Asymmetric fluorination of β-keto esters catalyzed by chiral rare earth perfluorinated organophosphates

Article abstract of DOI:10.1016/j.tetasy.2005.12.029

Novel chiral rare earth metal complexes bearing perfluorinated binaphthyl phosphate ligand RE[(R)-F₈BNP]₃ (RE = rare earth; F₈BNP = 5,5′,6,6′,7,7′,8,8′-octafluoro-1,1′-binaph thyl-2,2′-diyl phosphate) have been synthesized

Full text of DOI:10.1016/j.tetasy.2005.12.029

Tetrahedron: Asymmetry 17 (2006) 504–507
Asymmetric fluorination of b-keto esters catalyzed by chiral
rare earth perfluorinated organophosphates
Shoko Suzuki,a Hiroshi Furuno,b Yasuo Yokoyamac and Junji Inanagab,*
aDepartment of Molecular Chemistry, Graduate School of Sciences, Kyushu University, Hakozaki,
Higashi-ku, Fukuoka 812-8581, Japan
bInstitute for Materials Chemistry and Engineering (IMCE), Kyushu University, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
cDepartment of Chemistry, Faculty of Science and Technology, Sophia University, Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
Received 16 November 2005; accepted 10 December 2005
Available online 20 February 2006
Abstract—Novel chiral rare earth metal complexes bearing perfluorinated binaphthyl phosphate ligand RE[(R)-F8BNP]3 (RE = rare
earth; F8BNP = 5,50,6,60,7,70,8,80-octafluoro-1,10-binaphthyl-2,20-diyl phosphate) have been synthesized and used as a catalyst for
the asymmetric electrophilic fluorination reaction of b-keto esters. The use of Sc[(R)-F8BNP]3 catalyst in combination with 1-fluoro-
pyridinium triflate (NFPY–OTf) as a fluorinating agent was found to give the desired a-fluoro-b-keto esters in high chemical yields
and enantiomeric excesses (up to 88% ee) under mild conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
as the effective catalyst and the fluorinating agent,
respectively.4d In 2002, remarkable progress was
brought about by Sodeoka et al. They reported that
certain cationic Pd–BINAP complexes could work quite
effectively as a catalyst for the asymmetric fluorination
of various cyclic and acyclic b-keto esters with NFSI
to attain high enantioselectivities (up to 94% ee).4e
Furthermore, the fluorination system was successfully
applied to the reaction in ionic liquids, and the catalyst
could be reused 10 times without losing its high activ-
ity.4f More recently, some other useful methods using
NFSI in the presence of bis(oxazoline)–Cu(II) or –Ni(II)
catalysts have been reported.4g–j
Chiral fluoroorganic compounds have attracted much
attention in various fields such as biological, medicinal,
and materials chemistry.1 For example, such com-
pounds bearing fluorine atoms, in particular at stereo-
genic centers, have been effectively utilized in the
mechanistic study of enzymatic reactions and also in
the synthetic study of artificial medicines with some
special biological activities.2 Thus, the development of
efficient methods for the direct enantioselective
construction of fluorinated stereogenic carbon centers
has been strongly desired. Quite recently, some useful
catalytic methods using electrophilic fluorinating
reagents such as SelectfluorTM or N-fluorobenzenesulfon-
imide (NFSI) have been devised.3–7 The first successful
example of a catalytic asymmetric fluorination of b-keto
esters was reported by Hintermann and Togni in 2000.4a
They used sterically hindered esters as the substrates and
SelectfluorTM as a fluorinating reagent in the presence of
a chiral Lewis acid catalyst [TiCl2(TADDOLato)] to
obtain the a-fluorinated compounds with up to 90% ee
and high yields. Kim and Park also reported a successful
result (69% ee), in which the chinchonine-derived
quaternary ammonium salt and NFSI were employed
As described above, useful protocols for the catalytic
asymmetric a-fluorination of b-keto esters have rapidly
been accumulated. However, they have some drawbacks
including poor substrate-generality and the use of
expensive fluorinating reagents, thus, the development
of more general and practical methods is still desired.
In the present study, we examined the possibility of
some chiral rare earth complexes acting as a Lewis acid
catalyst for the enantioselective fluorination of b-keto
esters. Previously, we found that the chiral rare earth
organophosphates, RE[(R)-BNP]3, where RE = Sc or
Yb and BNP = 1,10-binaphthyl-2,20-diyl phosphate,
effectively act as a novel and storable chiral Lewis acid
catalyst for the hetero-Diels–Alder reaction of aldehydes
or a-keto esters with Danishefsky’s diene,8 and also for
*
Corresponding author. Tel.: +81 92 642 2733; fax: +81 92 642
2715; e-mail: inanaga@ms.ifoc.kyushu-u.ac.jp
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.029

S. Suzuki et al. / Tetrahedron: Asymmetry 17 (2006) 504–507
505
Table 1. Effect of the reaction conditions on the M[(R)-F8BNP]3-catalyzed asymmetric fluorinationa
O
O
10 mol% cat.
rt
CO2-t-Bu
CO2-t-Bu
+
Fluorinating reagent
*
F
4a
3a
R
Cl
PhSO2
PhSO2
N
N
NF
Fluorinating reagent:
2BF4
SelectfluorTM
Solvent
X
NFPY-OTf: R = H, X = TfO
NFPY-BF4: R = H, X = BF4
NFCO-OTf: R = Me, X = TfO
R
N
R
F
F
NFSI
F-source
NFSI
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
Sc[(R)-F8BNP]3
Sc[(R)-F8BNP]3
Sc[(R)-F8BNP]3
Sc[(R)-F8BNP]3
Sc[(R)-F8BNP]3
Sc[(R)-F8BNP]3
Sc[(R)-F8BNP]3
Sc[(R)-F8BNP]3
Sc[(R)-F8BNP]3
Sc[(R)-F8BNP]3
Sc[(R)-F8BNP]3
Sc[(R)-F8BNP]3
La[(R)-F8BNP]3
Gd[(R)-F8BNP]3
Yb[(R)-F8BNP]3
In[(R)-F8BNP]3
Sc[(R)-BNP]3
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
24
48
5
6
6
6
6
48
24
6
6
6
6
6
6
6
6
85
7
39 (ꢀ)
SelectfluorTM
NFPY–OTf
NFPY–OTf
NFPY–OTf
NFPY–OTf
NFPY–OTf
NFPY–OTf
NFPY–OTf
NFPY–OTf
NFPY–BF4
NFCO–OTf
NFPY–OTf
NFPY–OTf
NFPY–OTf
NFPY–OTf
NFPY–OTf
NDd
99
96
13
76
99
94
12
52
12
40
Trace
9
40 (ꢀ)
33 (ꢀ)
53 (ꢀ)
60 (ꢀ)
79 (ꢀ)
84 (ꢀ)
84 (ꢀ)
43 (ꢀ)
54 (ꢀ)
15 (ꢀ)
NDd
6
7
Et2O
Toluene
Toluene
Toluene
Hexane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
8e
9f
10
11
12
13
14
15
16
17
12 (+)
14 (+)
5 (+)
24
18
57
11 (+)
a The reactions were carried out by using 1.2 equiv of the fluorinating reagents in the presence of 10 mol % of the catalysts at room temperature unless
otherwise stated.
b Isolated yield.
c Enantiomer excess of 4a was determined by HPLC analysis [DAICEL CHIRALPAK AD-H, 2-propanol–hexane (1:100), 0.4 mL/min, 300 nm, tR
(major) = 21.2 min, tR (minor) = 25.9 min]. The sign of the optical rotation is shown in parentheses.
d Not determined.
e The reaction was carried out at 0 °C.
f The reaction was carried out at ꢀ20 °C.
the Michael addition reaction of O-alkylhydroxylamines
to a,b-unsaturated ketones.9 Subsequently, we first
examined the efficacy of the scandium catalyst Sc[(R)-
BNP]3 for the present fluorination reaction, however,
the reaction proceeded very slowly and the enantioselec-
tivity was low (e.g., see entry 17 in Table 1). To improve
this situation, we designed and prepared new chiral rare
earth octafluorobinaphthyl phosphates, RE[(R)-
F8BNP]3, which are expected to have stronger Lewis
acidity than the corresponding non-fluorinated complex
RE[(R)-BNP]3, because F8BINOL is reported to be
more acidic than BINOL (pK0a ¼ 9:28 for F8BINOL vs
10.28 for BINOL).10 We report here a new and econom-
ical method using Sc[(R)-F8BNP]3 catalyst and 1-fluoro-
pyridinium triflate (NFPY–OTf) for the enantioselective
fluorination of b-keto esters.
2. Results and discussion
Enantiopure (R)- and (S)-F8BINOL were synthe-
sized according to the literature with a slight modifica-
tion.10a The phosphorylation of (R)-F8BINOL using
phosphoryltrichloride and triethylamine in THF at
0 °C gave the corresponding chlorophosphate, which
was then hydrolyzed by water in the same flask to yield
the hydrogen phosphate (R)-F8BNP–H as a colorless
solid (Scheme 1). This compound was found to be more
soluble than the corresponding non-fluorinated deriva-
tive [(R)-BNP–H] in common organic solvents such as
THF, and it could be easily purified by recrystallization
from hexane–THF. The enantiopure (R)-F8BNP–H was
first treated with 2% aqueous Na2CO3 and the resulting
sodium salt was mixed with various trivalent metal
chlorides (MCl3; M = Sc, La, Gd, Yb, and In) in a 3:1
ratio and stirred at 60 °C in aqueous methanol for
19 h to yield the corresponding metal complexes M[(R)-
F8BNP]3 as white solids.11 They were collected by filtra-
tion, washed with water and aqueous MeOH, and then
dried at 100 °C under reduced pressure before use.
F
F
F
O
O
O
O
O
O
O
O
F
F
P
P
F
F
The effectiveness of these novel Lewis acid catalysts,
M[(R)-F8BNP]3, was checked by performing the
F
(R)-BNP
(R)-F8BNP

506
S. Suzuki et al. / Tetrahedron: Asymmetry 17 (2006) 504–507
Table 2. The Sc[(R)-F8BNP]3-catalyzed fluorination of various b-keto
estersa
F
F
F
F
F
F
O
O
O
O
OH
OH
O
O
O
a
NFPY-OTf (1.2 eq.)
F
F
F
F
P
R1
OR3
R1
OR3
O
*
OH
10 mol% Sc[(R)-F8BNP]3
toluene, rt
F R2
F
F
F
F
R2
3b-h
4b-h
F
F
O
(R)-F8BNP-H
(R)-F8BINOL
CO2R3
CO2R3
Ph
F
n
F
F
3b: n = 1, R3 = Me
3c: n = 1, R3 = Et
3d: n = 1, R3 = i-Pr
3e: n = 1, R3 = Bn
3f: n = 2, R3 = Me
3g: R3 = Me
O
O
O
3h: R3 = t-Bu
b
F
F
P
M
O
F
F
3
Entry
Substrate
Time (h)
Yieldb (%)
eec (%)
F
1
3b
3b
3c
3d
3e
3f
6
24
6
6
6
48
24
48
97
94
87
90
87
77
63
16
84 (ꢀ)
88 (ꢀ)
76 (ꢀ)
74 (ꢀ)
47 (ꢀ)
81 (ꢀ)
75 (+)
78 (+)
M[(R)-F8BNP]3 (M = Sc, La, Gd, Yb and In)
2d
3
Scheme 1. Reagents and conditions: (a) POCl3 (2 equiv), Et3N
(3 equiv), THF, 0 °C; H2O, 80%; (b) 2% Na2CO3 aq, MCl3ÆnH2O
(n = 4, 6, or 7) [(R)-F8BNP–Na/MCl3 = 3.5:1], MeOH/H2O, 60 °C.
4
5
6e
7
3g
3h
8
catalytic asymmetric fluorination of tert-butyl 2-oxo-
cyclopentanecarboxylate 3a with various fluorinating
reagents under various conditions. Some of the results
are summarized in Table 1. The reactions were carried
out by using 10 mol % M[(R)-F8BNP]3 and 1.2 equiv
of the fluorinating reagents at room temperature. The
fluorination using the Sc[(R)-F8BNP]3 catalyst and
NFSI in CH2Cl2 proceeded slowly to give, after 24 h,
the desired a-fluoro-b-keto ester 4a in 85% yield with
39% ee (entry 1). SelectfluorTM was found to be an
unsuitable fluorinating reagent for the present catalytic
reaction (entry 2). Fortunately, when NFPY–OTf was
used, the reaction proceeded rapidly and the product
was obtained in quantitative yield although the enantio-
selectivity was not satisfactory (entry 3). Screening of
the reaction conditions revealed that toluene is the sol-
vent of choice (entry 7) and when the Sc[(R)-F8BNP]3
catalyzed reaction was conducted at 0 °C, the desired
product was obtained in high enantioselectivity (84%
ee) and chemical yield (94%) (entry 8). The reaction per-
formed at ꢀ20 °C did not improve the enantioselectivity
(entry 9) and the use of other 1-fluoropyridinium salts
(NFPY–BF4 or NFCO–OTf) brought about unsatisfac-
tory results (entries 11 and 12). As seen in entries 13–16,
other metal complex catalysts were less effective than
Sc[(R)-F8BNP]3. The importance of the octafluorinated
BNP ligand (F8BNP) is apparent from the result of
the Sc[(R)-BNP]3 catalyzed reaction (entry 17).
a The reaction was carried out by using 1.2 equiv of 1-fluoropyridinium
triflate (NFPY–OTf) and 10 mol % of the catalyst in toluene at room
temperature unless otherwise stated.
b Isolated yield.
c Determined by HPLC analysis.
d The reaction was carried out in presence of 20 mol % of the catalyst
at 0 °C.
e The reaction was carried out at 0 °C.
94% yield when the reaction was carried out at 0 °C in
the presence of 20 mol % of the catalyst (entry 2). Simi-
larly, methyl 2-oxocyclohexanecarboxylate 3f could be
converted to the corresponding a-fluoro derivative with
high enantioselectivity (81% ee) in good yield (entry 6).
This is an advantageous point since, in existing methods,
bulky esters such as tert-butyl esters are often required
to realize such a high enantioselectivity. It is also
The optimized reaction conditions were applied to the
reactions of a variety of b-keto esters (Table 2).12 As
shown in entries 1–4, various 2-oxo-cyclopentanecarb-
oxylates 3b–d were successfully converted to the corre-
sponding a-fluoro-b-keto esters 4b–d in good yields
and high stereoselectivities except for the case of benzyl
ester 3e where unexpectedly low enantioselectivity was
observed (entry 5). It should be noted that the most
commonly used methyl ester 3b can be an effective sub-
strate, thus giving the desired product with 88% ee in
Figure 1. The time course of the yield and the enantiomeric excess of
the product (c.f. entry 7 in Table 1).

S. Suzuki et al. / Tetrahedron: Asymmetry 17 (2006) 504–507
507
4. (a) Hintermann, L.; Togni, A. Angew. Chem., Int. Ed.
2000, 39, 4359; (b) Piana, S.; Devillers, I.; Togni, A.;
Rothlisberger, U. Angew. Chem., Int. Ed. 2002, 41, 979; (c)
Frantz, R.; Hintermann, L.; Perseghini, M.; Broggini, D.;
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E. J. Org. Lett. 2002, 4, 545; (e) Hamashima, Y.; Yagi, K.;
important to note that the reactions of acyclic b-keto
esters 3g and 3h showed comparable enantioselectivities
to cyclic ones (entries 7 and 8).
In the present reaction, the production of pyridinium tri-
flate increases as the fluorination reaction proceeds.
Since contamination by the Brønsted acid-catalyzed
nonasymmetric process was feared, the time course of
the yield and the ee of the product was checked. As
shown in Figure 1, the observed ee values are almost
constant throughout the reaction suggesting that the
scandium complex is the only catalytically active species.
´
Takano, H.; Tamas, L.; Sodeoka, M. J. Am. Chem. Soc.
2002, 124, 14530; (f) Hamashima, Y.; Takano, H.; Hotta,
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A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007; (i)
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Synlett 2004, 1703; (j) Shibata, N.; Kohno, J.; Takai, K.;
Ishimaru, T.; Nakamura, S.; Toru, T.; Kanemasa, S.
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5. For the asymmetric fluorinations of aliphatic aldehydes,
see: (a) Marigo, M.; Fielenbach, D.; Braunton, A.;
Kjærsgaard, A.; Jørgensen, K. A. Angew. Chem., Int.
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3. Conclusion
A novel chiral rare earth perfluorinated binaphthyl
phosphate, Sc[(R)-F8BNP]3, catalyzed the a-fluorination
of either cyclic or acyclic b-keto esters with NFPY–OTf,
thus producing the fluorinated quaternary stereogenic
centers with high enantioselectivities (up to 88% ee).
To the best of our knowledge, this is the first successful
catalytic asymmetric fluorination using NFPY–OTf,
which is commercially available, inexpensive and easy
to handle. Thus, the protocol provides a new economical
route to the synthesis of optically active a-fluoro-b-keto
esters. The detailed mechanism of this reaction is now
under investigation.
6. For the asymmetric fluorinations of b-keto phosphonates,
see: (a) Bernardi, L.; Jørgensen, K. A. Chem. Commun.
2005, 1324; (b) Hamashima, Y.; Suzuki, T.; Shimura, Y.;
Shimizu, T.; Umebayashi, N.; Tamura, T.; Sasamoto, N.;
Sodeoka, M. Tetrahedron Lett. 2005, 46, 1447; (c) Kim, S.
M.; Kim, H. R.; Kim, D. Y. Org. Lett. 2005, 7, 2309.
7. (a) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.;
Sodeoka, M. J. Am. Chem. Soc. 2005, 127, 10164; (b) Kim,
H. R.; Kim, D. Y. Tetrahedron Lett. 2005, 46, 3115.
8. (a) Hanamoto, T.; Furuno, H.; Sugimoto, Y.; Inanaga, J.
Synlett 1997, 79; (b) Furuno, H.; Hanamoto, T.; Sugi-
moto, Y.; Inanaga, J. Org. Lett. 2000, 2, 49; (c) Furuno,
H.; Kambara, T.; Tanaka, Y.; Hanamoto, T.; Kagawa, T.;
Inanaga, J. Tetrahedron Lett. 2003, 44, 6129; (d) Hayano,
Acknowledgements
The present work was supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan and
Joint Project of Chemical Synthesis Core Research
Institutions.
ꢀ
T.; Sakaguchi, T.; Furuno, H.; Ohba, M.; Okawa, H.;
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Hayano, T.; Kambara, T.; Sugimoto, Y.; Hanamoto, T.;
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hedron 2003, 59, 10509.
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11. The complexes were isolated as the corresponding
hydrates. The detailed procedure and the physical data
will be reported elsewhere.
12. General procedure: To a suspension of Sc[(R)-F8BNP]3
(15.7 mg, 0.01 mmol) and NFPY–OTf (29.6 mg, 0.12
mmol) in toluene (1 mL) was added a b-keto ester (0.1
mmol) at room temperature. After being stirred for a
certain period of time, the whole mixture was passed
through a short column of silica gel and eluted with ether.
The eluate was then concentrated and purified by column
chromatography on silica gel.
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