Efficient dynamic kinetic resolution of racemic secondary alcohols by a chemoenzymatic system using bifunctional iridium complexes with C-N chelate amido ligands

Article abstract of DOI:10.1039/c2cc30333g

The combined catalyst system of bifunctional amidoiridium complexes derived from benzylic amines with CALB was found to provide a range of chiral acetates from racemic secondary alcohols in excellent yields with nearly perfect enantioselectivities via dyn

Full text of DOI:10.1039/c2cc30333g

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COMMUNICATION
Efficient dynamic kinetic resolution of racemic secondary alcohols by a
chemoenzymatic system using bifunctional iridium complexes with C–N
chelate amido ligandswz
Yasuhiro Sato, Yoshihito Kayaki and Takao Ikariya*
Received 15th January 2012, Accepted 15th February 2012
DOI: 10.1039/c2cc30333g
The combined catalyst system of bifunctional amidoiridium
complexes derived from benzylic amines with CALB was found
to provide a range of chiral acetates from racemic secondary
alcohols in excellent yields with nearly perfect enantioselectivities
via dynamic kinetic resolution.
synthesis of chiral acetates (2).5a,d–f To broaden the perspective
on chiral technologies involving the chemoenzymatic protocol,
there still remains some unsolved drawbacks, low turnover
numbers of metal catalysts, relatively high temperature
and/or basic conditions required for the racemisation, as well
as an excess use of acylating agents.
Group 8 and 9 complexes bearing chelate protic amine
ligands have also been established as highly effective hydrogen
transfer catalysts between alcohols and ketones via interconversion
between amido and hydrido(amine) complexes based on a metal/
NH bifunctionality.6 Whilst some precursory Ru or Ir complexes
derived from achiral amine ligands7 such as N-tosylethylene-
diamine, diphenylphosphinoethylamine and benzylamine have
shown to be effective for racemisation of enantiomerically
enriched 1-phenylethanol derivatives, it turns out to be hardly
amenable to the DKR process, possibly due to a lack of their
compatibility with lipase and acyl donors. We have recently
developed a new family of bifunctional amidoiridium complexes,
Cp*Ir[k2(N,C)-(NHCR2-2-C6H4)] (Cp* = 1,2,3,4,5-pentamethyl-
cyclopentadienyl; R = CH3 (3a) and C6H5, (3b)), as highly
efficient catalysts for transfer hydrogenation of ketones and
aerobic oxidation of alcohols.8 We envisioned that the catalytic
performance of these two complexes can be utilised for the
racemisation of secondary alcohols and we found that a
chemoenzymatic system including the amido-Ir catalyst and
CALB provides an efficient procedure for synthesis of enantio-
merically pure acetates from a racemic mixture of secondary
alcohols under ambient and neutral conditions.
Synthesis of optically pure secondary alcohols has been one of
the promising methods to access chiral building blocks in
asymmetric transformations. Among them, kinetic resolution
of racemic mixture using enzymes is a traditional and versatile
procedure and can be applied to practical processes; however,
the maximum yield is inherently limited to 50%.1 Dynamic
kinetic resolution (DKR) including the enzymatic kinetic
resolution of racemic alcohols and the in situ racemisation of
the remaining enantiomer has been regarded as an expedient
idea, allowing complete conversion to single enantiomeric
compounds as shown in Scheme 1.2 Since Backvall3 and other
¨
groups4 established DKR systems based on Shvo’s complex or
the related Ru complexes as racemisation catalysts for secondary
alcohols (1) and CALB (Candida antarctica lipase B immobilised
on polyacrylamide; Novozym 435) as a practical biocatalyst for
enantioselective transesterification, more efficient racemisation
catalysts for alcohols have been extensively explored5 and their
combined use with biocatalysts has been tested in a one-pot
We initially examined racemisation of (R)-1-phenylethanol (1a)
(>99% ee; 0.5 M in toluene) using 1 mol% of the C–N chelate
amidoiridium complexes at 30 1C under an argon atmosphere as
illustrated in Scheme 2. After the 2 h reaction with 3a and 3b, the
optical purities were reduced to 47% and 58% ee, respectively,
and 3a led to complete racemisation within 14 h. This experiment
Scheme 1 DKR of racemic secondary alcohols by combination of
metal-catalyzed racemisation with enzymatic transesterification.
Department of Applied Chemistry, Graduate School of Science and
Engineering, Tokyo Institute of Technology,
O-okayama 2-12-1-E4-1, Meguro-ku, Tokyo 152-8552, Japan.
E-mail: tikariya@apc.titech.ac.jp, +81 3 5734 2637
w This article is part of the ChemComm ‘Chirality’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
section and characterisation data for the products 2a–2h. See DOI:
10.1039/c2cc30333g
Scheme 2 Racemisation of (R)-1-phenylethanol with bifunctional
amidoiridium complexes under neutral conditions.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3635–3637 3635

Table 1 Chemoenzymatic DKR of racemic 1a using the bifunctional
C–N chelate Ir complex and CALB with acyl donors
Conc./ Time/ Yielda
Entry Ir cat Acyl donor
S/C
M
h
(%)
eeb (%)
1
2
3
4
5
6
7
3a
3b
4ac
4bc
3a
3a
3a
Phenyl acetate
Phenyl acetate
Phenyl acetate
Phenyl acetate
Phenyl acetate
Phenyl acetate
1,2-Diacetoxy-
benzene
20 0.2
20 0.2
20 0.2
20 0.2
30 0.2
100 1.0
30 0.2
6
6
6
6
6
88
81
70
69
92
98
68
>99, R
>99, R
>99, R
99, R
>99, R
>99, R
>99, R
12
6
8
9
10
3a
3a
3a
3-Pyridyl acetate
Isopropenyl acetate 30 0.2
30 0.2
6
6
6
52
50
25
>99, R
>99, R
>99, R
Scheme 3 DKR of racemic secondary alcohols with the combined
catalysts of 1a with CALB under neutral conditions. Yields were
determined after isolation.
1-Ethoxyvinyl
acetate
30 0.2
a
b
c
Determined by GC analysis. Determined by HPLC. KOtC4H9
(6 mol%; 1.2 equiv./Ir) was added.
acetate was employed as a suitable acylating agent in the
following experiments. The concomitantly generated phenol
was found to be inert during the reaction.
clearly shows that the coordinatively unsaturated amido complexes
exhibit good activities for the racemisation of chiral alcohols even
in the absence of base, whereas an addition of KOC(CH3)3 is
required for the analogous C–N chelate amine–Ru and Ir
complexes reported by Feringa and de Vries et al.7c,d
With the combined catalyst system of 3a (S/C = 50 or 100)
with CALB (7 mg), the DKR of several secondary alcohols
was investigated at 30 1C in toluene (1 M) as the standard
conditions, and the results are summarised in Scheme 3. In all
cases, the R-enantiomers with >99% ee were obtained from
the reaction under mild conditions. Phenylethanol derivatives
(1b and 1c) bearing Cl and OCH3 substituents on the phenyl
ring can be transformed into the corresponding acetates
(2b and 2c) with high chemical yields, although a prolonged
reaction time of 18 h was needed for 1c due to a relatively slow
rate of racemisation. Chiral acetates (2d and 2e) derived from
1-indanol and 1-tetralol were obtained with comparable
results in terms of yield and enantioselectivity. Because of a limited
solubility of the 1-(2-naphthyl)ethanol, the DKR was undertaken
at a concentration of 0.5 M, and the chiral acetate (2f) was
obtained in 81% yield. For the sterically congested substrate of
1-(1-naphthyl)ethanol, the racemisation took place as well under
the standard conditions but the use of two molar amounts of
phenyl acetate was beneficial for a complete conversion into the
product (2g). Notably, a successful result of an isolated yield of
92% with >99% ee for the pyridine derivative (2h) represents an
efficient nature of the combined catalyst system.
Based on promising catalytic performance of the amido
complexes for the racemisation, the DKR of racemic 1-phenyl-
ethanol (1 mmol) with an equimolar amount of an acyl donor in
toluene (0.2 M) in the presence of the Ir catalyst with a substrate/
catalyst ratio (S/C) of 20 and CALB (7 mg) was examined. As
listed in Table 1, both amido complexes 3a and 3b showed good
compatibility with the lipase and phenyl acetate as the acyl
donor to afford (R)-1-phenylethyl acetate (2a) in good yields
(88% and 81%) with excellent enantiomeric excesses exceeding
99% after the 6 h reaction at 30 1C (entries 1 and 2). Compared
to the direct use of 3, in situ generation of amido-Ir species by
treatment of the precursory amine complexes, Cp*IrCl[k2(N,C)-
(NH2CR2-2-C6H4)] (R = CH3, 4a; C6H5, 4b), with 1.2 equiv. of
KOC(CH3)3 spoiled the reaction, resulting in a lower yield of
the ester under otherwise identical conditions (entries 3 and 4).
With the superior combination of 3a with CALB, the amount
of Ir catalyst can be diminished (entries 5 and 6). Notably, a
desirable yield of 98% with an almost perfect optical purity
(>99% ee) was accomplished with a reduced catalyst loading
of 1 mol% by increasing the concentration of substrates to 1 M.
The possible acceleration of racemisation at a higher concentration
of alcoholic substrate may fulfill requirements to enhance the total
catalytic activity.
In summary, we have found that the coordinatively unsaturated
amidoiridium complexes 3 behave as racemisation catalysts
for secondary alcohols under mild and base-free conditions.
Moreover, the well-defined complex 3a derived from cumyl-
amine proved to be highly effective for the DKR of racemic
alcohols by combination with enzymatic transesterification
using CALB and phenyl acetate. This chemoenzymatic
system is characterised by excellent catalytic performance
and operational simplicity. Even at ambient temperature a
complete conversion of racemic alcohols is readily attainable
using an equimolar amount of acyl donor and no additional
bases are needed for racemisation.
Screening of suitable acyl donor reagents for the DKR
system revealed that an almost pure single enantiomer of
acetate was produced in all experiments, but catalytic efficacy
of 3a was not observed by use of 1,2-diacetoxybenzene (entry 7).
In addition, the DKR system did not accord with 3-pyridyl acetate
and enol acetates such as isopropenyl acetate and 1-ethoxyvinyl
acetate to give unsatisfactory results (entries 8–10). Thus, phenyl
c
3636 Chem. Commun., 2012, 48, 3635–3637
This journal is The Royal Society of Chemistry 2012

This work is supported by the grant-in-aid for Scientific
Research (S) (22225004) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan, and partly
supported by the GCOE Program.
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Chem. Commun., 2012, 48, 3635–3637 3637