Enantioselective reduction of 3-aryl-2-oxo-propanoic acids: A comparison of enzymatic and transition-metal-catalyzed methods

Article abstract of DOI:10.1002/ejoc.201201506

Phenyllactic acids are important constituents of depsipeptides, which are a large class of natural products expressing a wide range of biological activities. Despite there being several methods for the enantioselective synthesis of α-hydroxy acids, almost no studies are available addressing the substrate selectivity of transition-metal and enzyme-catalyzed methods for the preparation of substituted phenyllactic or more general aryllactic acids. We report herein comparative results for Rh-DiPAMP (DiPAMP = 1,2-ethandiylbis[(o- methoxyphenyl)phenylphosphane]) and lactate dehydrogenase catalyzed enantioselective reductions of several 3-aryl-2-oxopropanoic acids. Phenyllactic acids are important constituents of depsipeptides, which are a large class of natural products expressing a wide range of biological activities. A comparative study of transition-metal and lactate dehydrogenase catalyzed enantioselective reductions of several 3-aryl-2-oxopropanoic acids as valuable sources for enantiomerically pure phenyllactic acids is described. Copyright

Full text of DOI:10.1002/ejoc.201201506

FULL PAPER
DOI: 10.1002/ejoc.201201506
Enantioselective Reduction of 3-Aryl-2-oxo-propanoic Acids: A Comparison of
Enzymatic and Transition-Metal-Catalyzed Methods
Sebastian Lüttenberg,[a] Tien Dat Ta,[a] Jan von der Heyden,[a] and Jürgen Scherkenbeck*[a]
Keywords: Synthetic methods / Enzyme catalysis / Hydrogenation / Rhodium / Carboxylic acids / Hydroxy acids
Phenyllactic acids are important constituents of depsipep-
tides, which are a large class of natural products expressing
a wide range of biological activities. Despite there being sev-
eral methods for the enantioselective synthesis of α-hydroxy
acids, almost no studies are available addressing the sub-
strate selectivity of transition-metal and enzyme-catalyzed
methods for the preparation of substituted phenyllactic or
more general aryllactic acids. We report herein comparative
results for Rh-DiPAMP (DiPAMP = 1,2-ethandiylbis[(o-meth-
oxyphenyl)phenylphosphane]) and lactate dehydrogenase
catalyzed enantioselective reductions of several 3-aryl-2-
oxopropanoic acids.
Introduction
α-Hydroxy acids are found in numerous natural prod-
ucts, as well as in pharmaceutical and plant-protection
agents.[1] In particular, α-hydroxy acids are essential con-
stituents of depsipeptides where they function as mimetics
for the corresponding natural amino acids; thus causing a
wide range of biological activities.[2–8] During our studies
on the solid-phase synthesis of the anthelmintic PF1022A
and related biologically active cyclodepsipeptides, we re-
quired a set of enantiomerically pure d-aryllactic and d-
hetaryllactic acids.[9,10] Despite there being different routes
to α-hydroxy acids, no general methods are available that
allow the synthesis of a broad variety of structurally diverse
aryllactic acids. The basic methods to enantiomerically
pure, or at least enantiomerically enriched, phenyllactic ac-
ids can be attributed to four basic strategies (Figure 1).
Conventionally, substituted phenylalanines are diazo-
tized in acetic acid to produce acetyl-protected phenyllactic
acids with retention of configuration (Figure 1). However,
substituted phenylalanines have to be synthesized by Pd-
catalyzed couplings of functionalized serine derivatives with
a suitable aryl–metal species.[11–13] More recent alternatives
utilize enantioselective catalytic methods such as the asym-
metric dihydroxylation of cinnamic acids followed by a hy-
drogenolytic removal of the benzylic hydroxy group (Fig-
ure 1).[14] Oxynitrilase-catalyzed transcyanations represent
another strategy to phenyllactic acids albeit the enantio-
selectivities are not excellent.[15] The broadest variability re-
Figure 1. Synthetic routes to phenyllactic acids.
garding the aryl moieties provide enantioselective hydrogen-
ations of α-oxo acids available in a simple two-step synthe-
sis from benzaldehydes (Figure 1). Enantioselective re-
ductions can be achieved either by equivalent amounts of
chiral reductants, such as (–)-B-chlorodiisopinocampheyl-
borane (DIP-Cl) and oxazaborolidines, or by organometal-
lic and enzyme catalysts.[5,16–18] In particular, the catalytic
methodologies have the potential for producing multigram
quantities of aryl- and hetaryllactic acids.
Numerous chiral rhodium catalysts, among those the
benchmark ligands TangPhos and ZhangPhos, as well as
many others, have been reported to produce excellent
enantioselectivities in hydrogenations of α-(acylamino)-
acrylic acids, enol acetates, and β-enamino esters.[19–23]
However, the number of suitable catalysts for α-(acyloxy)-
acrylates performing well at low hydrogen pressures
(Ͻ 10 bar) in standard laboratory equipment is limited. Ad-
[a] Department of Chemistry, University of Wuppertal,
Gaußstraße 20, 42119 Wuppertal, Germany
Fax: +49-202-439-3464
E-mail: Scherkenbeck@uni-wuppertal.de
Homepage: http://www2.uni-wuppertal.de/fb9/oc/
scherkenbeck/index.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201506.
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Eur. J. Org. Chem. 2013, 1824–1830

Enantioselective Reduction of 3-Aryl-2-oxo-propanoic Acids
ditionally, these types of hydrogenations are frequently im-
paired by reduced yields, mediocre enantioselectivities, or
complex ligands.[24–26] With respect to commercial availabil-
ity and reported enantioselectivities, RhI-DuPhos, RuII-
BINAP, and RhI-DiPAMP (DuPhos = 1,2-bis(2,5-diethyl-
phospholano)benzene, BINAP = 2,2Ј-bis(diphenylphos-
phanyl)-1,1Ј-binaphthyl, DiPAMP = 1,2-ethandiylbis[(o-
methoxyphenyl)phenylphosphane]) still remain promising
standard catalysts for the hydrogenation of α-(acyloxy)-
acrylates (Figure 2).[27,28]
A complementary strategy for the synthesis of α-hydroxy
acids is based on the enantioselective enzymatic reduction
of 2-oxo acids (Figure 1). Compared with other enzymatic
strategies, such as kinetic resolution of racemic α-hydroxy
esters with hydrolases or oxynitrilase-catalyzed enantiose-
lective formation of cyanohydrins and subsequent hydroly-
sis, the stereospecific reduction of a 2-oxo precursor with
Figure 2. Structures of Rh-DuPhos, Ru-BINAP, and Rh-DiPAMP
catalysts.
an alcohol dehydrogenase appears to be the most promising LDH) and formate dehydrogenase (FDH) in a membrane
biocatalytic method.[29–32] Moreover, by using a coupled en- reactor, a continuous multigram production of the respec-
zyme system consisting of d-lactate dehydrogenase (d- tive phenyllactic acid can be accomplished.[33]
Scheme 1. Synthesis of starting compounds and enantioselective hydrogenations with a rhodium catalyst and lactate dehydrogenase.
Reagents and conditions: (i) NaH, MeOH, ethyl ether, 0 °C Ǟ room temp., 18 h; (ii) 1 m HClaq, room temp.; (iii) 3a, 3b: benzoic acid,
N,NЈ-diisopropylcarbodiimide (DIC), 4-dimethylaminopyridine (DMAP), CH2Cl2, room temp., 6 h; 3a–j: pivaloyl chloride, triethylamine
(TEA), CH2Cl2, 0 °C Ǟ room temp., 16 h; (iv) LiOH, H2O/THF, 0 °C, 4 h; (v) d-LDH, nicotinamide adenine dinucleotide (NADH),
FDH, NH4HCO2, ethylenediaminetetraacetic acid (EDTA), water, pH = 7, room temp., 15 h; (vi) 5: 2 mol-% Rh-DuPhos, H2 (8 bar),
CH2Cl2, room temp., 24 h; 5: 1 mol-% Ru-BINAP, H2 (50 bar), MeOH, 50 °C, 4 d; 6b: 1 mol-% Ru-BINAP, H2 (50 bar), MeOH, 50 °C,
4 d; 6a–j: 1 mol-% Rh-DiPAMP, H2 (5.0 bar), MeOH, room temp., 4 d; (vii) 1 m LiOH (THF/water, 3:5), 0 °C Ǟ room temp., 18 h.
Eur. J. Org. Chem. 2013, 1824–1830
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S. Lüttenberg, T. D. Ta, J. von der Heyden, J. Scherkenbeck
FULL PAPER
While Rh-DuPhos-catalyzed hydrogenation gave only a low
yield (22%) of phenyllactic ester 7, which was highly enantio-
selective (ee 98%), the Ru-BINAP catalyst was disappointing
with respect to both yield (33%) and enantioselectivity (ee
34%). A good yield (79%) and an excellent enantiomeric ex-
cess (ee 98%) was obtained for aryllactic ester 8b with Rh-
DiPAMP and pivaloate ester 6b as the substrate after a reac-
tion time of 4 d and 5 bar H2. Consequently, the Rh-
DiPAMP/pivaloate system was chosen for all other hydrogen-
ations (Table 2).[25,37] The somewhat reduced yields of 4-benz-
yloxyphenyllactic ester 8j and 4-bromophenyllactic ester 8i
can be attributed to incomplete conversion and losses during
chromatographic purification. Remarkably, no reaction could
be observed for 3-pyridino-2-oxo acrylate 6g, which presum-
ably acted as a catalyst poison.[38] The R configuration of the
resulting aryllactic acids was established by X-ray structural
analysis of compound 8h.[35]
Results and Discussion
Preparation of the Starting Materials
2-Oxo acids are common substrates for both rhodium
and lactate dehydrogenase catalyzed reductions. They can
be easily prepared as E/Z mixtures by condensation of an
aromatic aldehyde (1) with an N,N-dimethylglycine methyl
ester (2), followed by acidic hydrolysis of the intermediate
α-(dimethylamino)acrylic esters, according to a procedure
by Horner and Renth (Scheme 1).[34] Hydrolysis of the in-
termediate enamines with HCl (1 m) afforded the 2-oxocar-
boxylic esters 3a–j in yields between 54 and 90% (Table 1)
after crystallization or distillation (compound 3e).
Table 1. Yields of starting compounds for rhodium- and enzyme-
catalyzed hydrogenations.
Entry
Yield [%]
Yield [%]
Yield [%]
3
4
6
a
b
c
d
e
f
79
88
73
69
72
58
78
90
73
54
75
Ͻ 1
86
Ͻ 1
44
73
91
62
53
72
77
87
97
98
84
74
78
100
94
97
Table 2. Rhodium and lactate dehydrogenase catalyzed reductions
of arylpyruvates.
Yield [%]
Rh-DIPAMP
ee[a]
[%]
Yield [%]
d-LDH
ee[a]
[%]
8a
8b
8c
8d
8e
8f
90
79
96
81
92
91
–
91
60
73
99
95
96
96
96
98
–
9a
66
–
37
–
75
72
95
44
68
60
Ͼ 99
–
96
–
82
Ͼ 99
Ͼ 99
Ͼ 99
98
g
h
i
9b[b]
9c
9d[b]
9e
9f
9g
j
Depending on the type of ligand, specific enol esters are
required for high yields and enantioselectivities in Rh- and
Ru-catalyzed hydrogenations. Thus, benzoate 5 was pre-
pared as a substrate for Rh-DuPhos and the corresponding
pivaloates (6a–j) for the Rh-DiPAMP and Ru-BINAP cata-
lysts. All acylation products were found to have exclusively
the thermodynamic more stable Z configuration, as proved
by NOESY NMR spectroscopy and X-ray structural analy-
sis of enol esters 6b, 6d, and 6i.[35] However, as already dem-
onstrated by Burk et al., the stereochemical course of Rh-
DuPhos-catalyzed hydrogenations is independent of the
E/Z configuration of the enol esters used as substrates.[27]
Unfortunately, the synthesis of 2-oxo esters 3k–m failed due
to extensive formation of aldol condensation products dur-
ing hydrolysis.
In contrast to the rhodium-catalyzed hydrogenation,
lactate dehydrogenase reduces directly the carbonyl group
by transferring a hydride anion from NADH. Additionally,
it accepts the unprotected 2-oxo acids as available substrates
by a carefully controlled basic hydrolysis of the methyl es-
ters (1.1 equiv. LiOH, THF/H2O, 0 °C, 4 h; Table 1).
Even under these mild conditions, the electron-rich aryl-
pyruvates 4b and 4d tended to undergo aldol condensations
(Scheme 1 and Table 1). An enzymatic ester cleavage with
Candida rugosa lipase under strict pH control resulted in
similar problems that were probably caused by the extended
reaction times of 1–2 days at room temperature.[36]
8g
8h
8i
Ͼ 99 9h
96
69
9i
9j
8j
88
[a] The ee values were obtained by chiral HPLC with comparison
to the racemic material. [b] Starting material decomposed under
the reaction conditions.
Finally, the esters were cleaved without loss of enantio-
meric purity in one step with an aqueous solution of LiOH
(3 equiv.), to obtain the α-hydroxy acids 9a–j in yields rang-
ing from 72 to 95% after a prolonged reaction time (2–3 d)
caused by the bulky pivaloyl group.
Enzymatic reductions with d-LDH require NADH as a
cofactor, which is oxidized to NAD during the reaction.
Due to the high price of NADH, in situ cofactor regenera-
tion is essential for the synthesis of preparative amounts of
aryllactic acids. A coupled two-enzyme redox system utiliz-
ing FDH as the second biocatalyst allows the reduction of
NAD back to NADH in the presence of formate, which is
oxidized to CO2. This experimental setup renders the over-
all process catalytic in NADH (Figure 3).[31–33,39]
In principle, LDH reductions can be performed under
either continuous-flow or batch-process conditions in an ul-
trafiltration-membrane reactor.[33,40] A fundamental advan-
tage of a continuous-flow reactor is its high degree of flexi-
bility regarding control of reaction time and flow rate as
well as recovery of products and enzymes. However, with a
continuous reactor we were unable to obtain more than
30% turnover with the reference compound phenylpyruvate
Enantioselective Reductions
In a preliminary study, benzoate 5 was used as a model (10) due to significant enzyme inactivation after 10–15 h
substrate for the Rh-DuPhos and Ru-BINAP catalysts.[24] reaction time.
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Eur. J. Org. Chem. 2013, 1824–1830

Enantioselective Reduction of 3-Aryl-2-oxo-propanoic Acids
Experimental Section
General: The starting materials 4-morpholinobenzaldehyde, 4-(di-
methylamino)benzaldehyde, 4-ethoxybenzaldehyde, 2-furancarb-
aldehyde, 4-(methoxyethoxymethoxy)benzaldehyde, 4-(tert-but-
oxy)benzaldehyde, 4-pyridinecarbaldehyde, 4-chlorobenzaldehyde,
4-bromobenzaldehyde, and 4-(benzyloxy)benzaldehyde were either
purchased or prepared by standard literature procedures.[42] All re-
actions, except the saponifications, hydrolysis reactions, and the en-
zymatic reductions, were performed in dried solvents. Dichloro-
methane and TEA were heated at reflux for 1 h over calcium hy-
dride and distilled. Ethyl ether was heated at reflux for several
hours over LiAlH4 and then distilled. Methanol was heated at re-
flux over magnesium oxide and distilled. The instrumentation used
Figure 3. Scheme for LDH-catalyzed reductions with cofactor re-
generation.
In a batch run, the reactor was initially charged with a
solution of the substrate phenylpyruvate (10) or 2-oxo acids
4a–j (10 mm) in water (50 mL), containing EDTA
(0.025 mm), mercaptoethanol (0.05 mm), NAD (0.1 mm),
and HCOONH4 (40 mm), followed by d-LDH (20 U/mL)
and FDH (1 U/mL).[41] After an overall reaction time of
around 24 h, the turnover was complete (Table 2). The reac-
tor was flushed with argon or nitrogen (0.1–0.2 bar pres-
sure) and the reaction was filtered slowly (40–80 min)
through the membrane (polyethersulfone, cutoff: 10 kDa).
Only minor inactivation of the enzyme system was observed
under these conditions. A new run with fresh starting mate-
rial and buffer solution afforded almost complete conver-
sion (95%).
The generally somewhat lower yields of the enzymatic
reduction can be attributed to limited stability, in particular,
of electron-rich 2-oxo-carboxylic acids (Table 2). Long-
chain aryl–alkyl ether 4e turned out to be a poor substrate
for the enzyme-catalyzed reduction. Apparently, the bind-
ing pocket of d-LDH is not able to accommodate long-
chain para substituents in the correct position for a highly
enantioselective reduction. This behavior can already be ob-
served to a minor extent for ethyl ether 9c, which shows
slightly reduced enantiomeric purity. Remarkably, 3-pyr-
idino-2-oxopropanoic acid 4g, which had completely failed
in the rhodium-catalyzed hydrogenation, was an excellent
substrate for d-LDH (yield 95%, ee Ͼ 99%, Table 2).
1
was as follows: H NMR: Bruker Avance 400, Bruker Avance III
600 13C NMR: Bruker Avance 400, Bruker Avance III 600. FTIR:
Nicolet PROTÉGÉ 460 E.S.P. MS: (Bruker microTOF): ESI-MS,
(Varian IT 500-MS) Iontrap. LC: Preparative low-pressure
chromatography (LPLC) was performed by using silica gel 60 μm
(230–400 mesh, Macherey–Nagel), Büchi pump. TLC: silica gel 60
F254 (Merck). Enantiomeric excess values were determined by chi-
ral HPLC in comparison to racemic material, which was prepared
either by reduction of the 2-oxo esters 3a–j with NaBH4 for the
enzymatic route or by hydrogenation of enol esters 6 with Pd(OH)2/
C (20%, 8 mol-%) for the rhodium-catalyzed procedure. For better
HPLC analysis the methyl esters (MeOH, SOCl2) of the chiral 2-
hydroxy acids 9 were used.
General Procedure for the Preparation of the Enamines: Sodium hy-
dride (2 equiv.) was suspended in Et2O then methanol (0.2 equiv.)
and aldehydes 1a–c (1 equiv.) were added under vigorous stirring.
The suspensions were cooled to 0 °C and N,N-dimethylglycine
methyl ester (3 equiv.) was added dropwise. After stirring in an ice–
water bath, the reactions were warmed to room temperature over-
night (18 h). Ice water and CH2Cl2 were added at 0 °C. The aque-
ous layers were extracted three times with CH2Cl2; the combined
organic phases were dried with Na2SO4, evaporated, and dried in
vacuo. The crude products were purified by kugelrohr distillation
in vacuo.
(E/Z)-Methyl 2-(Dimethylamino)-3-(4-morpholinophenyl)acrylate:
Starting material: p-morpholinobenzaldehyde (1a; 3.81 g,
19.31 mmol). Yield after distillation (220 °C, 8ϫ10–3 mbar): 91%
(5.11 g, 17.58 mmol), yellow solid, m.p. 70 °C. 1H NMR (600 MHz,
CDCl3): δ = 2.67, 2.72 (2 s, 6 H, NCH3), 3.14, 3.23 (2 t, J = 4.9 Hz,
4 H, NCH2), 3.72, 3.81 (2 s, 3 H, OCH3), 3.87 (m, J = 4.9 Hz, 4
H, OCH2), 5.59, 6.93 (2 s, 1 H, olefinic-H), 6.82, 6.88 (2 d, J = 8.9,
9.0 Hz, 2 H, Ar-H), 7.05, 7.71 (2 d, J = 8.8, 9.0 Hz, 2 H, Ar-H)
ppm. 13C NMR (150 MHz, CDCl3): δ = 40.6, 42.4, 48.4, 49.2, 51.3,
52.1, 66.7, 66.8, 107.0, 129.3, 114.4, 115.4, 126.2, 127.9, 131.6,
Conclusions
A comparative study on transition-metal (Rh-DiPAMP)
and enzyme-catalyzed (d-LDH) reductions of a series of 3-
aryl-2-oxopropanoic acids was conducted to provide a
straightforward access to enantiomerically enriched aryl-
and hetaryllactic acids on a gram scale.
While the yields of the rhodium-catalyzed hydrogena-
tions were slightly better, enantiomeric excesses were com-
parable for both the metal- and enzyme-catalyzed pro-
cedures. Nevertheless, the enzymatic route is more efficient,
since it does not need any protecting-group chemistry. Thus,
for multigram syntheses the enzymatic process appears to
be advantageous. d-LDH and FDH are reasonably priced
and are stable in a batch reactor for at least 48 h. The cofac-
tor NADH is needed only in catalytic amounts
(0.01 equiv.), and thus, is not a relevant cost factor. In con-
trast to rhodium-catalyzed hydrogenation, 2-oxo-3-(4-pyr-
idyl)propanoic acid (4g) is an excellent substrate for d-
LDH, providing easy access to almost enantiomerically
pure pyridinolactic acids.
137.8, 142.0, 149.2, 151.0, 167.3, 168.5 ppm. IR (KBr): ν = 1717
˜
(C=O) cm–1. MS (ESI): m/z (%) = 231 (46), 291 (100). HRMS
(ESI): calcd. for C16H23N2O3 [M + H]+ 291.1703, found 291.1704.
(E/Z)-Methyl 2-(Dimethylamino)-3-(4-dimethylaminophenyl)acryl-
ate: Starting material: p-N,N-dimethylaminobenzaldehyde (1b;
4.50 g,
29.86 mmol).
Yield
after
distillation
(195 °C,
2.9ϫ10–2 mbar): 87% (6.45 g, 26.03 mmol), yellow solid, m.p. 36–
38 °C. 1H NMR (400 MHz, CDCl3): δ = 2.68, 2.71 (2 s, 6 H,
NCH3-enamine), 2.94, 3.01 (2 s, 6 H, NCH3), 3.74, 3.81 (2 s, 3 H,
OCH3), 5.64, 7.00 (2 s, 1 H, olefinic-H), 6.66, 6.71 (2 d, J = 9.0,
9.1 Hz, 2 H, Ar-H), 7.03, 7.75 (2 d, J = 8.5, 9.1 Hz, 2 H, Ar-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 40.1, 40.5, 40.7, 42.3, 51.1,
52.2, 108.5, 131.3, 111.5 112.5, 123.0, 128.0, 132.1, 136.2, 150.5,
167.5 ppm. IR (KBr): ν = 1701 (C=O) cm–1. MS (ESI): m/z (%) =
˜
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S. Lüttenberg, T. D. Ta, J. von der Heyden, J. Scherkenbeck
FULL PAPER
189 (99), 249 (100). HRMS (ESI): calcd. for C14H20N2NaO2 [M + argon atmosphere. Pivaloyl chloride (4 equiv.) and TEA (2 equiv.)
Na]+ 271.1417, found 271.1414.
were added dropwise. The mixtures were warmed up to ambient
temperature and stirring was continued for 16 h. Water was then
added, the layers were separated, and the aqueous phases were ex-
tracted twice with CH2Cl2. The combined organic layers were dried
with Na2SO4, filtered, and the solvents evaporated. The crude
product was dried in vacuo and purified by column chromatog-
raphy.
(E/Z)-Methyl 2-(Dimethylamino)-3-(4-ethoxyphenyl)acrylate: Start-
ing material: p-ethoxybenzaldehyde (1c; 3.49 g, 23.00 mmol). Yield
after distillation (175 °C, 8.0ϫ10–2 mbar): 96% (5.52 g,
22.15 mmol), yellow liquid. 1H NMR (600 MHz, CDCl3): δ = 1.45
(t, J = 7.0 Hz, 3 H, CH3-ethoxy), 2.68, 2.73 (2 s, 6 H, NCH3), 3.71,
3.82 (2 s, 3 H, OCH3), 4.08 (q, J = 7.0 Hz, 2 H, OCH2), 5.64, 6.92
(2 s, 1 H, olefinic-H), 6.90 (d, J = 8.6 Hz, 2 H, Ar-H), 7.71 (d, J =
8.6 Hz, 2 H, Ar-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 14.6,
14.8, 40.6, 42.4, 51.4, 52.1, 63.3, 63.9, 114.1, 114.5, 131.8, 131.9,
(Z)-Methyl 3-(4-Morpholinophenyl)-2-(pivaloyloxy)acrylate (6a):
Starting material: enol ester 3a (1.30 g, 4.79 mmol). Solvent for
chromatographic purification: cyclohexane/ethyl acetate (9:1), yield
77% (1.29 g, 3.70 mmol), green–yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 1.41 (s, 9 H, CH3-tBu), 3.25 (t, J = 4.9 Hz, 4 H,
NCH2), 3.82 (s, 3 H, OCH3), 3.86 (t, J = 4.9 Hz, 4 H, OCH2), 6.87
(d, J = 8.9 Hz, 2 H, Ar-H), 7.28 (s, 1 H, olefinic-H), 7.53 (d, J =
8.9 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.3,
39.0, 48.1, 52.2, 66.7, 114.4, 123.2, 127.3, 131.7, 134.4, 151.9, 163.5
127.6, 128.6, 138.3, 142.4, 157.1, 167.3 ppm. IR (film): ν = 1708
˜
(C=O) cm–1. MS (ESI): m/z (%) = 190 (92), 250 (100), 272 (2).
HRMS (ESI): calcd. for C14H20NO3 [M + H]+ 250.1438, found
250.1442.
General Procedure for Hydrolysis of the Enamines: Enamines were
dissolved in aqueous HCl (ca. 100 mL, 1 m). The mixtures were
stirred at room temperature (30 min) and then washed twice with
CH2Cl2. The pH was adjusted to 8 with NaHCO3. The resulting
slurries were filtered off and washed with water. The crude products
were dried in vacuo and purified by recrystallization.
176.3 ppm. IR (film): ν = 1754 (C=O), 1722 (C=O) cm–1. MS
˜
(ESI): m/z (%) = 348 (100), 695 (20). HRMS (ESI): calcd. for
C19H26NO5 [M + H]+ 348.1805, found 348.1806.
(Z)-Methyl 3-(4-Dimethylaminophenyl)-2-(pivaloyloxy)acrylate (6b):
Starting material: enol ester 3b (1.07 g, 4.82 mmol). Solvent for
chromatographic purification: cyclohexane/ethyl acetate (9:1), yield
87% (1.28 g, 4.18 mmol), yellow crystalline solid, m.p. 88–89 °C.
1H NMR (600 MHz, CDCl3): δ = 1.45 (s, 9 H, CH3-tBu), 3.03 (s,
6 H, NCH3), 3.83 (s, 3 H, OCH3), 6.68 (d, J = 9.1 Hz, 2 H, Ar-
H), 7.29 (s, 1 H, olefinic-H), 7.52 (d, J = 9.1 Hz, 2 H, Ar-H) ppm.
13C NMR (150 MHz, CDCl3): δ = 27.4, 39.1, 40.2, 52.2, 111.7,
Methyl 2-Hydroxy-3-(4-morpholinophenyl)acrylate (3a): Starting
material: methyl 2-(dimethylamino)-3-(4-morpholinophenyl)acryl-
ate (6.00 g, 20.66 mmol). Solvent for recrystallization: acetone,
1
yield 79% (4.30 g, 16.32 mmol), yellow solid, m.p. 160–162 °C. H
NMR (400 MHz, CDCl3): δ = 3.23 (t, J = 4.8 Hz, 4 H, NCH2),
3.88 (t, J = 4.7 Hz, 4 H, OCH2), 3.92 (s, 3 H, OCH3), 6.51 (s, 1 H,
olefinic-H), 6.91 (d, J = 9.0 Hz, 2 H, Ar-H), 7.72 (d, J = 9.0 Hz, 2
H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 49.0, 53.3, 66.9,
120.0, 128.1, 132.0, 133.7, 151.3, 163.9, 176.4 ppm. IR (KBr): ν =
˜
1751 (C=O), 1713 (C=O) cm–1. MS (ESI): m/z (%) = 306 (100),
328 (5), 611 (16), 633 (6). HRMS (ESI): calcd. for C17H24NO4 [M
+ H]+ 306.1700, found 306.1700.
111.9, 115.3, 125.5, 131.7, 137.5, 150.7, 166.9 ppm. IR (KBr): ν =
˜
3403 (O–H), 1685 (C=O) cm–1. MS (ESI): m/z (%) = 204 (9), 264
(100), 286 (15). HRMS (ESI): calcd. for C14H18NO4 [M + H]+
264.1230, found 264.1232.
(Z)-Methyl 3-(4-Ethoxyphenyl)-2-(pivaloyloxy)acrylate (6c): Start-
ing material: enol ester 3c (2.20 g, 7.85 mmol). Solvent for chroma-
tographic purification: cyclohexane/ethyl acetate (20:1), yield 97%
(2.38 g, 7.65 mmol), white crystalline solid, m.p. 55–56 °C. 1H
NMR (600 MHz, CDCl3): δ = 1.41 (s, 9 H, CH3-tBu), 1.44 (t, J =
6.9 Hz, 3 H, CH3-ethoxy), 3.84 (s, 3 H, OCH3), 4.08 (q, J = 6.9 Hz,
2 H, OCH2), 6.90 (d, J = 8.8 Hz, 2 H, Ar-H), 7.31 (s, 1 H, olefinic-
H), 7.55 (d, J = 8.8 Hz, 2 H, Ar-H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 14.7, 27.1, 39.0, 52.3, 63.5, 114.5, 124.6, 127.0, 131.8,
Methyl 3-(4-Dimethylaminophenyl)-2-hydroxyacrylate (3b): Starting
material: methyl 2-(dimethylamino)-3-(4-dimethylaminophenyl)-
acrylate (1.02 g, 2.64 mmol). Solvent for recrystallization: acetone,
yield 88% (0.51 g, 2.31 mmol), yellow solid, m.p. 124–126 °C. 1H
NMR (400 MHz, CDCl3): δ = 3.02 (s, 6 H, NCH3), 3.91 (s, 3 H,
OCH3), 5.94 (s, 1 H, OH), 6.53 (s, 1 H, olefinic-H), 6.74 (d, J =
8.2 Hz, 2 H, Ar-H), 7.72 (d, J = 8.2 Hz, 2 H, Ar-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 40.4, 52.7, 112.0, 112.4, 122.3, 131.3,
135.5, 160.1, 163.3, 176.1 ppm. IR (KBr): ν = 1755 (C=O), 1715
˜
(C=O) cm–1. MS (ESI): m/z (%) = 307 (100), 324 (31), 329 (6).
HRMS (ESI): calcd. for C17H22NaO5 [M + Na]+ 329.1359, found
329.1359.
136.3, 150.1, 167.1 ppm. IR (KBr): ν = 3440 (O–H), 1676 (C=O)
˜
cm–1. MS (ESI): m/z (%) = 147 (10), 162 (20), 222 (100), 244 (9).
HRMS (ESI): calcd. for C12H16NO3 [M + H]+ 222.1125, found
222.1126.
General Procedure for Asymmetric Rh-Catalyzed Hydrogenations:
Acrylic esters 6 and Rh-DiPAMP (1 mol-%) were dissolved under
a nitrogen atmosphere in dry methanol (60 mL) and hydrogenated
at room temperature under a hydrogen pressure of 5 bar. After stir-
ring for 4 d, the solvent was evaporated and the crude products
were purified by column chromatography.
Methyl 3-(4-Ethoxyphenyl)-2-hydroxyacrylate (3c): Starting mate-
rial: methyl 2-(dimethylamino)-3-(4-ethoxyphenyl)acrylate (5.48 g,
19.01 mmol). The crude product was recrystallized with Et2O, yield
73% (4.58 g, 13.81 mmol), yellow solid, m.p. 102–105 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.44 (t, J = 7.0 Hz, 6 H, CH3-ethoxy), 3.80,
3.85, 3.92 (3 s, 6 H, OCH3), 4.05 (m, 4 H, OCH2), 4.07 (m, 2 H,
CH2-keto form), 5.94 (br. s, 1 H, OH), 6.53 (s, 1 H, olefinic-H),
6.90 (m, 4 H, Ar-H), 7.16 (d, J = 8.0 Hz, 1 H, Ar-H), 7.74 (d, J =
8.0 Hz, 3 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.7,
44.9, 52.9, 53.0, 53.3, 63.2, 63.4, 63.5, 111.3, 113.9, 114.0, 114.5,
114.8, 123.2, 126.7, 129.1, 130.8, 131.4, 132.7, 137.5, 158.4, 158.8,
(R)-Methyl 3-(4-Morpholinophenyl)-2-(pivaloyloxy)propanoate (8a):
Starting material: methyl acrylate 6a (0.55 g, 1.59 mmol). Solvent
for chromatographic purification: cyclohexane/ethyl acetate (9:1),
yield 90% (0.50 g, 1.43 mmol, 99% ee), colorless oil. [α]2D5 = +3.4
1
(c = 0.35 in MeOH). H NMR (400 MHz, CDCl3): δ = 1.20 (s, 9
H, CH3-tBu), 3.05 (dd, J = 8.3, 14.4 Hz, 1 H, CβH2), 3.13 (m, 1
H, CβH2), 3.15 (t, J = 4.6 Hz, 2 H, NCH2), 3.73 (s, 3 H, OCH3),
3.87 (t, J = 4.7 Hz, 2 H, OCH2), 5.16 (m, 1 H, CαH), 6.87 (d, J =
8.4 Hz, 2 H, Ar-H), 7.15 (d, J = 8.7 Hz, 2 H, Ar-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 27.1, 36.6, 38.6, 49.4, 52.1, 66.9,
166.8 ppm. IR (KBr): ν = 3414 (O–H), 1687 (C=O) cm–1. MS
˜
(ESI): m/z (%) = 163 (100), 223 (92), 245 (19). HRMS (ESI): calcd.
for C12H14NaO4 [M + Na]+ 245.0784, found 245.0780.
General Procedure for the Preparation of Pivaloates 6: Enol esters
3 were dissolved in CH2Cl2 and stirred for 5 min at 0 °C under an
72.8, 115.6, 127.5, 130.1, 150.2, 170.3, 177.8 ppm. IR (Film): ν =
˜
1828
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1824–1830

Enantioselective Reduction of 3-Aryl-2-oxo-propanoic Acids
1767 (C=O), 1735 (C=O) cm–1. MS (ESI): m/z (%) = 350 (100),
(R)-3-(4-Ethoxyphenyl)-2-hydroxypropanoic Acid (9c): Starting ma-
372 (23). HRMS (ESI): calcd. for C19H28NO5 [M + H]+ 350.1962, terial: ester 8c (1.26 g, 4.10 mmol). Solvent for chromatographic
found 350.1963.
purification: ethyl acetate/MeOH (9:1 + 0.05% HOAc), yield 86%
(0.74 g, 3.52 mmol), white solid, m.p. 156–160 °C. [α]2D5 = +28.3 (c
= 0.23 in MeOH). 1H NMR (400 MHz, [D4]methanol): δ = 1.37
(t, J = 6.9 Hz, 3 H, CH3-ethoxy), 2.84 (m, 1 H, CβH2), 3.07 (m, 1
H, CβH2), 4.00 (q, J = 7.0 Hz, 2 H, OCH2), 4.27 (m, 1 H, CαH),
6.82 (d, J = 8.6 Hz, 2 H, Ar-H), 7.18 (d, J = 8.6 Hz, 2 H, Ar-H)
ppm. 13C NMR (100 MHz, [D4]methanol): δ = 15.1, 40.8, 64.3,
(R)-Methyl 3-(4-Dimethylaminophenyl)-2-(pivaloyloxy)propanoate
(8b): Starting material: methyl acrylate 6b (0.18 g, 0.57 mmol). Sol-
vent for chromatographic purification: cyclohexane/ethyl acetate
(9:1), yield 79% (0.14 g, 0.45 mmol, 95% ee), colorless oil. [α]2D5
=
1
+2.4 (c = 0.17 in MeOH). H NMR (400 MHz, CDCl3): δ = 1.22
(s, 9 H, CH3-tBu), 2.94 (s, 6 H, NCH3), 3.04 (dd, J = 8.6, 14.4 Hz,
1 H, CβH2), 3.12 (dd, J = 4.3, 14.3 Hz, 1 H, CβH2), 3.73 (s, 3 H,
OCH3), 5.14 (m, 1 H, CαH), 6.70 (d, J = 8.8 Hz, 2 H, Ar-H), 7.12
(d, J = 8.8 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 27.0, 38.5, 40.9, 36.4, 52.0, 73.1, 112.7, 123.9, 130.0, 149.6, 170.4,
73.5, 115.1, 131.0, 131.4, 135.9, 158.8, 178.5 ppm. IR (KBr): ν =
˜
3466 (O–H), 3187 (O–H), 1739 (C=O) cm–1. MS (ESI): m/z (%) =
209 (100). HRMS (ESI): calcd. for C11H13O4 [M – H]– 209.0819,
found 209.0813.
177.8 ppm. IR (KBr): ν = 1765 (C=O), 1725 (C=O) cm–1. MS
General Procedure for the Hydrolysis of Enol Esters 3 and Enantio-
selective Enzymatic Reduction: Enol esters 3 were suspended at 0 °C
in an aqueous solution of LiOH (1.1 equiv.). After stirring for 5 h
at room temperature, the reaction mixtures were extracted twice
with CH2Cl2. The organic layers were combined and the solvents
evaporated. The dried raw materials were used without further pu-
rification for the enzymatic reductions. Solutions of EDTA
(0.025 mm), mercaptoethanol (0.05 mm), ammonium formate
(40 mm), 2-oxo acids 4 (10 mm), and NAD (0.1 mm) were dissolved
in water (50 mL) in an ultrafiltration cell (polyethersulfone mem-
brane, cutoff = 10 kDa). The pH was adjusted to 7.0 by using 1 m
HCl. Then the enzymes d-LDH (200 U, Staphylococcus epidermis,
activity: 97 U/mg solid) and FDH (5 U, Candida boidinii, activity:
0.45 U /mg solid) were added. The solutions were stirred between
15 h and 24 h at room temperature. After that time the solutions
were filtered through the membrane by using a low argon pressure
(0.1–0.3 bar). The crude products were purified by column
chromatography (ethyl acetate/MeOH, 7:3 + 0.1% AcOH) after
evaporation of water.
˜
(ESI): m/z (%) = 308 (100), 330 (14). HRMS (ESI): calcd. for
C17H26NO4 [M + H]+ 308.1856, found 308.1856.
(R)-Methyl 3-(4-Ethoxyphenyl)-2-(pivaloyloxy)propanoate (8c):
Starting material: methyl acrylate 6c (1.50 g, 4.90 mmol). Solvent
for chromatographic purification: cyclohexane/ethyl acetate (9:1),
yield 96% (1.44 g, 4.68 mmol, 96% ee), colorless oil. [α]2D0 = +8.1
1
(c = 1.56 in MeOH). H NMR (400 MHz, CDCl3): δ = 1.20 (s, 9
H, CH3-tBu), 1.42 (t, J = 7.0 Hz, 3 H, CH3-ethoxy), 3.06, 3.14 (2
dd, J = 4.3, 9.1 Hz, 2 H, CβH2), 3.73 (s, 3 H, OCH3), 4.03 (q, J =
7.0 Hz, 2 H, OCH2), 5.16 (dd, J = 4.3, 9.1 Hz, 1 H, CαH), 6.83 (d,
J = 8.6 Hz, 2 H, Ar-H), 7.14 (d, J = 8.6 Hz, 2 H, Ar-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 14.8, 26.9, 36.5, 38.6, 52.1, 63.4,
72.8, 114.3, 127.9, 130.3, 157.9, 170.2, 177.8 ppm. IR (film): ν =
˜
1760 (C=O), 1737 (C=O) cm–1. MS (ESI): m/z (%) = 207 (100),
309 (2), 326 (20), 331 (3). HRMS (ESI): calcd. for C17H24NaO5 [M
+ Na]+ 331.1517, found 331.1516.
General Procedure for Ester Cleavage to 2-Hydroxy Acids 9: 2-Hy-
droxy esters 8 were dissolved in THF (5 mL) at room temperature
and solutions of LiOH (3 equiv.) in water (30 mL) were added. Af-
ter stirring for 4 d at ambient temperature, the solutions were ex-
tracted twice with CH2Cl2. The aqueous phases were evaporated
and the crude products were purified by column chromatography.
3-(4-Morpholinophenyl)-2-oxopropanoic Acid (4a): Starting mate-
rial: 2-oxo ester 3a (1.73 g, 6.58 mmol), yield 75% (1.24 g,
1
4.95 mmol), yellow solid. H NMR (400 MHz, [D4]methanol): δ =
3.19 (t, J = 4.7 Hz, 1 H, NCH2), 3.21, 3.40 (2 m, 1 H, NCH2), 3.79
(t, J = 4.9 Hz, 1 H, OCH2), 3.84, 3.87 (2 t, J = 4.8 Hz, 1 H, OCH2),
6.75, 7.12, 7.79 (3 d, J = 9.1 Hz, 2 H, Ar-H), 7.02, 7.05, 7.08 (3 m,
2 H, Ar-H) ppm. 13C NMR (100 MHz, [D4]methanol): δ = 46.2,
50.5, 51.0, 51.4, 67.6, 67.7, 68.0, 114.6, 115.2, 116.9, 130.9, 131.9,
(R)-2-Hydroxy-3-(4-morpholinophenyl)propanoic Acid (9a): Starting
material: ester 8a (1.07 g, 3.06 mmol). Solvent for chromatographic
purification: CHCl3/MeOH (7:3), yield 84% (0.65 g, 2.57 mmol),
bright red solid, m.p. 115–117 °C. [α]2D2 = +2.9 (c = 0.21 in MeOH).
1H NMR (400 MHz, [D4]methanol): δ = 2.81 (dd, J = 8.2, 14.0 Hz,
1 H, CβH2), 3.07 (dd, J = 3.2, 14.0 Hz, 1 H, CβH2), 3.10 (t, J =
4.8 Hz, 4 H, NCH2), 3.84 (t, J = 4.8 Hz, 4 H, OCH2), 4.19 (m, 1
H, CαH), 6.90 (d, J = 8.6 Hz, 2 H, Ar-H), 7.21 (d, J = 8.6 Hz, 2
H, Ar-H) ppm. 13C NMR (100 MHz, [D4]methanol): δ = 40.9, 51.2,
133.7, 153.5, 165.0, 192.6 ppm. IR (KBr): ν = 3439 (O–H), 1602
˜
(C=O) cm–1. MS (ESI): m/z (%) = 248 (100). HRMS (ESI): calcd.
for C13H16NO4 [M + H]+ 250.1074, found 250.1074.
(R)-2-Hydroxy-3-(4-morpholinophenyl)propanoic Acid (9a): Starting
material: 2-oxo acid 4a (248.3 mg, 1.0 mmol), yield 66% (166.4 mg,
0.66 mmol), orange solid, m.p. 115–117 °C. [α]2D2 = +2.9 (c = 0.21
1
68.2, 73.0, 117.2, 130.6, 131.4, 151.5, 177.4 ppm. IR (KBr): ν =
˜
in MeOH). H NMR (400 MHz, [D4]methanol): δ = 2.81 (dd, J =
3427 (O–H), 1586 (C=O) cm–1. MS (ESI): m/z (%) = 250 (100).
HRMS (ESI): calcd. for C13H18NO4 [M + H]+ 252.1230, found
252.1235.
8.2, 14.0 Hz, 1 H, CβH2), 3.07 (dd, J = 3.2, 14.0 Hz, 1 H, CβH2),
3.10 (t, J = 4.8 Hz, 4 H, NCH2), 3.84 (t, J = 4.8 Hz, 4 H, OCH2),
4.19 (m, 1 H, CαH), 6.90 (d, J = 8.6 Hz, 2 H, Ar-H), 7.21 (d, J =
8.6 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz, [D4]methanol): δ =
40.9, 51.2, 68.2, 73.0, 117.2, 130.6, 131.4, 151.5, 177.4 ppm. IR
(R)-3-(4-Dimethylaminophenyl)-2-hydroxypropanoic Acid (9b):
Starting material: ester 8b (0.77 g, 2.49 mmol). Solvent for chroma-
tographic purification: ethyl acetate/MeOH (9:1) + 0.1% HOAc,
yield 100% (0.52 g, 2.49 mmol), bright yellow foam. [α]2D5 = +11.9
(c = 0.32 in MeOH). 1H NMR (400 MHz, [D4]methanol): δ = 2.76
(KBr): ν = 3427 (O–H), 1586 (C=O) cm–1. MS (ESI): m/z (%) =
˜
250 (100). HRMS (ESI): calcd. for C13H18NO4 [M + H]+ 252.1230,
found 252.1230.
(dd, J = 8.0, 14.0 Hz, 1 H, CβH2), 2.88 (s, 6 H, NCH3), 3.03 (dd, 3-(4-Ethoxyphenyl)-2-oxopropanoic Acid (4c): Starting material: 2-
J = 3.5, 14.0 Hz, 1 H, CβH2), 4.14 (m, 1 H, CαH), 6.74 (d, J = oxo ester 3c (0.97 g, 4.34 mmol), yield 86% (0.78 g, 3.75 mmol),
8.8 Hz, 2 H, Ar-H), 7.16 (d, J = 8.8 Hz, 2 H, Ar-H) ppm. 13C white solid. 1H NMR (400 MHz, [D4]methanol): δ = 1.38 (m, 3 H,
NMR (100 MHz, [D4]methanol): δ = 40.9, 41.6, 75.1, 114.7, 129.2,
CH3-ethoxy), 3.40, 3.49 (2 m, 2 H, CH2), 3.99, 4.13 (2 m, 2 H,
131.3, 151.0, 181.3 ppm. IR (KBr): ν = 3431 (O–H), 1562 (C=O) OCH2), 6.67–7.86 (m, 4 H, Ar-H) ppm. 13C NMR (100 MHz, [D4]-
˜
cm–1. MS (ESI): m/z (%) = 208 (100). HRMS (ESI): calcd. for methanol): δ = 12.7, 37.9, 42.6, 62.9, 112.5, 112.8, 113.0, 113.3,
C11H16NO3 [M + H]+ 210.1125, found 210.1129.
113.9, 126.3, 126.9, 129.1, 129.9 ppm. IR (KBr): ν = 3426 (O–H),
˜
Eur. J. Org. Chem. 2013, 1824–1830
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1829

S. Lüttenberg, T. D. Ta, J. von der Heyden, J. Scherkenbeck
FULL PAPER
1607 (C=O) cm–1. MS (ESI): m/z (%) = 207 (100). HRMS (ESI):
[9] S. Lüttenberg, F. Sondermann, J. Scherkenbeck, Tetrahedron
2012, 68, 2068–2073.
calcd. for C11H11O4 [M – H]– 207.0663, found 207.0665.
[10] J. Scherkenbeck, S. Lüttenberg, M. Ludwig, K. Brücher, A.
Kotthaus, Eur. J. Org. Chem. 2012, 1546–1553.
[11] T. Storz, P. Dittmar, Org. Process Res. Dev. 2003, 7, 559–570.
[12] S. G. Cohen, S. Y. Weinstein, J. Am. Chem. Soc. 1964, 86,
5326–5330.
[13] A. J. Ross, F. Dreiocker, M. Schäfer, J. Oomens, A. J. H. M.
Meijer, B. T. Pickup, R. F. W. Jackson, J. Org. Chem. 2011, 76,
1727–1734.
[14] H. C. Kolb, M. S. VanNieuwenzhe, K. B. Sharpless, Chem. Rev.
1994, 94, 2483–2547.
[15] V. I. Ognyanov, V. K. Datcheva, K. S. Kyler, J. Am. Chem. Soc.
1991, 113, 6992–6996.
[16] T. Doi, Y. Hoshina, H. Mogi, Y. Yamada, T. Takahashi, J.
Comb. Chem. 2006, 8, 571–582.
[17] E. J. Corey, R. K. Bakshi, S. Shibata, C.-P. Chen, V. K. Singh,
J. Am. Chem. Soc. 1987, 109, 7925–7926.
[18] L. Pretlow, R. Williams, M. Elliot, Chirality 2003, 15, 674–679.
[19] W. Tang, X. Zhang, Chem. Rev. 2003, 103, 3029–3069.
[20] T. P. Clark, C. R. Landis, Tetrahedron: Asymmetry 2004, 15,
2123–2137.
(R)-3-(4-Ethoxyphenyl)-2-hydroxypropanoic Acid (9c): 2-Oxo acid
4c (424.7 mg, 2.04 mmol) was reduced by using the procedure de-
scribed above, yield 37% (159 mg, 0.75 mmol), white solid, m.p.
156–160 °C. [α]2D5 = +28.3 (c = 0.23 in MeOH). 1H NMR
(400 MHz, [D4]methanol): δ = 1.37 (t, J = 6.9 Hz, 3 H, CH3-
ethoxy), 2.84 (m, 1 H, CβH2), 3.07 (m, 1 H, CβH2), 4.00 (q, J =
7.0 Hz, 2 H, OCH2), 4.27 (m, 1 H, CαH), 6.82 (d, J = 8.6 Hz, 2 H,
Ar-H), 7.18 (d, J = 8.6 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz,
[D4]methanol): δ = 15.1, 40.8, 64.3, 73.5, 115.1, 131.0, 131.4, 135.9,
158.8, 178.5 ppm. IR (KBr): ν = 3466 (O–H), 3187 (O–H), 1739
˜
(C=O) cm–1. MS (ESI): m/z (%) = 209 (100). HRMS (ESI): calcd.
for C11H13O4 [M – H]– 209.0819, found 209.0813.
2-Oxo-3-(pyridin-4-yl)propanoic Acid (4g): Starting material: 2-oxo
ester 3g (0.32 g, 1.77 mmol), yield 91% (0.28 g, 1.61 mmol), yellow
1
foam. H NMR (400 MHz, [D4]methanol): δ = 4.70 (s, 2 H, CH2),
7.44 (d, J = 6.1 Hz, 2 H, Ar-H), 8.49 (d, J = 6.1 Hz, 2 H, Ar-H)
ppm. 13C NMR (100 MHz, [D4]methanol): δ = 63.3, 122.8, 127.6,
[21] W. Zhang, Y. Chi, X. Zhang, Acc. Chem. Res. 2007, 40, 1278–
146.0, 149.9, 160.5, 173.0 ppm. IR (KBr): ν = 3431 (O–H), 1735
˜
1290.
(C=O) cm–1. MS (ESI): m/z (%) = 164 (100). HRMS (ESI): calcd.
[22] J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011, 111, 1713–
1760.
for C8H6NO3 [M – H]– 164.0353, found 164.0354.
[23] M. G. Vinogradov, E. V. Starodubtseva, O. V. Turova, Russ.
Chem. Rev. 2008, 77, 725–737.
[24] X. Han, X.-J. Jiang, R. L. Civiello, A. P. Degnan, P. V. Chatur-
vedula, J. E. Macor, G. M. Dubowchik, J. Org. Chem. 2009, 74,
3993–3996.
[25] Y. X. Chi, W. J. Tang, X. M. Zhang, in: Modern Rhodium-Cata-
lyzed Organic Reactions, 1st ed. (Ed.: P. A. Evans), Wiley-VCH,
Weinheim, Germany, 2005, pp. 1–263.
(R)-2-Hydroxy-3-(pyridin-4-yl)propanoic Acid (9g): Starting mate-
rial: 2-oxo acid 4g (116.3 mg, 0.71 mmol), yield 95% (112 mg,
1
0.67 mmol), red foam. [α]2D5 = +1.7 (c = 0.94 in MeOH). H NMR
(400 MHz, [D4]methanol): δ = 2.94 (dd, J = 8.0, 13.9 Hz, 1 H,
CβH2), 3.17 (dd, J = 3.7, 13.9 Hz, 1 H, CβH2), 4.24 (m, 1 H, CαH),
7.40 (d, J = 6.1 Hz, 2 H, Ar-H), 8.41 (d, J = 6.1 Hz, 2 H, Ar-H)
ppm. 13C NMR (100 MHz, [D4]methanol): δ = 41.5, 72.1, 126.9,
[26] S. Li, S.-F. Zhu, J.-H. Xie, S. Song, C.-M. Zhang, Q.-L. Zhou,
J. Am. Chem. Soc. 2010, 132, 1172–1179.
149.5, 151.1, 179.9 ppm. IR (KBr): ν = 3427 (O–H), 1736 (C=O)
˜
cm–1. MS (ESI): m/z (%) = 166 (100). HRMS (ESI): calcd. for
[27] M. J. Burk, C. S. Kalberg, A. Pizzano, J. Am. Chem. Soc. 1998,
C8H10NO3 [M + H]+ 168.0655, found 168.0659.
120, 4345–4353.
[28] W. S. Knowles, Acc. Chem. Res. 1983, 16, 106–112.
[29] T. Ziegler, B. Hörsch, F. Effenberger, Synthesis 1990, 575–578.
[30] I. Osprian, M. H. Fechter, H. Griengl, J. Mol. Catal. B 2003,
24–25, 89–98.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data and NMR spectra of all compounds.
[31] M.-J. Kim, G. M. Whitesides, J. Am. Chem. Soc. 1988, 110,
Acknowledgments
2959–2964.
[32] H. K. Chenault, G. M. Whitesides, Appl. Biochem. Biotechnol.
1987, 14, 147–197.
[33] J. Tao, K. McGee, Org. Process Res. Dev. 2002, 6, 520–524.
[34] L. Horner, E. O. Renth, Justus Liebigs Ann. Chem. 1967, 703,
37–43.
Generous financial support by Bayer Animal Health GmbH is
gratefully acknowledged. The authors thank Prof. U. Kragl and A.
Mell, University of Rostock, for introducing S. L. to the mem-
brane-reactor technology.
[35] CCDC-905270 (for 6b), -905271 (for 6d), -905272 (for 6i), and
-905273 (for 8h) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[1] G. M. Coppola, H. F. Schuster, α-Hydroxy Acids in Enantiose-
lective Syntheses, Wiley-VCH, Weinheim, Germany, 1997.
[2] A. Tripathi, J. Puddick, M. R. Prinsep, P. Peng Foo Lee, L.
Tong Tan, Phytochemistry 2010, 71, 307–311.
[36] A. Sutherland, C. L. Willis, J. Org. Chem. 1998, 63, 7764–7769.
[3] S. Bunyajetpong, W. Y. Yoshida, N. Sitachitta, K. Kaya, J. Nat. [37] U. Schmidt, J. Langner, B. Kirschbaum, C. Braun, Synthesis
Prod. 2006, 69, 1539–1542.
1994, 1138–1140.
[4] M. Taniguchi, K.-I. Suzumura, K. Nagai, T. Kawasaki, T.
Saito, J. Takasaki, K.-I. Suzuki, S. Jujita, S.-I. Tsukamoto, Tet-
rahedron 2003, 59, 4533–4538.
[38] H. Sajiki, K. Hirota, Chem. Pharm. Bull. 2003, 51, 320–324.
[39] E. S. Simon, R. Plante, G. M. Whitesides, Appl. Biochem. Bio-
technol. 1989, 22, 169–179.
[5] N. Valls, M. López-Canet, M. Vallribera, J. Bonjoch, Chem.
Eur. J. 2001, 7, 3446–3460.
[6] R. Lemmens-Gruber, M. R. Kamyar, R. Dornetshuber, Curr.
Med. Chem. 2009, 16, 1122–1137.
[40] U. Kragl, W. Kruse, W. Hummel, C. Wandrey, Bio-
technol. Bioeng. 1996, 52, 309–319.
[41] Millipore Corporation, Data Sheet, Series 8000 Stirred Cells
and Ultrafiltration Membranes.
[7] J. Scherkenbeck, P. Jeschke, A. Harder, Curr. Top. Med. Chem.
2002, 2, 759–777.
[8] P. Jeschke, K. Iinuma, A. Harder, M. Schindler, T. Murakami,
Parasitol. Res. 2005, 97, 11–16.
[42] M. Yoshida, T. Doi, S. Kang, J. Watanabe, T. Takahashi, Chem.
Commun. 2009, 19, 2756–2758.
Received: November 9, 2012
Published Online: February 4, 2013
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