An efficient enantioselective fluorination of various β-ketoesters catalyzed by chiral palladium complexes

Article abstract of DOI:10.1021/ja028464f

Reflecting the importance of fluorinated organic compounds in medicinal chemistry, development of an efficient method for catalytic enantioselective fluorination is increasingly desirable. Using a novel palladium complex 2 (1-2.5 mol %), various β-ketoest

Full text of DOI:10.1021/ja028464f

Published on Web 11/14/2002
An Efficient Enantioselective Fluorination of Various â-Ketoesters Catalyzed
by Chiral Palladium Complexes
Yoshitaka Hamashima, Kenji Yagi,1 Hisashi Takano, La´szlo´ Tama´s, and Mikiko Sodeoka*
Institute of Multidisciplinary Research for AdVanced Materials, Tohoku UniVersity, Katahira, Sendai,
Miyagi 980-8577, Japan, and PRESTO, Japan Science and Technology Corporation (JST)
Received September 9, 2002
Table 1. Optimization of the Reaction Conditions
Organic molecules containing fluorine atoms have attracted much
attention because they often show different characters from the
parent compounds due to the unique properties of the carbon-
fluorine bond.2 Replacement of hydrogen(s) or hydroxyl group(s)
in bioactive compounds with fluorine atom(s) is now a common
strategy in the field of medicinal chemistry.2 For this reason, an
efficient method for direct enantioselective construction of fluori-
nated stereogenic carbon centers is extremely important.3 Most
approaches so far have relied on the use of a stoichiometric amount
of chiral fluorinating reagents4 or chiral starting materials.5 Recently,
the first example of a catalytic asymmetric fluorination of â-keto-
esters was reported by Togni et al.6 They examined the reaction of
several substrates with a chiral Ti catalyst, and reported an excellent
enantioselectivity (90%), but only for one substrate having an
unusual ester group. Another example using chinchonine-derived
quaternary ammonium salts was reported by Kim and Park,7 but
the best selectivity obtained was 69% ee. Thus, a novel reaction
system affording satisfactory selectivity as well as versatility is still
required. Herein we wish to report a highly efficient catalytic
enantioselective fluorination reaction of various â-ketoesters using
chiral palladium complexes.
Optically active R-substituted R-fluorinated â-ketoesters are
attractive compounds, because they are regarded as nonenolizable
â-ketoesters. In fact, it is known that introduction of a fluorine atom
at the R-position of the â-ketoester unit of ketolides such as
telithromycin increases their antibiotic activity.8 In addition, since
ketone is easily converted to other functional groups, R-substituted
R-fluorinated â-ketoesters would be versatile synthetic precursors
of various R-fluorinated carboxylic acid derivatives. Thus, we
decided to focus on the enantioselective fluorination of â-ketoesters.
Recently we found that a chiral palladium enolate was formed
directly from â-ketoesters using palladium complexes 1 or 2, and
reacted with enone to give a highly optically active Michael
product.9
entry
catalyst (mol %)a
solvent
temp (°C)
time (h)
yield (%)
eeb (%)
1
2
3
4
5
6
1a (5)
1b (5)
1c (5)
2c (2.5)
2c (2.5)
2c (2.5)
THF
THF
THF
THF
acetone
EtOH
-20
-20
0
10
10
12
39
72
48
48
18
72
99
89
83
93
73
79
88
90
92
92
92
20
a Catalyst amount. b Determined by HPLC analysis.
3a with NFSI (1.5 equiv) proceeded smoothly with 5 mol % of 1a
in THF. The desired product was isolated in 72% yield and the ee
was determined to be 79% by HPLC (Table 1, entry 1). It should
be noted that the palladium complex retained its catalytic activity
until the completion of the reaction even though a sulfonimide
[(PhSO2)2NH] with high acidity was increasingly formed during
the reaction.
To improve the enantioselectivity, we examined a series of chiral
phosphine ligands.11 The substituents at the meta positions of the
aryl group on phosphine were found to be important. When (R)-
DM-BINAP and (R)-DTBM-SEGPHOS were used, the ee’s were
improved to 88 and 90%, respectively (entries 2, 3). In contrast to
the Michael reaction,12 the use of Pd µ-hydroxo complex 2c (2.5
mol %) also promoted the reaction smoothly and gave the best
selectivity (92% ee) (entry 4). This reactivity difference may be
attributed to the higher electrophilicity of NFSI than that of enone.
Further optimization of the reaction conditions revealed that the
reaction proceeded more rapidly in polar solvents (entries 5, 6).
The chemical yield was improved in acetone. Interestingly, EtOH
dramatically accelerated the reaction. The reaction was completed
within 18 h without any loss of enantioselectivity.
As summarized in Table 2, various substrates were fluorinated
smoothly using 2.5 mol % of catalyst.13 A five-membered ring
substrate 3a reacted similarly in i-PrOH and gave a better chemical
yield (90%) than that in EtOH (79%). Other cyclic compounds 3b
and 3c were converted into the desired products in 94 and 83% ee,
respectively (entries 2, 3). The reactions of acyclic substrates 3d,
3e, and 3f also afforded fluorinated products with excellent
enantioselectivity (91, 91, and 87% ee, respectively) (entries 4-6).
In entry 7, the amount of catalyst was reduced to 1 mol %, and
comparable results were obtained (82%, 91% ee). In addition, we
found that this reaction could be easily scaled up. A representative
example is as follows (entry 8). One gram of 3d (4.3 mmol) was
treated with NFSI in EtOH (reagent grade, not distilled) using 5
mol % of 1b (X ) TfO). The desired product 4d (1.1 g) was
obtained without any loss of reaction efficiency (48 h, 96%, 91%
On the basis of these results, we examined the reaction of tert-
butyl 2-oxo-cyclopentanecarboxylate 3a under various conditions,
and found that N-fluorobenzenesulfonimde (NFSI) was the most
effective among the fluorinating reagents tested.10 The reaction of
* To whom correspondence should be addressed. E-mail: sodeoka@
tagen.tohoku.ac.jp.
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J. AM. CHEM. SOC. 2002, 124, 14530-14531
10.1021/ja028464f CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Enantioselective Fluorination of â-Ketoesters
fluorinated compounds, and the availability of R-fluoro â-hydroxy-
or â-amino acid derivatives for drug design should be valuable in
medicinal studies. Further details and an extension of this work
will be reported in due course.
Acknowledgment. This work was supported in part by The
Sumitomo Foundation. We thank Dr. Takao Saito of Takasago
International Corporation for providing their chiral phosphine
ligands. We also thank Dr. Norio Shibata of Toyama Medical and
Pharmaceutical University for providing unpublished analytical data
for their fluorinated compound.
entry
ketoester
catalyst (X)
temp (°C)
time (h)
yield (%)
ee (%)
1a
2
3
4
5
3a
3b
3c
3d
3e
3f
2c (TfO)
2b (BF4)
2b (TfO)
2b (BF4)
2c (TfO)
2b (TfO)
2b (BF4)
1b (TfO)
20
-10
-20
20
20
20
18
20
36
40
72
42
20
48
90
91
85
92
49c
88
82
96
92
94
83b
91b
91
87
91
91
Supporting Information Available: Experimental details of the
determination of the absolute configuration of 4c and 4d, and the
transformation of 5 into 6 and 7, as well as spectroscopic characteriza-
tion of new compounds (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
6
7d
8e
3b
3d
0
20
a i-PrOH was used instead of EtOH. b The absolute configuration was
determined to be R after the conversion. c Lower yield due to the volatility
of 4e. d 2b (1 mol %) was used. 2.5 M 3b. e 1-g scale.
References
(1) Visiting Scientist from Takasago International Corporation. Address: 1-4-
11 Nishi-Yawata, Hiratsuka, Kanagawa 254-0073, Japan.
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C., Eds.; Organofluorine Chemistry: Principles and Commercial Ap-
plications; Plenum: New York, 1994.
Scheme 1. Conversion into â-Hydroxy and â-Amino Estersa
(3) (a) Ramachandran, P. V.; Ed. Asymmetric Fluoroorganic Chemistry:
Synthesis, Application, and Future Directions; ACS Symposium Series
746; American Chemical Society: Washington, DC, 2000. (b) Soloshonok,
V. A., Ed. Enantiocontrolled Synthesis of Fluoro-Organic Compounds.
Stereochemical Challenge and Biomedicinal Targets; Wiley: New York,
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(4) (a) Differding, E.; Lang, R. E. Tetrahedron Lett. 1988, 29, 6087-6090.
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2273-2280. (c) Liu, Z.; Shibata, N.; Takeuchi, Y. J. Org. Chem. 2000,
65, 7583-7587. (d) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am.
Chem. Soc. 2001, 123, 7001-7009. (e) Mohar, B.; Baudoux, J.; Plaque-
vent, J.-C.; Cahard, D. Angew. Chem., Int. Ed. 2001, 40, 4214-4216.
(5) (a) Iwaoka, T.; Murohashi, T.; Sato, M.; Kaneko, C. Tetrahedron
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Tetrahedron Lett. 1998, 39, 6135-6138. (c) Enders, D.; Faure, S.; Potthoff,
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a Conditions: a. PhMe2SiH (3.0), TBAF (2.0), DMF, 0 °C, 10 min, 83%
(dr ) >95/5); b. Ph3SiH (3.0), TFA, rt, 3 h, 75% (dr ) >95/5); c. Ph3P
(1.5), DEAD (1.5), DPPA (1.2), THF, rt, 2 h, 79% from syn-6, 73% from
anti-6; d. Pd/C, H2, (Boc)2O, MeOH, 1 h, 80% for anti-7, 57% for syn-7.
ee). In these reactions, we found that 2b and 2c were effective
catalysts, and various substrates were selectively fluorinated by
employing either of these two catalysts according to the nature of
the â-ketoester.
The absolute configurations of the products 4c and 4d were
determined to be R after conversion into a known compound.11 This
selectivity was in accord with the prediction based on the structure
of the square-planar chiral Pd enolate.9,11
Because â-hydroxy or â-amino acids are one of the fundamental
units in various natural or unnatural compounds, their R-fluorinated
derivatives are of particular interest.14 Therefore, we next turned
our attention to the transformation of the products (Scheme 1). We
found that the methyl ester 511 corresponding to 4d was converted
to both diastereomers of the R-fluoro â-hydroxy ester 6 in a highly
diastereoselective manner by simply changing the reducing condi-
tions.15 These compounds were subjected to azidation with inversion
of configuration. Reduction of the azide group, followed by
protection of the amino group, afforded the R-fluoro â-amino ester
7 in good yields.
In conclusion, we have developed a highly efficient catalytic
enantioselective fluorination of various â-keotesters with excellent
enantioselectivity (83-94% ee). It is environmentally advantageous
that this reaction proceeds well in alcoholic solvents, in particular,
EtOH, and is not sensitive to water. In addition, the transformation
of the product into both diastereomers of R-fluoro â-hydroxy- and
â-amino acid derivatives was successfully demonstrated. This report
provides a new method for the synthesis of optically active
(6) (a) Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39, 4359-
4362. (b) Piana, S.; Devillers, I.; Togni, A.; Rothlisberger, U. Angew.
Chem., Int. Ed. 2002, 41, 979-982.
(7) Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545-547.
(8) Denis, A.; Bretin, F.; Fromentin, C.; Bonnet, A.; Piltan, G.; Bonnefoy,
A.; Agouridas, C. Bio. Med. Chem. Lett. 2000, 10, 2019-2022.
(9) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
11240-11241.
(10) In contrast, no reaction was observed in THF using salt-type fluorine
sources such as Selectfluor and N-fluoro-4-methylpyridinium-2-sulfonate.
(11) See Supporting Information.
(12) In the case of the Michael reaction, no reaction occurred with Pd complex
2. The addition of TfOH, which promoted the reaction as an activator of
the enone, was necessary. See ref 9.
(13) General Procedure: To a solution of the chiral palladium complex 2 (5
µmol) in EtOH (0.2 mL) was added â-ketoester (0.2 mmol) at room
temperature. At the temperature indicated in Table 2, NFSI (95 mg, 0.3
mmol) was added, and the resulting suspension was stirred for the time
given in Table 2. After the completion of the reaction (TLC), saturated
NH4Cl was added for quenching. Extraction with Et2O, followed by flash
column chromatography on SiO2 (hexane/Et2O ) 10/1) gave the pure
product.
(14) Recently, the effects of the stereochemistry of the carbon-fluorine bond
on the biological activity of HIV protease inhibitor, indinavir, have been
described. See: (a) Myers, A. G.; Barbay, J. K.; Zhong, B. J. Am. Chem.
Soc. 2001, 123, 7207-7219. In addition, â-amino acids are reported to
show a unique protease-resistant character as components of peptidomi-
metics. The availability of R-fluorinated derivatives will facilitate studies
in this field. See: (b) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F.
Chem. ReV. 2001, 101, 3219-3232. (c) Gademann, K.; Ernst, M.; Hoyer,
D.; Seebach, D. Angew. Chem., Int. Ed. 1999, 38, 1223-1226.
(15) The relative configurations of products were tentatively assigned by
analogy with the results obtained in the literature. See: Kitazume, T.;
Kobayashi, T.; Yamamoto, T.; Yamazaki, T. J. Org. Chem. 1987, 52,
3218-3223.
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