Synthesis of Diverse α-Fluoroalkoxyaryl Derivatives and Their Use for the Generation of Fluorinated Macrocycles

Article abstract of DOI:10.1002/chem.201804440

Introduction of difluorinated functionality has emerged as a powerful means for conformational design with minimal steric footprint. Synthetic approaches for the preparation of aryl difluoromethylene ether containing novel building blocks were established, enabling the inclusion of the aryl difluoromethylene ether system into macrocyclic scaffolds for the first time.

Full text of DOI:10.1002/chem.201804440

A Journal of
Accepted Article
Title: Synthesis of Diverse α-Fluoroalkoxyaryl Derivatives and their Use
for the Generation of Fluorinated Macrocycles
Authors: Laurent Knerr, Thomas Cogswell, and Anders Dahlén
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Synthesis of Diverse α-Fluoroalkoxyaryl Derivatives and their Use
for the Generation of Fluorinated Macrocycles.
Thomas Cogswell*, Anders Dahlén and Laurent Knerr*
inhibitors (Figure 1).14 These results were generated exclusively
Abstract: Introduction of difluorinated functionality has emerged as
on acyclic systems and, to the best of our knowledge,
introduction of the α-fluoroalkoxyaryl group in macrocyclic
scaffold is unprecedented. In a first step, it was our aim to
develop flexible synthetic approaches enabling the introduction
of the α-fluoroalkoxyaryl moiety into diverse macrocyclic
systems.
a powerful means for conformational design with minimal steric
footprint. Synthetic approaches for the preparation of aryl
difluoromethylene ether containing novel building blocks were
established, enabling the inclusion of the aryl difluoromethylene
ether system into macrocyclic scaffolds for the first time.
The rational introduction of fluorine atoms has become a key tool
for organic chemists to modulate not only the physico-chemical
but also the conformational properties of a molecule. With the
tremendous progress made to extend the variety of synthetic
fluorination methods1 available, it is no surprise to see the
increasing impact of fluorination in contemporary catalysis,2
Figure 1. Hyperconjugative π–σ*C–F interaction rationale for the reduced in-
plane conformational preference of a fluoroalkoxyaryl group as exemplified by
PhOCF2CF2H.14
pharmaceutical3 and agrochemical4 design.
Among the
properties of the C-F bond,5 its capacity to engage in charge-
dipole interactions, dipole–dipole interactions as well as
hyperconjugation have all been exploited to fine-tune the
conformation of a wide range of biomolecules including fatty
acids,6 alpha,7 beta8 and gamma9 amino acids and their
oligomers. Some of these approaches have recently been
applied to the modulation of the conformation of macrocyclic
scaffolds. O’Hagan and coworkers have, for example, probed
the introduction of difluoromethylene units as conformational
constrains in macrocyclic musk lactones.10 Furthermore Hunter
and coworkers have elegantly demonstrated the pronounced
impact that the gauche effect of a vicinal difluorinated alkyl chain
has on the conformation of derivatives of Unguisin A.11 Based on
these precedents and in view of the importance of macrocycles
in drug discovery,12 we became interested in the possibility of
using α-fluoroalkoxyaryl groups13 as a potential manifold to
increase shape diversity of macrocyclic scaffolds. Indeed, while
in the absence of steric hindrance alkoxyphenyl groups are
known to align in the plane of the aryl ring, α-fluoroalkoxyaryl
groups ArOCF2R and ArOCF3 have been shown to reduce the
in-plane conformational preferences (Figure 1).3e,3j,13 This can be
rationalized by the hyperconjugation taking place between the
low energy σ*C-F antibonding orbitals and the oxygen lone pairs.5
Although this effect has been reported to be more pronounced
for ArOCF3,3e,3j,13 it has found some application in drug design
with other fluorinated groups as exemplified by Massa and
coworkers, who demonstrated the use of the ArOCF2CF2H
functionality in the design of cholesteryl ester transfer protein
As interest into this functionality has grown, there has been much
synthetic effort made towards the installation of a variety of CF2
bearing groups into important scaffolds resulting in numerous
innovative and efficient approaches.13 One such approach was
recently reported by Ichikawa and coworkers and is based on an
α-selective Tsuji-Trost allylation to introduce a difluoropropene
chain onto a number of substituted 2-bromophenols 4 (Scheme
1).15
Scheme 1. 1,1-Difluoroallylation of ortho bromophenol according to Ichikawa
et al.15
This methodology gives rapid entry to the ArOCF2R functionality
and therefore was deemed to be a great starting point for this
work. With this in mind, the current scope, reported by Ichikawa
and coworkers, was examined and expanded (Scheme 2). The
reaction, which had previously been demonstrated only on
substituted 2-bromophenols, could be applied to further
examples including 3- and 4-bromophenols, which gave 6b and
6c with no loss of yield. Ester and alkene functionalities were well
tolerated, allowing formation of 6d-6f in good yields, giving
access to a wider variety of synthetic handles for further
chemical modification. A range of pharmaceutically relevant
[a]
Dr. T. J. Cogswell, Dr. A. Dahlén, Dr. L. Knerr
Cardiovascular and Metabolic Disease, Innovative Medicines and
Early Development, AstraZeneca R&D, Mölndal, SE-431 89,
Sweden
E-mail: Laurent.Knerr@astrazeneca.com
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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heterocyclic examples were also examined; sterically hindered
and highly functionalized systems could be tolerated as
demonstrated with the formation of trisubstituted pyridine 6g.
The substituted quinoline 6h was isolated in a good 70% yield.
The dihydroquinolinone 6i and indole 6j could also be prepared
via this approach albeit in moderate yield. Interestingly, a
protected tyrosine was subjected to the conditions producing the
difluoroallylated tyrosine 6k in good yield with no loss in
enantiomeric purity. This highlights the potential of this reaction
for the synthesis of fluorinated peptides and peptidomimetics.
The diol
8
was formed in good yield using standard
dihydroxylation conditions. The primary alcohol could be
accessed using reductive ozonolysis giving compounds 9 and 10
in high yield. The success of the ozonolysis demonstrated that
the alkene was a good dipolarophile for 1,3-dipolar cycloaddition
and therefore a subsequent reaction was attempted in the aim of
generating a 5-membered heterocycle. This was achieved, using
an oxime and oxidizing agent PhI(OAc)2,16 to produce
heterocycle 11 in 81% yield. Finally, using some conditions
optimized for trifluoropropene,17 a hydroformylation reaction was
utilized to convert alkene 6b to aldehyde 12.
Scheme 3. Reactivity scope of 1,1 difluoroallylated phenols. Reagents and
conditions: i). Pd/C, triethylsilane, MeOH, rt, 1 h. ii) K2OsO4.2H2O, NMO,
acetone/H2O, rt, 17 h. iii). O3, CH2Cl2 then NaBH4. iv) (E)-4-
(phenylethynyl)benzaldehyde oxime, PhI(OAc)2, TFA, MeOH, rt, 24 h. v)
[Rh(OH)(1,5-cod)]2, Xantphos, 1 atm 50:50 CO/H2, DMF, 80 °C, 24 h.
Further manipulation of alcohol 10 was investigated (Scheme 4).
To our delight several alkylation reactions in mild conditions
could be used to give access to a range of chemical handles
suitable for further functionalisation. Reaction with propargyl
bromide and allyl bromide produced the subsequent alkyne and
alkene products 13 and 14 in 91% and 92% yield, respectively.
The benzyl ester 16 could be generated in excellent yield
Scheme 2. Expanded scope of the Tsuji-Trost 1,1-difluoroallylation of
phenols and heterocyclic alcohols.
through reaction with
a a further
α-bromo ester.18 In
With a significantly expanded scope established, we then turned
our attention to the difluoroallyloxy moiety as its reactivity and
stability is largely unexplored. Ichikawa and coworkers
demonstrated that an intramolecular Heck reaction worked in
good to excellent yield (Scheme 1).15 To build on this result and
to access more complex difluorinated compounds by this
approach, it would be desirable to modify the resulting alkene
into a range of functionalities. To achieve this, the reactivity of
this group was explored (Scheme 3).
transformation, the alcohol 10 was successfully converted into
the corresponding triflate before treatment with H-Ala-OEt to
yield fluorinated N-alkyl-amino acid 15.19
The hydrogenation of 6b could be achieved in 90% yield using
mild conditions to give access to the difluoropropane moiety 7.
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Scheme 4. Functionalization of 2-(4-bromophenoxy)-2,2-difluoro-ethanol.
Reagents and conditions: i) propargyl bromide, Cs2CO3, DMF, rt, 48 h. ii) allyl
bromide, Cs2CO3, DMF, rt, 24 h. iii) benzyl 2-bromoacetate, Cs2CO3, DMF, rt,
17 h. iv) Tf2O, pyridine, CH2Cl2, 0 °C, 2h. v) H-L-Ala-OEt*HCl, DIPEA, DMF, rt,
17 h.
Scheme 6. Non-peptidic macrocycle synthesis.
In conclusion, the scope of the α-selective Tsuji-Trost
difluoroallylation reaction has been extended to include a variety
of substituted phenols, heterocycles and amino acid examples.
The resulting difluoroallyloxy functionality has been converted
into an array of different useful building blocks, such as primary
alcohols, aldehyde and a substituted alkene. Based on these
novel reagents, and for the first time, the synthesis of α-
fluoroalkoxyaryl containing macrocycles was completed.
Extension of this methodology to biologically relevant
macrocyclic scaffolds is ongoing. The study of the impact of the
introduction of α-fluoroalkoxyaryl groups on the conformational,
physicochemical and ADME properties of model macrocycles
will be reported in due course.
With a deeper understanding of the chemistry at hand, the
original goal of synthesizing a difluorinated macrocycle was
undertaken (Scheme 5). The fluorinated tyrosine 6k was chosen
as an interesting starting point and so was subjected to
ozonolysis/reduction conditions to yield the alcohol 17. This in
turn could be alkylated with benzyl 2-bromoacetate to give 18 in
good yield. Boc group removal and amide coupling gave access
to dipeptide 19. Subjection of 19 to hydrogenation conditions
removed both the Cbz and benzyl protection groups, allowing a
macrolactamisation reaction to be undertaken which, to our
delight, produced the desired difluorinated macrocycle 20 in a
good yield.
Acknowledgements
This work was supported by the Initial Training Network,
FLUOR21 (TC), funded by the FP7 Marie Curie Actions of the
European Commission (FP7-PEOPLE-2013-ITN-607787). The
authors would like to acknowledge the support of the Structure
Analysis and Separation Science group of AstraZeneca
Gothenburg.
Keywords: Difluorinated • Macrocycles • 1,1-Difluoroallylation •
α-Fluoroalkoxyaryl • germinal fluorination
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Thomas Cogswell*, Anders Dahlén and
Laurent Knerr*
Page No. – Page No.
Synthesis of Diverse α-
Fluoroalkoxyaryl Derivatives and
their Use for the Generation of
Fluorinated Macrocycles.
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This article is protected by copyright. All rights reserved.