Enantioselective synthesis of 2,2-difluoro-3-hydroxycarboxylates by rhodium-catalyzed hydrogenation

Article abstract of DOI:10.1016/S0040-4039(00)01744-5

The highly enantioselective synthesis of 2,2-difluoro-3-hydroxycarboxylates has been achieved by hydrogenating 2,2-difluoro-3-oxocarboxylates in the presence of chiral rhodium-(amidephosphine-phosphinite) complexes. Ethyl 4,4,4-trifluoroacetoacetate can be successfully transformed into the enantiomerically enriched 4,4,4-trifluoro-3-hydroxybutanoate in the same manner. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01744-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9853–9858
Enantioselective synthesis of
2,2-difluoro-3-hydroxycarboxylates by rhodium-catalyzed
hydrogenation
Yoshichika Kuroki, Daisuke Asada and Katsuhiko Iseki*
Chemical Division, Daikin Industries, Ltd., Miyukigaoka, Tsukuba, Ibaraki 305-0841, Japan
Received 21 August 2000; revised 18 September 2000; accepted 29 September 2000
Abstract
The highly enantioselective synthesis of 2,2-difluoro-3-hydroxycarboxylates has been achieved by
hydrogenating 2,2-difluoro-3-oxocarboxylates in the presence of chiral rhodium-(amidephosphine-phos-
phinite) complexes. Ethyl 4,4,4-trifluoroacetoacetate can be successfully transformed into the enantiomer-
ically enriched 4,4,4-trifluoro-3-hydroxybutanoate in the same manner. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: asymmetric synthesis; catalysts; fluorine and compounds; hydrogenation.
The catalytic asymmetric synthesis of chiral fluoroorganic compounds has played an impor-
tant role in the development of medicines and materials based on the influence of fluorine’s
unique properties.1 Fluorine, due to its high electronegativity, has a considerable electronic
effect on its neighboring groups in a molecule. The introduction of a difluoromethylene residue
into bioactive peptides has led to the discovery of potent protease inhibitors mimicking the
transition state for hydrolytic amide bond cleavage,2 and optically active 2,2-difluoro-3-hydroxy-
carboxylates are versatile intermediates for the synthesis of these fluorinated peptides. We have
previously reported the enantioselective aldol reaction of a difluoroketene silyl acetal catalyzed
by chiral Lewis acids to provide 2,2-difluoro-3-hydroxycarboxylates with high enantiomeric
excesses.3 However, this transformation has a drawback such that the decrease in the amount of
the catalyst to less than 20 mol% dramatically suppresses the enantioselectivity. This paper
discloses herein the catalytic asymmetric hydrogenation of 2,2-difluoro-3-oxocarboxylates (1)
catalyzed by less than 1 mol% chiral rhodium-(amidephosphine-phosphinite) complexes to
provide the corresponding 2,2-difluoro-3-hydroxycarboxylates (2) with high enantioselectivity.
* Corresponding author. Tel: +00 81 298 58 5060; fax: +00 81 298 5082; e-mail: katsuhiko.iseki@daikin.co.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01744-5

9854
The b-keto ester 1 was prepared using the method developed by Hosomi and collaborators.4
Difluoroketene silyl acetal 3 was treated with acyl halide in the presence of CuCl in 1,3-
dimethyl-2-imidazolidinone (DMI) at 50°C for 30 min to give the b-keto ester 1 in a yield that
ranged between 54 and 90% (Scheme 1).
O
O
F
OSiMe3
CuCl (1.11 equiv.)
DMI, 50 °C, 30 min
+
RCOCl
R
OEt
F
OEt
F
F
54-90% yield
3 (1.11 equiv.)
1
Scheme 1. Preparation of ethyl 2,2-difluoro-3-oxocarboxylate (1)
First, the asymmetric hydrogenation reactions of ethyl 3-cyclohexyl-2,2-difluoro-3-oxo-
propanoate (1a) and ethyl 2,2-difluoro-3-oxododecanoate (1b), chosen as the model substrates,
were carried out using chiral ruthenium and rhodium complexes in order to examine their ability
as chiral catalysts (Table 1). A variety of efficient homogeneous transition metal catalysts have
been developed for the enantioselective hydrogenation of b-keto esters,5 and halogen-containing
BINAP-Ru(II) complexes are the most useful catalysts for various b-keto esters.6 However, the
hydrogenation of the b-keto ester 1a using a 0.1 mol% RuBr2((R)-binap) (4)7 in EtOH under 100
atm H2 at 100°C for 24 h afforded ethyl (R)-3-cyclohexyl-2,2-difluoro-3-hydroxypropanoate (2a)
with only 77% ee (entry 1). A 1.0 mol% cationic ruthenium catalyst, [RuCl((R)-biphemp)(p-
cymene)]Cl (5),8 also gave an unsatisfactory enantioselection during the hydrogenation of the
b-keto ester 1b under similar conditions (entry 2, 81% ee).9,10 A series of amidephosphine-phos-
phinites derived from homochiral 5-(hydroxymethyl)-2-pyrrolidinone have shown to be highly
effective ligands for the rhodium-catalyzed enantioselective hydrogenation reactions of 2-oxo-
3,3-dimethyl-g-butyrolactone and a-keto amides.11 We have found that the rhodium-
(amidephosphine-phosphinite) catalysts give the b-hydroxy ester 2 with high enantioselectivity
during the hydrogenation of the b-keto ester 1.12 The hydrogenation of 1a using 0.5 mol%
[Rh((S)-Cy,Cy-oxoProNOP)OCOCF3]2 (6)11c was conducted in toluene under 20 atm H2 at 70°C
for 20 h to afford the (R)-b-hydroxy ester 2a in 94% ee and 81% yield (entry 3). The use of 0.1
mol% [Rh((S)-Cp,Cp-oxoProNOP)OCOCF3]2 (7)11c under the same conditions improved the
hydrogenation rate without decreasing the enantioselectivity (entry 4, 99% yield and 94% ee).
The reaction of 1b using 0.1 mol% of catalyst 6 was carried out under 20 atm H2 at 30°C for
20 h to provide ethyl (R)-2,2-difluoro-3-hydroxydodecanoate (2b) with 97% ee in 98% yield
(entry 5). The use of 0.5 mol% [Rh((S)-Cy,Cy-oxoProNOP)Cl]2 (8) in which the trifluoroacetoxy
moiety of catalyst 6 was replaced with a chloride suppressed both the chemical and optical yields
(entry 6, 43% yield and 90% ee). Newly prepared catalysts, [Rh((S)-C7,C7-oxo-
ProNOP)OCOCF3]2 (9)13 and [Rh((S)-i-Pr,i-Pr-oxoProNOP)OCOCF3]2 (10),13 also gave excel-
lent optical yields although catalyst 9 showed a slightly lower chemical yield (entries 7 and 8).
Table 2 summarizes the results obtained from the hydrogenation of a variety of b-keto esters
1c–h using 0.5 mol% of catalyst 6 in toluene under 20 atm H2 at 30 or 70°C for 20 h. The
hydrogenation reaction of ethyl 2,2-difluoro-3-oxobutanoate (1c) proceeded smoothly at 30°C to
give the corresponding (R)-product 2c with 96% ee in 93% yield (entry 1). A b-keto ester having
a branched alkyl group R (1d) was hydrogenated using catalyst 4 at 70°C to afford the
(R)-product 2d with an enantiomeric excess of 92% in 95% yield (entry 2). Ethyl 2,2-difluoro-3-
oxo-3-phenylpropanoate (1e) gave a poor enantioselectivity (entry 3, 84% ee). The hydrogena-
tion of ethyl 2,2-difluoro-3-oxo-4-phenylbutanoate (1f) was carried out with an excellent level of

Table 1
Enantioselective hydrogenation reactions of ethyl 2,2-difluoro-3-oxocarboxylates (1a and 1b) in the presence of chiral ruthenium and rhodium
complexes
Entry
b-Keto ester 1
Catalysta (mol%)
H2 (atm)
Solvent
Temp. (°C)
Time (h)
Product 2
R
Yield (%)b
ee (%)c (config.)d
1
2
3
4
5
6
7
8
c-C6H11
CH3(CH2)8
c-C6H11
(1a)
(1b)
(1a)
(1a)
(1b)
(1b)
(1b)
(1b)
4 (0.1)
5 (1.0)
6 (0.5)
7 (0.1)
6 (0.1)
8 (0.5)
9 (0.1)
10 (0.1)
100
100
20
20
20
50
10
10
EtOH
EtOH
100
100
70
70
30
30
30
30
24
5
96
100
81
99
98
43
80
99
77 (R) (2a)
81 (R) (2b)
94 (R) (2a)
94 (R) (2a)
97 (R) (2b)
90 (R) (2b)
96 (R) (2b)
97 (R) (2b)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
20
20
20
18
20
20
c-C6H11
CH3(CH2)8
CH3(CH2)8
CH3(CH2)8
CH3(CH2)8
a 4: RuBr2[(R)-binap], 5: [RuCl((R)-biphemp)(p-cymene)]Cl, 6: [Rh((S)-Cy,Cy-oxoProNOP)OCOCF3]2, 7: [Rh((S)-Cp,Cp-oxoProNOP)OCOCF3]2,
8: [Rh((S)-Cy,Cy-oxoProNOP)Cl]2, 9: [Rh((S)-C7,C7-oxoProNOP)OCOCF3]2, 10: [Rh((S)-i-Pr,i-Pr-oxoProNOP)OCOCF3]2.
b Isolated yield.
c Determined by HPLC using a chiral column (CHIRALCEL® OD-H, Daicel Chemical Industries, Ltd.).
d The absolute configuration was assigned using the modified Mosher method. See reference 14.

9856
Table 2
Enantioselective hydrogenation of various b-keto esters 1c–h catalyzed by chiral rhodium complex 6
Entry
b-Keto ester 1
Temp. (°C)
Product 2
Ee (%)b (config.)
R
Yield (%)a
1
2
3
4
5
6
CH3
(CH3)2CHCH2
Ph
PhCH2
PhCH2CH2
PhCH2OCH2
(1c)
(1d)
(1e)
(1f)
(1g)
(1h)
30
70
30
30
30
30
93
95
97
63
100
95
96 (R)c (2c)
92 (R)c (2d)
84 (R)d (2e)
94 (R)c (2f)
96 (R)c (2g)
95 (R)c (2h)
a Isolated yield.
b Determined by HPLC using a chiral column (CHIRALCEL® OD-H or OB-H, Daicel Chemical Industries, Ltd.).
c The absolute configuration was assigned using the modified Mosher method. See reference 14.
d The b-hydroxy ester 2e was shown to have the (R)-configuration by conversion to the known corresponding
methyl ester. See reference 15.
enantioselectivity although the chemical yield was not very good (entry 4, 94% ee and 63%
yield). Two b-keto esters, 1g and 1h, bearing a phenyl moiety, were hydrogenated at 30°C and
gave the corresponding products in excellent chemical and optical yields (entries 5 and 6). In all
cases, the rhodium-((S)-amidephosphine-phosphinite) complexes gave predominantly the (R)-
enantiomers (Table 1, entries 3–8 and Table 2).
Finally, the asymmetric hydrogenation of ethyl 4,4,4-trifluoroacetoacetate (11) using 0.5 mol%
of catalyst 6 was examined in toluene under 20 atm H2 at 70°C for 20 h, and ethyl
(R)-4,4,4-trifluoro-3-hydroxybutanoate (12) was obtained in 91% ee and 92% yield (Scheme 2).16
O
O
OH
O
[Rh((S)-Cy,Cy-oxoProNOP)(OCOCF3)]2 (6) (0.5 mol%)
(R)
F3C
OEt
F3C
OEt
H2 (20 atm), toluene, 70 °C, 20 h
12
11
92% yield, 91% ee
Scheme 2. Enantioselective hydrogenation of ethyl 4,4,4-trifluoroacetoacetate (11) catalyzed by 6
The enantioface differentiation cannot be simply explained by the coordination of the
rhodium atom with two carbonyl oxygens of the b-keto ester (1 and 11). Interestingly, the
2,2-difluoro-3-oxocarboxylate 1 is hydrogenated on the under surface (a-side), while the reaction
of the 4,4,4-trifluoroacetoacetate 11 occurs on the upper surface (b-side), suggesting that the
fluorine atoms exert a pronounced influence on the enantiotopic face selection (Fig. 1).17
In conclusion, we have described the highly enantioselective hydrogenation of 2,2-difluoro-3-
oxocarboxylates mediated by chiral rhodium-(amidephosphine-phosphinite) catalysts. Ethyl
4,4,4-trifluoro-3-hydroxybutanoate of 91% ee was obtained from the 4,4,4-trifluoroacetoacetate
in the same manner. The origin of the enantiofacial selection and application of this method to
the synthesis of versatile chiral fluorinated molecules is currently under investigation.

9857
[H]
O
O
F
O
O
F
F
R
OEt
OEt
F
H H
F
[H]
Figure 1. Stereochemical course of the hydrogenation catalyzed by 6
General procedure for the 2,2-difluoro-3-hydroxycarboxylates. Toluene was distilled from
sodium ketyl. A solution of [Rh(COD)OCOCF3]2 (6.5 mg, 0.01 mmol) and (S)-Cy,Cy-oxo-
ProNOP (11.2 mg, 0.022 mmol) in toluene (1 mL) was stirred for 15 min in a glove box. The
resulting catalyst solution (150 mL) was transferred to a 100 mL stainless steel autoclave. A
solution of the 2,2-difluoro-3-hydroxycarboxylate (3.0 mmol) in toluene (4 mL) was transferred
to the autoclave, hydrogen (20 atm) was introduced, and the reaction mixture was stirred
magnetically at 30 or 70°C. After the desired reaction time, hydrogen was removed and the
solution was concentrated in vacuo. The crude residue was analyzed by GLC and chro-
matographed to furnish the hydrogenation product.
References
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temperature for 13 h to give ethyl 2-benzoylbutanoate in 88% yield. See: Ito, H.; Ishizuka, T.; Tateiwa, J.;
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7. The ruthenium catalyst 4 was prepared from Ru(OAc)2((R)-binap) and HBr according to the procedure given for
RuCl2((R)-binap). See reference 6a.
8. The ruthenium catalyst 5 was prepared using (R)-BIPHEMP (Schmid, R.; Cereghetti, M.; Heiser, B.; Scho¨n-
holzer, P.; Hansen, H.-J. Helv. Chim. Acta 1988, 71, 897–929) according to the procedure given for [RuCl((R)-

9858
binap)(p-cymene)]Cl. See: Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.; Kumobayashi, H.;
Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya, H. J. Org. Chem. 1994, 59, 3064–3076.
9. Ruthenium complexes bearing BIPHEMP are also good catalysts for the asymmetric hydrogenation of b-keto
esters. See: Heiser, B.; Broger, E. A.; Crameri, Y. Tetrahedron: Asymmetry 1991, 2, 51–62.
10. Recently, Geneˆt et al. reported the asymmetric hydrogenation of fluorinated b-keto esters using 1 mol%
ruthenium(II) complexes having chiral diphosphines such as BINAP and MeO-BIPHEP. Methyl 2,2-difluoro-3-
oxopentanoate was hydrogenated in MeOH under 20 bar H2 at 99°C to give the corresponding b-hydroxy ester
with >95% ee. See: Blanc, D.; Ratovelomanana-Vidal, V.; Gillet, J.-P.; Geneˆt, J.-P. J. Organomet. Chem. 2000,
603, 128–130.
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12. However, these catalysts are not useful for the hydrogenation of b-keto esters other than 1. The hydrogenation
of ethyl 3-oxohexanoate using 0.5 mol% [Rh((S)-Cy,Cy-oxoProNOP)OCOCF3]2 (6) was conducted in toluene
under 20 atm H2 at 30°C for 20 h to give the corresponding b-hydroxy ester with 32% ee in 47% yield. The
hydrogenation of methyl 3-oxo-2,2-dimethylbutanoate under the same conditions gave the product with 12% ee
and only a 2% yield.
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given for 6–8. See reference 11c.
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19–23. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096.
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16. The absolute configuration was assigned by comparing the sign of the optical rotations with literature data. See:
Seebach, D.; Renaud, P.; Schweizer, W. B.; Zu¨ger, M. F.; Brienne, M.-J. Helv. Chim. Acta 1984, 67, 1843–1853.
17. The fluorine atom in 1 and 11 may make five-membered chelate rings with the rhodium atom to determine the
enantioface selection.
.