Chiral anion phase-transfer catalysis applied to the direct enantioselective fluorinative dearomatization of phenols

Article abstract of DOI:10.1021/ja311798q

Chiral anion phase-transfer catalysis has enabled the direct and highly enantioselective fluorinative dearomatization of phenols catalyzed by a BINOL-derived phosphate. The process efficiently transforms simple, readily available phenols into fluorinated chiral small molecules bearing reactive functionality under ambient reaction conditions with high enantioselectivity. The close relationship of the products with well-studied o-quinols provides numerous avenues for synthetic elaboration and exciting opportunities for bioisosteric replacement of hydroxyl with fluorine in natural products.

Full text of DOI:10.1021/ja311798q

Communication
pubs.acs.org/JACS
Chiral Anion Phase-Transfer Catalysis Applied to the Direct
Enantioselective Fluorinative Dearomatization of Phenols
Robert J. Phipps and F. Dean Toste*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
the lipophilic chiral anion and thus eliminating significant
racemic background reaction. Compared with conventional
phosphoric acid (PA) catalysis, the electrophile in chiral anion
PTC is associated with the catalyst via ion-pairing rather than H-
bonding interactions (Figure 1a).12 This distinction is crucial in
ABSTRACT: Chiral anion phase-transfer catalysis has
enabled the direct and highly enantioselective fluorinative
dearomatization of phenols catalyzed by a BINOL-derived
phosphate. The process efficiently transforms simple,
readily available phenols into fluorinated chiral small
molecules bearing reactive functionality under ambient
reaction conditions with high enantioselectivity. The close
relationship of the products with well-studied o-quinols
provides numerous avenues for synthetic elaboration and
exciting opportunities for bioisosteric replacement of
hydroxyl with fluorine in natural products.
he rapid and controlled generation of complex, readily
Tfunctionalizable three-dimensional structures from simple
planar starting materials is a highly attractive goal, as it allows fast
access to diverse molecular architectures. Dearomatization of
arenes is a powerful approach that has been proposed as a key
component in putative biosynthetic pathways for a range of
bioactive natural products, inspiring a range of elegant
syntheses.1 A highly desirable factor in such constructions is
the induction of asymmetry into the product, which has generally
been achieved by three distinct chemical approaches: diaster-
eoselective dearomatization of a substrate bearing an existing
stereocenter;1b,2 dearomatization followed by enantioselective
desymmetrization of the prochiral intermediate;3 and finally,
direct asymmetric dearomatization, which requires discrim-
ination between the enantiotopic faces of the arene during the
dearomatizing event. The last category represents a significant
challenge, and to date, several elegant albeit noncatalytic metal-4
and hypervalent iodine-mediated5 approaches have been
reported. To the best of our knowledge, only a handful of direct
catalytic asymmetric arene dearomatization protocols exist (all
but one6 being intramolecular), although the benefits are
evident.7 Herein we report an intermolecular dearomatization
that incorporates a quaternary fluorine stereocenter into the
product, which is desirable because of the current interest in the
effect of fluorine incorporation into pharmaceuticals but has been
restricted by the limited number of general approaches to the
asymmetric construction of such stereocenters.8
Figure 1. (a) Distinction of our approach from existing PA catalysis. (b)
Initial hypothesis for fluorinative phenol dearomatization.
that the privileged BINOL-derived PA catalyst scaffold can
potentially be combined with new classes of electrophiles for
which ionic charge rather than Brønsted basicity is a prerequisite.
Specifically, we anticipated that moving away from protonative
activation to “phase-transfer” activation should enable the use of
less reactive nucleophiles than are typically employed with chiral
PA catalysts, since highly reactive cationic electrophilic reagents
(such as Selectfluor) may be used without the excessive
background reaction that may be anticipated in more conven-
tional homogeneous variants. In particular, while there exist
many reports on the use of more reactive heteroarene
nucleophiles such as indoles, pyrroles, and furans in combination
with chiral PA catalysts,12b there are few examples of the use of
less activated, more ubiquitous arene nucleophiles such as
phenols.13 This limitation presumably arises due to insufficient
reactivity of these aromatic nucleophiles with reagents that are
activated by protonation alone.
We anticipated that our strategy might enable simple phenols
to act as nucleophiles in an asymmetric dearomatizing
fluorination process. On the basis of our previous observations
in enamide fluorination,11a we hypothesized that H-bonding of
the chiral phosphate−Selectfluor ion pair with a phenol −OH
group by means of the remaining phosphoryl oxygen might
enable discrimination between the enantiotopic faces of the
phenol (Figure 1b). In our previous chiral anion-catalyzed
fluorinations,9b,10,11 the presence of an N-benzoyl group in the
substrate, presumably acting as a H-bond donor, was crucial for
We recently reported a chiral anion phase-transfer catalysis
(PTC) strategy9 enabling the development of highly enantiose-
lective halocyclization of alkenes9b,10 and fluorination of
enamides.11 This strategy hinges upon the ability of a chiral
BINOL-derived phosphate to undergo anion exchange with
poorly soluble cationic halogenating reagents such as Select-
fluor® reagent, permitting solubility only upon association with
Received: December 3, 2012
Published: January 18, 2013
© 2013 American Chemical Society
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obtaining the highest levels of enantioselectivity. Thus, we were
aware that progressing to a simple phenol could present a
significant challenge, especially in light of the dearth of examples
in which phenols have successfully been employed with PA
catalysts. Furthermore, the reaction of Selectfluor with phenols
under homogeneous conditions was previously shown to give
multiple products, including those of dearomatizing addition,
electrophilic aromatic substitution, ipso substitution, and
oxidation, depending on substrate and conditions.14
nevertheless suggested that the intended catalyst-directed
fluorination (via binding to the phenol oxygen; Figure 1b) likely
occurred. Indeed, with TCYP (produced from the parent PA in
situ using Na2CO3) as the catalyst, we observed para and ortho
fluorination in a net ratio of ∼1:1. In contrast, in the absence of
catalyst, para fluorination was favored by a factor of 3, albeit with
low conversion (Scheme 1b). Hence, we next examined isomeric
5,6,7,8-tetrahydro-1-naphthol (1b) with the intent not only that
ortho-selective fluorinative dearomatization would constitute the
major product but also that the greater steric differentiation
between the two sides of the substrate close to the putative point
of binding to the catalyst would increase the enantioselectivity
(Figure 1b). Gratifyingly, under our thus-far optimal conditions,
1b exclusively formed ortho-fluorinated product 3a in 75% yield
with 96% ee (Scheme 1c). When a more elementary substrate, o-
cresol, was tested, the isolated product was found to be dimer 4a
resulting from [4 + 2] cycloaddition of the chiral 2,4-
cyclohexadienone intermediate (Scheme 1d). While the
enantioselectivity was still short of excellent (79% ee), we regard
this as remarkable given the simplicity of the substrate. In
accordance with our earlier hypothesis, increasing the steric
demand of the ortho substituent by using o-benzylphenol gave
4b with excellent enantioselectivity (97% ee), and the relative
and absolute stereochemistries were confirmed by X-ray
crystallography. The observed product dimerization in the
absence of substitution at the 3-position is in agreement with
precedent from studies on o-quinols and is completely regio- and
diastereoselective.2
We began by using 5,6,7,8-tetrahydro-2-naphthol (1a), as this
had previously been shown to selectively deliver 2a under
racemic conditions (Scheme 1b).14a Using C8-TRIP (Scheme
Scheme 1. Preliminary Investigation and Selected
Optimization of the Effect of Phenol Substitution
a b
,
We first focused on 2,3-di- and 2,3,4-trisubstituted phenols
(Table 1). A 4-bromo analogue of our initial substrate delivered a
a
Table 1. Scope of Fluorinative Phenol Dearomatization
a
b
Isolated yields after chromatography on silica gel are shown. The ee
c
1
values were determined by HPLC. Yield determined by H NMR
a
Absolute stereochemistries were assigned by analogy with 4b.
analysis using an internal standard.
versatile vinyl bromide-containing product (3b). Two isomeric
N-heterocyclic versions of this scaffold having potential utility in
medicinal chemistry also gave high selectivity (3c and 3d);
however, in the case where the N was directly substituted on the
phenol ring, the yield of the doubly vinylogous amide product 3d
was reduced due to formation of ring fluorination byproducts.
Simple 2,3-dimethylphenol was an effective substrate (3e), as
were its 4-bromo (3f), 4-chloro (3g), and even 4-iodo (3h)
analogues.16 Despite the reduced yield, the last case highlights
the relatively benign and functional-group-tolerant nature of our
solid−liquid PTC conditions. Specifically, aryl iodides are readily
oxidized to I(III) by Selectfluor; attempts at homogeneous
1a) as the catalyst and toluene as the solvent gave 2a in low yield
but with an encouraging 27% ee. The balance of the material
consisted of a regioisomeric mixture of ortho-fluorinated phenols
2b and 2c and geminally difluorinated 2d. A solvent screen
revealed that toluene gave an optimal balance of yield and
enantioselectivity and a survey of catalysts showed that among a
range of chiral PAs, our previously reported catalyst TCYP15
gave the highest enantioselectivity [63% ee; see the Supporting
Information for details]. Under our PTC conditions, the evident
inclination of 1a toward ortho fluorination, while frustrating our
efforts to achieve high yields of dearomatized product,
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fluorination of this substrate in MeCN led to an intractable
mixture.17 Other moderate yields were largely due to incomplete
conversion rather than byproduct formation. Finally, a methoxy-
substituted phenol delivered doubly vinylogous ester 3i.
Scheme 2. Retro-[4 + 2]/[4 + 2] Derivatization of Products
Substrates with various substituents at the 2-, 2,4-, and 2,5-
positions (Table 2), including benzyl (4b), phenyl (4c),
Table 2. Fluorination/[4 + 2] Dimerization of Phenols
Lacking 3-Substitution
two carbons away. Our earlier observation that a clear steric
distinction between the two sides of the phenol was required to
achieve the highest enantioselectivities for ortho fluorination
(e.g., Scheme 1d, 4a vs 4b; Table 2, 4f vs 4g) led us to
hypothesize that our original peak selectivity of 63% ee for para
fluorination of 1a (Scheme 1b) might be improved by
incorporating geminal 8,8′ disubstitution to better sterically
distinguish the enantiotopic faces of the phenol without the
possibility of ortho dearomatization. As previously, competitive
SEAr arene fluorination at the ortho position led to impaired
yields, but the para-fluorinated products 2e and 2g were formed
with much-improved 86% ee and indanol-derived 2f with 85% ee
(Scheme 3a). Although its practicality is at present limited by the
Scheme 3. (a) Para-Selective Fluorinative Dearomatization;
(b) Predictable Selectivity Based on Phenol Sterics; (c)
Asymmetric Synthesis of Grandifloracin Analogue 7
isopropyl (4f), and cyclohexyl (4g), delivered the [4 + 2]
dimer products with high enantioselectivities. The participation
of phenols bearing allyl (4e, 4h) and homoallyl (4d) groups
shows the highly chemoselective nature of our transformation.
Under these mild conditions, the alkene functionality remained
untouched by Selectfluor, as did a silyl-protected primary alcohol
(4j). Furthermore, substitution at the phenol 4-position (4h, 4i)
was well-tolerated without affecting the selectivity. Interestingly
5-substitution (4g) decreased the enantioselectivity somewhat,
suggesting that steric differentiation of the two sides of the
phenol is important. Elegant prior work has shown that closely
related o-quinol dimers are effectively masked dienes and can be
readily made to undergo retro-[4 + 2] reactions in the presence
of a broad range of dienophiles.2,18 We demonstrated the
compatibility of our fluorinated products in the form of retro-[4
+ 2]/[4 + 2] reactions with N-phenylmaleimide and cyclo-
pentadiene dimer (Scheme 2).18c These reactions gave single
diastereoeomers with no loss of enantioenrichment, and the
similar sequences could potentially provide rapid access to a
diverse range of complex fluorinated scaffolds.19
low yields, we believe that this method for rapid access to
enantioenriched, fluorinated 2,5-cyclohexadienones, in addition
to the 2,4-cyclohexadienones above, represents a powerful new
strategy for the synthesis of versatile small molecules of potential
pharmaceutical relevance. The absolute stereochemistry of 2g
was determined by X-ray crystallography, which suggested that
for both ortho and para fluorination, the facial selectivity of
fluorination may be reliably predicted by a mnemonic that takes
into account both the phenol structure and the catalyst
enantiomer employed (Scheme 3b). This outcome is also
consistent with the tentative stereochemical model depicted in
Figure 1b, in which the substrate is bound with the aromatic ring
of the phenol residing in an “open” quadrant of the catalyst and
the sterically demanding substituents being projected away from
the catalyst.
Having shown that our catalytic system delivers fluorine to the
ortho position of a range of substituted phenols with high
enantioselectivity, we returned to our initial challenge of
dearomatizing para fluorination to test whether the fluorine
may still be delivered with high selectively to a position a further
To underline the general utility and expediency of our
approach, we demonstrate the asymmetric synthesis of 7, a fluoro
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Communication
analogue of the natural product (−)-grandifloracin (8)20 in
which the −OH groups of the natural product are substituted
with −F, an established bioisostere for −OH (Scheme 3c).8a,21
Fluorination of readily prepared silyloxymethylphenol 6
proceeded with moderate conversion (the corresponding
benzoyloxymethylphenol gave only trace conversion) but
excellent enantioselectivity to give a dimer in which the TBS
groups could be readily exchanged to benzoyl, delivering 7 in
three steps. In contrast, while racemic 8 has been accessed in two
steps,22a the only asymmetric synthesis of 8 to date employs
seven steps to access the unnatural isomer using enzymatic
methods.22b
In summary, we have demonstrated the broad generality of our
chiral anion phase-transfer catalysis strategy by applying it to the
asymmetric fluorinative dearomatization of phenols. Notably, it
represents a rare application of chiral phosphoric acid catalysts to
simple phenol nucleophiles by virtue of our chiral-anion PTC
approach to activation of Selectfluor. The small but densely
functionalized products incorporating an enantioenriched
quaternary F-containing stereocenter represent valuable building
blocks of potential interest in synthetic and medicinal chemistry.
Their close relationship to well-studied o-quinols provides
numerous avenues for elaboration as well as exciting
opportunities for bioisosteric replacement of −OH with −F in
the numerous natural products thought to be derived from o-
quinols.
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(13) For limited examples, see: (a) Lv, J.; Luo, S. Chem. Commun.
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AUTHOR INFORMATION
Corresponding Author
fdtoste@berkeley.edu
Notes
■
The authors declare no competing financial interest.
(16) For solvent, catalyst, and base optimization using 3e and the
effects of the Selectfluor anion, see the Supporting Information.
(17) Ye, C.; Twamley, B.; Shreeve, J. M. Org. Lett. 2005, 7, 3961.
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aid of 1D F−H HOESY NMR experiments. See: Combettes, L. E.;
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ACKNOWLEDGMENTS
■
We thank the University of California for financial support. R.J.P.
is grateful to the European Commission for a Marie Curie
International Outgoing Fellowship. We thank William J. Wolf
and Dr. Antonio DiPasquale for obtaining X-ray crystallographic
data, Dr. Tim Claridge (University of Oxford, U.K.), and Dr.
Christian Canlas for NMR assistance, and Yi-Ming Wang for
synthesizing a batch of TCYP.
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