A Transient Directing Group Strategy Enables Enantioselective Multicomponent Organofluorine Synthesis

Article abstract of DOI:10.1021/jacs.1c03178

The vicinal fluorofunctionalization of alkenes represents an expedient strategy for converting feedstock olefins into valuable fluorinated molecules and as such has garnered significant attention from the synthetic community; however, current methods remain limited in terms of scope and selectivity. Here we report the site-selective palladium-catalyzed three-component coupling of alkenylbenzaldehydes, arylboronic acids, and N-fluoro-2,4,6-trimethylpyridinium hexafluorophosphate facilitated by a transient directing group. The synthetically enabling methodology constructs vicinal stereocenters with excellent regio-, diastereo-, and enantioselectivities, forging products that map onto bioactive compounds.

Full text of DOI:10.1021/jacs.1c03178

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A Transient Directing Group Strategy Enables Enantioselective
Multicomponent Organofluorine Synthesis
Zhonglin Liu, Lucas J. Oxtoby, Mingyu Liu, Zi-Qi Li, Van T. Tran, Yang Gao, and Keary M. Engle*
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ABSTRACT: The vicinal fluorofunctionalization of alkenes represents an expedient strategy for converting feedstock olefins into
valuable fluorinated molecules and as such has garnered significant attention from the synthetic community; however, current
methods remain limited in terms of scope and selectivity. Here we report the site-selective palladium-catalyzed three-component
coupling of alkenylbenzaldehydes, arylboronic acids, and N-fluoro-2,4,6-trimethylpyridinium hexafluorophosphate facilitated by a
transient directing group. The synthetically enabling methodology constructs vicinal stereocenters with excellent regio-, diastereo-,
and enantioselectivities, forging products that map onto bioactive compounds.
he incorporation of carbon−fluorine (C−F) bonds into
With the previous efforts in mind, we wondered if we could
address these issues by implementing a chiral transient
directing group (TDG) strategy (Figure 1C). The viability of
catalytic TDGs has previously been established in several
mechanistically distinct transition-metal catalyzed reactions,
including notably in the field of C−H activation;16 however,
the scope of transiently directed asymmetric alkene function-
alizations remains quite limited, and 1,2-difunctionalization
reactions using a TDG approach remain unknown. Herein, we
report a highly enantioselective 1,2-arylfluorination of alkenyl
benzaldehydes that is able to form two vicinal chiral centers,
including fully substituted C(sp3)−F and C(sp3)−Ar stereo-
centers, in synthetically useful yields with broad functional
group tolerance.
To reduce this idea to practice, we based our initial reaction
design on our recently reported enantioselective reductive
Heck hydroarylation of alkenyl benzaldehydes using an amino
acid TDG.17 In our previous work, a stabilized
alkylpalladium(II) intermediate is intercepted with formate,
which decarboxylates to generate an alkylpalladium(II)−
hydride species that subsequently undergoes reductive
elimination. In the case of the envisioned transiently directed
arylfluorination, the stabilized alkylpalladium(II) intermediate
would react with a fluorinating oxidant (an [F+] reagent) to
generate a palladium(IV) species (which can more readily
undergo stereoretentive C−F reductive elimination than a
palladium(II)−fluoride).18 This seemingly simple extension is
fraught with challenges, including undesired oxidation of the
native aldehyde functional handle by [F+], competitive
homocoupling of arylboronic acids in the presence of
T
drug molecules can often improve their pharmacokinetic
properties, including increasing oral bioavailability, protein
binding affinities, and metabolic stability, especially in the case
of replacement of benzylic C−H bonds prone to metabolic
oxidation.1,2 As such, the development of strategies that enable
the enantioselective formation of C−F bonds has become a
major research area of both industrial and academic
importance in recent years.3−5 In particular, intermolecular
1,2-carbofluorination of alkenes is an attractive transformation
as it allows for the conversion of alkene feedstocks into
fluorinated molecules with potential applications in the
pharmaceutical, agrochemical, and material sectors;6 however,
this type of transformation remains challenging to execute due
to issues with regio-, stereo-, and chemoselectivity. In early
7
8
9
10
́
work, the groups of Ma, Gagne, Alexakis, and Gouverneur
reported pioneering examples of asymmetric fluorocyclizations
of prochiral alkenes, in which a functional group tethered to
the alkene reacts in the cyclization process (Figure 1A).
More recently, Toste and co-workers have reported an
elegant series of intermolecular (three-component) asymmet-
ric arylfluorination reactions to construct chiral benzyl
fluorides using palladium/N,N-ligand systems. This strategy
has been used for both 1,1-arylfluorination (where regiose-
lectivity is governed by substrate electronics)11,12 and 1,2-
arylfluorination (where selectivity is governed by substrate
directivity)13 as depicted in Figure 1B. While the aforemen-
tioned work represents a great deal of progress, significant
limitations remain. Palladium-catalyzed arylfluorination reac-
tions are sensitive to alkene substitution patterns; for instance,
disubstituted alkenes require double activation to enhance
reactivity,14 and no existing methods are able to construct fully
substituted C(sp3)−F or C(sp3)−Ar stereocenters. Addition-
ally, achieving high levels of pathway selectivity for a given
substrate class (favoring 1,2-arylfluorination over 1,1-aryl-
fluorination, β-hydride elimination, or other side reactions)
often requires extensive ligand optimization and the use of
potentially synthetically restrictive directing groups.15
Received: March 25, 2021
Published: June 2, 2021
https://doi.org/10.1021/jacs.1c03178
J. Am. Chem. Soc. 2021, 143, 8962−8969
© 2021 American Chemical Society
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components would have strong interactions with each other
that would impact the final yield of the reaction, our system
appeared better suited for optimization via design of
experiments (DoE) as opposed to typical “one variable at a
time” (OVAT) screening.20,21
We elected to use a modified definitive screening design
(DSD) (Table 1), which allowed us to develop a linear
Table 1. Optimization of Reaction Conditions
regression model that describes the sensitivity of a response (in
this case reaction yield) to a variety of input parameters with
continuous levels (reagent loadings).22 The high- and low-end
values for each reagent loading in the subsequent experiments
were set based on what we expected to be the most extreme
values the reaction would tolerate. We then ran just 18
experiments using values within those ranges to train a model,
which subsequently predicted conditions that more than
doubled our initial yield. While the arylboronic acid loading
of 4.67 equiv is relatively high, we deemed this acceptable in
our system, as the arylboronic acid was not among the most
valuable components of the reaction.23
Having optimized the conditions, we began investigating the
scope of alkene substitution (Table 2). The reaction with
1,2,2-trisubstituted alkenes to form quaternary carbon−aryl
bonds proceeded in moderate to good yields with excellent
enantioselectivity and broad functional group tolerance.
Successful reaction of 1,1,2-trisubstituted alkene substrates
with our conditions would form tertiary C(sp3)−F stereo-
centers, which would be a valuable addition to previously
reported methods;24 however, this requires an unprecedented
asymmetric formation of a fully substituted C(sp3)−F
stereocenter through C−F reductive elimination. Gratifyingly,
the reaction with 1,1,2-trisubstituted alkenes was able to form
tertiary C(sp3)−F stereocenters with somewhat lower, but still
high, enantioselectivity ranging from 90−96% ee. Next, we
explored the effects of other alkene and benzaldehyde
substitutions on the reaction. Both electron-rich and
electron-poor benzaldehydes gave good yields with excellent
enantioselectivity, with performance being similar between E-
and Z-isomers of the alkene starting material (2y to 3y and 2z
to 3z, respectively). Unfortunately, the method is ineffective
Figure 1. (A) Pioneering examples of asymmetric fluorocyclizations
of alkenes. (B) State of the art in palladium-catalyzed alkene
arylfluorination. (C) General depiction of an arylfluorination
facilitated by an in situ formed imine using a chiral TDG strategy.
palladium(II) and oxidant, and deleterious interactions
between the TDG and [F+].
In a series of pilot experiments, we found that L-tert-leucine
(the optimal TDG in our previous system) did not lead to
product formation, suggesting that a different TDG design was
needed to support palladium(IV) formation. In their study on
enantioselective C−H fluorination of electron-deficient
benzaldehydes, Yu and co-workers found that switching from
an LX-type amino acid to an L2-type α-amino amide TDG
promoted C−F reductive elimination through formation of a
pentacoordinate cationic Pd(IV) complex.19 We reasoned our
system would benefit from the same effect and carried out a
new screen using a library of TDGs that offered the potential
of L2-type binding after aldehyde condensation (see Supple-
mentary Figure S1). An initial hit was observed reacting alkene
starting material 1 with N-fluoro-2,4,6-trimethylpyridinium salt
([F+]) and phenylboronic acid in the presence of a
palladium(II) catalyst, previously unreported TDG-A, silver
fluoride additive, and water in a 2:1 mixture of DCM/MeCN.
A variety of unproductive side reactions were observed,
including formation of palladium black and decomposition of
the [F+] reagent and benzaldehyde SM. Other [F+] oxidants
including Selectfluor and NFSI resulted in oxidation to the
carboxylic acid. Because it was expected that most of the
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c
Table 2. Alkenylbenzaldehyde Scope of the Arylfluorination Reaction
a
b
c
Reaction carried out using TDG-A. Reaction carried out using TDG-B. Reactions were carried out on 0.1 mmol scale. All reported yields are
isolated yields.
for alkenes that are tetrasubstituted or whose functionalization
results in dearomatization (see Supplementary Figure S5).
We explored the scope of arylboronic acids with 1a as the
model alkene substrate (Table 3). Both electron-rich and
electron-poor para-substituted arylboronic acids afforded the
desired products in good yields with excellent enantioselectiv-
ity. Arylboronic acids with electron-withdrawing meta-sub-
stituents (4f) performed markedly worse than those with
electron-donating substituents (4g), requiring either prolonged
reaction time or higher temperatures. The reaction did proceed
with benzofuran and benzodioxole boronic acids (giving 4h
and 4i, respectively), but it did not tolerate other heterocycles,
including substituted pyridines and pyrazoles (presumably due
to competitive binding to the metal center). Additional
limitations include both alkenyl and alkyl boronic acids. In
order to demonstrate the potential synthetic utility of the
reaction, multiple diversifications were performed. Both
oxidation (5a) and reduction (5c) of the aldehyde proceeded
in high yields while maintaining the high ee of 4a. Olefination
(5b) and decarbonylation (5d) gave the desired products in
moderate yields with little to no erosion in ee.
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a
Table 3. Arylboronic Acid Scope of the Arylfluorination Reaction and Synthetic Derivations
a
Reactions for the arylboronic acid scope and synthetic diversifications were run on 0.1 mmol scale unless otherwise noted. See SI for details
regarding scale and specific conditions for the synthesis of MCJ001F.
To further demonstrate the synthetically enabling nature of
this method, we targeted the synthesis of the bioactive
compound MCJ001F.25 The reported patent route to the
(R,R)-stereoisomer involves a chiral resolution of a racemic
intermediate and late-stage separation of diastereomers in a 10-
step sequence. In contrast, our procedure is both enantio- and
diastereoselective, affording MCJ001F-RR in fewer steps from
commercially available materials and in overall higher yield. By
starting from the opposite alkene isomer (Z-configured), we
were also able to prepare the (R,S)-stereoisomer in higher
overall yield than the reported patent route (see Supple-
mentary Figure S7).
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In an attempt to gain insight into the reaction mechanism,
we performed several control reactions and kinetic experiments
(Figure 2). First, we confirmed that the TDG was essential by
excluding it from a standard reaction with 7f as well as
subjecting ester 7e, which cannot condense with the TDG, to
standard conditions. In both cases, only recovered starting
material was observed. Next, we confirmed the reaction does
not occur through C−H activation by subjecting substrate 7g
to our standard conditions and observing that it was
unreactive. The role of AgF was also briefly considered.
While the reaction of model substrate 1a does proceed without
silver fluoride, the reaction only reaches roughly 40% yield by
1H NMR, with the remaining mass balance of 1a being
decomposed material. We observe the formation of palladium
black when stirring a mixture of 1a, various loadings of TDG-
A, and Pd(MeCN)4(BF4)2 (10 mol %) in the standard solvent
conditions, raising the possibility of catalyst deactivation in the
reaction system. Palladium black was qualitatively observed
forming over the course of roughly 6 h at 35 °C for loadings of
TDG higher than 75 mol %. Competitive homocoupling of the
boronic acid (confirmed by GC-MS) helps explain the high
amount of boronic acid required. It may also indicate a
potential beneficial effect of Ag(I) for reoxidation of inactive
Pd(0).
Experiments aimed at establishing the robustness of the
palladium catalyst and the concentration dependencies of the
reaction components were carried out according to the “same-
excess” and “different-excess” protocols of reaction progress
kinetic analysis (RPKA), respectively.26 RPKA allows for visual
analysis of the kinetic data over the entire time course of the
reaction at synthetically relevant conditions. The lack of
overlay between these profiles indicates that product inhibition
or catalyst deactivation is occurring.27 These possibilities can
be discerned by running a third experiment with the amount of
product generated by the reaction until this reaction point
added. This reaction is identical by composition, but the
catalyst has completed fewer turnovers; therefore, the lack of
overlay in this case is indicative of mild catalyst deactivation.28
Having confirmed the presence of catalyst deactivation,
initial rates from reaction progress profiles were employed to
probe concentration dependencies of the reaction components.
A series of “different-excess” experiments showed the reaction
to have a positive dependence on [Pd] and a negative rate
dependence on [TDG]. Studies established the absence of a
nonlinear effect of TDG ee, showing that product ee varies
linearly with TDG ee. This, coupled with an observed first-
order dependence on palladium, confirms the absence of Pd
dimers or other higher order Pd species either on or off the
cycle, but does not preclude the possibility of monomeric off-
cycle species.29 The reaction was shown to be zero-order in
water, silver fluoride, and alkene. The initial rates for reactions
with lower [PhB(OH)2] or lower [F+] were reduced compared
to the reaction run under standard conditions, suggesting a
positive rate dependence; however, when comparing increased
concentrations of these reagents during the “different excess”
experiments, the resulting rates showed an apparent zero-order
dependence in [F+] and boronic acid, pointing to saturation
kinetics in both of these components.
Figure 2. Summary of control experiments and kinetics investigation
(see SI for experimental details and all data) and proposed catalytic
cycle.
Taken together, the kinetics data are consistent with the
mechanism proposed in Figure 2 where transmetalation is
turnover-limiting at low concentrations of boronic acid and
oxidative addition is turnover-limiting at low concentrations of
[F+]. A zero-order dependence in all components under
standard conditions is consistent with the C−F reductive
elimination step being turnover-limiting. Negative-order rate
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dependence on the concentration of TDG is consistent with
the TDG mediating decomposition of [F+] or potentially
forming an off-cycle TDG·PdII complex. Analogous to our
previous studies, we hypothesize that the chiral TDG mediates
enantiodetermining migratory insertion by attenuating geo-
metric distortion in the favored metallatricyclic transition
state.17 The kinetics data as a whole underscore the
mechanistic complexity of this TDG-mediated arylfluorination
reaction and highlight the value of DoE for optimization of
complicated dual catalytic systems of this type in the absence
of a detailed a priori mechanistic picture. Not only does the
highly enantioselective 1,2-arylfluorination of alkenyl benzal-
dehydes presented here allow expedient access to organo-
fluorine compounds that are otherwise difficult to prepare, but
also its successful development sets the stage for expansion of
chiral TDG strategies across increasingly diverse alkene
difunctionalization reactions.
ACKNOWLEDGMENTS
■
We thank Dr. Dee-Hua Huang and Dr. Laura Pasternack for
assistance with NMR spectroscopy. We also thank Dr. Gary J.
Balaich (UCSD) for X-ray crystallographic analysis. Dr. Jason
Chen, Brittany Sanchez, and Emily Sturgell (Scripps Research
Automated Synthesis Facility) are acknowledged for HPLC,
SFC, and HRMS analysis. We also thank Dr. Joseph Derosa
and Dr. Donna Blackmond for helpful discussion. Financial
support for this work was provided by the National Institutes
of Health (R35GM125052) and the Cottrell Scholars program.
Additional support was provided through an SIOC Fellowship
(Z.L.) and a National Science Foundation Graduate Research
Fellowship (NSF/DGE-184247, L.J.O.).
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03178.
Experimental details, analytical data, and H, 13C, and
1
19F NMR spectra (PDF)
NMR data (ZIP)
Accession Codes
CCDC 2048393 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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AUTHOR INFORMATION
■
Corresponding Author
Keary M. Engle − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States;
orcid.org/0000-0003-2767-6556; Email: keary@
scripps.edu
Authors
Zhonglin Liu − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Lucas J. Oxtoby − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Mingyu Liu − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States;
orcid.org/0000-0003-4649-7393
Zi-Qi Li − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States
Van T. Tran − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Yang Gao − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03178
Notes
The authors declare no competing financial interest.
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(23) It should be noted that while this technique can be used for
rapid optimization and identification of major interactions, it does not
suggest an explanation for why a given response is dependent on a
particular input parameter; moreover, the DSD model does not
necessarily accurately predict reaction performance in totally different
chemical space. Multiple powerful techniques have emerged for the
statistical prediction of out-of-sample reactions, including multivariate
regression of physical organic descriptors [see: (a) Reid, J. P.; Sigman,
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reactions will have the same concentration of starting materials, but
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Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
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NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was published ASAP on June 2, 2021, with an
incorrect reagent in the Table 3 synthesis of 5d. The corrected
version was posted on June 8, 2021.
8969
https://doi.org/10.1021/jacs.1c03178
J. Am. Chem. Soc. 2021, 143, 8962−8969