Cubanes in medicinal chemistry: Synthesis of functionalized building blocks

Article abstract of DOI:10.1021/ol501750k

A collection of novel, pharmaceutically relevant cubane-containing molecules has been prepared from the commercially available cubane-1,4- dimethylester. A range of synthetic methods have been applied to prepare these cubane building blocks with one or two functional handles to allow easy incorporation into existing medicinal chemistry programs.

Full text of DOI:10.1021/ol501750k

Letter
pubs.acs.org/OrgLett
Cubanes in Medicinal Chemistry: Synthesis of Functionalized
Building Blocks
Joanna Wlochal,*,† Robert D. M. Davies,*,† and Jonathan Burton‡
†Oncology, Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
‡Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: A collection of novel, pharmaceutically relevant cubane-
containing molecules has been prepared from the commercially available
cubane-1,4-dimethylester. A range of synthetic methods have been applied to
prepare these cubane building blocks with one or two functional handles to allow
easy incorporation into existing medicinal chemistry programs.
edicinal chemists are continually striving to reduce the
attrition rates of candidate drug molecules. Recent
monoamine oxidase B (MAO B), an enzyme involved in
Parkinson’s disease.14 In further work, Kassiou and co-workers
found that a range of aromatic cubane carbinylamides15,16 were
effective against P2X7 ion channels which are involved in many
biological functions.17 Pellicciari, Pin, and co-workers18
reported that carboxycubaneglycine was found to be a selective
inhibitor of the glutamatergic pathway commonly affected in
neurological disorders. Furthermore, Al Hussainy, Booij, and
co-workers19 developed cubane-containing ligands with high
metabolic stability, as analogues of 5-hydroxytryptamine
antagonists for use in positron emission tomography. We
believe that the limited use of cubane in medicinal chemistry is
largely due to the perceived synthetic complexity of this highly
strained molecule coupled with its undesired high intrinsic
energy that has been extensively investigated by the explosives
industry.3,9 A limited commercial supply chain for cubane-
containing reagents has also served to discourage its use.
To further explore the utility of cubane in medicinal
chemistry, we decided to develop the synthesis of gram
quantities of cubane building blocks containing pharma-
ceutically relevant functionality that can be used in drug
discovery programs. The most accessible starting point for
cubane derivatization is the commercially available cubane-1,4-
diester 1.7,10 From this, we planned to make building blocks
conforming to the following four categories (Figure 2): (i)
cubane as a terminal group with one functional handle for
derivitization; (ii) bifunctional cubanes to be used as terminal
groups or linkers; (iii) cubane heterocycles with a functional
M
reports highlight complexity and, by extension, degree of
saturation as a useful metric in predicting success.1,2 This idea
led us to consider the cubane framework as an alternative to the
usual aromatic and heteroaromatic motifs routinely deployed in
medicinal chemistry. As early as 1992, Eaton had discussed the
potential use of cubane in the synthesis of new pharmaceuticals
based on its rigid framework and size with respect to a para-
disubstituted benzene ring (Figure 1).3 Cubane’s compact,
Figure 1. Body diagonal of (a) cubane and (b) xylene.
saturated three-dimensional structure offers different binding
modes compared with aromatic systems and is incapable of
undergoing intermolecular π-stacking, thereby potentially
improving solubility. Furthermore, the cubane core has been
shown to be a poor substrate in cytochrome P450 metabolic
pathways,4 which may lead to enhanced metabolic stability. The
distance between substituents in 1,4-disubstituted cubanes is
5.64 Å5 versus a para-substituted phenyl ring of 5.79 Å,6 which
suggests a potential use for cubane as a phenyl ring isostere
(Figure 1).
Despite being known since 1964,7,8 and extensively
reviewed,3,9 cubane10 has found only limited use in medicinal
chemistry. Such examples include work by Bashir-Hashemi,11
where tetra-substituted cubane amides demonstrated anti-HIV
properties. In another example, cubane carbinylamines
synthesized by Eaton12,13 were found to act as inhibitors of
Received: June 18, 2014
Published: July 28, 2014
© 2014 American Chemical Society
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Scheme 2. Synthesis of Various Building Blocks from
Cubane Monoester with Functional Handle on Cubane or
Heterocycle
Figure 2. Different classes of cubane building blocks.
handle on the heterocycle; (iv) cubane heterocycles with a
functional handle on the cubane.
The synthesis of the known monosubstituted cubane20
2
(Scheme 1) was accomplished in two steps from cubane-1,4-
Scheme 1. Preparation of Monosubstituted Cubane Building
Blocks
chose a Kowalski homologation procedure, over the Arndt-
Eistert reaction24 due to safety concerns with the latter
procedure. In the first step, dibromoketone 8 was prepared in
88% yield by treatment of monoester 2 with the anion of
dibromomethane (Scheme 2). Dibromoketone 8 was then
transformed27,28 into cubane acetic acid 724 in 60% yield by
sequential addition of strong bases. Dibromoketone 8 also
underwent basic hydrolysis29 to α-hydroxy acid 9 in 70% yield.
The dibromoketone 8 could also be utilized to make our first
example of a cubane heterocycle with a functional handle on
the unsaturated ring. Treatment of 8 with acetaldehyde and
ammonium hydroxide in toluene30 at elevated temperatures
provided cubane imidazole 10 in a moderate 33% yield.
Another example in this class of cubane is the pyridine-
substituted cubane 11. This was prepared using the Bohlmann-
Rahtz reaction31 as outlined in Scheme 2. Treatment of the
Weinreb amide derived from ester 2 with the anion of TMS-
acetylene gave novel ketone 12 in 86% yield. Condensation
with ethyl 3-aminocrotonate was performed at 60 °C
(microwave), followed by isomerization and cyclization at
100 °C (microwave) to form the pyridine core in 77% overall
yield. Subsequent hydrolysis completed the synthesis of 11.
In the final example of this type, cubane-isoxazole 13 was
synthesized (Scheme 2) using a protocol for 5-amino isoxazole
synthesis recently published by Mainolfi and co-workers.32
Rowbottom and co-workers33 used similar reaction conditions
for the synthesis of a wide range of amino isoxazoles. Under the
conditions investigated during this study, formation of the
isomeric 3-amino isoxazole was not observed.
diester 1 using a modification of the Barton decarboxylation
recently reported by Williams and Tsanaktsidis.21,22 The
synthesis began with hydrolysis of 1 to provide known acid
ester20 in 95% yield. Preparation of the intermediate acid
chloride, followed by photoinduced decarboxylation of the
corresponding thioester gave known cubane20,21 2 in 60% yield
on a 40.0 mmol scale. Due to the requirements for a large
quantity of the cubane monoester 2 and the scale limitation of
the batch system, we investigated the synthesis of 2 in flow. A
photoflow reactor was constructed in accordance with the
method reported by Booker-Milburn,23 and the subsequent
decarboxylation delivered 2 in an improved 80% yield.
Application of this method produced 10.0 g of monocubane
ester 2 in less than 1 h.
With monoester 2 in hand, we looked to make our first set of
terminal cubane building blocks. First, known cubanecarbinol
324 was prepared in multigram scale and excellent yield via
lithium borohydride reduction of 2. Alcohol 3 was readily
transformed into a novel thioester in 94% yield under mild
Mitsunobu conditions, which on treatment with N-chloro-
succinimide and a substoichiometric amount of HCl gave
access to gram quantities of the novel cubane sulfonyl 4 as a
white crystalline, bench-stable solid in 89% yield. This
intermediate could then be exposed to various nucleophiles,
exemplified here by treatment with ammonia, which gave the
novel cubane carbinylsulfonylamide 5 in good yield. Cubane
amine hydrochloride 625 was also prepared according to the
recent report by Sklyarova et al.26 in very good yield and large
quantity.
As a potential replacement for commonly used biaryl
systems, we prepared known phenylcubane carboxylic acid
1512 and novel phenylcubane amine hydrochloride 16.
Synthesis of amine 16 (Scheme 3) utilized the protocol
published by Eaton and co-workers,12,20,34 whereby the diester
1 was converted into phenyl iodocubane which was
subsequently converted into the carboxylic acid 15 on
We next looked to prepare the C-homologated analogue 7 of
cubane carboxylic acid along with a number of related
compounds (Scheme 2). For the preparation of 7 from 2, we
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Scheme 3. Synthesis of 1,4-Disubstituted Cubane Building
Blocks
Scheme 5. Synthesis of 1,4-Disubstituted Cubane Building
Blocks with Different Heterocycles
treatment with t-BuLi and gaseous carbon dioxide. Our only
modification to this route was the reverse addition of phenyl
iodocubane to the solution of t-BuLi and use of solid carbon
dioxide in place of the gas which gave phenylcubanecarboxylic
acid 1512 in 89% yield. In situ azide formation with
diphenylphosphoryl azide34 and rearrangement upon heating
provided the novel phenylcubane carbamate in very good yield;
subsequent acid hydrolysis completed the synthesis of the novel
4-phenylcubane-1-amine hydrochloride 16. This route deliv-
ered multigram quantities of both 15 and 16.
Next, we prepared some examples of 1,4-bifunctional
cubanes that would have additional potential to be used as
linkers or cores in future work. The synthesis of known cubane
carbinylamine 17 was accomplished in excellent 80% overall
yield by application of the existing protocol35 starting from
cubane acid ester 18 with facile H-cube reduction of nitrile 19
using Adams’ catalyst being the only modification (Scheme 4).
of benzamidine with 18 and treatment with hydrazine in acidic
media gave 25. Basic hydrolysis provided 26 in 40% overall
yield. We also synthesized a disubstituted cubane-bearing
imidazole by converting acid 18 into the known aldehyde 2718.
This underwent a van Leusen reaction with toluenesulfonyl-
methyl isocyanide38 to give the corresponding imidazole in a
moderate 27% yield, which could be hydrolyzed to the acid 28.
The next heterocycle we looked to prepare was pyrazole 29.
As shown in Scheme 6, after the introduction of the bulky t-Bu
ester onto 18, reaction with the enolate of acetone gave the
novel 1,3-diketone 30 in modest yield. Treatment of 30 with
hydrazine hydrate under acidic conditions and acid cleavage of
the ester with TFA completed the synthesis of pyrazole 29 in
68% overall yield.
Scheme 4. Synthesis of 1,4-Disubstituted Cubane Building
Blocks
Scheme 6. Synthesis of 1,4-Disubstituted Cubane Building
Blocks with Different Heterocycles
The known cubane cyanoester 19 was further elaborated
through hydrolysis and previously explored Yamada−Curtius
reaction34 to give the novel cyano-Boc-amine 20. Deprotection
of 20 with trifluoroacetic acid gave the desired novel
cyanoamine trifluoroacetate salt 21, which decomposed upon
recrystallization. Alternatively, treatment of 20 with anhydrous
HCl in methanol gave the hydrochloride salt of amino cubane
ester 22.
Lastly, we prepared examples of the final class of cubane
heterocycles with a functional handle on the cubane. This
necessitated building up the heterocycles from the cubane acid
ester 18, as cross-coupling chemistry using transition metals is
documented to induce structural rearrangements in cubanes.3,36
The synthesis of oxazole 23 outlined in Scheme 5 began with
EDC coupling of 1-amino-2-propanol and 18 to give 24 in
good yield. Dess-Martin oxidation of the novel amido alcohol
24 followed by dehydration gave the corresponding oxazole 23
in 53% overall yield. Subsequent hydrolysis of the methyl ester
with sodium hydroxide delivered multigram quantities of the
novel cubane oxazole acid 23. Next, attention was directed to
the synthesis of novel triazole 25 (Scheme 5), applying the
method developed by Castanedo and co-workers.37 Coupling
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Letter
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A useful intermediate in the preparation of cubane
heterocycles, which was accessible by carbonyl group
manipulation, was the α-bromoketone 31 which we prepared
in four steps from 18. Conversion of 18 into the corresponding
Weinreb amide followed by reaction with MeMgBr gave the
cubane ketoester 32. Formation of the corresponding silyl enol
ether followed by treatment with N-bromosuccinimide gave the
novel α-bromoketone cubane 31 in good overall yield.
With ample quantities of 31 in hand, conversion to
benzimidazole 33 and thiazole 34 was investigated. First,
heating 31 and thioacetamidine in methanol under microwave
conditions for 2 h allowed clean formation of the
corresponding thiazole in 98% yield, which on hydrolysis
delivered multigram quantities of the required cubane building
block 34. Similarly, treatment of 31 with 2-amino pyridine in
methanol at reflux produced the cubane imidazo-pyridine
heterocycle with basic hydrolysis completing the formation of
33 in excellent yield.
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ASSOCIATED CONTENT
* Supporting Information
■
S
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Experimental procedures and spectral data for all new
1
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AUTHOR INFORMATION
Corresponding Authors
(29) Kontos, Z.; Huszthy, P.; Bradshaw, J. S.; Izatt, R. M.
̈
̈
■
Tetrahedron: Asymmetry 1999, 10, 2087−2099.
(30) Beight, D. W.; Burkholder, T. P.; Clayton, J. R.; Eggen, M.;
Henry, K. J. J.; Johns, D. M.; Parthasarathy, S.; Pei, H.; Rempala, M. E.;
Sawyer, J. S. U.S. Patent WO 2011050016 A1, 2011.
*E-mail: joanna.wlochal@astrazeneca.com.
*E-mail: rob.davies@astrazeneca.com.
(31) Bagley, M. C.; Brace, C.; Dale, J. W.; Ohnesorge, M.; Phillips, N.
G.; Xiong, X.; Bower, J. J. Chem. Soc., Perkin Trans. 1 2002, 14, 1663−
1671.
Notes
The authors declare no competing financial interest.
(32) Johnson, L.; Powers, J.; Ma, F.; Jendza, K.; Wang, B.; Meredith,
E.; Mainolfi, N. Synthesis 2013, 45, 171−173.
ACKNOWLEDGMENTS
■
The authors would like to thank Howard Beeley for NMR
spectroscopy, Paul Davey for mass spectrometry, and James S.
Scott for helpful discussions.
(33) Rowbottom, M. W.; Faraoni, R.; Chao, Q.; Campbell, B. T.; Lai,
A. G.; Setti, E.; Ezawa, M.; Sprankle, K. G.; Abraham, S.; Tran, L.;
Struss, B.; Gibney, M.; Armstrong, R. C.; Gunawardane, R. N.;
Nepomuceno, R. R.; Valenta, I.; Hua, H.; Gardner, M. F.; Cramer, M.
D.; Gitnick, D.; Insko, D. E.; Apuy, J. L.; Jones-Bolin, S.; Ghose, A. K.;
Herbertz, T.; Ator, M. A.; Dorsey, B. D.; Ruggeri, B.; Williams, M.;
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