Ruthenium- and lipase-catalyzed inversion of l-lactates

Article abstract of DOI:10.1016/j.tetlet.2012.08.126

The ruthenium catalyzed inversion of l-lactic acid esters in the presence of Novozym 435 is described which give d-lactates in good yields and with >99% ee. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.08.126

Tetrahedron Letters 53 (2012) 6326–6328
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ruthenium- and lipase-catalyzed inversion of L-lactates
Ivan A. Shuklov a, , Natalia V. Dubrovina a, Joachim Schulze b, Wolfgang Tietz b, Klaus Kühlein c,
⇑
Armin Börner a,d,
⇑
a Leibniz-Institut für Katalyse an der Universität Rostock e.V., A.-Einstein-Str. 29a, 18059 Rostock, Germany
b Uhde GmbH, Hans-Weigel-Str. 2a, 04319 Leipzig, Germany
c Fasanenstr. 41, 65779 Kelkheim, Germany
d Institut für Chemie der Universität Rostock, A.-Einstein-Str. 3a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The ruthenium catalyzed inversion of L-lactic acid esters in the presence of Novozym 435 is described
Received 15 June 2012
Revised 1 August 2012
Accepted 29 August 2012
Available online 13 September 2012
which give D-lactates in good yields and with >99% ee.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Inversion
Lactate
Stereoisomers
Ruthenium
Lipase
Introduction
More advantageous seems to be the use of L-lactic acid as start-
ing material. Indeed, base mediated racemization of corresponding
L,L-dilactides gives a mixture of racemic dilactides and meso-dilac-
tide, which can be separated by crystallization.6 However, by this
Lactic acid and its derivatives are important chemicals and syn-
thetic building blocks for food and polymer industry. Of particular
interest is poly(
L
-lactide) (PLLA) derived from natural
L
-(+)-lactic
methodology the maximum yield of the desired
D-dilactide and
acid. PLLA is a biodegradable polymer.1 This property gives it a
consequently of -lactic acid cannot exceed 33% due to the estab-
D
broad potential for applications with special focus on ecological
lished equilibrium of all three stereoisomeric dilactides.
and medicinal aspects.
is produced in a large scale preferentially via fermentation of sugar
feedstocks (biomass).
nature, but it is less abundant and occurs frequently as a mixture
of both optical isomers in variable proportions. Since a couple of
L
-Lactic acid displaying (S)-configuration
Other traditional methods of conversion of one enantiomer of
hydroxyl-compound into another were also applied to
L-lactates.
D
-(R)-(À)-Lactic acid is also present in
The two-step inversion of -ethyl lactate via corresponding sulfonates
L
proceeds either in good yield or in good stereoselectivity, but requires
additional modification steps.7 The oxidation of hydroxyl group lead-
ing to pyruvates, followed by asymmetric hydrogenation was inten-
sively investigated and proceeds with excellent stereoselectivities.
This approach seems to be the most powerful known synthetic pro-
years, there is a large need for
mer for PDLA or as a co-monomer for polymerization with
D
-lactic acid especially as a mono-
-lactic
L
acid, since polymers containing both enantiomers show some
special material properties in comparison to homochiral PLA.1e,2
Currently PLLA is dominating the market.3
cedure for inversion of L-lactates. Nevertheless it could be performed
only in two synthetic steps with separation.8 Mitsunobu inversion of
lactates was also investigated. Application of DEAD or other azodi-
carboxylates in the presence of phosphines for the transformation
shows very good enantioselectivities but slow reaction rates.9
In this Letter we suggest a catalytic one-step conversion of
Besides numerous biochemical methods4 there are also some
chemical approaches for the production of enantiopure
D-lactic
acid. For example, the Rh-catalyzed asymmetric hydrogenation of
unsaturated lactic ester precursors in propylene carbonate gives
access to both enantiomers in >99% ee.5 However, the preparation
of the substrates is rather costly.
L
- into
achieved by combination of the ruthenium(II) catalyzed epimeriza-
tion of -lactates combined with a stereodiscriminating lipase
D-lactates. We will demonstrate that this inversion can be
L
mediated transesterification. In the results the O-acetylated optical
antipode is obtained in excellent enantioselectivities and good
yields (Scheme 1).
⇑
Corresponding authors.
E-mail addresses: ivan.shuklov@catalysis.de (I.A. Shuklov), armin.boerner@
catalysis.de (A. Börner).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.126

I. A. Shuklov et al. / Tetrahedron Letters 53 (2012) 6326–6328
6327
enzyme,
OH
O
clearly shows that under these conditions O-acetylation with iso-
propenylacetate is much faster than racemization of methyl lactate.
Since partial oligomerization of the starting material was observed
with the ruthenium-complex 1/t-BuOK, in turn only Shvo’s catalyst
(2) was used in the subsequent trials.
OH
OAc
O
Ru-cat.,
Ru-cat.,
acylating agent
OR
OR
OR
OR
O
O
O
Scheme 1. Principle of the inversion of L-lactic acid esters.
These initial experiments have shown that substrate and reac-
tion conditions should be more carefully selected in order to
achieve epimerization and subsequent kinetic resolution. In order
to invert the ratio of the rates between racemization and enzy-
matic O-acetylation in the next trials we turned to the n-butyl es-
ter of (S)-lactic acid. As acylating agents besides isopropenyl
acetate, p-chlorophenyl acetate and 2-pyridinylacetate were tested
(Table 1). The reaction with 2-pyridinylacetate is extremely slow
and the desired product (R)-O-acetyl-(n-butyl)lactate was formed
in only moderate enantioselectivities (Run 2). In contrast to (S)-
methyl lactate the acylation of (S)-butyl lactate with isopropeny-
lacetate inverted the starting material with high conversion and
provided the product with 95% ee (Run 1). Application of p-chloro-
phenyl acetate slightly increased the conversion, but did not affect
the high enantioselectivity (Run 3).
The suggested transformation of one enantiomer of chiral alco-
hol into another is based on the possibility of ruthenium-catalyzed
epimerization of alcohol bearing hydroxyl-group on the stereocen-
ter followed by stereoselective enzyme catalyzed acetylation. The
inversion could be an attractive alternative for the synthesis of
non-natural chiral alcohols such as D-lactates from their natural
counterparts. This transformation was up to our knowledge never
executed, despite of intensive work on the transformation of race-
mic alcohols and diols into the single stereoisomer of chiral alcohol
with ruthenium or palladium catalysts and lipases.10
The dynamic kinetic resolution (DKR) of racemates of some
a-
hydroxy carboxyl acids was investigated. However higher temper-
atures and longer reaction times are required.11 Neither dynamic
kinetic resolution nor epimerization of enantiomerically pure lactic
acid esters were reported up to now.
An increase of the reaction temperature up to 100 °C did not im-
prove the conversion. Surprisingly the enantioselectivity remained
constantly high also at high temperatures (Run 4).
Results and discussion
Addition of sodium carbonate in the ruthenium catalyzed epi-
merization frequently improves the reaction rates in DKR of alco-
hols.14 The positive effect of Na2CO3 is attributed to the removal
of traces of acids originating either from the polyacrylate support,
the acetyl donor, or the enzyme itself, which interfere with the
ruthenium catalyst. In our case the addition of Na2CO3 led to a de-
cline of the ee-values without a significant improvement of the
reaction rate (Runs 5–6). Probably the inorganic base initiates the
competitive chemical acylation of the starting material.
Examination of the reaction rate showed that the ruthenium
catalyzed epimerization is slightly decelerated in the presence of
the enzyme. Therefore, in subsequent trials Novozym 435 and
the best acylating reagent 4-Cl-C6H4OAc were added when the epi-
merization was almost finished. A comparison of the results shows
that not only the conversion, but also the stereochemical outcome
of the inversion takes benefit from these modified reaction
conditions (Table 2, Runs 2, 4 and 6). When Novozym 435 and
the acylation reagent are added after 24 h reaction time an enanti-
oselectivity of >99% for the formation of (R)-O-acetyl-(n-butyl)lac-
tate is observed (Run 2). The enantioselectivity is dependent on the
nature of the ester group. Replacement of n-butyl by ethyl dimin-
ished the ee-values. Thus, (R)-O-acetyl-methyllactate was formed
only in 90% ee under the optimized conditions (Run 6).
Our initial experiments revealed that racemization of (S)-methyl
lactate takes place only at high temperatures. Thus, the substrate
could be completely converted into the racemic compound within
20 h at 80 °C in the presence of the ruthenium–complex 1 and
potassium tert-butylate or by using the ‘Shvo catalyst’ 2.12
O
O
Ph
Ph
Ph
Ph
H
Ph
Ph
Ph
Ph
Ph Ph
Ph
Ph
Ph
H
Ru
Ru Cl
Ru
OC
OC
OC
CO
CO
2 (Shvo's catalyst)
OC
1
For the kinetic resolution of racemic lactates, Candida antarctica
B at 25–65 °C on acrylic resin (Novozym 435) has been suggested.13
Our first experiments revealed that also the non-enzymatic and
therefore non-stereoselective chemical acetylation of lactate may
occur at higher temperatures in the presence of metal catalyst. Thus
the reaction of (S)-methyl lactate in the presence of isopropenylac-
etate, Novozym 435 and Ru-complex 1/t-BuOK at 80 °C gave (S)-O-
acetyl-methyllactate without loss of enantioselectivity (>99% ee). It
Table 1
Inversion of (S)-(n-butyl)lactate with different acetylating agentsa
Ru-cat.2, Novozym 435,
acylating agent, toluene
OAc
O
OH
O
O
O
Run
Acylation agent
Additive
Temperature (°C)
Time (h)
Conversionb (%)
eec (%)
1
2
3
4
5
6
Isopropenyl acetate
2-AcOPy
4-Cl-C6H4OAc
4-Cl-C6H4OAc
4-Cl-C6H4OAc
4-Cl-C6H4OAc
None
None
None
None
Na2CO3
Na2CO3
80
80
80
100
80
80
84
130
110
90
90
90
78
11
80
65
72
60
95 (R)
73 (R)
95 (R)
97 (R)
57 (R)
69 (R)
d
e
a
b
c
Reaction conditions: 80 °C, 10 mL toluene; 100 units Novozym 435, 0.5 mmol (n-butyl)lactate, 1.8 mmol 4-Cl-C6H4OAc.
For the determination of conversion GC was used (50 m HP5).
GC (Lipodex E).
150 mg Na2CO3.
50 mg Na2CO3.
d
e

6328
I. A. Shuklov et al. / Tetrahedron Letters 53 (2012) 6326–6328
Table 2
added and the mixture was stirred at 80 °C for additional 80 h.
The composition of the reaction mixture was analyzed by gas
Inversion of (S)-alkyl lactates with 4-Cl-C6H4OAc
chromatography.
OAc
O
OH
Ru-cat. 2, toluene, 80 °C, 24 h
OR
OR
Novozym 435, 4-Cl-C6H4OAc, 80 °C
Acknowledgments
O
We acknowledge financial support by Uhde GmbH Leipzig. The
authors thank Dr. C. Fischer, S. Buchholz, and S. Schareina for excel-
lent analytical support.
Run
R
Conditionsa
Time (h)
Conversionb (%)
ee (%)
1
2
3
4
5
6
Bu
Bu
Et
Et
Me
Me
A
B
A
B
A
B
110
82
82
82
82
82
80
88
95
>99
88
94
88
90
85c
90c
90c
91c
References and notes
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a
General reaction conditions: 80 °C, 10 mL toluene, 100 units Novozym 435,
0.5 mmol alkyl lactate, 1.5 mmol p-chlorophenyl acetate: Condition A: 4-Cl-
C6H4OAc was added at the beginning of the reaction; Condition B: 4-Cl-C6H4OAc
and Novozym 435 were added to the reaction mixture after 24 h.
b
GC-conversion.
Without calibration.
c
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OH
(R)
LiAlH4
, Et2O
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>99 %ee
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:
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isolated by column chromatography on SiO2 with gradient elution
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In conclusion, a metal- and lipase- catalyzed inversion of L-lactic
acid esters was demonstrated. This method allows to convert (S)-
butyl lactate in the presence of Ru-catalysts, lipase Novozym 435
and 4-Cl-C6H4OAc as acylating agent with up to 88% conversion
and gives (R)-O-acetyl-(n-butyl)lactate in >99% ee.
Experimental section
General procedure A for inversion of L-alkyl lactates: A Schlenk
tube was charged with Shvo’s catalyst 2 (27 mg, 0.045 mmol), alkyl
lactate (0.5 mmol), Novozym 435 (10 mg, 100 units), p-chloro-
phenyl acetate (0.21 mL, 1.5 mmol), and abs. degassed toluene
(5 mL) at rt. The mixture was stirred for 82 h at 80 °C. The compo-
sition of the reaction mixture was analyzed by gas
chromatography.
General procedure B for inversion of L-alkyl lactates: A Schlenk
tube was charged with Shvo’s catalyst 2 (27 mg, 0.045 mmol), alkyl
lactate (0.5 mmol), and abs. degassed toluene (5 mL) at rt. The
mixture was stirred for 24 h at 80 °C. Then Novozym 435 (10 mg,
100 units) and p-chlorophenyl acetate (0.21 mL, 1.5 mmol) were