Stereodivergent Construction of Tertiary Fluorides in Vicinal Stereogenic Pairs by Allylic Substitution with Iridium and Copper Catalysts

Article abstract of DOI:10.1021/jacs.9b04440

Although much effort has been spent on the enantioselective synthesis of tertiary alkyl fluorides, the synthesis of compounds containing such a stereogenic center within an array of stereocenters, particularly two vicinal ones, remains a synthetic challenge, and no method to control the configuration of each stereogenic center independently has been reported. We describe a strategy to achieve such a stereodivergent synthesis of vicinal stereogenic centers, one containing a fluorine atom, by forming the connecting carbon-carbon bond with a catalyst system comprising an iridium complex that controls the configuration at the electrophilic carbon and a copper catalyst that controls the configuration at the nucleophilic fluorine-containing carbon. These reactions occur with alkyl- and aryl-substituted allylic esters and the unstabilized enolates of azaaryl ketones, esters, and amides in high yield, diastereoselectivity, and enantioselectivity (generally >90% yield, >20:1 dr, 97-99% ee). Access to all four stereoisomers of products demonstrates the precise control of the two configurations independently. This methodology extends to the stereodivergent construction of vicinal quaternary and tertiary stereocenters in similarly high yield and selectivity. DFT calculations uncover the origin of stereoselectivity of copper enolate in allylic substitution.

Full text of DOI:10.1021/jacs.9b04440

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Article
Stereodivergent Construction of Tertiary Fluorides in Vicinal Stereogenic
Pairs by Allylic Substitution with Iridium and Copper Catalysts
Zhi-Tao He, Xingyu Jiang, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04440 • Publication Date (Web): 25 Jul 2019
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Stereodivergent Construction of Tertiary Fluorides in Vicinal Stere-
ogenic Pairs by Allylic Substitution with Iridium and Copper Cata-
lysts
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Zhi-Tao He,† Xingyu Jiang,†,‡ and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720, United States.
Although much effort has been spent on the enantioselective synthesis of tertiary alkyl fluorides, the synthesis of compounds con-
taining such a stereogenic center within an array of stereocenters, particularly two vicinal ones, remains a synthetic challenge, and no
method to control the configuration of each stereogenic center independently has been reported. We describe a strategy to achieve
such a stereodivergent synthesis of vicinal stereogenic centers, one containing a fluorine atom, by forming the connecting carbon-
carbon bond with a catalyst system comprising an iridium complex that controls the configuration at the electrophilic carbon and a
copper catalyst that controls the configuration at the nucleophilic fluorine-containing carbon. These reactions occur with alkyl and
aryl-substituted allylic esters and the unstabilized enolates of azaaryl ketones, esters and amides in high yield, diastereoselectivity
and enantioselectivity (generally >90% yield, >20:1 dr, 99% ee). Access to all four stereoisomers of products demonstrates the precise
control of the two configurations independently. This methodology extends to the stereodivergent construction of vicinal quaternary
and tertiary stereocenters in similarly high yield and selectivity. DFT calculations uncover the origin of stereoselectivity of copper
enolate in allylic substitution.
reacts with carbonyl nucleophiles to form chiral enamine5-6 or
INTRODUCTION
enolate7-9 intermediates in situ and an iridium complex that
Enantioselective synthesis of chiral alkyl fluorides has been
forms a chiral allyl intermediate to afford products containing
studied intensively in recent years, due to the favorable physi-
vicinal stereocenters. All four stereoisomers of the products can
cochemical and biological properties of such structures.1 The
be generated by permutation of the enantiomers of the iridium
most synthetically challenging fluorine-containing sites to es-
catalyst and the co-catalyst.
tablish are fully substituted, fluorine-containing stereocenters,
and many approaches to set such sites have been reported.1c
We envisioned a strategy to address the unsolved synthetic
problem of preparing compounds containing vicinal fluorine-
containing stereodyads by enlisting our iridium catalyst to set
one stereogenic center and a Lewis-acid cocatalyst to set the
second fluorine-containing center simultaneously. If unstabi-
lized carbonyl enolates comprising a basic heteroarene, which
are common in pharmaceuticals and agrochemicals, and a fluo-
rine atom at the nucleophilic carbon would react, such a system
might result. However, reactions of the enolates of α-fluoro ke-
tones, esters and amides that we envisioned to use as nucleo-
philes are not straightforward to achieve. It is known that α-
fluoro carbonyl compounds are much less stable than nonfluor-
inated enolates,10 and prior iridium-catalyzed allylic substitu-
tions of fluoroalkyl nucleophiles have occurred only with stabi-
lized nucleophiles containing two carbonyl, nitro or sulfone
groups at the nucleophilic carbon.11 Because the iridium cata-
lyst alone does not typically control the configuration at a nu-
cleophilic carbon, these reactions form just one of two diastere-
omers as the major isomer with diastereoselectivity less than
5:1, more typically between 1:1 and 4:1.11 Lewis acids that
might control the configuration of the nucleophile could ab-
stract the α-fluorine atom, and the combination of enhanced
acidity and weaker Lewis basicity of the fluorine-containing
carbonyl compounds than of the parents lacking fluorine12
makes it possible that reactions with two catalysts could suffer
from competing allylations occurring without the involvement
of the Lewis-acid catalyst, resulting in the low diastereoselec-
tivities of prior work.11,13
However, the construction of such sites in molecules containing
multiple stereogenic centers with control of diastereoselectivity
is an even greater challenge and is largely unaddressed. Such
reactions are important because different relative configurations
of stereoisomeric alkyl fluorides can engender distinct proper-
ties,2 and such motifs in which a tertiary fluoride stereocenter is
located vicinal to a second stereogenic center are contained in
pharmaceuticals, such as dexamethasone, fludrocortisone,
fluticasone propionate, and sofosbuvir.1c
The most versatile approach to the synthesis of such com-
pounds would provide independent control over the configura-
tion at each of the stereogenic centers to form each of the four
stereoisomers, one containing a fluorine atom, selectively, but
such stereodivergent reactions have not been reported. A few
methods have been reported for the enantioselective synthesis
of ctertiary fluorides bearing an adjacent stereocenter favoring
one of two possible relative configurations,3 but these existing
methods have not been amenable to forming all stereoisomers
of such fluorine-containing structures. To form such a set of ste-
reoisomers, the catalyst system must control the configuration
at two sites separately with two regulating elements.2
Enantioselective, iridium-catalyzed allylic substitutions with
prochiral enolates can construct compounds containing vicinal
stereogenic centers with high diastereo- and enantioselectivity.4
Recently, Carriera,5 Jørgensen,6 Zhang,7 Wang8 and our own
group9 disclosed catalytic systems comprising one catalyst that
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While cognizant of these issues, we sought to apply a dual Table 1. Evaluation of Reaction Conditions for the Allyla-
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catalyst system to this synthetic problem, and we report our re-
sults on the stereodivergent synthesis of acyclic compounds
containing a fully substituted, fluorine-containing stereocenter
vicinal to a second stereocenter by allylic substitution catalyzed
by the combination of a chiral cyclometallated iridium catalyst
and a chiral, copper enolate catalyst (Scheme 1). The copper
catalyst contains a bisphosphine that provides remarkable con-
trol over the configuration at the enolate carbon, and the iridium
and copper complexes independently dictate the configurations
of the two stereogenic centers in the products arising from the
electrophile and nucleophile, respectively. Thus, simple permu-
tations of enantiomers of the iridium and copper catalysts afford
all four possible configurations of the two stereogenic centers
with excellent diastereo- and enantioselectivity. Computational
studies elucidate the origin of the stereoselectivity of the chiral
copper enolate in the reaction.
a
tion of 2-Pyridyl -Fluoro Acetate (1a)
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Scheme 1. Our Design for the Stereodivergent Construction
of Acyclic Tertiary Fluoride with a Vicinal Stereocenter
R2
R2
N
N
Entry
1
L
L1
Yield (%)a
dra
14:1
2:1
ee (%)b
n.d.
n.d.
n.d.
n.d.
n.d.
>99
n.d.
n.d.
n.d.
n.d.
Ar
Ar
N
Ar
R1
99
70
R1
R2
R1
R2
[Cu]*/[Ir]*
F
F
F
+
2
L2
Synergistic
Catalysis
N
N
Ar
Ar
R2
3
L3
99
1:1
OCO2Me
R1
R1
R1: C(O)R, C(O)OR, C(O)NR2
R2=alkyl, aryl, heteroaryl
F
F
4
L4
99
1:2
All four stereoisomers accessible
5
L5
99
99 (>99)c
2:1
6
(R,R)-BPE
none
>20:1
1:1
RESULTS AND DISCUSSION
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Reaction Development. Our initial studies on the stereodi-
vergent synthesis of products containing a fully substituted F-
containing stereocenter and a vicinal tertiary center began with
reactions of a-fluoro pyridinyl acetate 1a as the nucleophile and
cinnamyl methyl carbonate 2a as electrophile (Table 1). With
the combination of catalysts and base we reported previously9b
(5 mol% of [Cu(CH3CN)4]PF6, 5.5 mol% of Walphos L1, 2
mol% of metallacyclic iridium catalyst (Ra,R,R)-[Ir], and 5
mol% of DBU), the allylation occurred in quantitative yield and
with a good 14:1 dr (entry 1). Reactions with most other
bisphosphine ligands for the copper catalyst gave the product in
high yield but low diastereoselectivity (1:1 to 2:1, entry 2-5).
Yet, we found that reactions conducted with (R,R)-BPE as the
ligand for copper occurred in quantitative yield (>99%) to give
just one detectable diastereomer (>20:1) and enantiomer (>99%)
(entry 6).
8d
9e
10f
none
18
1:1
(R,R)-BPE
(R,R)-BPE
<1
n.d.
14:1
27
aDetermined by 1H NMR spectroscopy of the crude reaction with
1,3,5-trimethylbenzene as internal standard. Combined yield of two
b
diastereomers. Determined by chiral SFC analysis of the major
isomer. cIsolated yield in the parenthesis. dWithout copper catalyst.
eWithout iridium catalyst. fWithout DBU. n.d., not determined.
Scope of Fluorinated Nucleophiles for Allylic Substitu-
tion. Having identified conditions for reaction of α-fluoro pyri-
dinyl acetate 1a, we assessed the scope of these conditions for
the allylation of a series of fluorinated azaaryl acetates and ac-
etamides for the construction of products containing vicinal ter-
tiary alkyl fluoride and tertiary alkyl stereogenic centers (Table
2). A variety of fluorinated acetates bearing pyridinyl, quino-
linyl and isoquinolinyl moieties underwent allylation smoothly,
providing products 3a-3e with excellent yields and excellent
relative and absolute stereoselectivity (84-99% yield, >20:1 dr,
99% ee). Azaaryl units, such as benzoxazolyl, benzothiazolyl,
benzimidazolyl, and pyrazinyl, which contain multiple sites that
could coordinate to copper, underwent the allylic substitution
with high 88-99% yields, >20:1 diastereoselectivity, and 98-
99% enantioselectivity (3f-3i). The absolute configuration of
ent-7g, a diastereomer of 3m formed from the combination of
(R,R)-BPE and (Sa,S,S)-[Ir], was determined by X-ray analysis.
A set of control experiments were conducted to reveal the in-
fluence of the dual catalysts on the reaction efficiency and ste-
reoselectivity. Without (R,R)-BPE ligated to copper, the reac-
tion occurred in 86% yield, but the dr was nearly 1:1, indicating
that a competitive background reaction without the copper co-
catalyst would lead to lower diastereoselectivity (entry 7). In
the absence of both copper and (R,R)-BPE, only 18% of product
3a was observed (entry 8). The reaction without the iridium cat-
alyst gave no product (entry 9). The presence of base was im-
portant for the reaction to occur; in the absence of DBU the re-
action gave only 27% product, but the observed high 14:1 dr
value showed that the product formed in the absence of base
resulted from the combination of copper and iridium catalysts
(entry 10).
In addition to alpha-fluoro azaaryl acetates, the less acidic,
but more Lewis basic alpha-fluoro azaaryl acetamides under-
went the allylic substitution (3j-3p). Products 3j & 3k were
obtained in >90% yield, >20:1 dr, and 99% ee to form the cor-
responding fluoro pyridinyl and benzoxazolyl acetamides as
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Table 2. Scope of the Fluorinated Nucleophiles that Un-
dergo the Diastereoselective Allylic Substitutiona
a
Table 3. Scope of -Alkyl Acetates that Undergo the Dia-
stereoselective Allylic Substitutiona
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aIsolated yield. Diastereomeric ratios were determined by 1H NMR
spectroscopy of the crude reaction. Enantiomeric excesswas deter-
mined by chiral SFC or HPLC analysis of the major isomers.
allylation in perfect yield, dr and ee (3m), and the absolute con-
figuration of its enantiomer was determined by X-ray analysis.
The allylic substitution also tolerated secondary amides and
Weinreb amides as nucleophiles, greatly extending the scope of
transformations of the products and applications of the process
(3o-3p). Finally, alpha-fluoro pyridinyl ketone 1q underwent
allylic substitution to give compound ent-3q in excellent yield
and selectivity (99% yield, > 20:1 dr, 99% ee).
Scope of Alkylated Nucleophiles for Allylic Substitution.
Although this work focused on the formation of products con-
taining chiral tertiary fluorides, we did assess whether the scope
of the formation of products containing vicinal fully substituted
and tertiary stereogenic centers was limited to those containing
fluorine at the fully substituted site, particularly because stereo-
divergent approaches to form products containing acyclic vici-
nal quaternary and tertiary stereocenters with high diastereose-
lectivity and enantioselectivity from ester and amide enolates
are rare.5a,14 Indeed, the reaction of alkyl-substituted aza-aryl
esters with allylic esters formed the allylation products with
high yield and stereoselectivity, modifications of the conditions
from those used to form the products containing fluorine at the
nucleophilic carbon of the aza-aryl ester increased yields and
stereoselectivities. The reaction of methyl 2-pyridyl propionate
4a with cinnamyl methyl carbonate 2a under the conditions de-
veloped for reaction of the fluorinated substrates in Table 2
gave 5a in a good 72% yield with 14:1 dr. However, a series of
aIsolated yield. Diastereomeric ratios were determined by 1H NMR
spectroscopy of the crude reaction. Enantiomeric excess was deter-
mined by chiral SFC or HPLC analysis of the major isomers.
nucleophiles. Azaaryl units bearing three and even four nitro-
gen atoms (3l, 3n) reacted exclusively in excellent yield (90-
96%), diastereoselectivity (10:1->20:1) and enantioselectivity
(96-99%). Fluorinated benzothiazolyl acetamides underwent
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experiments with various bases and ligands (See SI for details)
showed that reactions with Cs2CO3 (1.0 equiv) as the base in-
stead of DBU formed 5a containing adjacent quaternary and
tertiary stereocenters in a high 92% yield as a single detectable
(>20:1) diastereomer with 97% enantioselectivity.
Page 4 of 8
Scope of Allylic Carbonates as Electrophiles for Allylic
Substitution. A series of allylic carbonates containing various
substituted aryl, heteroaryl and alkyl moieties underwent the al-
lylation with α-fluoro ester 1a in high 80-99% yields to give a
single detectable diastereomer (6a-6i, 6k, >20:1 dr) in 97-99%
ee (Table 4). Reactions of cinnamyl esters containing both elec-
tron-donating and electron-withdrawing groups on the cin-
namyl aryl rings occurred to give the substitution product with
excellent yields and stereoselectivities (6a-6f). Carbonates
bearing furanyl, thienyl, thiazolyl and pyrimidinyl substituents
also reacted with 1a smoothly products containing vicinal ste-
reogeneic centers containing consecutive heteroaryl groups, as
well as the fluorine atom (6g-6j). The substitution reaction even
occurred with the simple crotyl carbonate to give compound 6k
in 87% yield with >20:1 dr and 99% ee.
1
2
3
4
5
6
7
8
A broad range of azaaryl acetates containing various alkyl
substituents on the reactive α-carbon also underwent the allyla-
tion process, as summarized in Table 3. Alkyl substituents con-
taining cyclopropyl, aryl, alkenyl, alkynyl, OTBS, and imide
groups were well tolerated, affording products 5a-5h in 77 to
99% yield, with 7:1 to 20:1 dr, and 96-99% ee.15 Ester 4i for
which the reactive center lies in a ring reacted in excellent yield
and stereoselectivity (98% yield, >20:1 dr, 99% ee). Changes to
the structure of the azaaryl units had little effect on the reaction
(5j-5k). Finally, the ketone α-methyl pyridnyl acetone (4l) re-
acted with carbonate 2a in a similar fashion as the esters to give
product 5l in 86% yield, >20:1 dr, and 99% ee. In this case,
allylation of 4l occurred exclusively at the tertiary α-carbon
over the primary α-site.
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Table 5. Stereodivergent Synthesis of Four Stereoisomers
a
from Reaction of Methyl Cinnamyl Carbonate with an
-
a
a
Fluoro and -Methyl Azaaryl Acetate
Table 4. Scope of allylic carbonates that undergo the dia-
a
stereoselective Allylic Substitution with Methyl 2-Pyridyl -
fluoroacetate (1a)a
aIsolated yield. Diastereomeric ratios were determined by 1H NMR
spectroscopy of the crude reactions. Enantiomeric excess was de-
termined by chiral SFC analysis of major isomers. The conditions
for reactions of fluorinated substrates were the same as those de-
scribed for the reactions in Table 2; the conditions for reacitons of
alkylated substrates were the same as those described for reactions
in Table 3.
Stereodivergent Reactions. Having observed high diastere-
oselectivity from the reactions conducted with the copper cata-
lyst, but nearly 1:1 diastereoselectivity from reactions con-
ducted without the copper catalyst, we conducted experiments
to confirm that the configurations of the two stereogenic centers
were determined independently by the two catalysts. We con-
ducted these experiments with the fluorine-substituted acetate
1a and the alkyl-substituted ester 4b. Indeed, permutation of the
enantiomers of iridium and copper complexes gave all four ste-
reoisomers in excellent yields and stereoselectivities (Table 5).
For example, the reaction of 1a with the four combinations of
stereoisomers of the catalysts gave all four steroisomers of the
a-fluoro esters 3a in >99% yield, as a single detectable diastere-
omer with 99% ee. This method provides the first access to all
aIsolated yield. Diastereomeric ratios were determined by 1H NMR
spectroscopy of the crude reaction. Enantiomeric excess was deter-
mined by chiral SFC analysis of the major isomers.
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stereoisomers of vicinal fluorine-contained centers and tertiary
group. This rationale for the stereochemical outcome is con-
sistent with the absolute configuration of the allylation product
obtained by X-ray crystallography analysis.
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3
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5
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centers. Likewise, the reaction of ethyl 2-pyridyl propionate 4b
with cinnamyl carbonate catalyzed by the four combinations of
stereoisomers of the two catalysts formed the four stereoiso-
meric products in high yield as a single detectable diastereomer
and nearly perfect (97-99%) enantioselectivity. This result,
along with the related results to form vicinal quaternary and ter-
tiary stereogenic centers from the alpha-alkyl esters, indicates
the independent control of the configurations of electrophiles
and nucleophiles with the iridium and copper catalysts.
To further assess the interactions that lead to the steric asym-
metricity of the si and re face of C1, we analyzed the overall
geometry of the copper complex. In an ideal tetrahedral struc-
ture of a copper enolate, the enolate carbon atom should lie in
the plane bisecting the plane defined by the two phosphorus at-
oms and the copper. This geometry is observed for the com-
puted structure of an achiral copper enolate derived from the
azaaryl ester 1a and bearing methyl groups at phosphorus
(Scheme 3d). However, in the computed minimum-energy
structure of the chiral copper enolate complex Cu-1 containing
BPE-phos, the nucleophilic enolate carbon C1 lies out of this
plane in the fourth quadrant (Scheme 3d, right).
To probe the origin of this distortion, an NCIPLOT analysis17
and NBO analysis18 were performed on the minimum-energy
structure of Cu-1 (Scheme 3e, see SI for details). This analysis
revealed three substantial interactions that likely lead to rotation
of the enolate, such that its si face is exposed for reaction with
the electrophile. First, the distance between carbonyl oxygen
atom O and the ortho hydrogen H3 of a BPE-phos aryl group is
2.26 Å, shorter than the sum of their van de Waals radii (2.72
Å) and an NBO second-order perturbation analysis reveals a
substantial stabilizing energy C2−H3···O of 2.41 kcal/mol (in-
teraction a, Scheme 3e, left). Second, one of the hydrogen atoms
of the methyl ester moiety H4 is located near the centroid of a
second ligand phenyl group Ph1 (2.91 Å) with an C3−H4−Ph1
(centroid) angle of 132.1°. The proximity of the hydrogen to the
centroid suggests the presence of a C3−H4···π interaction (in-
teraction b).19 Third, the C5−H5 bond ortho to the nitrogen N
of the pyridine moiety interacts attractively with the π system
of a third ligand aryl group Ph2 (2.67 Å, C5−H5−Ph2 = 121.4°;
interaction c).20 As the result of these attractive non-covalent
interactions between the substrate and the ligand, the distance
between C1 and phenyl group Ph1 (in the same quadrant) is
significantly shorter than that between C1 and Ph2 (in the op-
posite quadrant), and this difference in distance likely leads to
the observed high facial selectivity of the copper enolate during
the allylation reaction.21,22
9
The utility and robustness of the present protocol was further
demonstrated by conducting the allylic substitution on 0.1
mmol to multi-mmol scale. The reaction of 3.0 mmol of fluori-
nated nucleophile 1a with cinnamyl carbonate 3a occurred in
an identical fashion as the reaction on 0.1 mmol scale described
in Table 5 (Scheme 2A). Likewise, as shown in Scheme 2B, the
reaction of fluorinated nucleophile 1m with carbonate 3a on a
1.0 mmol scale catalyzed by the combination of (R,R)-BPE and
(Sa,S,S)-[Ir] formed the diastereomer of 3m, namely, ent-7m,
in the same high yield and selectivity (>99% yield, 20:1 dr and
>99% ee) as that to form 3m.
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Scheme 2. Large-Scale Allylation Reactions.
Origin of Stereoselectivity from the Copper Enolate. The
allylation reaction is well established to occur by external attack
of a nucleophile, in this case a copper enolate (A), at the allyl-
iridium intermediate (B) (Scheme 3a). Previous mechanistic
studies demonstrated that the geometry, facial selectivity and
regioselectivity of the allyl moiety in the asymmetric allylic
substitution reactions are governed by the metallacyclic iridium
catalysts.16 To understand the origin of stereoselectivity of the
copper enolate in the allylation reaction, DFT calculations were
performed to elucidate the ground state structure of the α-fluoro
copper enolate Cu-1 derived from 1a (Scheme 1b). The
ωB97X-D/6-31G(d) level of theory was used with the SMD
solvation model (THF).
CONCLUSION
We report a strategy for the stereodivergent construction of
products containing fluorine within vicinal stereogenic centers
by forming the carbon-carbon bond joining the two sites with
an allylic substitution process. The reactions occur with the
combination of an iridium catalyst to control the configuration
at the electrophilic carbon of an allylic carbonate and a copper
catalyst to control the configuration at the nucleophilic carbon
of an unstabilized enolate. The fluorine-containing site in the
products is fully substituted. The catalytic system also enables
the construction of vicinal quaternary and tertiary stereogenic
centers. In general, the products are obtained in >90% yield,
>20:1 dr and 97-99% ee. Stereodivergent synthesis of all four
isomers of the products from reaction of one alpha-fluoro and
one alpha-alkyl enolate highlights the high degree of stereocon-
trol over the nucleophile and electrophile independently. Com-
putational studies suggest that the stereoselectivity of copper
enolate during the allylic substitution results from a series of C-
H•••O and C-H•••π interactions, and an analysis of the structure
In the optimized structure of Cu-1, the enolate carbon C1 is
close to the hydrogen atoms H1 (3.10 Å) and H2 (3.21 Å) of
one of the phenyl groups of the ligand (Scheme 3c, front view).
A top view and side view (Scheme 3c) of the structure clearly
show that one face of C1 (the re face) is substantially blocked
by H1 and H2, but the opposite face of C1 (the si face) is open.
Therefore, the allyl iridium intermediate would approach C1
preferentially from the face of the enolate opposite to this aryl
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Scheme 3. Computational Studies on the Origin of Stereoselectivity by the Copper Enolate
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Journal of the American Chemical Society
hydes: the Challenge of Facing the Construction of a Quaternary Fluor-
by NBO strongly suggests that these attractive, non-covalent in-
teractions contribute to the distortion from a tetrahedral geom-
etry that leads to asymmetric induction.
inated Stereocenter. Eur. J. Org. Chem. 2016, 3223. (f) Cosimi, E.;
Engl, O. D.; Saadi, J.; Ebert, M. O.; Wennemers, H. Stereoselective
Organocatalyzed Synthesis of α-Fluorinated β-Amino Thioesters and
Their Application in Peptide Synthesis. Angew. Chem., Int. Ed. 2016,
55, 13127. (g) Cosimi, E.; Saadi, J.; Wennemers, H. Stereoselective
Synthesis of α-Fluoro-γ-nitro Thioesters under Organocatalytic Condi-
tions. Org. Lett. 2016, 18, 6014.
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ASSOCIATED CONTENT
Supporting Information. This material is available free of charge
via the Internet at http://pubs.acs.org.
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9
Experimental details and procedures, spectra for all unknown com-
pounds (PDF)
Crystal structure for ent-3m (CCDC: 1907850). (CIF)
Crystal structure for ent-7g (CCDC: 1907851). (CIF)
(4) For recent reviews, see (a) Shockley, S. E.; Hethcox, J. C.; Stoltz,
B. M. Intermolecular Stereoselective Iridium-Catalyzed Allylic Alkyl-
ation: An Evolutionary Account. Synlett 2018, 29, 2481. (b) Cheng, Q.;
Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen, G.; You, S.-L. Iridium-Cat-
alyzed Asymmetric Allylic Substitution Reactions. Chem. Rev. 2019,
119, 1855.
(5) (a) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M.
Enantio- and Diastereodivergent Dual Catalysis: α-Allylation of
Branched Aldehydes. Science 2013, 340, 1065. (b) Krautwald, S.;
Schafroth, M. A.; Sarlah, D.; Carreira, E. M. Stereodivergent α-Allyla-
tion of Linear Aldehydes with Dual Iridium and Amine Catalysis. J.
Am. Chem. Soc. 2014, 136, 3020. (c) Sandmeier, T.; Krautwald, S.;
Zipfel, H. F.; Carreira, E. M. Stereodivergent Dual Catalytic α-Allyla-
tion of Protected α-Amino- and α-Hydroxyacetaldehydes. Angew.
Chem. Int. Ed. 2015, 54, 14363.
(6) Næsborg, L.; Halskov, K. S.; Tur, F.; Mønsted, S. M. N.; Jørgen-
sen, K. A. Asymmetric γ-Allylation of α,β-Unsaturated Aldehydes by
Combined Organocatalysis and Transition-Metal Catalysis. Angew.
Chem. Int. Ed. 2015, 54, 10193.
(7) (a) Huo, X.; He, R.; Zhang, X.; Zhang, W. An Ir/Zn Dual Catal-
ysis for Enantio- and Diastereodivergent α-Allylation of α-Hy-
droxyketones. J. Am. Chem. Soc. 2016, 138, 11093. (b) He, R.; Liu, P.;
Huo, X.; Zhang, W. Ir/Zn Dual Catalysis: Enantioselective and Dia-
stereodivergent α-Allylation of Unprotected α-Hydroxy Indanones.
Org. Lett. 2017, 19, 5513. (c) Huo, X.; Zhang, J.; Fu, J.; He, R.; Zhang,
W. Ir/Cu Dual Catalysis: Enantio- and Diastereodivergent Access to
α,α- Disubstituted α-Amino Acids Bearing Vicinal Stereocenters. J.
Am. Chem. Soc. 2018, 140, 2080.
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AUTHOR INFORMATION
Corresponding Author
*jhartwig@berkeley.edu
ORCID
John F. Hartwig: 0000-0002-4157-468X
Present Addresses
‡Department of Discovery, Pharmacyclics Inc., Sunnyvale, CA
94085
Author Contributions
†
Z.-T. H. and X. J. contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the NIH 1R35GM130387 for support of this work. Dr.
Nicholas Settineri is acknowledged for X-ray crystallographic anal-
ysis.
(8) Wei, L.; Zhu, Q.; Xu, S.-M.; Chang, X.; Wang, C.-J. Stereodi-
vergent Synthesis of α,α-Disubstituted α-Amino Acids via Synergistic
Cu/Ir Catalysis. J. Am. Chem. Soc. 2018, 140, 1508.
(9) (a) Jiang, X.; Beiger, J. J.; Hartwig, J. F. Stereodivergent Allylic
Substitutions with Aryl Acetic Acid Esters by Synergistic Iridium and
Lewis Base Catalysis. J. Am. Chem. Soc. 2017, 139, 87. (b) Jiang, X.;
Boehm, P.; Hartwig, J. F. Stereodivergent Allylation of Azaaryl Acet-
amides and Acetates by Synergistic Iridium and Copper Catalysis. J.
Am. Chem. Soc. 2018, 140, 1239.
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Comm. 2004, 6, 130. (b) Takahashi, O.; Kohno, Y.; Iwasaki, S.; Saito,
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(20) The distance between the fluorine atom F and H2 (2.91 Å) is
slightly longer than the sum of their van de Waals radii (2.67 Å), and
the NBO analysis implies that this C4−H2···F interaction is only very
weakly attractive (0.08 kcal/mol).
(21) When (S,S)-Me-BPE was used as the chiral ligand instead of
Ph-BPE for the model reaction under the standard conditions, no prod-
uct 3a was observed. These data are consistent with the importance of
phenyl group in the BPE ligand.
(22) The ground-state structure of copper enolates Cu-2, Cu-3 and
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fluoro pyridyl acetate were also calculated by DFT. Results and corre-
sponding analysis are summarized in the supporting information.
Table of Contents Graphic
R2
R2
N
N
Ar
Ar
N
Ar
R1
R1
R2
R1
R2
[Cu]*/[Ir]*
F
F
F
+
Synergistic
Catalysis
N
N
Ar
Ar
R2
OCO2Me
R1
R1
R1: C(O)R, C(O)OR, C(O)NR2
R2=alkyl, aryl, heteroaryl
F
F
All four stereoisomers accessible of
vicinal, fluorine-containing stereogenic centers
Generally >90% yield, >20:1 dr, 97-99% ee
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