Catalytic, asymmetric α-fluorination of acid chlorides: Dual metal-ketene enolate activation

Full text of DOI:10.1021/ja807792c

Published on Web 12/02/2008
Catalytic, Asymmetric r-Fluorination of Acid Chlorides: Dual Metal-Ketene
Enolate Activation
Daniel H. Paull, Michael T. Scerba, Ethan Alden-Danforth, Leland R. Widger, and Thomas Lectka*
Johns Hopkins UniVersity, Department of Chemistry, 3400 North Charles Street, Baltimore, Maryland 21218
Received October 8, 2008; E-mail: lectka@jhu.edu
Table 1. Metal Complexes Tested for Dual System
In many ways, medicinal chemistry has entered the “age of fluorine”.
The number of drugs and drug candidates that contain fluorine has
increased exponentially over the past few years, making its installation
in a stereoselective (especially an enantioselective) manner of vital
importance to the synthetic chemist.1 Along these lines, several
impressive examples of catalytic, enantioselective fluorination have
recently appeared in which ꢀ-keto esters, imides, and aldehydes serve
as substrates to produce products in high enantioselectivity and yield.2
However, one very important complementary piece of the puzzle would
be an enantioselective R-fluorination of ketene enolates that could
produce simple, optically enriched R-fluorinated carboxylic acid
derivatives directly.3 In this Communication, we report a catalytic,
highly enantioselective R-fluorination of acid chlorides to produce
products of broad scope and in excellent yield. This new reaction
exploits a recently developed “dual activation” strategy from our
laboratories in which a chiral nucleophile is combined with a transition
metal-based Lewis acid cocatalyst to access metal-coordinated, chiral
ketene enolates.4 In this instance, these catalytically generated, dually
activated enolates are efficiently fluorinated with commercially avail-
able N-fluorodibenzenesulfonimide (NFSi)5 to produce configuration-
ally stable R-fluorinated carboxylic acid derivatives in high enantio-
meric excess (ee) (eq 1). The power of this new method is demonstrated
in the broad range of different derivatives that can be synthesized
depending on the work up conditions; fluorinated carboxylic acids,
amides, esters, and even peptides are all accessible depending on the
nucleophile employed to quench the reaction.
a Reactions run with 1 equiv acid chloride, base, NFSi, and catalysts:
10 mol % BQd, and 10 mol % metal complex, except where noted;
reactions quenched with methanol after
8
h; yield for pure
product. b Used 1 mol %. c Used 3 mol %.
base, 10 mol % benzoylquinidine (BQd), and 1 equiv NFSi in THF
at -78 °C (followed by a methanol quench)7 produces a modest
yield of the chiral, R-fluorinated methyl ester 2a, including 10 mol
% trans-(Ph3P)2PdCl2 as a cocatalyst dramatically increases the yield
of product 2a to 76% (98% ee). Isolation of the initially formed,
putative bis(sulfonimide) intermediate (5) is difficult owing to its
lability; this fact necessitated a quenching reaction that turned out
to be a blessing in disguise. A number of middle-transition series-
based cocatalysts were then screened, with the results summarized
in Table 1. For example, the metal-free reaction (entry 1) optimized
at 39% yield of 2a (97% ee).8 Wilkinson’s catalyst (entry 2)
produced a marginal increase, whereas (PPh3)2PtCl2 (entries 3 and
4) produces a notable increase in yield. Although the yields for the
metal screen vary, the ee’s for the test reaction stay consistently
high. trans-(PPh3)2PdCl2 (76%) and the chelating complex (dppp)-
NiCl29 (83%) performed the best, producing the desired product in
98% and 99% ee, entries 6 and 8, respectively.
Accordingly, both achiral Pd- and Ni-based phosphine complexes
were chosen (interchangeably) for further screening on a range of
acid chlorides, as presented in Table 2. Acid halides containing
aromatic as well as heterocyclic substituents proved to be good
substrates, producing products in very high ee and good to excellent
yields.10 Protected aminoalkyl-substituted acid chlorides also work
well, leading to R-fluorinated ꢀ-amino acid derivatives. Another
salient example is shown in the fluorination of readily available
acid chloride 3 to provide fluorinated product 4 (84% yield and
95% ee), a derivative of the anti-inflammatory drug indomethacin11
(eq 2). Other examples, such as the fluorination of an aldol adduct
to form 2l, show that the reaction is also compatible with
isomerizable carbon-carbon double bonds.
Our interest in catalytic, enantioselective halogenation extends
back over several years.6 We originally reported an enantioselective
chlorination and bromination of acid chlorides using cinchona
alkaloid derivatives as catalysts and polyhalogenated quinones as
mild sources of halogen in conjunction with a variety of stoichio-
metric bases. Unfortunately, we could never adequately extend this
method to an analogous enantioselective fluorination. At best, only
low yields of product were observedsthe ketene enolate nucleo-
philicity was seemingly never high enough to allow a smooth
reaction with standard fluorinating agents, including NFSi. We
returned to the challenge after a lengthy recess upon our discovery
that the reactivity of ketene enolates toward o-quinones in enan-
tioselective oxygenation reactions could be substantially enhanced
by the inclusion of a transition metal cocatalyst, namely
(Ph3P)2PdCl2.4 Extensive evidence showed that this metal species
binds to the ketene enolate oxygen, thereby enhancing both its
reactivity and chemoselectivity. Consequently, whereas the “metal-
free” reaction of p-methoxyphenylacetyl chloride (1a), Hu¨nig’s
Additionally, simply by modifying the quench conditions, an
array of chiral, R-fluorinated carboxylic acid derivatives can be
produced. Along with an alcohol quench that provides esters, a
water workup affords R-fluoro carboxylic acids, compounds that
should be of potentially broad utility. An amine-based workup
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17260 J. AM. CHEM. SOC. 2008, 130, 17260–17261
10.1021/ja807792c CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric, Bifunctional Catalytic R-Fluorination
Finally, one of the prime advantages of generating chiral,
R-fluorinated reactive intermediates “in a flask” is the ability to
quench them with drugs, natural products, and other exotic
nucleophiles to produce interesting and potentially useful deriva-
tives. For example, work up of a standard fluorination of 3-phthal-
imidopropionyl chloride (1b) with the antiprotozoal isoquinoline
alkaloid12 natural product (+)-emetine produces the diastereomeri-
cally pure fluorinated derivative 7 in 91% yield (eq 4).
Along these lines, one can imagine a wide range of fluorinated
intermediates coupled with a vast array of natural nucleophiles to
produce a virtually limitless number of derivatives. Future work
on enantioselective fluorination will concentrate on the synthesis
of other medicinally significant intermediates and on a detailed
mechanistic investigation of this new method.
Acknowledgment. T.L. thanks the NIH (Grant GM064559) and
the John Simon Guggenheim Memorial Foundation for support.
D.H.P. thanks Johns Hopkins for a Zeltmann Fellowship.
Supporting Information Available: Procedures and compound
characterization. This material is available free of charge via the Internet
at http://pubs.acs.org.
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a Reactions run with 1 equiv acid chloride, Hu¨nig’s base, NFSi, and
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nucleophile after 6-15 h; yield for pure product based on limiting
reagent. An excess of NuH was used except: b Run using 1.1 equiv
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affords amides; accordingly, thioesters can be readily accessed. In
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From a mechanistic standpoint, the absence of observable concen-
trations of free, protonated dibenzenesulfonimide during the course
of the reaction suggests that it indeed reacts to form intermediate 5.
This leads us to propose a mechanism (eq 3), which is also based on
our previous data on metal-bound zwitterionic ketene enolates.4
Fluorination of the dually activated enolate leads to an acyl ammonium
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(8) Screening of an early transition metal salt, Sc(OTf)3, produced only a
marginal increase in yield over the base reaction and lower ee (96%).
(9) “Dppp” is an abbreviation for 1,3-bis(diphenylphosphino)propane.
(10) Under standard reaction conditions, simple aliphatic acid halides react very
slowly; further studies are addressing this low reactivity.
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salt that reacts with the liberated dibenzenesulfonimide anion to form
the active amide intermediate 5. As established, this species effects a
transacylation with added nucleophiles to generate the final products
in high ee and excellent yields.
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