Inverting Small Molecule–Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H→F Bioisosterism

Article abstract of DOI:10.1002/anie.201905452

Fluorinated motifs have a venerable history in drug discovery, but as C(sp³)?F-rich 3D scaffolds appear with increasing frequency, the effect of multiple bioisosteric changes on molecular recognition requires elucidation. Herein we demonstrate that installation of a 1,3,5-stereotriad, in the substrate for a commonly used lipase from Pseudomonas fluorescens does not inhibit recognition, but inverts stereoselectivity. This provides facile access to optically active, stereochemically well-defined organofluorine compounds (up to 98 % ee). Whilst orthogonal recognition is observed with fluorine, the trend does not hold for the corresponding chlorinated substrates or mixed halogens. This phenomenon can be placed on a structural basis by considering the stereoelectronic gauche effect inherent to F?C?C?X systems (σ→σ*). Docking reveals that this change in selectivity (H versus F) with a common lipase results from inversion in the orientation of the bound substrate being processed as a consequence of conformation. This contrasts with the stereochemical interpretation of the biogenetic isoprene rule, whereby product divergence from a common starting material is also a consequence of conformation, albeit enforced by two discrete enzymes.

Full text of DOI:10.1002/anie.201905452

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Inverting Small Molecule-Protein Recognition by the Fluorine
Gauche Effect: Selectivity Regulated by Multiple H → F
Bioisosterism
Authors: Patrick Bentler, Klaus Bergander, Constantin G. Daniliuc,
Christian Mück-Lichtenfeld, Ravindra P. Jumde, Anna K. H.
Hirsch, and Ryan Gilmour
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905452
Angew. Chem. 10.1002/ange.201905452
Link to VoR: http://dx.doi.org/10.1002/anie.201905452
http://dx.doi.org/10.1002/ange.201905452

10.1002/anie.201905452
Angewandte Chemie International Edition
COMMUNICATION
Inverting Small Molecule-Protein Recognition by the Fluorine Gauche
Effect: Selectivity Regulated by Multiple H → F Bioisosterism
Patrick Bentler,a Klaus Bergander,a Constantin G. Daniliuc,a Christian Mück-Lichtenfeld,a Ravindra P. Jumde,b
Anna K. H. Hirsch,b,c and Ryan Gilmoura*
Dedicated to Prof. Dr. François Diederich on the occasion of his retirement
not inhibit recognition.[6]
Abstract: Fluorinated motifs have a venerable history in drug discovery,
but as C(sp3)-F-rich 3D scaffolds appear with increasing frequency, the
effect of multiple bioisosteric changes on molecular recognition requires
elucidation. Herein we demonstrate that installation of a 1,3,5-stereotriad,
in the substrate for a commonly used lipase from Pseudomonas fluorescens
does not inhibit recognition, but inverts stereoselectivity. This provides
facile access to optically active, stereochemically well-defined
organofluorine compounds (up to 98% ee). Whilst orthogonal recognition
is observed with fluorine, the trend does not hold for the corresponding
chlorinated substrates or mixed halogens. This phenomenon can be placed
on a structural basis by considering the stereoelectronic gauche effect
inherent to F-C-C-X systems (σ→σ*). Docking reveals that this change in
Figure 1. Stereochemical interpretation of the biogenetic isoprene rule.
selectivity (H versus F) with a common lipase results from inversion in the
orientation of the bound substrate being processed as a consequence of
Multiple hydrogen to fluorine substitution is ideally suited to the task,
conformation. This contrasts with the stereochemical interpretation of the
since this subtle steric modification induces a localised partial charge
biogenetic isoprene rule, whereby product divergence from a common
starting material is also a consequence of conformation, albeit enforced by
inversion (C-Hδ+ → C-Fδ-). This strategy enabling physicochemical
modulation[7] also provides
a potentially expansive platform to
two discrete enzymes.
modulate molecular recognition in a manner distinct from the role of
fluorine in interrogating enzyme function.[8] The strategic introduction
of configurationally defined C(sp3)-F centres offers an additional
degree of versatility in allowing the structural and electronic topology
to be regulated by stereoelectronic and electrostatic effects.[9]
Arigoni and Eschenmoser’s stereochemical interpretation of the
biogenetic isoprene rule is synonymous with placing enzyme function
on
a
structural level.[1] Predicated on efficient substrate pre-
organisation governed by a specific cyclase (Figure 1), this treatise
rationalises the conversion of oxidosqualene to either lanosterol or β-
amyrin. Described as the “apotheosis of the isoprene rule” by
Cornforth,[2] this interpretation has proven to be expansive and
continues to inform and inspire the design of cyclisation cascades for
the rapid generation of structural complexity.[3] This study, together
with the contemporaneous work from Stork and Burgstahler,[4]
nucleates upon an acyclic conformational analysis of oxidosqualene.[5]
The manifest selectivity of these two, discrete enzymatic processes is a
consequence of (i) minimisation of non-bonding interactions, and (ii)
further conformational refinement in the enzyme-substrate ensemble.
Whilst the latter is pervasive in enzyme catalysis and ultimately
responsible for structural divergence, achieving orthogonal reactivity
encoded at the substrate conformation level is comparatively
underexplored. This is a logical consequence of enzyme specificity and
the need for effective bioisosteres that modulate conformation but do
[a]
Dr. P. Bentler, Dr. K. Bergander, Dr. C. G. Daniliuc, Dr. C. Mück-
Lichtenfeld, Prof. Dr. R. Gilmour
Organisch Chemisches Institut, Westfälische Wilhelms-Universität
Münster, Corrensstraße 40, 48149 Münster, Germany.
E-mail: ryan.gilmour@uni-muenster.de
Homepage: www.uni-muenster.de/Chemie.oc/gilmour/
Dr. R. P. Jumde, Prof. Dr. A. K. H. Hirsch
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) –
Helmholtz Centre for Infection Research (HZI), Department of Drug
Design and Optimization, University Campus E8.1, D-66123
Saarbrücken, Germany.
[b]
[c]
Figure 2. Conceptual framework of this study (EWG: Electron Withdrawing
Group).
Department of Pharmacy, Saarland University, 66123 Saarbrücken,
Germany, D-66123 Saarbrücken, Germany.
This article is protected by copyright. All rights reserved.

10.1002/anie.201905452
Angewandte Chemie International Edition
COMMUNICATION
The stereoelectronic gauche effect[10] intrinsic to the 1,2-difluoro
motif,[11] together with electrostatic 1,3-repulsion, validate the potential
of synergistic fluorine effects and multiple bioisosterism in achieving
acyclic conformational control. Consequently, stereochemically
complex, fluorine-rich architectures are suited to divert the intrinsic
selectivity of a given enzyme, observed with the non-fluorinated case,
via two discrete substrate-enzyme ensembles (Figure 2, top).[12] As a
model for this study, the desymmetrisation of a meso-acetate (X = H)
utilising lipase from Pseudomonas fluorescence was investigated
(Figure 2, bottom).[13,14] This scaffold is a convenient platform to
interrogate multiple bioisosterism (X = H, F and Cl) as a function of
Van der Waals radii, and allows for conformational regulation by
virtue of the fluorine gauche effect and 1,3-repulsion. The
desymmetrisation platform would also provide facile access to
stereochemically complex, multiply fluorinated systems in an optically
active form.[15] Derivatives of the parent scaffold continue to be
produced on an industrial scale for the production of various
blockbuster pharmaceuticals such as Lipitor® and related statins.[16]
Moreover, 1,3-syn diols are ubiquitous in polyketides, and construction
of the 1,3,5-trifluoro motif is a highlight of Carreira’s synthesis of a
fluorosulfolipid (Figure 2, bottom).[17]
site of the Pseudomonas fluorescens HU380 lipase to establish if the
bound topologies showed appreciable differences. This analysis
revealed a striking difference in both the orientation and conformation
of these closely similar molecules in the active site. The conformation
of the bound, fluorinated meso-substrate clearly manifested fluorine-
ester gauche effects, and partial miminisation of 1,3-repulsion (Figure
3a,b. For a computational analysis of unbound 1 and 2, see SI).
Most importantly, the effect of fluorine bioisosterism is to reposition
the internal carbonyl groups of 1 compared to the non-fluorinated
congener 2, without inhibiting recognition. Whilst the carbonyl groups
diverge slightly in their spatial orientation (Figure 3b), both are
proximal to the nucleophilic serine residue (S374). This computational
analysis thus provided confidence to proceed to experimental
validation to establish that ground state changes achieved via
molecular editing with fluorine can have significant implications for
enzyme function (Figure 3c).
Table 1. Optimisation of the hydrolytic enzymatic desymmetrisation of 1.[a]
enzyme
loading
[mg/µmol]
ratio
[v/v]
conversion
[%][b]
entry
solvent
1
2
3
4
5
6
7
8
aq. buffer
-
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.1
n.d.
n.d.
50
aq. buffer / methanol
aq. buffer / ethanol
aq. buffer / isopropanol
aq. buffer / acetonitrile
aq. buffer / THF
1:1
1:1
1:1
1:1
1:1
1:1
1:1
< 5
< 5
< 5
aq. buffer / chloroform
aq. buffer / DMF
< 5
> 95
> 95
9[c]
[a]
aq. buffer / DMF
3:1
Standard
reaction
conditions:
meso-2,4,6-trifluoro-1,3,5,7-
tetrahydroxyheptane-1,7-diacetate (1) (17 mg, 50 µmol), aq. phosphate buffer
(0.2 M) / co-solvent (1:1 v/v, 10 mL), lipase 15 mg (Pseudomonas fluorescens,
≥600 U/g immobilised on Immobead 150), ambient temperature, 18 h. [b]
Conversion was monitored via GC analysis. [c] 1 (150 µmol), aq. phosphate
buffer (0.2 M) / DMF (3:1 v/v, 20 mL).
Figure 3. Comparative orientations of the fluorinated and non-fluorinated
meso-substrates docked in the active site of Pseudomonas fluorescens
HU380 lipase. a) Fluorinated (1) and non-fluorinated (2) meso-acetates with
protein surface and their interaction with amino acid residues in the binding
pocket. b) Interaction of fluorinated and non-fluorinated meso-acetates with
important amino acid residues. c) Superimposed
Encouraged by the computational data, the tolerance of the lipase to the
1,3,5-trifluoro motif was explored in the desymmetrisation of meso-
substrate 1 (Table 1). This required the identification of conditions that
were compatible with both the trifluorinated substrate 1 and the non-
fluorinated control (2). Full details regarding the stereocontrolled
synthesis of the substrates are provided in the Supporting Information.
An optimisation process identified a solvent ratio of aq. buffer / DMF
(3:1) and an enzyme loading of 0.1 mg/µmol to be highly effective,
resulting in >95% conversion to the product 3.
fluorinated and non-fluorinated meso-acetates.
Hydrogen bonds below 3.6
Å are shown as
dashed, black lines. Colour code: protein surface:
grey; protein skeleton: C: grey; fluorinated meso-
acetate: C: cyan; non-fluorinated meso-acetate:
C: yellow; O: red; N: blue; F: green. This figure
was generated using PyMOL (Schrödinger).[18]
With these optimised conditions, the effect of fluorine introduction on
the selectivity of the reaction with lipase from Pseudomonas
fluorescens was investigated and compared directly to the non-
fluorinated analogue (Figure 4, top). Gratifyingly, after 18 h the all-
Initially, the notion of inverting the intrinsic sense of stereoselection by
multiple H to F substitution was interrogated by docking studies using
LeadIT.[19] To that end, substrates 1 and 2 were docked into the active
This article is protected by copyright. All rights reserved.

10.1002/anie.201905452
Angewandte Chemie International Edition
COMMUNICATION
anti substrate (1) was cleanly processed to alcohol 3 in 98% yield and
with exquisite selectivity (99:1 e.r.). The key control experiment with
the non-fluorinated analogue (2) required doubling of the enzyme
loading to 0.2 mg/µmol and stirring in neat aq. phosphate buffer (0.2
M, pH = 7) for 112 h. Whilst the reaction proved to be efficient both in
terms of yield (4, 98%) and selectivity (3:97 d.r., determined by
derivatisation to the Mosher ester, see SI), the effect of deleting the
fluorine motif was to invert the intrinsic sense of stereoselection. To
explore this phenomenon further, the C4 epimer 5 (anti,syn,syn,anti,
see the SI) was investigated (Figure 4): Again, the sense of selectivity
was in line with product 3 and furnished 6 in 95% yield (94:6 d.r.
determined by derivatisation to the Mosher ester, see SI). As an
important set of control substrates, the tris-chloro and mixed
interhalogen examples were prepared (Figure 4, bottom). In all four
cases, < 5% conversion was observed (7-10) further underscoring the
ability of fluorinated arrays to effectively mimic hydrocarbon
scaffolds. For completion, the desymmetrisation of the meso-diol 11
was also explored and compared with the non-fluorinated counterpart
(12). Gratifyingly, this compound proved to be crystalline. Structural
analysis by single crystal X-ray diffraction revealed the gauche
(σC-H→σC-F*) and 1,3-repulsion effects that were part of the working
hypothesis.
e.r.).[13] This key experiment thereby illustrates that selectivity is
encoded at the substrate level thereby allowing product enantiomers to
be generated depending on the starting material (diol versus bis-
acetate) (Figure 6).
Figure 5. X-ray structural analysis of the meso-2,4,6-trifluoro-1,3,5,7-
tetrahydroxyheptanol 11. [a] Reference [13]: Meso diol 12 (100 µmol), Et2O (4
mL), Pseudomonas fluorescens Lipase (100 mg, 4.0 mass eq.), vinyl acetate
(20.0 eq.), ambient temperature, 18 h. [b] Meso diol 11 (100 µmol), Et2O (4
mL), Pseudomonas fluorescens Lipase (50 mg, 2.0 mass eq.), vinyl acetate
(2.0 eq.), ambient temperature, 4 h; 64 % recovered starting material 11.
To demonstrate the synthetic utility of the enzymatic desymmetrisation
in the generation of optically active, multiply fluorinated systems, the
diol chain common to a series of blockbuster HMG-CoA reductase
inhibitors was prepared (Figure 7). Synthesis of the drug chemotype
analogue common to Lipitor®, Cerivastatin®, Fluvastatin® and
Rosuvastatin® was achieved by enzymatic desymmetrisation, and
subsequent oxidation to the ester (13/14).[20] Conversion to the azide
(15/16) provides a valuable handle to install a multitude of aryl
fragments as represented by the triazole (23/24). Reduction to the
amine (17/18) and subsequent amidation furnished a crystalline
derivative (19/20) thereby allowing the absolute and relative
stereochemistry to be unequivocally established by X-ray analysis
(Figure 7, inset). These structural data are in line with the docking
studies and support the gauche effect as being instrumental in inverting
the selectivity of enzyme function.
Figure 4. Exploring the effect of F versus H on the selectivity of the
transformation. [a] Enantiomeric ratio (e.r.) determined by chiral GC analysis.
[b] Enantiomeric ratio could not be directly determined by GC or HPLC.
Diastereomeric ratio (d.r.) determined by converting the alcohol to the Mosher
ester and subsequent 19F NMR analysis (See Supporting Information).
Bonini and co-workers have reported that the formation of ent-4 arises
from the lipase catalysed transesterification of the meso-diol with vinyl
acetate (Figure 5, top).[13] However, upon repeating these conditions
with the trifluorinated substrate 11 using 20 eq. of vinyl acetate, only
the diacetate (1) was isolated. By reducing the equivalents of vinyl
acetate it was possible to demonstrate that the selectivity of his process
using the fluorinated substrate was inverted, furnishing ent-3 (7:93
Figure 6. Demonstrating that 1,3,5-trifluorination alters the intrinsic selectivity
of catalysis in both directions (hydrolysis and esterification).
This article is protected by copyright. All rights reserved.

10.1002/anie.201905452
Angewandte Chemie International Edition
COMMUNICATION
the effect of multiple C(sp3)-H to C(sp3)-F substitutions on enzyme
function will become more urgent. Whereas single-point alterations
may well be tolerated, such as in Streptomyces cattleya,[22] delineating
the bioisosteric nature of larger fluorinated arrays requires
clarification.[7c] The study also demonstrates the value of simple lipases
in accessing optically active, stereochemically complex fluorinated
species to modulate the physicochemical properties of bioactive small
molecules.
Acknowledgements
We acknowledge financial support from the WWU Münster, the
Deutsche Forschungsgemeinschaft (SFB 858, P.B.), and the
Helmholtz-Association’s Initiative and Networking Fund. The
European Commission is acknowledged for an Intra-European
Marie Skłodowska-Curie actions fellowship under Horizon-2020
(796089–NovInDXS, R. P. J.) and an ERC Consolidator Grant
(RG, 818949 RECON ERC-2018-CoG).
Keywords: biocatalysis • conformation • fluorine • gauche effect
• molecular recognition
[1]
a) A. Eschenmoser, L. Ruzicka, O. Jeger, D. Arigoni, Helv. Chim. Acta 1955,
38, 1890-1904; b) A. Eschenmoser, D. Arigoni, Helv. Chim. Acta 2005, 88,
3011-3048.
[2]
[3]
J. W. Cornforth, Pure Appl. Chem. 1961, 2, 607.
K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis, Wiley VCH,
Weinheim (1996); K. C. Nicolaou, S. A. Snyder, Classics in Total Synthesis II,
Wiley VCH, Weinheim (2003).
[4]
[5]
G. Stork, A. W. Burgstahler, J. Am. Chem. Soc. 1955, 77, 5068-5077.
For excellent reviews of acyclic conformational analysis, see a) R. W.
Hoffmann, Angew. Chem. Int. Ed. 1992, 31, 1124-1134; b) R. W. Hoffmann,
Angew. Chem. 2000, 112, 2134-2150; Angew. Chem. Int. Ed. 2000, 39, 2054-
2070.
[6]
[7]
a) K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881-1886; b) M.
Salwiczek, E. K. Nyakatura, U. I. M. Gerling, S. Ye, B. Koksch, Chem. Soc.
Rev. 2012, 41, 2135-2171; c) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J.
Donnelly, N. A. Meanwell, J. Med. Chem. 2015, 58, 8315−8359; d) A.
Harsanyi, G. Sandford, Green Chem. 2015, 17, 2081-2086.
a) Q. A. Huchet, B. Kuhn, B. Wagner, N. A. Kratochwil, H. Fischer, M.
Kansy, D. Zimmerli, E. M. Carreira, K. Müller, J. Med. Chem. 2015, 58, 9041-
9060; b) I. G. Molnár, C. Thiehoff, M. C. Holland, R. Gilmour, ACS Catalysis
2016, 6, 7167–7173. c) N. A. Meanwell, J. Med. Chem. 2018, 61, 5822–5880;
d) N. Erdeljac, G. Kehr, M. Ahlqvist, L. Knerr, R. Gilmour, Chem. Commun.
2018, 54, 12002-12005.
Figure 7. Generation of 1,3,5-trifluoro modified chemotypes common to
blockbuster HMG-CoA reductase inhibitors such as Lipitor®. a) TEMPO,
NaOCl, CH2Cl2/H2O 6:1, 0 °C to rt, 1 h; b) NaClO2, tBuOH, 2-methyl-2-butene,
phosphate buffer, rt, pH = 7, 3 h; c) MeI, KHCO3, DMF, rt, 16 h; 21 70% (3
steps), 22 70% (3 steps), ent-23 86% (3 steps), ent-24 86% (3 steps); d)
NaOMe, MeOH/THF 1:1, 0 °C, 3 h, d.r. > 12:1; 13 90%, 14 quant.; e) NEt3,
DMAP, TsCl, CH2Cl2, rt, 18 h; 23 90%, 24 65%, 25 91%, 26 94%; f) NaN3,
DMF, 80 °C, 18 h; 15 70%, 16 94%, ent-15 70%, ent-16 94%; g) Pd/C, H2,
EtOAc, rt, 20 h; 17 quant., 18 quant., ent-17 quant., ent-18 quant.; h) RCOCl,
Et3N, CH2Cl2, 16 h; 19 30%, 20 45%; i) CH2Cl2, TFA, H2O, 100:10:1, rt, 16 h;
21 68%, 22 35%, 23 75%, 24 54%; j) Phenylacetylene, Na-ascorbate, CuSO4 •
5 H2O, DMF, 50 °C, 16 h; 27 98%, 28 96%; k) KOH, MeOH, rt, 2 h, 25 80%,
26 quant.
[8]
[9]
D. B. Berkowitz, K. R. Karukurichi, R. De la Salud-Bea, D. L. Neslson, C. D.
McCune, J. Fluorine Chem. 2008, 129, 731-742.
a) L. E. Zimmer, C. Sparr, R. Gilmour, Angew. Chem. 2011, 123, 12062;
Angew. Chem. Int. Ed. 2011, 50, 11860; b) F. Scheidt, P. Selter, N. Santschi,
M. C. Holland, D. V. Dudenko, C. Daniliuc, C. Mück-Lichtenfeld, M. R.
Hansen, R. Gilmour, Chem. Eur. J. 2017, 23, 6142-6149.
[10] a) D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308-319; b) C. Thiehoff, Y. P. Rey,
R. Gilmour, Isr. J. Chem. 2017, 57, 92-100; c) M. Aufiero, R. Gilmour, Acc.
Chem. Res. 2018, 51, 1701-1710.
[11] For direct, catalytic approaches to generate this motif see: a) S. M. Banik, J. W.
Medley, E. N. Jacobsen, J. Am. Chem. Soc. 2016, 138, 5000-5003; b) I. G.
Molnꢀr, R. Gilmour, J. Am. Chem. Soc. 2016, 138, 5004-5007; c) F. Scheidt,
M. Schäfer, J. C. Sarie, C. G. Daniliuc, J. J. Molloy, R. Gilmour, Angew. Chem.
Int. Ed. 2018, 57, 16431-16435; d) M. K. Haj, S. M. Banik, E. N. Jacobsen,
Org. Lett. 2019, 10.1021/acs.orglett.9b00938.
In conclusion, this study reveals that a seemingly subtle 1,3,5-trifluoro
bioisostere motif inverts enzyme selectivity relative to the
non-fluorinated substrate. Curiously, this change does not inhibit
activity, in contrast to the chlorinated analogues. This behaviour has
been demonstrated for both the hydrolysis and transesterification to
generate all possible stereoisomers. From a translational perspective,
and as drug discovery expands into 3D chemical space,[21] clarifying
[12] For an example of a surprisingly high level of discrimination for F-acetyl-CoA
versus acetyl-CoA (i.e. single F versus H), see: a) A. W. Weeks, M. C. Y.
This article is protected by copyright. All rights reserved.

10.1002/anie.201905452
Angewandte Chemie International Edition
COMMUNICATION
Chang, Proc. Natl. Acad. Sci. USA 2012, 109, 19667-19672; b) A. M. Weeks,
N. S. Keddie, R. D. P. Wadoux, D. O’Hagan, M. C. Y. Chang, Biochemistry,
2014, 53, 2053–2063.
[13] C. Bonini, R. Racioppi, L. Viggiani, G. Righi, L. Rossi, Tetrahedron
Asymmetry 1993, 4, 793-805.
[14] For an application in the synthesis of the C1–C13 fragment of amphotericin B,
see C. Bonini, L. Chiummiento, A. Martuscelli, L. Viggiani, Tetrahedron
Asymmetry 2004, 45, 2177-2179.
[15] For selected examples of stereochemically rich fluoroalkanes, see a) D. Farran,
A. M. Z. Slawin, P. Kirsch, D. O’Hagan, J. Org. Chem. 2009, 74, 7168–7171;
b) L. Hunter, A. M. Z. Slawin, P. Kirsch, D. O’Hagan, Angew. Chem. Int. Ed.
2007, 46, 7887-7890; c) D. O’Hagan, J. Org. Chem. 2012, 77, 3689–3699.
[16] a) B. D. Roth, Prog. Med. Chem. 2008, 40, 1-22; b) B. D. Roth, C. J. Blankley,
A. W. Chucholowski, E. ferguson, M. L. Hoefle, D. F. Ortwine, R. S. Newton,
C. S. Sekerke, D. R. Sliskovic, M. Wilson, J. Med. Chem. 1991, 34, 357-366;
c) L. Tabernero, D. A. Bochar, V. W. Rodwell, C. V. Stauffacher, Proc. Natl
Acad. Sci. USA 1999, 96, 7167–7171; d) E. S. Istvan, J. Deisenhofer, Science
2001, 292, 1160-1164; e) M. Müller, Angew. Chem. Int. Ed. 2005, 44, 362 –
365; f) H. Yasukouchi, K. Machida, A. Nishiyama, M. Mitsuda, Org. Proc.
Res. Dev. 2019, 23, 654-659.
[17] S. Fischer, N. Huwyler, S. Wolfrum, E. M. Carreira, Angew. Chem. Int. Ed.
2016, 55, 2555-2558.
[18] PyMol-Schrödinger: The PyMOL Molecular Graphics System, Version 1.8
Schrödinger, LLC
[19] a) BioSolveIT GmbH, Sankt Augustin. http://www.biosolveit.de, LeadIT,
version 2.3.2; b) BioSolveIT GmbH, Sankt Augustin. http://www.biosolveit.de,
SeeSAR, version 8.1.
[20] For an example of a mono-fluorinated analogue of this drug chemotype, see J.
Saadi, H. Wennemers, Nat. Chem. 2016, 8, 276-280.
[21] F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752-6756; F.
Lovering, Med. Chem. Commun. 2013, 4, 515-519.
[22] a) D. O'Hagan, C. Schaffrath, S. L. Cobb, J. T. Hamilton, C. D. Murphy,
Nature 2002, 416, 279; b) C. Dong, F. Huang, H. Deng, C. Schaffrath, J. B.
Spencer, D. O'Hagan, J. D. Naismith, Nature 2004, 427, 561–565.
This article is protected by copyright. All rights reserved.

10.1002/anie.201905452
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Patrick Bentler, Klaus Bergander,
Constantin G. Daniliuc, Christian Mück-
Lichtenfeld, Ravindra P. Jumde, Anna K.
H. Hirsch,* and Ryan Gilmour*
Page No. – Page No.
Text for Table of Contents
Inverting Small Molecule-Protein
Recognition by the Fluorine Gauche
Effect: Selectivity Regulated by
Multiple H → F Bioisosterism
This article is protected by copyright. All rights reserved.