMP)
after 1 hour furnished the desired oxalyl boronates (4a–h) in
good to excellent yields as bench-stable solids (Table 1). This
route is not only amenable to electron-rich (4g,h), electron-
poor aromatics (4 f), and alkyl (4a–c) derivatives, but also
highly scalable as the reactions were performed on a 1.0–
5.0 gram scale without significant effect on product yields.
We investigated the synthetic utility of oxalyl boronates in
the synthesis of imidazoles. In the presence of NH4OAc and
benzaldehyde, phenyl oxalyl boronate (4d) smoothly con-
verted into the corresponding 2,4,5-trisubstituted borylated
[*] C. F. Lee, A. Holownia, Dr. J. D. St. Denis, Dr. S. Adachi,
Prof. Dr. A. K. Yudin
Davenport Research Laboratories, Department of Chemistry
University of Toronto
80 St. George St., Toronto, ON, M5S 3H6 (Canada)
E-mail: ayudin@chem.utoronto.ca
Dr. J. M. Bennett, Dr. J. M. Elkins
Structural Genomics Consortium (SGC), Nuffield Department of
Medicine, University of Oxford, Old Road Campus Research Building
Roosevelt Drive, Oxford, OX3 7DQ (UK)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611006.
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Table 1: Synthesis of oxalyl MIDA boronates.[a]
imidazole product was formed after 1–2 hours without any
decomposition or oxazole byproduct formation.[11] This
allowed us to modularly control the C2 position on the
heterocycle, wherein a wide variety of aldehydes, including
alkyl N-Boc protected aldehydes (5h), were well tolerated in
the synthesis without any observed deprotected material or
oxazole byproducts. Electron-rich (5d, 5e), electron-poor
(5c, 5 f), and heterocyclic carboxaldehydes were all tolerated,
thus yielding bis-heterocyclic hub-like scaffolds (5b, 5g). This
regioselective route towards borylated imidazoles enables the
heterocycle to become a hub of controlled functionalization,
where each spoke is introduced in one step. In addition, the
boryl imidazole products are intensely colored, thus high-
lighting the potential utility of these compounds in photo-
physical/chemical applications.[12]
Alkyne
R
cis-Diol
Yield
[%][b]
Oxalyl
boronate
Yield
[%][b]
1a
1b
1c
1d
1e
1f
cyclohexyl
cyclopropyl
phenethyl
phenyl
1-naphthyl
4-FC6H4
3a
3b
3c
3d
3e
3f
76
78
83
92
63
84
91
65
4a
4b
4c
4d
4e
4f
36
84[c]
90[c]
72
51
50
67
58
1g
1h
4-OMeC6H4
6-OMeC10H6
3g
3h
4g
4h
Finally, with the C2 and C5 positions functionalized, the
resulting borylated imidazoles were subjected to standard
cross-coupling conditions with aryl bromides to complete
a facile method for generating densely functionalized imida-
zoles. Unfortunately, employing cross-coupling conditions for
MIDA boronates (variations of Buchwald precatalysts)[13] led
to quantitative formation of the undesired protodeboronation
product and trace amounts of the desired product by LC/MS
analysis (see the Supporting Information). The boryl imida-
zole scaffold, similar to the analogous 2-boryl pyridine
system, is notoriously prone to protodeboronation under
cross-coupling conditions because of the electronic nature of
the heterocycle and the position of the boronic acid/ester
group on the ring.[14] Employing the slow-release method
developed by Burke, et al.[15] also led to exclusive protode-
boronation product. An improved product ratio, as indicated
by LC/MS analysis, was observed with a modified slow-
release method. Furthermore, switching to [Pd(dppf)Cl2] and
sodium carbonate in a 10:1 mixture of DMF/H2O led to the
best product ratio (see the Supporting Information) where the
products were isolated by reverse-phase column chromatog-
raphy (Scheme 2).
[a] Reactions were carried out using 1.0 equiv of alkyne, 1.5 equiv of
catecholborane in tetrahydrofuran (THF: 0.5m) at 658C for 24 hours;
1.5 equiv of N-methyliminodiacetic acid (MIDA) in dimethylsulfoxide
(DMSO: 0.1m) at 808C for 1–5 hours. Dihydroxylation was achieved
using 1–2 mol% of osmium tetroxide (4 wt% in H2O) and 1.5 equiv of
N-methylmorpholine N-oxide (NMO) in an 18:1:1 solvent ratio of
acetone/tert-butanol/water (0.05m). Oxidations were executed using
2.2 equiv of Dess–Martin periodinane (DMP) in acetonitrile (MeCN:
0.1m) at room temperature for 1 hour. [b] Yield is that of product isolated
after silica gel chromatography. [c] Products were unstable towards
column chromatography. Yield determined by NMR analysis using
trimethoxybenzene as the internal standard. DMSO=dimethylsulfoxide,
THF=tetrahydrofuran.
imidazole in a highly regioselective fashion (5a; Scheme 1).
Contrary to classical Debus conditions,[7d,10] our modified
method of utilizing AcOH as the reaction medium allowed
the reaction to occur at room temperature as the borylated
To highlight the versatility of our approach, we decided to
use this method to tackle the kinase STK10, a serine/
threonine-protein kinase highly expressed in lymphocytes
and involved in regulating lymphocyte migration,[16] for the
discovery of a chemical probe. STK10 and the related kinase
SLK are involved in regulating PLK1 (polo-like kinase 1).[17]
PLKs are critical regulators of cell-cycle progression, mitosis,
cytokinesis, and DNA damage response.[18] Kinases are well-
known drug targets because of their roles in the regulation of
cellular physiology and pathology,[19] and as of January 2016
there were 28 FDA-approved drugs that target kinases.[20]
With more than 500 protein kinases in the human genome,
many of which have strong links to fundamental cellular
processes, there is a strong need for efficient methods of
elaborating kinase inhibitors. After analyzing the co-crystal
structures of SB-633825 and SB-440719 (Figure 2) where SB-
633825 inhibited STK10 to 44% maximal activity at
100 nm,[21] we were prompted to use oxalyl boronates to
rapidly generate a series of STK10 inhibitors by varying the
substituent at C2 of the heterocycle. This series would allow
the optimization of modulating hydrogen-bond interactions
with either amino-acid residues or the protein backbone.
Scheme 1. Scope of borylated imidazoles. Reactions were carried out
using 1.0 equiv of oxalyl boronate, 1.1 equiv of aldehyde (R’CHO), and
15 equiv of ammonium acetate (NH4OAc) in acetic acid (AcOH:
0.1m) at room temperature for 1–2 hours. [a] Yield is that of product
isolated after silica gel chromatography. Boc=tert-butyloxycarbonyl.
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Figure 3. Percentage inhibition for compounds 6e and 7 against
STK10 and SLK as measured in a binding–displacement assay. Each
measurement was measured in duplicate and repeated on a subse-
quent day. One example of each duplicate is shown.
actions. However, swapping the pyridyl group with an N-acyl
piperidyl group (7) resulted in an improved Ki value. With the
added flexibility of the saturated heterocycle (7) compared to
a flat aromatic group (6e), it may allow the molecule to adopt
a more optimal geometry in the binding pocket. With the ease
of modifying the groups on the imidazole core, efforts to
generate a more comprehensive library of compounds are
currently ongoing.
Scheme 2. Suzuki–Miyaura cross-coupling of borylated imidazoles.
Reactions were achieved using 1.0 equiv of boryl imidazole, 1.5 equiv
of R’’X, 10 mol% of Pd(dppf)Cl2, 3.0 equiv of sodium carbonate
(Na2CO3) in a 10:1 solvent mixture of dimethylformamide (DMF), and
water at 708C for 1 hour in a Biotage microwave reactor. [a] Yield is
that of isolated product after reverse-phase silica gel chromatography.
dppf=1,1’-bis(diphenylphosphino)ferrocene, MW=microwave.
In summary, we have developed a modular approach
towards the construction of densely functionalized imidazole
scaffolds through our oxalyl boronate technology. The use of
a multicomponent double condensation reaction with a wide
range of aldehydes followed by a cross-coupling of MIDA-
boryl imidazoles provided an efficient method to regioselec-
tively vary the groups on the central heterocycle. Current
investigations are aimed at leveraging oxalyl boronates to
provide further insight into the physiological significance of
novel imidazole inhibitors and target validation of the protein
kinase STK10.
Acknowledgments
We would like to thank the Natural Science and Engineering
Research Council (NSERC), the Canadian Institute of
Health Research (CIHR), Astex Pharmaceuticals, and the
Canadian Foundation for Innovation, project number 19119,
for financial support, and the Ontario Research Fund for
funding of the Centre for Spectroscopic Investigation of
Complex Organic Molecules and Polymers. This work was in
part supported by a Collaborative Research and Training
Experience grant from NSERC. Helpful discussions with
Joanne Tan, Dr. Santha Santhakumar, Dr. Christopher
Asquith, and Dr. William Zuercher are gratefully acknowl-
edged. C.F.L. would like to thank the Government of Ontario
and OGS for QEII funding and NSERC for PGS-D funding.
The SGC is a registered charity (number 1097737) that
receives funds from AbbVie, Bayer Pharma AG, Boehringer
Ingelheim, Canada Foundation for Innovation, Eshelman
Institute for Innovation, Genome Canada, Innovative Med-
icines Initiative (EU/EFPIA) [ULTRA-DD grant no.
115766], Janssen, Merck & Co., Novartis Pharma AG,
Ontario Ministry of Economic Development and Innovation,
Pfizer, S¼o Paolo Research Foundation-FAPESP, Takeda,
and Wellcome Trust [106169/ZZ14/Z].
Figure 2. X-ray co-crystal structures of STK10:SB-633825 (PDB 4USD,
left) and SLK:SB-440719 (PDB 4USF, right)[21] that were used for
compound design.
The compounds 6e and 7 (Scheme 3) were tested against
STK10 and SLK. Preliminary results have shown that 6e and
7 exhibited Ki values of 250 nm and 130 nm, respectively,
against STK10, and 340 nm and 180 nm, respectively, against
SLK (Figure 3; see the Supporting Information). The intro-
duction of a heteroatom at C2 (6e) lowered the Ki value,
presumably because of an increase in hydrogen-bond inter-
Scheme 3. Synthesis of N-acyl piperidine derivative. Reaction was
carried out using 1.0 equiv of imidazole 6 f and 20 equiv of trifluoro-
acetic acid (TFA) in dichloromethane (0.1m) at room temperature for
1 hour. Followed by 1.0 equiv of Amberliteꢀ IRA-67 resin and 1.5 equiv
of acetic anhydride (Ac2O) in acetonitrile (MeCN: 0.1m) at room
temperature for 30 minutes. [a] Yield is that of product isolated after
reverse-phase silica gel chromatography.
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Conflict of interest
The authors declare no conflict of interest.
[11] Use of acetic acid at high temperatures was first reported by
Davidson et al.: the authors observed a substantial improvement
in the formation of imidazole compared to reactions performed
in alcoholic solvents: D. Davidson, M. Weiss, M. Jelling, J. Org.
Chem. 1937, 2, 319 – 327.
Keywords: biological activity · boron · cross-coupling ·
heterocycles · synthetic methods
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Manuscript received: November 10, 2016
Revised: January 16, 2017
Final Article published: && &&, &&&&
4
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Communications
Heterocycles
C. F. Lee, A. Holownia, J. M. Bennett,
J. M. Elkins, J. D. St. Denis, S. Adachi,
A. K. Yudin*
&&&& — &&&&
Oxalyl Boronates Enable Modular
Synthesis of Bioactive Imidazoles
A variety of aromatic, heteroaromatic,
and alkyl carboxaldehydes were con-
densed with oxalyl boronates to afford
substituted boryl imidazoles in a regio-
controlled fashion. Subsequent palla-
dium-catalyzed cross-coupling with halo-
arenes furnished the desired trisubsti-
tuted imidazole scaffolds. To demon-
strate the utility of these scaffolds, potent
inhibitors of the serine/threonine-protein
kinase STK10 were synthesized.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!