New synthetic approaches towards analogues of bedaquiline

Article abstract of DOI:10.1039/c6ob01893a

Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-

Full text of DOI:10.1039/c6ob01893a

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New synthetic approaches towards analogues of bedaquiline
Daniel L. Priebbenow, Lisa Barbaro and Jonathan B. Baell*
Received 00th January 20xx,
Accepted 00th January 20xx
Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to
control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to
specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been
associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access
pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to
facilitate the preparation bedaquiline and analogues thereof have been discovered.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Janssen Pharmaceuticals.[6] A whole-cell screen of more than
70,000 compounds was performed against the Mtb surrogate
Mycobacterium smegmatis, which led to the identification of
Introduction
Tuberculosis (TB) is an ancient infectious disease, caused
primarily by Mycobacterium tuberculosis (Mtb).[1] Its impact on
humanity throughout history has been devastating, claiming
more lives than any other known infectious disease.[2] Despite
the emergence of multiple anti-TB drugs more than half a
century ago,[3] TB is still the greatest infectious killer
worldwide,[4] and elimination of the disease at a global level
remains elusive. Alarmingly, one-third of the world’s
population is estimated to be asymptomatically infected with
the DARQ fragment
1 (Figure 1), as a promising structure
warranting further optimization. Janssen’s hit-to-lead effort
produced a series of several hundred DARQ derivatives with in
vitro activity against Mtb, eventually leading to the
identification and development of bedaquiline (2) as the most
effective anti-TB agent in its (R,S) enantiomeric form.[6,7]
OH
OH
dormant Mtb, resulting in
a lifelong risk of disease
(R)
Br
N
Br
N
reactivation.[5] Effective eradication of TB is complicated due
to its ability to remain in persistent lesions, requiring extended
treatment regimens involving multiple drugs. Furthermore, the
emergence of multi- and extensively drug-resistant (MDR-TB
and XDR-TB) strains has significantly added to the disease
burden. Such cases have become increasingly difficult to
manage, and as such, drug-resistant strains have led to
increased morbidity and mortality.[4] Given the shortcomings
of the currently available therapies, there remains a desperate
need for the discovery of new anti-TB drugs that can simplify
treatment regimes. Drugs that operate at novel biological
targets and are effective against drug-resistant strains are
deemed highly desirable.
(S)
N
O
N
O
2
1
initial fragment hit
bedaquiline
Figure 1. Janssen developed bedaquiline from an initial fragment screening hit.
Despite its novel mode of action and potent activity,
bedaquiline’s widespread use for the treatment of MDR-TB has
been relatively limited as a result of the associated adverse
side-effects. Of greatest concern is its ability to interfere with
the heart's electrical activity, resulting in prolongation of the
QT interval, which serves as a biomarker for the development
of potentially fatal ventricular arrhythmias.[8] Almost all cases
of drug-induced QT prolongation have been attributed to
blockage of the potassium ion channel encoded by the human
ether-a-go-go related gene (hERG).[9] Multiple studies aimed at
probing the structural basis for hERG blockage have identified
a lipophilic binding domain within the central cavity of the
channel,[10-14] potentially implicating the relatively high
lipophilicity of bedaquiline (ClogP 7.3) as a major source of its
hERG mediated toxicity. Furthermore, the basic amine
functional group present in bedaquiline, which is
predominantly protonated at physiological pH (pKa 9.6),
The development of bedaquiline (2), the first new anti-TB drug
commercialized in over 40 years promised to revolutionize the
treatment of MDR-TB due to its novel mode of action against
mycobacterial ATP synthase.[6] Diarylquinolines (DARQs) that
were highly active against MDR-TB were discovered in 1996 at
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forming π-cation interactions with specific aromatic residues providing substrates that could be further elaborated using
within this region,[15] further increasing affinity for the hERG allyl-derived organometallic reagents (such as allyl zinc
channel. In addition to promoting hERG binding, the high bromide). To access the final bedaquiline analogues
3,
lipophilicity of bedaquiline may be responsible for additional conversion of the allyl group within 4 to the requisite ethyl
undesirable side-effects such as phospholipidosis (the dimethylamine functionality could be accomplished. To render
accumulation of phospholipids within cells), and CYP450 this synthetic approach useful, the main focus became the
(isoenzyme 3A4) mediated drug-drug interactions.[16]
identification and development of efficient methods to access
tri-aryl ketone derivatives . For the synthetic routes employed
In order to facilitate the effective treatment of MDR-TB, highly to be practical for the preparation of bedaquiline analogues
active bedaquiline analogues that exhibit an improved safety orthogonal pathways that facilitate the use of either an
profile are urgently needed. One avenue considered worthy of heterocyclic boronic acid ( ) or a heteroaryl halide ( ) are
5
3,
6
7
exploration in an effort to improve the safety profile of required to efficiently facilitate the inclusion of any number of
bedaquiline involved replacing the quinoline motif with an heterocyclic derivatives. To this end, we herein present
alternative heterocyclic system. To the best of our knowledge, multiple synthetic strategies that provide access to
there appeared to be no attempt to explore variations in the bedaquiline analogues
heterocyclic moiety during the drug discovery program. One
apparent reason for the lack of heterocyclic diversity explored
in this region during the development of bedaquiline could be
a result of the synthetic methods utilized during the drug
discovery process which were predominantly limited to
quinolines. In fact, the only report of bedaquiline analogues
whereby the quinoline heterocycle was not present is a very
recent publication by Li and co-workers where the nitrogen
atom of the quinoline was substituted with a C-H to afford 2-
methoxynaphthyl derivatives.[17]
3 from readily available reagents.
During the drug discovery phase, Janssen prepared
bedaquiline analogues by employing an LDA-mediated
addition of 3-benzylquinolines to ethyl-amino substituted aryl
ketones.[7] Since that time, two alternative asymmetric
syntheses of bedaquiline have been reported, however, these
require the initial use of substituted anilines to prepare the
quinoline motif from which the remainder of the molecule is
constructed.[18,19] In our hands, when attempting to replace the
quinoline with alternative heterocyclic systems such as
pyridines and pyrimidines, we found these methods to be
inapplicable or inefficient. As such, to facilitate the discovery
of pharmaceutical agents for the treatment of MDR-TB that
exhibit improved safety profiles, it proved necessary that new
synthetic methods to access analogues of bedaquiline were
identified. To this end, we herein report the development of
novel strategies towards the synthesis of bedaquiline
analogues that will enable the incorporation of various carbo-
and heterocyclic motifs. To validate the chemistry, 2-
methoxyquinoline was utilized throughout this project,
however, it is envisaged that any number of heterocyclic
precursors could be applied to these synthetic pathways to
readily vary the heterocyclic motif in bedaquiline analogues.
Scheme 1. Retrosynthetic analysis of the synthesis of bedaquiline analogues.
The first approach towards bedaquiline analogues was
designed to facilitate the incorporation of the heterocyclic
moiety from the corresponding heteroaryl halide. To explore
this,
a
suitable coupling partner in 3-bromo-2-
) was prepared in 4 steps from 3-
methoxyquinoline (
9
bromoquinoline (refer to the supporting information). Initially,
this approach was conducted in a step-wise fashion. Employing
sodium tert-butoxide to generate the enolate from 1-
acetonaphthone (
between bromoquinoline
afford -substituted ketone 10 in 92% yield (Scheme 2). A
8),
a
palladium-catalyzed Heck reaction
9
and the enolate took place to
α
second Heck reaction utilizing iodobenzene as the coupling
partner under similar reaction conditions was undertaken to
yield the α,α-disubstituted naphthone derivative 12.
Alternatively, the Heck reaction with iodobenzene could be
accomplished first to afford 11 which was subsequently
coupled to the bromoquinoline
9 to furnish ketone 12, both in
good yields (Scheme 2). During optimization of this pathway, it
was observed that subsequent to the second Heck reaction—if
elevated temperatures and excess base were used—unwanted
cyclization of the enolate onto the quinoline occurred to
displace the methoxy group at the quinoline-2-position to
afford furan 13 (Scheme 3). To avoid this cyclization process,
the secondary Heck reaction (Scheme 2) was conducted at 40
oC by employing only 1.5 equivalents of sodium tert-butoxide.
Results and Discussion
The focus of this investigation was the discovery of alternative
approaches towards the synthesis of bedaquiline analogues
that would facilitate the substitution of the quinoline motif
with any number of other suitable heterocycles (
3, Scheme 1).
To achieve this, α,α-disubstituted acetophenone derivatives
5
were identified as key intermediates in the synthetic pathway,
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Scheme 4. The one-pot palladium-catalysed di-arylation of ketones
Scheme 2. Two alternative pathways provide access to tri-substituted ketones from 1-
acetonaphthone
Utilizing either the step-wise (Scheme 2) or one-pot (Scheme
4) process to access the α,α-disubstituted aryl ketones, it can
be envisaged that diversely foliated triaryl ketones (that are
able to be readily converted to bedaquiline analogues 3) could
be rapidly prepared from acetophenones, aryl halides and
heteroaryl halides containing various substitution patterns.
A second strategy to access bedaquiline analogues from
heteroaryl halides was then developed with the key reaction
being the palladium catalysed Suzuki-Miyaura cross-coupling
of bromoquinoline
9 with a di-boronate alkene derived from
phenylacetylene (Scheme 5). Initially, diphenylacetylene (16
)
Scheme 3. At elevated temperatures, ketone 12 cyclizes to form the furan by-product
13.
was reacted with bis(pinacolato)diboron in the presence of 2
mol% of Pt(PPh3)4 to afford the bis-boronate alkene 17 in 88%
yield.[21] This boronic ester was then subjected to a palladium-
With the step-wise preparation of the
α,α-disubstituted
catalysed Suzuki-Miyaura reaction with bromoquinoline
9.
naphthone derivative 12 achieved, attention turned to
determining if these two Heck reactions could be
accomplished in a ‘one-pot’ process. Employing the stable tert-
butyl phosphine ferrocene-derived palladium catalyst
Shimizu and co-workers reported that this reaction required
o
heating at 65 C for 48 hours to achieve full conversion,[22,23]
however, in our hands it was discovered that high yields could
o
be obtained by heating the reaction mixture at 100 C for only
PdCl2(DtBPF) 14 [20]
initial Heck reaction of the bromoquinoline
,
a one-pot, two-step process involving the
with the enolate,
1 hour in a microwave reactor (Scheme 5). In some cases, trace
amounts of the di-coupled product were observed following
LCMS analysis of the crude reaction mixture, however
predominantly this reaction process afforded exclusively
mono-coupled alkene 18. The vinyl boronic ester obtained was
then converted to the requisite tri-substituted ketone 15
under oxidative conditions using sodium perborate in 81%
yield (Scheme 5). This approach provides an alternative
pathway to access similar α,α-disubstituted acetophenones to
that obtained previously, however in this case they can be
prepared from the corresponding disubstituted alkyne.
9
followed by a second Heck reaction of the enolate with
iodobenzene efficiently furnished the tri-substituted ketones
containing the requisite phenyl and quinoline aromatic groups
(Scheme 4).[20] This reaction was carried out with both
acetophenone and 1-naphthone to afford the di-phenyl and
phenyl-naphthyl derivatives 12 and 15 in good yield. Again for
this reaction process, the second step was performed at
moderate temperatures to avoid the formation of furan 13
.
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The synthesis of the corresponding naphthyl derivative 12 was
then conducted utilizing a similar approach. Bromo-enol
acetate 23 was prepared from 1-acetonaphthone in four steps
(Scheme 7).[27] The Suzuki-Miyaura cross-coupling of bromo
alkene 23 with quinolyl boronic acid 20 was then performed.
Initially, the conditions that were previously applied for this
type of cross-coupling process (see Scheme 6) afforded only
trace amounts of the desired product. Subsequent
optimization identified that a catalytic system of palladium
acetate and X-Phos in toluene in the presence of potassium
phosphate under reflux for 48 hours was better suited to this
reaction process. Under these conditions, subsequent
hydrolysis of the enol acetate also occurred to afford the tri-
substituted ketone 12 in 82% yield (Scheme 7). Again, it can be
envisaged that by employing this approach, the rapid
preparation of diversely foliated bedaquiline analogues could
be achieved utilizing diphenylacetylenes, or ketones and
heteroaryl boronic acids that contain varying substitution
patterns.
Scheme 5. The conversion of diphenylacetylene to a trisubstituted ketone with the key
step being a Suzuki-Miyaura reaction using a heteroaryl bromide
With two alternative pathways identified for the preparation
of tri-substituted ketones from heteroaryl halides
attention then turned to an orthogonal route that would
facilitate the use of heterocyclic boronic acids . To achieve
this, a Suzuki-Miyaura reaction was employed, in this case
between 2-methoxyquinolinyl-3-boronic acid 20 and
suitable vinyl halide. Boronic acid 20 can be synthesized from
2-methoxyquinoline,[24] or 3-bromo-2-methoxy quinoline (
) by
7, our
6
(
)
a
9
reaction with n-butyl lithium in the presence of trimethyl
borate (refer to the supporting information).[25]
Scheme
7.
The
synthesis
of
a
trisubstituted
ketone
from
1-acetonaphthone with the key step being a Suzuki-Miyaura reaction using a heteroaryl
boronic acid
With multiple methods now identified for the synthesis of α,α-
disubstituted aryl ketones 12 and 15 containing the requisite
heteroaryl motif, our attention turned to the elaboration of
the ketone to install the dimethylethylamino tether. Although
Scheme 6. The conversion of diphenylacetylene to a trisubstituted ketone with the key
analogous
transformations
have
been
previously
step being a Suzuki-Miyaura reaction using a heteroaryl boronic acid
reported,[18,19] optimization of this pathway was still required
to identify reproducible and high-yielding reaction conditions.
The initial step involved the 1,2 carbonyl addition of an allyl
To enable the efficient preparation of the requisite iodo-
alkene 19 from diphenylacetylene (16), our group recently
reported a new iodoacyloxylation protocol of alkynes utilizing
iodobenzene diacetate and iodine.[26] This method facilitated
the introduction of both a halide and acetoxy group to afford
an enol ester that can readily undergo palladium cross-
coupling reactions. The Suzuki-Miyaura reaction between 19
and 20 yielded tri-aryl substituted enolate 21 in 85% yield. The
enolate was subsequently hydrolyzed under basic conditions
to afford quinoline substituted acetophenone 15 (Scheme 6).
During the Suzuki-Miyaura reaction, the formation of trace
amounts of the by-product 2,2'-dimethoxy-3,3'-biquinoline
was observed as a result of dimerization of the quinoline
boronic acid.
group across ketone 12 to afford the tertiary allyl alcohol 24
.
Despite numerous attempts by our group and others[19] to
react various organometallic reagents with the ketone
including Grignard reagents, aryl and alkyl lithiums and zinc
enolates (under Reformatsky conditions), the only reaction
that proved successful in this case was the use of freshly
prepared allyl-ZnBr (Scheme 8).[19] It was proposed that due to
the acidity of the
α-proton of the ketone, basic Grignard
reagents led to deprotonation and enolization of the ketone
before 1,2-addition to the carbonyl group could occur.
Organozincates are non-basic reagents and as such, the use of
allyl zinc bromide did not promote enolization but facilitated
the addition of the allyl group to the carbonyl to afford the
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requisite tertiary alcohol 24 in excellent yield of 92% (Scheme
8).[19] An alternative approach towards enhancing the
reactivity of Grignard reagents during the 1,2-addition to
enolisable carbonyl compounds through the formation of
29]
LaCl3∙2LiCl complexes has been recently reported,[28,
however in our hands, the use of allyl-ZnBr proved
satisfactory. During optimization, it was observed that if the
reaction was performed at lower temperatures (for example,
0oC), the formation of the R,R & S,S diastereoisomeric pair was
favored. However, typically a diastereomeric ratio of 1:1 could
be achieved when the reaction was undertaken at 30 oC. If
excess allyl-ZnBr (>2.0 equiv.) was employed or the reaction
time prolonged (>1h), cleavage of the 2-methoxy group to
afford the 2-desmethoxy version of 24 took place.
Scheme 9. Conversion of the allyl group to the dimethylamino tether
As demonstrated, multiple synthetic approaches have been
identified to access analogues of bedaquiline from either
heteroaryl boronic acids or heteroaryl halides . These
3
6
7
pathways facilitate access to a diverse range of bedaquiline
analogues whereby the quinoline motif would be readily
replaceable by any number of heterocyclic functional groups.
Scheme 8. Allylation of ketone 12 afforded the tertiary alcohol 24
With the allyl motif installed, the next step was oxidative
cleavage of the alkene to afford an aldehyde which could be
subsequently reduced to the alcohol. Literature reports
described the use of ozonolysis to achieve this
transformation,[18] however, in our hands, ozonolysis resulted
in highly variable yields and, in some cases, substrate
degradation (particularly in the case of electron rich N-
heterocycles). To circumvent this, a more mild ruthenium
chloride catalysed oxidative cleavage protocol was employed
using sodium periodate in an acetonitrile/water solvent
combination (Scheme 9).[30] These reaction conditions reliably
converted alkene 24 to aldehyde 25 which was subsequently
reduced using NaBH4 in MeOH to afford diol 26 in 57% yield
over two steps. During the early stages of this investigation,
reductive amination of aldehyde 25 with various amines was
To further highlight the value of the synthetic approaches
described herein, bedaquiline analogues were prepared
whereby the 2-methoxyquinoline was replaced with either 2-
methoxypyridine or 2,6-dimethoxypyridine (Scheme 10).
Preparation of the 2-methoxypyridine analogue 32 involved a
key palladium-catalysed Suzuki-Miyaura cross-coupling
reaction between a commercially available 2-methoxypyridine-
3-boronic acid (28) and diphenyl-iodoacetate 19 (scheme 10,
left). Subsequent hydrolysis of the triaryl enol acetate 29
afforded the requisite ketone 30. During optimization, it was
observed that bromination of the 5-pyridyl position of 30 to
form 31 was required prior to reaction with allyl zinc bromide
to avoid allylation at this position. Allylation of 31, followed by
conversion of the allyl group to the ethyl dimethylamino tether
afforded the bedaquiline analogue 32 in 49% yield over five
steps. To access the 2,6-dimethoxypyridyl analogue 37, a key
palladium catalysed Suzuki-Miyaura cross-coupling reaction
between bis-boronate 17 and 3-bromo-2,6-dimethoxypyridine
explored, however in each case,
a retro-aldol reaction
predominated to regenerate ketone 12. To complete this
pathway, tosylation of the primary alcohol, which was
subsequently displaced by dimethylamine afforded the final
compound 27 in an excellent yield of 85% over two steps
(Scheme 9). The diastereomeric pairs (RR & SS) and (RS & SR)
were readily separable by preparative HPLC (refer to the
supporting information).
(
33) afforded 34 as a masked enol in 77% yield (Scheme 10,
right). Oxidation of the remaining boronate group provided
ketone 35 in 90% yield, which was subsequently brominated to
afford 5-bromopyridine 36, which was then able to be
converted to bedaquiline analogue 37 in 38% yield over five
steps using methods analogous to that described previously
(Scheme 10, right).
Conclusion
To enable the preparation of novel pharmaceutical agents for
the treatment of MDR-TB that exhibit improved safety profiles,
novel synthetic pathways to access bedaquiline analogues
were required. To this end, multiple synthetic approaches that
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facilitate the efficient incorporation of heterocyclic motifs Experimental details including NMR spectra for all compounds
other than quinoline have been developed. Importantly, are included in the supporting information.
orthogonal approaches that allow the use of either heteroaryl
halides or heteroaryl boronic acids as substrates were
Notes and references
identified. Infact, through judicious reagent choice, the
methods described herein will facilitate substitution of the
quinoline, phenyl and/or naphthyl groups present in
bedaquiline. Application of these synthetic pathways in a drug
discovery program focused on the development of bedaquiline
analogues with an improved safety profile is underway in our
laboratories and these results will be reported in due course.
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10.
Preparation
of
2-methoxypyridine
and
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Experimental Section
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29 For selected recent applications refer to (a) S. A. Ruider, T.
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