Catalytic enantioselective synthesis of difluorinated alkyl bromides

Article abstract of DOI:10.1021/jacs.0c07043

We report an iodoarene-catalyzed enantioselective synthesis of β,β-difluoroalkyl bromide building blocks. The transformation involves an oxidative rearrangement of α-bromostyrenes, utilizing HF-pyridine as the fluoride source and m-CPBA as the stoichiometric oxidant. A catalyst decomposition pathway was identified, which, in tandem with catalyst structure-activity relationship studies, facilitated the development of an improved catalyst providing higher enantioselectivity with lower catalyst loadings. The versatility of the difluoroalkyl bromide products was demonstrated via highly enantiospecific substitution reactions with suitably reactive nucleophiles. The origins of enantioselectivity were investigated using computed interaction energies of simplified catalyst and substrate structures, providing evidence for both CH-πand π-πtransition state interactions as critical features.

Full text of DOI:10.1021/jacs.0c07043

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Communication
Catalytic Enantioselective Synthesis of Difluorinated Alkyl Bromides
Mark D. Levin, John M. Ovian, Jacquelyne A Read, Matthew S Sigman, and Eric N. Jacobsen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07043 • Publication Date (Web): 17 Aug 2020
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Journal of the American Chemical Society
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Catalytic Enantioselective Synthesis of Difluorinated Alkyl Bromides
Mark D. Levin†, John M. Ovian†‡, Jacquelyne A. Read†⁋‡ , Matthew S. Sigman⁋ *, Eric N. Jacobsen†*
† Department of Chemistry & Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States
⁋ Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
Supporting Information Placeholder
7
8
9
O
A)
HO
HO2C(H2C)
O
6 H
ABSTRACT: We report an iodoarene-catalyzed enantioselective
synthesis of β,β-difluoroalkyl halide building blocks. The
transformation involves an oxidative rearrangement of α-
bromostyrenes, utilizing HF–pyridine as the fluoride source and m-
CPBA as the stoichiometric oxidant. A catalyst decomposition
pathway was identified, which, in tandem with catalyst structure–
activity relationship studies, facilitated the development of an
improved catalyst providing higher enantioselectivity with lower
catalyst loadings. The versatility of the difluoroalkyl bromide
products was demonstrated via highly enantiospecific substitution
reactions with suitably reactive nucleophiles. The origins of
enantioselectivity were investigated using computed interaction
energies of simplified catalyst and substrate structures, providing
evidence for both CH– and – transition state interactions as
critical features.
N
O
F
nBu
NH2
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N
F
F
O
HO
F
H
OH
Gemcitabine (Gemzar)
Lubiprostone (Amitiza)
chemotherapy
IBS treatment
F
F
Difluoromethylene Bioisosterism
HO
1.85 D
2.30 D
OPh
1.96 D
F
F
O
O
R
R
(CH2)3CO2iPr
HO
R
R
R
R
Tafluprost (Zioptan)
110
116
116
hypertension
B)
m-CPBA
HF-pyridine
I
Ar*
Ar
F
m-CBA
H2O
The disparity between the prevalence of fluorine in
anthropogenic and naturally occurring compounds is striking.1 Few
natural products contain carbon–fluorine linkages, whereas
medicinal, agricultural, and materials chemistry are replete with
examples where fluorination is critical for optimal functional
properties.2 This difference manifests synthetically as an absence
of naturally occurring chiral-pool sources of enantioenriched alkyl
fluorides, necessitating the continuing development of chemical
strategies for their selective synthesis.3 In this regard, fluorinated
building blocks amenable to diversification are of particular
interest.
We envisioned that compounds with the general structure 1
could be of high synthetic value given the unique properties of
geminally difluorinated compounds (Figure 1A). The
difluoromethylene motif has the highest dipole moment of the
fluoromethane series and exerts a bond-angle-widening effect
commensurate with sp2 centers, implicating geminal difluorides as
both ketone and ether bioisosteres.4 These properties, together with
the well-documented effects of fluorination on metabolic stability,
lipophilicity, and potency of drug compounds, indicate that
compounds such as 1 could be useful building blocks for the
preparation of enantioenriched molecules containing geminal
difluorides. Though deoxyfluorination and related transformations
of carbonyl derivatives provide established approaches to gem-
difluorination, they are generally not applicable to the synthesis of
compounds bearing α-stereocenters because of epimerization and
other nonproductive decomposition pathways.5
To access 1 and related building blocks, we turned to the
chemistry of chiral iodoarenes, which have been applied recently
by our group and others in catalytic, enantioselective
fluorofunctionalizations of diverse olefinic substrates.6-8 We
envisioned such catalysts could enable the enantioselective
synthesis of β,β-difluorinated alkyl bromides from vinyl bromides
of type 2 through a pathway involving initial, enantiodetermining
fluoroiodination of the alkene. Subsequent intramolecular,
stereospecific displacement of intermediate alkyliodane A to
generate bromonium ion B and regioselective ring opening by
fluoride would then afford the desired product (Figure 1B). We
were encouraged by a
Br
B
R
Ar Br
(HF)n
F(HF)n
F
(HF)n
F
I
F
F
I
R
Br
Ar*
A
Ar*
Ar
R
F
F
1
R
Br
F
I
R
Br
Ar
Ar
valuable fluorinated
building block
2
F(HF)n
Ar*
Figure 1. A) Examples of difluroromethylene-containing
medicinal compounds and properties of difluoromethylenes as
bioisosteres. B) Catalytic cycle for oxidative bromonium formation
leading to enantioenriched alkyl bromides.
report of a related oxidative hydrolysis of vinyl halides, affording
racemic α-haloketones using stoichiometric Koser’s reagent.8h
Vinyl bromide 2a was evaluated as a model substrate for the
proposed fluorinative bromonium rearrangement (Figure 2A). The
α-benzyl-substituted Ishihara-type8c catalyst 3a that was identified
previously as optimal in other alkene fluorofunctionalization
reactions7a afforded desired product 1a in high conversion and
promising levels of enantioselectivity. Systematic evaluation of
catalysts bearing varied substitution on the α-benzyl groups (R1)
led to the identification of para-tert-butyl-substituted derivative 3b
as optimal. We hypothesized initially that the beneficial effect of
tert-butyl substituents might have a steric origin, and this notion
was seemingly supported by a good correlation between Charton
parameters for the alkyl substituents and enantioselectivity (Figure
2B, black diamonds, R2
= 0.91).9,10 However, the correlation
alkyl
fails if electron-withdrawing para-substituents are included (R2
=
all
0.22). We will return to an analysis of the intriguing catalyst
substituent effects below.
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A)
monofluorinated derivative of the vinyl bromide substrate.
NO2
Br
Catalyst (x mol%)
m-CPBA, py9HF
1
2
3
4
5
6
7
8
Reactions carried out with 4 as the catalyst produced the same
difluorinated product 1a as parent catalyst 3b, but with
substantially lower levels of conversion and diminished
enantioselectivity.
Br
O2N
Me
DCM
Me
40 o
C
F
F
2a
Entry Catalyst
1a
We reasoned that the formation of 4 results from attack of a
carbonyl group of catalyst 3b on the bromonium ion intermediate
(Figure 2A).11 Catalysts bearing electron-withdrawing substituents
on the benzyl ester (R2) were therefore prepared and evaluated with
the goal of attenuating the nucleophilicity of the ester carbonyl and
thereby limiting the decomposition pathway. Indeed, after
examining several candidates, the p-SF5 derivative (3c) was
identified as optimal for both conversion and enantioselectivity.
Use of 3c at 10 mol% loading in the model transformation resulted
in generation of 1a in 84% isolated yield and 92% ee with no
decomposition products analogous to 4 observed (Figure S7).
Having identified 3c as an effective catalyst for the
enantioselective difluorinative rearrangement with model substrate
2a, we evaluated the scope of this transformation with respect to
the substitution pattern on the aromatic and aliphatic portions of the
substrate (Figure 3). Styrenyl bromides bearing electron-
withdrawing meta- and para-substituents were effective substrates
(products 1a–1q), affording products in 52–84% yield and 70–93%
ee. Substrates bearing free alcohol (1s) or primary aliphatic
bromide (1t) substituents also reacted smoothly, affording the
desired products with 90% ee and 76% ee, respectively. However,
substrates possessing more electron-rich aromatic substituents or
ortho-substituted arenes were either too unstable to isolate in
sufficient quantities or decomposed under the reaction conditions,
precluding their evaluation in this reaction.
R1
R2
H
ee (%)
80
x
Conversion (%)
100
1a
2a
3b
3a
3b
3b
H
20 mol%
20 mol%
10 mol%
tBu
tBu
H
100
74
91
H
88
92
78
4b
5a
tBu SF5 10 mol%
100 (84)
9
3c
4
10
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-
-
20 mol%
I
26
O
O

O
O
O
O
R2
R2
CO2Me
R1
R1
3
Catalyst
4
Isolated catalyst decomposition product
:
Br
Me
F
O
I
O
Br
Ar
O
O
O
BnO
O
F
Me
RO
via
CO2Me
NO2
tBu
B)
tBu
NO2
NO2
NH2
Br
NaN3
N3
(1)
Me
DMSO
Me
Me
100 o
C
O
F
F
F F
, 74%
Cathinone
5
1a
99% es
O2N
O2N
Br
6
70%
99% es
O
NaH
THF
OH
(2)
(3)
F
1s
F
F
F
Br
Br
NaH
DMF
Figure 2. A) Reaction optimization and isolation of catalyst
decomposition product 4. Conditions: 0.05 mmol scale, 11 equiv.
py•9HF, 1.42 equiv. m-CPBA, 0.08M. a16 h. b48 h. Isolated yield
in parentheses. B) Charton plot of catalyst substituents (R1) vs.
experimental enantioselectivity (G‡ = −RTln(e.r.)).
7
68%
99% es
Br
SH
S
90 o
C
F
F
F
F
2 steps from 1t
To assess the synthetic utility of the fluorinated alkyl bromide
products, a series of derivatization reactions were explored (eqs 1–
3). Both intermolecular (eq 1) and intramolecular substitution (eqs
2 and 3, respectively) occurred smoothly with nitrogen, oxygen,
and sulfur nucleophiles to afford the corresponding products with
complete enantiospecificity. Such ready access to azide 5 and its
derivatives provides an appealing entry to gem-difluorinated
bioisosteric analogues of the
Lowering the catalyst loading of 3b from 20 mol% to 10 mol%
led to a substantial decrease in reaction conversion with a
concomitant decrease in enantioselectivity, the latter being
unexpected given the lack of an observable background reaction in
the absence of an iodoarene catalyst. The decrease in conversion
was not offset by extending reaction times, indicating that catalyst
deactivation was occurring. Indeed, efforts to recover the catalyst
led to the identification of catalyst decomposition product 4, in
which one benzyloxy substituent was replaced with
a
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Journal of the American Chemical Society
O
I
O
O
O
1
2
3
4
5
6
7
8
3c
10 mol%
m-CPBA, py9HF
Br
Br
O
O
R'
R
F5S
SF5
R
DCM
R'
40 o
C
F
F
CO2Me
tBu
tBu
2
1
3c
OTf
CO2Et
CF3
CN
Br
NO2
Br
Br
Br
Br
Br
Br
nBu
Me
Me
R
Me
R
9
F
F
F
,R = Et, 78%, 89% ee
, R = nBu, 84%, 82% ee
F
F
F
F
F
F
F
F
F
1c
1d
1g
1h
, R = Et, 52%, 90% ee
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1a
1b
1e
1f,
, 84%, 92% ee
, 81%, 79% ee
, 60%, 80% ee
65%, 81% ee
i
, R = Pr, 73%, 70% ee
O2N
TfO
EtO2C
F3C
nBu
NC
Br
Br
Br
Br
Br
Br
Br
R
Me
Me
R
Me
F
F
F
F
F
F
F
F
F
F
F
F
1i
1n
1o
, R = Et, 83%, 92% ee
, R = nBu, 84%, 93% ee
, R = Et, 73%, 89% ee
, R = nBu, 76%, 88% ee
1k
1l
1m
1p
, 81%, 82% ee
, 80%, 80% ee
, 84%, 79% ee
, 55%, 83% ee
Br
1j
Br
Cl
O2N
Br
N
Br
Br
MeN
OH
Me
Br
Me
F
F
F
F
F
F
F
F
1q
1r,
1s
1t
, 98%, 76% ee
, 71%, 79% ee
82%, 63% ee
, 75%, 90% ee
Figure 3. Scope studies. Enantiomeric excess determined by chiral HPLC or GC. Conditions: 0.2 mmol scale, 11 equiv. py•9HF, 1.2 equiv.
m-CPBA, 0.08 M, 48 h, isolated yields. Absolute configuration of 1i established through X-ray crystal structure determination of a derivative
(S4), remaining products assigned by analogy.
ketone-containing cathinone subclass of phenethylamines.12
Invertive nucleophilic substitution of the bromide in 1 required
more forcing conditions than substitutions with typical secondary
aliphatic alkyl bromides.13 However, the deactivating effect of
gem-difluorination in SN2 pathways does not preclude
stereospecific substitution by strong nucleophiles, presumably
because of an even greater deactivation toward SN1-like
pathways.14,15
Examining a wide range of DFT-calculated molecular properties
(including natural bond orbital charges, IR frequencies/intensities,
and NMR chemical shifts) did not produce good correlations with
experimental enantioselectivity unless incorporated into complex
multivariate statistical models. Recognizing that such multivariate
correlations can result from overfitting the limited data set,18 we
sought to identify other computational descriptors that could
capture the relevant NCIs more directly.19
As noted above, catalyst enantioselectivity is subject to strong
substituent effects that do not correlate with steric parameters.
Given that the substituted arenes of the catalyst are insulated
electronically and remote from the reactive iodine center, we
hypothesized that attractive secondary noncovalent interactions
(NCIs) influenced by the electronic properties of the substituents
may play a critical role. This idea was also supported by earlier
computational studies conducted in collaboration with Houk and
Xue of related styrene difluorination reactions, wherein several key
attractive NCIs were invoked to underlie enantioinduction.16
We anticipated any attractive NCIs might be analyzed
effectively using linear free energy relationships (LFERs) between
experimental enantioselectivities and catalyst parameters. Such an
approach is not predicated on knowledge of the enantiodetermining
step because G‡ (calculated from e.r.) provides an intrinsic
readout of the energy difference in the competing major and minor
transition states in that step. While the LFER approach does not
provide a three-dimensional transition state structure as might be
attainable with density functional theory (DFT) calculations, it
leverages the full body of experimental data to evaluate the factors
governing stereocontrol.
This endeavor was facilitated by the use of symmetry-adapted
perturbation theory (SAPT),20 wherein interaction energies were
evaluated between R1-substituted benzenes serving as truncated
versions of the catalysts and probe molecules serving as
representative partners for different NCIs (Figure 4A). These
calculated interaction energies provided significantly improved
correlations to the experimental enantioselectivity data.18
A
particularly strong univariate correlation (with R2 = 0.93, training
set) was obtained using the CH– interaction energy between the
truncated catalyst arene and an orthogonally disposed benzene
probe (Figure 4B). This correlation enabled the successful
prediction and experimental validation of two new catalysts,
defining both more (1-adamantyl-substituted) and less (3,4,5-
trifluoro-substituted) enantioselective catalysts than those in the
training set. Significant correlations were also obtained using
certain cation– interaction energies (R2 ≤ 0.84, training set), but
such correlations displayed systematic curvatures indicating that
the beneficial effect on enantioselectivity of electron-donating
substituents was being captured less accurately. Moreover, the
cation– correlations also failed to predict the performance of 1-
adamantyl- and 3,4,5-trifluoro-substituted catalysts as accurately as
the CH– correlation. Thus, the SAPT analysis validated the
conclusion that the substituent effect on catalyst enantioselectivity
is not steric in nature, and reveals instead that it is best ascribed to
a selective, attractive CH– interaction in the enantiodetermining
transition state(s).21
A modest linear correlation (R2 = 0.76) was obtained between
the experimental enantioselectivities and the classical Hammett
σp/m values of the catalyst arene substituents examined in the
original optimization process (defined as the training set). The σm
parameter has previously been correlated to the strength of NCIs
with arenes,17 but the relationship is indirect given that σ values are
derived from experimental pKa values of substituted benzoic acids.
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Catalyst truncation for IEs
A)
B)
A)
O
1
probe
molecule
OR2
2
3
catalyst
portion
used for
IEs
2g
H
2c
4
5
R1
R1
Br
Me
MeN
6
7
N
2r
8
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2h
F
F
F
B)
probe
molecule
substrate
arene only
R’
collinear R2 = 0.96
–
LUMO energy correlates to  IEs
C)
Figure 4. A) Catalyst truncation for computed arene–arene
interaction energies (IEs). B) Correlation of experimental
enantioselectivity (G‡ = –RTln(e.r.)) with computed interaction
energies between substituted catalyst arenes and a benzene probe.
The line of best fit for the training set was used to extrapolate
catalyst performance.
---
C–H
F
I
Me
R
O
O
Br
H
H
---
CO2Me
NO2
To further interrogate the role of attractive NCIs as important
features of this enantioselective process, both DFT properties and
SAPT-derived interaction energies were computed for the vinyl
bromide substrates 2a–2t and compared to experimental
enantioselectivities.15 From a training set of thirteen substrates
(defined chronologically by the first substrates evaluated), a
univariate correlation was obtained using the LUMO energies of
the substrates (R2 = 0.90, Figure 5A). External validation of this set
with seven additional entries revealed a poorer overall correlation
with the LUMO energy (R2 = 0.68) as a result of three outliers.
Nevertheless, this simple model could be used to predict the
performance of pyrazole-containing substrate 2r, despite structural
dissimilarities compared to the training set. Multivariable linear
regression analysis was also conducted on the entire data set in
attempts to reconcile outliers in the LUMO correlation; however,
expansion to two-parameter models did not afford any significant
tBu
Figure 5. A) Univariate correlation of experimental
enantioselectivity (G‡ = –RTln(e.r.)) to the calculated LUMO
energy of each vinyl bromide substrate. The line of best fit for the
training set (red) was extended to the full range of values in the data
set without recalculating the fit to include the validation set. B)
LUMO energies likely reflect the ability of substrates to participate
in – interactions. C) Representation of how catalyst 3c and
substrate 2a may interact in the enantiodetermining transition state
based on SAPT studies (R = CO2CH2C6H4(p-SF5), one catalyst
sidearm omitted for clarity).
In conclusion, we have developed a synthetic method that
leverages the chemistry of chiral iodoarene difluoride intermediates
to generate enantioenriched, gem-difluorinated, secondary
aliphatic bromides with high enantioselectivity. Systematic
optimization of the catalyst structure and identification of a catalyst
decomposition pathway led to a protocol that was both more
enantioselective and more efficient. A single SAPT-derived
interaction energy was sufficient to correlate enantioselectivities to
catalyst substituent effects. Efforts to capture substrate effects on
enantioselectivity with calculated parameters proved more
challenging, although a correlation with substrate electrophilicity
was established and interpreted as the ability for the substrate to
participate in selective -interactions. Together, these studies add
to a growing body of evidence for the important structural features
underpinning the activity, stability, and enantioselectivity of this
increasingly important class of iodoarene catalysts.24
improvement
to
the
observed
correlation
with
enantioselectivity.22,23
To interpret the correlation of calculated substrate LUMO
energies to enantioselectivity, we assessed the LUMO energies
against a wide set of other DFT-derived parameters and SAPT
interaction energies. The best correlation was with calculated
energies of a directly stacked – interaction between the substrate
arene and a benzene probe (R2 = 0.96, Figure 5B).17b We therefore
hypothesize that the LUMO correlation reflects the degree to which
the substrates can engage in selective -interactions in the
enantiodetermining transition states Taken together with the
catalyst correlation and the previous computational study,16 these
observations are consistent with a network of attractive NCIs being
responsible for enantioinduction.
ASSOCIATED CONTENT
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and Properties of Selected Organic Compounds. Pure Appl. Chem.
Supporting Information
2012, 84, 1587–1595. https://doi.org/10.1351/PAC-CON-11-09-26. (c)
Corr, M. J.; Cormanich, R. A.; Hahmann, C. N. von; Bühl, M.; Cordes,
D. B.; Slawin, A. M. Z.; O’Hagan, D. Fluorine in Fragrances: Exploring
the Difluoromethylene (CF2) Group as a Conformational Constraint in
Macrocyclic Musk Lactones. Org. Biomol. Chem. 2015, 14, 211–219.
https://doi.org/10.1039/C5OB02023A. (d) Callejo, R.; Corr, M. J.;
Yang, M.; Wang, M.; Cordes, D. B.; Slawin, A. M. Z.; O’Hagan, D.
Fluorinated Musk Fragrances: The CF2 Group as a Conformational
Bias Influencing the Odour of Civetone and (R)-Muscone. Chem. –
Eur. J. 2016, 22, 8137–8151. https://doi.org/10.1002/chem.201600519.
5. (a) Singh, R. P.; Shreeve, J. M. Recent Advances in Nucleophilic
Fluorination Reactions of Organic Compounds Using Deoxofluor and
1
2
3
4
5
6
7
8
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures and characterization data (PDF)
Computational procedures and data (PDF)
Crystallographic data for derivatized product S4 (CIF)
9
AUTHOR INFORMATION
Corresponding Authors
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60
DAST.
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ACKNOWLEDGMENT
This work was supported by the NIH (GM043214 to E.N.J. and
GM121383 to M.S.S.), NIH postdoctoral fellowships to M.D.L.
(F32GM125187) and J.A.R. (F32GM128351), and an NSF
predoctoral fellowship to J.M.O. (DGE1745303). We thank Shao-
Liang Zheng (Harvard University) for determination of X-Ray
crystallographic structures. Dr. Adam Trotta (Harvard University),
Dr. Tobias Gensch (TU Berlin), and Dr. Nathaniel Kenton (Ohio
State) are thanked for helpful discussions.
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Chatterjee, I. A Survey of Chiral Hypervalent Iodine Reagents in
Asymmetric Synthesis. Beilstein J. Org. Chem. 2018, 14 (1), 1244–
1262. https://doi.org/10.3762/bjoc.14.107. (i) Parra, A. Chiral
Hypervalent Iodines: Active Players in Asymmetric Synthesis. Chem.
22. More traditional parameters such as σp/m andσ+ failed to account for the
variation in enantioselectivity as a function of substrate structure (R2
values with ΔΔG‡ of 0.45 and 0.41, respectively).
23. Introduction of a second parameter into the LUMO model corrects for
outlier 2h, bearing a branched alkyl group, but does not reconcile the
remaining outliers. See Figure S14 in the computational SI for details.
24. (a) Hirt, U. H.; Spingler, B.; Wirth, T. New Chiral Hypervalent Iodine
Compounds in Asymmetric Synthesis. J. Org. Chem. 1998, 63 (22),
7674–7679. https://doi.org/10.1021/jo980475x. (b) Zhdankin, V. V.;
Protasiewicz, J. D. Development of New Hypervalent Iodine Reagents
Rev.
2019,
119
(24),
12033–12088.
https://doi.org/10.1021/acs.chemrev.9b00338.
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Computational Modeling
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SF5
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CO2Me
tBu
Br
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R'
m-CPBA, py9(HF)
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CH2Cl2
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20 examples
up to 93% ee
improved
selectivity
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