Enantioselective synthesis of 1-aryl-2-propenylamines: A new approach to a stereoselective synthesis of the Taxol side chain

Article abstract of DOI:10.1016/j.tetasy.2004.01.035

A variety of substituted 1-aryl-2-propenylamines of high enantiomeric purity were prepared via lipase-catalysed resolution of the corresponding racemates. (R)-1-Phenyl-2-propenylamine was further synthesised into (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropanoic acid methyl ester, the side chain of Taxol.

Full text of DOI:10.1016/j.tetasy.2004.01.035

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 941–949
Enantioselective synthesis of 1-aryl-2-propenylamines: a new
approach to a stereoselective synthesis of the Taxolꢀ side chain
Daniele Castagnolo, Silvia Armaroli, Federico Corelli* and Maurizio Botta*
Dipartimento Farmaco Chimico Tecnologico, Universitꢀa degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
Received 3 December 2003; accepted 28 January 2004
Dedicated to Professor R. Nicoletti on the occasion of his 70th birthday
Abstract—A variety of substituted 1-aryl-2-propenylamines of high enantiomeric purity were prepared via lipase-catalysed reso-
lution of the corresponding racemates. (R)-1-Phenyl-2-propenylamine was further synthesised into (2R,3S)-3-benzoylamino-2-hy-
droxy-3-phenylpropanoic acid methyl ester, the side chain of Taxolꢁ.
ꢂ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
are important components of biologically active com-
pounds, such as angiotensin-converting enzyme (ACE)
and HIV-1 protease inhibitors. Both the syn- and anti-
stereoisomer of this class of compounds are found in
drugs and natural products. Thus, phenylisoserine, the
most important representative for syn aminoalcohols, is
present as a side chain in Taxolꢁ and Taxotereꢁ, two of
the most potent antitumour agents currently used in
cancer chemotherapy. In contrast, the anti-isomers show
biological activities when incorporated in structures
such as sphingosine and phytosphingonsine, which are
involved in various functions of the central nervous
system.7
Chiral amines are important building blocks and auxil-
iaries for the stereoselective synthesis of biologically
active compounds and natural products.1 As a result, a
number of methodologies have been developed for their
preparation in enantiomerically pure form as well as to
determine their absolute configurations.2 Nevertheless,
only two methodologies for obtaining 1-aryl-2-propen-
ylamines in nonracemic form have been described so far.
Recently, Pallavicini et al.3a reported the resolution of
racemic allylamines by selective precipitation of their
diastereomeric salts with isopropylideneglyceryl hydro-
gen phthalate. Kibayashi et al.3b reported the synthesis
of the enantiopure (R)-allylamine by the reaction of
benzaldehyde oxime ether with vinyl lithium and the
subsequent cleavage using Zn–AcOH.
Herein we report the lipase-catalysed resolution of
racemic 1-aryl-2-propenylamines 2 to give the corre-
sponding (R)- and (S)-enantiomers with high enantio-
meric excess as well as the further elaboration of (R)-1-
phenyl-2-propenylamine into (2R,3S)-3-benzoylamino-
2-hydroxy-3-phenylpropanoic acid methyl ester 3, which
has previously been used8 as a synthon to insert the side
chain of Taxolꢁ.
Following our previous work concerning the synthesis
of chiral 1-aryl-2-propynylamines 14 in high enantio-
meric excess by stereoselective amidation via acyl tranfer
reactions catalysed by Candida antarctica lipase (CAL),5
we decided to explore the possibility of obtaining homo-
chiral 1-aryl-2-propenylamines 2 via lipase-catalysed
resolution of their corresponding racemates. Our inter-
est in these compounds stemmed from our current
synthetic and molecular modeling studies on taxoids.6 In
particular, we have identified 1-aryl-2-propenylamines
as possible intermediates for developing a new enan-
tioselective synthesis of a-hydroxy-b-amino acids. These
2. Results and discussion
In an attempt to provide easy access to the required
compounds and based on our experience in this field,1;4
we synthesised the racemic starting materials 2a–h
(Scheme 1, Table 1) by hydrolysis of the corresponding
acetamides 4a–h, in turn obtained by catalytic hydro-
genation of the triple bond of acetamides 5a–h in the
* Corresponding authors. Tel.: +39-0577234306; fax: +39-0577234333;
e-mail: botta@unisi.it
0957-4166/$ - see front matter ꢂ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.035

942
D. Castagnolo et al. / Tetrahedron: Asymmetry 15 (2004) 941–949
O
OH
MeCN
H2SO4
MgBr
H
R
R
6a-h
O
O
NH2
H2 / Lindlar
catalyst
HCl
(22-55%)
NH
NH
R
(36-99%)
R
R
2a-h
4a-h
5a-h
Scheme 1.
Table 1. Preparation of ( )-N-1-aryl-2-propenylacetamides 4a–h and
( )-N-1-aryl-2-propenylamines 2a–h
donor, and diethyl ether as a solvent (Scheme 2, Table
2).
Compound
R
Time (h)
Yield (%)a
Mp (ꢃC)
4a
4b
4c
4d
4e
4f
H
3
3
99
60
63
78
97
99
95
36
38
49
35
55
36
27
22
32
Oil
O
4-Cl
4-F
81–84
Oil
Oil
NH2
NH2
2
CAL
NH
3-F
3
+
R
R
AcOEt
(29-47%)
3-Me
2-Me
4-Me
4-Br
H
2
83–85
93–94
77–80
85–89
Oil
R
2
(S)-2a-h
(R)-4a-h
2a-h
4g
4h
2a
2b
2c
2d
2e
2f
2
1.5
12
22
16
18
14
12
18
20
O
NH2
4-Cl
4-F
Oil
Oil
NH
HCl
(30-48%)
R
3-F
Oil
Oil
R
3-Me
2-Me
4-Me
4-Br
Oil
Oil
(R)-4a, b, c, h
(R)-2a, b, c, h
2g
2h
Oil
Scheme 2.
a Referred to isolated and purified materials.
Monitoring of the reaction by GC on a chiral column
allowed the simultaneous determination of conversion
and enantiomeric excesses of both educt and product.
The transformations were stopped as soon as the desired
conversion (approximately 50%) was achieved. Follow-
ing the usual workup, compounds (S)-2 and (R)-4 were
purified by flash column chromatography and their eeÕs
determined again by chiral GC. In no case was there a
loss of ee due to work-up and silica gel chromatography.
As can be seen from the data reported in Table 2, CAL
presence of LindlarÕs catalyst,9 using DMF as a solvent
and ethylenediamine as a poisoning agent to avoid the
overreduction of the double bond.10;11 The latter com-
pounds were synthesised from aryl propargylic alcohols
6a–h12 via a Ritter reaction (acetonitrile/sulfuric acid).
We then investigated the enantioselective acetylation of
( )-2 using CAL as a catalyst, ethyl acetate as an acyl
Table 2. CAL-catalysed resolution of ( )-N-1-aryl-2-propenylamines 2a–h
Conv.a (%)
E
(R,S)-2
(S)-2
(R)-4
Time (h)
20
½aꢀ CHCl3
20
½aꢀ CHCl3
Yieldb (%)
Ee (%)
Yieldb (%)
Ee (%)
c
D
D
2a
2b
2c
2d
H
4-Cl
4-F
66
72
49.4
49.5
43.4
38.6
98
98
93
61
34
37
91
95
)10.2
)9.0
46.0
41.0
>98
98
+63.0
+71.3
+69.7
N.D.d
N.D.d
N.D.d
+75.0
+12.0
420
390
110
168
168
168
120
118
52.0
55.5
N.D.d
34.2
)4.9
44.5
87
48
N.D.d
51.3
5.0
N.D.d
3.5
N.D.d
195
3-F
N.D.d
N.D.d
N.D.d
29.0
N.D.d
N.D.d
N.D.d
)8.0
N.D.d
N.D.d
N.D.d
38.0
2e
2f
3-Me
2-Me
4-Me
4-Br
47.5
N.D.d
50.0
42
N.D.d
96
2g
2h
32.0
)11.0
47.0
a Determined by chiral GC (FS-CYCLODEX-BETA-I/P).
b Referred to isolated and purified materials.
c Measured in CHCl3 solution.
d N.D. ¼ not determined.

D. Castagnolo et al. / Tetrahedron: Asymmetry 15 (2004) 941–949
943
proved to be an effective catalyst (E > 100) for the
O
NH2
ClCOPh, Py
DMAP
resolution of substrates 2a,b and h, leading to both
(S)-2a,b,h and (R)-4a,b,h in good yields and high enan-
tiomeric excesses (95–98%). Acceptable results were also
obtained with substrates 2c and g, whereas compounds
2d–f, bearing an ortho/meta-substituted aromatic ring,
proved to be resistant to enantioselective bioconversion,
even after a prolonged reaction time (>160 h).
Ph
NH
(99%)
(R)-2a
7
H2 / Lindlar
catalyst
(quant.)
The absolute configuration of 2 and 4 was assigned
based on the specific rotation of ())-2a, which is de-
scribed in the literature,3 establishing an (S)-configura-
tion for (S)-2a and hence an (R)-configuration for the
amide (R)-4a. This result is in perfect agreement with the
reported preference of CAL for the acylation of (R)-
amines.2;13
O
NH2
ClCOPh, Py
Ph
NH
DMAP
(89%)
(R)-1
(R)-8
Scheme 3.
Acidic hydrolysis of acetamides (R)-4a,b,c and h, under
the same experimental conditions as described for their
racemic counterparts, afforded amines (R)-2a,b,c and h
without loss of enantiomeric excess (Table 3).
We then turned our attention to the development of a
new stereoselective synthesis of (2R,3S)-3-benzoyl-
amino-2-hydroxy-3-phenylpropanoic acid methyl ester
3. The key intermediate for this synthesis was envisaged
in the homochiral N-benzoylallylamine 7 (Scheme 3),
obtained by benzoylation of (R)-1-phenyl-2-propenyl-
amine 2a or by partial hydrogenation10;11 of enantio-
merically pure N-benzoylpropargylamine (R)-8, in turn
obtained from (R)-1.4
Table 3. Preparation of (R)-N-1-aryl-2-propenylamines (R)-2a, b, c
and h
20
D
(R)-(2)
Yieldb (%) Eea (%)
½aꢀ CHCl3
2a
2b
2c
2h
H
32
48
30
32
98
98
87
97
+10.2
+12.3
+8.8
4-Cl
4-F
4-Br
+12.0
Our first approaches to syn-diol 9a and b (Scheme 4),
based on the asymmetric dihydroxylation of carbon–
carbon double bond of 7 using chiral ligands, proved to
a Determined by chiral GC (FS-CYCLODEX-BETA-I/P).
b Referred to isolated and purified materials.
O
O
Ph
NH
Ph
NH
OsO4, NMO
+
7
OR
OR
OH
OH
(63%)
9a,b R= H
TBDPSCl
Imidazole
10a,b R= TBDPS
(76%)
O
O
Jones reag.
L-Selectride
Ph
NH
Ph
NH
(84%)
(99%)
OTBDPS
OTBDPS
O
OH
10b
11
O
Ph
Ph
1.PCC
2.CH2N2
Ph
NH
O
HCl
N
N
O
O
Deoxo-Fluor
OMe
(85%)
(50%)
OR
OMe
OH
O
3
14
(99%)
12 R = TBDPS
(94%)
13 R = H
Scheme 4.

944
D. Castagnolo et al. / Tetrahedron: Asymmetry 15 (2004) 941–949
be unsuccessful, leading to a mixture of 9a and b with
low diasteromeric excess.
measured at 200 MHz. Chemical shifts are reported
relative to CDCl3 at d 7.24 ppm and tetramethylsilane at
d 0.00 ppm. EI low resolution mass spectra were re-
corded with an electron beam of 70 eV. Elemental
analyses (C, H, N) were performed in-house.
These results are in agreement with previous studies on
asymmetric dihydroxylation of allylamines.14 As a re-
sult, we preferred converting 7 into a 1:1 diastereomeric
mixture (OsO4, NMO)15 of amino alcohols 9a and 9b,
which, after selective protection at the primary hydroxyl
as tert-butyldiphenylsilyl ether16 10a and 10b, were
subjected to JonesÕ oxidation to the enantiomerically
pure ketone 11 followed by stereoselective reduction
using L-Selectride17;18 to provide compound 10b in 98%
de.
4.1. General procedure for the preparation of ( )-N-1-
acetyl-1-phenyl-2-propynylamines 5g and h
A solution of 96% H2SO4 (490 mg, 5 mmol) in dry ace-
tonitrile (2 mL) was added to a stirred mixture of 1-aryl-
2-propynyl-1-ol (1 mmol) and anhydrous Na2SO4
(142 mg, 1 mmol) in dry acetonitrile (3.1 mL) at )20 ꢃC.
The mixture was allowed to reach room temperature,
and stirring then continued for the required time. The
mixture was concentrated, poured on ice, and extracted
with ether and dichloromethane. The combined organic
layers were dried over Na2SO4, filtered and concen-
trated. Flash chromatography, using ethyl acetate/
petroleum ether (1:1) as eluant, afforded pure ( )-N-1-
acetyl-1-aryl-2-propynylamines 5g and h.
The anti-diastereoisomer 10b was transformed into the
trans-oxazoline 12 through dehydrative cyclisation using
bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-
Fluorꢁ)19 entailing inversion of configuration at C-2.
The trans-configuration of oxazoline 12 was assigned by
1H NMR analysis by comparison of the coupling con-
stant values of the deprotected compound 13 with those
of already known compounds.20 No trace of cis-oxazo-
line could be detected.
Oxidation of 13 with freshly prepared pyridinium chlo-
rochromate (PCC) gave the corresponding carboxylic
acid, which was directly treated with an ethereal solution
of diazomethane to provide methyl ester 14. Acid
catalysed opening of the oxazoline 14 gave (2R,3S)-
3-benzoylamino-2-hydroxy-3-phenylpropanoic acid me-
thyl ester 3 in 85% yield; spectroscopic and analytical
data for compound 3 were in agreement with those re-
ported in the literature (see Experimental).20;21;8
4.1.1. ( )-N-1-Acetyl-1-(methylphenyl)-2-propynylamines
5g. Time 14 h, yield 51%, mp 94–97 ꢃC. 1H NMR
(CDCl3): d 7.39–7.35 (2H, d, J ¼ 8:0 Hz, Ph), 7.16–7.12
(2H, d, J ¼ 8:0 Hz, Ph), 5.94 (1H, s, CHO), 2.44 (1H, s,
CCH), 2.32 (3H, s, CH3), 1.98 (3H, s, CH3). IR (KBr):
1676, 1497 cmꢁ1. MS: 197 (Mþ). Anal. Calcd for
C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 76.62;
H, 6.87; N, 7.32.
4.1.2. ( )-N-1-Acetyl-1-(bromophenyl)-2-propynylamines
5h. Time 16 h, yield 89%, mp 119–123 ꢃC. 1H NMR
(CDCl3): d 7.49–7.44 (2H, d, J ¼ 8:7 Hz, Ph), 7.37–7.33
(2H, d, J ¼ 7:0 Hz, Ph), 5.97 (1H, d, J ¼ 1:6 Hz, CHO),
2.49 (1H, d, J ¼ 1:5 Hz CCH), 2.00 (3H, s, CH3). IR
(KBr): 1669, 1486 cmꢁ1. MS: 251 [M)H]þ. Anal. Calcd
for C11H10BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C,
51.98; H, 3.78; N, 5.23.
3. Conclusions
Resolution of ( )-1-arylallylamines via acyl transfer
catalysed by C. antarctica lipase proved to be a quite
efficient route, both in terms of chemical yield and stereo-
selectivity, to (R)- and (S)-1-aryl-2-propenylamines
substituted at the para-position of the aryl moiety. These
compounds are versatile intermediates for the prepara-
tion of diasteromerically and enantiomerically pure
forms of biologically relevant compounds, such as syn-
and anti-a-hydroxy-b-amino acids. In particular, start-
ing from (R)-N-benzoyl-1-phenyl-2-propenylamine 7,
a new synthesis of a paclitaxel side chain, namely
(2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropanoic
acid methyl ester 3, can be performed with 16% overall
yield.
4.2. General procedure for the preparation of ( )-N-1-
acetyl-1-phenyl-2-propenylamines 4a–h
To
a solution of ( )-N-1-acetyl-1-aryl-2-propynyl-
amines6 (1 mmol) in dry DMF, under magnetic stirring,
ethylenediamine (66 lL) and Lindlar catalyst (8 mg)
were added. The mixture was submitted to hydrogen
atmosphere (1 atm) and stirred at room temperature for
the required time. The mixture was filtered on Celite and
washed with ethyl acetate. The organic layer was washed
with NH4Cl (3 mL) and water, dried over Na2SO4, fil-
tered and concentrated. The crude product was purified
with flash chromatography, using ethyl acetate/petro-
leum ether (1:1) as eluant (Table 1).
4. Experimental
Reagents were obtained from commercial suppliers
and used without further purification. Merck silica
gel 60 was used for both column chromatography
(70–230 mesh) and flash chromatography (230–400mesh).
4.2.1. ( )-N-1-Acetyl-1-phenyl-2-propenylamine 4a. Time
3 h, yield 99%, oil. H NMR (CDCl3): d 7.32–7.28 (5H,
m, Ph), 6.07–5.91 (1H, ddd, J ¼ 5:1 Hz, J ¼ 10:5 Hz,
1
1
Melting points are uncorrected. H NMR spectra were

D. Castagnolo et al. / Tetrahedron: Asymmetry 15 (2004) 941–949
945
J ¼ 16:2 Hz, CH2CHC), 5.65–5.62 (1H, m, CHN), 5.25
(1H, m, CH2CHC), 5.20–5.15 (1H, d, J ¼ 10:8 Hz,
CH2CHC), 2.00 (3H, s, CH3). IR (KBr): 3295, 1656,
1545 cmꢁ1. MS: 175 (Mþ). Anal. Calcd for C11H13NO:
C, 75.12; H, 7.31; N, 8.13. Found: C, 75.42; H, 7.42; N,
8.00.
5.61 (1H, m, CHN), 5.24 (1H, m, CH2CHC), 5.19–5.14
(1H, d, J ¼ 9.4 Hz, CH2CHC), 2.32 (3H, s, CH3) 2.00
(3H, s, CH3). MS: 189 (Mþ). IR (KBr): 1672, 1504 cmꢁ1
.
Anal. Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40.
Found: C, 76.15; H, 7.96; N, 7.39.
4.2.8.
( )-N-1-Acetyl-1-(4-bromophenyl)-2-propenyl-
amine 4h. Time 1.5 h, yield 36%, mp 84–89 ꢃC. 1H
NMR (CDCl3): d 7.42–7.34 (4H, m), 6.85–6.81 (1H, d,
J ¼ 7:9 Hz, NH), 5.94–5.77 (1H, ddd, J ¼ 5:4 Hz,
J ¼ 10:26 Hz, J ¼ 16:2 Hz, CH2CHC), 5.45 (1H, m,
CHN), 5.17–5.05 (2H, m, CH2CHC), 1.87 (3H, s, CH3).
IR (KBr): 1664, 1507 cmꢁ1. MS: 253 (M)H)þ, 212
(100%). Anal. Calcd for C11H12BrNO: C, 51.99; H, 4.76;
N, 5.51. Found: C, 51.96; H, 4.73; N, 5.49.
4.2.2.
( )-N-1-Acetyl-1-(4-chlorophenyl)-2-propenyl-
1
amine 4b. Time 3 h, yield 60%, mp 81–84 ꢃC. H NMR
(CDCl3): d 7.25–7.18 (4H, m, Ph), 6.68 (1H, d,
J ¼ 8:2 Hz, NH), 5.95–5.84 (1H, m, CH2CHC), 5.68–
5.66 (1H, m, CHN), 5.50–5.24 (2H, m, CH2CHC), 2.00
(3H, s, CH3). MS: 211/209 (M+H)þ, 210/208 (Mþ), 130
(100%). Anal. Calcd for C11H12ClNO: C, 63.01; H, 5.77;
N, 6.68. Found: C, 63.05; H, 5.81; N, 6.69.
4.2.3. ( )-N-1-Acetyl-1-(4-fluorophenyl)-2-propenylamine
4c. Time 2 h, yield 63%, oil. H NMR (CDCl3): d 7.22–
4.3. General procedure for the preparation of ( )-1-aryl-
2-propenylamines 2a–h
1
7.15 (2H, dd, J ¼ 8:4 Hz, J ¼ 5:6 Hz, Ph), 6.97–6.98
(2H, m, Ph), 6.68–6.65 (1H, d, J ¼ 7:3 Hz, NH), 5.93–
5.82 (1H, ddd, J ¼ 5:6 Hz, J ¼ 10:5 Hz, J ¼ 16:4 Hz,
CH2CHC), 5.55–5.48 (1H, m, CH N), 5.18–5.16 (1H, d,
J ¼ 4:7 Hz, CH2CHC), 5.13–5.07 (1H, d, J ¼ 12:3 Hz,
CH2CHC), 1.91 (3H, s, CH3). MS: 193 (Mþ). Anal.
Calcd for C11H12FNO: C, 68.38; H, 6.26; N, 7.25.
Found: C, 68.39; H, 6.23; N, 7.22.
A suspension of ( )-N-1-acetyl-1-aryl-2-propenylamines
(1 mmol) and 1.2 M aqueous HCl (5.7 mL) was heated to
90 ꢃC for the required time. The resulting solution was
extracted with Et2O (5 mL). The aqueous layer was
alkalinised by the addition of solid NaHCO3 to pH 8.5
and extracted with Et2O (4 · 5 mL). The combined
organic solution was dried over Na2SO4, filtered and
concentrated in vacuo. The oil residue was subjected to
flash chromatography, using ethyl acetate/petroleum
ether 1:1 as eluant, affording pure ( )-1-aryl-2-prope-
nylamines (Table 1).
4.2.4. ( )-N-1-Acetyl-1-(3-fluorophenyl)-2-propenylamine
4d. Time 3 h, yield 78%, oil. H NMR (CDCl3): d 7.31–
1
6.89 (4H, m, Ph), 5.92–5.76 (1H, m, CH2CHC), 5.64–
5.46 (1H, m,CHN), 5.14–5.05 (2H, m, CH2CHC), 1.84
(3H, s, CH3). MS: 194 (M+Hþ), 150 (100%). Anal.
Calcd for C11H12FNO: C, 68.38; H, 6.26; N, 7.25.
Found: C, 68.31; H, 6.25; N, 7.23.
4.3.1. ( )-1-Phenyl-2-propenylamine 2a. Time 12 h, yield
1
38%, oil. H NMR (CDCl3): d 7.33–7.24 (5H, m, Ph),
6.10–5.93 (1H, ddd, J ¼ 17 Hz, J ¼ 10 Hz, J ¼ 6:1 Hz,
CH2CHC), 5.26–5.18 (1H, d, J ¼ 17 Hz, CH2CHC),
5.12–5.07 (1H, d, J ¼ 10 Hz, CH2CHC), 4.52–4.49 (1H,
d, J ¼ 5:9 Hz, CHN), 1.76 (2H, br s, NH2). IR (KBr):
4.2.5.
( )-N-1-Acetyl-1-(3-methylphenyl)-2-propenyl-
1
amine 4e. Time 2 h, yield 97%, mp 83–85 ꢃC. H NMR
(CDCl3): d 7.18–7.04 (4H, m, Ph), 6.34–6.30 (1H, d,
J ¼ 6:9 Hz, NH), 6.04–5.87 (1H, m, CH2CHC), 5.58–
5.52 (1H, m, CHN), 5.20–5.13 (2H, m, CH2CHC), 2.30
(3H, s, CH3Ph), 1.95 (3H, s, CH3). MS: 189 (Mþ). Anal.
Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found:
C, 76.13; H, 7.93; N, 7.39.
3353, 3265, 2095, 1590 cmꢁ1
.
MS: 133 (Mþ),
131[(M)H)þ, 100%], 117, 105. Anal. Calcd for C9H11N:
C, 81.16; H, 8.32; N, 10.52. Found: C, 81.20; H, 8.27; N,
10.50.
4.3.2. ( )-1-(4-Chlorophenyl)-2-propenylamine 2b. Time
22 h, yield 49%, oil. 1H NMR (CDCl3): d 7.14–7.28 (4H,
m, Ph), 5.93–5.77 (1H, ddd, J ¼ 5:1 Hz, J ¼ 10:0 Hz,
J ¼ 16:3 Hz, CH2CHC), 5.22–5.13 (1H, d, J ¼ 16:5 Hz,
CH2CHC), 5.08–5.03 (1H, d, J ¼ 10 Hz, CH2CHC),
4.84–4.82 (1H, d, J ¼ 5:3 Hz, CHN), 1.48 (2H, br s,
NH2). MS: 169/167 (Mþ), 168/166 (M)H)þ, 132 (100%).
Anal. Calcd for C9H10ClN: C, 64.60; H, 5.80; N, 7.13.
Found: C, 64.58; H, 5.78; N, 7.10.
4.2.6.
( )-N-1-Acetyl-1-(2-methylphenyl)-2-propenyl-
1
amine 4f. Time 2 h, yield 99%, mp 93–94 ꢃC H NMR
(CDCl3): d 7.37–7.33 (1H, d, J ¼ 8:09, NH), 7.25–7.11
(4H, m, PhCH2CHC), 6.03–5.80 (1H, m, CH2CHC),
5.77–5.74 (1H, m, CHN), 5.18–5.05 (2H, m, CH2CHC),
2.33 (3H, s, CH3Ph), 1.88 (3H, s, CH3). MS: 189 (Mþ).
Anal. Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40.
Found: C, 76.19; H, 7.97; N, 7.41.
4.3.3. ( )-1-(4-Fluorophenyl)-2-propenylamine 2c. Time
16 h, yield 35%, oil. 1H NMR (CDCl3): d 7.30–6.92 (4H,
m, Ph), 6.12–5.93 (1H, m, CH2CHC), 5.05–5.12 (2H, m,
CH2CHC), 4.92–4.94 (1H, d, J ¼ 6:5 Hz, CHN), 1.88
(2H, br s, NH2). MS: 150 [(M)H)þ, 100%]. Anal. Calcd
4.2.7.
amine 4g. Time 2 h, yield 95%, mp 76–80 ꢃC. H NMR
(CDCl3): 7.15 (4H, m), 6.06–5.90 (1H, ddd,
J ¼ 4:64 Hz, J ¼ 10:23 Hz, J ¼ 16:45 Hz, CH2CHC),
( )-N-1-Acetyl-1-(4-methylphenyl)-2-propenyl-
1
d

946
D. Castagnolo et al. / Tetrahedron: Asymmetry 15 (2004) 941–949
for C9H10FN: C, 71.29; H, 6.35; N, 9.24. Found: C,
71.22; H, 6.32; N, 9.27.
(immobilised form NOVOZYM 435ꢁ) (100 mg) in Et2O
(5 mL) was stirred at room temperature, and the reac-
tion monitored by GC with chiral column (FS-CY-
CLODEX-BETA-I/P). After the desired conversion was
reached, the reaction mixture was diluted with Et2O and
filtered to remove the enzyme. The organic layer was
washed twice with HCl (1.0 M), obtaining the hydro-
chloride of amines, and the two phases then separated.
The organic layer, containing the amide was washed
once with brine, dried over Na2SO4, filtered and evap-
orated to give crude (R)-4. The aqueous phase con-
taining the (S)-2 hydrochloride was alkalinised with
solid NaHCO3 to pH 7–8 and extracted three times
with Et2O. The combined organic layers was washed
with brine, dried over Na2SO4, filtered and evaporated
to give crude (S)-2. The crude products were purified by
flash chromatography on silica gel, using ethyl acetate/
petroleum ether 1:1 as eluant. The enantiomeric excesses
of the purified products were determined by GC on the
above mentioned chiral column (Table 2).
4.3.4. ( )-1-(3-Fluorophenyl)-2-propenylamine 2d. Time
18 h, yield 55%, oil. 1H NMR (CDCl3): d 7.31–6.85 (4H,
m, Ph), 6.00 (1H, ddd, J ¼ 6:4 Hz, J ¼ 10:3 Hz,
J ¼ 16:7 Hz, CH2CHC), 5.21 (1H, d, J ¼ 17 Hz,
CH2CHC), 5.09 (1H, d, J ¼ 10:3 Hz, CH2CHC), 4.49
(1H, d, J ¼ 6:2 Hz, CHN), 1.74 (2H, br s, NH2). MS:
151 (Mþ), 150 [(M)H)þ, 100%]. Anal. Calcd for
C9H10FN: C, 71.29; H, 6.35; N, 9.24. Found: C, 71.26;
H, 6.34; N, 9.21.
4.3.5. ( )-1-(3-Methylphenyl)-2-propenylamine 2e. Time
14 h, yield 36%, oil. 1H NMR (CDCl3): d 7.32–7.04 (4H,
m, Ph), 6.06–5.94 (1H, m, CH2CHC), 5.28–5.03 (2H, m,
CH2CHC), 4.39 (1H, d, J ¼ 6:5 Hz, CHN), 2.31 (3H, s,
CH3), 1.88 (2H, br s, NH2). MS: 146 (M)H)þ, 130
(100%). Anal. Calcd for C10H13N: C, 81.61; H, 8.65; N,
9.49. Found: C, 81.63; H, 8.64; N, 9.52.
4.5. General procedure for synthesis of (R)-1-aryl-2-
propenylamines (R)-2a,b,c and h
4.3.6. ( )-1-(2-Methylphenyl)-2-propenylamine 2f. Time
12 h, yield 27%, oil. 1H NMR (CDCl3): d 7.38–7.35 (1H,
m, Ph), 7.24–7.13 (3H, m, Ph), 6.07–5.91 (1H, m,
CH2CHC), 5.27–5.22 (2H, m, CH2CHC), 4.73 (1H, d,
J ¼ 5:4 Hz, CHN), 2.35 (3H, s, CH3), 1.19 (2H, br s,
NH2). MS: 146 (M)H)þ, 130 (100%). Anal. Calcd for
C10H13N: C, 81.61; H, 8.65; N, 9.49. Found: C, 81.60; H,
8.63; N, 9.47.
A suspension of (R)-N-1-acetyl-1-aryl-2-propenylamines
(1 mmol) and 1.2 M aqueous HCl (5.7 mL) was heated to
90 ꢃC for the required time. The resulting solution was
extracted with Et2O (5 mL). The aqueous layer was al-
kalinised by addition of solid NaHCO3 to pH 8.5 and
extracted with Et2O (4 · 5 mL). The combined organic
solution was dried over Na2SO4, filtered and concen-
trated in vacuo. The oily residue was subjected to flash
chromatography, using ethyl acetate/petroleum ether
(1:1) as eluant, affording pure (R)-1-aryl-2-propenyl-
amines. The enantiomeric excesses of the products were
determined by GC with chiral column (FS-CYCLO-
DEX-BETA-I/P). In all cases the enantiomeric purity of
starting materials was conserved (Table 3).
4.3.7. ( )-1-(4-Methylphenyl)-2-propenylamine 2g . Time
18 h, yield 22%, oil. 1H NMR (CDCl3): d 7.13–7.09 (2H,
d, J ¼ 7:8 Hz, Ph), 7.03–6.99 (2H, d, J ¼ 7:8 Hz, Ph),
5.89 (1H, ddd, J ¼ 18:0 Hz, J ¼ 11:2 Hz, J ¼ 6:1 Hz,
CH2CHC), 5.15–5.06 (1H, d, J ¼ 18:06 Hz, CH2CHC),
4.99–4.93 (1H, d, J ¼ 11:16 Hz, CH2CHC), 4.35 (1H, d,
J ¼ 6:04 Hz, CHN), 2.21 (3H, s, CH3), 1.74 (2H, br s,
NH2). IR (KBr): 1670, 1512 cmꢁ1. MS: 147 (100%).
Anal. Calcd for C10H13N: C, 81.61; H, 8.65; N, 9.49.
Found: C, 81.64; H, 8.66; N, 9.44.
4.6. (R)-N-Benzoyl-1-phenyl-2-propenylamine 7
To a stirred solution of (R)-1-phenyl-2-propenylamine
2a (1 mmol) in dry pyridine (2.7 mL), a solution of
benzoyl chloride (1.2 mmol) in dry dichloromethane
(2 mL) was added slowly at 0 ꢃC. The reaction was
stirred in inert atmosphere at room temperature for 3 h.
The mixture was concentrated under reduced pressure,
dissolved in chloroform, washed with a solution of
NaHCO3 (2 · 1 mL) and brine. The organic layer was
dried over Na2SO4, filtered and concentrated. The resi-
due was subjected to flash chromatography, using ethyl
acetate/petroleum ether 1:4 as eluant, affording pure
(R)-N-benzoyl-1-phenyl-2-propenylamine 7. Time 4 h,
4.3.8. ( )-1-(4-Bromophenyl)-2-propenylamine 2h. Time
20 h, yield 32%, oil. 1H NMR (CDCl3): d 7.45–7.40 (2H,
d, J ¼ 8:3 Hz, Ph), 7.22–7.18 (2H, d, J ¼ 8:3 Hz, Ph),
6.02–5.86 (1H, ddd, J ¼ 5:9 Hz, J ¼ 10:3 Hz,
J ¼ 16:7 Hz, CH2CHC), 5.24–5.15 (1H, d, J ¼ 16:9 Hz,
CH2CHC), 5.11–5.06 (1H, d, J ¼ 10:3 Hz, CH2CHC),
4.48–4.44 (1H, d, J ¼ 6:0 Hz, CHN), 1.83 (2H, br s,
NH2). IR (KBr): 1665, 1507 cmꢁ1. MS: 212, 132 (100%).
Anal. Calcd for C9H10BrN: C, 50.97; H, 4.75; N, 6.60.
Found: C, 50.65; H, 4.69; N, 6.57.
1
yield 99%, mp 103–105 ꢃC. H NMR (CDCl3): d 7.79–
7.28 (10H, m, Ph), 6.76–6.72 (1H, d, J ¼ 7:5 Hz, NH),
6.16–6.00 (1H, ddd, J ¼ 5:5 Hz, J ¼ 10:0 Hz,
J ¼ 15:7 Hz, CH2CHC), 5.85–5.78 (1H, m, CHN), 5.30
(1H, m, CH2CHC), 5.25 (1H, d, J ¼ 11:5 Hz,
4.4. General procedure for the CAL-catalysed resolution
of ( )-1-aryl-2-propenylamines 2a–h
A mixture of racemic amines 2a–h (2 mmol), ethyl ace-
tate (0.78 mL, 8 mmol) and lipase B from C. antarctica
CH2CHC). IR (KBr): 3290, 1670, 1530 cmꢁ1. MS: 237
20
(Mþ). ½aꢀ +57.0 (c 1.0). Anal. Calcd for C16H15NO: C,
D

D. Castagnolo et al. / Tetrahedron: Asymmetry 15 (2004) 941–949
947
81.02; H, 6.31; N, 5.73. Found: C, 81.01; H, 6.32; N,
5.70.
3430, 3140, 2929, 1720, 1656 cmꢁ1. MS: 271 (Mþ). Anal.
Calcd for C16H17NO3: C, 70.02; H, 6.21; N, 5.13. Found:
C, 70.14; H, 6.27; N, 5.16.
4.7. (R)-N-Benzoyl-1-phenyl-2-propynylamine 8
4.10. (1S,2R)-N-1-(3-{[(1-tert-Butyl)-1,1-diphenylsilyl]-
oxy}-2-hydroxy-1-phenylpropyl)benzamide 10a;
(1S,2S)-N-1-(3-{[(1-tert-butyl)-1,1-diphenylsilyl]oxy}-
2-hydroxy-1-phenylpropyl)benzamide 10b
To a stirred solution of (R)-1-phenyl-2-propynylamine 1
(1 mmol) in dry pyridine (2.7 mL), a solution of benzoyl
chloride (1.2 mmol) in dry dichloromethane (2 mL) was
added slowly at 0 ꢃC. The reaction was stirred in an inert
atmosphere at room temperature for 3 h. The mixture
was concentrated under reduced pressure, dissolved with
chloroform, washed with a solution of NaHCO3
(2 · 1 mL) and brine. The organic layer was dried over
Na2SO4, filtered and concentrated. The residue was
subjected to flash chromatography, using ethyl acetate/
petroleum ether (1:4) as eluant, affording pure (R)-N-
benzoyl-1-phenyl-2-propynylamine 8. Time 3 h, yield
Imidazole (1 mmol) and tert-butyldiphenylsilyl chloride
(1.1 mmol) were added to the mixture of compounds 9a
and 9b (1 mmol) dissolved in dry DMF (2.2 mL). The
mixture was stirred under an inert atmosphere for 14 h.
The mixture was diluted in CH2Cl2, washed with a 5%
solution of KHSO4 (1 · 2 mL), water (2 · 3 mL) and
brine, dried over Na2SO4, filtered and concentrated. The
crude product was purified by flash chromatography,
using ethyl acetate/petroleum ether (4:1) as eluant.
Analytical and spectroscopic data of the mixture of dia-
stereoisomers are reported. Time 14 h, yield 76%, oil. 1H
NMR (CDCl3) 10a: d 7.74–7.24 (20H, m, Ph), 7.08–7.04
(1H, d, J ¼ 7:8 Hz, NH), 5.28–5.23 (1H, dd, J ¼ 7:9 Hz,
J ¼ 3:3 Hz, CHN), 4.13–4.08 (1H, m, CHO), 3.82–3.45
(2H, m, CH2O), 2.79 (1H, bs, OH), 1.06 (9H, s,
(CH3)3C). 10b: d 7.74–7.23 (20H, m, Ph), 5.40–5.34 (1H,
dd, J ¼ 8:2 Hz, J ¼ 4:4 Hz, CHN), 4.13–4.08 (1H, m,
CHO), 3.68–3.45 (2H, m, CH2O), 2.72 (1H, d,
J ¼ 5:4 Hz, OH), 1.03 (9H, s, (CH3)3C). IR (KBr): 3436,
2932, 1737, 1656, 1506 cmꢁ1. MS: 452, 298, 149 (100 %).
Anal. Calcd for C32H35NO3 Si: C, 75.42; H, 6.81; N,
2.71. Found: C, 75.44; H, 6.87; N, 2.75.
1
89%, mp 135–137 ꢃC. H NMR (CDCl3): d 7.79–7.24
(10H, m, Ph), 6.80–6.56 (1H, d, J ¼ 7:8 Hz, NH), 6.22
(1H, d, J ¼ 8:5 Hz, CH N), 2.52 (1H, d, J ¼ 1:7 Hz, CH).
20
IR (KBr): 3290, 1665, 1535 cmꢁ1. MS: 235 (Mþ).
½aꢀ +14.8 (c 2.0). Anal. Calcd for C16H13NO: C, 81.12;
D
H, 5.31; N, 5.13. Found: C, 81.10; H, 5.33; N, 5.20.
4.8. (R)-N-Benzoyl-1-phenyl-2-propenylamine 7
To a solution of (R)-N-benzoyl-1-phenyl-2-propynyl-
amine 8 (1 mmol) in dry DMF, under magnetic stirring,
ethylenediamine (66 lL) and Lindlar catalyst (8 mg)
were added. The mixture was submitted to a hydrogen
atmosphere (1 atm) and stirred at room temperature for
the 2 h. The mixture was filtered on Celite and washed
with ethyl acetate. The organic layer was washed with
NH4Cl (3 mL) and water, dried over Na2SO4, filtered
and concentrated. The crude product was purified by
flash chromatography, using ethyl acetate/petroleum
ether (1:1) as eluant.
4.11. (S)-N-1-(3-[(1-tert-Butyl)-1,1-diphenylsilyl]oxy-2-
oxo-1-phenylpropyl)benzamide 11
Freshly prepared Jones reactive (0.79 mL) [1 mL of CrO3
(0.20 g) in H2SO4 (98%)/water, 3:7] was added to a
stirred solution of the mixture of products 10a and 10b
(0.11 mmol) in acetone (16 mL). The mixture was stirred
for 30 min, then diluted with ethyl acetate and washed
with a solution of NaHCO3 and brine. The organic layer
was dried over Na2SO4, filtered and concentrated. The
crude product was purified by flash chromatography,
using ethyl acetate/petroleum ether (1:1) as eluant. Time
4.9. (1S,2R)-N-1-(1-Phenyl-2,3-dihydroxypropyl)benz-
amide 9a; (1S,2S)-N-1-(1-phenyl-2,3-dihydroxypropyl)-
benzamide 9b
To a stirred solution of (R)-N-benzoyl-1-phenyl-2-
propenylamine 7 (3 mmol) in THF with 10% of water,
1.05 g (9 mmol) of 4-methylmorpholine N-oxide (NMO)
were added. The solution was cooled to 0 ꢃC, then OsO4
(0.1 mmol) added and the reaction stirred at room
temperature for 48 h. The mixture was concentrated
under reduced pressure, diluted with ethyl acetate and
extracted (2 · 3 mL). The combined organic layers were
washed with brine, dried over Na2SO4, filtered and
concentrated. The crude product was purified by flash
chromatography, using ethyl acetate/petroleum ether
(4:1) as eluant. Analytical and spectroscopic data of the
mixture of diastereoisomers are reported. Time 48 h,
yield 63%. 1H NMR (CDCl3) 9a: d 7.77–7.24 (10H, m, Ph),
7.13 (1H, d, J ¼ 7:9 Hz, NH), 5.32–5.26 (1H, m, CHN),
4.10–3.93 (1H, m, CHO), 3.70–3.42 (2H, m, CH2O). 9b: d
7.77–7.24 (10H, m, Ph), 5.32–5.26 (1H, m, CHN), 4.10–
3.93 (1H, m, CHO), 3.70–3.42 (2H, m, CH2O). IR (KBr):
1
30 min, yield 84%, oil. H NMR (CDCl3): d 7.87–7.23
(20H, m, Ph), 6.16–6.12 (1H, d, J ¼ 6:8 Hz, CHN), 4.28
(2H, s, CH2O), 1.05 (9H, s, (CH3)3C). IR (KBr): 2929,
20
D
1659, 1509, 1481 cmꢁ1. MS: 147 (100%). ½aꢀ +79.3 (c
1.4). Anal. Calcd for C32H33NO3Si: C, 75.62; H, 6.31; N,
2.73. Found: C, 75.73; H, 6.50; N, 2.76.
4.12. (1S,2S)-N-1-(3-{[(1-tert-Butyl)-1,1-diphenylsilyl]-
oxy}-2-hydroxy-1- phenylpropyl)benzamide 10b
A 1 M solution of L-Selectride in THF (1.5 mL) was
added to a solution of (S)-N-1-(3-[(1-tert-butyl)-1,1-
diphenylsilyl]oxy-2-oxo-1-phenylpropyl)benzamide 11
in dry THF that had been cooled to 0 ꢃC for a few
minutes under magnetic stirring. After 4 h at the same
temperature 1 mL of NaOH (3.0 M) and 1 mL of H2O2

948
D. Castagnolo et al. / Tetrahedron: Asymmetry 15 (2004) 941–949
(30%) were added and the solution stirred for 30 min.
The mixture was extracted with ethyl acetate (2 · 2 mL),
washed with brine and dried over Na2SO4. After filter-
ing, the solvent was removed under reduced pressure
and the crude product purified by flash chromatography
(diethyl ether/petroleum ether 2:3).
Calcd for C16H15NO2: C, 72.12; H, 6.01; N, 5.11.
Found: C, 72.45; H, 6.03; N, 5.28.
4.15. (4S,5R)-Methyl-2,4-Diphenyl-1,3-oxazoline-5-
carboxylate 14
Time 4 h, yield 99%, oil. 1H NMR (CDCl3): d 7.74–7.23
(20H, m, Ph), 5.40–5.34 (1H, dd, J ¼ 8:2 Hz, J ¼ 4:4 Hz,
CHN), 4.13–4.08 (1H, m, CHO), 3.68–3.45 (2H, m,
CH2O), 2.72 (1H, d, J ¼ 5:4 Hz, OH), 1.03 (9H, s,
To a stirred solution of (4S,5R)-[2,4-diphenyl-(5-hy-
droxymethyl)]-1,3-oxazoline 13(1 mmol) in dry DMF
(20 mL), freshly prepared PCC (3.5 mmol) was added.
The reaction was stirred for 2 h under an inert atmo-
sphere, then treated with an excess of a freshly prepared
ethereal solution of diazomethane. After a few minutes,
the mixture was concentrated under reduced pressure
and extracted with ethyl acetate (2 · 3 mL). The com-
bined organic layers were dried over Na2SO4, filtered
and concentrated. The crude product was purified by
flash chromatography, using diethyl ether/petroleum
(CH3)3C). IR (KBr): 3436, 2932, 1737, 1656, 1506 cmꢁ1
.
20
MS: 452, 298, 149 (100%). ½aꢀ )16.0 (c 1.0). Anal.
D
Calcd for C32H35NO3Si: C, 75.42; H, 6.81; N, 2.71.
Found: C, 75.44; H, 6.87; N, 2.75. de > 98%.
4.13. (4S,5R)-5-({[1-(tert-Butyl)-1,1-diphenylsilyl]-oxy}-
methyl)-2,4-diphenyl-1,3-oxazoline 12
1
ether (3:1) as eluant. Time 2 h, yield 50%, oil. H NMR
(CDCl3): d 8.21–7.07 (10H, m, Ph), 5.43 (1H, d,
J ¼ 6:6 Hz, CHN), 4.89 (1H, d, J ¼ 6:7 Hz, CHO), 3.85
1.0). MS: 281 (Mþ), 222 (100%), 193. Anal. Calcd for
C17H15NO3: C, 72.42, H, 5.31; N, 4.91. Found: C, 72.59;
H, 5.33; N, 4.98.
A stirred solution of (1S, 2S)-N-1-(3-{[(1-tert-butyl)-1,1-
diphenylsilyl]oxy}-2-hydroxy-1-phenylpropyl)benzamide
10b (1 mmol) in dry CH2Cl2 (1 mL) under an inert
atmosphere was cooled at )20 ꢃC and 20 lL of Deoxo-
Fluorꢁ (1.1 mmol) were added. The mixture was stirred
for 30 min at the same temperature. A saturated solution
of NaHCO3 (0.1 mL) was added and the mixture
warmed to room temperature. The solution was diluted
with CHCl3, extracted and washed with brine. The
organic layer was dried over Na2SO4, filtered and con-
centrated. The crude product was purified by flash
chromatography, using diethyl ether/petroleum ether 2:3
as eluant. Time 30 min, yield 99%, oil. 1H NMR
(CDCl3): d 8.07–8.03 (2H, m, Ph), 7.71–7.25 (18H, m,
Ph), 5.24 (1H, d, J ¼ 6:8 Hz, CHN), 4.60 (1H, ddd,
J ¼ 4:3 Hz, J ¼ 6:8 Hz, J ¼ 4:8 Hz, CHO), 3.99 (1H, dd,
J ¼ 4:3 Hz, J ¼ 11:2 Hz, CH2O), 3.90 (1H, dd,
20
D
(3H, s, CH3). IR (KBr): 1760, 1650 cmꢁ1. ½aꢀ +14.0 (c
4.16. (2R,3S)-3-Benzoylamino-2-hydroxy-3-phenylpropa-
noic acid methyl ester 3
A solution of (4S,5R)-methyl-2,4-diphenyl-1,3-oxazo-
line-5-carboxylate 14 in methanol (6.5 mL) and HCl
(1 M, 2.2 mL) was refluxed under magnetic stirring for
5 h. The solvents were removed under reduced pressure.
The product was dissolved with CH2Cl2 and washed
twice with water. The organic layer was dried over
Na2SO4, filtered and concentrated; the crude product
was purified by flash chromatography, using ethyl acet-
ate/petroleum ether (1:4) as eluant. Time 5 h, yield 85%,
J ¼ 4:8 Hz, J ¼ 11:2 Hz, CH2O), 1.05 (9H, s, (CH3)3C).
20
IR (KBr): 1649 cmꢁ1. ½aꢀ )29.2 (c 1.9). MS: 491 (Mþ).
1
D
mp 185–186 ꢃC. H NMR (CDCl3): d 7.77–7.42 (10H,
Anal. Calcd for C32H33NO2 Si: C, 78.12; H, 6.71; N,
2.81. Found: C, 78.20; H, 6.72; N, 2.85.
m, Ph), 6.94 (1H, d, J ¼ 9:1 Hz, NH), 5.73 (1H, dd,
J ¼ 2:0 Hz, 9.1 Hz, CHN), 4.62 (1H, d, J ¼ 2:0 Hz,
CHO), 3.83 (3H, s, CH3), 2.48 (1H, br s, OH). IR (KBr):
20
1730, 1638 cmꢁ1. ½aꢀ )49.0 (c 0.4, CH3OH). MS: 299
D
4.14. (4S,5R)-[2,4-Diphenyl-(5-Hydroxymethyl)]-1,3-
oxazoline 13
(Mþ). Anal. Calcd for C17H17NO4: C, 68.22; H, 5.68; N,
4.68. Found: C, 68.20; H, 5.56; N, 4.78. Spectroscopic
data reported for 3 in the literature:21b mp: 184–185 ꢃC.
1H NMR (CDCl3): d 7.59–7.18 (10H, m, Ph), 6.98 (1H,
d, J ¼ 9:0 Hz, NH), 5.74 (1H, dd, J ¼ 2:0 Hz, 9.0 Hz,
CHN), 4.63 (1H, d, J ¼ 2:0 Hz, CHO), 3.84 (3H, s,
A 1 M solution in THF in tetrabutylammonium fluoride
(1.1 mL) was added dropwise to a solution of (4S,5R)-5-
([1-(tert-butyl)-1,1-diphenylsilyl]-oxy-methyl)-2,4-diphen-
yl-1,3-oxazoline 12 (1 mmol) in dry THF (21 mL). The
mixture was stirred for 1 h, then treated with a saturated
solution of NaHCO3 (2 mL), diluted with ethyl acetate
and extracted. The organic layer was dried over Na2SO4,
filtered and concentrated. The crude product was puri-
fied by flash chromatography, using diethyl ether/
petroleum ether (3:1) as eluant. Time 1 h, yield 94%,
foam. 1H NMR (CDCl3): d 8.03–7.20 (10H, m, Ph), 5.02
(1H, d, J ¼ 7:4 Hz, CHN), 4.49 (1H, ddd, J ¼ 7:4 Hz,
J ¼ 5:4 Hz, J ¼ 3:8 Hz, CHO), 3.78 (1H, dd, J ¼ 3:8 Hz,
J ¼ 12:2 Hz, CH2O), 3.66 (1H, dd, J ¼ 5:4 Hz,
CH3), 3.26 (1H, br s, OH). IR (KBr): 1740, 1640 cmꢁ1
.
26
½aꢀ )48 (c 0.92, CH3OH). MS: 300 (Mþ+1).
D
Acknowledgements
Support from the Research Training Network (HPRN-
CT-2000-00018) ÔDesign and Synthesis of Novel Paclit-
axel (Taxolꢁ) Mimics Using a Common Pharmacophore
Model for Microtubule-stabilising Anticancer Agents
(MSAAs)Õ and FIRB (RBAU01LR5P) ÔDevelopment of
J ¼ 12:2 Hz, CH2O). IR (KBr): 3248, 1649 cmꢁ1
.
20
D
½aꢀ )26.6 (c 1.4). MS: 253 (Mþ), 193 (100%). Anal.

D. Castagnolo et al. / Tetrahedron: Asymmetry 15 (2004) 941–949
949
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R. D.; Reider, P. J. Org. Chem. 2001, 66, 3634–3635.
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a Common Pharmacophore Model for Microtubule-
stabilising Anticancer Agents to be used to Design and
Synthesise Novel Paclitaxel MimicsÕ are gratefully
acknowledged. We are also indebted to Indena S.p.A.
(Milano, Italy) for the financial support. One of us
(M.B.) thanks the Merck Research Laboratories for the
2002 Academic Development Program (ADP) Chemis-
try Award.
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