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Enantioselective -Fluorination of Carbonyl Compounds Organocatalysis or Metal Catalysis.

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DOI: 10.1002/anie.200502425
Enantioselective a-Fluorination of Carbonyl
Compounds: Organocatalysis or Metal Catalysis?
Petri M. Pihko*
aldehydes · asymmetric catalysis · electrophilic
substitution · fluorination · organocatalysis
luorine occupies a very special position in the periodic table. As the most
electronegative element, incorporation
of fluorine into organic molecules perturbs the electron density of the compound over several sigma bonds, affecting the pKa values of X H bonds over a
long range. In contrast to other carbon–
halogen bonds, the carbon–fluorine
bond is very strong and aliphatic fluorinated compounds are attacked by nucleophiles only with difficulty.[1] In medicinal chemistry applications, fluorinated compounds impart substantial metabolic stability to drug candidates.[2]
These highly advantageous effects associated with fluorine substitution have
motivated a truly intense effort into the
synthesis and characterization of novel
fluorine-containing compounds.
The level of synthetic control that is
required for the effective utilization of
fluorinated compounds presents serious
challenges. Successful fluorination reactions must be chemoselective and regioselective—not at all a trivial task given
the extremely high reactivity of elemental fluorine, and the fact that monofluorinated compounds are much more
easily deprotonated than the nonfluorinated starting materials! Furthermore,
introduction of fluorine in a diastereoand enantiocontrolled manner presents
enormous challenges, especially under
catalytic conditions. The catalyst must
be compatible with and stable in the
[*] Dr. P. M. Pihko
Laboratory of Organic Chemistry
Department of Chemical Technology
Helsinki University of Technology
02015 TKK (Finland)
Fax:(+358) 9-451-2538
presence of the fluorinating reagent, yet reactive
enough towards the starting material to facilitate
efficient catalysis. The
catalyst should also clearly differentiate between
the starting material and
the product; again this is
highly challenging given
the small size of fluorine
and its potential effects
on the reactivity of the
of enantioselective fluorination by
In spite of these chal- Scheme 2. Seminal example
lenges, several highly suc- Togni and Hintermann.
cessful strategies for catalytic
fluorination have been developed. The 2002, Sodeoka and co-workers disclosed
development of stable sources of elec- a highly practical method for enantiosetrophilic fluorine, selectfluor[3] and N- lective fluorination of b-ketoesters with
(NFSI),[4] NFSI.[7] Later, the groups of Togni,
have had a tremendous impact on the Cahard, and Shibata also extended the
development of fluorine chemistry range of useful metal–ligand combina(Scheme 1),[5] and they have facilitated tions to CuII– and NiII–bisoxazoline
complexes as well as RuII–complexes.[8]
These pioneering developments have
been elegantly summarized in the recent
review on asymmetric fluorination by
Ma and Cahard.[8d]
As an alternative to metal-based
catalysis, organocatalytic methods in
which the catalyst is devoid of metals
Scheme 1. Sources of electrophilic fluorine.
have enjoyed an explosive growth in
recent years. The first example of an
the first truly catalytic asymmetric fluo- organocatalytic fluorination process was
rination reactions. The first example of the phase-transfer-catalyzed fluorinaan enantioselective catalytic a-fluorina- tion reported by Kim and Park in 2002
tion was disclosed by Togni and Hinter- (Scheme 3).[9] This is, of course, not an
mann in 2000 (Scheme 2).[6] The taddol– entirely organo-mediated process since
titanium complex 4 effectively catalyzes a stoichiometric amount of metal carthe a-fluorination of b-ketoesters with bonate or hydroxide is used as the base.
33–90 % ee in the presence of selectfluor Independent work from the laboratories
as the source of electrophilic fluorine. In of Cahard and Shibata also identified
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 544 – 547
By the time the work
of Enders and H@ttl was
published, three more
organocatalytic enantioselective a-fluorination
reactions had been submitted for publication
and were released within a few weeks of each
other. In these papers,
the Jørgensen,[13] Barbas,[14] and MacMillan[15]
groups each describe
highly enantioselective
variants of organocataScheme 3. Enantioselective fluorination with a phase-transfer
lytic a-fluorinations of
aldehydes by using a
cinchona alkaloids and their derivatives amines or amine salts as catalysts
as viable reagents for enantioselective (Scheme 5).
fluorinations with selectfluor.[10] How-
Scheme 4. Organocatalytic fluorination study by Enders and H:ttl and examples of typical
catalysts used.[12]
ever, in these cases, an excess of the
alkaloid must be employed, and the Nfluoro species derived from the alkaloids have been identified as the true
fluorinating reagents.[11]
In March 2005, Enders and H@ttl
published the first example of a purely
organocatalytic fluorination process.[12]
In this study, proline and its derivatives
emerged as successful catalysts for the
a-fluorination of aldehydes and ketones
with selectfluor (Scheme 4). With aldehydes, the reaction times were as short
as 2.5 h; however, prolonged reaction
times were still required for ketones.
Unfortunately, the observed enantioselectivities were still very low, ranging
from 0 to 36 % ee with cyclohexanone as
the test substrate.
Angew. Chem. Int. Ed. 2006, 45, 544 – 547
In contrast to Enders and H@ttl, the
three groups reported success with NFSI
as the fluorine source. Barbas and coworkers point out that in the fluorination of 2-phenylpropionaldehyde, NFSI
gave significantly higher enantioselectivities than selectfluor, although both
were equally reactive. The success of
NFSI with aldehydes but not with ketones might, in part, be attributed to the
considerably higher reactivity of aldehydes under enamine catalysis.[16] Interestingly, Beeson and MacMillan document that acetone could even be used as
a solvent in the a-fluorination reaction
without detectable loss in efficiency.
Although all three studies recommend the use of NFSI, the optimized
conditions described by each of these
groups are quite different.[17] In agreement with Enders, both Jørgensen and
Barbas report that proline is an active
catalyst but affords the product with low
ee values only. The Jørgensen group has
developed a number of proline-based
organocatalysts for enamine and iminium catalysis.[18] Of these, the bulky
silylated prolinol derivative 14 emerged
as a highly active and enantioselective
catalyst (Scheme 5), with methyl tertbutyl ether (MTBE) as the solvent of
choice. In contrast, the Barbas group
finally converged on the use of the freebase form of the imidazolidinone 15 as
the catalyst. N,N-dimethylformamide
turned out to be the solvent of choice
since it greatly inhibited the formation
of the a,a-difluorinated product.
Scheme 5. Highly enantioselective organocatalytic a-fluorination of aldehydes from the groups
of Jørgensen,[13] Barbas,[14] and MacMillan.[15] Bn = benzyl; TMS = trimethylsilyl.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
By employing the dichloroacetic
acid salt 16 of the imidazolidinone,
MacMillan and co-workers were able
to develop a highly enantioselective afluorination protocol in which a mixture
of THF and 2-propanol was employed as
the reaction medium.[15] Notably, catalyst loadings as low as 2.5 mol % were
also feasible when the reaction was
performed at room temperature.
These organocatalytic a-fluorination
reactions were not limited to linear
aldehydes. Both Jørgensen and Barbas
also report the direct a-fluorination of
a-branched aldehydes, resulting in the
generation of fluorine-substituted quaternary stereogenic centers (Scheme 6).
Given the difficulties experience by
Enders and H@ttl with the enantioselective a-fluorination of ketones,[12] the
development of a highly enantioselective organocatalytic a-fluorination of
other carbonyl compounds still presents
a formidable challenge. In the case of
as 23 and 26. The catalyst loading could
be decreased to 2 mol % without loss of
yield or enantioselectivity.
What makes this catalyst system
highly remarkable is that it also provides
direct access to a-fluorinated oxindoles
such as 29 (Scheme 8). The fluorooxin-
Scheme 8. Catalytic enantioselective synthesis of MaxiPost (30; BMS-204352) by using the
Shibata/Toru fluorination protocol.[19] Boc = tert-butoxycarbonyl.
Scheme 6. Examples of organocatalytic enantioselective a-fluorinations of a-branched aldehydes from the Jørgensen and Barbas
groups.[13, 14] DMF = N,N-dimethylformamide;
TIPS = triisopropylsilyl.
readily enolizable substrates, a suitable
metal catalyst might, however, be able
to assist in enolization and promote a
highly enantioselective reaction provided that the appropriate ligand is chosen.
In June 2005, another success story
in enantioselective fluorination was
published: the Shibata and Toru groups,
working in collaboration with Kanemasa, disclosed a highly enantioselective
catalytic fluorination and chlorination
reaction protocol with the NiII–dfbox
catalyst system (Scheme 7).[19] Compared with previous results obtained
with simple bisoxazoline ligands, the
dbfox-Ph ligands turned out to be exceptionally enantioselective in the catalytic a-fluorination of b-ketoesters such
dole product was readily converted into
BMS-204352 (30), also known as MaxiPost, a potent opener of maxi-K channels.[20] The Shibata/Toru study represents the first catalytic enantioselective
route to this highly interesting drug
In summary, in a matter of three
months, five ground-breaking, highly
successful examples of catalytic enantioselective fluorination reactions appeared in the chemical literature. Of
course, there are still important gaps to
be filled by future studies, such as the
direct, highly enantioselective fluorination of ketones. Nevertheless, together
these studies illustrate very nicely both
the power of organocatalysis to promote
highly chemo- and enantioselective reactions with reactive aldehydes and the
ability of metal catalysts to promote
highly enantioselective reactions under
highly demanding circumstances.[21] The
story of catalytic enantioselective fluorinations, as it unfolded in mid-2005,
shows clearly how organocatalytic and
the metallocatalytic approaches are now
truly complementary.
Published online: December 21, 2005
Scheme 7. Examples of NiII–dbfox-catalyzed highly enantioselective a-fluorination reactions of
carbonyl compounds from the Shibata and Toru groups.[19] M.S. = molecular sieves.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
[1] For general overviews of fluorine
chemistry, see: a) M. Shimizu, T. Hiyama, Angew. Chem. 2005, 117, 218;
Angew. Chem. Int. Ed. 2005, 44, 214,
and references therein; b) P. Kirsch,
Modern Fluoroorganic Chemistry, WiAngew. Chem. Int. Ed. 2006, 45, 544 – 547
ley-VCH, Weinheim, 2004; c) B. E.
Smart, J. Fluorine Chem. 2001, 109, 3.
a) For an important early review on the
subject, see: J. T. Welch, Tetrahedron
1987, 43, 3123; b) Special Issue on
“Fluorine in the Life Sciences”, ChemBioChem 2004, 5, 557 – 726.
For a recent Review on selectfluor, see:
P. T. Nyffeler, S. G. DurNn, M. D. Burkart, S. P. Vincent, C.-H. Wong, Angew.
Chem. 2005, 117, 196; Angew. Chem. Int.
Ed. 2005, 44, 192.
E. Differding, H. Ofner, Synlett 1991,
For reviews of electrophilic fluorinating
agents, see: a) reference [1a]; b) K. Mikami, Y. Itoh, M. Yamanaka, Chem. Rev.
2004, 104, 1; c) G. S. Lal, G. P. Pez, R. G.
Syvret, Chem. Rev. 1996, 96, 1737;
d) J. A. Wilkinson, Chem. Rev. 1992,
92, 505.
L. Hintermann, A. Togni, Angew. Chem.
2000, 112, 4530; Angew. Chem. Int. Ed.
2000, 39, 4359.
Y. Hamashima, K. Yagi, H. Takano, L.
Tamas, M. Sodeoka, J. Am. Chem. Soc.
2002, 124, 14 530.
a) Cu: J.-A. Ma, D. Cahard, Tetrahedron: Asymmetry 2004, 15, 1007; b) Cu
and Ni: N. Shibata, T. Ishimaru, T.
Nagai, J. Kohno, T. Toru, Synlett 2004,
1703; c) The work of Togni, Mezzetti,
and co-workers on RuII complexes in
enantioselective fluorination has been
described in a recent review: H. Ibrahim,
A. Togni, Chem. Commun. 2004, 1147;
d) for an informative and up-to-date
review on the development of enantioselective fluorination reactions, see: J.A. Ma, D. Cahard, Chem. Rev. 2004, 104,
6119; e) for previous highlights on ahalogenation reactions, see: S. France,
Angew. Chem. Int. Ed. 2006, 45, 544 – 547
A. Weatherwax, T. Lectka, Eur. J. Org.
Chem. 2005, 475; f) M. Oestreich, Angew. Chem. 2005, 117, 2376; Angew.
Chem. Int. Ed. 2005, 44, 2324.
D. Y. Kim, E. J. Park, Org. Lett. 2002, 4,
a) D. Cahard, C. Audouard, J.-C. Plaquevent, N. Roques, Org. Lett. 2000, 2,
3699; b) N. Shibata, E. Suzuki, Y. Takeuchi, J. Am. Chem. Soc. 2000, 122,
10 728; c) N. Shibata, E. Suzuki, T.
Asahi, M. Shiro, J. Am. Chem. Soc.
2001, 123, 7001.
The cinchona alkaloid mediated enantioselective fluorination can be equally
well performed with N-fluoro cinchona
alkaloid (Shibata et al.) or with the
isolated N-fluoroammonium salts (Cahard et al.) generated in situ. For highly
informative discussions, see reference [8d].
D. Enders, M. R. M. H@ttl, Synlett 2005,
M. Marigo, D. Fielenbach, A. Braunton,
A. Kjærsgaard, K. A. Jørgensen, Angew.
Chem. 2005, 117, 3769; Angew. Chem.
Int. Ed. 2005, 44, 3703.
D. D. Steiner, N. Mase, C. F. Barbas III,
Angew. Chem. 2005, 117, 3772; Angew.
Chem. Int. Ed. 2005, 44, 3706.
T. D. Beeson, D. W. C. MacMillan, J.
Am. Chem. Soc. 2005, 127, 8826.
The higher reactivity of aldehydes over
ketones in enamine catalysis has been
documented in aldol, a-amination, and
a-oxygenation processes: P. I. Dalko, L.
Moisan, Angew. Chem. 2004, 116, 5248;
Angew. Chem. Int. Ed. 2004, 43, 5138.
With the exception of the study by
Barbas and co-workers, all a-fluoroaldehydes were immediately reduced to
the corresponding a-fluoroalcohols 13
owing to the instability and volatility of
the aldehyde products; see: F. A. Davis,
P. V. N. Kasu, G. Sundarababu, H. Qi, J.
Org. Chem. 1997, 62, 7546.
For examples, see: M. Marigo, T. C.
Wabnitz, D. Fielenbach, K. A. Jørgensen, Angew. Chem. 2005, 117, 804;
Angew. Chem. Int. Ed. 2005, 44, 794.
N. Shibata, J. Kohno, K. Takai, T.
Ishimaru, S. Nakamura, T. Toru, S.
Kanemasa, Angew. Chem. 2005, 117,
4276; Angew. Chem. Int. Ed. 2005, 44,
Development of MaxiPost: V. K. Gribkoff, D. J. Post-Munson, S. W. Yeola,
C. G.
WO0230868, 2002 [Chem. Abstr. 2002,
136, 319398].
A direct comparison of metal catalysts
and organocatalysts is provided by the
recently published studies on the aamination of b-ketoesters. The a-amination products can be obtained in up to
90 % ee by using cinchona alkaloids as
catalysts: a) S. Saaby, M. Bella, K. A.
Jørgensen, J. Am. Chem. Soc. 2004, 126,
8120; b) P. M. Pihko, A. Pohjakallio,
Synlett 2004, 2115; in contrast, the
CuII–bisoxazoline complexes afford the
a-amination products in outstanding
enantioselectivity (up to 99 % ee in
many cases): c) M. Marigo, K. Juhl,
K. A. Jørgensen, Angew. Chem. 2003,
115, 1405; Angew. Chem. Int. Ed. 2003,
42, 1367; clearly, other factors such as
chemoselectivity, reaction rate, ease of
operation, and cost of the catalyst are
also issues that need to be taken into
account in selecting the asymmetric
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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carbonyl, compounds, metali, catalysing, fluorination, organocatalytic, enantioselectivity
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