Achiral bis-imine in combination with CoCI2: A remarkable effect on enantioselectivity of lipasemediated acetylation of racemic secondary alcohol

Article abstract of DOI:10.3762/bjoc.6.134

A bis-imine (prepared via a new FeCl₃-based method) in combination with CoCl₂ facilitated lipase-mediated acetylation of the (R)-isomer of a racemic benzylic secondary alcohol with 91% ees. The methodology was used for the preparation of the known drug rivastigmine.

Full text of DOI:10.3762/bjoc.6.134

Achiral bis-imine in combination with CoCl2:
A remarkable effect on enantioselectivity of lipase-
mediated acetylation of racemic secondary alcohol
K. Arunkumar1,2, M. Appi Reddy1, T. Sravan Kumar1, B. Vijaya Kumar1,
K. B. Chandrasekhar2, P. Rajender Kumar1 and Manojit Pal*3
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, 1174–1179.
1Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited,
Bollaram Road Miyapur, Hyderabad 500 049, India, 2Department of
Chemistry, Jawaharlal Nehru Technological University of Anantapur,
Anantapur 515002, Andhra Pradesh, India, and 3Institute of Life
Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad
500 046, Andhra Pradesh, India
doi:10.3762/bjoc.6.134
Received: 26 August 2010
Accepted: 09 November 2010
Published: 10 December 2010
Associate Editor: S. Flitsch
Email:
Manojit Pal* - manojitpal@rediffmail.com
© 2010 Arunkumar et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
acetylation; bis-imine; cobalt chloride; enantioselectivity; lipase
Abstract
A bis-imine (prepared via a new FeCl3-based method) in combination with CoCl2 facilitated lipase-mediated acetylation of the
(R)-isomer of a racemic benzylic secondary alcohol with 91% ees. The methodology was used for the preparation of the known
drug rivastigmine.
Introduction
The development and use of newer synthetic methods for the viability [10,11]. Recently, we have observed that achiral bis-
stereoselective synthesis of chiral molecules have increased imines in combination with CoCl2 improved the enantio-
enormously in recent years especially in the chemical and phar- selectivity substantially in CAL-B (Candida antarctica lipase
maceutical industry [1]. Biocatalysis, being an environmentally B) [12,13] mediated acetylation of a racemic secondary alcohol
friendly process, has attracted particular attention for this with vinyl acetate. Here we report our preliminary results on the
purpose [2-6]. For example, high enantioselectivity was synthesis and identification of a novel ligand for this process
observed in lipase-mediated preparation of alcohols and amines (Scheme 1) and its application in the preparation of the known
[7-9]. These biocatalysts work under mild reaction conditions, drug rivastigmine [14]. While the uses of bis-imine/transition-
and their immobilized forms, being stable in organic solvents, metal complexes have been reported for the enantioselective
have allowed an easy separation of products and the potential synthesis of chiral compounds [15-19], their use as activators in
recycling of the enzyme, thereby enhancing their economic an enzymatic reaction has not been previously explored.
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Beilstein J. Org. Chem. 2010, 6, 1174–1179.
reported to prepare Schiff bases by reacting an amine with a
carbonyl compound [20-24], in our hands the reaction of 1,2-
amines with aromatic aldehydes under these reaction condi-
tions provided a mixture of mono and bis-Schiff bases. We
therefore developed a new and efficient method for the prepar-
ation of bis-imines 3 by reacting ethane-1,2-diamine (1) with a
number of aryl and heteroaryl aldehydes 2 in the presence of
anhydrous FeCl3 (Scheme 2, Table 1). Aldehydes containing
electron donating (e.g., methoxy, hydroxy, fluoro and bromo) or
withdrawing groups (e.g., nitro) were found to be equally effec-
tive in terms of product yields. The reactions were completed
within 30 min in most cases.
Scheme 1: Lipase-catalyzed acetylation of racemic benzylic second-
ary alcohol [(RS)-4] and its application.
Results and Discussion
The report that bis-imine/Cu(I)-complexes were able to promote
the direct and enantioselective addition of imines to alkylacetyl-
enes [15] prompted us to evaluate a variety of bis-imines in
combination with CoCl2 [16] in the lipase-mediated acetylation
Scheme 2: FeCl3-meditated synthesis of bis-imines.
of a benzylic secondary alcohols. Accordingly, a number of All bis-imines prepared were then screened in combination with
achiral bis-imines were prepared and used to generate the CoCl2 for CAL-B mediated acetylation of a racemic secondary
desired complex. While a number of methods have been alcohol. Thus, 3-(1-hydroxyethyl)phenyl ethyl(methyl)carba-
Table 1: FeCl3-meditated synthesis of bis-imines (3) from (hetero)aryl aldehydes (2).
Entry
Aldehyde (2)
Product (3)
Yielda (%)
Reaction Time
1
90
0.5
2a
2b
3a
3b
2
90
0.15
3
4
88
80
0.5
0.5
2c
2d
3c
3d
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Beilstein J. Org. Chem. 2010, 6, 1174–1179.
Table 1: FeCl3-meditated synthesis of bis-imines (3) from (hetero)aryl aldehydes (2). (continued)
5
80
0.5
2e
3e
6
88
0.5
2f
3f
7
80
85
90
90
0.5
0.5
0.5
0.5
2g
3g
8
9
2h
2i
3h
3i
10
2j
3j
aIsolated yield.
mate [(RS)-4], prepared via the reaction of 3-hydroxyaceto-
phenone (6) with N-ethyl-N-methylcarbamoyl chloride fol-
lowed by reduction with NaBH4 (Scheme 3), was selected for
our purpose. Subsequently, the enzymatic processes were
carried out and the isolated reaction mixture was analysed by
chiral HPLC.
Initially, the CAL-B mediated acetylation of (RS)-4 was carried
out in the absence of any ligand and CoCl2. Vinyl acetate was
used as a solvent as well as the acyl donor. No reaction was
observed at room temperature even after 48 h. An increase in
reaction temperature to 50–55 °C for 24 h facilitated the acetyl-
ation, however, the selectivity was not greater than 30%. In
Scheme 3: Preparation of racemic 3-(1-hydroxyethyl)phenyl
ethyl(methyl)carbamate [(RS)-4]
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Beilstein J. Org. Chem. 2010, 6, 1174–1179.
order to achieve better selectivity, we assessed the use of achiral tion was complete within 12 h. The absolute configuration of
bis-imines in combination with CoCl2 (Table 2). The reactions the resolved chiral alcohol and its acetate was in accordance
were complete within 10 h when diarylidene-ethane-1,2-di- with Kazlauskas’ rule [25] (see Supporting Information File 1
amines were used (entries 1–8, Table 2). While 35% enan- for optical rotation values).
tiomeric excess was achieved in some of these cases (entries 2,
3 and 5, Table 2), the best results, however, were obtained with Mechanistically [12], the special H-bonding rearrangement of
bis(heteroarylmethylene)ethane-1,2-diamines (entries 9 and 10, the “catalytic triad” (i.e., serine, histidine, and aspartate) at the
Table 2), especially 3i. The bis-imine 3i facilitated enantiose- active site of CAL-B increases the nucleophilicity of the serine
lective acetylation of the (R)-isomer over the (S)-antipode with residue. This then interacts with the carbonyl group of the vinyl
high enantiomeric excess (91% ees) and yield (80%). The reac- acetate to form the “acyl-enzyme intermediate” T-1 (Scheme 4)
Table 2: Screening of bis-imines as achiral ligands in CAL-B mediated acetylation of (RS)-4 (step 1, Scheme 1)a.
Entry
Ligand 3
Time (h)
ees
eep
Conversionb (%)
Ec
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3e
3f
10
5
0
35
35
0
0
>99
>99
0
0
~26
~26
0
0
>200
>200
0
5
10
5
35
0
>99
0
~26
0
>200
0
5
3g
3h
3i
5
0
0
0
0
5
0
0
0
0
12
10
91
83
>99
>99
~48
~46
>500
>300
3j
aAll the reactions were carried out at 1.0 g scale of (RS)-4 with vinyl acetate (20 mL) as acyl donor, in the presence of CAL-B (150 mg), bis-imine (3,
0.3 mmol) and CoCl2 (0.3 mmol); ees = enantiomeric excess of substrate (the ees is mentioned as the enzyme is active with only one enantiomer) and
eep = enantiomeric excess of product. Both ees and eep were determined by HPLC [column: chiralpak IC (250 x 4.6 mm, 5.0 μm), mobile phase A:
0.05% TFA in water, mobile phase B: n-hexane: IPA (80:20), concentration: 0.5 mg/mL, diluent: ethanol, run time: 30.0 min, temperature: 25 °C, flow:
1.0 mL/min, UV: 220 nm]. bConversion = ees/(ees + eep). cE = {ln[eep(1-ees)]/(eep+ees)}/{ln[eep(1 + ees)]/(eep + ees)}.
Scheme 4: Proposed reaction mechanism of lipase-catalyzed acetylation of racemic alcohol 4.
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Beilstein J. Org. Chem. 2010, 6, 1174–1179.
Scheme 5: Complete synthesis of rivastigmine.
which finally transfers the acyl group to the substrate alcohol 4 Acknowledgements
via T-2, affording the desired product 5. The CoCl2 in combina- The authors (K.A.) thank Dr. V. Dahanukar, Mr. A. Mukherjee
tion with 3i perhaps forms a tight complex with T-1 as well as 4 for encouragemets and the analytical group of DRL for spectral
which facilitates the acyl transfer process (Scheme 4). However, support.
the reason for selective acylation was not clearly understood. It
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