Dynamic kinetic resolution of a wide range of secondary alcohols: Cooperation of dicarbonylchlorido(pentabenzylcyclopentadienyl)ruthenium and CAL-B

Article abstract of DOI:10.1002/ejoc.201001703

The substrate scope in the dynamic kinetic resolution ofsecondary alcohols was studied by using 31 structurallydifferent alcohols and isopropenyl acetate in the presence ofdicarbonylchlorido(pentabenzylcyclopentadienyl)rutheniumand Candida antarctica lipase B (Novozym 435, CAL-B) in toluene. The enzyme and the ruthenium complex were shown to function in a highly compatible manner allowing the conversion of the racemic alcohols into the (R)-acetates in practically theoretical yields and, in most cases, ee values exceeding 99%. The results are fully comparable to those published previously by using earlier reported, state-of-the-art ruthenium-based catalysts for the alcohol racemization. A clear benefit of the dicarbonylchlorido(pentabenzylcyclopentadienyl)ruthenium system, when compared to other (cyclopentadienyl)ruthenium racemization catalysts, is its simple and cost-efficient preparation. The substrate scope of 31 secondary alcohols was studied in the dynamic kinetic resolution by utilizing dicarbonylchlorido(pentabenzylcyclopentadienyl)rutheniumand Candida antarctica lipase B (CAL-B) in the acylation with isopropenyl acetate in toluene at room temperature. The secondary alcohols were transformed into highly enantiopure (R)-acetates (in most cases ee > 99%) in close to quantitative isolatedyields. Copyright

Full text of DOI:10.1002/ejoc.201001703

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001703
Dynamic Kinetic Resolution of a Wide Range of Secondary Alcohols:
Cooperation of Dicarbonylchlorido(pentabenzylcyclopentadienyl)ruthenium and
CAL-B
Mari Päiviö,[a] Denys Mavrynsky,[b] Reko Leino,*[b] and Liisa T. Kanerva*[a]
Keywords: Dynamic kinetic resolution / Enzyme catalysis / Cyclopentadienyl ligands / Racemization / Enantioselectivity
The substrate scope in the dynamic kinetic resolution of
secondary alcohols was studied by using 31 structurally
different alcohols and isopropenyl acetate in the presence of
dicarbonylchlorido(pentabenzylcyclopentadienyl)ruthenium
and Candida antarctica lipase B (Novozym 435, CAL-B) in
toluene. The enzyme and the ruthenium complex were
shown to function in a highly compatible manner allowing
the conversion of the racemic alcohols into the (R)-acetates
in practically theoretical yields and, in most cases, ee values
exceeding 99%. The results are fully comparable to those
published previously by using earlier reported, state-of-the-
art ruthenium-based catalysts for the alcohol racemization. A
clear benefit of the dicarbonylchlorido(pentabenzylcyclopen-
tadienyl)ruthenium system, when compared to other (cyclo-
pentadienyl)ruthenium racemization catalysts, is its simple
and cost-efficient preparation.
DKR combines the enzyme with a chemical or enzymatic
racemization catalyst, allowing continuous racemization of
the unreacted alcohol enantiomer and accordingly the
transformation of the racemic mixture into the product es-
ter in 100% theoretical yield, not reachable in the corre-
sponding kinetic resolution. The absolute configuration of
the acylated product then depends on the enantiopreference
of the enzyme, the fact which may limit the use of DKR in
cases where a lipase [usually (R)-selective when the large
group at the asymmetric center has priority over the me-
dium-size group like with (R)-1-phenylethanol] produces
the product as the undesired enantiomer. In some cases,
Subtilisin Carlsberg (a serine protease) with opposite en-
antiopreference to that of most lipases has been used in
overcoming the problem.[2]
Candida antarctica lipase B (CAL-B as a Novozym 435
preparation) and suitable transition-metal catalysts form
combinations extensively studied in the DKR of racemic
alcohols.[3] The concept was first introduced by Williams[4]
and Bäckvall[5] in the late 1990s. Thereafter, various metal
catalysts have been shown to racemize alcohols. However,
only certain metal catalysts maintain the crucial require-
ments of full racemization power together with stability
during DKR. Half-sandwich ruthenium complexes 1–3 rep-
resent this far the most successful and applied racemization
catalyst design for the DKR of various types of secondary
alcohols with CAL-B (Figure 1). The initially employed
Shvo catalyst 1 requires elevated temperatures for generat-
ing the active monoruthenium species,[3] whereas the mono-
meric ruthenium complexes 2[6] and 3[7] can be utilized at
ambient temperatures by activation with potassium tert-but-
oxide. Nevertheless, the ruthenium-based complexes 1–3
Introduction
Lipases (EC 3.1.1.3) are most commonly used as enan-
tioselective biocatalysts in the kinetic (KR) and dynamic
kinetic (DKR) resolutions of racemic alcohols.[1] This is a
natural consequence of their good availability and excellent
regio- and stereoselectivity in addition to their stability in a
variety of reaction media, including organic solvents and
ionic liquids, which dissolve organic substrates better than
aqueous environments do. Lipases also accept a broad
range of structurally different alcohols (or more generally
nucleophiles) and carboxylic acids and their derivatives as
substrates in addition to the natural substrates, triglycerides.
The KR method, affording in the best case both enantio-
mers of a racemic mixture at 50% conversion in a single
reaction, is beneficial when both enantiomers are impor-
tant. In such a case, one enantiomer remains unchanged,
while the other becomes the new reaction product. Espe-
cially lipase-catalyzed enantioselective acylation of racemic
secondary alcohols with achiral esters in organic solvents
has afforded a large number of alcohol enantiomers to be
used as such or as intermediates for further transformations
into pharmaceutically active compounds and fine chemi-
cals. On the other hand, the concept of lipase-catalyzed
[a] Institute of Biomedicine, Department of Pharmacology, Drug
Development and Therapeutics/Laboratory of Synthetic Drug
Chemistry and Department of Chemistry, University of Turku,
20014 Turku, Finland
E-mail: lkanerva@utu.fi
[b] Laboratory of Organic Chemistry, Åbo Akademi University,
20500 Åbo, Finland
E-mail: reko.leino@abo.fi
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001703.
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Dynamic Kinetic Resolution of a Wide Range of Secondary Alcohols
can be considered far from optimal, especially in terms of ate in the presence of CAL-B and ruthenium catalyst 4 in
cost and ease of preparation. With this in mind, we have toluene (Scheme 1). The reactions were performed in a
earlier reported the simple and cost-efficient preparation of glovebox under nitrogen.
dicarbonylchlorido(pentabenzylcyclopentadienyl)ruthe-
nium (4) bearing benzyl substituents on the cyclopen-
tadienyl ring instead of the phenyl groups of 1–3.[8] A clear
benefit in the synthesis of complex 4 is the simple prepara-
Results and Discussion
tion of its ligand precursor by alkylation of cyclopentadiene
The scope and limitations of the dynamic kinetic resolu-
with benzyl alcohol facilitated by azeotropic water removal tion method utilizing complex 4 and CAL-B (Novo-
under basic conditions.[9] An additional advantage of com- zym 435) were studied by subjecting a wide range of struc-
plex 4 is its considerably higher solubility induced by the turally varying secondary alcohols (substrates S1–S31) to
benzyl substituents when compared with the polyphenylcy- acylation with isopropenyl acetate in toluene at room tem-
clopentadienyl-ligated catalysts, which – in some cases, in perature (23 °C) in a glovebox under nitrogen with water
solvents commonly used for DKR reactions – may operate and oxygen contents below 1 ppm (Scheme 1). Due to the
at the limits of solubility. In previous work we have shown low racemization rate of substrate S24 its DKR was per-
that complex 4 forms an active racemization catalyst for the formed at 60 °C in a tightly closed glass bomb. The bomb
DKR of 1-phenylethanol and 1-(furan-2-yl)ethanol with was charged in the glovebox and heated in an oil bath in a
CAL-B in toluene, providing effectiveness in terms of yield fume hood. Toluene was chosen as a solvent as it had al-
and enantiopurity comparable to the best ruthenium cata- ready been proved to be well accepted by both the lipase
lyst 3 reported in the literature.[8a] It was also previously and the ruthenium complex 4.[8] Toluene also dissolves the
demonstrated that both 3 and 4 are applicable in a large- aromatic secondary alcohols and ester products relatively
scale DKR, transforming racemic 1-phenylethanol [at a well and is accepted for industrial applications. One of the
1 mol (122 g) scale] into the (R)-acetate with excellent yield benefits of enzymatic synthesis is that enzymes allow effec-
and ee Ͼ 99%.[8b,10]
tive reactions at ambient temperatures, reducing the forma-
tion of possible side products. Such a side product, the for-
mation of which was avoided herein, is the formation of
the ketones from the corresponding alcohol substrates. To
ensure reproducibility and reliability of the system, parallel
reactions were performed. The (R)-ester products were iso-
lated for each substrate by column chromatography in ex-
cellent (90–99%) yields as shown in Table 1. The alcohols
S1, S3, S7–S10), S18, S19, S22–S28 and S30 were selected
due to their previously reported promising behavior in the
DKRs employing (pentaphenylcyclopentadienyl)ruthenium
complex 3 and CAL-B. The DKR results reported for these
substrates earlier are shown in Table 1 in italics.[7c] The re-
maining 14 secondary alcohols were selected for extending
the structural diversity and due to their importance as
enantiopure compounds for different purposes in synthetic
chemistry. To exemplify, alcohols S7, S13 and S16 are versa-
tile building blocks for cross-coupling reactions.[11] The
DKRs of polyfunctional substrates bearing conventional
and easy to remove protective groups in turn, such as meth-
oxymethyl ether (MOM) and tert-butoxycarbonyl (Boc) in
S11 and S12, have not been described before. Also the
DKRs of ortho-substituted alcohols S14–S16 and that of
S17 have not been disclosed earlier. The reactions reaching
full conversion (no remaining substrate alcohol detected by
chiral GC analysis) are indicated with yields Ͼ 99%. Pos-
sible formation of the corresponding ketone (a side prod-
uct) from the alcohol in question was also carefully moni-
tored by GC. In most cases ketones were not detected, and
when observed (substrates S7, S20, S21, and S25), the levels
were negligible (Յ 1%).
Figure 1. Half-sandwich ruthenium complexes 1–4.
Our aim herein has been to study further the general
usability of complex 4 as a racemization catalyst in the
DKR of secondary alcohols. For this purpose, 31 alcohols
(structures S1–S31, in accordance with the entries in
Table 1) were subjected to acylation with isopropenyl acet-
Compatibility of the chemo- and the enzymatic biocata-
lysts in DKR indicates that the enzymatic KR of the race-
mic alcohol remains enantioselective and that the racemiza-
tion of the less reactive alcohol enantiomer is fast compared
Scheme 1. DKR of secondary alcohols with 4; alcohols involved
shown in Table 1.
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M. Päiviö, D. Mavrynsky, R. Leino, L. T. Kanerva
SHORT COMMUNICATION
Table 1. Dynamic kinetic resolution of secondary alcohols (1 mmol) with isopropenyl acetate (1.2 mmol) catalyzed by 4 (2 mol-%) and
CAL-B (10 mg) in the presence tBuOK (2.5 mol-%) and Na2CO3 (0.5 mmol) under nitrogen in toluene (2 mL) at 23 °C. Data in italics
from ref.[7c]: substrate (1 mmol), 3 (5 mol-%), CAL-B (6 mg), tBuOK (5–8 mol-%), Na2CO3 (1 mmol) in toluene (2 mL). Conversions and
ee values are averages of at least 3 reaction runs.
[a] Unless otherwise noted, determined by chiral GC. [b] Isolated yield in parentheses. [c] Toluene/THF mixture (4:1, 5 mL). [d] Deter-
mined by NMR spectroscopy. [e] Determined by NMR spectroscopy as the corresponding Mosher’s ester. [f] Toluene used 4 mL. [g]
Toluene/THF mixture (4:1, 2.5 mL). [h] 60 °C. [i] CAL-B (40 mg).
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Dynamic Kinetic Resolution of a Wide Range of Secondary Alcohols
to the enzymatic acylation. Moreover, other reagents such optimizing the reaction system especially with respect to the
as added bases used to activate the chemocatalyst should catalyst loadings. After thorough drying of all the compo-
not influence the enzyme nor should they result in chemo- nents and transferring of the mixture under nitrogen into a
catalytic ester formation/decomposition. Products of enzy- glovebox, we were able to decrease the Ru-catalyst loading
matic reactions, such as acetone, should not destroy the by one half (from 4 mol-% to 2 mol-%) in a 1 mmol scale
chemocatalyst. Under the conditions of such compatibility, reaction without loosing in efficiency of the system. Earlier
the less reactive alcohol can be expected to remain racemic the decrease in the catalyst loading from 4 mol-% has re-
throughout the DKR, allowing the estimation of the theo- quired a significant increase in reaction scale to ensure ef-
retical enantiomeric excess (ee) attainable for the ester prod- ficient racemization.[10] Reduction in the amount of iso-
uct in DKR by extrapolating the plot of product ee vs. con- propenyl acetate to 1.2 equiv. over the substrate alcohol
version in the corresponding KR to zero conversion as en- (1.5 equiv. was previously used[8b]) affected the acetic acid
ables the use of the Sih and Chen equation and the E content of the mixture, allowing the amount of Na2CO3 to
value.[12] It is often concluded that E = 20 is a limit for be reduced to half of what was used before. Under such
successful KR. It may be worth to emphasize that the KR conditions the (R)-esters were obtained in excellent enantio-
then can produce only the unreacted enantiomer enantio- purities [ee mostly Ͼ 99%, i.e., only one enantiomer was
pure at over 60% conversions, while the theoretical maxi- observed by chiral GC analysis (Table 1)]. This is in accord-
mum product ee (and the theoretical ee in DKR) is only ance with the excellent enantiopurities observed earlier by
90%. For the DKR to lead to product formation with ee = Bäckvall and co-workers under their DKR conditions for
99%, E = 200 or higher is necessary in the corresponding secondar alcohols (Table 1).[7c]
KR.
The time required for reaching full conversion in DKR
In the DKR of the alcohols S1–S31 with isopropenyl is one measure of its effectiveness. The comparison of litera-
acetate catalyzed by complex 4 and CAL-B in dry toluene, ture results that are based on the use of lipase catalysis in
possible side reactions (other than ketone formation from KR and DKR is not always straightforward (although
the alcohol) are the hydrolysis of isopropenyl acetate/(R)- often performed in the literature), as the activity of the en-
ester produced by enzymatic action and the formation of zyme is rarely given and may differ from case to case. Com-
racemic esters P1–P31 caused by the presence of tBuOK. parison of the DKR results of our work with catalyst 4 and
Water (often called residual water) for ester hydrolysis origi- the published work[7c] with catalyst 3 is not an exception in
nates from the seemingly dry enzyme preparation. This is this respect. For the results in Table 1, the amount of CAL-
particularly possible with CAL-B as the Novozym 435 B was set to 10 mg to match such reactivity that the DKR
preparation (CAL-B adsorbed on
a divinylbenzene- of 1-phenylethanol (1 mmol) reached full conversion in 3 h
crosslinked, hydrophobic macroporous polymer based on as given in the published method by utilizing complex 3[7c]
methyl and butyl methacrylic esters), because this lipophilic (Entry 1). Based on initial rate measurements for the acyl-
immobilization material will readily release any water into ation of racemic 1-phenylethanol (0.5 m) with isopropenyl
the dry reaction mixture.[13] Moreover, a water tunnel, exi- acetate (0.6 m) in toluene, enzymatic activity of
sting in some enzymes and allowing an easy access for water 2.6 mmolmin–1 g–1 was obtained for the CAL-B prepara-
directly from the medium to the active site, was previously tion used throughout the present work. In spite of the
found in CAL-B.[14] Accordingly, the residual water as a above-mentioned discrepancy, clear reactivity differences
nucleophile can easily hydrolyze the acyl-enzyme intermedi- can be proposed for DKRs with complexes 3 and 4 with
ate [formed in the first mechanistic step of a reaction cata- alcohols S8, S10, S25–S27 and S30. Differences in reactivity
lyzed by serine hydrolases when an achiral acyl donor/the are observed both ways, alcohols S8, S26, S27 and S30 be-
(R)-ester or -acid produced reacts with the serine hydroxy ing more reactive in the presence of complex 4, whereas the
group] at the active site in an otherwise dry system. As a opposite is observed for alcohols S10, S19 and S22. This
consequence, some acetic acid from isopropenyl acetate is may reflect some mechanistic differences between the two
formed when the DKR proceeds. An active intermediate racemization catalysts but may also be due to the presence
formed from the ruthenium catalyst 4 when activated with of minor impurities acting as enzyme inhibitors or poisons
tBuOK is unstable in the presence of acids. One reason for for the racemization catalyst.
the good compatibility of CAL-B and complex 4 (as well
The results in Table 1 show that in the DKRs using
as complexes 1–3)[3,7] observed in toluene is certainly the CAL-B with either complex 3 or 4, the nature of the para
hydrophobic nature of the solvent minimizing the ability to substituents (electron-donating/electron-withdrawing) in 1-
stipe the residual water from the immobilized CAL-B. Thus, phenylethanols has not a clear effect on the reactivity (S2–
Na2CO3 must be added to neutralize the formed acetic acid S7, S11 and S12 vs. S1), the most electronegative substitu-
in situ. The strongly basic tBuOK in equivalent amounts to ents p-CF3, p-CN and p-NO2 in S8–S10 being exceptions.
complex 4 is used for the activation. Care is needed to re- As is shown for products P4 and P5 in the Supporting In-
tain the content of tBuOK as low as possible in order to formation, dehalogenated P1 was seen in the GC chromato-
prevent nonenzymatic chemical formation of racemic esters, grams. As the dehalogenated products (3 mass-% with S4
lowering the product ee. If not carefully controlled, chemi- and 1.5 mass-% with S5) were detected also in the 1H NMR
cal ester formation can be considerable, especially in the spectra of isolated products it is possible that the product
beginning of the DKR. With this in mind, we focused on is formed in the DKR process. In the DKR of 1-(4-ni-
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M. Päiviö, D. Mavrynsky, R. Leino, L. T. Kanerva
SHORT COMMUNICATION
trophenyl)ethanol (S10), the observations suggest the decay nitrophenyl)ethanol (S10), the observation suggests the de-
of the ruthenium catalyst 4 but not that of the catalyst 3. cay of the ruthenium catalyst 4.
When the DKR was performed with catalyst 3 under other-
The simple, cost-effective and high-yield preparation of
wise similar conditions, conversion over 95% was reached 4 together with its high performance makes this complex
in only 8 h, whereas the same conversion took 4 d in the an attractive candidate as leading racemization catalyst for
presence of complex 4 (conversions monitored by 1H NMR future DKR applications.
spectroscopy). Moreover, the color of the activated complex
4 changed immediately to an intensive dark cherry color
when S10 was added; ortho and meta substitutions both in-
Experimental Section
Dynamic Kinetic Resolution: Ruthenium complex
4 (14 mg,
creased the time required to complete the DKR (S13–S17
vs. S1). With ortho-substituted 1-phenylethanols consider-
able retardations in the reactivity were observed with S14–
S16 possibly due to steric effects, the effect of the o-Br sub-
stituent in the DKR of S16 being more than expected (7 d
to full conversion). The transformation of bulky bicyclic
secondary alcohols S18–S21 into the corresponding (R)-
acetates in quantitative yields was also possible in the pres-
ence of complex 4. The DKR of 1-naphthylethanols, that of
1-(1-naphthyl)ethanol in particular (Entry 19), is interesting
since again the presence of 4 leads to a low reactivity com-
pared to the reported result with 3.[7c] Also, different het-
erocyclic secondary alcohols S22–S24 were converted into
the corresponding highly enantiopure acetates within rea-
sonable reaction times. In the case of 1-(4-pyridyl)ethanol
(S24) elevated reaction temperature (60 °C) was needed to
accomplish the DKR. 2-Octanol (S25) and 1-cyclohexyl-
ethanol (S26) were also smoothly transformed into the cor-
responding (R)-acetates in high yields. The DKR of aro-
matic secondary alcohols S27–S29 with the alcoholic hy-
droxy function at different positions of the carbon chain
gave fast reactions and excellent yields. The DKRs of S30
and S31 produced the (R)-acetates in high yield and enantio-
purity without side reactions with our complex 4. Signifi-
cant ketone formation was previously reported for the
DKR of S30 in the presence of catalyst 3.[7c] Ketone forma-
tion was not a problem in our studies with complex 4.
20 μmol), CAL-B (10 mg) and Na2CO3 (53 mg, 0.5 mmol) were
weighed into a pre-dried test tube in a glovebox, and toluene
(1 mL) was added. The mixture was stirred for 2 min before a solu-
tion of tBuOK (0.25 m in THF; 100 μL, 0.025 mol) was added. Af-
ter stirring for 5 min, one of the substrates S1–S31 (1 mmol) was
introduced, and the mixture was stirred for another 5 min before
the addition of isopropenyl acetate (135 μL, 1.2 mmol). The reac-
tions were monitored by taking samples (10 μL), derivatizing them
with propionic anhydride in the presence of DMAP in pyridine
(1%), filtering the samples through silica by using ethyl acetate as
an eluent in order to prevent contamination of the gas chromato-
graph with ruthenium and analyzing them by GC. Isolation of the
products was performed by silica gel column chromatography elut-
ing with hexane/CH2Cl2 (nonvolatile products), with pentane/
CH2Cl2 (volatile products) or with hexane/AcOEt [(R)-1-(4-pyr-
idyl)ethyl acetate]. NMR spectroscopic data and optical rotation
values for isolated products can be found in the Supporting Infor-
mation.
Initial Rate Measurements and Enzyme Activity: 1-Phenylethanol
(120 μL, 1 mmol) was added to a reaction vessel containing CAL-B
(3 mg) and toluene (2 mL). The acylation was initialized by adding
isopropenyl acetate (135 μL, 1.2 mmol). The reactions were moni-
tored by taking samples at intervals, filtering off the enzyme and
analyzing the samples by GC equipped with a chiral column after
derivatization with propionic anhydride in the presence of DMAP
in pyridine (1%).
Determination of the Enantiomeric Excess by NMR Spectroscopy:
Isolated acetates were first subjected to alkaline hydrolysis,[15]and
the obtained alcohols were then converted into the corresponding
(+)-(S)-MTPA esters[16] according to standard procedures. Dichlo-
romethane was used as a solvent instead of tetrachloromethane due
to the toxicity of the latter. Determination of the ee values was
performed by comparing integral intensity of the minor and the
major diastereomers.
Conclusions
After thorough optimization, the dicarbonylchlorido-
(pentabenzylcyclopentadienyl)ruthenium (4) and CAL-B
catalyzed DKR of a wide range of structurally varying sec-
ondary alcohols was studied by using the acylation with
isopropenyl acetate in toluene. The use of a glovebox al-
lowed convenient and controlled conditions for reliable and
reproducible reactions and convenient sample taking. The
secondary alcohols studied were transformed into highly
enantiopure (R)-acetates (mostly ee Ͼ 99) in close to quan-
titative yields, the reaction times needed for full conversions
considerably depending on the substrate structure. Since the
ruthenium complex 4 catalyzed the in-situ racemization of
the less reactive alcohol enantiomers effectively, the lipase-
catalyzed resolution reaction became rate-limiting in the
overall reaction. The DKR results in the presence of race-
mization catalysts 3 and 4 are comparable in most cases.
However, clear differences in the reactivity can be seen with
alcohols S8, S10, S25–S27 and S30. In the DKR of 1-(4-
Supporting Information (see footnote on the first page of this arti-
cle): Experimental Section, GC and spectral analyses of the pre-
pared (R)-acetate esters of secondary alcohols P1–P31 obtained in
the DKR of S1–S31.
Acknowledgments
M. P. and D. M. thank professor J.-E. Bäckvall for a research study
visit to the Arrhenius Laboratory of the Stockholm University.
Magnus Perander and Yury Brusentsev are thanked for technical
assistance. Financial support from the Finnish Funding Agency
for Technology and Innovation (Technology Programme SYMBIO
Project #40168/07: Developing New Chemoenzymatic Methods
and Biocatalysts) is gratefully acknowledged.
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Received: December 20, 2010
Published Online: February 3, 2011
Eur. J. Org. Chem. 2011, 1452–1457
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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