Dynamic kinetic resolution of a tertiary alcohol

Article abstract of DOI:10.1039/c9cc09103c

In spite of the tremendous success of dynamic kinetic resolutions for a broad range of compound classes, tertiary alcohols and their corresponding esters have still remained as one of the most challenging substrates for this type of process. This is due t

Full text of DOI:10.1039/c9cc09103c

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DOI: 10.1039/C9CC09103C
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Dynamic Kinetic Resolution of a Tertiary Alcohol
Franziska Kühn,a Satoko Katsuragi,b Yasuhiro Oki,b Cedric Scholz,a Shuji Akai,*b and Harald
Gröger*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
represents an important drug for the treatment of HIV
infections.3
Abstract: In spite of the tremendous success of dynamic kinetic
resolutions for a broad range of compound classes, tertiary alcohols
and their corresponding esters have still remained as one of the
most challenging substrates for this type of process. This is due to
the size and steric hindrance of the tertiary alcohol as well as to the
difficulty in finding reaction conditions for the racemization of such
From a synthetic point of view, one of the favoured overall concepts
for the enantioselective approach to tertiary alcohols is dynamic
kinetic resolution (DKR), since such a process engineering could
compounds being at the same time compatible with the resolution provide access to a wide range of enantiomerically pure tertiary
reaction, which preferably is carried out with an enzyme. In this
study the first example of a dynamic kinetic resolution of a racemic
tertiary alcohol is presented. The desired synthesis of the resulting
enantiomerically pure ester was achieved by combining a lipase-
catalyzed kinetic resolution with an in situ racemization utilizing a
bio-compatible oxovanadium-catalyst. First, the two individual
reactions were examined, improved and adjusted to be compatible
with each other. Subsequently, addition of both catalysts in tailor-
made portions led to the desired combined process and delivered
the product with >99% ee and a conversion exceeding 50%, thus
proving such a desired dynamic kinetic resolution of a tertiary
alcohol.
alcohols. An advantage of this DKR approach is that the racemic
substrates are typically easily accessible by various chemical
methods and that the desired product could be obtained in an
irreversible fashion in theoretically 100% yield and in
enantiomerically pure form (>99% ee). The chemoenzymatic
DKR is very well established in the field of secondary alcohols by
combining metal-catalyzed racemization and a lipase-catalyzed
acylation as concurrently occurring reaction steps.4 Prominent
examples of such DKRs have been demonstrated by Bäckvall et
7
al.,4,5 Kim et al.,6 and Berkessel et al. with the first one being
applied already on technical scale in modified form.4
Remarkably, however, no successful extension of this concept
towards tertiary alcohols was achieved so far. Very recently, an
efficient racemization protocol for tertiary alcohols has been
reported for the first time by the Bäckvall group,8 although
compatibility with an enzymatic resolution, thus leading to a
DKR, has remained an unsolved task up to now. The difficulty in
developing racemization strategies for tertiary alcohols might
be in particular due to two reasons: first, the well-established
metal-catalyzed racemization through a redox process being
successful for secondary alcohols cannot be utilized in the case
of tertiary alcohols, as there is a lack of an oxidizable C–H-bond.
Second, the tertiary alcohols are prone to decomposition
leading to elimination side-products even under slightly acidic
conditions and the resulting esters are even more sensitive.4b
Recently, some of us developed an alternative way for a DKR of
secondary alcohols proceeding by means of oxovanadium-
catalyzed C–O bond cleavage generating a cation followed by
the reformation of the C–O bond.4b,9 We envisioned that such a
Despite of tremendous achievements in the field of asymmetric
catalysis in general 1 and its application to tertiary alcohols in
particular,1 enantioselective synthesis of tertiary alcohols with
the aid of dynamic kinetic resolution using enzymes has
remained an unsolved challenge so far. Such an access would be
highly desirable due to the need of enantiomerically pure forms
of tertiary alcohols or acylated derivatives thereof in the field of
pharmaceuticals and natural product synthesis.2 For example;
the tertiary alcohol-derived pharmaceutical Efavirenz®
a. Chair of Organic Chemistry and Biotechnology, Faculty of Chemistry
Bielefeld University
Universitätsstraße 25, 33615 Bielefeld, Germany
E-mail: harald.groeger@uni-bielefeld.de
b. Graduate School of Pharmaceutical Sciences
Osaka University
1-6 Yamadoka, Suita, Osaka 565-0871, Japan
E-mail: akai@phs.osaka-u.ac.jp
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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type of racemization could also be suitable for tertiary alcohols,
and in the following we report the first example of a DKR of a
tertiary alcohol, which is based on the combination of an
oxovanadium-catalyzed racemization and enzymatic resolution
through esterification with a lipase in an organic medium
(Scheme 1). In order to make such a DKR process efficient, the
KR should proceed in a highly enantioselective fashion (ka>>kb),
thus enabling the formation of the desired enantiomer in
enantiomerically pure form.
Table 1. Impact of catalysts and temperatures on the racemization of alcohol (S)-1. The
DOI: 10.1039/C9CC09103C
reactions were carried out in an Eppendorf tube under argon atmosphere.
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OH
oxovanadium-
catalyst
OH
+
(1 mol%)
1
rac-
vinyl acetate
temp, 24 h, 1200 rpm
1
(S)-
A
0.08 M
44% ee
+
3
4
O
O
Oxo-
vanadium
catalyst
T
(°C)
Yield of
ee-
value
Yield of
side-
producta
3
Yield of
side-
producta
4
OH
O
alcohola
lipase
,
O
1
(%)
1
(%)
ka
(%)
(%)
1
2
(R)-
(R)-
O=V(OSiPh3)3
PS-POVO
V-MPS4
25
25
25
15
50
86
100
66
73
1
41
38
16
34
0
11
0
3
0
5
4
8
racemization
catalyst
k-rac
krac
O
29
23
91
O
OH
O
V-MPS4
lipase
,
O
V-MPS4
kb
krac = k-rac > ka >> kb
a NMR yield.
1
2
(S)-
(S)-
Another critical parameter, which has been identified to have a
significant influence on the course of the racemization, is the
type of solvent component (Table 2). Isooctane and diisopropyl
ether provided the best results, since with these solvents the
side-product formation could be completely suppressed and in
addition the racemization rates (44% ee to 15% ee in isooctane
and 44% ee to 21% ee in diisopropyl ether) were acceptable.
Scheme 1. General principle of a DKR of the model substrate rac-1.
Toward this end, we first focused on the development of a
robust racemization process of the tertiary alcohol 1 as a key
step for such a DKR process. Starting from enantiomerically
enriched (S)-1 (44% ee) three different oxovanadium-catalysts,
namely O=V(OSiPh3)3,9a,12 V-MPS4 (immobilized on mesoporous
silica (MPS))9c,d and PhosphonicSTM POVO (immobilized on
silica)9b were evaluated with respect to their potential for
catalyzing a racemization process (Table 1). The V-MPS4 (pore
diameter of the MPS is 4 nm), which was prepared as reported
in literature1c yielded promising results in terms of the
racemization rate and an acceptable racemization was achieved
within 24 hours when using this V-MPS4-catalyst (Table 1,
entries 3-5). The ee-value could be reduced from 44% ee to
16% ee. However, when using this catalyst, a relatively large
amount of side-products 3 and 4 was observed, in contrast to
the use of the other two catalysts (entries 1,2), O=V(OSiPh3)3
and the PhosphonicSTM POVO. In addition, the racemization was
tremendously decreased when using the PS-POVO (44% ee to
38% ee) and the tris(triphenylsilyloxy)oxovanadium catalyst
(44% ee to 41% ee). In order to further enhance the
racemization process, different reaction temperatures were
tested (Table 1, entries 3-5). It turned out that the side-product
formation could be somewhat reduced at lower reaction
temperature (15 °C), although the racemization proceeded
much slower. On the other hand, complete formation of side-
products 3 and 4 was observed at higher temperature (50 C).
Based on these findings, we decided to use 25 °C for all further
experiments.
Table 2. Impact of organic solvents on the racemization of alcohol (S)-1. The reactions
were carried out in a Schlenk-tube under argon atmosphere.
V-MPS4
OH
OH
(1 mol%)
+
+
solvent
25 °C, 24 h, 1200 rpm
1
3
4
(S)-
-
rac 1
0.08 M
44% ee
Solvent
Yield of
alcohola
1
ee-
value
1
Yield of side-
Yield of side-
producta
producta
3
4
(%)
(%)
(%)
(%)
Vinyl acetateb
Isooctane
67
100
90
4
28
0
5
0
2
0
0
15
16
28
21
Cyclohexane
MeOtBu
8
94
6
Diisopropyl ether
100
0
a NMR yield.
2 | J. Name., 2012, 00, 1-3
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Methyl tert-butyl ether (MTBE) and cyclohexane provided resolution), which indicated that a racemization ViniewpAartricalelleOlnlitnoe
higher side-product formation, thus being less suitable. These the kinetic resolution of rac-1 took placeDaOsI:d1e0s.1ir0e3d9/.C9CC09103C
results show that the choice of solvent is of high importance for
the reaction process.
lipase
CAL-A
V-MPS4
O
Based on these results (Table 2), kinetic resolution of rac-1 was
tested in various solvents being suited for the racemization as
both processes have to be combined later with each other for
achieving the envisaged chemoenzymatic DKR. As an enzyme
we chose the Candida antarctica lipase A (CAL-A) as this
biocatalyst has been described to be useful for tertiary
alcohols.10,11 In our kinetic resolution study (Table 3),
cyclohexane and diisopropyl ether turned out as the most
promising solvents with 28% or 32% conversion to the desired
product after 48 hours reaction time (Table 3, entries 1, 3).
OH
OH
O
(1 mol%) (1 w/w)
+
+ vinyl acetate (10 eq.)
diisopropyl ether
25 °C, 1200 rpm, 96 h
1
rac-
1
2
(R)-
29% NMR yield
(S)-
0.08 M
81% NMR yield
23% ee
>99% ee
Scheme 2. DKR of rac-1 in a one pot process.
As in this initial DKR experiment the formation of the desired
product (R)-2 was relatively low with 29%, this result indicates
that the CAL-A was deactivated in the reaction solution over a
certain period of time. This hypothesis could be confirmed by a
stability test of CAL-A (see Supporting Information), in which
fresh solution of starting material and vinyl acetate were added
to a recycled portion of the lipase CAL-A.
Table 3. Kinetic resolution of alcohol rac-1 in different solvents.
lipase CAL-A
O
(Candida antarctica)
OH
OH
O
O
(1 w/w)
+
+
O
solvent
With this insight into enzyme stability under process conditions
in hand and in order to increase the conversion, we added
CAL-A and V-MPS4 stepwise. Under these experimental
conditions, it was ensured that fresh, active CAL-A was
constantly added to the reaction mixture and that the kinetic
resolution could therefore be maintained over the whole
reaction time (Scheme 3). For the stepwise addition we started
initially with a kinetic resolution of rac-1 in the presence of only
CAL-A and could reach a formation of (R)-2 in 38% yield
(according to NMR) after 72 hours with 0.5 w/w of CAL-A. At this
stage, we added a mixture of V-MPS4 (1 mol%) and CAL-A
(0.5 w/w) and stirred the reaction mixture for another 24 hours.
A further addition of CAL-A (2 w/w) yielded in 41% of (R)-2.
Although at this point the consumption of 1 was still below 50%,
we were glad to find that side-product formation was
completely suppressed even after such a prolonged reaction
time. Therefore, we decided to conduct the second cycle of DKR
after filtration, evaporation and re-dissolving the reaction
mixture of the first cycle in diisopropyl ether. These steps were
not necessary from the perspective of the DKR, but turned out
to be beneficial in terms of practicability and handling reasons.
Since still a large portion of lipase is needed due to the known
low activity of existing lipases for tertiary alcohols10 in
combination with their limited stability, for better stirring ability
we decided to remove the inactivated biocatalyst portion by
filtration prior to adding new portions of lipase and
oxovanadium racemization catalyst to the reaction mixture.
Thus, the resulting solution was then again treated with further
portions of the enzyme CAL-A and oxovanadium-complex
V-MPS4 for racemization (for details, see Supporting
Information). After the catalysts had been filtered off, we
obtained a 77% yield of (R)-2 with an excellent excess of
>99% ee (determined again by NMR), thus indicating that
through this stepwise catalyst addition a DKR process has been
realized. Thus, by means of this approach, to the best of our
25 °C, 48 h 1200 rpm
1
1
2
(R)-
rac-
0.08 M
(S)-
10 eq.
Solvent
Yield of
ee-
value
(S)-1
(%)
Yield of
ee-
E-
value
alcohola
(S)-1
(%)
acetatea
(R)-2
(%)
value
(R)-2
(%)
Isooctane
77
72
91
68
23
39
14
50
23
28
9
>99
>99
>99
>99
>200
>200
>200
>200
Cyclohexane
MeOtBu
Diisopropyl ether
32
a NMR yield.
In every case the ee-value of the resulting acetate was excellent
with >99% ee, which corresponds to an E-value of each reaction
of >200. In addition, no side-products were observed in these
kinetic resolutions of rac-1 with lipase CAL-A.
For the combined DKR process diisopropyl ether turned out as
a promising solvent since racemization as well as kinetic
resolution furnished good results when conducting these
reactions in separated fashion. Thus, our initial attempt for a
combined process consisted in a one pot process in diisopropyl
ether. Accordingly, a 0.08 M solution of the substrate rac-1 in
diisopropyl ether, containing 10 eq. of vinyl acetate, was
treated with CAL-A (1 w/w) and V-MPS4 (1 mol%) under argon
atmosphere (Scheme 2). Although in this initial experiment we
observed a conversion of only 29% to the expected product
(R)-2 after 96 h, we were pleased to find that no side-product
formation was observed under these reaction conditions.
Another promising result was the relatively low optical purity
(23% ee) of the remaining alcohol 1 (in comparison to the
calculated theoretical ee-value of 41% ee for a “pure” kinetic
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
Innovative Drug Discovery and Life Science Research (BINDS))
DOI: 10.1039/C9CC09103C
from AMED under Grant Number JP19am0101084.
knowledge, for the first time a DKR of a tertiary alcohol was
successfully carried out.
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Conflicts of interest
There are no conflicts to declare.
O
L
V
O
O
pore
size:
4nm
Si
Si
O
Notes and references
OH
lipase
CAL-A
V-MPS4
1
Overviews: a) I. Ojima (ed.), Catalytic Asymmetric Synthesis,
3rd ed., John Wiley & Sons, Hoboken, New Jersey, 2010; b) H.
U. Blaser, H.-J. Federsel (eds.), Asymmetric Catalysis on
Industrial Scale: Challenges, Approaches and Solutions, 2nd
ed., Wiley-VCH, Weinheim, 2010; c) K. Sugiyama, Y. Oki, S.
Kawanishi, K. Kato, T. Ikawa, M. Egi, S. Akai, Catal. Sci.
Technol. 2016, 6, 5023-5030; d) Y.-L. L, Liu, X. Touglin, Adv.
Synth. Catal. 2019, 361, 876-918.
a) D.J. Ramón, M. Yus, Angew. Chem. Int. Ed. 2004, 43, 284-
287; b) Review: O. Riant, J. Hannedouche, Org. Biomol.
Chem. 2007, 5, 873-888; c) J. Christoffers, A. Mann, Angew.
Chem. Int. Ed. 2001, 40, 4591-4597; d) Review: J.
Christoffers, A. Baro, Adv. Synth. Catal. 2005, 347, 1473-
1482.
OH
sequential addition of
chemo- & biocatalyst
1
(S)-
23%
1
rac-
in portions
66% ee
0.08 M
(for details, see text & experim. part)
+
+
25 °C, 312 h
O
O
diisopropyl ether
O
2
O
10 eq.
2
(R)-
77%
> 99% ee
3
4
N. Yasuda, L. Tan in: The Art of Process Chemistry, Wiley-
VCH, Weinheim, 2011, chapter 1, p. 1-43.
Scheme 3. DKR of rac-1 in a sequential batch process. All reactions were done with a
stirring rate of 1200 rpm under an argon atmosphere.
Reviews: a) I. Hussain, J.-E. Bäckvall in: Enzyme Catalysis in
Organic Synthesis (eds.: K. Drauz, H. Gröger and O. May), 3rd
ed., vol. 2, Wiley-VCH, Weinheim, 2012, chapter 43, p. 1777;
b) S. Akai, Chem. Lett. 2014, 43, 746-754; c) O. Verho, J.-E.
Bäckvall, J. Am. Chem. Soc. 2015, 137, 3996-4009; d) S.
Takizawa, H. Gröger, H. Sasai, Chem. Eur. J. 2015, 21, 8992-
8997; e) A. S. de Miranda, L. S. M. Miranda, R. O. M. A. de
Souza, Biotechnol. Adv. 2015, 33, 372-393; f) S. Akai in
“Future Directions in Biocatalysis, 2nd ed.” Ed. by Matsuda, T.,
Elsevier: Amsterdam, 2017, Chapter 16; g) Z. S. Seddigi, M. S.
Malik, S. A. Ahmed, A.O. Babalghith, A. Kamal, Coordination
Chem. Rev. 2017, 348, 54-70.
In conclusion, the first example of a DRK of a tertiary alcohol,
exemplified for the transformation of rac-1 into (R)-2, has been
achieved. The concept is based on a chemoenzymatic approach
combining a lipase-catalyzed resolution and an oxovanadium-
catalyzed racemization. In a sequential batch process with a
stepwise addition of the catalysts in various portions, we could
overcome the limitations caused by the deactivation of the
biocatalyst CAL-A under the process conditions. The continuous
addition of fresh, active CAL-A ensures that kinetic resolution
can take place permanently in combination with the desired
racemization, so that a final conversion of 77% to the desired
acetate (R)-2 with an excellent ee-value of >99% ee was
achieved, thus representing a proof-of-concept for such a DKR.
Tasks for future work are the improvement of the reaction
conditions and the extension of this method to other
substrates. As a major hurdle is not the DKR itself but the
stability of enzyme and, in part, esters, as well as the substrate
scope13 of enzyme and racemization catalyst. Thus, currently
our major focus is on developing CAL-A mutants and vanadium
catalysts with improved performance in the DKR.
5
6
L. E. Larsson, B. A. Persson, J. E. Bäckvall, Angew. Chem. Int.
Ed. 1997, 36, 1211-1212.
a) S. Kim, Y. K. Choi, J. Hong, J. Park, M.-J. Kim, Tetrahedron
Lett. 2013, 54, 1185-1188, b) Y. Kim, J. Park, M.-J. Kim,
ChemCatChem 2011, 3, 271-277; c) J. H. Choi, Y. H. Kim, S.H.
Nam, S. T. Shin, M.-J. Kim, J. Park, Angew. Chem. Int. Ed.
2002, 41, 2373-2376.
7
8
9
A. Berkessel, M. L. Sebastian-Ibarz, T. N. Müller, Angew.
Chem. Int. Ed. 2006, 45, 6567-6570.
T. Görbe, T. Lihammar, J.-E. Bäckvall, Chem. Eur. J. 2018, 24,
77-80.
Selected examples: a) S. Akai, K. Tanimoto, Y. Kanao, M. Egi,
T. Yamamoto, Y. Kita, Angew. Chem. Int. Ed. 2006, 45, 2592-
2595; b) S. Akai, R. Hanada, N. Fujiwara, Y. Kita, M. Egi, Org.
Lett. 2010, 12, 4900-4903; c) M. Egi, K. Sugiyama, M. Saneto,
R. Hanada, K. Kato, S. Akai, Angew. Chem. Int. Ed. 2013, 52,
3654-3658; d) S. Kawanishi, S. Oki, D. Kundu, S. Akai, Org.
Lett. 2019, 21, 2978-2982.
Acknowledgements
10 a) D. Özdemirhan, S. Sezer, Y. Sönmez, Tetrahedron:
Asymmetry 2008, 19, 2717-2720; b) D. Özdemirhan, Synth.
Commun. 2017, 47, 629-645.
11 For an excellent overview about the field of enantioselective
synthesis of tertiary alcohols using hydrolases, see: R.
Kourist, P. Domínguez de María, U. T. Bornscheuer,
ChemBioChem 2008, 9, 491-498.
12 F. Preuss, H. Noichl, Z. Naturforsch. 1987, 42b, 121-129.
13 The challenge of the substrate scope is illustrated by some
selected examples in the Supporting Information.
The authors gratefully acknowledge generous support from the
German Academic Exchange Service (DAAD) and Japan Society
for the Promotion of Science (JSPS) within the joint DAAD-JSPS
funding program “DAAD PPP Japan 2017/2018” (DAAD grant no.
57345562). S.A. also acknowledges financial supports by JSPS
KAKENHI 18H02556 and Platform Project for Supporting Drug
Discovery and Life Science Research (Basis for Supporting
4 | J. Name., 2012, 00, 1-3
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