An expedient chemo-enzymatic method for the synthesis of optically active masked 1,2-amino alcohols

Article abstract of DOI:10.1016/j.tetasy.2008.08.004

The expedient synthesis of enantiopure masked 1,2-amino alcohols (ee >99%) including their alkyl substituted analogues has been achieved by the regioselective ring opening of epoxides using phthalimide, followed by highly efficient kinetic resolution under mild and environmentally friendly conditions. The addition of co-solvents during kinetic resolution significantly improved the enantioselectivity with reduction in time.

Full text of DOI:10.1016/j.tetasy.2008.08.004

Tetrahedron: Asymmetry 19 (2008) 1898–1903
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An expedient chemo-enzymatic method for the synthesis of optically
active masked 1,2-amino alcohols
a
a
a
Pankaj Gupta a, Subhash C. Taneja a, , Bhahwal A. Shah , Debaraj Mukherjee , Rajinder Parshad ,
*
Swapandeep S. Chimni b, Ghulam N. Qazi a
a Bioorganic Chemistry Section, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi 180 001, India
b Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The expedient synthesis of enantiopure masked 1,2-amino alcohols (ee >99%) including their alkyl substi-
tuted analogues has been achieved by the regioselective ring opening of epoxides using phthalimide,
followed by highly efficient kinetic resolution under mild and environmentally friendly conditions. The
addition of co-solvents during kinetic resolution significantly improved the enantioselectivity with
reduction in time.
Received 12 June 2008
Accepted 5 August 2008
Available online 28 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
enzymes as biological catalysts,13 we report herein an efficient
and facile methodology for the synthesis of optically active masked
The importance of vicinal amino alcohols continues to stimulate
the development of new efficient methods for their synthesis in
enantiomerically pure form.1 1,2-Amino alcohols are not only the
key pharmacophores in many drug molecules,1a,2 but also consti-
tute as substructures in various important natural products.1a,3
Non-aromatic vic amino alcohols are used as inhibitors of phenyl-
ethanolamine N-methyltransferase (PNMT),4 as perfumes,5 and
exhibit potent inhibitory activity against human platelet phospho-
lipase (PLA2).6
In addition to their biological importance, enantiomerically
pure amino alcohols, especially 1,2-amino alcohols, have also been
successfully employed as chiral auxiliaries and resolving agents for
acids, and as chiral ligands for applications in catalytic asymmetric
synthesis.7 Chiral 1,2-amino alcohols are generally prepared from
naturally occurring amino acids,8 whose products are restricted
to chiral secondary amines with primary hydroxy groups. Those
containing secondary hydroxyl groups can be obtained from the
stereo-, regio-, and enantioselective ring opening of epoxides9 cat-
alyzed by chiral metal complexes, and by chemocatalytic10 or
microbial11 reduction of masked amino ketones. The importance
of biocatalytic methods for the preparation of optically active com-
pounds is now well recognized.12 Moreover, the resolution of alkyl
substituted 1,2-amino alcohol analogues are difficult to achieve by
chemical methods due to the possibility of a non-crystalline nature
of their diastereomeric salts. Therefore, in continuation of our
research programme, which is aimed at synthesizing natural and
non-natural compounds of biomedical importance utilizing
1,2-amino alcohols 1–6 (Fig. 1). The generation of optically active
amino alcohols from their masked precursors can easily be
achieved by the known methods.14
The successful strategy involved the tagging of a phthalimide as
a masking group, since free amino functions generally cause inhi-
bition of lipases. The other advantages of incorporating a phthali-
mide subunit are the facilitation of their separation and UV
detection by HPLC, also easy handling; additionally, phthalimide
analogues are also reported to have anti-inflammatory,15 analge-
sic,16 anticonvulsant,17 herbicidal,18 and insecticidal19 activities.
Recently, we have reported the chemoenzymatic synthesis of
masked vic amino alcohols through reduction of protected amino
ketones; however, this protocol had some limitations as it was
generally difficult to introduce bromine and thereafter amines at
a less substituted position in unsymmetrical ketones.20 The alter-
native strategy herein involved an efficient method of preparation
of masked amino alcohols through regioselective ring opening of
the epoxides using phthalimide.21
2. Results and discussion
Our attempts began with the synthesis of racemic 2-phthali-
mide alcohols 1–4 via regioselective ring opening of epoxides with
phthalimide. The optimized conditions involved refluxing the
epoxy compound with phthalimide in isopropyl alcohol using pyr-
idine as catalyst; the final isolated yield varied from 75% to 85%
(Scheme 1).
For the kinetic resolution and preparation of target molecules,
enantioselective hydrolysis of racemic 2-phthalimide acetates 8
and 9 was carried out with a panel of micro organisms bearing
* Corresponding author. Tel.: +91 191 2569011; fax: +91 191 2569017/2569333.
E-mail address: sc_taneja@yahoo.co.in (S. C. Taneja).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.004

P. Gupta et al. / Tetrahedron: Asymmetry 19 (2008) 1898–1903
1899
OH
OH
OH
OH
NPhth
NPhth
NPhth
NPhth
4
3
2
1
OH
OH
O
NPhth
O
NPhth
MeO
6
5
Figure 1.
O
O
O
O
HO
O
O
R
R
i
ii
NH
R
N
N
O
O
O
7 10
(RS)- -
(RS)-1-4
R = CH2CH3 1; CH2CH2CH3 2;
7
8
;
R = CH2CH3 ; CH2CH2CH3
C6H5 9; CH2(CH2)4CH3 10.
3
4
C6H5 ; CH2(CH2)4CH3
.
Scheme 1. Reagent and conditions: (i) IPA, Py, reflux; (ii) Ac2O, DMAP/DCM.
Table 1
ous phosphate buffer (0.1 M, pH 7.0); however, the rate of hydro-
lysis was found to be slow while the enantioselectivity was also
poor (Table 1). Therefore, in order to improve the rate of hydroly-
sis, as well as the enantioselectivity, the use of co-solvents was
envisaged as a convenient option, and the kinetic resolution reac-
tions of ( )-7–10 were carried out in biphasic systems.
A biphasic system using an organic solvent proved to be highly
advantageous. Both non-polar and polar solvents in the ratio 10%
(v/v) in buffer were used. Finally, the use of ether solvents for
the hydrolysis of ( )-7 and ( )-8 and toluene for the hydrolysis of
( )-9 and ( )-10 was considered to be the best (Table 2). Here, a
native strain Arthrobacter sp. lipase22 designated as ABL (MTCC
no. 5125) has been identified for its excellent performance in the
kinetic resolutions of ( )-7, ( )-8, ( )-9, and ( )-10 (E values 397,
1059, 1059, and 54, respectively).
While commercial lipase PSC-II was most suited for the resolu-
tion of racemic 2-hydroxy butyl amine precursor 7 (E = 397), the
higher alkyl analogues 8 and 10 were easily resolved using ABL,
so also the phenyl analogue 9.
In the experiments for the resolution of the substrate 7 with
ABL, it was observed that the enantiomeric excess was strongly
dependent on the extent of hydrolysis and so it was important to
carry the reaction beyond 50% hydrolysis (ꢀ58%) in order to obtain
the enantiopure acetate 7 in good yields. It was thus necessary to
Enzymatic hydrolysis of 2-phthalimide acetates, that is, ( )-8 and ( )-9 in aqueous
phosphate buffer
Substrate
Lipase
Conversion
(%)
Time
(h)
eep
(%)
ees
(%)
Amano AS
PSL
MM
PSC-II
ABL
CRL
ND
2.6
ND
8.5
29.3
ND
24
24
24
120
6
—
38.5
—
5.8
13.3
—
—
1.0
—
0.5
5.5
—
OAc
NPhth
NPhth
8
24
PSL
ND
ND
46.5
24.3
17.8
ND
120
120
16
46
46
—
—
8.6
13.5
38.2
—
—
—
9.2
0.9
9.2
—
MM
ABL
CCL
AA
MM
PSC-II
OAc
C6H5
9
120
46
ND
—
—
CCL: Candida cylindrica lipase; MM: Mucor miehei; CRL: Candida rugosa lipase; CAL:
Candida antarctica lipase; PSL: Pseudomonas cepacia lipase; PSC-II: Pseudomonas
cepacia lipase on ceramics; ABL: Arthrobacter sp. lipase; AA: Amano acylase; AS:
Lipase from Aspergillus niger; ND = not detected.
lipases belonging to the institute’s repository as well as being
obtained from commercial sources (Table 1, Scheme 2). The kinetic
resolution reactions of ( )-8 and ( )-9 were carried out in an aque-
O
O
O
O
Lipase
ABL
O
HO
O
O
R
R
R
Buffer
pH 7.1.
N
N
N
O
O
O
ee = 93->99%
(S)-1-4
7-10
(R)-
(RS)-7-10
Scheme 2.

1900
P. Gupta et al. / Tetrahedron: Asymmetry 19 (2008) 1898–1903
Table 2
Enzymatic hydrolysis of racemic 2-phthalimide acetates 7, 8, 9, and 10 at 20 g/L concentration in biphasic systems
Substrate
Lipase
Co-solvent
Conversion (%)
Time (h)
eep (%)
ees (%)
E
PPL
CCL
MM
CRL
PSC-II
PSL
AS
ABL
Lipase M
ABL
ABL
ABL
ABL
ABL
ABL
ABL
ABL
ABL
Toluene
Tetrahydrofuran
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1.7
46.7
4.6
23.7
30.6
14.4
22.5
39.8
2.1
33.1
58
46.5
ND
39.8
30.3
38.7
2.8
32.9
30.6
40
25.7
49.1
18.9
30.7
90
90
90
44
90
90
90
6
90
6
5
3
6
88.2
22.1
60.8
33.3
98.4
93.1
3.1
71.8
38.1
54.6
67
1.5
21.2
5.2
15.9
1.8
4.3
2.2
154
32.9
1.1
9.7
2.3
4.4
9.3
43.3
15.8
3.2
47.5
0.5
27.1
>99
72.5
—
47.5
35.7
54.6
2.8
35.9
43.3
66.6
34.6
91.3
21.9
40.3
Nil
OAc
Diisopropylether
Diisopropylether
Tetrahydrofuran
Toluene
Dimethoxyethane
Diethylether
DMF
16.1
29.3
NPhth
85.8
—
6
6
6
6
71.8
82.2
86.6
>99
73.2
98.4
>99
>99
97
9.7
14.5
24.1
57
7
DMSO
Toluene
6
9.4
PSC-II
PSC-II
PSC-II
PSC-II
PSC-II
PSC-II
90
120
120
120
120
120
194.5
397.4
278.4
230.4
41.9
49.5
Tetrahydrofuran
Diisopropylether
Dimethoxyethane
Diethylether
Hexane
94.2
94.1
ABL
ABL
ABL
ABL
Tetrahydrofuran
Diethylether
Toluene
Diisopropylether
Dimethoxyethane
Toluene
Diisopropylether
Tetrahydrofuran
DMF
ND
50
4.8
50
47
18.3
24.8
17.6
11.2
9.4
6
6
6
6
6
120
120
120
120
120
—
—
>99
5.5
>99
88.7
15.8
26.1
16.3
9.5
—
1059
>99
87.5
>99
>99
70.5
87.1
76.1
65.1
19.1
15.6
1059
580
OAc
ABL
NPhth
NPhth
PSC-II
PSC-II
PSC-II
PSC-II
PSC-II
6.8
19.1
8.6
5.2
1.5
8
Hexane
2.2
ABL
ABL
ABL
ABL
Tetrahydrofuran
Toluene
DMF
5.0
50
50
26
30
32
40
>99
>99
>99
95
5.2
>99
>99
80
105
OAc
1059
1059
203
C6H5
Diisopropylether
51
9
ABL
ABL
ABL
ABL
ABL
ABL
PSL
Nil
Toluene
26.6
35.6
21
46.4
27.8
1.6
20
16
12
20
20
20
20
24.8
93.8
85.7
75.4
90
8.9
51.8
22.8
65.3
35.5
1.6
1.8
54.3
16.4
13.8
26.7
32.3
12.9
OAc
Diisopropylether
Diisopropylether
DMF
Tetrahydrofuran
Diisopropylether
NPhth
3
99
82.3
20.4
21.2
10
Experimental conditions: all the reactions were performed at 25 °C in a shaker at 320 rpm, ee (%) and conversions (%) were measured by a chiral HPLC.
determine the enantiomeric excess of the product as a function of
conversion. Figure 2 shows the results of these investigations.
Encouraged by the efficacy of Arthrobacter sp. lipase on the
kinetic resolution of 2-phthalimide acetates of an aryl and alkyl
ethanolamine series, we also examined its versatility in the kinetic
resolution of 1-aryloxy-3-phthalimide-2-propanol derivatives,
which are the precursors of aryloxy propanolamines. This class of
compounds of which propranolol23 is a prominent example has
found widespread applications in medicine.24 Their synthetic strat-
egy involves the coupling of epichlorohydrin with the substituted
phenols in butanone, followed by the ring opening of epoxides
with phthalimide (Scheme 3).
In the kinetic resolution under the optimized conditions, the
addition of 10% organic co-solvent with buffer was again found
to be the best option, in terms of both hydrolysis and enantioselec-
tivity (E values >250) (Table 3).
100
80
The absolute configurations of the final products 1 and 3 were
assigned by comparing the signs of the observed specific rotations
with those reported in the literature, whereas for unknown com-
pounds such as 2, 4, 5, and 6, an analogy was made with Kazlaus-
kas’s rule25 for assignments.
60
OH
40
20
0
Unhydrolysed OAc
It is evident from our earlier report20 that Arthrobacter sp. lipase
exhibited preference for the opposite configuration in a chiral mol-
ecule as predicted by Kazlauskas’s rule, whereas PSC-II follows
Kazlauskas’s rule (Fig. 3). On applying the Cahn–Ingold–Prelog pri-
ority rules to 1, the highest priority is assigned to sterically larger
group (N-Phth) and a lower priority to sterically medium group
31.2
46.5
54.3
Conversion (%)
58
Figure 2. Enantioselective hydrolysis of N-(2-acetoxy)-butylphthalimide 7 using
Arthrobacter sp. lipase.

P. Gupta et al. / Tetrahedron: Asymmetry 19 (2008) 1898–1903
1901
OH
O
OH
O
O
NPhth
i
ii
Cl
O
R
R
(RS)-5-6
iii
R
11
R = H, 5;
R = OMe, 6.
NPhth = phthalimide.
OH
O
O
O
O
O
O
NPhth
NPhth
iv
O
NPhth
(S)-12-13
(R)-5-6
(RS)-12-13
R
R
R
12
R = H,
;
13
R = OMe,
.
Scheme 3. Reagents and conditions: (i) K2CO3, butanone, reflux, yield 95%; (ii) phthalimide, Py/IPA, reflux, yield 85%; (iii) Ac2O/DMAP, DCM, yield 98%; (iv) lipase, buffer.
Table 3
Enzymatic hydrolysis of acetyl derivatives of racemic 1-aryloxy-3-phthalimide-2-propanols (12 and 13) at 20 g/L concentration in biphasic systems
Substrate
Lipase
Co-solvent
Conversion (%)
Time (h)
eep (%)
ees (%)
E
12
12
12
12
12
12
13
13
13
13
13
13
13
13
13
13
ABL
ABL
ABL
ABL
ABL
ABL
RRLY-15
PPL
PLAP
PSL
Amano AS
Amano AS
ABL
ABL
ABL
Benzene
DIE
DME
DMSO
Toluene
Toluene
Toluene
Toluene
Toluene
DIE
30
52
52
50
12
22
15
36
36
36
40
40
40
36
40
40
14
48.2
37.9
84.2
77.4
87.5
>99
13.4
99
12.6
99
10.4
82
20.7
16.7
34.5
21.9
85.7
63
2.7
11
11
4.7
9.6
13.1
30
24.7
22.9
34.3
3.5
2.6
15.9
9.8
30.5
28.9
22
50.5
38.3
16.4
9.2
46.5
4.5
45.9
13.8
23.2
40
45.0
375
1.3
224
1.4
93.7
1.3
11.5
266.9
2.7
DIE
Toluene
Dioxane
DIE
DMSO
Toluene
99
37
17.4
>99
56.9
24
1.7
270
ABL
RRLY-15 = Trichosporon sp.; PLAP, pig liver acetone powder; PPL, porcine pancreatic lipase.
OH
OH
OH
OH
O
O
H
H
O
NPhth
NPhth
R
R
N
N
L
M
M
L
High priority
CIP
High priority
CIP
O
O
1 2 3
4
5 and 6
,
,
and
Preferred enantiomer with
Arthrobacter sp.Lipase
Preferred enantiomer with
PSC-II (Kazlauska's rule)
L= large group, M= medium sized group
Figure 3. Preferred enantiomer of 1 using Arthrobacter simplex and PSC-II.
(CH2CH3), which results in our assigning an (R)-configuration [(S)
with ABL] to its hydrolyzed enantiomer (Fig. 3). This observation
is also supported by the absolute configuration determined, on
the basis of the comparison of the signs of the specific rotations,
with those reported in the literature for 111a and 3.10a Similar argu-
ments can be applied for assigning the absolute configurations of 2
and 4. On the other hand, a lower priority can be assigned to steri-
cally larger group (N-Phth) in compounds 5 and 6, and a higher pri-
ority to a sterically medium group (ArOCH2), which results in our
assigning an (S)-configuration [(R) with ABL] to its hydrolyzed
enantiomers (Fig. 3).
mic alkyl, aryl, and aryloxypropyl masked b-amino alcohols
through an efficient lipase catalyzed hydrolysis in presence of co-
solvents has been demonstrated.
4. Experimental
4.1. General
1H NMR spectra in CDCl3 were recorded on Bruker 200 MHz
spectrometers with TMS as the internal standard. Chemical shifts
were expressed in parts per million (d ppm). Reagents and solvents
used were mostly 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 GC–Mass
spectrometer. IR was recorded on a FT-IR Bruker (270–30) spectro-
photometer. Elemental analyses were performed on Elementar
3. Conclusion
In conclusion, an efficient chemoenzymatic approach for the
preparation and resolution to high enantiomeric purity from race-

1902
P. Gupta et al. / Tetrahedron: Asymmetry 19 (2008) 1898–1903
Vario EL-III. Optical rotations were measured on Perkin-Elmer 241
polarimeter at 25 °C using sodium D light. Enantiomeric excess (ee)
was determined on a chiral stationary phase HPLC column.
5.01 (dd, J = 4.2 Hz, 3.3 Hz, 1H), 7.1–7.3 (m, 5H), 7.73–7.77 (m,
2H), 7.84–7.86 (m, 2H). 13C NMR: d 45.8, 72.6, 123.4, 123.5,
125.9, 127.8, 128.5, 128.9, 131.9, 134.0, 134.1, 141.1, 168.8. ESI-
MS (m/z): 267.
4.2. General procedure for the hydrolysis of acetyl derivatives
of protected amino alcohols
4.3.4. N-(2-Hydroxy)-octylphthalimide 4
(C16H21NO3): HPLC purity >99%; HPLC ee = 93.8%; ½a D25
ꢂ
= +7.5 (c
Racemic acetate (50 mg), aqueous phosphate buffer (2.5 mL,
0.1 M, pH. 7.0), toluene (250 lL), and whole cells of Arthrobacter
1, CHCl3); mp = 76–78 °C; Abs. config (S); HPLC condition {OJH chi-
ral column, eluent 2-propanol-hexane-acetic acid (2:98:0.1), flow
rate: 0.8 mL/min, t1 = 13.7 min and t2 = 16.7 min}. 1H NMR: d 0.84
(t, J = 6.6 Hz, 3H), 1.28–1.50 (m, 10H), 3.71–3.79 (m, 2H), 3.84–
3.90 (m, 1H), 7.71–7.77 (m, 2H), 7.82–788 (m, 2H). 13C NMR: d
14.4, 23.0, 25.8, 29.6, 32.2, 35.5, 44.9, 71.1, 123.8, 132.4, 134.7,
169.4. ESI-MS (m/z): 275. Anal. Calcd for C16H21NO3: C, 69.79; H,
7.69; N, 5.09. Found: C, 69.80; H, 7.75; N, 5.07.
sp. lipase (150 mg) were shaken (320 rpm) continuously at
25 1 °C. After a certain degree of conversion (ꢀ50%) as indicated
by thin layer chromatography (TLC) and chiral high performance li-
quid chromatography (HPLC), the reaction was terminated by add-
ing ethyl acetate and centrifuging the mixture at 10,000–15,000g
to remove the enzyme and the suspended particles. The clear solu-
tion was decanted, and the centrifuged mass was extracted sepa-
rately with ethyl acetate (3 ꢁ 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 comprising of hydrolyzed alcohol and unhydrolyzed es-
ter, which were separated by column chromatography (100–200
mesh) using a gradient of ethyl acetate and hexane as eluent.
4.3.5. N-(2-Hydroxy-3-phenoxy)propylphthalimide 5
(C17H15NO4): HPLC purity >99%; HPLC ee >99%; ½a D25
ꢂ
= +23.2 (c
0.5, CHCl3), mp = 83–85 °C; Abs. config (R); HPLC condition {ODH
chiral column, eluent 2-propanol-hexane-acetic acid (7:93:0.1),
flow rate: 0.5 mL/min, t1 = t2 = 81.5 min}. 1H NMR: d 3.72 (m,
2H), 3.92 (d, J = 5.3 Hz, 2H), 4.13–4.19 (m, 1H), 6.85–6.96 (m,
3H), 7.23–7.31 (m, 2H), 7.81–7.89 (m, 4H). 13C NMR: d 41.3, 68.4,
69.8, 114.5, 121.2, 123.4, 129.2, 131.6, 132.8, 158.4, 168.8. ESI-
MS (m/z): 297. Anal. Calcd for C17H15NO4: C, 68.68; H, 5.09; N,
4.71. Found: C, 68.65; H, 5.12; N, 4.77.
4.3. General procedure for the synthesis of b-phthalimide
alcohols
A catalytic amount of pyridine was added to a solution of epoxy
compound (1 mmol) and phthalimide (1.2 mmol) in isopropyl
alcohol (20 mL) and the mixture was refluxed for two hours. After
the reaction was completed as indicated by TLC, solvent was re-
moved by distillation at reduced pressure bringing the total vol-
ume to one-fourth. The contents were then poured into cold
water and extracted with ethylacetate (4 ꢁ 20 mL). The organic
layer was dried over anhydrous sodium sulfate and concentrated
under reduced pressure to give a crude product. The mixture was
separated by column chromatography on silica gel to obtain the
pure product (yield 75–85%).
4.3.6. N-[2-Hydroxy-3-(p-methoxy-phenoxy)]-
propylphthalimide 6
(C18H17NO5): HPLC purity >99%; HPLC ee >99%; ½a D25
ꢂ
= +25.5 (c
0.5, CHCl3); mp = 115–117 °C; Abs. config (R); HPLC condition
{OJH chiral column, eluent 2-propanol–hexane–acetic acid
(15:85:0.1), flow rate: 0.8 mL/min, t1 = t2 = 28.8 min}. 1H NMR: d
3.76 (s, 3H), 3.88–4.01 (m, 4H), 4.08–4.27 (m, 1H), 6.78–6.88 (m,
4H), 7.71–7.77 (m, 2H), 7.83–7.89 (m, 2H). 13C NMR: d 40.7, 55.2,
68.3, 70.0, 114.1, 115.2, 122.9, 131.4, 133.5, 151.9, 153.7, 167.2.
ESI-MS (m/z): 327. Anal. Calcd for C18H17NO5: C, 66.05; H, 5.23;
N, 4.28. Found: C, 66.08; H, 5.22; N, 4.27.
4.3.1. N-(2-Hydroxy)-butylphthalimide 1
(C12H13NO3): HPLC purity >99%; HPLC ee >99%; ½a D25
ꢂ
= +18.4 (c
4.4. Acylation of protected amino alcohols 1, 2, 3, 4, 5 and 6
0.5, CHCl3); {lit.11a
½
a 2D5
= +5.6 (c 1.08, CHCl3); ee = 15%};
ꢂ
mp = 70–72 °C; Abs. config (S); HPLC condition {OJH chiral column,
eluent 2-propanol-hexane-acetic acid (2:98:0.1), flow rate: 1 mL/
min, t1 = 29.7 and t2 = 38.3 min}. 1H NMR: d 1.65 (t, J = 7.4 Hz,
3H), 1.54–1.67 (m, 2H), 3.75–3.88 (m, 3H), 7.74–7.81 (m, 2H),
7.85–7.93 (m, 2H); 13C NMR: d 8.7, 27.0, 43.1, 70.8, 122.4, 130.9,
133.1, 167.9; ESI-MS (m/z): 219; Anal. Calcd for C12H13NO3: C,
65.74; H, 5.98; N, 6.39. Found: C, 65.70; H, 6.03; N, 6.38.
Acetic anhydride (1.2 mmol) and a catalytic amount of DMAP
were added to a solution of racemic protected amino alcohols
(1 mmol) in dry dichloromethane after which the reaction mixture
was kept overnight at room temperature. The contents of the reac-
tion mixture were poured into ice-cold water and extracted with
dichloromethane. The organic layer was washed, dried, and evapo-
rated to give the protected amino acetoxy derivatives.
4.3.2. N-(2-Hydroxy)-pentylphthalimide 2
4.4.1. N-(2-Acetoxy)-butylphthalimide 7
(C13H15NO3): HPLC purity >99%; HPLC ee >99%; ½a D25
ꢂ
= +10.7 (c
(C14H15NO4): HPLC purity >99%; HPLC ee >99%; ½a D25
ꢂ
= +35.9 (c
1, CHCl3); mp = 73–75 °C; Abs. config (S); HPLC condition {OJH chi-
ral column, eluent 2-propanol-hexane-acetic acid (1:99:0.1), flow
rate: 1.5 mL/min, t1 = 19.6 and t2 = 22.3 min}. 1H NMR: d 0.84 (t,
J = 6.7 Hz, 3H), 1.41–1.45 (m, 4H), 3.67–3.71 (m, 2H), 3.80–3.85
(m, 1H), 7.64–7.70 (m, 2H), 7.75–7.81 (m, 1H). 13C NMR: d 14.0,
18.7, 37.2, 44.5, 70.3, 123.4, 132.0, 134.1, 169.1. ESI-MS (m/z):
233. Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found:
C, 66.90; H, 6.55; N, 6.07.
1, CHCl3); mp = 67–69 °C; Abs. config (R); HPLC condition {OJH chi-
ral column, eluent 2-propanol-hexane-acetic acid (2:98:0.1), flow
rate: 1 mL/min, t1 = 17.2 and 18.3 min}. 1H NMR: d 1.03 (t,
J = 7.4 Hz, 3H), 1.61–1.74 (m, 2H), 2.05(s, 3H), 3.89 (d, J = 5.0 Hz,
2H), 5.07–5.14 (m, 1H), 7.75–7.81 (m, 2H), 7.86–7.92 (m, 2H), 13C
NMR: d 8.6, 19.5, 24.6, 40.3, 73.3, 122.8, 131.8, 134.1, 168.3,
171.4. ESI-MS (m/z): 261. Anal. Calcd for C14H15NO4: C, 64.36; H,
5.79; N, 5.36. Found: C, 64.32; H, 5.72; N, 5.37.
4.3.3. N-(2-Hydroxy-2-phenyl)ethylphthalimide 3
4.4.2. N-(2-Acetoxy)-pentylphthalimide 8
HPLC purity >99%; HPLC ee >99%; ½a D25
ꢂ
= +23.2 (c 1, CHCl3);
(C15H17NO4): HPLC purity >99%; HPLC ee >99%; ½a D25
ꢂ
= +23.5 (c
{lit.10a for (R)-enantiomer ½a 2D5
ꢂ
= –25.6 (c 1, CHCl3)}; mp = 161–
1, CHCl3); mp = 55–57 °C; Abs. config (R); HPLC condition {OJH chi-
ral column, eluent 2-propanol-hexane-acetic acid (1:99:0.1), flow
rate: 1.5 mL/min, t1 = t2 = 8.7 min}. 1H NMR: d 0.92 (t, J = 7.1 Hz,
3H), 1.39–1.43 (m, 2H), 1.59–1.62 (m, 2H), 1.90 (s, 3H), 3.82 (d,
163 °C; Abs. config (S); HPLC condition {(R,R)-Whelk-01 chiral col-
umn, eluent 2-propanol-hexane (5:95), flow rate: 0.8 mL/min,
t1 = 19.0 min and t2 = 21.9 min}. 1H NMR: d 3.88–4.02 (m, 2H),

P. Gupta et al. / Tetrahedron: Asymmetry 19 (2008) 1898–1903
1903
J = 5.2 Hz, 2H), 5.10–5.16 (m, 1H), 7.74–7.80 (m, 2H), 7.85–7.92 (m,
References
2H). 13C NMR: d 13.1, 18.6, 19.9, 33.9, 41.0, 72.1, 123.2, 131.2,
134.5, 165.0, 169.9. ESI-MS (m/z): 275. Anal. Calcd for
1. (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561; (b) Kolb, H. C.; Sharpless, K. B. In
Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, 1998; p 243.
2. (a) Howarth, J.; Lloyd, D. G. J. Antimicrob. Chem. 2000, 46, 625; (b) Caballero, E.;
Puebla, P.; Medarde, M.; Sanchez, M.; Salvado, M. A.; Granda, S. G.; Feliciano, A.
S. J. Org. Chem. 1996, 61, 1890; (c) Schnur, R. C.; Corman, M. L.; Gallaschun, R. J.;
Cooper, B. A.; Dee, M. F.; Doty, J. L.; Muzzi, M. L.; Moyer, J. D.; Diorio, C. I.;
Barbacci, E. G.; Miller, P. E.; O’Brien, A. T.; Morin, M. J.; Foster, B. A.; Pollack, V.
A.; Sloan, D. E.; Pustilnik, L. R.; Moyer, M. P. J. Med. Chem. 1995, 38, 3806.
3. Guillou, Y.; Robin, Y. J. Biol. Chem. 1973, 248, 5668.
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1981, 24, 7.
5. Yang, Y.; Wahler, D.; Reymond, J.-L. Helv. Chim. Acta 2003, 86, 2928.
6. Kokotos, G.; Padron, J. M.; Noula, C.; Gibbons, W. A.; Martin, V. S. Tetrahedron:
Asymmetry 1996, 7, 857.
7. (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835; (b) Eliel, E. L.;
Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley, 1994;
(c) Tomioka, K. Synthesis 1990, 541; (d) Noyari, R.; Kitamura, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 49.
8. (a) Abiko, A.; Masamune, S. Tetrahedron Lett. 1992, 33, 5517; (b) Periasamy, M.;
Kanth, J. V. B. Tetrahedron 1993, 49, 5127; (c) Drauz, K.; Schwarm, M.;
Mckennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 3568.
9. (a) Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 7420;
(b) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421; (c) Bartoli, G.; Bosco, M.;
Carlone, A.; Locatelli, M.; Melchiorre, P.; Sambri, L. Org. Lett. 2004, 6, 3973.
10. (a) Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 1626; (b) Hu, A.;
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11. (a) Fujisawa, T.; Hayashi, H.; Kishioka, Y. Chem. Lett. 1987, 19, 129; (b) Sorrilha,
Anna E. P. M.; Marques, M.; Joekes, I.; Moran, P. J. S.; Rodriques, A. R. Bioorg.
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C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.40; H, 6.18;
N, 5.00.
4.4.3. N-(2-Acetoxy-2-phenyl)ethylphthalimide 9
(C18H15NO4): HPLC purity >99%; HPLC ee >99%; ½a D25
ꢂ
= –21.7 (c
1, CHCl3); mp = 111–113 °C; Abs. config (R); HPLC condition
{(R,R)-Whelk-01 chiral column, eluent 2-propanol-hexane (5:95),
flow rate: 0.8 mL/min, t1 = 13.9 and t2 = 16.9 min}. 1H NMR: d
2.03 (s, 3H, CH3CO), 3.93 (dd, J = 10.5 Hz, 3.8 Hz, 1H), 4.17 (dd,
J = 8.9 Hz, 5.3 Hz, 1H), 6.13 (dd, J = 3.7 Hz, 5.2 Hz), 7.35–7.45 (m,
5H), 7.70–7.75 (m, 2H), 7.84–7.86 (m, 2H). 13C NMR: d 21.0, 43.0,
73.3, 123.4, 126.6, 128.6, 128.7, 134.1, 137.2, 167.9, 170.3. ESI-
MS (m/z): 309. Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N,
4.53. Found: C, 69.73; H, 5.03; N, 4.37.
4.4.4. N-(2-Acetoxy)-octylphthalimide 10
(C18H23NO4): HPLC purity >99%; HPLC ee 65.3%; ½a D25
ꢂ
= +11.1 (c
1, CHCl3); mp = 50–52 °C; Abs. config (R); HPLC condition {OJH chi-
ral column, eluent 2-propanol-hexane-acetic acid (2:98:0.1), flow
rate: 0.8 mL/min, t1 = 7.0 and t2 = 8.1 min}. 1H NMR: d 0.84 (t,
J = 6.8 Hz, 3H), 1.27–1.52 (m, 8H), 1.56–1.67 (m, 2H), 3. 88 (d,
J = 5.2 Hz, 2H), 5.09–5.16 (m, 1H), 7.70–7.76 (m, 2H), 7.81–788
(m, 2H). 13C NMR: d 13.55, 20.53, 20.05, 24.73, 28.49, 31.15,
31.37, 40.55, 71.59, 122.85, 131.44, 133.53, 167.89, 170.52. ESI-
MS (m/z): 317. Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30; N,
4.41. Found: C, 68.08; H, 7.35; N, 4.40.
12. Faber, K. Biotransformations in Organic Chemistry, 4th ed.; Institute of Organic
Chemistry: University of Graz, 2000.
13. (a) Kapoor, M.; Anand, N.; Ahmad, K.; Koul, S.; Chimni, S. S.; Taneja, S. C.; Qazi,
G. N. Tetrahedron: Asymmetry 2005, 16, 717; (b) Anand, N.; Kapoor, M.; Ahmad,
K.; Koul, S.; Parshad, R.; Manhas, K. S.; Sharma, R. L.; Qazi, G. N.; Taneja, S. C.
Tetrahedron: Asymmetry 2007, 18, 1059.
14. (a) Ing, H. R.; Manske, R. H. F. J. Chem. Soc. 1926, 2349; (b) Arffin, A.; Khan, M.
N.; Lan, L. C.; May, F. Y.; Yun, C. S. Synth. Commun. 2004, 34, 4439.
15. (a) Machado, A. L.; Lima, L. M.; Araujo-Jr, J. X.; Fraga, C. A. M.; Koatzc, V. L. G.;
Barreiro, E. J. Bioorg. Med. Chem. Lett. 2005, 15, 1169; (b) Collin, X.; Robert, J.;
Wielgosz, G.; Le Baut, G.; Bobin-Dubigeon, C.; Grimaud, N.; Petit, J. Eur. J. Med.
Chem. 2001, 36, 639.
16. Antunes, R.; Batista, H.; Srivastava, R. M.; Thomas, G.; Araujo, C. C. Bioorg. Med.
Chem. Lett. 1998, 8, 3071.
17. Abdel-Hafez, A. A. Arch. Pharm. Res. 2004, 27, 495.
18. Kawagushi, S.; Ikeda, O. Jpn. Pat. Appl. JP2001328911, 2001.
19. Ebihara, K.; Oora, T.; Nakaya, M.; Shiraishi S.; Yasui, N. Jpn. Pat. Appl.
JP08245585, 1996.
20. Gupta, P.; Shah, B. A.; Parshad, R.; Qazi, G. N.; Taneja, S. C. Green Chem. 2007, 9,
1120.
4.4.5. N-(2-Acetoxy-3-phenoxy)propylphthalimide 12
(C19H17NO5): HPLC purity >99%; HPLC ee 51%; ½a D25
= ꢃ10.5 (c 1,
ꢂ
CHCl3); mp = 89–91 °C; Abs. config (S); HPLC condition {ODH chiral
column, eluent 2-propanol-hexane-acetic acid (7:93:0.1), flow
rate: 0.5 mL/min, t1 = 39.3 and t2 = 44.4 min}. 1H NMR: d 4.03–
4.17 (m, 4H), 5.44–5.48 (m, 1H), 6.86–6.93 (m, 3H), 7.21–7.26
(m, 2H), 7.80–787 (m, 4H). 13C NMR: d 20.7, 40.0, 68.8, 71.5,
116.1, 122.7, 124.9, 130.9, 133.4, 135.6, 159.7, 167.3, 171.2. ESI-
MS (m/z): 339. Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N,
4.13. Found: C, 67.31; H, 5.03; N, 4.17.
21. Henryk, M.; Leonard, G.; Barbara, F. Acta Polym. Pharm. EN 1996, 53, 47.
22. (a) Arthrobacter sp. cell biomass was prepared in shake flasks and in a 10 L
fermentor containing medium (1% peptone, 0.5% NaCl and 0.5% beef extract,
pH 7.0). The medium was inoculated with an overnight preculture prepared in
the same broth. The culture was grown at 30 °C for 16–18 h at 200 rpm. The
cell pellet was separated from the broth by centrifugation at 10,000ꢁg for
15 min at 4 °C and was preserved at ꢃ20 °C until further use. Arthrobacter sp.
microbial culture (ABL, MTCC no. 5125), isolated at institute has been
deposited in the MTCC culture collection under the Budapest Treaty (2004);
(b) Johri, S.; Verma, V.; Parshad, R.; Koul, S.; Taneja, S. C.; Qazi, G. N. Bioorg. Med.
Chem. 2001, 9, 269; (c) Koul, S.; Taneja, S. C.; Parshad, R.; Qazi, G. N.
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4.4.6. N-(2-Acetoxy-3-(p-methoxy-phenoxy)propylphthalimide
13
(C20H19NO6): HPLC purity >99%; HPLC ee >99%; ½a D25
= ꢃ14.4 (c
ꢂ
0.5, CHCl3); mp = 90–92 °C; Abs. config (S); HPLC condition {OJH
chiral column, eluent 2-propanol-hexane-acetic acid (15:85:0.1),
flow rate: 0.8 mL/min, t1 = 36.6 and t2 = 40.4 min}. 1H NMR: d
2.03 (s, 1H), 3.76 (s, 3H), 4.00–4.11 (m, 4H), 5.39–5.47 (m, 1H),
6.83–6.86 (m, 4H), 7.71–7.77 (m, 2H), 7.83–7.89 (m, 2H). 13C
NMR: d 20.2, 37.4, 54.5, 67.2, 69.0, 113.5, 114.7, 122.3, 130.5,
132.9, 149.8, 152.6, 167.2, 169.1. ESI-MS (m/z): 369. Anal. Calcd
for C20H19NO6: C, 65.03; H, 5.18; N, 3.79. Found: C, 65.10; H,
5.15; N, 3.77.
Acknowledgments
The authors are thankful to M/S AMANO Enzymes Inc. Japan, for
the gift of enzymes and the CSIR, New Delhi for granting SRF to PG.