Highly enantioselective hydrogenation of β-alkyl and β-(ω-chloroalkyl) substituted β-keto esters

Article abstract of DOI:10.1080/00397910701196538

Highly enantioselective hydrogenation of β-alkyl and β-(ω-chloroalkyl) substituted β-keto esters was achieved with Ru catalysts based on chiral diphosphines in EtOH at 50°C under 50-bar initial hydrogen pressure, affording the corresponding β-hydroxy esters in >98% ee. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701196538

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Highly Enantioselective Hydrogenation of
β‐Alkyl and β‐(ω‐Chloroalkyl) Substituted
β‐Keto Esters
Iyad Karamé a , Esen Bellur b , Sven Rotzoll a c , Peter Langer a c , Christine
Fischer a , Jens Holz a & Armin Börner a c
a Leibniz‐Institut für Katalyse an der Universität Rostock e.V. , Rostock,
Germany
b Institut für Biochemie, Universität Greifswald , Greifswald, Germany
c Institut für Chemie, Universität Rostock , Rostock, Germany
Published online: 13 Oct 2010.
To cite this article: Iyad Karamé , Esen Bellur , Sven Rotzoll , Peter Langer , Christine Fischer , Jens Holz
& Armin Börner (2007) Highly Enantioselective Hydrogenation of β‐Alkyl and β‐(ω‐Chloroalkyl) Substituted
β‐Keto Esters, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:7, 1067-1076, DOI: 10.1080/00397910701196538
To link to this article: http://dx.doi.org/10.1080/00397910701196538
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Synthetic Communicationsw, 37: 1067–1076, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701196538
Highly Enantioselective Hydrogenation
of b-Alkyl and b-(v-Chloroalkyl)
Substituted b-Keto Esters
´
Iyad Karame
¨
Leibniz-Institut fu¨r Katalyse an der Universitat Rostock e.V., Rostock,
Germany
Esen Bellur
¨
Institut fu¨r Biochemie, Universitat Greifswald, Greifswald, Germany
Sven Rotzoll and Peter Langer
¨
Leibniz-Institut fu¨r Katalyse an der Universitat Rostock e.V., Rostock,
¨
Germany and Institut fu¨r Chemie, Universitat Rostock, Rostock,
Germany
Christine Fischer and Jens Holz
¨
Leibniz-Institut fu¨r Katalyse an der Universitat Rostock e.V., Rostock,
Germany
¨
Armin Borner
Leibniz-Institut fu¨r Katalyse an der Universitat Rostock e.V., Rostock,
¨
Germany and Institut fu¨r Chemie, Universitat Rostock, Rostock,
Germany
¨
Abstract: Highly enantioselective hydrogenation of b-alkyl and b-(v-chloroalkyl)
substituted b-keto esters was achieved with Ru catalysts based on chiral diphosphines
Received in Poland August 23, 2006
¨
¨
Address correspondence to Armin Borner, Leibniz-Institut fur Katalyse an der Uni-
¨
versitat Rostock e.V., Albert Einstein Str. 29a, 18059, Rostock, Germany. E-mail:
armin.boerner@catalysis.de
1067

´
I. Karame et al.
1068
in EtOH at 508C under 50-bar initial hydrogen pressure, affording the corresponding
b-hydroxy esters in .98% ee.
Keywords: diphosphines, enantioselective hydrogenation, b-hydroxy esters, b-keto
esters, ruthenium
Chiral b-hydroxy esters are important building blocks for the synthesis of bio-
logically active compounds and natural products.[1] For example, (R)-3-hydro-
xytetradecanoic acid is the most common fatty acid constituent of the lipid A
component of bacterial lipopolysaccharides (LPS).[2] (R)-Ethyl 3-hydroxydo-
decanoate is an interesting intermediate for the synthesis of Arthrobacilin, a
cell-growth inhibitor.[3] (R)-Ethyl 6-chloro-3-hydroxy-hexanoate can be
converted into (R)-(þ)-a-lipoic acid, which is a cofactor in the biochemical
decarboxylation of a-keto acids and has also been reported to be a growth
factor for a variety of microorganisms.[4] Ethyl 7-chloro-3-hydroxyheptanoate
can be transformed into 7-amino-3-hydroxyheptanoic acid, used in the prep-
aration of spergualins, powerful antitumor agents.[5]
Catalytic asymmetric hydrogenation of b-keto esters is considered one of
the most efficient methods for the preparation of b-hydroxy esters and acids.[6]
Pioneering work came from Noyori et al., who showed that a Ru catalyst based
on BINAP as a chiral diphosphine ligand may be highly useful for the
reduction of b-keto esters.[7] Even ethyl g-chloroacetoacetate could be
reduced with this catalytic system. However, to obtain good enantioselectivity
(97% ee), the reduction had to be conducted at 1008C.[8] More recently, the
asymmetric hydrogenation of other b-alkyl and b-aryl substituted b-keto
ester was reported.[9] Zhang and coworkers could achieve high enantioselec-
tivities in the Ru-catalyzed hydrogenation of b-aryl substituted b-keto ester
and of ethyl 4-chloroacetoacetate with TangPHOS as a chiral ligand.[10]Inter-
estingly, homologues b-(v-chloroalkyl) substituted b-keto esters were not
used as prochiral substrates for the asymmetric reduction. One of the crucial
problems is the availability of the required prochiral substrates. These
b-keto esters are available by reaction of the dianion of ethyl acetoacetate
with alkyl iodides (Scheme 1).[11] Based on this methodology, a large set of
v-chloro-functionalized and nonfunctionalized b-keto esters bearing a long
alkyl chain could be prepared.
Scheme 1.

Hydrogenation of b-Keto Esters
1069
Herein, we report the highly enantioselective hydrogenation of these functio-
nalized ketones using Ru catalysts containing the diphosphines I–III as ligands.
BINAP and Tol-BINAP are commercially available at low prices. Ligand III can
be derived from an economically beneficial cross-self-breeding process.[12]
Resultant b-hydroxy esters have great synthetic potential. Those that
contain a chloro substituent may serve as intermediates for the synthesis of
chiral v-hydroxy acids, v-amino acids, and lactones.
Results of the enantioselective hydrogenation are summarized in Table 1.
Required precatalysts were prepared in situ by reaction of
[Ru(p-cymene)Cl2]2 with the chiral ligand in DMF prior to the catalytic
reaction. Hydrogenations of both b-alkyl and b-(v-chloroalkyl) substituted
b-keto ethyl esters 1 were performed under an initial hydrogen pressure of
50 bar at 508C in ethanol as solvent. Under these conditions, b-hydroxy
esters 2 were obtained with excellent enantioselectivities. The use of MeOH
as a solvent led to transesterification (Scheme 2).
Table 1. Enantioselective hydrogenation of 1a–f with Ru-diphosphine catalysts
Entry
Ligand
Substrate
Producta
Ee (%)b
Prod. conf.d
1
2
I (BINAP)
II (Tol-BINAP)
III
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1e
1e
1f
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
2f
98.1
98.7
89.0
98.1
98.5
86.0
98.0c
98.7
91.0
98.3c
98.6c
86.0c
98.0
98.4
91.0
98.6
98.7
91.0
(R)-(2)
(R)-(2)
(S)-(þ)
(R)-(2)
(R)-(2)
(S)-(þ)
(R)-(2)
(R)-(2)
(S)-(þ)
(2)
3
4
I (BINAP)
II (Tol-BINAP)
III
5
6
7
I (BINAP)
II (Tol-BINAP)
III
8
9
10
11
12
13
14
15
16
17
18
I (BINAP)
II (Tol-BINAP)
III
(2)
(þ)
I (BINAP)
II (Tol-BINAP)
III
(2)
(2)
(þ)
I (BINAP)
II (Tol-BINAP)
III
(2)
(2)
1f
2f
1f
2f
(þ)
aConditions: catalyst/substrate ratio ¼ 1/200; H2 (initial pressure 50 bar), 508C,
EtOH; complete conversion, products were isolated in quantitative yields.
bEnantiomeric excess was determined by 31P NMR after coupling with the chiral
phosphorus derivatizing agent 3 derived from (S)-BINOL.
cDetermined by chiral GC (Lipodex E column, 50 m).
dAbsolute configurations of 2a, 2b, and 2c were assigned by comparison of the sign
of the optical rotation with that of known alcohols.[13]

´
I. Karame et al.
1070
Scheme 2.
In all cases, enantioselectivities obtained with Ru-[(R)-TolBINAP] were
slightly superior to those obtained with Ru-[(R)-BINAP]. Interestingly, the use
of diphosphine III also gave good enantioselectivities (87–91% ee) (Scheme 3).
The use of the commercial Ru[(R)-BINAP]Cl2 gave the same results as
those obtained with a catalyst prepared in situ from (R)-BINAP and [Ru(p-
cymene)Cl2]2. In contrast to results reported in the asymmetric hydrogenation
of 4-chloroacetoacetate,[8] we did not observe any effect of the chloro substi-
tuent on the activity as well as on the enantioselectivity (Scheme 4).
The ee of the chiral products was determined by a method similar to that
reported by Tang et al.,[14] reaction of b-hydroxy esters with enantiopure chlor-
ophosphite 3 derived from (S)-BINOL and subsequent integration of the signals
in the 31P NMR spectrum. The derivatizing agent (31P NMR, d 179.2) reacted
immediately and quantitatively with alcohol 2 to give diastereomeric phosphites
4 and 40. The 31P NMR spectrum of both diastereomeric products is characterized
by signals separated at the base line (Table 2); therefore it was possible to
determine precisely the enantiomeric composition of the hydrogenation products.
Scheme 3.
Scheme 4.

Hydrogenation of b-Keto Esters
1071
Table 2. 31P NMR chemical shifts of 1:1 mixtures of diastereomeric phosphites 4 and 40
31P NMR chemical shifts
b-Hydroxy
ester 2
Entry
4
40
Dd (ppm)
Ratioa
1
2
3
4
5
2a
2b
2c
2e
2f
153.35
153.31
153.34
153.35
152.72
151.33
151.23
150.44
150.31
150.44
2.02
2.08
2.9
50.4/49.6
49.9/50.1
50.5/49.5
49.9/50.1
50.3/49.7
3.04
2.28
a31P NMR integral ratio of 4 and 40.
In summary, a highly enantioselective hydrogenation catalyzed by
Ru-BINAP, catalysts of b-alkyl and b-(v-chloroalkyl) substituted b-keto
ethylesters prepared by a unique method, afforded biologically interesting
b-hydroxy esters with high enantioselectivities.
EXPERIMENTAL
General Procedure of the Asymmetric Hydrogenation
A dry 20-mL Schlenk tube containing a Teflonw-coated stirring bar was
charged with [Ru(p-cymene)Cl2]2 (2 mg, 6.5 mmol), chiral diphosphine
ligand (6.75 mmol), and DMF (1 mL) under an argon atmosphere. The
resulting reddish brown suspension was heated at 1008C under argon for
15 min to give a clear reddish brown solution. DMF was removed under
vacuum at 50 8C; EtOH (3 or 4 mL) and b-keto ester (1.3 mmol) were
added. The resultant solution containing precatalyst and substrate was trans-
ferred with a syringe under argon inside an autoclave, which was charged
with hydrogen (50 bar). The reduction was performed under this pressure at
508C overnight. b-Hydroxy esters (yield .95%) were purified by silica-gel
column chromatography (n-heptane–AcOEt ¼ 80:20) and characterized by
NMR and HRMS. Enantiomeric excesses were determined by chiral
capillary GC (Lipodex E column, 50 m) or by 31P NMR analysis after
coupling with chiral chlorophosphite derived from BINOL.
Determination of Ee Based on 31P NMR
Preparation of chlorophosphite of (S)-BINOL was carried out according to
the protocol of Minnaard et al.[15] For example, a dry NMR analysis tube
was charged under argon with ethyl 3-hydroxytetradecanoate (20 mg,
0.073 mmol), (S)-BINOL-chlorophosphite (0.4 mL, 0.14 mmol) in toluene

´
I. Karame et al.
1072
(0.35 M), d8-toluene (0.2 mL), and one drop of triethylamine. The resulting
mixture was analyzed by 31P NMR (d8-toluene, 300 or 400 MHz). Three
signals are obtained: one of nonreacted chlorophosphite and two related to
the diastereomeric triesters.
Data
(R)-Ethyl 3-hydroxytetradecanoate (2a). Yellow oil; [a]2D0 ¼ 26.1 (c 1,
1
CH2Cl2; 98.5% ee); H NMR (300 MHz, CDCl3) d 4.14 (q, J ¼ 7.23 Hz,
2H), 3.97 (m, 1H), 3.00 (bs, 1H, OH), 2.50–2.30 (m, 2H), 1.60–1.10
(m, 23H), 0.85 (t, J ¼ 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 173.0
(C55O), 68.1 (CH), 60.6 (CH2), 43.8 (CH2), 41.3 (CH2), 36.5 (CH2), 31.9
(CH2), 29.6 (CH2), 29.6 (CH2), 29.5 (CH2), 29.3 (CH2), 25.5 (CH2), 23.8
(CH2), 22.7 (CH2), 14.1 (CH3), 14.1 (CH3); HRMS (EI, 70 eV): m/z
271.22577 (M-Hþ exact mass calcd. for C16H31O3: 271.22677); ee determined
by 31P NMR (300 MHz, d8-toluene) d 153.35, 151.33.
(R)-Ethyl 3-hydroxydodecanoate (2b). Yellow oil; [a]2D0 ¼ 29.4 (c 0.5,
1
CH2Cl2; 98% ee); H NMR (300 MHz, CDCl3) d 4.15 (q, J ¼ 7.13 Hz, 2H),
3.97 (m, 1H), 2.84 (bs, 1H, OH), 2.43 (m, 2H), 1.60–1.10 (m, 19H), 0.85
(t, J ¼ 6.5 Hz, 3H); 13C NMR (75 MHz CDCl3) d 173.1 (C55O), 68.0 (CH),
60.6 (CH2), 43.8 (CH2), 41.3 (CH2), 36.5 (CH2), 31.9 (CH2), 29.6 (CH2),
29.5 (CH2), 29.3 (CH2), 24.5 (CH2), 22.7 (CH2), 14.15 (CH3), 14.08 (CH3);
HRMS (EI, 70 eV): m/z 243.19547 (M-Hþ exact mass calcd. for C14H27O3:
243.19461); ee determined by 31P NMR (300 MHz, d8-toluene) d 153.31,
151.23.
(R)-Ethyl 6-chloro-3-hydroxyhexanoate (2c). Yellow oil; [a]2D0 ¼ 23.7
(CH2Cl2, c 0.1; 98.0% ee); 1H NMR (300 MHz, CDCl3) d 4.14
(q, J ¼ 7.15 Hz, 2H), 4 (m, 1H), 3.55 (dt, J ¼ 6.52 and 2.6 Hz, 2H), 2.87
(bs, 1H, OH), 2.44 (m, 2H), 2.00–1.75 (m, 2H), 1.60 (m, 2H), 1.24
(t, J ¼ 7.147 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 173.2 (C55O), 67.5
(CH), 61.0 (CH2), 45.2 (CH2), 41.6 (CH2), 33.8 (CH2), 28.9 (CH2), 14.4
(CH3). HRMS (EI, 70 eV): m/z 193.06187 (M-Hþ exact mass calcd. for
C8H14O3Cl: 193.06260); ee determined by chiral capillary GC (Lipodex E
column (50 m), (R) t1 ¼ 88.929 min. and (S) t2 ¼ 92.944 min) and also by
quantitative 31P NMR (300 MHz, d8-toluene) d 153.34, 150.44.
Ethyl 7-chloro-3-hydroxyheptanoate (2d). Yellow oil; [a]2D0 ¼ 29.6
(CH2Cl2, c 0.25; 98.6% ee); 1H NMR (300 MHz, CDCl3) d 4.15
(q, J ¼ 7.17 Hz, 2H), 3.99 (m, 1H), 3.52 (t, J ¼ 6.64 Hz, 2H), 3.10 (bs, 1H,
OH), 2.54–2.33 (m, 2H), 1.85–1.72 (m, 2H), 1.65–1.40 (m, 4H), 1.25
(t, J ¼ 7.17 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 173.0 (C55O), 67.7
(CH), 60.7 (CH2), 44.8 (CH2), 41.2 (CH2), 35.6 (CH2), 32.4 (CH2), 22.8

Hydrogenation of b-Keto Esters
1073
(CH2), 14.2 (CH3); HRMS (EI, 30 eV): m/z 209.09361 and 211.09135
(M þ Hþ exact mass calcd. for C9H18O335Cl: 209.09390 and
for C9H18O337Cl: 211.09095); ee determined by chiral capillary GC
(Lipodex E column (50 m), 1008C, isothermal, (2) t1 ¼ 128.59 min. and
(þ) t2 ¼ 129.15 min).
Ethyl 9-chloro-3-hydroxynonanoate (2e). Yellow oil; [a]2D0 ¼ 211.5
(CH2Cl2,
c
0.2; 98% ee); 1H NMR (300 MHz, CDCl3) d 4.16
(q, J ¼ 7.15 Hz, 2H), 3.98 (m, 1H), 3.52 (t, J ¼ 6.7 Hz, 2H), 2.97 (bs, 1H,
OH), 2.55–2.33 (m, 2H), 1.76 (m, 2H), 1.30–1.60 (m, 8H), 1.27
(t, J ¼ 7.15 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 173.0 (C55O), 67.9
(CH), 60.7 (CH2), 45.0 (CH2), 41.3 (CH2), 36.3 (CH2), 32.5 (CH2), 28.8
(CH2), 26.8 (CH2), 25.3 (CH2), 14.2 (CH3); HRMS (EI, 30 eV): m/z
235.10901 (M-Hþ exact mass calcd. for C11H20O3Cl: 235.10955); ee deter-
mined by 31P NMR (300 MHz, d8-toluene) d 153.35, 150.31.
Ethyl 10-chloro-3-hydroxydecanoate (2f). Yellow oil; [a]2D0 ¼ 215
(CHCl3,
c d 4.13
0.5; 98.6% ee); 1H NMR (75 MHz, CDCl3)
(q, J ¼ 7.13 Hz, 2H), 3.95 (m, 1H), 3.50 (t, J ¼ 6.72 Hz, 2H), 3.02 (bs, 1H,
OH), 2.50–2.30 (m, 2H), 1.73 (m, 2H), 1.26–1.54 (m, 10H), 1.24
(t, J ¼ 7.13 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 173.0 (C55O), 67.9
(CH), 60.7 (CH2), 45.0 (CH2), 41.3 (CH2), 36.4 (CH2), 32.6 (CH2),
29.3 (CH2), 28.8 (CH2), 26.8 (CH2), 25.3 (CH2), 14.2 (CH3); HRMS (EI,
30 eV): m/z 251.14027 and 253.13830 (M þ Hþ exact mass calcd. for
C12H24O335Cl: 251.14085 and for C12H24O337Cl: 253.13790); ee determined
by 31P NMR (300 MHz, d8-toluene) d 152.72, 150.44.
ACKNOWLEDGMENTS
We acknowledge financial support from Wirtschaftsministerium von
Mecklenburg-Vorpommern.
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