Investigating the Influence of (Deoxy)fluorination on the Lipophilicity of Non-UV-Active Fluorinated Alkanols and Carbohydrates by a New log P Determination Method

Article abstract of DOI:10.1002/anie.201509460

Property tuning by fluorination is very effective for a number of purposes, and currently increasingly investigated for aliphatic compounds. An important application is lipophilicity (log P) modulation. However, the determination of log P is cumbersome fo

Full text of DOI:10.1002/anie.201509460

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201509460
German Edition: DOI: 10.1002/ange.201509460
Lipophilicity Very Important Paper
Investigating the Influence of (Deoxy)fluorination on the Lipophilicity
of Non-UV-Active Fluorinated Alkanols and Carbohydrates by a New
logP Determination Method
Bruno Linclau,* Zhong Wang, Guillaume Compain, Vincent Paumelle, Clement Q. Fontenelle,
Neil Wells, and Alex Weymouth-Wilson
Abstract: Property tuning by fluorination is very effective for
a number of purposes, and currently increasingly investigated
for aliphatic compounds. An important application is lip-
ophilicity (logP) modulation. However, the determination of
logP is cumbersome for non-UV-active compounds. A new
variation of the shake-flask logP determination method is
presented, enabling the measurement of logP for fluorinated
compounds with or without UV activity regardless of whether
they are hydrophilic or lipophilic. No calibration curves or
measurements of compound masses/aliquot volumes are
required. With this method, the influence of fluorination on
the lipophilicity of fluorinated aliphatic alcohols was deter-
mined, and the logP values of fluorinated carbohydrates were
measured. Interesting trends and changes, for example, for the
dependence on relative stereochemistry, are reported.
lower lipophilicity. Examples include the replacement of gem-
dimethyl groups by oxetanes,[7] or using 1,3,4-oxadiazoles
instead of their 1,2,4-isomers.[8]
Lipophilicity is also influenced by fluorination.[9,10]
Whereas it is still frequently stated that fluorination increases
lipophilicity, this is typically limited to aromatic sub-
strates.[9,11] For aliphatic compounds, C H!C F, or even
CH3!CF3 exchange, can lead to a logP decrease.[9,10a] As
fluorine is introduced in lead optimization for the optimiza-
tion/introduction of an ever-increasing list of properties, it is
important to understand how the compound lipophilicity will
be influenced when fluorination is applied for this purpose, or
indeed how it can be directly used to modulate lipophilicity.
For aromatic substrates, the influence of fluorination on
logP has been studied in detail. In contrast, few systematic
studies are available for aliphatic compounds.[12] In a seminal
contribution,[12b] Carreira, Müller, and co-workers showed
that two competing effects affect lipophilicity, namely
À
À
P
otency optimization is a natural focus in drug development.
However, potency gain achieved at the expense of physico-
chemical and pharmacokinetic properties compromises drug
efficacy and safety, increasing attrition rates.[1] In this regard,
the inappropriate use of lipophilicity (logP) to increase
potency, which is referred to as “molecular obesity”, has been
identified as a key problem.[2] The ability to maintain low
lipophilicity levels while increasing molecular weight is
regarded as one of the keys to a successful drug-discovery
program.[3] New efficiency metrics have been introduced for
gauging the lipophilicity contribution to potency.[1a,4,5]
À
changes in polarity (polar C F bond) and in the hydro-
phobicity of the surface (non-polarizable fluorine atoms).
They also showed for a series of trifluoromethylated aromatic
compounds, that this balance depends on the absolute logP
value of the compound: For highly lipophilic compounds,
changes in polarity tend to dominate (logP tends to decrease
upon F introduction), whereas for polar compounds, changes
in the hydrophobic surface area dominate (logP tends to
increase). Later on, Müller introduced a straightforward bond
vector analysis as a qualitative method for assessing the
polarity of partially fluorinated alkyl and alkoxy groups, and
its repercussions on compound lipophilicity.[13]
Hence, given that late-stage drug attrition is a very costly
and major contemporary problem, new insights for control-
ling lipophilicity (which is related to important properties
such as bioavailability)[6] are of great interest. An attractive
strategy is substituting substructures for alternatives with
The presence of functional groups close to fluorination
sites further affects logP, often in unpredictable ways, which
are yet to be fully explored. A clear barrier for progress in this
field is the actual logP determination process. Whereas many
methods are available, these are cumbersome (requiring
calibration curves). HPLC-based methods[14] are less suitable
when accurate logP values are required and subject to
limitations.[15] Above all, quantification typically rests on UV
spectroscopy, which hampers the measurement of non-UV-
active solutes (even commercially). NMR-based meth-
ods[12a,16] are cumbersome or not easily amenable for use in
typical multiuser NMR facilities. The calculation of logP is
also possible (clogP), but accuracy is strongly dependent on
the training sets used, stereochemistry cannot be taken into
account, and errors of multiple logP units are no exception.[17]
[*] Prof. Dr. B. Linclau, Z. Wang, Dr. G. Compain, V. Paumelle,
Dr. C. Q. Fontenelle, Dr. N. Wells
Chemistry, University of Southampton
Highfield, Southampton, SO17 1BJ (UK)
E-mail: bruno.linclau@soton.ac.uk
Dr. A. Weymouth-Wilson
Dextra Laboratories Ltd, The Science and Technology Centre
Earley Gate, Whiteknights Road, Reading RG6 6BZ (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509460.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Herein, we present
a practical and experimentally
straightforward method for the accurate determination of
674
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 674 –678

Angewandte
Communications
Chemie
the lipophilicity (Æ 0.01logP) of fluorinated compounds that
point (O1P) is ideally set equidistant between the fluorine
is based on 19F NMR spectroscopy. The method is illustrated
by determining the logP values of fluorinated alkanols, as
representatives of a biologically relevant group, and we
present the first logP values of fluorohydrin diastereomers as
well as of mono- and polyfluorinated carbohydrates. The
remarkable power of even single fluorination to modulate
logP in both directions is highlighted.
signals to ensure that both are equally excited (important
when applying a reduced SW). Indeed, the 1 values signifi-
cantly changed upon varying the O1P value (Table S3), but
virtually no effect was seen on the logP value owing to the
aforementioned compensation effect. Accurate integration
also rests on complete nuclear relaxation, requiring a suffi-
ciently long pulse delay time (D1). It was determined that the
1 values did depend on the D1 value, with a non-negligible
effect on the logP values (Æ 0.04 units, Table S4). This is due
to the solvent dependence of the fluorine spin–lattice
The principle of the method (Figure 1) is based on the use
of an internal (fluorinated) reference (ref): A mixture of ref
relaxation times (T1), invalidating the compensation
effect for this parameter. Hence, the T1 values of
a number of compounds were determined prior to
logP measurement (Table S5), revealing that the T1
values are generally higher in water than in octanol,
and tend to be higher for monofluorinated com-
pounds (up to 8 s) than for the corresponding di- and
trifluorinated compounds (up to 4.5 s). Given that T1
determinations are time-consuming, very conserva-
tive D1 settings (ideally 5 ” T1) of 30 s (octanol) and
60 s (water) were chosen. Finally, the S/N ratio is also
Figure 1. Principle of the logP determination method. See the Supporting
positively influenced by an increased number of
Information for a detailed procedure.
scans (NS). However, reducing SW and increasing
NS significantly increases experiment time, and for
and an unknown compound (X) is partitioned between (non-
deuterated) octanol and H2O. An aliquot of each phase is
transferred to an NMR tube, and its 19F NMR spectrum is
taken. By reprocessing each FID, the integration ratio
between the peaks of X and ref can be determined. These
ratios are defined as 1aq and 1oct, and correspond to the ratio
of the respective concentrations. If the peaks represent
a different number (n) of fluorine substituents, then a correc-
tion factor is applied [Eq. (1)]. The ratio of the 1 values is
equal to the ratio of the respective P values [Eq. (2)].
Rewriting this as Eq. (3) then results in Eq. (4), which
shows that the logP value of the unknown compound can
be obtained by adding the logarithm of the ratio of the
measured 1 values to the known logP value of the reference
compound.
typical experiments, SW= 300 ppm and NS = 64 were used.
Because of the compensation effect, the identity of the
reference compound is less important. However, when
a reduced SW is used, the window must encompass both
chemical shifts. Furthermore, to achieve an optimal integra-
tion ratio between 0.1 and 10, the relative compound
quantities should be adjusted, and a reference compound
with an appropriate relative logP value (guided by clogP of
the unknown) should be selected. The method rests on the
assumption that the intermolecular interactions between X
and ref are negligible or at least do not influence the logP
value, which was confirmed experimentally (Table S6). In any
case, this compares favorably to most high-throughput shake-
flask logP determinations, where compounds are typically
added to octanol/water as a solution in DMSO.[19]
There are a number of practical advantages associated
with this method. Because of the compensation effect
inherent to the determination of a ratio of a ratio, systematic
errors are eliminated, and no quantitative measurement is
required for an absolute amount of material, phase volumes
(respecting solubilities), and NMR aliquot volumes. Small
impurities are tolerated given only the compound signals are
integrated.
Accurate quantitative integration is crucial to the method.
Further to standard data processing (window function (LB),
zero filling, phasing, and baseline correction), a good signal to
noise ratio (S/N) is essential, which is significantly enhanced
for fluorine signals by proton decoupling. The use of inverse
gated decoupling minimizes any potential interference from
nuclear Overhauser effects (nOes; see the Supporting Infor-
mation, Table S1).[18] Narrowing the spectral width (SW)
increases digital resolution and the S/N ratio, but we
experimentally found that these settings did not influence
the determined logP value (Table S2). The frequency offset
The method was validated by the determination of known
logP values. The complete set of results is given in the
Supporting Information (Tables S7–S12), and shows that the
values are generally very similar to reported data (Table S12)
despite the fact that a number of different logP values can
often be found in the literature. Furthermore, the internal
consistency of the method was confirmed by a control
experiment (Tables S9–S11). Lipophilicity measurements
were typically carried out in triplicate, and excellent repro-
ducibility was observed (generally < 0.005 logP units). Devi-
ations occurring by different reprocessings of the same FID
were very minimal (Table S8). We then embarked on
determining the logP values of a range of known and novel
fluorinated alkanols (Figure 2). The color coding visualizes
how for the library investigated, for a given scaffold, mono-
fluorination lowers the logP value—in contrast to aromatic
monofluorination—which then increases upon further fluori-
nation, with few exceptions.
Angew. Chem. Int. Ed. 2016, 55, 674 –678
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
675

Angewandte
Communications
Chemie
Figure 2. Lipophilicity map of fluorinated alcohols. See the Supporting Information, Figure S1–S10 for detailed maps and further comments.
The increase in logP upon alcohol b-trifluorination (ca.
0.65 units; compounds 3 and 6), as well as the steady reduction
in this increase—even reverting into a logP decrease—as the
trifluorinated carbon atom is positioned further away from
the alcohol group upon chain elongation (12, 23, 35) was
known,[12a] and could be explained by the increasing impor-
tance of the CF3 polarity upon increasing the lipophilicity of
the parent alcohol (see the Carreira/Müller observation).[12b]
However, our determination that a shift of approximately
0.65 logP is maintained for the much more lipophilic 29,
a novel compound, shows that the actual b-trifluorination
effect is independent of the absolute logP value. Double
b-trifluorination, as in 7 and 15, causes a significant logP
increase. Pentafluorinated substrates (13, 20, 24, and 36) show
a further increase in lipophilicity. Interestingly, the DDlogP
value for the corresponding trifluorinated derivatives is
strongly dependent on whether the pentafluoroethyl group
is in the a-position of the alcohol group or not (12/13, 18/20 vs.
23/24, 35/36).
In all cases except 2 (D =+ 0.01), the introduction of
a gem-difluoro group (Figure S4) leads to a decrease in logP,
which can be substantial (32: D = À0.80) regardless of
whether it occurred at a terminal or internal alkane position.
Interestingly, b-difluorination (as in 11) leads to a decrease in
logP, which is markedly different from the increase caused by
b-trifluorination as discussed above.
Monofluorination, as expected, always leads to a decrease
in the logP value regardless of the position; this change can
be very substantial: For the 1-pentanol series, a decrease of
0.99 logP units was observed when the 4- or the 5-position
was fluorinated (30 and 31). For the same parent compound,
fluorination in the 2-position (33) results in a much smaller
logP decrease. For the parent compounds F and C, there is
a small logP difference between 3- versus 4- and 2- versus 3-
fluorination despite the fact that in the latter case (8), the
fluorine is in the b-position of the alcohol. We also deter-
mined the logP values of diastereomeric fluorohydrins. The
syn diastereomer 37 is less lipophilic than anti diastereomer
38, likely because the (more polar) conformation with aligned
À
À
C O/C F dipoles will be more stabilized in water than the
equivalent conformer of the anti isomer (Figure S6). Inter-
estingly, a second monofluorination at a different position
only leads to a minor further decrease (5!4). The vicinally
difluorinated diols 39 and 40 only have a slightly reduced
logP value compared to J, with a minimal difference between
the diastereomers.
The decrease in logP observed upon replacing CH with
CF is not seen when the carbon atom already had a fluorine
substituent: for the compounds investigated, the gem-difluori-
nated substrates were always more lipophilic than the
corresponding monofluorinated substrate(s). Equally, replac-
ing a CHF2 group with a CF3 group leads to an increase in
logP, which is substantial with an a-hydroxy group (2!3).
The same effect was seen when going from CF2CF2H to
CF2CF3 (19!20; 34!36), but it is more pronounced the
greater the distance to the hydroxy group. The much lower
lipophilicity of the tetrafluorinated compound 34 compared
to trifluorinated 35 (DDlogP = 0.25) is interesting, and reveals
a higher polarity of the CF2CF2H group compared to CH2CF3
despite it having one more fluorine substituent, which is likely
due to a conformation effect (see Figure S9). The identifica-
tion of such space-filling groups is of great interest in
medicinal chemistry.
676
www.angewandte.org
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 674 –678

Angewandte
Communications
Chemie
Figure 3. Lipophilicities of conformationally rigid cyclohexanols.
The influence of fluorination on rigid cyclohexanols was
also investigated (Figure 3). For K, equatorial or axial
fluorination at the 2-position gave very similar effects on
logP (42, 43; DlogP = À0.47 Æ 0.01). In contrast, axial
monofluorination of cyclohexanol L in the 2- or 3-position
led to very different changes of logP: for vicinal trans
fluorohydrin 44, an increase in logP was observed. This
represents, to the best of our knowledge, the first example of
an increase in logP induced by monofluorination of an
aliphatic alcohol. Interestingly, the clogP values of 44 are
vastly underestimated (Table S14). Conversely, 1,3-diaxial
fluorohydrin 45 showed a significant decrease in logP,
exceeding that observed for acyclic 1,3-fluorohydrins. The
Figure 4. Lipophilicities of fluorinated carbohydrates.
differ in the stereochemistry at the fluorine-substituted
2-position, is only 0.1 logP units. The lipophilicity of sugars
in which two hydroxy groups have been removed further
increases by another logP unit: 2,3-Dideoxy-2,3-difluoroglu-
cose 52 is about 2.1 logP units more lipophilic than Glc.
Interestingly, 2,3-dideoxymonofluorinated 51 is much more
À
À
aligned C O and C F dipoles in 45 will be responsible for the
À
À
significant decrease in logP. In contrast, the C O/C F dipoles
À
are opposed in 44, which leads to a logP increase. The
hydrophilic. The change from 51 to 52 represents CH H for
À
À
unavoidable antiperiplanar C F/
CH F replacement, and this is only the second example here
À
C OH orientation in a-trifluoromethylated alcohols will
with a logP increase for such a change. A further increase by
one logP unit is achieved by trideoxyfluorination as in 2,3,4-
trideoxy-2,3,4-trifluoroglucose 55.[23] Interestingly, this 103
fold increase in the P value can also be achieved by mere
dideoxygenation if the individual CHOH groups are both
replaced by CF2 groups (as in 53, 54). For these sugar
derivatives, the relative configuration of the remaining
CHOH group also strongly impacts on the lipophilicity.
In conclusion, we have presented a new and facile logP
determination method, which is suitable for fluorinated
compounds, whether they are UV-active or not, and appli-
cable to lipophilic and hydrophilic compounds with a logP
range of up to Æ 3 and for different solvents besides octanol.
The lipophilicities of a range of acyclic and conformationally
rigid fluorohydrins were reported. We showed that mono-
fluorination can lead to very large decrease in logP, that
relative stereochemistry has a measurable effect on logP,
which is especially pronounced for rigid, cyclic fluorohydrins,
and that the DlogP value upon introducing a certain motif
does not always depend on the absolute logP value. We have
also quantified the lipophilicity changes upon sugar deoxy-
fluorination, showing the significant dependence on position,
stereochemistry, number of fluorination sites, and fluorina-
tion motif. Given the contemporary emphasis on developing
three-dimensional C(sp3)-containing scaffolds,[24] the need for
similarly contribute to the strong increase in their logP
values (see above).
Fluorinated carbohydrates find application as mecha-
nism-based inhibitors,[20] for the stabilization of glycosidic
bonds,[21] and have historically also been used as probes for
sugar epitope mapping.[22] Briefly, a decreased binding affinity
upon monodeoxyfluorination indicates a hydrogen bond
(HB) donor function for the replaced alcohol, whereas
a similar binding affinity suggests that it functions as an HB
acceptor. However, it is difficult to take the altered lip-
ophilicity of fluorinated carbohydrates into account in bind-
ing data interpretations, in part because there are no
quantitative data regarding the influence of deoxyfluorina-
tion on carbohydrate lipophilicity. Given the difficult quan-
tification of carbohydrate concentrations, as well as the fact
that the clogP values for diastereomeric sugars are identical,
these substrates were deemed an ideal test case to demon-
strate the usefulness of our logP determination method,
taking into account that the fluorine signals of both anomers,
and possibly the furanose forms, need to be integrated. The
results (Figure 4) show that the influence of monodeoxy-
fluorination on lipophilicity is already significant, and clearly
depends upon position and sugar stereochemistry (46–50).
However, the logP difference between 49 and 50, which only
Angew. Chem. Int. Ed. 2016, 55, 674 –678
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
677

Angewandte
Communications
Chemie
[10] a) H. J. Bçhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K.
Müller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637 –
643; b) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem.
Soc. Rev. 2008, 37, 320 – 330; c) D. OꢀHagan, Chem. Soc. Rev.
2008, 37, 308 – 319.
facile analysis of non-UV-active compounds will increase
considerably. Hence, the convenience of this method, which
does not require specialist/cumbersome operations such as
solvent suppression or concentration determinations, brings
logP measurements of fluorinated compounds within reach of
scientists with access to NMR spectrometers, which should
rapidly and significantly boost knowledge in this important
field, and easily allow for experimental verification of logP
predictions. Further method development is in progress in our
laboratory.
[11] K. Mueller, C. Faeh, F. Diederich, Science 2007, 317, 1881 – 1886.
[12] For examples, see: a) N. Muller, J. Pharm. Sci. 1986, 75, 987 –
991; b) Q. A. Huchet, B. Kuhn, B. Wagner, H. Fischer, M. Kansy,
D. Zimmerli, E. M. Carreira, K. Müller, J. Fluorine Chem. 2013,
152, 119 – 128; c) S. A. Samsonov, M. Salwiczek, G. Anders, B.
Koksch, M. T. Pisabarro, J. Phys. Chem. B 2009, 113, 16400 –
16408; d) A. Orliac, J. Routier, F. B. Charvillon, W. H. Sauer, A.
Bombrun, S. S. Kulkarni, D. G. Pardo, J. Cossy, Chem. Eur. J.
2014, 20, 3813 – 3824; e) A. V. Chernykh, D. S. Radchenko, A. V.
Chernykh, I. S. Kondratov, N. A. Tolmachova, O. P. Datchenko,
M. A. Kurkunov, S. X. Zozulya, Y. P. Kheylik, K. Bartels, C. G.
Daniliuc, G. Haufe, Eur. J. Org. Chem. 2015, 29, 6466 – 6471.
[13] K. Müller, Chimia 2014, 68, 356 – 362.
[14] R. J. Young, D. V. S. Green, C. N. Luscombe, A. P. Hill, Drug
Discovery Today 2011, 16, 822 – 830.
[15] G. Caron, M. Vallaro, G. Ermondi, MedChemComm 2013, 4,
1376 – 1381.
[16] H. Mo, K. M. Balko, D. A. Colby, Bioorg. Med. Chem. Lett. 2010,
20, 6712 – 6715.
Acknowledgements
We thank the EPSRC (fellowship EP/K016938/1 and core
capability EP/K039466/1), Dextra (CASE studentship), and
the European Community (INTERREG IVa Channel Pro-
gramme, AI-Chem, project 4494/4196) for funding. We thank
Prof. David OꢀHagan for a gift of 2,3,4-trideoxy-2,3,4-
trifluoroglucose (55), and Dextra Laboratories for a donation
of monodeoxofluorinated sugars.
[17] M. J. Waring, Expert Opin. Drug Discovery 2010, 5, 235 – 248.
[18] T. Claridge, High-Resolution NMR Techniques in Organic
Chemistry, Pergamon, New York, 1999.
[19] M. Shalaeva, G. Caron, Y. A. Abramov, T. N. OꢀConnell, M. S.
Plummer, G. Yalamanchi, K. A. Farley, G. H. Goetz, L. Philippe,
M. J. Shapiro, J. Med. Chem. 2013, 56, 4870 – 4879, and refer-
ences therein.
Keywords: fluorinated carbohydrates · fluorine · fluoroalcohols ·
lipophilicity · NMR spectroscopy
How to cite: Angew. Chem. Int. Ed. 2016, 55, 674–678
Angew. Chem. 2016, 128, 684–688
[20] J.-H. Kim, R. Resende, T. Wennekes, H.-M. Chen, N. Bance, S.
Buchini, A. G. Watts, P. Pilling, V. A. Streltsov, M. Petric, R.
Liggins, S. Barrett, J. L. McKimm-Breschkin, M. Niikura, S. G.
Withers, Science 2013, 340, 71 – 75.
[21] a) S. S. Lee, I. R. Greig, D. J. Vocadlo, J. D. McCarter, B. O.
Patrick, S. G. Withers, J. Am. Chem. Soc. 2011, 133, 15826 –
15829; b) M. N. Namchuk, J. D. McCarter, A. Becalski, T.
Andrews, S. G. Withers, J. Am. Chem. Soc. 2000, 122, 1270 –
1277.
[22] a) C. P. J. Glaudemans, Chem. Rev. 1991, 91, 25 – 33; b) R. U.
Lemieux, Chem. Soc. Rev. 1989, 18, 347 – 374.
[23] a) S. Bresciani, T. Lebl, A. M. Z. Slawin, D. OꢀHagan, Chem.
Commun. 2010, 46, 5434 – 5436; b) M. J. Corr, D. OꢀHagan, J.
Fluorine Chem. 2013, 155, 72 – 77.
[1] a) A. Tarcsay, G. M. Keseru, J. Med. Chem. 2013, 56, 1789 – 1795;
b) M. P. Gleeson, A. Hersey, D. Montanari, J. Overington, Nat.
Rev. Drug Discovery 2011, 10, 197 – 208.
[2] a) J. A. Arnott, S. L. Planey, Expert Opin. Drug Discovery 2012,
7, 863 – 875; b) M. M. Hann, MedChemComm 2011, 2, 349 – 355;
c) P. D. Leeson, B. Springthorpe, Nat. Rev. Drug Discovery 2007,
6, 881 – 890.
[3] E. Perola, J. Med. Chem. 2010, 53, 2986 – 2997.
[4] a) M. D. Shultz, Bioorg. Med. Chem. Lett. 2013, 23, 5992 – 6000;
b) K. D. Freeman-Cook, R. L. Hoffman, T. W. Johnson, Future
Med. Chem. 2013, 5, 113 – 115.
[5] A. Tarcsay, K. Nyiri, G. M. Keseru, J. Med. Chem. 2012, 55,
1252 – 1260.
[6] F. Yoshida, J. G. Topliss, J. Med. Chem. 2000, 43, 2575 – 2585.
[7] G. Wuitschik, E. M. Carreira, B. Wagner, H. Fischer, I. Parrilla,
F. Schuler, M. Rogers-Evans, K. Mueller, J. Med. Chem. 2010, 53,
3227 – 3246.
[24] F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52,
6752 – 6756.
[8] J. Bostrçm, A. Hogner, A. Llinas, E. Wellner, A. T. Plowright, J.
Med. Chem. 2012, 55, 1817 – 1830.
Received: October 9, 2015
[9] B. E. Smart, J. Fluorine Chem. 2001, 109, 3 – 11.
Published online: November 23, 2015
678
www.angewandte.org
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 674 –678