Catalytic asymmetric mono-fluorination of α-keto esters: Synthesis of optically active β-fluoro-α-hydroxy and β-fluoro-α-amino acid derivatives

Article abstract of DOI:10.1002/anie.201201303

Enantioselective mono-fluorination of α-keto esters was achieved using a mildly basic palladium μ-hydroxo complex as catalyst. Subsequent one-pot reduction afforded optically active β-fluoro-α-hydroxy esters. These compounds were then converted into β-fluoro-α-amino esters, which are potentially useful in medicinal chemistry research. Copyright

Full text of DOI:10.1002/anie.201201303

Angewandte
Chemie
DOI: 10.1002/anie.201201303
Organofluorine Chemistry
Catalytic Asymmetric Mono-Fluorination of a-Keto Esters: Synthesis
of Optically Active b-Fluoro-a-Hydroxy and b-Fluoro-a-Amino Acid
Derivatives**
Shoko Suzuki, Yuki Kitamura, Sylvain Lectard, Yoshitaka Hamashima, and Mikiko Sodeoka*
In the field of medicinal chemistry, it is widely recognized that
the replacement of a hydrogen atom or a hydroxy group with
a fluorine atom often improves the pharmacological activity
of the parent compound.[1] Although fluorine substitution on
aromatic rings is a common tactic, several drug candidates
with fluorine on a stereogenic carbon center have appeared in
recent years.[2] Consequently, the development of effective
methods for the preparation of optically active fluorinated
compounds is attracting considerable attention.[3] We and
others have already devised elegant systems for catalytic
asymmetric fluorination reactions of carbonyl compounds,
including b-keto esters,[4] b-keto phosphonates,[4c,5] a-cyano
phosphonates and a-cyano acetates,[6] oxindoles,[4d,7] acid
derivatives,[8] and aldehydes.[9]
Scheme 1. Enantioselective mono-fluorination of a-keto esters.
As an extension of our acid–base catalytic system using
late transition metal complexes, we recently reported the first
example of catalytic diastereo- and enantioselective conju-
gate addition of a-keto esters to nitroolefins.[10] Focusing on
a-keto esters as useful nucleophiles, we next became inter-
ested in asymmetric fluorination (Scheme 1). As the keto
group in the product provides a good handle for further
transformations, such reactions are expected to be useful for
producing medicinally important chiral building blocks.
Among them, b-fluoro-a-hydroxy and b-fluoro-a-amino
acid derivatives are potentially useful as synthons for obtain-
ing novel bioactive compounds[11] and may contribute to
pharmaceutical and chemical biology research. However, to
date there is no example of an asymmetric reaction to access
these compounds, because it has generally been believed that
the monofluorinated products would tend to undergo facile
OTf=trifluoromethanesulfonate.
enolization, resulting in the loss of optical purity.[12] Difluor-
inated compounds might also be formed, albeit with diffi-
culty.[13] Based on our previous results, we envisaged that the
use of mildly basic catalysts would permit the asymmetric
fluorination of a-keto esters.[10,14] Herein we report the first
example of highly enantioselective mono-fluorination of
a-keto esters catalyzed by Pd-m-hydroxo complexes 1. The
resulting fluorinated products were successfully converted
into chiral b-fluoro-a-hydroxy esters and b-fluoro-a-amino
esters. As there are few generally applicable methods for the
preparation of a substituted b-fluoro carboxylic acids,[15] the
present procedure is expected to be useful in medicinal
chemistry research.
Initially, we investigated the reaction of commercially
available ethyl ester 2a with N-fluorobenzenesulfonimide
(NFSI). Though our Pd-catalyzed fluorination reactions of
1,3-dicarbonyl compounds proceeded well in ethanol, no
reaction was observed with a-keto ester 2a in this solvent
(Table 1, entry 1). Careful solvent screening resulted in
identification of methyl tert-butyl ether (MTBE) and cyclo-
pentyl methyl ether (CPME) as the best solvents for the
reaction. The yields and enantioselectivities obtained in the
two solvents were comparable, but the fluorination reaction
at À208C reached completion in 12 h in CPME, while it
required 22 h in MTBE (Table 1, entries 8 and 9). Thus,
CPME became our solvent of choice.[16] As the corresponding
fluorinated a-keto ester 3a was readily converted into the
hydrate form during purification, the product was isolated
after in situ reduction with diisobutylaluminium hydride
(DIBAL-H). The low diastereoselectivity shown in Table 1
was later improved (see below). Furthermore, as the tert-butyl
[*] Dr. S. Suzuki, Dr. Y. Kitamura, Dr. S. Lectard, Dr. Y. Hamashima,
Prof. Dr. M. Sodeoka
RIKEN, Advanced Science Institute (ASI)
2-1, Hirosawa, Wako-shi, Saitama 351-0198 (Japan)
E-mail: sodeoka@riken.jp
Dr. Y. Hamashima
School of Pharmaceutical Science, University of Shizuoka
52-1 Yoda, Suruga-ku, Shizuoka 422-8526 (Japan)
[**] This work was supported in part by a Grant-in-Aid for Scientific
Research on a Priority Area (19028065, “Chemistry of Concert
Catalysis”) and by Project Funding for Basic Science from RIKEN.
We thank Dr. Daisuke Hashizume (RIKEN) for X-ray analyses of
compounds syn-4b, anti-4b, and syn-5b. We also thank the Takasago
International Corporation for providing chiral ligands and the
NIPPON ZEON Corporation for the generous gift of cyclopentyl
methyl ether.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201303.
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Table 1: Optimization of the reaction conditions.
Entry
2
Solvent
Pd cat. 1
t
[h]
Yield[a]
[%]
ee[b]
[%]
syn/anti[c]
Figure 1. X-ray structure determination of the relative and absolute
stereochemistry of fluorohydrins syn-4b and anti-4b. Ellipsoids set at
50% probability. Fluorine atoms are shown in yellow, oxygen atoms are
shown in red.
1
2
3
4
5
6
7
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
EtOH
Et2O
THF
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
72
4
1
12
2
6
–
–
–
63
92
75
73
67
80
81
86
85
87
85
79
44
36
50
53
62
73
84
85
90
89
92
94
1:3.0
1:2.6
1:2.7
1:2.8
1:2.6
1:3.2
1:3.2
1:3.1
1:2.8
1:3.0
1:3.2
1:3.2
toluene
MTBE
MTBE
MTBE
MTBE
CPME
CPME
CPME
CPME
CPME
1
8[d]
9[d]
10[d]
11[d,e]
12[d,f]
13[d,g]
22
12
16
20
22
36
[a] Combined yield of isolated product over two steps (major and minor
diasteromers). [b] The ee of the major anti diastereomer was determined
by HPLC analysis using a chiral stationary phase. [c] The diasteromeric
ratio was determined by 19F NMR and 1H NMR spectroscopy. [d] The
reaction was carried out at À208C. [e] 0.5m. [f] 0.2m. [g] 0.1m.
CPME=cyclopentyl methyl ether, DIBAL-H=diisobutylaluminium
hydride, MTBE=methyl tert-butyl ether, NFSI=N-fluorobenzenesulfo-
nimide.
Figure 2. Model for the palladium-catalyzed fluorination of a-keto
esters. NFSI=N-fluorobenzenesulfonimide.
would be located on one enolate face to avoid steric repulsion
with the neighboring equatorial 3,5-dimethylphenyl group of
the ligand. Hence, one of the enolate faces would be
effectively shielded by the other equatorial aryl group of
the ligand and the tert-butyl ester moiety. Consequently, NFSI
would preferentially approach from the less hindered re face
of the Pd–enolate.
Having established the optimum reaction conditions for
highly enantioselective fluorination and assigned the relative
and absolute configurations of syn-4b and anti-4b, we next
turned our attention to the diastereoselective reduction of the
remaining keto group to obtain chiral b-fluoro-a-hydroxy
esters[20] (Scheme 2). Various reducing agents, solvents, and
ester generally gave better enantioselectivity with bulkier
catalysts, a catalyst screening was carried out using a-keto
ester 2b as the substrate. In the presence of the palladium
catalyst 1b (2.5 mol%), the desired fluorohydrin 4a was
obtained in 86% yield with 85% ee (Table 1, entry 9). Among
the catalysts examined, 1c, which has (R)-DM-Segphos as
a chiral ligand,[17] was found to be the best. As shown in
entry 10, the desired fluorohydrin 4b was obtained with 90%
ee when the reaction was performed at À208C. In this
reaction, the undesired difluorinated compound was not
formed, whereas a small amount of the corresponding
difluorinated alcohol was isolated after reaction at room
temperature. Further optimization revealed that reducing the
concentration of the reaction mixture improved the enantio-
selectivity, albeit at the cost of longer reaction times. An
excellent enantioselectivity of 94% was achieved when the
reaction was conducted at 0.1m (Table 1, entry 13). Surpris-
ingly, the initial fluorinated a-keto ester product was stable
under the reaction conditions, and its racemization was
minimal.
A single recrystallization of syn-4b or anti-4b gave the
corresponding fluorohydrin with 99% ee. Moreover, crystals
suitable for X-ray structure determination were obtained, and
the relative and absolute configurations of syn-4b and anti-4b
were unequivocally elucidated (Figure 1).[18] It was thus
determined that syn-4b was obtained as the (2R,3R) enan-
tiomer and anti-4b was obtained as the (2S,3R) enantiomer.
The sense of enantioselection in the present fluorination
reaction can be explained by assuming the involvement of
a square-planar bidentate Pd–enolate structure, as depicted in
Figure 2.[19] In this case, the bulky tert-butyl ester moiety
Scheme 2. Stereoselective reduction to give b-fluoro-a-hydroxy esters.
CPME=cyclopentyl methyl ether, DIBAL-H=diisobutylaluminium hy-
dride, L-Selectride=lithium tri-sec-butylborohydride, NFSI=N-fluoro-
benzenesulfonimide.
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temperatures were examined. The reagent of choice to
produce the syn diastereomer was found to be lithium tri-
sec-butylborohydride (L-Selectride). Thus, after completion
of the initial fluorination reaction, the solvent was removed
under reduced pressure and the reduction was then carried
out in THF at À788C. The desired fluorohydrin syn-4b was
isolated in 89% yield (2 steps) with a 6.9:1 diastereomeric
ratio. On the other hand, reduction with DIBAL-H was anti-
selective, and the anti-4b diastereomer was obtained in 68%
yield with modest diastereoselectivity (1:3.2). To improve the
anti selectivity, we examined enzymatic reduction using
DAICEL Chiralscreen OH,[21] expecting that such a reduction
would be a good complement to the L-Selectride syn-
reduction. Among the enzymes examined, E007 was found
to give the anti product in good yield and with excellent
stereoselectivity (1: > 30 d.r.). It should be noted that these
reactions proceeded without detectable loss of enantioselec-
tivity.
synthesis of b-fluoro-a-amino acid derivatives such as 5b
remains largely unexplored and only a few examples have
been reported to date.[24] Therefore, we next focused on the
synthesis of b-fluoro-a-amino acids.
In light of the simplicity and selectivity observed during
the enzymatic reduction of the b-fluoro-a-keto ester 3b, we
examined the enzymatic reductive amination of 3b using
DAICEL Chiralscreen NH.[21] However, this proved unsuc-
cessful. Therefore, a step-by-step approach from fluorohydrin
4b was next investigated. Both diastereomers of 4b were first
converted into the corresponding triflates.[25] Nucleophilic
substitution with sodium azide, followed by palladium-
catalyzed reduction and in situ protection with tert-butoxy-
carbonyl (Boc) gave the desired protected b-fluoro-a-amino
esters 5b in good overall yield in three steps. It is noteworthy
that the three-step sequence could be performed without
purification of any of the intermediates (Scheme 3). Com-
To probe the generality of the reaction, various a-keto
ester substrates were examined (Table 2). In these reactions,
Table 2: Reaction scope.
Entry
R
2
t
[h]
Yield[a]
[%]
ee[b]
[%]
syn/anti[c]
Scheme 3. Synthesis of b-fluoro-a-amino esters. Boc=tert-butoxycar-
bonyl, DMAP=4-(dimethylamino)pyridine, Tf=trifluoromethanesul-
fonyl.
1[d]
2[e]
3[e]
4[e]
5[d]
6[e]
7[d,f]
Ph
2b
2c
2d
2e
2 f
36
36
30
24
24
34
36
89
83
75
68
69
65
66
94
91
94
95
95
83
83
6.9:1
4.6:1
4.7:1
6.5:1
7.6:1
4.2:1
1.4:1
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-Cl-C6H4
PhCH2
plete inversion of the a carbon was confirmed by an X-ray
structure analysis of racemic syn-5b.[18]
2g
2h
BnOCH2
In summary, we have developed the first example of the
catalytic enantioselective mono-fluorination of a-keto esters
using a chiral palladium m-hydroxo complex. Surprisingly,
racemization of the product was minimal under the optimized
reaction conditions. Further transformations afforded
b-fluoro-a-hydroxy esters 4 and b-fluoro-a-amino esters 5b
in good yields and with good to excellent stereoselectivities.
Moreover, all possible diastereomers were easily accessible
by slightly modifying the reaction conditions. These com-
pounds and their derivatives should be of interest in the field
of medicinal chemistry. Further studies to improve the
reaction efficiency and scope are underway in our laboratory.
[a] Combined yield of isolated product over two steps (major and minor
diasteromers). [b] The ee of the major syn diastereomer was determined
by HPLC analysis using a chiral stationary phase. [c] Diastereomeric ratio
of isolated compounds.[22] [d] CPME/THF=100:0. [e] CPME/THF=
95:5. [f] 0.2m. Bn=benzyl, CPME=cyclopentyl methyl ether,
L-Selectride=lithium tri-sec-butylborohydride, NFSI=N-fluorobenz-
enesulfonimide.
the products were isolated after reduction with L-Selectride
and both diastereomers were separated. For less soluble
substrates, the addition of a small amount of THF was
effective in accelerating the reaction. Substrates variously
substituted with methyl, ether, or halogen groups were all
available, and the reactions proceeded in a highly enantiose-
lective manner (Table 2, entries 1–5). Also, both a substrate
bearing a longer alkyl chain (2g) and a benzyloxy-substituted
compound (2h) underwent the fluorination–reduction
sequence, and the desired fluorohydrins were obtained with
acceptable enantioselectivities (Table 2, entries 6 and 7).
We considered that our catalytic asymmetric fluorination
reaction might provide a convenient entry to optically active
b-fluoro-a-amino acids, which have numerous applications
owing to their biological activity.[23] Nevertheless, the selective
Experimental Section
Palladium complex 1c (50 mg, 0.025 mmol, 2.5 mol%), a-keto ester
(1.00 mmol), and NFSI (473.0 mg, 1.50 mmol) were added to a dry
round-bottomed flask under argon and cooled to À208C. Freshly
distilled CPME (10 mL) was then added under argon. The reaction
mixture was stirred under argon for 36 h with the strict exclusion of
moisture. The resulting mixture was warmed to room temperature
and concentrated under reduced pressure. The residue was cooled to
À788C and dissolved in anhydrous THF (10 mL). L-Selectride (1m in
THF, 3.5 mL, 3.5 mmol) was added dropwise at À788C and the
reaction mixture was stirred at this temperature for 30 min. Then,
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30% aqueous H2O2 solution (5 mL) and aqueous NaOH solution
(3m, 5 mL) were added and the reaction mixture was slowly warmed
to room temperature. The resulting solution was extracted with ether
(3 ꢀ 25 mL). The organic layers were combined, washed with brine
(3 ꢀ 30 mL), filtered through a pad of Celite, dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash column
chromatography on silica gel using n-hexane/ethyl acetate (5:1) as the
eluent to give the desired fluorohydrin 4.
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Published online: March 30, 2012
Keywords: a-keto esters · asymmetric catalysis · fluorohydrins ·
.
fluorination · palladium
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[18] CCDC-863422 (racemic syn-5b), CCDC-863423 (syn-4b), and
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graphic data for this paper. These data can be obtained free of
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Angewandte
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