Enantioselective Construction of Tertiary Fluoride Stereocenters by Organocatalytic Fluorocyclization

Article abstract of DOI:10.1021/jacs.0c09323

1,1-Disubstituted styrenes with internal oxygen and nitrogen nucleophiles undergo oxidative fluorocyclization reactions with in situ generated chiral iodine(III)-catalysts. The resulting fluorinated tetrahydrofurans and pyrrolidines contain a tertiary carbon-fluorine stereocenter. Application of a new 1-naphthyllactic acid-based iodine(III)-catalyst allows the control of tertiary carbon-fluorine stereocenters with up to 96% ee. Density functional theory calculations are performed to investigate the details of the mechanism and the factors governing the stereoselectivity of the reaction.

Full text of DOI:10.1021/jacs.0c09323

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Enantioselective Construction of Tertiary Fluoride Stereocenters by
Organocatalytic Fluorocyclization
§
§
§
̈
Qiang Wang, Marvin Lubcke, Maria Biosca, Martin Hedberg, Lars Eriksson, Fahmi Himo,*
́
́
́
and Kalman J. Szabo*
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ABSTRACT: 1,1-Disubstituted styrenes with internal oxygen and
nitrogen nucleophiles undergo oxidative fluorocyclization reactions
with in situ generated chiral iodine(III)-catalysts. The resulting
fluorinated tetrahydrofurans and pyrrolidines contain a tertiary
carbon−fluorine stereocenter. Application of a new 1-naphthyllactic
acid-based iodine(III)-catalyst allows the control of tertiary carbon−
fluorine stereocenters with up to 96% ee. Density functional theory
calculations are performed to investigate the details of the mechanism
and the factors governing the stereoselectivity of the reaction.
were first applied by Nevado and co-workers for the
asymmetric synthesis of fluorinated compounds, such as
piperidines and azepanes.34 This seminal work has been
followed by several catalytic asymmetric protocols.35−40
INTRODUCTION
■
Carbon−fluorine bonds frequently occur in drug substances,
agrochemicals, and substances used for medical diagnostics.1−3
The predominant structures are aryl fluorides and trifluor-
omethylated arenes.4,5 In contrast, alkyl fluoride motifs are far
less abundant in small molecules relevant for life sciences.
Nevertheless, recent studies have highlighted the beneficial
properties of alkyl fluorides for the modification of molecular
conformation, polarity, acid−base properties, and electronic
interactions based on gauche/anomeric effects.6−14 There are a
few examples of marketed alkyl fluoride drugs, such as
macrolide antibiotics solithromycin, fluticasone, and sofosbu-
vir, which are used for treatment of asthma and hepatitis C
(Figure 1a).4 One of the main reasons for the relatively low
abundance of fluoroalkyl motifs in pharmaceutical compounds
is attributed to methodological limitations for the selective
synthesis of alkyl fluorides, especially with tertiary C−F
stereocenters (Figure 1a).15 On the basis of our previous
results on fluorocyclization of alkenes with fluorobenziodoxol
(a hypervalent iodine reagent),16 we decided to develop an
asymmetric version of this reaction to access heterocyclic
compounds with endocyclic tertiary fluoride motifs.
As mentioned above, enantioselective construction of
tertiary fluorides is considered to be particularly challenging
but relevant for drug design (Figure 1a) and for modern
synthetic methodology development.15 Although many ex-
cellent techniques were reported for the synthesis of these
species,41−51 relatively few methods are based on hypervalent
iodine reagents.32,37,38,52−54 Jacobsen and co-workers pre-
sented studies on asymmetric aziridination38 and 1,2-
difluorination reactions32,37 (Figure 1b) leading to tertiary
fluorides. The groups of Rueping52 and Lu/Zheng53 described
a method for the synthesis of chiral tertiary fluoro β-ketoesters
using hypervalent iodine based catalysts. Fluorocyclization with
hypervalent iodides16,55−59 is a challenging but very efficient
approach for accessing pharmaceutically important hetero-
cycles, such as tetrahydrofurans and pyrrolidines. However,
fluorocyclization for the synthesis of endocyclic chiral tertiary
fluorides with hypervalent iodides (Figure 1c) has not been
reported so far. In addition, the mechanistic features governing
Chiral hypervalent iodines have become attractive catalysts
and mediators for asymmetric oxidation reactions.17−20 These
species have been successfully employed for a wide range of
enantioselective C−C,21−23 C−O,24−28 and C−N29,30 bond
formation reactions using alkene derivatives as substrates. The
groups of Kitamura,31 Jacobsen,32 and Gilmour33 reported
pioneering methods for catalytic fluorination of olefins with in
situ generated iodine(III) fluorides. Chiral iodine(III) fluorides
Received: August 30, 2020
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(R,R)-1a−c are particularly suitable for asymmetric fluorina-
tion reactions of alkenes (Figure 2).34,38,56,60
Table 1. Optimization of Reaction Conditions for the
a
Asymmetric Oxyfluorination Reaction
a
b
c
entry
catalyst
conditions
ee (%)
yield (%)
1
2
3
4
5
6
7
8
9
(R,R)-1a
(R,R)-1b
(R,R)-1c
(R,R)-1d
(R,R)-1e
(R,R)-1c
(R,R)-1c
(R,R)-1c
(R,R)-1c
(R,R)-1c
(R,R)-1c
no cat.
as indicated
as indicated
as indicated
as indicated
as indicated
CH2Cl2 as solvent
toluene as solvent
0 °C
0.1 M in CHCl3
9 equiv of HF
5 mol % cat.
as indicated
72
88
90
93
88
74
61
70
89
85
73
41
50
75
83
66
63
70
75
75
78
83
0
10
11
12
a
Conditions: 2a (0.1 mmol), (R,R)-1 (0.01 mmol), pyr·9HF (0.2
mmol, pyr = pyridine), and mCPBA (0.15 mmol) dissolved in CHCl3
(0.5 mL) at −35 °C and stirred for 24 h. Enantiomeric excess
determined by chiral SFC. Isolated yield.
b
c
Figure 1. (a) Examples of drugs featuring tertiary fluoride centers. (b)
Asymmetric construction of tertiary C−F stereocenters by difluori-
nation. (c) Oxy- and aminofluorocyclization.
Optimization of the Reaction Conditions. We selected
p-nitrostyryl alcohol 2a as a model compound for the
optimization of the reaction conditions. When the reaction
was carried out under the conditions given in Table 1, using
lactate-derived catalyst (R,R)-1a,38 fluorotetrahydrofuran
derivative 3a was obtained with encouraging levels of ee
(72%) and yield (41%) (Table 1, entry 1). The absolute
configuration of the tertiary carbon−fluorine stereocenter in 3a
is (S) based on X-ray diffraction studies. When (R,R)-1a was
replaced by phenyllactate catalyst (R,R)-1b,38 both the yield
(50%) and the enantioselectivity (88%) increased, probably
because of the increased steric demand of the α-substituent in
the so-called “side arm” of the ester group (entry 2).
Possibilities to improve the stereoselectivity were further
studied by increasing the size of the side arm substituent.
Indeed, the use of mesityl lactate derivative (R,R)-1c60
increased the enantioselectivity to 90% (entry 3).
the reactivity and selectivity in these types of fluorocyclization
reactions have been unexplored.
RESULTS AND DISCUSSION
■
In the initial fluorocyclization reactions we employed 1,1-
disubstituted styrenes with tethered hydroxy groups as
substrates in the presence of C2-symmetric aryl iodide catalysts
(Figure 2) with HF-pyridine as fluorine source and mCPBA as
oxidant (Table 1). According to previous reports, catalysts
This selectivity enhancement prompted us to study the
subtle steric effect of the ortho substitution of the side arms.
Therefore, we prepared two new catalysts, with naphthyl
(R,R)-1d and phenanthryl (R,R)-1e groups in the side arms.
To our delight, by use of the newly developed 1-
naphthyllactate catalyst (R,R)-1d, the ee could be increased
to 93%, affording 3a with a high yield of 83% (entry 4). The
naphthyl substituents of (R,R)-1d probably exert the ideal
substituent effects in the stereoinduction step, as the ee of the
reaction declined to 88% (entry 5) with the bulkier
phenanthryllactate catalyst (R,R)-1e. An in-depth analysis on
the substituent effects of the side-arms on the stereoinduction
is given in the DFT/stereoinduction section below.
We briefly studied the solvent effects on the reaction. By use
of catalyst (R,R)-1c, chloroform was replaced by methylene
chloride and toluene. In both cases the enantioselectivities
Figure 2. C2-symmetric aryl iodine catalysts (R,R)-1a−e and new
catalysts (R,R)-1d,e developed in this study. The so-called “side-
arms” are given in blue color.
B
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a
Scheme 1. Scope of the Oxyfluorination Reaction
a
Conditions: 2a (0.1 mmol), (R,R)-1 (0.01 mmol), pyr·9HF (0.2 mmol), and mCPBA (0.15 mmol) dissolved in CHCl3 (0.5 mL) at −35 °C and
b
c
stirred for 24 h. Enantiomeric excess determined by chiral SFC. Isolated yield. 0.5 mmol scale reaction with catalyst (R,R)-1c. 1 mmol scale
reaction with catalyst (R,R)-1d. The reaction was conducted at −50 °C for 60 h.
d
decreased (cf. entry 2 with entries 6 and 7). Conducting the
reaction at 0 °C did not influence the yield, but the
enantioselectivity was lower (entry 8). Dilution (entry 9)
and decrease of the amount of HF-pyridine (entry 10) led to a
slight decrease of the ee and the same or improved yield.
Decreasing of the amount of catalyst from 10% to 5% (entry
11) decreased the ee to 73%. The decrease of the ee was
surprising as in the absence of catalyst formation of 3a was not
observed (entry 12). This indicates that there is no racemic
background reaction in the absence of iodoaryl catalyst. We
found (see Supporting Information for experimental studies,
page S65) that the catalyst did not undergo racemization under
the applied reaction conditions. This control experiment
(Supporting Information, page S65) suggests that the catalyst
underwent transformation/degradation under the applied
oxidative conditions and perhaps these products also catalyzed
the fluorocyclization, albeit with lower selectivity than (R,R)-
1c,d. Unfortunately, we were unable to isolate these
degradation products of the catalyst. In a very recent
publication, Sigman, Jacobsen, and co-workers54 reported the
isolation of chiral iodoresorcinol derivatives, which were
formed under the oxidative conditions and still catalyzed the
difluorination reactions.
substituted ones (2i−k). The fluorocyclization of ortho-
substituted styrenes (2l,m) proceeded with low selectivity
and decreased reactivity. Both catalysts induced high
enantioselectivity, but the ee values were higher with the
newly developed 1-naphthyllactate catalyst (R,R)-1d, than
with the mesityl analog (R,R)-1c. Nitro-, trifluoromethyl-, and
methyl sulfone-substituted fluorotetrahydrofurans 3a−c
formed with high ee (92−93%) and good yield (54−83%)
using naphthyllactate catalyst (R,R)-1d.
Somewhat lower enantioselectivities (73−88% ee) were
observed for the formation of nitrile-, keto-, and ester-
substituted products 3d−f. Interestingly, benzamide 3g and
tertiary benzamide 3h were formed with high levels of
enantioselectivity (up to 92% ee). However, the yield of the
primary amide 3g was only 27%/41% (with (R,R)-1d/(R,R)-
1c) probably because of poor solubility of the corresponding
substrate (2g) in chloroform. As mentioned above, meta-
substituted products 3i−k were formed with lower selectivity.
While para-nitro derivative 3a was formed with 93% ee, its
meta-nitro analog 3i was obtained with 86% ee using catalyst
(R,R)-1d. Similarly, meta-methylcarbonyl compound 3j was
obtained with 82% ee, while the para-substituted isomer 3e
was formed with 86% ee. In the case of meta-benzyl ether
substitution (3k) the fluorocyclization proceeded with
relatively low ee (61%) and poor yield (36%). Fluorocycliza-
tion of ortho-cyano-substituted styrene 2l with catalyst (R,R)-
1d resulted in formation of 3l with 39% ee. Surprisingly, the
reaction with catalyst (R,R)-1c gave the opposite enantiomer
ent-3l with 33% ee. In the case of an ortho-chloro substituent,
the major enantiomer formed with the same configuration
using either (R,R)-1c or (R,R)-1d, albeit with low ee of 16% or
30%, respectively. While para- and meta-substituted nitro aryl
Tetrahydrofurans by Asymmetric Fluorocyclization.
Since both catalysts (R,R)-1c and (R,R)-1d induced high
levels of enantioselectivities and good yields, we decided to
explore the substrate scope of the reaction with both catalysts
(Scheme 1). We studied the effects of the aromatic
substituents on the reactivity of the styrene substrates and
on the enantioselectivity of the fluorocyclization (Scheme 1).
Para-substituted styrenes (2a−h) reacted with somewhat
higher selectivity (typically around 90% ee) than the meta-
C
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Scheme 2. Control Experiments
derivatives 3a and 3i formed with high ee’s and yields,
formation of the ortho-substituted analog 3n was not observed.
The effects of the ortho-nitro substitution on fluorination and
fluorocyclization reactions have been previously reported.39,60
As shown in Table 1, the reaction of 2a gave a higher
enantioselectivity at a lower temperature (cf. Table 1, entries 3
and 8). Therefore, we carried out the reaction of some
substrates at −50 °C using (R,R)-1d as catalyst, to see whether
the enantioselectivity could be further increased. We found
that the para-substituted substrates 2a, 2c, 2e and meta-
substituted substrate 2i reacted with higher enantioselectivities
(94−96%) at −50 °C than at −35 °C (86−93%). However,
the yields were lower at −50 °C than at −35 °C. The lower
yields at −50 °C have been a consequence of the lower
reactivity, which may be caused by solubility issues. The
reactions can be easily scaled up without significant change of
the selectivity or yield. For example, under the standard
optimized conditions 3a was obtained with 89% ee (0.5 mmol
scale) and 90% ee (1 mmol scale) using catalysts (R,R)-1c and
(R,R)-1d, respectively.
We have also studied the effects of the alteration of the
aliphatic tether of the alcohol nucleophile (Scheme 2a−c).
When the carbon chain was elongated by a single methylene
unit, the corresponding tetrahydropyran 3o was formed in
lower yield (24%/39%) and selectivity (57%/65% ee) than 3a
using (R,R)-1c or (R,R)-1d as catalyst (Scheme 2a). We did
not observe formation of tetrahydrofuran products. The lack of
five membered ring (tetrahydrofuran) products indicates that
the elongation of the tether did not lead to change of the
mechanism of the fluorocyclization involving a phenonium ion
intermediate.36,57,59,61−63 Possible reasons to explain the drop
of the ee on elongation of the tether are given below in the
DFT/stereoinduction section. We have also attempted to
study the Thorpe−Ingold effect64,65 on the reactivity of the
substrates by dimethyl substitution of the tether (Scheme
2b,c). However, formation of fluorocyclization products 3p,q
was not observed using para-iodotoluene as catalyst. In the
case of the attempted fluorocyclization of 2p, allyl fluoride 4
formed (Scheme 2b). The mechanism of this reaction
involving a formal extrusion of a CH2O molecule is unclear.
When fluorocyclization of 2q was attempted, a complex
reaction mixture of various fluorinated products was obtained
(Scheme 2c). In addition, we also studied the effects of
protection of the alcohol nucleophile (Scheme 2d). In the
reaction of benzyl protected substrate 2r, the same
fluorocyclization product 3a was observed as with the parent
alcohol (2a), albeit with lower yield (38%) and selectivity
(73% ee). Formation of the identical major enantiomer with 2a
and 2r under the same reaction conditions indicates that the
enantioselectivity is not controlled by the nucleophilicity of the
oxygen, which means that the cyclization process is not
involved in the enantiodetermining step of the oxyfluorination.
This suggests that the enantioselectivity is determined in the
fluorination process.60,62
Extension to Pyrrolidines. The asymmetric fluorocycliza-
tion reaction of alcohol nucleophiles 2 can be extended to
sulfonate-protected nitrogen nucleophiles 5 (Table 2). We
have found that the selectivity of the aminofluorination
reaction is dependent on the sulfonyl protecting group. The
fluorocyclization of sulfonamide analogs (6a−c) of nitro
compound 3a was studied (Table 2) under the optimal
conditions of the oxyfluorination (Table 1, entry 4). Formation
of pyrrolidine derivatives 6a and 6c (70%/72% ee) with nosyl
and mesyl protecting groups (Table 2, entries 1 and 3)
occurred with higher selectivity than with tosyl-substituted
(entry 2) analog 6b (56% ee). Similar to the results obtained
for oxyfluorination reactions, application of our newly
developed 1-naphthyllactate catalyst (R,R)-1d gave higher
selectivity than the mesityl derivative (R,R)-1c (cf. entries 1
and 4). A slight change of the applied amount of pyr•9HF
reagent and dilution of the reaction mixture led to an increase
of the ee from 70% to 75% (cf. entries 1 and 5). The difference
D
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a
Table 2. Screening of N-Protection for the Asymmetric
Aminofluorination Reaction
Scheme 3. Scope of Aminofluorination Reaction
a
b
c
entry
catalyst
ee (%)
yield (%)
1
2
3
4
(R,R)-1d
(R,R)-1d
(R,R)-1d
(R,R)-1c
(R,R)-1d
6a R = Ns
6b R = Ts
6c R = Ms
6a
70
56
72
62
75
58
68
63
59
76
d
5
6a
a
Conditions: Unless otherwise stated 5 (0.1 mmol), (R,R)-1 (0.01
mmol), pyr·9HF (0.2 mmol), and mCPBA (0.15 mmol) dissolved in
b
CHCl3 (0.5 mL) at −35 °C and stirred for 24 h. Enantiomeric excess
c
d
determined by chiral SFC. Isolated yield. Using pyr·9HF (0.3
mmol) in CHCl3 (1.0 mL).
in selectivity for the nosyl- (6a) and mesyl-substituted (6c)
products was relatively small. As the nosyl protection group is
easier to remove than the mesyl group, we selected nosyl
protection for the study of the synthetic scope of the reaction.
By use of the optimal conditions (Table 2, entry 5),
pyrrolidine derivatives with tertiary C−F bonds were obtained
(Scheme 3) with high selectivity (up to 94% ee, 6e). The
enantioselectivity of the aminocyclization reactions (Scheme
3) was slightly lower, but the yields were somewhat higher
than for the oxyfluorination reactions (Scheme 2). Pyrrolidine
derivatives with trifluoromethyl- (6d), cyano- (6f), and methyl
ester- (6h) substitution formed with the highest selectivity
(86−92% ee). Nitro- (6a), methyl sulfonyl- (6e), methyl
carbonyl- (6g), and dimethylamide (6i) products were
obtained with lower enantioselectivity (72−82% ee) than the
corresponding tetrahydrofuran analogs (86−93% ee). The
absolute configuration of 6e is (S) according to the X-ray
crystallography data. The fact that the absolute configuration
of tetrahydrofuran 3a and pyrrolidine 6e formed under similar
reaction conditions with the same (S) absolute configuration
and with similar levels of enantioselectivities indicates that the
mechanism and stereoinduction in the asymmetric oxy-
fluorination and aminofluorination reactions are closely similar.
Similar to the oxyfluorination processes, the aminofluorina-
tion reactions of meta-substituted substrates (5j,k) proceeded
with similar or lower selectivity (75%/68% ee) than the para-
substituted analogs (75%/82% ee for 6a/6g). Alkyl-substituted
alkene derivative 5l also underwent fluorocyclization reaction
affording 6l in 56% yield. However, the enantioselectivity (39%
ee) was much lower than for the aromatic analogs indicating
the important role of the aromatic substituent in the
stereoselection process. As expected, some of the amino-
fluorination reactions proceeded with higher selectivity at −50
°C than at −35 °C. Using (R,R)-1d as catalyst, we also carried
out the fluorocyclization reactions of para-substituted com-
pounds 5a, 5e, 5g and meta-substituted compounds 5j and 5k
at −50 °C. The enantioselectivity increased in all reactions, but
the yield decreased. A substantial improvement of the
selectivity was observed for the formation of sulfone-
substituted fluoropyrrolidine 6e, which was obtained with
excellent ee (94%) and in good yield (56%) at −50 °C. Similar
to the oxyfluorination reactions, several other substrates
reacted with very low yield at −50 °C. The nosyl group can
a
Conditions: 5 (0.1 mmol), (R,R)-1d (0.01 mmol), pyr·9HF (0.3
mmol), and mCPBA (0.15 mmol) dissolved in CHCl3 (1.0 mL) at
−35 °C and stirred for 24 h. Enantiomeric excess determined by
b
chiral SFC. Isolated yield. The reaction was conducted at −50 °C for
60 h.
be easily removed from the pyrrolidine ring without affecting
the enantiopurity of the products (Scheme 4). For example,
Scheme 4. Deprotection of Product 6d
treatment of 6d with 2-mercaptobenzoic acid in the presence
of K2CO3 leads to the free amine product 7. We were not able
to determine the enantiopurity of 7, and therefore it was
protected with a tosyl group (8). The ee of the tosylated
product 8 indicated that the deprotection of the nosyl
derivative 6d did not lead to decrease of the enantiopurity.
DFT Modeling Studies. In order to gain mechanistic
insights into the fluorocyclization reactions, we performed
density functional theory (DFT) calculations, using nitro-
phenyl styrene 2a as a model substrate, with (R,R)-1c as
catalyst (Table 1, entry 3). The calculations were carried out
using the B3LYP-D3 functional,66−69 and implicit solvation
using the SMD70 model with the parameters for chloroform
E
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was included in the geometry optimizations (see Supporting
Information for computational details).
Catalytic Cycle and Reaction Profile. The reaction
mechanism for the fluorocyclization of 2a obtained from the
calculations is shown in Scheme 5. The associated free energy
Supporting Information for the computational part. The
catalytic cycle starts with the formation of (R,R)-1c-F2 by
oxidation and deoxyfluorination of iodoarene (R,R)-1c. This
step was not considered explicitly by the calculations, but the
formation of (R,R)-1c-F2 is supported by experiments that
confirm the oxidation of iodoarene by mCPBA to form the
iodosylarene (ArIO), which is readily converted to the
difluorinated species by reaction with HF.35,71−73
The next step of the cycle is the loss of a fluoride from
(R,R)-1c-F2 to yield the cationic fluoroiodonium active
catalytic species Int1. Similar to the mechanism proposed by
Jacobsen, Xue, and Houk for the aryl iodine-catalyzed
asymmetric difluorination of β-substituted styrenes,62 we
employed two molecules of HF as an activation model for
the iodoarene difluoride. Coordination of the two HF
molecules results in the formation of the hydrogen-bonded
difluoride complex (R,R)-1c-F2-2HF, which is 0.6 kcal/mol
lower than (R,R)-1c-F2. Then, abstraction of fluoride occurs
through transition state TS1, which is 18.7 kcal/mol higher
than (R,R)-1c-F2-2HF, resulting in intermediate Int1.
Scheme 5. Catalytic Cycle Based on DFT Calculations for
Fluorocyclization of 2a with Hypervalent Iodine Catalyst
(R,R)-1c
In line with the results on the aryl iodine-catalyzed
asymmetric difluorination of β-substituted styrenes,62 the
transformation of (R,R)-1c-F2 to Int1 is assisted by one of
the carbonyl groups of the side chain of the catalyst through an
I+···O interaction that also stabilizes the cationic species Int1.
Note that Int1 here is modeled as an ion-pair, consisting of a
cationic catalyst species and an (HF)2F− counterion. Many
(>20) initial geometries of this ion-pair complex were
considered in order to make sure that the lowest-energy
conformation is located (the same applies to Int2, Int4, TS3,
and Int5 below). We have also calculated the case in which the
ions (i.e., (HF)2F− and the cationic part) are separated. The
two different approaches led to some significant changes in the
energy profiles but not to the mechanistic conclusions (see
comparison in the Supporting Information for computational
details on page S3).
profile is displayed in Figure 3, and the optimized geometries
of the intermediates and transition states are given in the
Figure 3. Calculated free energy profile (kcal/mol) for the aryl iodine-catalyzed oxyfluorination of 2a with (R,R)-1c.
F
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In the next step, substrate 2a coordinates to Int1 to give
iodonium ion intermediate Int2(S), which is calculated to be
12.2 kcal/mol lower in energy than Int1. The coordination can
take place with either the Si or Re face of the double bond. In
this case it was found that the coordination to Re-face was
lower in energy, which will have implications on the
enantioselectivity of the reaction (see “stereoinduction” section
below). We made many attempts to locate the transition state
for the coordination of the olefin but without success. The
optimizations led always to Int2(S).
agreement with the experimentally observed ee of 90% in
favor of the S-product (Table 1, entry 3), indicating that the
factors governing the enantioselectivity can be deduced by
analyzing the geometries of Int2(S) and Int2(R), as shown in
Figure 4. Scrutiny of these geometries shows that the substrate
The olefin then undergoes a nucleophilic attack by the
(HF)2F− counterion at the most substituted carbon (via
TS2(S)), generating Int3, in which two new σ-bonds are
formed (C−I at 2.21 Å and C−F at 1.44 Å) and the double
bond of the substrate is converted into a single bond. The
barrier for this step is calculated to be 7.4 kcal/mol relative to
Int2(S). We also considered the possibility of intramolecular
attack by the hydroxyl group at the iodine(III)-activated alkene
(see Supporting Information for computational details, S5).
However, this mechanistic scenario was found to be associated
with a considerably higher barrier than TS2(S). These results
are also in line with our control experiment (Scheme 2d)
indicating that the enantioselectivity is determined in the
fluorination process prior to the cyclization step. The
formation of the C−I bond in Int3 weakens the I−F bond
(2.15 Å in Int3 vs 2.01 Å in Int2(S)), which makes the
dissociation of fluoride easier. According to the calculations,
two HF molecules can abstract the fluoride to yield ion-pair
intermediate Int4, which is 21.1 kcal/mol lower than the
neutral iodoarene intermediate Int3. Next, an intramolecular
nucleophilic attack by the oxygen atom of 2a displaces the
aryliodonium moiety, which is an excellent leaving group. The
step occurs via TS3, with a barrier of 11.6 kcal/mol, and the
resulting Int5 that contains the protonated form of the cyclic
product 3a is 15.3 kcal/mol lower than Int4 (Figure 3). The
last step of the cycle is the deprotonation of the protonated
cyclic compound to give the final product 3a and regenerate
the iodoarene catalyst (R,R)-1c. The (HF)2F− counterion can
achieve this step, which is calculated to be exergonic by 2.6
kcal/mol.
Factors Determining the Stereoselection. The overall
energy profile obtained for the mechanism (Figure 3) shows
that the coordination of substrate 2a to Int1 to form Int2(S) is
an irreversible process. The coordination of the substrate can
take place with either the Re or Si faces of the double bond,
resulting in Int2(S) or Int2(R), respectively, indicating that
this is the selectivity-determining step of the reaction. Int2(S)
leads ultimately to the S-enantiomer (major enantiomer
according to the experimental studies) of the product, while
Int2(R) leads to the R-enantiomer. As mentioned above, it was
not possible to locate the transition state for this coordination
step. Instead, we optimized the geometry of Int2(R), which
was found to be 1.7 kcal/mol higher in energy than Int2(S).
Subsequently, the potential energy surface was calculated
backward from these intermediates. Thus, we performed
constrained optimizations starting from Int2(S) and Int2(R),
in which the distance between the iodine center and the
double bond of the substrate was increased gradually (see S6 in
the Supporting Information for computational studies). This
procedure shows that the energy difference between the
intermediates is maintained along the reaction coordinate of
the coordination, even at long distances that resemble the TS
structures. The calculated energy difference is in good
Figure 4. Optimized geometries of the intermediates resulting from
the coordination of substrate 2a to Int1. (a) Int2(S): coordination
from the Re-face, leading to the S-product. (b) Int2(R): coordination
from the Si-face, leading to the R-product.
in Int2(S) fits better into the chiral pocket of the catalyst as
compared to the Int2(R) (Figure 4). Namely, Int2(R) is
destabilized by a steric repulsion between one of the ortho-
methyl substituents of the aryl group of the catalyst side arms
and one of the methylene carbons of substrate 2a (Figure 4b).
The ortho-substituents in the side arm of the catalyst thus
play an important role in the stereoinduction, explaining why
the enantioselectivity is affected by the variation of these
substituents in the experiments (Figure 2 and Table 1). On the
basis of this stereoselection model, we also conclude that
elongation of the tether, such as in 2o, leads to more repulsive
interactions in both homologs of Int2(S) and Int2(R), leading
to lower selectivity in fluorocyclization of 2o (57% ee) than for
2a (90% ee). In addition, this stereochemical model suggests
that the presence of ortho-substituents in the substrates (such
as in 3l−n) generates major clashes with the iodoresorcinol
catalysts in the intermediates corresponding to Int2(S) and
G
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Article
Int2(R), which leads to a major drop (3m) or even inversion
(3l) of the stereoselectivity.
Marvin Lubcke − Department of Organic Chemistry,
̈
Stockholm University, SE-106 91 Stockholm, Sweden;
orcid.org/0000-0002-7276-2755
CONCLUSIONS
Maria Biosca − Department of Organic Chemistry, Stockholm
University, SE-106 91 Stockholm, Sweden; orcid.org/
0000-0002-9116-6318
Martin Hedberg − Department of Organic Chemistry,
Stockholm University, SE-106 91 Stockholm, Sweden
Lars Eriksson − Department of Materials and Environmental
Chemistry, Stockholm University, SE-106 91 Stockholm,
Sweden
■
In summary, we have developed a new method for the
synthesis of chiral tetrahydrofurans and pyrrolidines with
endocyclic tertiary C−F stereocenters. The fluorocyclization
reactions of various 1,1-disubstituted styrene derivatives were
catalyzed by in situ generated hypervalent iodines. The best
selectivities (up to 96% ee) were achieved using a newly
developed catalyst, (R,R)-1d, with 1-naphthyl substituents in
the side arm. Our experimental findings suggest that the
selectivity of the reaction is dependent on the effects of
substituents attached to the aromatic ring in the styrene
substrates. DFT modeling was conducted to rationalize the
factors governing the enantioselectivity in the fluorocyclization
reaction resulting the tetrahydrofuran product. We present a
new stereoselection model for formation of a tertiary C*−F
bond using hypervalent iodine catalyst in an internal
oxyfluorination reaction. The calculations show that the
major factor determining the selectivity is a steric repulsion
between the side arm substituent of the chiral catalyst and one
of the methylene groups in the tether of the oxygen
nucleophile. Our stereoselection model also accounts for the
drop of the stereoselectivity on elongation of the tether of the
nucleophile, as well as the adverse effects of ortho substituents
in the aromatic ring of the styrene substrates. The above study
forwards the catalytic asymmetric syntheses of tertiary
fluorides, which are considered to be one of the most
challenging methodological problems in organic synthesis.15
Extension of the toolbox of asymmetric catalysis to access
tertiary fluorides is important to increase the molecular
diversity of complex organofluorine species used in life-
sciences, such as in drug development (Figure 1a).4,15
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09323
Author Contributions
§Q.W., M.L., and M.B. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Knut och Alice Wallenbergs Foundation
(Dnr 2018.0066) and Swedish Research Council (Dnr 2017-
04235) for financial support. A postdoctoral fellowship for
Q.W. is gratefully acknowledged to Stiftelsen Olle Engkvist
̈
Byggmastare (Dnr 192-0484). We thank Matteo Costantini for
his kind help with chiral HPLC analyses.
REFERENCES
■
(1) Jeschke, P. The Unique Role of Fluorine in the Design of Active
Ingredients for Modern Crop Protection. ChemBioChem 2004, 5,
570−589.
(2) Muller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals:
̈
Looking Beyond Intuition. Science 2007, 317, 1881−1886.
(3) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in
medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320−330.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09323.
■
sı
(4) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.;
̃
Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of Fluorine-
Containing Pharmaceuticals, Compounds Currently in Phase II−III
Clinical Trials of Major Pharmaceutical Companies: New Structural
Trends and Therapeutic Areas. Chem. Rev. 2016, 116, 422−518.
(5) Mei, H.; Han, J.; Fustero, S.; Medio-Simon, M.; Sedgwick, D.
M.; Santi, C.; Ruzziconi, R.; Soloshonok, V. A. Fluorine-Containing
Drugs Approved by the FDA in 2018. Chem. - Eur. J. 2019, 25,
11797−11819.
Experimental procedures, characterization data, and
NMR spectra of compounds (PDF)
Computational details and additional computational
results discussed in the text, absolute energies and
energy corrections, and Cartesian coordinates (PDF)
X-ray crystal structure file for compound 3a (CIF)
X-ray crystal structure file for compound 6e (CIF)
(6) Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer,
̈
H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Muller, K. Fluorination
Patterning: A Study of Structural Motifs That Impact Physicochem-
ical Properties of Relevance to Drug Discovery. J. Med. Chem. 2015,
58, 9041−9060.
(7) Linclau, B.; Wang, Z.; Compain, G.; Paumelle, V.; Fontenelle, C.
Q.; Wells, N.; Weymouth-Wilson, A. Investigating the Influence of
(Deoxy)fluorination on the Lipophilicity of Non-UV-Active Fluori-
nated Alkanols and Carbohydrates by a New log P Determination
Method. Angew. Chem., Int. Ed. 2016, 55, 674−678.
(8) Jeffries, B.; Wang, Z.; Graton, J.; Holland, S. D.; Brind, T.;
Greenwood, R. D. R.; Le Questel, J.-Y.; Scott, J. S.; Chiarparin, E.;
Linclau, B. Reducing the Lipophilicity of Perfluoroalkyl Groups by
CF2−F/CF2−Me or CF3/CH3 Exchange. J. Med. Chem. 2018, 61,
10602−10618.
AUTHOR INFORMATION
Corresponding Authors
Fahmi Himo − Department of Organic Chemistry, Stockholm
University, SE-106 91 Stockholm, Sweden; orcid.org/
0000-0002-1012-5611; Email: fahmi.himo@su.se
■
́
́
́
Kalman J. Szabo − Department of Organic Chemistry,
Stockholm University, SE-106 91 Stockholm, Sweden;
orcid.org/0000-0002-9349-7137;
Email: kalman.j.szabo@su.se
(9) Graton, J.; Compain, G.; Besseau, F.; Bogdan, E.; Watts, J. M.;
Mtashobya, L.; Wang, Z.; Weymouth-Wilson, A.; Galland, N.; Le
Questel, J.-Y.; Linclau, B. Influence of Alcohol β-Fluorination on
Hydrogen-Bond Acidity of Conformationally Flexible Substrates.
Chem. - Eur. J. 2017, 23, 2811−2819.
Authors
Qiang Wang − Department of Organic Chemistry, Stockholm
University, SE-106 91 Stockholm, Sweden; orcid.org/
0000-0003-4346-8714
H
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(10) Thiehoff, C.; Rey, Y. P.; Gilmour, R. The Fluorine Gauche
Effect: A Brief History. Isr. J. Chem. 2017, 57, 92−100.
(11) Aufiero, M.; Gilmour, R. Informing Molecular Design by
Stereoelectronic Theory: The Fluorine Gauche Effect in Catalysis.
Acc. Chem. Res. 2018, 51, 1701−1710.
(30) Muniz, K.; Barreiro, L.; Romero, R. M.; Martínez, C. Catalytic
̃
Asymmetric Diamination of Styrenes. J. Am. Chem. Soc. 2017, 139,
4354−4357.
(31) Kitamura, T.; Muta, K.; Oyamada, J. Hypervalent Iodine-
Mediated Fluorination of Styrene Derivatives: Stoichiometric and
Catalytic Transformation to 2,2-Difluoroethylarenes. J. Org. Chem.
2015, 80, 10431−10436.
(12) Bentler, P.; Bergander, K.; Daniliuc, C. G.; Muck-Lichtenfeld,
̈
C.; Jumde, R. P.; Hirsch, A. K. H.; Gilmour, R. Inverting Small
Molecule−Protein Recognition by the Fluorine Gauche Effect:
Selectivity Regulated by Multiple H→F Bioisosterism. Angew.
Chem., Int. Ed. 2019, 58, 10990−10994.
(13) O’Hagan, D. Polar organofluorine substituents: Multivicinal
fluorines on alkyl chains and alicyclic rings. Chem. - Eur. J. 2020, 26,
7981−7997.
(14) Nairoukh, Z.; Strieth-Kalthoff, F.; Bergander, K.; Glorius, F.
Understanding the Conformational Behavior of Fluorinated Piper-
idines: The Origin of the Axial-F Preference. Chem. - Eur. J. 2020, 26,
6141−6146.
(32) Banik, S. M.; Medley, J. W.; Jacobsen, E. N. Catalytic,
Diastereoselective 1,2-Difluorination of Alkenes. J. Am. Chem. Soc.
2016, 138, 5000−5003.
́
(33) Molnar, I. G.; Gilmour, R. Catalytic Difluorination of Olefins. J.
Am. Chem. Soc. 2016, 138, 5004−5007.
(34) Kong, W.; Feige, P.; de Haro, T.; Nevado, C. Regio- and
Enantioselective Aminofluorination of Alkenes. Angew. Chem., Int. Ed.
2013, 52, 2469−2473.
(35) Suzuki, S.; Kamo, T.; Fukushi, K.; Hiramatsu, T.; Tokunaga, E.;
Dohi, T.; Kita, Y.; Shibata, N. Iodoarene-catalyzed fluorination and
aminofluorination by an Ar-I/HF·pyridine/mCPBA system. Chem.
Sci. 2014, 5, 2754−2760.
(15) Zhu, Y.; Han, J.; Wang, J.; Shibata, N.; Sodeoka, M.;
Soloshonok, V. A.; Coelho, J. A. S.; Toste, F. D. Modern Approaches
for Asymmetric Construction of Carbon−Fluorine Quaternary
Stereogenic Centers: Synthetic Challenges and Pharmaceutical
Needs. Chem. Rev. 2018, 118, 3887−3964.
(36) Banik, S. M.; Medley, J. W.; Jacobsen, E. N. Catalytic,
asymmetric difluorination of alkenes to generate difluoromethylated
stereocenters. Science 2016, 353, 51−54.
(37) Haj, M. K.; Banik, S. M.; Jacobsen, E. N. Catalytic,
Enantioselective 1,2-Difluorination of Cinnamamides. Org. Lett.
2019, 21, 4919−4923.
́
(16) Yuan, W.; Szabo, K. J. Catalytic Intramolecular Amino-
fluorination, Oxyfluorination, and Carbofluorination with a Stable and
Versatile Hypervalent Fluoroiodine Reagent. Angew. Chem., Int. Ed.
2015, 54, 8533−8537.
(38) Mennie, K. M.; Banik, S. M.; Reichert, E. C.; Jacobsen, E. N.
Catalytic Diastereo- and Enantioselective Fluoroamination of Alkenes.
J. Am. Chem. Soc. 2018, 140, 4797−4802.
(17) Fujita, M. Mechanistic aspects of alkene oxidation using chiral
hypervalent iodine reagents. Tetrahedron Lett. 2017, 58, 4409−4419.
(18) Claraz, A.; Masson, G. Asymmetric iodine catalysis-mediated
enantioselective oxidative transformations. Org. Biomol. Chem. 2018,
16, 5386−5402.
(39) Woerly, E. M.; Banik, S. M.; Jacobsen, E. N. Enantioselective,
Catalytic Fluorolactonization Reactions with a Nucleophilic Fluoride
Source. J. Am. Chem. Soc. 2016, 138, 13858−13861.
(40) Sharma, H.; Mennie, K. M.; Kwan, E. E.; Jacobsen, E. N.
Enantioselective Aryl-Iodide-Catalyzed Wagner−Meerwein Rear-
rangements. J. Am. Chem. Soc. 2020, 142, 16090−16096.
(41) Wolstenhulme, J. R.; Gouverneur, V. Asymmetric Fluorocyc-
lizations of Alkenes. Acc. Chem. Res. 2014, 47, 3560−3570.
(42) Lozano, O.; Blessley, G.; Martinez del Campo, T.; Thompson,
A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.; Borman, R.;
Gouverneur, V. Organocatalyzed Enantioselective Fluorocyclizations.
Angew. Chem., Int. Ed. 2011, 50, 8105−8109.
̀
(19) Flores, A.; Cots, E.; Berges, J.; Muniz, K. Enantioselective
̃
Iodine(I/III) Catalysis in Organic Synthesis. Adv. Synth. Catal. 2019,
361, 2−25.
(20) Parra, A. Chiral Hypervalent Iodines: Active Players in
Asymmetric Synthesis. Chem. Rev. 2019, 119, 12033−12088.
(21) Farid, U.; Malmedy, F.; Claveau, R.; Albers, L.; Wirth, T.
Stereoselective Rearrangements with Chiral Hypervalent Iodine
Reagents. Angew. Chem., Int. Ed. 2013, 52, 7018−7022.
(22) Brown, M.; Kumar, R.; Rehbein, J.; Wirth, T. Enantioselective
Oxidative Rearrangements with Chiral Hypervalent Iodine Reagents.
Chem. - Eur. J. 2016, 22, 4030−4035.
(43) Wolstenhulme, J. R.; Rosenqvist, J.; Lozano, O.; Ilupeju, J.;
Wurz, N.; Engle, K. M.; Pidgeon, G. W.; Moore, P. R.; Sandford, G.;
Gouverneur, V. Asymmetric Electrophilic Fluorocyclization with
Carbon Nucleophiles. Angew. Chem., Int. Ed. 2013, 52, 9796−9800.
(44) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D.
Asymmetric Electrophilic Fluorination Using an Anionic Chiral
Phase-Transfer. Science 2011, 334, 1681−1684.
(23) Shimogaki, M.; Fujita, M.; Sugimura, T. Metal-Free
Enantioselective Oxidative Arylation of Alkenes: Hypervalent-
Iodine-Promoted Oxidative C−C Bond Formation. Angew. Chem.,
Int. Ed. 2016, 55, 15797−15801.
(24) Hirt, U. H.; Spingler, B.; Wirth, T. New Chiral Hypervalent
Iodine Compounds in Asymmetric Synthesis. J. Org. Chem. 1998, 63,
7674−7679.
(25) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.;
Minamitsuji, Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y. A Chiral
Hypervalent Iodine(III) Reagent for Enantioselective Dearomatiza-
tion of Phenols. Angew. Chem., Int. Ed. 2008, 47, 3787−3790.
(26) Uyanik, M.; Yasui, T.; Ishihara, K. Enantioselective Kita
Oxidative Spirolactonization Catalyzed by In Situ Generated Chiral
Hypervalent Iodine(III) Species. Angew. Chem., Int. Ed. 2010, 49,
2175−2177.
(45) Shunatona, H. P.; Fruh, N.; Wang, Y.-M.; Rauniyar, V.; Toste,
̈
F. D. Enantioselective Fluoroamination: 1,4-Addition to Conjugated
Dienes Using Anionic Phase-Transfer Catalysis. Angew. Chem., Int. Ed.
2013, 52, 7724−7727.
(46) Liu, J.; Yuan, Q.; Toste, F. D.; Sigman, M. S. Enantioselective
construction of remote tertiary carbon−fluorine bonds. Nat. Chem.
2019, 11, 710−715.
(47) Egami, H.; Niwa, T.; Sato, H.; Hotta, R.; Rouno, D.; Kawato,
Y.; Hamashima, Y. Dianionic Phase-Transfer Catalyst for Asymmetric
Fluoro-cyclization. J. Am. Chem. Soc. 2018, 140, 2785−2788.
(48) Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard, J.;
Jørgensen, K. A. Non-Biaryl Atropisomers in Organocatalysis. Chem. -
Eur. J. 2006, 12, 6039−6052.
̈
(27) Haubenreisser, S.; Woste, T. H.; Martínez, C.; Ishihara, K.;
Muniz, K. Structurally Defined Molecular Hypervalent Iodine
̃
Catalysts for Intermolecular Enantioselective Reactions. Angew.
Chem., Int. Ed. 2016, 55, 413−417.
(49) Xu, J.; Hu, Y.; Huang, D.; Wang, K.-H.; Xu, C.; Niu, T.
Thiourea-Catalyzed Enantioselective Fluorination of β-Keto Esters,
AsymF. Adv. Synth. Catal. 2012, 354, 515−526.
(50) Yang, X.; Phipps, R. J.; Toste, F. D. Asymmetric Fluorination of
α-Branched Cyclohexanones Enabled by a Combination of Chiral
Anion Phase-Transfer Catalysis and Enamine Catalysis using
Protected Amino Acids. J. Am. Chem. Soc. 2014, 136, 5225−5228.
(51) You, Y. e.; Zhang, L.; Luo, S. Reagent-controlled
enantioselectivity switch for the asymmetric fluorination of β-
(28) Hashimoto, T.; Shimazaki, Y.; Omatsu, Y.; Maruoka, K.
Indanol-Based Chiral Organoiodine Catalysts for Enantioselective
Hydrative Dearomatization. Angew. Chem., Int. Ed. 2018, 57, 7200−
7204.
(29) Farid, U.; Wirth, T. Highly Stereoselective Metal-Free
Oxyaminations Using Chiral Hypervalent Iodine Reagents. Angew.
Chem., Int. Ed. 2012, 51, 3462−3465.
I
https://dx.doi.org/10.1021/jacs.0c09323
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
ketocarbonyls by chiral primary amine catalysis. Chem. Sci. 2017, 8,
621−626.
(52) Pluta, R.; Krach, P. E.; Cavallo, L.; Falivene, L.; Rueping, M.
Metal-Free Catalytic Asymmetric Fluorination of Keto Esters Using a
Combination of Hydrogen Fluoride (HF) and Oxidant: Experiment
and Computation. ACS Catal. 2018, 8, 2582−2588.
(53) Wang, Y.; Yuan, H.; Lu, H.; Zheng, W.-H. Development of
Planar Chiral Iodoarenes Based on [2.2]Paracyclophane and Their
Application in Catalytic Enantioselective Fluorination of β-Ketoesters.
Org. Lett. 2018, 20, 2555−2558.
(54) Levin, M. D.; Ovian, J. M.; Read, J. A.; Sigman, M. S.; Jacobsen,
E. N. Catalytic Enantioselective Synthesis of Difluorinated Alkyl
Bromides. J. Am. Chem. Soc. 2020, 142, 14831−14837.
(55) Cortes Gonzalez, M. A.; Nordeman, P.; Bermejo Gomez, A.;
Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113,
6378−6396.
(71) Arrica, M. A.; Wirth, T. Fluorinations of α-Seleno Carboxylic
Acid Derivatives with Hypervalent (Difluoroiodo)toluene. Eur. J. Org.
Chem. 2005, 2005, 395−403.
(72) Kitamura, T.; Kuriki, S.; Morshed, M. H.; Hori, Y. A Practical
and Convenient Fluorination of 1,3-Dicarbonyl Compounds Using
Aqueous HF in the Presence of Iodosylbenzene. Org. Lett. 2011, 13,
2392−2394.
(73) Kitamura, T.; Muta, K.; Kuriki, S. Catalytic fluorination of 1,3-
dicarbonyl compounds using iodoarene catalysts. Tetrahedron Lett.
2013, 54, 6118−6120.
́
Meyer, D. N.; Antoni, G.; Schou, M.; Szabo, K. J. [18F]Fluoro-
benziodoxole: A no-carrier-added electrophilic fluorinating reagent.
Rapid, simple radiosynthesis, purification and application for fluorine-
18 labelling. Chem. Commun. 2018, 54, 4286−4289.
(56) Sarie, J.; Thiehoff, C.; Neufeld, J.; Daniliuc, C.; Gilmour, R.
Enantioselective Synthesis of 3-Fluorochromanes via I(I)/I(III)
Catalysis. Angew. Chem., Int. Ed. 2020, 59, 15069−15075.
(57) Geary, G. C.; Hope, E. G.; Stuart, A. M. Intramolecular
Fluorocyclizations of Unsaturated Carboxylic Acids with a Stable
Hypervalent Fluoroiodane Reagent. Angew. Chem., Int. Ed. 2015, 54,
14911−14914.
̈
(58) Ulmer, A.; Brunner, C.; Arnold, A. M.; Pothig, A.; Gulder, T. A
Fluorination/Aryl Migration/Cyclization Cascade for the Metal-free
Synthesis of Fluoro Benzoxazepines. Chem. - Eur. J. 2016, 22, 3660−
3664.
(59) Andries-Ulmer, A.; Brunner, C.; Rehbein, J.; Gulder, T.
Fluorine as a Traceless Directing Group for the Regiodivergent
Synthesis of Indoles and Tryptophans. J. Am. Chem. Soc. 2018, 140,
13034−13041.
̈
(60) Scheidt, F.; Schafer, M.; Sarie, J. C.; Daniliuc, C. G.; Molloy, J.
J.; Gilmour, R. Enantioselective, Catalytic Vicinal Difluorination of
Alkenes. Angew. Chem., Int. Ed. 2018, 57, 16431−16435.
́
(61) Ilchenko, N. O.; Tasch, B. O. A.; Szabo, K. J. Mild Silver-
Mediated Geminal Difluorination of Styrenes using an Air- and
Moisture-Stable Fluoroiodane Reagent. Angew. Chem., Int. Ed. 2014,
53, 12897−12901.
(62) Zhou, B.; Haj, M. K.; Jacobsen, E. N.; Houk, K. N.; Xue, X.-S.
Mechanism and Origins of Chemo- and Stereoselectivities of Aryl
Iodide-Catalyzed Asymmetric Difluorinations of β-Substituted Styr-
enes. J. Am. Chem. Soc. 2018, 140, 15206−15218.
̈
(63) Scheidt, F.; Neufeld, J.; Schafer, M.; Thiehoff, C.; Gilmour, R.
Catalytic Geminal Difluorination of Styrenes for the Construction of
Fluorine-rich Bioisosteres. Org. Lett. 2018, 20, 8073−8076.
(64) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. CXIX.The
formation and stability of spiro-compounds. Part I. spiro-Compounds
from cyclohexane. J. Chem. Soc., Trans. 1915, 107, 1080−1106.
(65) Wodrich, M. D.; Wannere, C. S.; Mo, Y.; Jarowski, P. D.; Houk,
K. N.; Schleyer, P. v. R. The Concept of Protobranching and Its Many
Paradigm Shifting Implications for Energy Evaluations. Chem. - Eur. J.
2007, 13, 7731−7744.
(66) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-
Salvetti correlation-energy formula into a functional of the electron
density. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−789.
(67) Becke, A. D. Density-functional Thermochemistry. III. The
Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648−5652.
(68) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and
accurate ab initio parametrization of density functional dispersion
correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010,
132, 154104−154119.
(69) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the damping
function in dispersion corrected density functional theory. J. Comput.
Chem. 2011, 32, 1456−1465.
(70) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal
Solvation Model Based on Solute Electron Density and on a
Continuum Model of the Solvent Defined by the Bulk Dielectric
J
https://dx.doi.org/10.1021/jacs.0c09323
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX