An in Situ Directing Group Strategy for Chiral Anion Phase-Transfer Fluorination of Allylic Alcohols

Article abstract of DOI:10.1021/ja507468u

An enantioselective fluorination of allylic alcohols under chiral anion phase-transfer conditions is reported. The in situ generation of a directing group proved crucial for achieving effective enantiocontrol. In the presence of such a directing group, a

Full text of DOI:10.1021/ja507468u

Communication
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Open Access on 09/09/2015
An In Situ Directing Group Strategy for Chiral Anion Phase-Transfer
Fluorination of Allylic Alcohols
Weiwei Zi,‡ Yi-Ming Wang,‡ and F. Dean Toste*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
Scheme 1. Directed Fluorination via Chiral Anion Phase-
Transfer Catalysis
ABSTRACT: An enantioselective fluorination of allylic
alcohols under chiral anion phase-transfer conditions is
reported. The in situ generation of a directing group
proved crucial for achieving effective enantiocontrol. In the
presence of such a directing group, a range of acyclic
substrates underwent fluorination to afford highly enantio-
enriched α-fluoro homoallylic alcohols. Mechanistic
studies suggest that this transformation proceeds through
a concerted enantiodetermining transition state involving
both C−F bond formation and C−H bond cleavage.
espite the unique importance of fluorine in biologically
Dactive compounds, the catalytic enantioselective introduc-
tion of stereogenic fluorine substituents remains a challenging
synthetic transformation.1 Although fluoride is readily available
and atom-economical, the use of F− in asymmetric catalysis is an
inherently demanding task, and nucleophilic fluorination has
only recently been realized through the development of
transition metal-based catalytic systems.2 The complementary
approach of using electrophilic reagents for the fluorination of
nucleophilic carbon centers has been more broadly applicable, in
part due to the commercial availability of N−F reagents covering
a broad range of reactivity. Several distinct strategies have been
advanced to achieve asymmetric induction using electrophilic
fluorinating reagents, including enamine catalysis,3a−e nucleo-
philic catalysis,3f,g cationic phase-transfer catalysis,3h−j Lewis acid
activation of 1,3-dicarbonyl compounds,3k−m transfer fluorina-
tion using chiral tertiary amines,3n−q and late transition metal-
catalyzed π-activation of olefins.3r With the exception of olefin π-
activation, these strategies generally employ activation modes
requiring electron-rich olefins (allylsilanes, metal enolates, silyl
enol ethers, enamines, or π-excessive heterocycles) as substrates
or reactive intermediates. Hence, only a few examples of the
enantioselective fluorination of unactivated or weakly activated
alkenes have been reported.4
Our group has developed chiral anion phase-transfer catalysis as
a general approach for asymmetric synthesis involving cationic
reagents or intermediates.5 The application of this approach to
enantioselective fluorination has been achieved using Selectfluor,
an ionic electrophilic reagent otherwise insoluble and unreactive
in nonpolar media, which is activated through ion-exchange with
a catalytic amount of a lipophilc chiral phosphate salt (Scheme 1,
top). The resulting chiral ion pair serves as the active
electrophilic species in solution, allowing for the fluorination of
olefin starting materials in an enantioselective manner. As a
consequence of this mode of activation, unselective background
reactivity is minimal, despite the large excess of bulk reagent
relative to catalyst and the high intrinsic reactivity of Selectfluor.
Notably, alkenes without activating heteroatomic substituents
can be fluorinated, suggesting that this approach may prove
applicable to the preparation of fundamental yet synthetically
formidable chiral fluorinated building blocks directly from readily
available olefins.
We were particularly intrigued by our recent discovery that a
carboxamide or phenol group at the allylic position of an alkene
could direct the fluorination of the double bond to deliver the
fluorination−elimination product with excellent enantio-
selectivity (Scheme 1, bottom).6,7 The scope of this method-
ology, however, was limited to relatively specialized substrates
bearing ring fusions or pendent phenols, and we were interested
in advancing this methodology toward more fundamental and
versatile substrates. In particular, we directed our attention to
allylic alcohols as a general and easily accessible class of
substrates, conjecturing that the hydroxyl group would direct
enantioselective fluorination. In initial studies, however,
subjecting cinnamyl alcohol 1a to the previously established
fluorination conditions provided fluorinated product with
essentially no enantiocontrol (eq 1).
Previously,6 we observed that length of the spacer between the
directing group and alkene was important for achieving effective
directed fluorination, with high enantioselectivities attained
when the double bond is δ to the terminus of the directing group.
Speculating that the hydroxyl group of the allylic alcohol was too
close to the alkene to serve as a directing group, we sought to
lengthen the spacer using a readily removed auxiliary group. A
report by Falck and co-workers describing the use of boronic
Received: July 22, 2014
Published: September 9, 2014
© 2014 American Chemical Society
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Table 1. Optimization of Reaction Conditions
acids to effect a formal enantioselective conjugate addition of
hydroxide inspired us to consider the use of boronic acid
monoesters as directing groups.8,9 The geometric analogy
between our previously successful directing groups and the
boronic acid monoester led us to suspect that the latter would be
appropriately positioned relative to the alkene to be a competent
directing group. In addition, the use of these boronic esters
would provide the opportunity to fine-tune the acidity (and, thus,
hydrogen-bonding properties) of the directing group, as well as
its steric bulk, both of which previously proved crucial for
obtaining high enantioselectivities.6 Since boronic acid mono-
esters are readily formed by condensation of boronic acids and
alcohols and also readily hydrolyzed, we postulated that such
esters could function as in situ directing groups (Scheme 2). We
Scheme 2. Proposed Boronic Acid Monoester-Directed
Transformation
a
b
p-xyl/EC = p-xylene/ethylcyclohexane (1:1). ee determined by
c
chiral HPLC. Negative sign indicates opposite sense of stereo-
d
induction relative to entry 1. Conversions determined by 1H NMR of
e
the crude reaction mixture. On 0.1 mmol scale, in 72% isolated yield.
resulted in complete loss of enantiocontrol, underscoring the
essentiality of this additive (entry 14).14
envisioned executing this strategy by using a stoichiometric
boronic acid additive to generate the directing group, which
would subsequently be removed upon chromatographic
purification. In this Communication, we report the successful
implementation of this tactic for the enantioselective fluorination
of allylic alcohols, including substrates with little steric or
electronic bias.
Under these optimized conditions, we explored the substrate
scope of the transformation. Substrates bearing weakly electron-
donating to moderately electron-withdrawing substituents at the
para position furnished fluorinated product in good to excellent
yields and enantioselectivities (entries 1−6). Substitution at the
meta and ortho positions afforded products with diminished but
still useful enantioselectivities (entries 7−11). Substituents larger
than methyl at the α position of the aryl ring were tolerated,
giving rise to fluorinated alcohols bearing trisubstituted double
bonds with good E/Z selectivity and excellent enantioselectivity
(entries 12 and 13). Finally, these conditions proved applicable
to non-styrenyl allylic alcohols (entries 14 and 15). Notably, an
allylic alcohol bearing methyl and primary alkyl substituents
reacted to form the fluorinated product in high yield and good
enantioselectivity (entry 15).15
We conducted kinetic isotope effect experiments to gain some
understanding of the basic mechanistic features of this system. A
significant isotope effect was found in both intra- and
intermolecular experiments, with the values for kH/kD agreeing
within experimental error (eqs 2a and 2b). The magnitude of the
observed KIE exceeds that attributable to hyperconjugative
stabilization of a carbocation, thus excluding a mechanism in
which rate-determining formation of a discrete fluorinated
carbocationic species occurs, followed by rapid loss of a proton
(Scheme 3, pathway I).16 On the other hand, these data are
consistent with the involvement of C−H bond cleavage in an
asynchronous rate-determining transition state, either in a one-
step process or after initial reversible formation of an alkene−
Selectfluor π-complex (pathway II).17 In support of this
interpretation, subjecting trideuterated substrate 1b-d3 to
standard reaction conditions resulted in significantly diminished
enantioselectivity (83% vs 93% ee) compared to unlabeled 1b
To probe the validity of our hypothesis, we first evaluated the
effect of incorporating phenylboronic acid (1.0 equiv) as an
additive under reaction conditions otherwise identical to the
ones shown in eq 1. We were encouraged to observe a significant
increase in enantioselectivity (Table 1, entry 1).10,11 A thorough
evaluation of commercially available boronic acids revealed that
substituents on the boronic acid strongly influenced enantio-
selectivity (selected results shown in Table 1). For instance, the
more acidic pentafluorophenylboronic acid (4b) delivered
racemic product (entry 2). Moreover, the presence of methyl
groups at the 3,5-positions resulted in the opposite sense of
enantioinduction compared to unsubstituted phenylboronic
acid, while 2,6-substitution inhibited reactivity (entries 3 and
4). p-Tolylboronic acid (4f) was found to be particularly effective
and was chosen as the boronic acid for further optimization. We
reasoned that enantioselectivity might be further improved by
removal of water to shift the equilibrium in favor of boronic ester
formation.12 Indeed, the addition of 4Å molecular sieves resulted
in a significant increase in enantioselectivity (entry 6 vs 7).
Catalyst 3c (AdDIP) bearing 4-(1-adamantyl)-2,6-diisopropyl
substituents on the 3,3′ position of the BINOL scaffold was
found to further enhance enantioselectivity (entry 9).13 Finally,
optimization of base (Na2HPO4) and fine-tuning of solvent and
desiccant provided conditions to generate fluorinated product 2a
in high yield and excellent enantioselectivity (entry 13).
Omitting the boronic acid under otherwise optimized conditions
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Table 2. Substrate Scope of the Enantioselective Fluorination
of Allylic Alcohols
Scheme 3. Two Mechanistic Possibilities for the Boronic
Acid-Mediated Enantioselective Fluorination−Elimination
Reaction
a
have previously been utilized in reactions in which protonation is
the enantiodetermining step,18 these results suggest that in chiral
anion catalysis, the microscopic reverse of this process (i.e.,
enantiodetermining deprotonation) may occur.
In summary, we have shown that the generation of an in situ
directing group, in conjunction with chiral anion phase-transfer
catalysis, allows for the enantioselective fluorination of simple
allylic alcohols. This approach significantly extends the scope of
electrophilic enantioselective fluorination to unactivated and
synthetically versatile substrates and potentially represents a
general strategy for other substrate-directed reactions. In
addition, mechanistic experiments suggest a process in which
C−F bond formation and C−H bond cleavage occur in a
concerted enantiodetermining transition state, with cleavage of
the C−H bond playing an unusually significant role in
asymmetric induction.
a
Absolute configurations assigned by analogy to that of 2d, which was
determined to be (S) by single-crystal X-ray diffraction (Figure 1).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization data for new compounds,
and crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
fdtoste@berkeley.edu
■
Figure 1. X-ray crystallographic structure of 2d (ellipsoids at 50%
probability).
Author Contributions
‡W.Z. and Y.-M.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Institute of General Medical Sciences (R01 GM104534). Y.-
M.W. thanks Amgen for a graduate fellowship. We gratefully
acknowledge College of Chemistry CheXray (NIH Shared
Instrumentation Grant S10-RR027172) and Antonio DiPasquale
for X-ray crystallographic data. We thank Andrew J. Neel for help
with NOE experiments and Gianpiero Cera for experimental
assistance. We thank Mark D. Levin, Yang Yang (MIT), and
Daniel T. Cohen (MIT) for useful suggestions on the manuscript
and Profs. Robert G. Bergman and David A. Nagib for helpful
discussions.
(eq 3), implicating the cleavage of the C−H bond in the
enantiodetermining step. In a broader context, while chiral acids
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Communication
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