Resolution of N-Protected amino alcohols by porcine pancreatic lipase

Article abstract of DOI:10.2174/157017810790796327

The resolution of 2-amino alcohols protected by urethane-type groups either via porcine pancreatic lipase (PPL) hydrolysis of the corresponding racemic acetates or via PPL catalyzed transesterification of racemic alcohols was studied. In both cases, Boc protecting group led to better chemical yields and enantiopurities than Z and Fmoc protecting groups. Furthermore, a simple and efficient method for the synthesis of the medicinally interesting optically pure (R)-2- aminohexadecanol was developed.

Full text of DOI:10.2174/157017810790796327

Letters in Organic Chemistry, 2010, 7, 159-162
159
Resolution of N-Protected Amino Alcohols by Porcine Pancreatic Lipase
Victoria Magriotia, Irene Fotakopouloub, Nicolaos Athinaiosa, Panoula Anastasopouloua,
Violetta Constantinou-Kokotoub and George Kokotos*,a
aLaboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771,
Greece
bChemical Laboratories, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece
Received June 30, 2008: Revised December 06, 2009: Accepted December 23, 2009
Abstract: The resolution of 2-amino alcohols protected by urethane-type groups either via porcine pancreatic lipase
(PPL) hydrolysis of the corresponding racemic acetates or via PPL catalyzed transesterification of racemic alcohols was
studied. In both cases, Boc protecting group led to better chemical yields and enantiopurities than Z and Fmoc protecting
groups. Furthermore, a simple and efficient method for the synthesis of the medicinally interesting optically pure (R)-2-
aminohexadecanol was developed.
Keywords: 2-Amino alcohols, enzymatic hydrolysis, enzymatic resolution, porcine pancreatic lipase, transesterification.
INTRODUCTION
inexpensive and commercially available porcine pancreatic
lipase (PPL). We demonstrate that (R)-amino alcohols may
Optically pure 2-amino alcohols are versatile
intermediates for the synthesis of peptaibiotics and
peptaibols [1, 2], as well as for the synthesis of a variety of
optically active intermediates, for example diamines and
triamines [3-5]. Their conversion to amino aldehydes and
peptide aldehydes [6] is of particular interest, because it may
lead to bioactive compounds [7, 8] and non-natural amino
acids and their bioisosteric analogues [9-12]. In addition,
saturated and unsaturated long chain 2-amino alcohols,
which may be considered as sphingosine analogues, have
been reported to display various biological activities [13], for
example cytotoxic activity against various cancer cell lines
[14], in vivo antiinflammatory activity [15, 16] and
immunosuppresant activity [17]. (R)-2-Aminohexadecanol
be produced by the resolution of racemic amino alcohols.
RESULTS AND DISCUSSION
Resolution of racemic alcohols may be accomplished
either by enzymatic hydrolysis of racemic acylated alcohols
or by enzymatic transesterification of racemic alcohols. In
the present work we studied the efficiency of PPL (EC
3.1.1.3) Type II from Sigma, using racemic N-protected 2-
amino alcohols and the corresponding acetates as substrates.
Racemic N-protected 2-amino alcohols 1a-f were
prepared by reduction of the corresponding amino acids as
described in literature [19], and were acetylated by treatment
with Ac2O in the presence of DMAP (Table 1). Three
urethane-type protecting groups, namely tert-butoxycarbonyl
(Boc), benzyloxycarbonyl (Z) and fluorenylmethoxy-
carbonyl (Fmoc), widely used in peptide chemistry, were
used in the present study. The PPL mediated hydrolysis of
acetates 2a-f was performed with a pH-stat apparatus. The
reaction took place in a two-phase system of phosphate
buffer pH 7.0 and a 1:1 mixture of toluene/hexane at 37 ºC
for 3 h. The configuration of the products was determined
comparing their specific rotation values with those existing
in the literature. The enantiomeric purity of the amino
alcohols produced was measured either by chiral HPLC
analysis or by NMR analysis of the corresponding Mosher
esters. We have previously shown [21] that an amino alcohol
can be esterified with (R)-(+)-ꢀ-methoxy-ꢀ-trifluoromethyl
phenyl acetic acid (Mosher acid) [26] using the DCC/DMAP
method. The absence of diastereomeric signals in the 1H and
19F NMR spectra of the Mosher ester indicates >95% ee.
Table 1 summarizes the data of products 3a-f.
displays
activity
comparable
to
2-amino-2-[2-(4-
octylphenyl)ethyl]-1,3-propanediol hydrochloride (FTY720)
[18], which is a novel synthetic immunosuppressant with
remarkable activity both in vitro and in vivo. (R)-2-
Aminohexadecanol has been reported to be more potent than
the (S)-isomer [17].
N-Protected amino alcohols can be prepared from the
corresponding chiral amino acids, by a variety of methods,
for example by reduction of mixed anhydrides [19, 20], acyl
fluorides [21] or pentafluorophenyl esters [22]. Enzymes
nowadays are widely recognized among the most active and
selective catalysts for the preparation of optically active
compounds such as N-protected amino alcohols [23], even
though there are reports for the kinetic resolution using non-
enzymatic asymmetric acylations [24, 25]. In the present
study our aim was to investigate the resolution of 2-amino
alcohols protected by urethane-type groups using the
As shown in Table 1, PPL hydrolyzed the acetate
derivatives of N-protected phenylalaninol 2a-c producing the
(R)-enantiomer in good to high yield and in excellent
*Address correspondence to this author at the Laboratory of Organic
Chemistry, Department of Chemistry, University of Athens,
Panepistimiopolis, Athens 15771, Greece; Tel: +30 210 7274462; Fax: +30
210 7274761; E-mail: gkokotos@chem.uoa.gr
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

160 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Table 1 Data for the PPL Catalyzed Enantiomer Selective Hydrolysis of Acetates
Magrioti et al.
R
R
R
Ac2O, DMAP
CH2Cl2
PPL buffer pH 7.0
toluene/hexane 1:1
OH
OAc
OH
NHX
NHX
NHX
2a-f
3a-f
1a-f
1-3
R
X
Hydrolysis Yielda (%)
[ꢀ]D observed
[ꢀ]D litb
% ee
a
b
c
d
e
f
C6H5CH2
C6H5CH2
Boc
Z
42
35
32
26
32
40
+22.0c
+38.0e
+23.0c
+23.0e
+12.8c
+10.7c
-23.5c [21]
-42.5e [27]
-23.2c [28]
-28.0e [29]
-28.0g [30]
-8.5h [31]
>95%d
95f
C6H5CH2
Fmoc
Boc
Z
99f
(CH3)2CHCH2
(CH3)2CHCH2
nC14H29
75f
50f
Boc
>95%d
aAfter column chromatography. bSpecific rotation of the enantiomer. c(c 1.0, CHCl3). dEnantiomeric excess was determined by NMR analysis of the corresponding Mosher esters.e(c
f
1.0, CH3OH). Enantiomeric excess was determined by chiral HPLC analysis [Chiralpak® AS-H column, 2-propanol (5-20%), acetic acid (0.4%), in hexane mobile phase, flow rate
0.8 ml/min]. g(c 1.0, EtOH). h(c 2.0, CHCl3).
enantioselectivity. PPL catalyzed hydrolysis of Boc and Z
acetate derivatives of leucinol 2d,e occurred in considerably
lower enantioselectivity compared to the corresponding
phenylalaninol derivatives, clearly showing the importance
of the side chain of the 2-amino alcohol used for the
reaction. Furthermore, the acetate derivative of 2-amino
hexadecanol 2f was tested. We demonstrate that lipase
catalysed resolution of 2f is an interesting route for the
synthesis of optically pure (R)-2-aminohexadecanol.
As shown in Table 2, the N-protecting group was found
to significantly influence the enzymatic transesterification.
Higher enantioselectivities were observed when Boc group
was used as protecting group in substrates 1a, d, f. The
lipase catalyzed transesterification of Z and Fmoc derivatives
of phenylalaninol and leucinol 1b,c,e proceeded in low
yields and moderate enantioselectivities, indicating that the
aromatic rings of Z and Fmoc groups obstruct the interaction
with the active site of the enzyme.
We also studied the lipase-catalyzed transesterification of
racemic N-protected 2-amino alcohols 1a-f using PPL and
vinyl acetate as acylating agent in a 1:1 mixture of
toluene/hexane at room temperature for 48 h (Table 2). The
absolute stereochemistry of acetates 4a, d, f, was confirmed
by comparison of the specific rotation with optically pure
acetates that were synthesized by chemical methods. The
PPL catalyzed transesterification reaction yielded the (R)-
enantiomers. The detailed data for products 4a-f are
presented in Table 2.
In conclusion, we studied the resolution of N-protected 2-
amino alcohols either via PPL hydrolysis of the
corresponding racemic acetyl derivatives or via PPL
catalyzed transesterification of racemic alcohols. In both
cases the presence of Boc group led to better chemical yields
and enantiopurities than Z and Fmoc groups. The Boc group
gave the best chemical yields (3a and 3f) in the case of the
enzymatic hydrolysis with an ee >95%, as well as in the
enzymetic transesterification reaction with chemical yield of
24% and an ee of 97% for acetate 4a. Comparing PPL
Table 2. Data for the PPL Catalyzed Transesterification Products
PPL, CH3COOCH=CH2
R
R
OAc
OH
toluene/hexane 1/1
NHX
NHX
4a-f
1a-f
b
4
R
X
Yielda (%)
[ꢀ]D observed
[ꢀ]D
% eec
a
b
c
d
e
f
C6H5CH2
C6H5CH2
Boc
Z
24
10
11
28
10
15
+14.9d
+12.0e
+10.4e
+31.2e
+21.3e
+14.9e
+14.5d
97
74
C6H5CH2
Fmoc
Boc
Z
56
(CH3)2CHCH2
(CH3)2CHCH2
nC14H29
-37.5e
-12.3e
n.d.f
63
Boc
n.d.f
aAfter column chromatography. bSpecific rotation of products of the same or opposite stereochemistry prepared by chemical methods. cEnantiomeric excess were determined by
chiral HPLC analysis [Chiralpak® AS-H column, 2-propanol (5-20%), in hexane mobile phase, flow rate 0.5 ml/min]. d(c 1.0, CH3OH). e(c 1.0, CHCl3). fNot determined.

Resolution of N-Protected Amino Alcohols
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
161
2-(Benzyloxycarbonylamino)-3-phenylpropyl acetate (4b)
catalyzed hydrolysis and transesterification, significant
improvements in reaction rates and enantioselectivities in the
case of PPL hydrolysis of acetates were observed. Moreover,
a simple and efficient method to prepare the medicinally
interesting optically pure (R)-2-aminohexadecanol was
developed.
White solid; mp 69-71 ºC; 1H NMR (CDCl3) ꢀ 7.38-7.17
(10H, m, arom. CH), 5.09 (2H, s, OCH2C6H5), 4.99 (1H, m,
OCONH), 4.16-4.00 (3H, m, CH, CH2OCO), 2.86 (2H, m,
CH2C6H5), 2.06 (3H, s, OCOCH3); 13C NMR (CDCl3) ꢀ
170.8, 155.7, 136.8, 136.1, 129.1, 128.6, 128.4, 128.1, 128.0,
126.7, 66.7, 64.8, 51.1, 37.7, 20.7. Anal. calcd for
C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.57; H,
6.58; N, 4.39.
MATERIALS AND METHODS
Melting points are uncorrected. Specific rotations were
measured on a Perkin Elmer 841 polarimeter using a 10 cm
cell. 1H NMR and 13C NMR spectra were recorded in CDCl3
using a Varian 200 MHz spectrometer. Chemical shifts are
reported in ꢀ units relative to tetramethylsilane (TMS) set at
0 ꢀ, and coupling constants are given in Hz. Porcine
pancreatic lipase (PPL) was purchased from Sigma (type II,
crude) and was used without further purification. All other
chemical reagents were purchased from Sigma-Aldrich
Chemicals C. and were of analytical grade. TLC plates
(silica gel 60 F254) and silica gel 60 (230-400 mesh) for
column chromatography were purchased from Merck.
Visualization of spots was effected with UV light and/or
phosphomolybdic acid and/or ninhydrin, both in EtOH stain.
2-(((9H-Fluoren-9yl)methoxy)carbonylamino)-3-phenyl-
propyl acetate (4c)
1
White solid; mp 125-127 ºC; H NMR (CDCl3) ꢀ 7.72
(2H, m, arom. CH), 7.51 (2H, m, arom. CH), 7.42-7.00 (9H,
m, arom. CH), 4.92 (1H, d, J = 8.0 Hz, OCONH), 4.70-4.52
(3H, m, OCH2CH), 4.20-4.00 (3H, m, CH, CH2OCO), 2.82
(2H, d, J = 6.6 Hz, CH2C6H5), 2.02 (3H, s, OCOCH3); 13C
NMR (CDCl3) ꢀ 170.9, 156.4, 143.8, 141.3, 137.5, 129.2,
128.6, 127.7, 127.0, 126.6, 124.4, 119.9, 66.6, 63.8, 54.0,
47.2, 37.8, 20.8. Anal. calcd for C26H25NO4: C, 75.16; H,
6.06; N, 3.37. Found: C, 74.88; H, 6.25; N, 3.44.
(R)-2-(tert-Butoxycarbonylamino)-4-methylpentyl acetate
(4d)
1
White solid; mp 45-46.5 ºC; H NMR (CDCl3) ꢀ 4.51
(1H, m, NH), 4.03 (2H, m, CH2OCO), 3.92 (1H, m, CHNH),
2.12 (3H, s, OCOCH3), 1.71 [1H, m, CH(CH3)2], 1.40 [9H, s,
C(CH3)3], 1.34 (2H, m, CH2CH), 0.91 [6H, d, J = 7.0 Hz,
CH(CH3)2]; 13C NMR (CDCl3) ꢀ 171.0, 155.3, 79.0, 66.7,
47.7, 40.9, 28.3, 24.7, 22.1. Anal. calcd for C13H25NO4: C,
60.21; H, 9.72; N, 5.40. Found: C, 59.97; H, 9.88; N, 5.52.
General Procedure for the Enzymatic Hydrolysis of the
Acetyl Derivatives
In a pH-stat apparatus, acetyl derivative 2a-f (100 mg)
was added to a 50:50 mixture of hexane and toluene (3 mL).
Then, 7 mL of phosphate buffer 100 mM pH 7.0 were added.
Finally, PPL (25 mg) was added and the hydrolysis was
monitored at the pH-stat. After 3 hours the reaction was
stopped and ethyl acetate (20 mL) and H2O (20 mL) were
added. The aqueous phase was washed twice with ethyl
acetate (2 ꢀ 20 mL). The combined organic phases were
washed with brine, dried, the solvent was evaporated and the
product was purified by column chromatography using
petroleum ether/EtOAc 8:2 as eluent. Physical constants and
spectroscopic data of 3a-f are in accordance with literature.
2-(Benzyloxycarbonylamino)-4-methyl pentyl acetate (4e)
1
Oil; H NMR (CDCl3) ꢀ 7.38-7.31 (5H, m, arom. CH),
5.11 (2H, m, CH2C6H5), 4.71 (1H, d, J = 7.8 Hz, OCONH),
4.10-4.00 (3H, m, CH, CH2OCO), 2.04 (3H, s, OCOCH3),
1.66 [1H, m, CH(CH3)2], 1.34 (2H, m, CH2CH), 0.94 [6H, d,
J = 6.8 Hz, CH(CH3)2]; 13C NMR (CDCl3) ꢀ 171.0, 155.1,
140.9, 128.5, 128.0, 127.4, 66.7, 66.5, 48.4, 40.8, 24.6, 23.0,
22.1, 20.8. Anal. calcd for C16H23NO4: C, 65.51; H, 7.90; N,
4.77. Found: C, 65.32; H, 8.02; N, 4.81.
(R)-2-(tert-Butoxycarbonylamino)hexadecyl acetate (4f)
General Procedure for the Enzymatic Transesterification
of Racemic Alcohols
1
White solid; mp 47-48 ºC; H NMR (CDCl3) ꢀ 4.50 (1H,
m, OCONH), 4.06 (2H, m, CH2OCO), 3.84 (1H, m, CH),
2.08 (3H, s, OCOCH3), 1.45 [9H, s, C(CH3)3], 1.25 (26H, m,
13ꢀCH2), 0.88 (3H, t, J = 6.2 Hz, CH3); 13C NMR (CDCl3) ꢀ
171.0, 155.4, 79.6, 66.3, 49.5, 31.9, 29.6, 29.5, 29.4, 29.3,
28.3, 25.8, 22.7, 20.9, 14.1. Anal. calcd for C23H45NO4: C,
69.13; H, 11.35; N, 3.51. Found: C, 68.87; H, 11.49; N, 3.86.
Alcohol 1a-f (100 mg) was dissolved in a 50:50 mixture
of hexane and toluene (3-4 mL, 0.1 M). Then, vinyl acetate
(184 μL, 2 mmol) and finally PPL (60 mg) were added. The
mixture was left under stirring for 2 days at room
temperature. Filtration of the enzyme and purification by
column chromatography using petroleum ether/EtOAc 8:2 as
eluent yielded the pure acetyl derivatives.
General Procedure for the Chemical Acetylation of 2-
Amino Alcohols
(R)-2-(tert-Butoxycarbonylamino)-3-phenylpropyl acetate
(4a)
White solid; mp 68-69 ºC; 1H NMR (CDCl3) ꢀ 7.32-7.15
(5H, m, arom. CH), 4.63 (1H, m, OCONH), 4.10-4.00 (3H,
m, CH, CH2OCO), 2.82 (2H, m, CH2C6H5), 2.08 (3H, s,
OCOCH3), 1.40 [9H, s, C(CH3)3]; 13C NMR (CDCl3) ꢀ
170.8, 155.1, 137.1, 129.2, 128.5, 126.5, 79.4, 65.0, 50.5,
37.8, 28.2, 20.8. Anal. calcd for C16H23NO4: C, 65.51; H,
7.90; N, 4.77. Found: C, 65.27; H, 8.07; N, 4.86.
To
a
solution of alcohol 1a-f (1 mmol) in
dichloromethane (3 mL), acetic anhydride (110 μL, 1.2
mmol) and then 4-dimethylaminopyridine (183 mg, 1.5
mmol) were added. The solution was stirred at room
temperature. After 30 min, the starting material was
consumed and the solvent was evaporated. The reaction
mixture was dissolved in ethyl acetate (20 mL) and was
quenched with H2O (20 mL). The aqueous phase was

162 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Magrioti et al.
secreted
IVA cytosolic phospholipase A2 and group
phospholipase A2. J. Med. Chem., 2007, 50, 4222.
V
washed once more with ethyl acetate (20 mL). The combined
organic phases were washed with 5% NaHCO3, brine, 10%
citric acid, brine, were dried and the solvent was evaporated
to yield the crude acetyl derivative. The product was purified
by column chromatography using petroleum ether/EtOAc
8:2 as eluent. All acetyl products were identified by 1H NMR
and 13C NMR spectrometry and their spectra were identical
to those of the corresponding acetyl derivatives prepared by
the enzymatic transesterification procedure.
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ACKNOWLEDGEMENT
This research was partially funded by the Univeristy of
Athens (Special Account for Research Grants).
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