Cyclic trans-β-amino alcohols: Preparation and enzymatic kinetic resolution

Article abstract of DOI:10.1016/j.tetasy.2011.11.019

Enantioenriched cyclic β-amino alcohols, trans-2-aminocyclohexanols (ee, >99%), trans-2-aminocyclopentanols (ee, >99%), trans-1-amino-2- indanols (ee, >99%) and trans-2-amino-1-indanols (ee, ～98%) were prepared in high yields via an Arthrobacter sp. Lipase/PLAP catalyzed kinetic resolution of racemic phthalimido acetates. The addition of toluene as a co-solvent dramatically improved the hydrolysis and enantioselectivity, whereas for indanols, substrate immobilization on Celite improved the efficacy of the kinetic resolution.

Full text of DOI:10.1016/j.tetasy.2011.11.019

Tetrahedron: Asymmetry 22 (2011) 2134–2143
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Cyclic trans-b-amino alcohols: preparation and enzymatic kinetic resolution
⇑
Abdul Rouf, Pankaj Gupta , Mushtaq A. Aga, Brijesh Kumar, Rajinder Parshad, Subhash C. Taneja
Bio-Organic Chemistry Division, Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, J&K, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioenriched cyclic b-amino alcohols, trans-2-aminocyclohexanols (ee, >99%), trans-2-aminocyclo-
pentanols (ee, >99%), trans-1-amino-2-indanols (ee, >99%) and trans-2-amino-1-indanols (ee, ꢀ98%) were
prepared in high yields via an Arthrobacter sp. Lipase/PLAP catalyzed kinetic resolution of racemic phtha-
limido acetates. The addition of toluene as a co-solvent dramatically improved the hydrolysis and enanti-
oselectivity, whereas for indanols, substrate immobilization on Celite improved the efficacy of the kinetic
resolution.
Received 7 November 2011
Accepted 30 November 2011
Available online 9 January 2012
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
last two decades has contributed significantly in the area of en-
zyme catalyzed kinetic resolution of cycloalkanols and indanols.
The recurrent vicinal amino alcohol moiety is an important
component of a large variety of natural products and biologically
active molecules.1 In particular, chiral cyclic 1,2-amino alcohols
are the vital structural components of a large number of pharma-
ceuticals,2 peptide nucleic acids (PNA),3 as a part of key enzymes
in the human immunodeficiency virus (HIV) protease inhibitors,4
and as metabolites of aminoindane in the urine of rabbits and rats5
(Fig. 1). They have also been used as potent chiral ligands6 and chi-
ral auxiliaries in asymmetric transformations7 including carbonyl
Thus, Maestro et al.16 reported the transesterfication of N-pro-
tected trans-2-aminocyclohexanol (ee 87%, yield 48%, 14 h) and
trans-2-aminocyclopentanol (ee 99%, yield 49%, 5 days) respectively
using Candida antarctica lipase (CAL). Gonzalez-Sabin et al.7f have
used the transesterfication of trans-2-(N,N-dialkylamino)cyclohexa-
nols with the lipase PS-C for the preparation of enantioriched trans-
2-(N,N-dialkylamino)cyclohexanols (ee 95%, yield 45%, 29 h). The
synthesis of optically active trans-2-azidocyclohexenol (ee 98.7%,
yield 42%, 20 h) and trans-2-azidocyclopentanol (ee 97.9%, yield
43%, 20 h) was reported by Ami et al.15k via the transesterfication
of racemic trans-azidocycloalkanols with various lipases (Fig. 2).
Honiget al.15q have reported thehydrolysisof N-protected cyclohex-
anol acetates by different lipases with a maximum enantioselectiv-
ity of 90%. Takada et al.15r also employed enzymatic hydrolyis for
( )-trans-2-aminocyclohexanol and obtained the product in
97–99% enantiomeric purity after 48% conversion.
Thus, lipase catalyzed transacylation has been the preferred
method for the preparation of optically active amino alcohols for
obvious reasons.17 The enzymatic hydrolysis methodology has
scarcely been reported for the preparation of optically active
2-amino cycloalkanols and 1/2-aminoindanols. The low reactivity
and selectivity of the substrates, difficulties in processing of the
hydrolyzed products and the increased inhibition of hydrolases
during the product formation are some of the possible
explanations.18
reductions,8 aldol reactions,9 diethylzinc addition to aldehydes7e,6a
,
and Diels–Alder reactions.10
Due to their vast chemical, biological, and economical impor-
tance, numerous efforts have been directed toward the develop-
ment of efficient methods for their synthesis in enantiomerically
pure form. Optically active cyclic b-amino alcohols are generally
obtained via the resolution of racemic compounds such as salts
of chiral acids.11 Reactions such as Friedel–Crafts cyclization of
(ꢁ)- and (+)-phenylalanine,12 ring opening of meso-epoxides by
TMS-azide in the presence of chiral metal catalysts followed by
reduction,13 asymmetric epoxidation and dihydroxylation of pro-
chiral olefins,14 and kinetic resolution15 are frequently used for
their synthesis. The literature review contains a number of at-
tempts to prepare both the enantiomers of 2-aminocycloalkanols,
however the high enantiopurity (>99%) of products and ease of
handling still remain a major challenge.
The biocatalytic resolution methods mostly employ stereoselec-
tive transesterifications. Pioneering work by Gotor et al. over the
In the past we have been working on the kinetic resolution of
several bioactive molecules, including drug intermediates, through
enzymatic hydrolysis using whole cells, and successfully generated
the products with high enantiopurity. In this respect one of the
indigenous microbial strains bearing Arthrobacter sp. lipase (ABL)
(MTCC No. 5125)19 has proven to be highly enantioselective on a
broad range of substrates, in particular secondary alcohols.20 We
therefore envisaged using an enzymatic hydrolysis methodology
⇑
Corresponding author.
E-mail address: sctaneja@iiim.ac.in (S.C. Taneja).
Present address: Department of Chemistry, Govt. Degree College, Kathua, J&K,
India.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.019

A. Rouf et al. / Tetrahedron: Asymmetry 22 (2011) 2134–2143
2135
O
O
H
N
H
H
O
O
N
H
N
O
H
OH
O
H
O
OtBu
n
N3
HN
anxiolytic activity
novel ion channel properties
Cl
O
HO
S
N
H
O
O
O
O
N
H
N
N
N
HN
N
H
N
OH
H
S
blood coagulation factor Xa inhibitors
malarial plasmepsin inhibitor KNI-10006
Et
O
O
S
N
HN
N
H
O
N
NH
OH
MeO
N
O
N
OH
O
aryl sulfonamide indane Kv1.5 inhibitor
OH
PDE5 inhibitor
N
OH
N
N
N
O
OH
N
NH
O
O
O
HN
affinity for h5-HT1A receptors
indinavir
HO
OH
O
H
HO
N
N
H
NH
O
aggrecanase inhibitor
Figure 1. Bioactive molecules containing vicinal aminocycloalkanols.
with Arthrobacter sp. lipase in the kinetic resolution of racemic
2-amino cycloalkanols and 1/2-aminoindanols. In these experi-
ments we also successfully employed PLAP (pig liver acetone pow-
der)21 in the kinetic resolution of one of the amino indanol
derivatives, where all other biocatalysts failed.
Herein we have used phthalimide protected amino alcohols
which proved to be very effective during the enantioselective
hydrolysis of racemic acetates. In addition to providing easy
manoeuvrability and recovery of the substrate/product, tagging
with a phthalimide moiety also facilitated the separation and
detection of the racemates during liquid chromatography; im-
proved miscibility with organic solvents, and also minimized
enzyme inhibition by the product.
Herein we report the synthesis of both enantiomers of
cyclic trans-aminoalcohols, that is, trans-2-aminocyclopentanols/
hexanols and trans-1/2-aminoindanols in high enantiomeric puri-
ties and yields using the whole cells of Arthrobacter sp. Lipase
and PLAP.

2136
A. Rouf et al. / Tetrahedron: Asymmetry 22 (2011) 2134–2143
NHR
OH
95%ee.
ref 15m
OH
n
NHR
n
N3
OH
n=1, 97.9%ee.
n=2, 98.7%ee.
ref. 16
n=1, 99%ee.
n=2, 96%ee.
ref. 17a
NH2
OH
n
NHR
O
OH
n
n
n=1, 99%ee.
n=1, 94%ee.
n=2, 88%ee.
ref. 13
n=2, 49%ee.
ref. 15n
Figure 2. Literature routes for the preparation of enantiomerically enriched cycloalkanols.
epoxide ring opening directly in the presence of phthalimide were
2. Results and discussion
only partially successful as the reaction required 5–6 days. Alterna-
tively, both substrates were synthesised in two steps in 12 h and a
90% yield via epoxide ring opening with ammonia, followed by
Our initial attempts to synthesize racemic trans-2-phthalimido-
cyclopentanol 3a and trans-2-phthalimidocyclohexanol 3b via
vii
OH
O
OAc
n
O
OH
O
ii
iii
i
N
N
NH2
n
n
n
O
O
( )-2
1
( )-3
( )-4
O
AcO
n
OH
O
iv
N
N
n
O
O
(-)-3
(+)-4
v
vi
HO
n
OH
H2N
NH2
n
(1S,2S)-2
(1R,2R)-2
a, n = 1 and b, n = 2
Scheme 1. Reagents and conditions: (i) 10% NH3 in MeOH, 60 °C; (ii) phthalic anhydride, Et3N, toluene, reflux; (iii) Ac2O, DMAP, CH2Cl2; (iv) Arthrobacter sp. lipase, 10%
toluene in phosphate buffer, pH 7.0; (v,vi) Hydrazine hydrate, H2O, 60 °C, 3 h; (vii) Phthalimide, pyridine, DMF or 2-propanol, reflux, 5–6 days.

A. Rouf et al. / Tetrahedron: Asymmetry 22 (2011) 2134–2143
2137
Table 1
Effect of co-solvents on Arthrobacter sp. lipase catalyzed hydrolysis of 4a and 4b at 20 g/L concn
b
Entry
Substrate
Co-solventa
Concnb (%)
Time (h)
eep (%)
ees (%)
Ec
2.6
17
375
—
355
—
1826
>2000
1
2
Nil
DMSO
DMF
THF
Dioxane
CH3CN
n-Butanol
Toluene
25.4
35.3
17
17
41
83
99
—
>99
—
>99
>99
15.6
45
61
—
17.6
—
72.4
>99
OAc
O
3
4
5
6
7
8
38
NR
15
NR
42
50
17
17
17
17
17
20
N
O
( )-4a
9
10
Nil
DMSO
DMF
THF
Dioxane
CH3CN
n-Butanol
Toluene
NR
15.6
24
60
—
99
—
—
>99
—
—
18.5
—
—
8.0
—
—
185
—
—
162
—
OAc
O
11
12
13
14
15
17
NR
NR
7.5
NR
NR
50
60
60
60
60
60
66
N
O
—
>99
—
>99
—
>2000
( )-4b
All reactions were carried out on a shaker at 250 rpm. Substrate/Enzyme 1:2 ratio (w/w).
a
10% (v/v) Co-solvent used with respect to buffer.
b
Conversion and ee were calculated from chiral HPLC.
c
E was determined by using E = [ln(1ꢁconvn(1 + eep)]/[ln(1ꢁconvn(1ꢁeep)],22 NR = No reaction.
refluxing with phthalic anhydride in toluene using triethylamine
as a catalyst. After converting the racemic trans-2-phthalimidocy-
cloalkanol into the corresponding acetate, the enantioselective
hydrolysis was performed using Arthrobacter sp. lipase (Scheme 1).
Initially, the kinetic hydrolysis of phthalimido acetates 4a and
4b was carried out in an aqueous phosphate buffer (0.1 M, pH
7.0); however, the rate of hydrolysis was found to be quite slow
with low enantioselectivity (ee ꢀ41% and 0% respectively). The
addition of an organic solvent in the aqueous phase dramatically
improved the hydrolysis as well as enantioselectivity. Both nonpo-
lar as well as polar solvents in a ratio ranging from 5% to 30% (v/v)
in the buffer were used; toluene (10% v/v) was found to be the opti-
mal co-solvent of choice (Table 1).
Figure 3. Concentration v/s conversion of 4a and 4b in toluene/buffer using
Arthrobacter sp. lipase.
The efficacy of the Arthrobacter sp. lipase for the hydrolysis of
( )-4a was compared with other commercially available lipases.
From the results (Table 2) it is apparent that ABL was better than
most of the commercial lipases.
Encouraged by the efficacy of Arthrobacter sp. lipase for the ki-
netic resolution of 2-phthalimidocycloalkanols, we next examined
its versatility in the kinetic resolution of racemic trans-1-phthalim-
ido-2-indanol 8 and trans-2-phthalimido-1-indanol 13. Similar to
amino alkanols, amino indanols are also essential components of
many bioactive compounds and organo-catalysts.7a Although sev-
eral publications and reviews7a have appeared reporting the syn-
thesis of enantiomerically pure cis-1-amino-2-indanol and cis-2-
amino-1-indanol, there are only a few successful attempts toward
the synthesis of optically active trans-1-amino-2-indanol and
trans-2-amino-1-indanol including chemo-enzymatic methods. A
chemo-enzymatic methodology by Luna et al.17c reported on the
transesterfication of N-benzyloxycarbonyl derivatives using Pseu-
domonas cepacia lipase to produce optically active trans-1-amino-
2-indanol (ee 99%, yield 50%, 3 days) and trans-2-amino-1-indanol
(ee 20%, yield 17%, 10 days) respectively. Mitrohikine et al.15d re-
ported the enantioselective lipase catalyzed transesterfication of
2-azido-1-indanols with CAL-A (ee 99%, yield 34%, 10 days) (Fig. 4).
The trans-amino indanol derivatives are known to be slow to re-
act and most of the biotransformation reactions require several
days to complete with unsatisfactory yields. Therefore, enzymatic
hydolysis has not been attempted for their kinetic resolution.
Herein we report the synthesis of enantioenriched trans-amino-
indanols in high yields using the phthalimide protection strategy
and enzymatic deacylation of trans-indanacetates. In both exam-
ples, the use of co-solvents and immobilization of the substrate
on a Celite surface, led to a significantly improved enantioselectiv-
ity and a reduction of the reaction time.
Table 2
Screening of different lipases for the hydrolysis of ( )-4a in toluene as a co-solvent
S. No.
Lipase
Concn (%)
Time (h)
eep (%)
ees (%)
1
2
3
4
5
6
ABL
PSL
AA
CAL-B
MM
CRL
41
3
NR
9
NR
NR
15
15
15
15
15
15
>99
>99
—
>99
—
69.5
3
—
9.8
—
—
—
All reactions were carried out on a shaker at 250 rpm. Substrate/Enzyme 1:2 ratio
(w/w). 10% (v/v) co-solvent used with respect to buffer, Conversion and ee were
calculated from chiral HPLC, E was determined by using E = [ln(1ꢁconvn(1 + eep)]/
[ln(1ꢁconvn(1ꢁeep)], NR = No reaction, ABL = Arthrobacter sp. lipase, PSL = Pseu-
domonas sp. lipase, AA = Amono acylase, CAL-B = Candida antarctica lipase-B,
MM = Mucor miehei, CRL = Candida rugosa lipase.
In order to optimize the yields, the kinetic resolution studies
were carried out at various concentrations ranging from 20 to
80 g/L. It was found that Arthrobacter sp. lipase was quite effective
up to 80 g/L. The enantioselectivity remained unchanged (>99%) in
concentrations up to 80 g/L, however, as expected, the rate of
hydrolysis decreased with higher concentrations (Fig. 3). From
the time-space yield calculations, it was established that 80 g/L
for 4a and 40 g/L for 4b were the optimum concentrations for
the kinetic resolution. At optimum concentrations, the average rate
of the product formation was calculated as 1.48 g/L/h for 4a and
0.29 g/L/h for 4b.

2138
A. Rouf et al. / Tetrahedron: Asymmetry 22 (2011) 2134–2143
OH
OH
Br
OH
85%ee.
ref. 15d
99%ee.
ref. 15g
OH
O
N3
85%ee
99%ee.
ref 15f.
ref. 13a, 15e
OH
NH2
NH2
OH
O
OH
OH
NHR
96%ee.
ref. 17c
NHR
OH
OH
Nphth
99%ee.
ref. 15b
79%ee
ref. 15l
Figure 4. Literature routes for the preparation of enantiomerically enriched amino-indanols.
OH
NH2
O
iii
i
ii
Br
OH
5
6
( )-7
O
O
O
N
N
O
N
O
O
N
O
O
v
AcO
iv
OH
OAc
OH
8
(+)-9
(-)-
( )-8
( )-9
vi
NH2
vii
H2N
OH
HO
(1S,2S)-7
(1R,2R)-7
Scheme 2. Reagents and conditions: (i) NBS, THF/H2O (4:1); (ii) concentrated NH4OH; (iii) phthalic anhydride, Et3N, toluene, reflux; (iv) Ac2O, DMAP, CH2Cl2; (v) Arthrobacter
sp. lipase, 10% toluene in phosphate buffer, pH 7.0; (vi, vii) hydrazine hydrate, H2O, 60 °C, 3 h.
For the kinetic resolution studies, racemic trans-1-phthalimido-
2-indanol 8 could not be synthesized via ring opening of the corre-
sponding epoxide. However, it was prepared from bromohydrin
derivative 6 in two steps (Scheme 2). On the other hand, the

A. Rouf et al. / Tetrahedron: Asymmetry 22 (2011) 2134–2143
2139
O
O
O
O
OH
O
i
ii
iii
Br
N
N
O
O
10
11
12
( )-13
OH
O
OAc
O
O
AcO
v
iv
N
N
N
O
(-)-13
O
O
(+)-14
( )-14
vi
vii
OH
HO
NH2
H2N
(1R,2R)-15
(1S,2S)-15
Scheme 3. Reagents and conditions: (i) Br2, dioxane; (ii) potassium phthalimide, [bmim]BF4, rt, 10–15 min, >95%; ionic liquid; (iii) NaCNBH3 in acetic acid; (iv) Ac2O, DMAP,
CH2Cl2; (v) PLAP, 10% toluene in phosphate buffer, pH 7.0; (vi, vii) hydrazine hydrate, H2O, 60 °C.
trans-2-phthalimido-1-indanol 13 was synthesized from bromo
indanone 1123 (Scheme 3).
Commercially available as well as indigenous lipases were
screened for the enantioselective hydrolysis of racemic substrates
9 and 14, and it was observed that Arthrobacter sp. lipase could
enantioselectively hydrolyze 9, while PLAP was the only esterase
which successfully hydrolyzed 14 (Table 3). In an aqueous phos-
phate buffer (0.1 M, pH 7.0) in the absence of a co-solvent, no
hydrolysis was observed.
Therefore, nonpolar as well as polar solvents in ratios ranging
from 5% to 30% (v/v) in a buffer were screened. Again toluene
(10% v/v) was found to be the preferred co-solvent (Table 3). In
Table 3
Screening of different enzymes for the hydrolysis of phthalimido-indan-acetates 9 and 14 in toluene co-solvent at 20 g/L
Entry
Substrate
Enzyme
Concn (%)
Time (h)
eep (%)
ees (%)
E
1
2
PSL
ABL
15
39
168
168
99
99
18
60
71
384
O
N
O
OAc
( )-9
3
4
5
6
7
8
9
10
11
12
13
9a
14
14
9,14
9,14
9,14
9,14
9,14
9,14
9,14
9
ABL
ABL
PSL
PLF
CALB
NOVAZYME
AA
MM
CRL
50
92
168
168
168
168
168
168
168
168
168
168
>99
—
—
—
—
—
—
—
—
—
—
>99
—
—
—
—
—
—
—
—
—
—
>1000
—
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
—
—
—
—
—
—
—
—
CCL
PLAP
—
OAc
O
N
14
15
PLAP
38
168
98
60
183
O
( )-14
14a
PLAP
48
120
98
90
311
a
Substrate immobilized on Celite. All reactions were carried out in a shaker at 250 rpm. Substrate/Enzyme 1:2 ratio (w/w), 10% (v/v) co-solvent used with respect to buffer,
conversion and ee were calculated from chiral HPLC, E was determined by using E = [ln(1ꢁconvn(1 + eep)]/[ln(1ꢁconvn(1ꢁeep)], NR = No reaction, ABL = Arthrobacter sp.
lipase, PSL = Pseudomonas sp. lipase, AA = Amono acylase, CAL-B = Candida antarctica lipase-B, MM = Mucor miehei, CRL = Candida rugosa lipase.

2140
A. Rouf et al. / Tetrahedron: Asymmetry 22 (2011) 2134–2143
both resolution reactions, due to the slow reaction rates the hydro-
lysis took longer time (6–7 days). Therefore, we envisaged immobi-
lizing the substrate on an inert support to improve the rate of
reaction, a methodology highly useful in the kinetic resolution of
spiro-b-lactams as reported in our recent work.24 The immobiliza-
tion of the substrate on Celite support (5% w/w) reduced the reac-
tion time from 168 to 92 h for 9 and 120 h for 14 at the same
substrate concentrations (20 g/L). The immobilization also resulted
in a substantial improvement in the enantioselectivity factor E
from 384 to >1000 and 183 to 311 respectively (Table 3, entries
3 and 15).
4.3. Synthesis of ( )-trans-2-phthalimidocyclohexanol 3b
Compound 3b was prepared from 2-aminocyclohexanol
(1 mmol) following the procedure described for 3a (yield 95%);
(C14H15NO3); mp 90–92 °C; 1H NMR: d 1.21–1.42 (m, 4H), 1.68–
1.83 (m, 2H), 2.13–2.24 (m, 2H), 3.97 (ddd, J = 3.7, 10.1 and
12.4 Hz), 4.26–4.37 (m, 1H), 7.67–7.74 (m, 2H), 7.78–7.85 (m,
2H). 13C NMR: d 24.2, 25.1, 28.6, 34.6, 57.1, 68.6, 122.7, 131.7,
133.8, 169.5. ESI-MS (m/z): 245. Anal. Calcd for C14H15NO3: C,
68.56; H, 6.16; N, 5.71. Found C, 68.59; H, 6.15; N, 5.73.
The enantiomerically pure masked 1,2-amino alcohols thus ob-
tained were quantitatively converted into 1,2-amino alcohols by an
improved Ing–Manske reaction.25 The improved methodology23 in-
volved stirring phthalimide protected amines in water at 60 °C in
the presence of 2 equiv of hydrazine hydrate. The amino alcohol
products were isolated in high purity simply by ethyl acetate
extraction without any chromatographic purification. The absolute
configurations of all of the optically active compounds were deter-
mined by comparing the sign of specific rotations with those re-
ported in the literature.15k,26
4.4. Synthesis of ( )-trans-1-phthalimidoindan-2-ol 8
Compound 8 was prepared from 1-amino indan-2-ol (1 mmol)
following the procedure described for 3a (yield 95%); (C17H13
-
NO3); mp 124.2 °C. 1H NMR, d 1.51 (s, OH), 2.94–2.99 (dd,
J = 6.7 Hz,15.8 Hz, 1H), 3.56–3.61 (dd, J = 7.5 Hz, 15.8 Hz, 1H),
5.11–5.15 (q, J = 6.1 Hz, 12.88 Hz, 1H), 5.67 (d, J = 6.3 Hz, 1H), 7.02
(d, J = 7.1 Hz, 2H), 7.2 (d, J = 4.3 Hz, 2H), 7.26 (m, 2H), 7.74 (q,
3.1 Hz, 5.3 Hz, 2H), 7.85 (q, 3.0 Hz, 5.4 Hz, 2H). 13C NMR: d 31.59,
62.81, 123.11, 123.43, 125.13, 127.08, 128.42, 131.90, 134.17,
137.78, 139.91, 168.16. ESI-MS (m/z): 279. Anal. Calcd for
C17H13NO3: C, 73.11; H, 4.69; N, 5.02. FoundC, 73.54; H, 4.15; N, 6.45.
3. Conclusions
4.5. Synthesis of ( )-2-phthalimidoindan-1-one 12
In conclusion an efficient and facile method for the preparation
of enantiomerically pure trans-2-aminocycloalkanols (ee, >99%)
and trans-1/2-amino-indanols (ee, 98–99%) by the whole cells of
Arthrobacter sp. lipase and the PLAP catalyzed kinetic resolution
of their phthalimido analogues has been demonstrated. In the case
of indanols, immobilization of the substrates on a celite support
improved the hydrolysis rates and significantly reduced the reac-
tion time.
A mixture of potassium phthalimide (1.1 mmol) and bromo ke-
tone 11 (1 mmol) in a 10 mL conical flask was added to 1 mL of ionic
liquid [1-butyl-3-methylimidazolium tetrafluoroborate] and the
resulting reaction mixture was stirred at room temperature for
10–15 min. The reaction mixture was extracted from the ionic liquid
phase with diethylether (2 ꢂ 5 mL). The organic layer was concen-
trated and evaporated under reduced pressure. The residue was
purified by column chromatography to obtain product 12 in a 96%
yield. The ionic liquid left in the flask was further washed with dieth-
ylether, dried under vacuum and reused in four to five subsequent
reactions without loss in activity. Mp 191 °C; 1H NMR, d 3.41 (dd,
J = 5.9 Hz and 16.5 Hz, 1H), 3.61 (dd, J = 8.4 Hz, 16.6 Hz, 1H), 5.09
(dd, J = 6.0 Hz, 8.4 Hz, 1H), 7.41–7.52 (m, 2H), 7.64–788 (m, 6H).
13C NMR, d 32.0, 53.8, 123.7, 124.7, 126.8, 128.2, 132.3, 134.4,
135.8. 151.1, 167.7, 200.2. ESI-MS (m/z): 277. Anal. Calcd for
4. Experimental
4.1. General
1H NMR spectra in CDCl3 were recorded on Bruker 200, 400 and
500 MHz spectrometers with TMS as the internal standard. Chem-
ical shifts are expressed in parts per million (d ppm). Reagents and
solvents used were mostly of LR grade. Silica gel coated aluminum
plates coated on alumina from M/s Merck were used for TLC. MS
were recorded on Jeol MSD-300 and Bruker Esquire 3000 LC-Mass
spectrometer. Optical rotations were measured on Perkin-Elmer
241 polarimeter at 25 °C using sodium D light. Melting points were
determined on Buchi B-542 apparatus by an open capillary method
and are uncorrected. Enantiomeric excess (ee%) was determined by
chiral HPLC on OJH and ADH chiral columns. Chemicals were pur-
chased from M/s Aldrich Chemicals, Mumbai.
C11H9NO3: C, 73.64; H, 4.00; N, 5.05. Found C, 73.63; H, 4.03; N, 5.02.
4.6. Synthesis of ( )-trans-2-phthalimidoindan-1-ol 13
NaCNBH3 (2 mmol) was added at room temperature to a solu-
tion of
a-phthalimido ketone 12 in acetic acid (1 mmol in
15 mL). After completion of the reaction (48 h) as indicated by thin
layer chromatography, the reaction was quenched by a saturated
NaHCO3 solution and extracted with ethyl acetate. The combined
extracts were washed with water, dried over anhydrous sodium
sulfate and concentrated under reduced pressure to obtain product
13 in an 85% yield. The product was purified on a silica gel column
(yield 85%); mp 217–219 °C; 1H NMR, d 1.56 (s, OH), 3.15–3.21 (dd,
J = 8.4 Hz, 16.0, 1H), 3.98–4.04 (dd, J = 8.4 Hz and 16.0 Hz, 1H),
5.11–5.18 (m, 2H), 7.29–7.37 (m, 3H), 7.50–7.52 (m, 1H), 7.73–
7.76 (m, 2H), 7.84–7.87 (m, 2H). 13C NMR, d 32.7, 52.9, 76.2,
123.4, 124.9, 125.6, 127.5, 129.4, 131.9, 134.2, 140.2, 142.5,
169.6. ESI-MS (m/z): 279. Anal. Calcd for C17H13NO3: C, 73.11; H,
4.69; N, 5.02. Found C, 73.13; H, 4.65; N, 5.03.
4.2. Synthesis of ( )-trans-2-phthalimidocyclopentanol 3a
A catalytic amount of triethylamine was added to a solution of
phthalic anhydride (1 mmol) and ( )-2-aminocyclopentanol 2
(1 mmol) in toluene (30 mL), and the solution was refluxed for 3 h.
After completion of the reaction as indicated by TLC, the reaction
mixture was extracted with water and ethyl acetate. The organic
layer was concentrated under reduced pressure to obtain crude 2-
phthalimidocyclopentanol 3a, which was purified by column chro-
matography (yield 95%); (C13H13NO3); mp 106–108 °C; 1H NMR: d
1.56–1.98 (m, 4H), 2.04–2.13 (m, 2H), 4.31 (dt, J = 7.1 Hz, 9.2 Hz,
1H), 4.60–4.66 (m, 1H), 7.59–7.65 (m, 2H), 7.71–7.76 (m, 2H). 13C
NMR: d 21.1, 27.2, 33.3, 59.3, 75.1, 123.2, 132.0, 134.0, 168.7. ESI-
MS (m/z): 231. Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N,
6.06. Found C, 67.59; H, 5.65; N, 6.03.
4.7. General method for the acylation of phthalimido amino
alcohols
Acetic anhydride (1.2 mmol) and a catalytic amount of DMAP
were added to a solution of racemic protected amino alcohols

A. Rouf et al. / Tetrahedron: Asymmetry 22 (2011) 2134–2143
2141
(1 mmol) in dry dichloromethane and the reaction mixture kept
4.13. (1R,2R)-(ꢁ)-2-Phthalimidocyclopentan-1-ol 3a
overnight at room temperature. The contents of the reaction mix-
ture were poured into ice-cold water and extracted with dichloro-
methane. The organic layer was washed, dried, and evaporated to
provide protected amino acetoxy derivatives in a quantitative
yield.
HPLC purity >99%; HPLC ee >99%; ½a D25
¼ ꢁ32:5 (c 1, CHCl3);
ꢃ
HPLC condition (OJH chiral column, eluent 2-propanol–hexane–
acetic acid (4:96:0.1), flow rate: 0.5 mL/min, t1 = 38.0, 42.0 min).
4.14. (1R,2R)-(ꢁ)-2-Phthalimidocyclohexan-1-ol 3b
4.8. ( )-trans-1-Acetoxy-2-phthalimidocyclopentane 4a
HPLC purity >99%; HPLC ee >99%; ½a D25
¼ ꢁ34:0 (c 1, CHCl3);
ꢃ
(C15H15NO4); mp 94–96 °C; 1H NMR: d 1.74–1.78 (m, 2H), 1.99
(s, 3H), 1.95–2.13 (m, 3H), 2.26–2.38 (m, 1H), 4.49–4.61 (m, 1H),
5.49–5.58 (m, 1H), 7.67–7.72 (m, 2H), 7.78–7.85 (m, 2H). 13C
NMR: d 21.1, 22.7, 28.7, 31.5, 56.7, 77.8, 123.3, 132.1, 133.9,
168.2, 170.9. ESI-MS (m/z): 273. Anal. Calcd for C15H15NO4: C,
65.92; H, 5.53; N, 5.13. Found C, 65.99; H, 5.55; N, 5.13.
HPLC condition (OJH chiral column, eluent 2-propanol–hexane–
acetic acid (1:99:0.1), flow rate: 1 mL/min, t1 = 31.5, 35.6 min).
4.15. (1R,2R)-(ꢁ)-1-Phthalimidoindan-2-ol 8
HPLC purity >99%; HPLC ee >99%; ½a D25
¼ ꢁ84:8 (c 0.25, CHCl3);
ꢃ
HPLC condition (ADH chiral column, eluent 2-propanol–hexane
4.9. ( )-trans-1-Acetoxy-2-phthalimidocyclohexane 4b
(20:80), flow rate: 0.8 mL/min, t1 = 15.3, 21.2 min).
(C16H17NO4); mp 90–92 °C; 1H NMR: d 1.30–1.47 (m, 4H), 1.78–
1.85 (m, 2H), 1.84 (s, 3H), 2.16–2.22 (m, 1H), 2.27–2.40 (m, 1H),
4.11–4.25 (m, 1H), 5.46 (dt, J = 4.7 Hz, 10.5 Hz, 1H), 7.68–7.74 (m,
2H), 7.79–785 (m, 2H). 13C NMR: d 19.9, 22.8, 24.0, 27.6, 30.6,
52.7, 70.8, 122.2, 130.8, 132.9, 169.3, 171.2. ESI-MS (m/z): 287.
Anal. Calcd for C15H15NO4: C, 66.89; H, 5.96; N, 5.96. Found C,
66.88; H, 5.95; N, 5.93.
4.16. (1R,2R)-(ꢁ)-2-Phthalimidoindan-1-ol 13
HPLC purity >98%; HPLC ee >98%; ½a D25
¼ ꢁ23:0 (c 1, CHCl3);
ꢃ
HPLC condition (ADH chiral column, eluent 2-propanol–hexane–
acetic acid (5:95:0.1), flow rate: 0.8 mL/min, t1 = 20.3, 22.3 min).
4.17. (1S,2S)-(+)-2-Phthalimido-1-acetoxy-cyclopentane 4a
4.10. ( )-trans-1-Phthalimido-2-acetoxyoindane 9
HPLC purity >99%; HPLC ee >99%; ½a D25
¼ þ10:0 (c 0.5, CHCl3);
ꢃ
HPLC condition (OJH chiral column, eluent 2-propanol–hexane–
(C19H15NO4); mp134.9 °C; 1H NMR: d 2.06 (s, 3H) 3.01–3.12 (dd,
J = 5.2 Hz, 16.6 Hz, 1H), 3.72–3.84 (dd, J = 7.9 Hz, 16.6 Hz, 1H), 5.80
(d, J = 4.8 Hz, 1H), 5.90 (m, 1H), 7.12- 7.29 (m, 4H), 7.70–7.74 (q,
J = 3.1 Hz, 5.6 Hz, 2H), 7.82–7.87 (q, J = 2.9 Hz, 5.5 Hz, 2H). 13C
acetic acid (4:96:0.1), flow rate: 0.5 mL/min, t1 = 16.1, 31.5 min).
4.18. (1S,2S)-(+)-2-phthalimido-1-acetoxy-cyclohexane (4b)
NMR:
d
20.90, 37.49, 60.44, 77.86, 123.28, 123.36, 124.87,
HPLC purity >99%; HPLC ee >99%; ½a D25
¼ þ7:5 (c 1, CHCl3);
ꢃ
127.26, 128.66, 131.88, 134.07, 137.61, 140.09, 167.62, 173.73.
ESI-MS (m/z): 321. Anal. Calcd for C19H15NO4: C, 71.02; H, 4.71;
N, 4.36. Found C, 71.32; H, 4.99; N, 5.23.
HPLC condition (OJH chiral column, eluent 2-propanol–hexane–
acetic acid (1:99:0.1), flow rate: 1 mL/min, t1 = 13.1, 13.1 min).
4.19. (1S,2S)-(+)-1-Phthalimido-2-acetoxyindan 9
4.11. ( )-trans-2-Phthalimido-1-acetoxyoindan 14
HPLC purity >99%; HPLC ee >99%; ½a D25
¼ þ96:0 (c 1, CHCl3);
ꢃ
(C19H15NO4); mp 117–119 °C; 1H NMR: d 1.85 (s, 3H) 3.14–3.19
(dd, J = 8.5 Hz, 15.8 Hz, 1H), 4.36–4.41 (dd, J = 8.7 Hz, 15.8 Hz, 1H),
5.11–5.16 (m, 1H), 6.27 (d, J = 6.2 Hz, 1H), 7.26–7.36 (m, 4H), 7.73–
7.75 (q, J = 3.0 Hz, 5.4 Hz, 2H), 7.85–7.87 (dd, J = 3.0 Hz, 5.4 Hz, 2H).
13C NMR: d 20.81, 31.97, 52.41, 75.93, 123.32, 124.74, 126.36,
127.21, 129.76, 131.75, 134.13, 138.33, 142.18, 168.35, 170.57.
ESI-MS (m/z): 321. Anal. Calcd for C19H15NO4: C, 71.02; H, 4.71;
N, 4.36. Found C, 71.62; H, 4.63; N, 4.87.
HPLC condition (ADH chiral column, eluent 2-propanol–hexane
(20:80), flow rate: 0.8 mL/min, t1 = 9.9, 12.9 min).
4.20. (1S,2S)-(+)-2-Phthalimido-1-acetoxyindan 14
HPLC purity >90%; HPLC ee >90%; ½a D25
¼ þ20:0 (c 1, CHCl3);
ꢃ
HPLC condition (ADH chiral column, eluent 2-propanol–hexane–
acetic acid (5:95:0.1), flow rate: 0.8 mL/min, t1 = 25.7, 48.2 min).
4.12. General procedure for the hydrolysis of acetyl derivatives
of 2-phthalimidocycloalkanols and phthalimidoindanols
4.21. (1R,2R)-trans-2-Amino-1-cyclopentanol 2a
(C5H11NO) ½a 2D5
¼ ꢁ31:3 (c 1.0, methanol); >99% ee; mp: 80 °C;
ꢃ
The racemic acetates (50 mg), aqueous phosphate buffer
{lit:15b
½
a 2D5
ꢃ
¼ ꢁ30:6 (c 0.78 methanol) >99% ee; mp: 82–83 °C}; 1H
(2.5 mL, 0.1 M, pH. 7.0), toluene (250
Arthrobacter sp. lipase/PLAP(150 mg) were shaken (320 rpm) con-
tinuously at 25 1 °C. After certain degree of conversion
ll), and wet whole cells of
NMR, d: 1.23–1.48 (m, 2H), 1.50–1.83 (m, 2H), 1.84–2.02 (m, 5H),
2.80–3.22 (m, 1H), 3.80–3.06 (m, 1H), 13C NMR, d: 13C NMR, d:
21.1, 31.1, 33.1, 60.6, 79.2, ESI-MS (m/z):101. Anal. Calcd for
C5H11NO: C, 59.36; H, 10.97; N, 13.85. Found C, 59.24; H, 10.99;
N, 13.80
a
(ꢀ50%) as indicated by high performance liquid chromatography
(HPLC), the reaction was terminated by adding ethyl acetate and
centrifuging the mixture at 10,000–15,000g to remove the enzyme
and the suspended particles. The clear solution was decanted and
the centrifuged mass was extracted separately with ethyl acetate
(3 ꢂ 25 mL). The organic layer was combined and washed with
water. The combined organic layer was then dried and evaporated
under reduced pressure to furnish a mixture of hydrolyzed alcohol
and unhydrolyzed ester, which was separated by column
chromatography.
4.22. (1S,2S)-trans-2-Amino-1-cyclopentanol 2a
(C5H11NO) ½a 2D5
ꢃ
¼ þ30:6 (c 1.0, methanol); >99% ee; mp: 80–
¼ þ30:65 (c 0.71 methanol) >99% ee, mp: 82–
82 °C; {lit:15b
½ ꢃ
a 2D5
83 °C}; 1H NMR, d: 1.23–1.48 (m, 2H), 1.50–1.83 (m, 2H), 1.84–
2.02 (m, 5H), 2.80–3.22 (m, 1H), 3.80–3.06 (m, 1H),13C NMR, d:
21.1, 31.1, 33.1, 60.6, 79.2, ESI-MS (m/z): 101. Anal. Calcd for

2142
A. Rouf et al. / Tetrahedron: Asymmetry 22 (2011) 2134–2143
C5H11NO: C, 59.36; H, 10.97; N, 13.85. Found C, 59.34; H, 10.92; N,
13.82.
Acknowledgements
The authors are highly thankful to the CSIR and the UGC, New
Delhi for financial support and the award of SRFs to A.R., M.A.A.
and B.K.
4.23. (1R,2R)-trans-2-Amino-1-cyclohexanol 2b
(C6H13NO) ½a 2D5
¼ ꢁ39:1 (c 0.50, methanol); >99% ee; mp: 86 °C;
ꢃ
{lit:15b
½
a 2D5
ꢃ
¼ ꢁ40:1 (c .41 MeOH) 100% ee, mp: 87 °C}; 1H NMR,, d:
References
0.90–1.40 (m, 2H), 1.51–1.83 (m, 2H), 1.84–2.12 (m, 2H), 2.21–2.50
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75.0; ESI-MS (m/z): 115. C6H13NO: C 62.55; H, 11.38; N, 12.17.
Found C, 62.35; H, 11.30; N, 12.19.
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(C6H13NO) ½a 2D5
¼ þ40:1 (c 0.50, methanol); >99% ee; mp: 86 °C;
ꢃ
{lit:15b
½
a 2D5
ꢃ
¼ þ40:4 (c .41 MeOH) 100% ee, mp: 87 °C}; 1H NMR, d:
0.90–1.40 (m, 2H), 1.51–1.83 (m, 2H), 1.84–2.12 (m, 2H), 2.21–2.50
(m, 2H), 3.10–4.23 (m, 1H), 13C NMR, d: 23.4, 24.6, 31.5, 34.4, 55.8,
75.0; ESI-MS (m/z): 115. Anal. Calcd for C6H13NO: C 62.55; H,
11.38; N, 12.17. Found C, 62.32; H, 11.33; N, 12.12.
4.25. (1R,2R)-trans-1-Amino-2-indanol 7
(C9H11NO) ½a 2D5
¼ ꢁ22:0 (c 0.54, CHCl3); >99% ee; mp: 143.0 °C;
ꢃ
{lit:26d
½
a 2D5
ꢃ
¼ ꢁ21:5 (c 0.58, MeOH); >99% ee; mp: 144.0–
145.0 °C}; 1H NMR, d: 2.04 (br s, 3H), 2.80–2.843 (dd, J = 15.4 Hz,
8.1 Hz, 1H), 3.19–3.23 (dd, 1H, J = 15.5 Hz, 7.1 Hz), 4.08–4.34 (m,
2H), 7.14–7.28 (m, 4H).13C NMR (CDCl3): 38.2, 64.0, 82.1, 123.1,
124.8, 127.1, 127.8, 138.9, 143.8. ESI-MS (m/z): 149. Anal. Calcd
for C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found C, 72.37; H, 7.58;
N, 9.47.
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4.26. (1S,2S)-trans-1-Amino-2-indanol 7
(C9H11NO) ½a 2D5
¼ þ22:4 deg (c 0.98, methanol); >99% ee; mp:
ꢃ
141.0–143.0 °C; {lit:26d
½
a 2D5
ꢃ
¼ þ22:8 (c 1.12, MeOH); >99% ee;
mp: 144.0–145.0 °C}; 1H NMR dH 2.04 (br s, 3H), 2.80–2.843 (dd,
J = 15.4 Hz, 8.1 HEz, 1H), 3.19–3.23 (dd, 1H, J = 15.5 Hz, 7.1 Hz),
4.08–4.34 (m, 2H), 7.14–7.28 (m, 4H).13C NMR (CDCl3): 38.2,
64.0, 82.1, 123.1, 124.8, 127.1, 127.8, 138.9, 143.8. ESI-MS (m/z):
149. Anal. Calcd for C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found C,
72.34; H, 7.54; N, 9.52.
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4.27. (1R,2R)-trans-2-Amino-1-indanol 15
(C9H11NO) ½a 2D5
¼ ꢁ14:3 (c 5, CHCl3); 98% ee; mp: 157 °C;
ꢃ
{lit:26d
½
a 2D5
ꢃ
¼ ꢁ15:0 (c 5, CHCl3); >99% ee; mp:160.0–161.0 °C};
1H NMR, d: 2.60 (dd, J = 15.3 Hz, 8.0 Hz, 1H), 3.22 (dd, J = 15.3 Hz,
8.0 Hz, 1H), 3.47 (dt, J = 8.0 Hz, 6.5 Hz, 1H) 4.79 (d, 6.5 Hz, 1H),
7.15–7.60 (m, 4H), 13C NMR, d: 38.8, 62.9, 82.2, 123.6,124.7,
126.9, 128.1, 139.5, 143.3. ESI-MS (m/z): 149. Anal. Calcd for
C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found C, 72.44; H, 7.52; N,
9.47.
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4.28. (1S,2S)-trans-2-Amino-1-indanol 15
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(C9H11NO) ½a 2D5
¼ þ10:3 (c 5, CHCl3); 90% ee; mp: 154–156 °C;
ꢃ
{lit:26d
½
a 2D5
ꢃ
¼ þ13:4 (c 5, CHCl3); >99% ee; mp:160.0–161.0 °C};
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DiMichele, L. M.; Ryan, K. M.; Liu, J.; Fredenburgh, L. E.; Foster, B. S.; Douglas, A.
W.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1995, 36, 3993–
3996; (e) Senanayake, C. H.; DiMichele, L. M.; Liu, J.; Fredenburgh, L. E.; Ryan, K.
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1H NMR, d: 2.60 (dd, J = 15.3 Hz, 8.0 Hz, 1H), 3.22 (dd, J = 15.3 Hz,
8.0 Hz, 1H), 3.47 (dt, J = 8.0 Hz, 6.5 Hz, 1H) 4.79 (d, 6.5 Hz, 1H),
7.15–7.60 (m, 4H), 13C NMR, d: 38.8, 62.9, 82.2, 123.6,124.7,
126.9, 128.1, 139.5, 143.3. ESI-MS (m/z): 149. Anal. Calcd for
C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found C, 72.40; H, 7.55; N,
9.43.

A. Rouf et al. / Tetrahedron: Asymmetry 22 (2011) 2134–2143
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