Heterogeneous Acid-Catalyzed Racemization of Tertiary Alcohols

Article abstract of DOI:10.1002/chem.201704691

Tertiary alcohols are important structural motifs in natural products and building blocks in organic synthesis but only few methods are known for their enantioselective preparation. Chiral resolution is one of these approaches that leaves one enantiomer (50 % of the material) unaffected. An attractive method to increase the efficiency of those resolutions is to racemize the unaffected enantiomer. In the present work, we have developed a practical racemization protocol for tertiary alcohols. Five different acidic resin materials were tested. The Dowex 50WX8 was the resin of choice since it was capable of racemizing tertiary alcohols without any byproduct formation. Suitable solvents and a biphasic system were investigated, and the optimized system was capable of racemizing differently substituted tertiary alcohols.

Full text of DOI:10.1002/chem.201704691

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Title: Heterogeneous Acid-Catalyzed Racemization of Tertiary Alcohols
Authors: Jan-E. Bäckvall, Tamas Gorbe, and Richard Lihammar
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10.1002/chem.201704691
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COMMUNICATION
Heterogeneous Acid-Catalyzed Racemization of Tertiary Alcohols
Tamás Görbe,[a] Richard Lihammar,[a] and Jan-E. Bäckvall*[a]
Abstract: Tertiary alcohols are important structural motifs in natural
products and building blocks in organic synthesis but only few
methods are known for their enantioselective preparation. Chiral
resolution is one of these approaches which leaves one enantiomer
(50% of the material) unaffected. An attractive method to increase
the efficiency of those resolutions is to racemize the unaffected
enantiomer. In the present work we have developed a practical
racemization protocol for tertiary alcohols. Five different acidic resin
materials were tested. The Dowex 50WX8 was the resin of choice
since it was capable of racemizing tertiary alcohols without any
byproduct formation. Suitable solvents and a biphasic system were
investigated, and the optimized system was capable of racemizing
differently substituted tertiary alcohols.
catalyst (e.g. an enzyme) a so called “dynamic kinetic resolution”
(DKR) can be achieved.6
Tertiary alcohols and their esters are important compounds,
which are found in a number of natural products. 7 These
compounds are also important building blocks in synthetic
chemistry.8 The synthesis of optically pure tertiary alcohols is still
a challenging problem in organic chemistry, not only in the field
of biocatalysis, but also in classical asymmetric synthesis.9 The
chemical or enzymatic resolution of tertiary alcohols have been
reported for a few different types of compounds. 10 , 11 The
chemical resolution of 3-hydroxy-3-substituted oxindoles was
studied by Zhao and coworkers.10 In their procedure they used
N-heterocyclic carbene (NHC) catalysis to obtain the
enantiomerically pure alcohols, and within the applied method it
was found that the protocol is highly substrate specific.10 Within
the field of biocatalysis, Bornscheuer and his research group
have studied different types of hydrolase enzymes for the
resolution of tertiary alcohols.11 They discovered that a specific
amino acid motif (GGGX-motif, where G denotes glycine and X
denotes any amino acid) located in the oxyanion hole of lipases
and esterases show activity towards tertiary alcohols. The ester
hydrolysis protocols reported provided the possibility to produce
enantiomerically enriched tertiary alcohols.11 However the
transesterification with the same enzyme is extremely slow.12
As mentioned above, resolution methods for tertiary alcohols
are known to some extent in the literature, although they are
limited; however racemization processes that can be combined
with kinetic resolution are unknown. Unfortunately, metal-
catalyzed racemization of tertiary alcohols via a redox reaction is
not possible. The only way to racemize tert-alcohols would seem
to be via cleavage of the C-O bond. This may occur via
protonation and formation of a carbocation, which is quenched
by water (Scheme 1). This pathway has been demonstrated for
racemization of secondary alcohols.13,14 In this communication,
we report a method for racemization of tertiary alcohols that is
based on the use of an acidic resin.
The stereoselective synthesis of organic molecules is of a high
demand in the pharmaceutical and agrochemical industry. Three
strategies are presently used for the preparation of
enantiomerically pure compounds, one of them being the chiral
pool synthesis, where chiral natural products are used as
building blocks for the synthesis of complex molecules.1 The
other two strategies include resolution of racemates 2 and
asymmetric synthesis, where in the latter case chiral reagents or
catalysts are used.3 Although asymmetric synthesis based on
catalysis, i.e. asymmetric catalysis, is a very powerful method for
obtaining enantiomerically pure compounds, the most common
method used in chemical industry for obtaining such compounds
is still via resolution. In
a resolution, which could be
crystallization, chiral chromatography, or kinetic resolution, two
enantiomers are separated and the desired enantiomer is
collected. The drawback of the resolution strategy is that only
50% of the material is used, and the unwanted enantiomer is
discarded. A solution of this problem is to racemize the
unwanted enantiomer and to recirculate the racemic mixture,
which increases efficiency. Therefore, there is a high demand of
efficient racemization methods in industrial applications.
Racemization can be achieved by a variety of techniques:
thermal racemization, enzyme-catalyzed racemization, racemi-
zation via meso-intermediates, racemization by nucleophilic
substitution, racemization via radical and redox reactions,
photochemical racemization, and acid or base-catalyzed
racemization. 4 The most common racemization catalysts for
secondary alcohols are transition metal-based hydrogen transfer
catalysts, which racemize the alcohol via a dehydrogenation-
hydrogenation (oxidation-reduction) pathway. 5 When such a
racemization catalyst is combined with a kinetic resolution
Scheme 1. Acid catalyzed racemization of our model tertiary alcohols.
The Brønsted acid-catalyzed racemization via a carbocation
is associated with alkene formation, which is a problematic side
reaction. If the reaction is performed in a water-rich environment,
elimination to alkene is suppressed. Acidic zeolites are
heterogeneous catalysts, which can racemize secondary
alcohols, however, with moderate success since alkene side
products were formed leading to a decrease in yield.14 Acidic
resins have proven to be excellent racemization catalysts and
are commercially available at low cost.14,15 Our research group
has already applied the acid-catalyzed racemization technique
[a]
T. Görbe, Dr. R. Lihammar, Prof. Dr. J.-E. Bäckvall
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University
SE-106 91, Stockholm (Sweden)
E-mail: jeb@organ.su.se
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201704691
Chemistry - A European Journal
COMMUNICATION
to a migratory DKR protocol, where we were able to use the
acidic resins in an isomerization step of a cyclic allylic alcohol.16
linked resin, these functional groups are spaced closer together
on a volume basis, and the volume of water is reduced by the
additional cross-linking. Due to these facts only Dowex 50WX4
and Dowex 50WX8 are enough acidic to be able to racemize
alcohol substrate (S)-1a (Table 1, entry 4, 5).
This racemization was combined with
a resolution using
Candida antarctica lipase B (CalB).
Our model substrate, 2-phenylbut-3-yn-2-ol (1a), was
chosen based on the previous studies of kinetic resolution of
tertiary alcohols with Candida antarctica lipase A (CalA).11 The
alcohol substrate was synthesized by Grignard reaction of the
corresponding acetophenone compound. The racemic 2-
phenylbut-3-yn-2-ol derivatives (rac)-1a-e were chemically
acylated with acetic anhydride in a Biotage® microwave reactor
to produce 2-phenylbut-3-yn-2-yl acetate (rac)-2a-e products.
The racemic acetate derivatives (rac)-2a-e were hydrolyzed
enzymatically towards the enantiomerically enriched alcohol
products. The applied enzyme, CalA wild type, was immobilized
by adsorption on the hydrophobic support Accurel MP-1001. The
enzymatic hydrolysis was performed in pH 7.6 phosphate buffer
solution.
Table 1. The screening of the acidic resins.
Entry[a]
Resin
Acidic group
Capacity
[meq/mL]
ee [%]
1
2
3
4
5
Ambelite 120
Amberlyst 15
Dowex 50WX2
Dowex 50WX4
Dowex 50WX8
–COOH
–SO3H
–SO3H
–SO3H
–SO3H
1.0
1.7
0.6
1.1
1.7
13
<1
23
<1
2
[a] 0.1 mmol substrate was solved in 1 mL of water, 40 mg of acidic resin
was added and stirred at room temperature for 5 h. 0.05 mL of samples
were taken, extracted with EtOAc. The organic phase was analyzed by
chiral-GC.
Scheme 2. Synthesis of enantiomerically enriched 2-phenylbut-3-yn-2-ol
derivatives (S)-1a-e.
During the racemization, the reaction mixtures were also
analyzed by 1H-NMR spectroscopy, with the aim to detect the
possible elimination products. It is known in the literature that
propargylic alcohols can undergo a Mayer-Schuster rearrange-
ment, where (E)- and (Z)-unsaturated aldehydes are formed. We
identified (E)-3-phenylbut-2-enal (4) and (Z)-3-phenylbut-2-enal
(5) as byproducts from such a rearrangement (Table 2).
The synthesized tertiary ester compounds are not highly
stable; chemical hydrolysis can occur in solution and the CalA
enzyme reacts rapidly with the substrate ester molecules.
Because of this high reactivity, the substrates 2a-e were over-
hydrolyzed. Afterwards, the enantiomerically enriched acetates
(S)-2a-e were separated by column chromatography and
chemically hydrolyzed to (S)-1a-e by a 4:1 mixture of MeOH and
an aqueous saturated solution of Na2CO3. In this way, the
desired enantiomerically enriched tertiary alcohols (S)-1a-e
required for the racemization studies, were obtained.
Table 2. By-product formation during the acidic resin screening.
Five different types of acidic resins were studied. These
resins are based on a styrene-divinylbenzene (gel) polymer
functionalized either with carboxylic acid or sulfonic acid groups
(Table 1). The heterogeneous acids were investigated in water
as solvent. The model reaction was done on a 0.1 mmol scale
using substrate (S)-1a in 1 mL of water with 40 mg of acid
catalyst. The racemization of benzylic alcohols requires an acid
of sufficient strength, and the weaker carboxylic acid-based
Amberlite 120 resulted in a moderate rate for racemization of
alcohol (S)-1a (Table 1, entry 1). Amberlyst 15 showed very
good capability of the racemization (Table 1, entry 2). Three
differently cross-linked Dowex resins (2, 4 and 8% cross-
linkage) were next examined (Table 1, entry 3, 4 and 5). The
amount of cross-linking is very important for the activity of the
catalyst, and 8% cross-linking led to the highest activity.
Although, fewer acidic groups are introduced into a higher cross-
Entry[a]
Resin
1a [%][b]
81
3 [%][b]
4 [%][b]
5 [%][b]
1
2
3
4
5
Amberlite 120
Ambelyst 15
Dowex 50WX2
Dowex 50WX4
Dowex 50WX8
0
10
10
0
9
8
0
0
0
53
29
0
100
100
100
0
0
0
0
[a] 0.1 mmol substrate was solved in 1 mL of water, 40 mg of acidic resin was
added and stirred at room temperature for 5 h. 0.05 mL of samples were
taken, extracted with EtOAc. The organic phase was collected and the solvent
was evaporated. The samples were dissolved in CDCl3 and analyzed by 1H
NMR spectroscopy. [b] Conversions based on 1H NMR.
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The results in Table 2 shows that Dowex resins (entries 3-5)
are the most selective catalysts without any formation of by-
products 3-5. Of these three resins the Dowex 50WX8 was
chosen for further studies since it was also the most effective
resin (Table 1). Five different solvents were studied for the
racemization of (S)-1a using Dowex 50WX8, and the reactions
were run for 5 h (Figure 1). As expected, for this type of
racemization, water is the best solvent, which led to good
reaction rate with no side products. Also, isooctane gave a good
reaction rate of the racemization, but unfortunately, 8% of 3 and
33% of 4-5 byproducts were formed with this solvent. However,
for Dowex 50WX8 in toluene and in acetonitrile racemization
was slower and after 5 h of reaction the alcohol 1a was of 54%
ee and 40% ee, respectively. The i-octane/water 1:1 system was
also examined, and this two-phase-system worked almost as
well as that with water as solvent and gave 1a with 9% ee
without any byproduct formation. This two-phase-system should
be suitable for applications that require an organic solvent.
Figure 2. Substrate scope. The racemic alcohols were recovered in >95%
yield according to 1H NMR spectroscopy. Compound (rac)-1a was also
obtained in 96% isolated yield. The half-life time for substrate (S)-1a is about 1
h and for substrates (S)-1b and (S)-1c it is almost identical. The half times for
(S)-1d and (S)-1e are 5 h and 12 h, respectively.
A practical and easy-to-use racemization of tertiary alcohols
has been developed. Several acidic resins with different acidity
were screened for the activity of the racemization. Dowex
50WX8 was found to be the optimal resin for racemization of
tertiary alcohols and it was tested in a few different solvents.
Water was found to be the best solvent giving excellent results
without any formation of byproducts. Tertiary alcohols were
racemized within 5-8 h at room temperature. Only in one case, it
was necessary to use more acid, elevated temperature and
longer reaction time. This new method would be useful in
combination with various resolution processes of tertiary
alcohols.
Experimental Section
Figure 1. Solvent screening. Reaction conditions: 0.1 mmol of substrate (S)-
1a was dissolved in 1 mL of solvent, 40 mg of Dowex 50WX8 resin was added
and stirred at room temperature. 0.05 mL of samples were taken, extracted
with EtOAc. The organic phase was analyzed by chiral-GC and by 1H NMR
spectroscopy.
General racemization protocol of (S)-2-phenylbut-3-yn-2-ol
derivatives ((S)-1a-e)
The alcohol (S)-1 (0.1 mmol) was placed in a vial, and 1 mL of water or
another solvent was added (see Figure 1. for solvent). The
corresponding acidic resin (40 mg) was added to the solution, and the
mixture was stirred at room temperature for the given times (see Figure
2.). Samples (0.05 mL) were taken and added to 2 mL 1:1 EtOAc/water
mixture. The organic phase was separated and analyzed by chiral-GC or
chiral-HPLC and 1H NMR.
With the optimized reaction conditions in hand differently
substituted tertiary alcohols were tested in the racemization
(Figure 2.). The Dowex 50WX8 resin was capable of racemizing
alcohols (S)-1a-b within 5 h of reaction time. The process was
tested with electron-withdrawing groups on the aromatic ring as
well. Whereas p-fluorophenyl derivative 1c was racemized within
5 h, the corresponding p-chlorophenyl compound 1d required 8h
to be racemized. For the p-nitro substrate 1e 120 mg of Dowex
50WX8 at 70 ºC had to be used for 52 h. In the latter case the
formation of the carbocation is much slower, then for the other
substrates. We tried to use the electron-donating 2-(4-
methoxyphenyl)but-3-yn-2-ol substrate. Unfortunately, the
synthesized acetate was too unstable, and it was self-
hydrolyzed during the work up of the reaction.
Acknowledgements
Financial support from the Swedish Research Council (2016-
03897), the Berzelii Center EXSELENT, and the Knut and Alice
Wallenberg Foundation is gratefully acknowledged.
Keywords: racemization • tertiary alcohols • heterogeneous
catalysis • acidic resins
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10.1002/chem.201704691
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COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
In the present work we have devel-
oped a practical racemization proto-
col for tertiary alcohols by the use of
resins. The Dowex 50WX8 was the
resin of choice since it was capable
of racemizing tertiary alcohols with-
out any byproduct formation. The
racemization is of synthetic interest
in chiral resolution processes where
one enantiomer is often discarded.
Tamás Görbe, Richard Lihammar, Jan-
E. Bäckvall*
Page No. – Page No.
Heterogeneous Acid-Catalyzed
Racemization of Tertiary Alcohols
Layout 2:
COMMUNICATION
Author(s), Corresponding Author(s)*
((Insert TOC Graphic here))
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Title
Text for Table of Contents
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