Lipase-mediated resolution of cis-1-amino-2-indanol, the key component of the HIV protease inhibitor indinavir

Article abstract of DOI:10.1016/S0957-4166(99)00260-8

The efficient and direct resolution of cis-1-amino-2-indanol using Candida antarctica lipase B catalyzing the alcoholysis of its N,O-diacetyl derivative is reported.

Full text of DOI:10.1016/S0957-4166(99)00260-8

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2501–2503
Lipase-mediated resolution of cis-1-amino-2-indanol, the key
component of the HIV protease inhibitor indinavir
A. T. Anilkumar, Kouhei Goto, Tomiki Takahashi, Kozo Ishizaki and Harumi Kaga
∗
Hokkaido National Industrial Research Institute, Sapporo 062-8517, Japan
Received 13 May 1999; accepted 17 June 1999
Abstract
The efficient and direct resolution of cis-1-amino-2-indanol using Candida antarctica lipase B catalyzing the
alcoholysis of its N,O-diacetyl derivative is reported. © 1999 Elsevier Science Ltd. All rights reserved.
Recently, much attention has been paid to the synthesis of enantiomerically pure cis-1-amino-2-indanol
®
1
1
as a key component of the HIV protease inhibitor, indinavir (Merck’s Crixivan ). In the commercial
2
synthesis of indinavir, (1S,2R)-1-amino-2-indanol ((1S,2R)-1) is used as a key component and also plays
an important role in the asymmetric control of the two central stereocenters. In addition, chiral ligands
and auxiliaries derived from both enantiomers of 1 have proven to be very effective in a number of
3
asymmetric reactions.
In order to obtain enantiomerically pure 1, many efforts have been attempted, e.g. asymmetric synthesis
4
5
via Jacobsen’s epoxidation of indene, synthesis from D-phenylalanine and various chemoenzymatic
approaches.
6–11
Resolution of the racemate is one of the most important and convenient methods for
preparing enantiomerically pure compounds, and the resolution of cyclic 1,2-aminoalcohols such as 2-
12
aminocyclopentanol and 2-aminocyclohexanol has been achieved using enzymes. Although classical
methods have been developed for the resolution of racemic 1,13 no effort has been made to resolve (ꢀ)-1
enzymatically. We now report the efficient and direct kinetic resolution of cis-1-amino-2-indanol through
CAL-B (Candida antarctica lipase B) mediated alcoholysis in an organic solvent (Scheme 1).
8
Racemic 1 was prepared from 2-bromo indanol via the Ritter reaction. A preliminary attempt for the
irreversible acylation of (ꢀ)-1 using vinyl acetate as the acyl donor was examined. However, no reaction
∗
Corresponding author. Fax: +81-11-857-8900; e-mail: kaga@hniri.go.jp
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00260-8

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A. T. Anilkumar et al. / Tetrahedron: Asymmetry 10 (1999) 2501–2503
Scheme 1.
occurred when using lipases such as CAL-B, lipase PS, PPL, etc. By using ethyl acetate as the acyl donor
and also the solvent, we obtained three acylated products with extremely low enantioselectivity. This was
expected because free aminoalcohols are not generally used as suitable substrates in a transesterification
reaction. Thus, the enzyme catalyzed alcoholysis of the N,O-diacetyl derivative of (ꢀ)-1 ((ꢀ)-2) in
organic solvent was considered, as shown in Scheme 1. Since (ꢀ)-2 was barely soluble in DIPE and
toluene, common organic solvents for enzymatic reactions, we examined several solvents as listed in
Table 1.
Table 1
a
CAL-B catalyzed alcoholysis of (ꢀ)-2 in organic solvents
Commercially available lipases (CAL-A, CAL-B, lipase PS, lipase AY, lipase AK, PPL) were exa-
®
mined for the alcoholysis of (ꢀ)-2 with n-BuOH in CHCl . CAL-B (Chirazyme L-2, c.-f. C2, lyo)
3
efficiently catalyzed the alcoholysis, while the reaction hardly proceeded using other enzymes. In general,
water-immiscible lipophilic solvents such as hexane, toluene and DIPE are widely used for enzymatic
reactions as they retain an enzyme’s catalytic activity.14 On the contrary, water-miscible hydrophilic
solvents such as dioxane, acetone and THF, in which most enzymes are denatured and deactivated, are
rarely used.
As listed in Table 1, not only in water-immiscible solvents (entries 5–7) but also in water-miscible
ones (entries 1–4), both the unreacted substrate 2 and product 3 are obtained in high enantiomeric purity.

A. T. Anilkumar et al. / Tetrahedron: Asymmetry 10 (1999) 2501–2503
2503
Furthermore, the enantiomeric ratio (E value)15 was calculated to be >500, showing excellent kinetic
resolution. Thus, this result shows that CAL-B is an exceptionally stable enzyme in the solvents examined
for the alcoholysis of (ꢀ)-2. As for the alcoholysis rate, solvents such as THF, acetone and CHCl
3
(
entries 3–5), which require a relatively longer reaction time to attain 50% conversion, are somewhat
less preferable.
A preparative reaction was carried out as follows. To a solution of (ꢀ)-2 (250 mg, 1.07 mmol) and n-
BuOH (0.4 ml, 4.32 mmol) in DIPE:dioxane (1:1, 16 ml) was added CAL-B (200 mg). The mixture was
shaken at 45°C and the progress of the reaction was monitored by GC. When the conversion reached 50%,
the lipase was filtered off. The products were purified by silica gel column chromatography to provide
2
0
(
4
+)-(1S,2R)-3 [89 mg, 43% yield, >99% ee, [α] +38.3 (c 0.84, EtOH)] and (+)-(1R,2S)-2 [120 mg,
D
20
8% yield, 99% ee, [α]D +76.2 (c 1.35, CHCl )]. The absolute configurations of the resolved products
were assigned after their conversion into the corresponding aminoalcohols and comparison of the specific
rotations with the literature values. Thus, the basic hydrolysis of (+)-2 and (+)-3 provided (+)-(1R,2S)-1
3
7
and (−)-(1S,2R)-1, respectively, without any racemization, establishing their absolute configurations as
shown in Scheme 1.
In conclusion, the present procedure represents a direct and practical access to both enantiomers of
cis-1-amino-2-indanol (−)-(1S,2R)- and (+)-(1R,2S)-1, a medicinally and chemically useful component,
in an enantiomerically pure form through CAL-B-mediated alcoholysis.
Acknowledgements
We gratefully acknowledge financial support from the Japan Science and Technology Corporation
(JST) in the form of an STA fellowship (ID number 296137) to A. T. Anilkumar and the generous gift of
various enzymes by Boehringer Mannheim GmbH and Amano Pharmaceutical Co. Ltd.
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