Enantiomerically pure N-aryl-β-amino alcohols by enzymatic resolution

Article abstract of DOI:10.1016/S0957-4166(99)00401-2

N-Aryl-β-amino acetates, obtained by opening epoxides with aromatic amines followed by acetylation of the hydroxyl group, were resolved using crude pig liver esterase (PLE) enzyme in DMSO in high enantiomeric excess.

Full text of DOI:10.1016/S0957-4166(99)00401-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3663–3666
Enantiomerically pure N-aryl-β-amino alcohols by enzymatic
resolution
Govindasamy Sekar, Rajesh M. Kamble and Vinod K. Singh ∗
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 4 August 1999; accepted 8 September 1999
Abstract
N-Aryl-β-amino acetates, obtained by opening epoxides with aromatic amines followed by acetylation of the
hydroxyl group, were resolved using crude pig liver esterase (PLE) enzyme in DMSO in high enantiomeric excess.
© 1999 Elsevier Science Ltd. All rights reserved.
Enantiomerically pure β-amino alcohols are an important class of organic compounds which have
found much use in asymmetric synthesis1–4 and medicinal chemistry.5 The most common method for
synthesis of this class of compounds is via reduction of optically active α-amino acids.6 Thus, the
availability of α-amino acids becomes a limiting factor in the synthesis of these amino alcohols. This
prompted organic chemists to develop a more flexible approach where optically active amino alcohols
were synthesized by opening epoxides with amines using chiral Lewis acids; however, so far not much
success has been achieved with this approach.7 As part of our program towards the synthesis of β-amino
alcohols via enantioselective epoxide opening with amines, we discovered that Cu(OTf)2 and Sn(OTf)2
can efficiently catalyze epoxide opening reactions with aromatic amines.8 Since we too could not obtain
much success (in terms of enantiomeric excesses) in epoxide opening reactions with amines where chiral
ligands were complexed with these metal salts, we directed our attention towards an enzymatic approach
to the synthesis of enantiopure β-amino alcohols. The kinetic resolution of racemic acetates with pig
liver esterase (PLE) enzyme has been very well studied.9,10 Although a variety of substrates have been
resolved using PLE enzyme, the resolution of (ꢀ)-β-amino acetates, to the best of our knowledge, has
not been reported.11 In this paper, we report our findings in this direction.
A variety of (ꢀ)-β-amino acetates were synthesized from corresponding amino alcohols8 which, in
turn, were obtained by epoxide opening reactions with amines. The amino acetates were treated with
crude PLE enzyme obtained12 from fresh pig liver at pH 8.0 (KH2PO4/K2HPO4; 15 mL aq. buffer) in
DMSO (2.5 mL) at 25°C and the reactions were monitored by TLC. After approximately 50% hydrolysis
(by TLC), the reaction was stopped and the products were isolated. The absolute stereochemistry of
∗
Corresponding author. E-mail: vinodks@iitk.ac.in
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00401-2

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Table 1
Enantiomerically pure N-aryl-β-amino alcohols by kinetic resolution of (ꢀ)-amino acetates with crude
PLE enzyme in DMSO at room temperature
amino alcohols for entries 1 and 2 (Table 1) was established by comparing their sign of rotation with that
of literature values.7 The absolute stereochemistry of other amino alcohols was assigned with the above
analogy.
In most cases, except for 5-membered amino acetate and acyclic terminal amino acetate, we obtained
very high enantioselectivity (up to 99% enantiomeric excess) in the hydrolysis reaction (Table 1). The
cases in which we obtained lower enantioselectivity were due to over hydrolysis and the enantiomeric
excess can be improved by optimizing the conditions. The reaction was also tried in other solvents such as

G. Sekar et al. / Tetrahedron: Asymmetry 10 (1999) 3663–3666
3665
Figure 1.
Figure 2.
DMF, MeOH, EtOH, hexane, acetone and ether,14 but only DMSO gave the maximum enantioselectivity.
The unusual aspect of this kinetic resolution was that it worked only when an aromatic group was present
on the ‘N’ atom of the amino group. The enzymatic hydrolysis reaction failed in the case of N-butyl
and N-benzyl substrates. This was confirmed from the results of the hydrolysis reaction of a mixture of
N-phenyl and N-benzyl substrates, where only the former was hydrolyzed and the latter remained intact.
This kind of result, to the best of our knowledge, is quite unprecedented in kinetic resolutions using crude
PLE enzyme.
The kinetic resolution using PLE enzyme in the above reaction could be explained using the cubic
active site model proposed by Jones and co-workers.15 The catalytically important region which is
denoted by a circle is a serine moiety which initiates the acetate hydrolysis. The model has two
hydrophobic sites, one large on the left and one small on the right (Figs. 1 and 2). The hydrolysis
will proceed only if the acetate is in the proximity of the serine moiety. Fig. 1 depicts the favorable
binding mode for the (R,R)-amino acetate–enzyme complex where a large aromatic ring is in the large
hydrophobic pocket. It is this mode which gives (R,R)-β-amino alcohols. The other binding mode (Fig. 2)
where the aromatic ring is in the small pocket is less favored because the size of the pocket is small,
thus (S,S)-β-amino acetate remains unhydrolyzed. It was observed that if the aromatic ring is ortho-
substituted, the hydrolysis is very slow and the enantiomeric excesses are not very high. This could be
because the ortho-substituted aromatic ring was unable to fit comfortably even in the large pocket, thus
making the hydrolysis reaction less selective. Meta- and para-substituted aromatic rings did not create
much steric hindrance in the large hydrophobic pocket. Although some rationale has been drawn from
these models, there are several aspects of the reaction left unclear relating to the specificity of enzymes
involved in the hydrolysis reactions.
In conclusion, we have synthesized a variety of enantiomerically pure N-aryl-β-amino alcohols which
should find a use in organic synthesis.
Acknowledgements
V.K.S. thanks DST (Government of India) for a Swarnajayanti Fellowship award (1998). G.S. and
R.M.K. thank CSIR for an SRF and UGC for a JRF, respectively.

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G. Sekar et al. / Tetrahedron: Asymmetry 10 (1999) 3663–3666
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