A Chiral Pentafluorinated Isopropyl Group via Iodine(I)/(III) Catalysis

Article abstract of DOI:10.1002/anie.202015946

An I(I)/(III) catalysis strategy to construct an enantioenriched fluorinated isostere of the ⁱPr group is reported. The difluorination of readily accessible α-CF₃-styrenes is enabled by the in situ generation of a chiral ArIF₂ species to forge a stereocentre with the substituents F, CH₂F and CF₃ (up to 95 %, >20:1 vicinal:geminal difluorination). The replacement of the metabolically labile benzylic proton results in a highly preorganised scaffold as was determined by X-ray crystallography (π→σ* and stereoelectronic gauche σ→σ* interactions). A process of catalyst editing is disclosed in which preliminary validation of enantioselectivity is placed on a structural foundation.

Full text of DOI:10.1002/anie.202015946

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 6430–6434
International Edition:
German Edition:
doi.org/10.1002/anie.202015946
doi.org/10.1002/ange.202015946
Organocatalysis
AChiral Pentafluorinated Isopropyl Group via Iodine(I)/(III) Catalysis
Stephanie Meyer, Joel Hꢀfliger, Michael Schꢀfer, John J. Molloy, Constantin G. Daniliuc, and
Ryan Gilmour*
In memory of Prof. Dr. FranÅois Diederich (1952–2020)
Abstract: An I(I)/(III) catalysis strategy to construct an
enantioenriched fluorinated isostere of the iPr group is
reported. The difluorination of readily accessible a-CF3-
styrenes is enabled by the in situ generation of a chiral ArIF2
species to forge a stereocentre with the substituents F, CH2F and
CF3 (up to 95%, > 20:1 vicinal:geminal difluorination). The
replacement of the metabolically labile benzylic proton results
in a highly preorganised scaffold as was determined by X-ray
crystallography (p!s* and stereoelectronic gauche s!s*
interactions). A process of catalyst editing is disclosed in which
preliminary validation of enantioselectivity is placed on
a structural foundation.
orbital symmetry to craft an isotopically orthogonal motif
(1H, H and H, Figure 1, top).[8] Whilst this isotope strategy
remains expansive in the field of mechanistic enzymology,
small fragment-based bioisosterism in drug design relies on
stable isotopes to enhance the pharmaco-kinetics and
-dynamics of drug candidate performance.[9] Molecular edit-
ing with fluorine (H!F) has proven to be particularly
effective,[10] and is reflected in the increasing number of
fluorinated small molecules reaching the market.[11] This is
a consequence of fluorineꢀs low steric demand, low polar-
isability and the stability of the C-F bond. Given the success of
achiral perfluoroalkyl groups in drug discovery, catalysis and
agrochemistry,[12] routes to small, chiral, 3D fluoroalkane
motifs would be advantageous to expand the available
chemical space. This includes the C2 (BITE group)[13] which
is a bioisosteric hybrid of the ethyl and trifluoromethyl
groups.[14] Cognisant of the prevalence of (C3) isopropyl units
in bioactive natural product leads and small molecule
2
3
Short, unfunctionalised aliphatic groups (C1–C4) are ubiq-
uitous structural features in the natural product repertoire,
and are particularly conspicuous in polyketides and ter-
penes.[1] This is a logical consequence of iterative biosynthesis
algorithms that process low molecular weight fragments into
higher homologues.[2] Introduced under the auspices of acetyl-
or propionyl-CoA,[3] complemented by electrophilic para-
digms involving methyltransferases (SAM),[4] these motifs
appear to be vestigial in nature. However, they often encode
for a highly specific function and thus delineating their
biosynthetic origins has been intensively pursued. Indeed the
value of harnessing small aliphatic groups to enhance the
physicochemical profiles of drug candidates is exemplified by
the “magic methyl effect”.[5] Interrogating the stereochemical
course of enzymatic methylation has a venerable history, due
to the achiral nature of this motif and the pre-conditions
associated with designing a chiral bioisostere to track the
possible translation of stereochemical information.[6,7] Arigo-
niꢀs celebrated synthesis of chiral acetic acid remains a tour de
force in stereocontrolled synthesis, and a master class in
[*] M. Sc. S. Meyer, M. Sc. J. Hꢀfliger, M. Sc. M. Schꢀfer, Dr. J. J. Molloy,
Dr. C. G. Daniliuc, Prof. Dr. R. Gilmour
Organisch Chemisches Institut
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Corrensstraße 36, 48149 Mꢁnster (Germany)
E-mail: ryan.gilmour@uni-muenster.de
Homepage: https://www.uni-muenster.de/Chemie.oc/gilmour/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202015946.
ꢂ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. 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.
Figure 1. Top: Chiral bioisosteres of common aliphatic chemotypes.
Centre: Selected functional small molecules containing the achiral iPr
(pharmaceutical) and CF(CF3)2 (catalysis and agrochemical) units.[12]
Bottom: Design of a main group catalysis approach to generate
i
a chiral fluorinated analogue of Pr.
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pharmaceuticals (Figure 1 centre), a catalysis-based strategy
those reported by Lal and co-workers using HF sources and
Selectfluorꢁ .[21]
To explore the scope and limitations of this catalysis-
based difluorination of a-CF3-styrenes, the effect of Brønsted
acidity[22] was probed as a function of the amine:HF ratio.[16b]
to access a differentially fluorinated analogue of the iPr group
was initiated. Harnessing I(I)/(III) catalysis,[15] it was envis-
aged that a formal 1,2-addition of fluorine across the alkene
moiety[16] of simple a-trifluoromethyl styrenes would gener-
ate a stereogenic centre bearing F, CH2F and CF3 groups
(Figure 1, bottom).
The success of this catalysis-based approach would be
contingent on the in situ oxidation of a chiral aryl iodide
organocatalyst to generate an ArIF2 species[17] that would be
sufficiently active to engage a sterically-congested, electron-
deficient alkene. If successful, the resulting pentafluoroiso-
propyl surrogate would constitute a chiral C3 building block in
which the lability of the methine proton is mitigated.[18]
Moreover, the constituent hyperconjugative interactions
intrinsic to the internal vicinal-difluoro motif[19] would
manifest themselves in conformation. To identify conditions
that would enable the target fluorinated isopropyl motif to be
generated from simple a-trifluoromethyl styrenes, a process
of reaction optimisation was conducted (Figure 2, 1a!2a).
To that end, simple aryl iodides were investigated as
inexpensive catalysts in conjunction with Selectfluorꢁ as the
terminal oxidant to generate the key ArI(III)F2 species.[17]
Initial studies were performed in chloroform at ambient
temperature using an amine:HF ratio of 1:7.5 and the
reactions were examined by 19F NMR spectroscopy using an
internal standard. Iodobenzene proved to be a perfectly
effective catalyst for this transformation to generate (ꢀ)-2a
and 3a in a 2.5:1 ratio (86% combined yield). The latter
product arises from phenonium ion rearrangement and has
been exploited in a range of catalysis-based geminal difluori-
nation processes.[20] Repeating the reaction with p-iodoto-
luene (5) led to a notable improvement in yield (> 95%) with
comparable regioselectivity in favour of the desired vicinal
product 2a (2.2:1). Electronic modulation was not well
tolerated with the ester derivative 6 proving to be a less
active catalyst under comparable conditions (26%). Control
experiments in the absence of catalyst led to < 5% yield and
demonstrate the strongly deactivating nature of the trifluor-
omethyl group that inhibits background reactions such as
Figure 3. Establishing the scope of the vicinal difluorination of a-CF3-
styrenes to generate a highly fluorinated isopropyl group. The yield is
the sum of vicinal and geminal difluorination products. The regioselec-
tivity ratio (vic:gem) and yield were determined by 19F NMR spectros-
copy using a,a,a-trifluorotoluene as internal standard. Isolated yields
of the vicinal products are given in parentheses. a Reaction time
increased to 48 h. Arbitrary enantiomer of the product shown. N.B.:
The products are often highly volatile and care must be taken in the
isolation.
Figure 2. Catalyst identification. Standard reaction conditions: a-CF3-p-
chlorostyrene 1a (0.2 mmol), catalyst (20 mol%), Selectfluorꢃ
(1.5 equiv), amine:HF 1:7.5 (0.5 mL), CHCl3 (0.5 mL), ambient temper-
ature, 24 h. The yield is the sum of vicinal and geminal difluorination
products. The regioselectivity ratio (vic:gem) and yield were determined
by 19F NMR spectroscopy using a,a,a-trifluorotoluene as internal
standard. Control experiment without catalyst: yield <5%.
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effective, balancing the electronic effects of the resorcinol
with a p-CO2Me in catalyst 9 led to notably superior catalysis
(87% yield, vicinal:geminal 3:1). As the logical next step, C2-
symmetric resorcinol derivatives were investigated as sum-
marised in Figure 5.[23,24] Reactions were performed under
standard conditions with an amine:HF ratio of 1:7.5 in CHCl3
at ambient temperature. Initially, the effect of modifying the
substituent X was assessed using the methyl esters 10–13.
Counterintuitively, augmenting the steric footprint at site X
had a detrimental effect on selectivity. Catalyst 10 (X = Me)
proved to be most effective, generating compound 2a with
86:14 e.r. (> 95% conversion, 88% combined yield). Struc-
tural editing at site Y was not tolerated as exemplified by
catalysts 14–16. As a control series, the C1-symmetric catalysts
17–19 were examined (Figure 5, lower). Direct comparison of
17 with the most promising scaffold 10 confirmed the
importance of C2 symmetry (72:28 versus 86:14 e.r.). Interest-
ingly, substituting the methyl ester for benzyl (catalyst 18) did
not erode selectivity, although efficiency was decreased.
Moreover, the a-Bn catalyst (19) proved to be less efficient
than the C2-symmetric derivative 12. Having identified
catalyst 10 as the most promising scaffold to validate an
Figure 4. The effect of Brønsted acidity on catalysis.
This led to the identification of methods A, B and C,
reflecting amine:HF ratios of 1:4.5, 1:6 and 1:7.5 respectively
(Figures 3 and 4). Method A proved to be highly effective in
generating the electron rich products 2b–2d with high levels
of regioselectivity favouring formation of the desired vicinal
product (> 20:1, up to 86%). The presence of the CF3 group
clearly distinguish this substrate class from the parent
styrenes, which rearrange to generate the geminal product.[20]
Control reactions again confirmed the necessity for the
catalyst. The seemingly subtle change to Method B proved
to be optimal for substrates 2e–2k, enabling the
generation of alkyl derivatives (2e–2h, up to > 20:1,
vic:gem) as well as the electron deficient aniline
derivative 2i (74%, 15.5:1).
Comparable efficiency and selectivity were also
noted for the biphenyl system 2j and adduct 2k.
Augmenting the amine:HF ratio further to Method C
provided optimised conditions to access products
2a,l–2q. Whereas employing higher HF ratios/
Brønsted acidities under the conditions developed
by this laboratory tend to favour 1,1-difluorination,[20f]
electron-deficient a-CF3-styrenes proved to be nota-
bly more recalcitrant to rearrangement and the vicinal
products predominated throughout. Given the impor-
tance of aryl bromides in contemporary medicinal
chemistry, where the C(sp2)-Br provides a handle for
subsequent cross-coupling, the synthesis of 2l was
conducted on a 1 mmol scale. Despite the volatility of
the product, the vicinal product could be isolated in
43% yield. Products 2m, 2n and 2o behaved similarly
and were generated in a vicinal:geminal ratio of ca.
3:1. Given the prominence of aniline fragments
bearing isopropyl units in drug and agrochemical
discovery (See Figure 1), the phthalimide 2p was
generated cleanly in 61% yield. Finally, access to the
disubstituted aryl 2q was realised, this time with an
improvement in regioselectivity (5.0:1). Having es-
tablished conditions to enable the vicinal difluorina-
tion of a-CF3-styrenes via I(I)/(III) catalysis, attention
was focussed on a preliminary validation of an
enantioselective variant. Whilst catalyst p-iodoto-
Figure 5. Catalyst optimisation to enable preliminary validation of enantioselec-
tion. The conversion and combined yield (in parentheses) was determined by
19F NMR spectroscopy of the crude reaction mixture using a,a,a-trifluorotoluene
as internal standard. Enantioselectivity determined by chiral HPLC. Standard
reaction conditions: a-CF3-p-chlorostyrene 1a (0.2 mmol), catalyst (20 mol%),
Selectfluorꢃ (1.5 equiv), amine:HF 1:7.5 (0.5 mL), CHCl3 (0.5 mL), ambient
luene 5 is a highly competent catalyst, sites to
append stereodirecting groups are conspicuously
absent. The investigation was therefore repeated
with resorcinol derivatives 7–9 in which proximal
stereocentres might induce enantioinduction.
Whereas catalysts 7 and 8 proved to be moderately temperature, 24 h.
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Figure 6. The yield is the sum of vicinal and geminal difluorination
products. The regioselectivity ratio (vic:gem) and yield were determined
by 19F NMR spectroscopy using a,a,a-trifluorotoluene as internal
standard. Isolated yield of the vicinal product is given in parentheses.
Enantioselectivity determined by chiral HPLC. a After recrystallisation.
N.B.: The products are often highly volatile and care must be taken in
the isolation.
enantioselective process (please see the ESI for additional
details) a representative selection of a-CF3-styrenes were
subjected to the general catalysis conditions using 10
(Figure 6).
Figure 7. Postulated induction model and the X-ray structure of
compound 2j and 2p. Thermal ellipsoids are shown at 15% proba-
bility. CCDC 2044630 (2j) and 2044631 (2p).
Gratifyingly, the methyl derivative underwent smooth
difluorination to generate 2e (> 95%, 17.1 vicinal:geminal,
83:17 e.r.). The fluorinated biaryl system 2j was compatible
with the conditions and could be prepared with a regioselec-
tivity of 7:1 vicinal:geminal and 85:15 e.r (95:05 e.r. after
recrystallisation). The p-Cl and p-Br derivatives 2a and 2l
were prepared with 86:14 and 87:13 e.r., respectively, 2m in
86:14 e.r. and the protected amine 2p in 87:13 e.r. (90:10 e.r.
after recrystallisation). Gratifyingly, compounds 2j and 2p
were crystalline allowing the (S)-configuration of the new
stereocentre to be assigned (vide infra).[25] Finally, the
phthalimide derivative 2p was processed to an analogue of
the TRPA1 antagonist HC-030031 2r in a short synthetic
sequence (Figure 6, lower. Full details in the ESI).
To complement the plenum of methods available to
construct short, unfunctionalised aliphatic groups for drug
discovery, a catalysis-based strategy to access chiral, fluori-
nated surrogates of the isopropyl group has been developed.
This serves to expands the current portfolio of fluorine drug
modules for drug discovery (Figure 7, centre).[26] Despite the
intrinsic steric and electronic challenges associated with
generating highly fluorinated stereocentres, this I(I)/I(III)
catalysis platform enables a-CF3-styrenes to undergo smooth
vicinal difluorination (up to > 20:1 vicinal:geminal). Impor-
tantly, the CF3 group effectively inhibits the dominant
phenonium ion rearrangement associated with electron rich
styrenes, allowing products such as 2b to be generated with
excellent levels of regiocontrol (> 20:1). Finally, preliminary
validation of an enantioselective variant is disclosed. Whilst
the sterically demanding phenyl and trifluoromethyl substitu-
ents (VvdW (CF3) = 39.8 ꢂ3)[10e,27] render this intermolecular
process challenging, it is gratifying to observe encouraging
levels of enantioselectivity. A tentative induction model is
proposed in which facial discrimination in the enantiodeter-
mining fluorination is a precondition of selectivity. Since X-
ray analyses of 2j and 2p confirm that the major enantiomer
is (S)-configured (Figure 7), it is conceivable that stabilising
electrostatic interactions (RCF2dꢁF···d+H-CH2R),[28] may bias
catalyst-substrate preorganisation.[29] Simple steric discrimi-
nation (CF3 vs. Ph) is not consistent with the selectivities
observed the C1-symmetric catalysts. The solid-state analysis
also reveals a stereoelectronic gauche effect (s!s*; fFCCF
=
69.98 and 518 for 2j and 2p, respectively) and that the CF3
group is orthogonal to the plane of the p system (p!s*).[30]
Exploring the physicochemical profile of this new motif in the
context of drug discovery and contemporary agrochemistry is
the focus of ongoing studies and will be reported in due
course.
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Acknowledgements
We acknowledge generous financial support from the West-
fꢃlische Wilhelms-Universitꢃt Mꢄnster, the European
Research Council (ERC Consolidator Grant—Project
Number 818949-RECON, to RG), the DFG (Cluster of
Excellence “Cells in Motion—CiM” (FF-2013-10) and SFB
858) and the Alexander von Humboldt Foundation (post-
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ˇ
doctoral research fellowship to JJM). We thank Mr. Tomꢅs
´
Nevesely (WWU Mꢄnster) for helpful discussions. Open
access funding enabled and organized by Projekt DEAL.
Conflict of interest
The authors declare no conflict of interest.
Keywords: agrochemistry · bioisostere · conformation ·
fluorine · organocatalysis
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Manuscript received: November 30, 2020
Revised manuscript received: January 8, 2021
Accepted manuscript online: January 11, 2021
Version of record online: February 9, 2021
6434 www.angewandte.org ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 6430 –6434