Asymmetric synthesis of 5-isopropyl-oxazoline-4-imide as syn-hydroxyleucine precursor

Article abstract of DOI:10.1016/S0957-4166(01)00084-2

The synthesis of syn N-acetyl-hydroxyleucinemethyl ester is reported through the ring expansion of aziridine-2-imides to oxazoline-4-imides. The key steps of the synthesis are the 1,4-addition of O-benzylhydroxylamine to unsaturated imides, promoted by Le

Full text of DOI:10.1016/S0957-4166(01)00084-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 563–569
Asymmetric synthesis of 5-isopropyl-oxazoline-4-imide as
syn-hydroxyleucine precursor
Giuliana Cardillo,* Luca Gentilucci, Massimo Gianotti and Alessandra Tolomelli
Dipartimento di Chimica ‘G.Ciamician’ and C.S.F.M., Universita` di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 19 December 2000; accepted 20 February 2001
Abstract—The synthesis of syn N-acetyl-hydroxyleucine methyl ester is reported through the ring expansion of aziridine-2-imides
to oxazoline-4-imides. The key steps of the synthesis are the 1,4-addition of O-benzylhydroxylamine to unsaturated imides,
promoted by Lewis acids, and the regio- and stereoselective ring expansion of trans-aziridines to trans-oxazolines. © 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
material in the synthesis of the neurotrophic factor
Lactacystin9 (Fig. 1).
We have recently developed a new general method to
prepare stereospecifically substituted oxazoline1 deriva-
tives which were used in the synthesis of naturally
occurring non-proteinogenic b-hydroxy-a-amino acids.2
Our strategy starts from the diastereoselective b-intro-
duction of O-benzylhydroxylamine to a,b-unsaturated
chiral imidates.3 The diastereoselectivity of this step can
be controlled by the use of (4S,5R)- or (4R,5S)-1,5-
dimethyl-4-phenylimidazolidin-2-one as a chiral auxil-
iary,4 that is commercially available in both
enantiomerically pure forms. The 1,4-addition is fol-
lowed by cyclisation to aziridines obtained in exclusive
trans-configuration.5 Their activation through N-acyla-
tion allowed ring expansion to the corresponding trans-
oxazolines.6 Since the configuration of the two new
stereogenic centres exclusively depends on the initial
addition of the nitrogen derivative, the chiral auxiliary
and the Lewis acid selected for the 1,4-addition deter-
mine the stereochemical outcome of the whole
sequence.
2. Results and discussion
The conjugate addition of nucleophiles to electron
deficient a,b-unsaturated carboxylic acid derivatives
provides an important route to b-substituted carbonyl
compounds.10 We have previously investigated the
nucleophilic 1,4-addition and in our experience the rate
of addition and the diastereomeric ratio strongly
depend on the unsaturated substrate and on the Lewis
acid selected.3a Concerning the addition of O-benzylhyd-
roxylamine to 4-methylpentenoyl imidate, several Lewis
acids have been tested in order to find the optimal
conditions in terms of diastereomeric ratio and yield
(Scheme 1). Some results are reported in Table 1.
Herein, we report the synthesis of the enantiomeric
trans-oxazolines 9 and 11. Oxazoline 9 is a protected
form of the corresponding b-hydroxy-a-amino acid,
which is present in the antibiotic Lysobactin,7 whose
total synthesis is the object of much interest in our
laboratory;8 11 has been recently reported as a starting
* Corresponding author. Fax: +39 051 2099456; e-mail: cardillo@
ciam.unibo.it
Figure 1.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00084-2

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G. Cardillo et al. / Tetrahedron: Asymmetry 12 (2001) 563–569
Scheme 1.
Table 1. Conjugate addition of O-benzylhydroxylamine to 1
Entry
Lewis acid (equiv.)
T (°C)
Time (h)
Yielda (%)
D.r.b 2/3
1
2
3
4
5
6
AlMe2Cl (1.1)
TiCl4 (1.1)
MgBr2·Et2O (0.5)
Sc(OTf)3 (0.05)
BF3·Et2O (1)
BF3·Et2O (2)
−78 to rt
−60 to rt
−10 to rt
−10 to rt
−10 to rt
−10 to rt
18
18
18
18
72
72
95
10
95
70
50
70:30
46:54
75:25
65:35
90:10
90:10
\95
a Calculated on isolated compounds.
1
b The diastereomeric ratio was determined at H NMR through the evaluation of the signal corresponding to the H4 in the chiral imidazolidinone
for 2 (5.23 ppm) and 3 (5.15 ppm).
When AlMe2Cl or MgBr2·Et2O were used as Lewis
acids, the conversion was almost quantitative and the
preferential formation of 2 was observed (entries 1 and
3). On the other hand, performing the reaction in the
presence of TiCl4 proceeded slowly and with a very low
diastereoselectivity (entry 2) affording 3 in slight excess.
When Sc(OTf)3 was used as catalyst, the preferential
formation of 2 was observed and a good yield was
obtained even with a catalytic amount of Lewis acid
(entry 4). In general, the presence of the bulky isopro-
pyl group lowered both the reaction rate and the d.r. in
comparison to addition to crotonyl or acryloyl imidates
(entry 1–5).3 In fact, in this case we observed incom-
plete conversion of the starting material to hydroxyl-
amino derivatives even after long reaction times. On
the other hand, better results have been obtained utilis-
ing 2 equivalents of BF3·Et2O over 3 days. Under these
conditions complete conversion and 9:1 d.r. was
observed. These results are surprising since 2 was
obtained as the major isomer in both aluminium or
magnesium and boron catalysed reactions. Considering
the behaviour of aluminium and magnesium, chelated
intermediate structures have previously been proposed11
and confirmed by us3 and Castellino11c through NMR
analysis. In these cases, as a consequence of the coordi-
nation of both carbonyl groups of unsaturated imides,
nucleophilic attack on the less hindered face of the
substrate–Lewis acid complex is preferred. In contrast,
boron has long been regarded as a non-chelating Lewis
acid and a reversal of diastereoselectivity would be
expected.12 The separation of 2 and 3 is not easy, so
cyclisation to the corresponding aziridines was per-
formed directly on the diastereomeric mixture using
AlMe2Cl and triethylamine in CH2Cl2, following our
previously reported protocol.3b,5 This reaction afforded
the two trans-aziridines 4 and 5 in 60% yield, the rest
being unreacted starting material. The diastereomeric
aziridines were separated by flash chromatography on
silica gel (Scheme 2).
In order to prepare N-activated aziridines, each deriva-
tive was then treated with benzoyl chloride and triethyl-
amine in CH2Cl2. Enantiomerically pure N-benzoyl-
aziridines 6 and 7 were obtained after purification by
flash chromatography in 86 and 88% yields, respec-
tively.
Scheme 2.

G. Cardillo et al. / Tetrahedron: Asymmetry 12 (2001) 563–569
565
The ring expansion reaction of 6 and 7 to the corre-
sponding trans-oxazolines easily occurs, under com-
plete regio- and stereocontrol, by treatment with boron
trifluoride–Et2O in CH2Cl2.13 The ring expansion of
N-acyl-aziridines is a well known behaviour for this
class of compounds and the mechanistic aspects of this
reaction have been recently discussed by Hori et al.6a
and by Lectka et al.6b,c We have successfully applied
this kind of rearrangement in the synthesis of hydrox-
yamino acids present in the antibiotic Lysobactin. Oxa-
zoline 8 was obtained from aziridine 6 as the exclusive
product in 98% yield. To confirm the regiochemical
course of the ring expansion reaction, 8 was stirred in
refluxing MeOH in the presence of triethylamine.14 This
allowed complete removal and subsequent recovery of
the chiral auxiliary and furnished the oxazoline methyl
ester 9 in 94% yield. Comparison of the spectroscopic
data and the specific rotation of 9 with the data
reported in the literature confirmed both the regio- and
stereochemical assignments9 (Scheme 3).
tion of the aqueous layer and extraction with CH2Cl2
(Scheme 4). The H NMR of compound 11 shows the
exclusive presence of the trans-isomer, thus showing
1
that the reaction proceeds without any racemisation.
Aziridine 4 was also transformed into its N-acetyl
derivative by treatment with acetyl chloride and triethy-
lamine in CH2Cl2. The activated aziridine product 12
rapidly rearranged to the corresponding trans-oxazoline
13 in the presence of BF3·Et2O in CH2Cl2 solvent. Ring
expansion occurs as usual with complete regiocontrol
and retention of configuration. The removal of the
chiral imidazolidinone auxiliary, performed with tri-
ethylamine in refluxing MeOH, allowed us to obtain
the oxazoline methyl ester 14. During purification by
flash chromatography on silica gel, spontaneous
hydrolysis of the oxazoline ring occurred and (2S,3R)-
N-acetyl-isoleucine methyl ester 15 was isolated in 90%
yield (Scheme 5). No racemisation products were
detected from the reaction mixture.
The ring expansion of aziridine 7 to oxazoline was
performed following the protocol reported above. In
this case the trans-oxazoline 10 was isolated in 95%
yield and subsequently treated with LiOOH in THF/
H2O.15 The chiral imidazolidinone auxiliary was recov-
ered in 90% yield from the basic organic layer, while
oxazoline 11 was obtained in 95% yield after acidifica-
3. Conclusion
We have reported a methodology for the synthesis of
syn-hydroxyleucine through the 1,4-addition of O-ben-
zylhydroxylamine to a,b-unsaturated imides, followed
by the cyclisation to trans-aziridines and ring expansion
Scheme 3.
Scheme 4.
Scheme 5.

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G. Cardillo et al. / Tetrahedron: Asymmetry 12 (2001) 563–569
to trans-oxazolines. The conjugate addition step is
fundamental to the determination of the stereochem-
istry of the final product, since different enantiomers
can be obtained by changing the configuration of the
chiral auxiliary. The transformation of the addition
products into aziridines and the ring expansion to
oxazolines occurs with complete regio- and stereocon-
trol. The removal of the imidazolidinone auxiliary was
performed following two different pathways in order
to obtain oxazoline-4-esters and oxazoline-4-acids,
which are useful precursors of syn-hydroxyleucine.
4.3. (4S,5R,3%R)-3-(3%-Benzyloxylamino-4%-methylpent-
anoyl)-1,5-dimethyl-4-phenylimidazolidin-2-one 2 and
(4S,5R,3%S)-3-(3%-benzyloxylamino-4%-methylpentanoyl)-
1,5-dimethyl-4-phenylimidazolidin-2-one 3
A mixture of 1 (1 g, 3.5 mmol) and Lewis acid in
CH2Cl2 (15 mL) was stirred under an inert atmo-
sphere. The amount of Lewis acid and the tempera-
ture of choice are reported in Table 1. After 30 min
NH2OBn (10.5 mL, 0.5 M in CH2Cl2, 5.25 mmol) was
added and the reaction mixture was stirred for the
time stated in Table 1, while the mixture was allowed
to warm to rt. The reaction was quenched with sat.
NaHCO3 (10 mL) and extracted with CH2Cl2. The
collected organic layers were dried over Na2SO4 and
the solvent was evaporated under reduced pressure.
Compounds 2 and 3 were purified by flash chro-
matography on silica gel (cyclohexane:EtOAc, 8:2)
and obtained as a mixture with the yield and the d.r.
reported in Table 1.
4. Experimental
4.1. General
Unless otherwise stated chemicals were obtained from
commercial sources and used without further purifica-
tion. CH2Cl2 was distilled from P2O5. Flash chro-
matography was performed on Merck silica gel 60
(230–400 mesh). NMR spectra were recorded with a
Gemini Varian spectrometer at 300 or 200 MHz (1H
NMR) and at 75 MHz (13C NMR). Chemical shifts
were reported as l values relative to the residual sol-
vent peak of CDCl3 set at l=7.27 (1H NMR) or
l=77.0 (13C NMR). Infrared spectra were recorded
with an FT-IR Nicolet 205 spectrometer. GC–MS
analysis were performed on HP5890 series II chro-
matograph with a HP5971 mass detector. Optical
rotation powers were recorded with Perkin–Elmer
polarimeter 343. 4-Methyl-pentenoyl chloride was pre-
pared following a procedure reported in the litera-
ture.16
1
(3%R)-2: IR (Nujol) w 3480, 1719, 1673, 1383 cm−1; H
NMR (CDCl3) l 0.76 (d, 3H, J=6.6 Hz); 0.91 (d,
3H, J=6.9 Hz); 0.93 (d, 3H, J=6.9 Hz); 1.94–2.23
(m, 1H); 2.80 (s, 3H); 3.00–3.28 (m, 3H); 3.80 (dq, 1H,
J=6.6 Hz, 8.7 Hz); 4.58 (s, 2H); 5.23 (d, 1H,
J=8.7 Hz); 5.80–6.05 (bs, 1H); 7.05–7.60 (m, 10H);
13C NMR (CDCl3) l 14.9, 17.9, 19.4, 28.1, 28.9, 34.2,
53.8, 59.4, 62.4, 76.0, 126.9, 127.4, 128.0, 128.2, 128.2,
128.3, 136.5, 138.1, 155.8, 172.0; MS (m/z): 409 (M+,
2), 366 (9), 302 (7), 232 (8), 191 (36), 132 (11), 91
(100), 58 (18); C24H31N3O3 (409.52); calcd: C, 70.39;
H, 7.63; N, 10.26. Found: C, 70.34; H, 7.65; N,
10.29%.
1
4.2. (4S,5R)-3-(4%-Methyl-pentenoyl)-1,5-dimethyl-4-
(3%S)-3: IR (Nujol) w 3480, 1719, 1673, 1383 cm−1; H
phenylimidazolidin-2-one 1
NMR (CDCl3) l 0.72 (d, 3H, J=6.6 Hz); 0.91 (d,
3H, J=6.9 Hz); 0.93 (d, 3H, J=6.9 Hz); 1.94–2.23
(m, 1H); 2.76 (s, 3H); 3.00–3.28 (m, 3H); 3.62 (m,
1H); 4.58 (s, 2H); 5.15 (d, 1H, J=8.4 Hz); 5.45–5.60
(bs, 1H); 7.05–7.60 (m, 10H); 13C NMR (CDCl3) l
14.9, 18.1, 19.4, 28.1, 29.1, 34.5, 53.7, 59.4, 62.4, 75.8,
126.9, 127.4, 127.9, 128.0, 128.2, 128.2, 128.3, 136.6,
138.1, 155.8, 172.0; MS (m/z): 409 (M+, 2), 366 (9),
302 (7), 232 (8), 191 (36), 132 (11), 91 (100), 58 (18);
C24H31N3O3 (409.52); calcd: C, 70.39; H, 7.63; N,
10.26. Found: C, 70.34; H, 7.65; N, 10.29%.
A mixture of (4S,5R)-1,5-dimethyl-4-phenylimidazo-
lidin-2-one (2.00 g, 10.5 mmol), 4-methyl-pentenoyl
chloride (1.53 g, 11.6 mmol), diisopropyl ethyl amine
(2.02 mL, 11.6 mmol), and catalytic CuCl in dry
CH2Cl2 (10 mL) was stirred under reflux under an
inert atmosphere. After 6 h water (10 mL) was added
and the mixture was extracted three times with
CH2Cl2. The collected organic layers were dried over
Na2SO4 and the solvent was evaporated under
reduced pressure. The oily residue was purified by
flash chromatography (cyclohexane:EtOAc, 9:1) afford-
ing 1 (3.15 g, 95%).
4.4. (4S,5R,2%S,3%R)-1,5-Dimethyl-4-phenyl-3-[(2%-
aziridinyl-3%-isopropyl)carbonyl]-imidazolidin-2-one 4
and (4S,5R,2%R,3%S)-1,5-dimethyl-4-phenyl-3-[(2%-
aziridinyl-3%-isopropyl)carbonyl]-imidazolidin-2-one 5
(4S,5R)-1: IR (Nujol) w 1716, 1669, 1628 cm−1; 1H
NMR (CD2Cl2) l 0.78 (d, 3H, J=6.6 Hz); 1.06 (d,
3H, J=6.9 Hz); 2.43–2.58 (m, 1H); 2.80 (s, 3H); 3.90
(dq, 1H, J=6.6 Hz, 8.7 Hz); 5.32 (d, 1H, J=8.7 Hz);
6.90 (dd, 1H, J=6.6 Hz, 15.3 Hz); 7.14–7.35 (m, 5H);
7.44 (d, 1H, J=15.3 Hz); 13C NMR (CD2Cl2) l 15.1,
21.5, 21.6, 28.3, 31.6, 54.1, 119.6, 127.3, 128.0, 128.6,
137.6, 155.0, 156.1, 165.1; [h]2D0=+40.4 (c 1.1; CHCl3);
MS (m/z): 286 (M+, 73), 217 (6), 191 (100), 132 (24),
117 (21), 96 (64); C17H22N2O2 (286.37); calcd: C,
71.30; H, 7.74; N, 9.78. Found: C, 71.28; H, 7.75; N,
9.77%.
To a solution of 2 and 3 (0.87 g, 2.12 mmol) in
CH2Cl2 (15 mL), AlMe2Cl (2.33 mL, 1 M in hexane,
2.33 mmol) in CH2Cl2 (4 mL) was added dropwise at
0°C. The mixture was stirred for 20 min and then
added via cannula to a solution of triethylamine (0.59
mL, 4.24 mmol) in CH2Cl2 (5 mL) at 0°C over 5 min.
The reaction was quenched after 3 h with sat.
NaHCO3 (10 mL) and the mixture was extracted
three times with CH2Cl2. The collected organic layers
were dried over Na2SO4 and the solvent was evapo-

G. Cardillo et al. / Tetrahedron: Asymmetry 12 (2001) 563–569
567
rated under reduced pressure. The mixture was purified
by flash chromatography (AcOEt:cyclohexane, 7:3) giv-
ing 4 and 5 in a 60% yield. The ratio between 4 and 5
corresponds to the ratio between 2 and 3 in the starting
material.
(4S,5R,2%R,3%S)-7 (0.36 g, 88%): IR (film) w 2940, 1786,
1
1731, 1687, 1374, 1215 cm−1; H NMR (CDCl3) l 0.71
(d, 3H, J=6.6 Hz); 1.09 (d, 3H, J=6.7 Hz); 1.13 (d, 3H,
J=6.7 Hz); 1.76–1.88 (m, 1H); 2.82–2.85 (m, 1H); 2.85
(s, 3H); 3.88 (dq, 1H, J=6.6 Hz, 8.7 Hz); 4.98 (d, 1H,
J=3.0 Hz); 5.10 (d, 1H, J=8.7 Hz); 6.63–6.78 (m, 2H);
6.95–7.41 (m, 6H); 7.72–7.82 (m, 2H); 13C NMR (CDCl3)
l 14.9, 19.2, 19.9, 28.2, 30.2, 41.6, 49.8, 54.0, 59.4, 126.1,
127.3, 128.1, 131.8, 133.9, 135.2, 155.2, 166.5, 176.2;
[h]2D0=+106.8 (c 1.0; CHCl3); MS (m/z) 405 (M+, 2), 362
(11), 300 (9), 191 (17), 105 (83), 91 (32), 77 (100);
C24H27N3O3 (405.49); calcd: C, 71.09; H, 6.71; N, 10.36.
Found: C, 71.08; H, 6.74; N, 10.34%.
(4S,5R,2%S,3%R)-4: IR (film) w 3056, 1724, 1667, 1382
cm−1; 1H NMR (CDCl3) l 0.82 (d, 3H, J=6.6 Hz); 1.03
(d, 3H, J=6.7 Hz); 1.04 (d, 3H, J=6.7 Hz); 1.39–1.51
(m, 1H); 1.73 (bs, 1H); 1.93 (dd, 1H, J=2.4 Hz, 7.5 Hz);
2.87 (s, 3H); 3.86 (d, 1H, J=2.4 Hz); 3.96 (dq, 1H, J=6.6
Hz, 8.7 Hz); 5.32 (d, 1H, J=8.7 Hz); 7.14–7.42 (m, 5H);
13C NMR (CDCl3) l 15.2, 19.6, 20.1, 28.3, 31.5, 35.0,
47.8, 54.1, 59.4, 126.9, 128.3, 128.6, 136.1, 155.6, 171.3;
[h]2D0=+79.7 (c 1.0; CHCl3); MS (m/z) 301 (M+, 20), 258
(20), 231 (20), 191 (100); C17H23N3O2 (301.38) calcd: C,
67.75; H, 7.69; N, 13.94. Found: C, 67.78; H, 7.66; N,
13.93%.
4.6. (4S,5R,4%S,5%R)-4,5-Dihydro-2-phenyl-4-[(1%,5%-
dimethyl-4%-phenylimidazolidin-2%-on-3%-yl)carbonyl]-5-
isopropyl-oxazole 8 and (4R,5S,4%S,5%R)-4,5-dihydro-
2-phenyl-4-[(1%,5%-dimethyl-4%-phenylimidazolidin-2%-on-3%-
yl)carbonyl]-5-isopropyl-oxazole 10
(4S,5R,2%R,3%S)-5: IR (film) w 2967, 1724, 1670, 1386
cm−1; 1H NMR (CDCl3) l 0.82 (d, 3H, J=6.6 Hz); 1.02
(d, 3H, J=6.7 Hz); 1.04 (d, 3H, J=6.7 Hz); 1.38–1.47
(m, 1H); 1.74 (dd, 1H, J=2.1 Hz, 7.5 Hz); 1.75 (bs, 1H);
2.86 (s, 3H); 3.84 (d, 1H, J=2.1 Hz); 3.99 (dq, 1H, J=6.6
Hz, 8.4 Hz); 5.25 (d, 1H, J=8.4 Hz); 7.07–7.42 (m, 5H);
13C NMR (CDCl3) l 14.9, 19.5, 20.0, 28.1, 31.5, 35.3,
47.5, 54.5, 59.7, 127.1, 128.1, 128.5, 136.2, 155.8, 171.2;
[h]2D0=+78.6 (c 0.6; CHCl3); MS (m/z) 301 (M+, 24), 258
(23), 231 (18), 191 (100); C17H23N3O2 (301.38); calcd: C,
67.75; H, 7.69; N, 13.94. Found: C, 67.74; H, 7.69; N,
13.91%.
To a solution of 6 or 7 (0.20 g, 0.49 mmol) in CH2Cl2
(7 mL), BF3·Et2O (62 mL, 0.49 mmol) was added at rt.
After 1 h the reaction was quenched with sat. NaHCO3
(4 mL), extracted three times with CH2Cl2 and dried over
Na2SO4. The solvent was evaporated under reduced
pressure and 8 or 10 was obtained pure after flash
chromatography (EtOAc:cyclohexane, 1:1).
(4S,5R,4%S,5%R)-8 (0.195 g, 98%): IR (film) w 2926, 1739,
1713, 1686, 1375 cm−1; 1H NMR (CDCl3) l 0.81 (d, 3H,
J=6.6 Hz); 0.96 (d, 3H, J=6.7 Hz); 0.99 (d, 3H, J=6.7
Hz); 1.94–2.05 (m, 1H); 2.87 (s, 3H); 3.95 (dq, 1H, J=6.6
Hz, 8.7 Hz); 4.86 (ddꢀt, 1H, J=6.0 Hz); 5.37 (d, 1H,
J=8.7 Hz); 6.05 (d, 1H, J=6.0 Hz); 7.20–7.45 (m, 8H);
7.92–7.95 (m, 2H); 13C NMR (CDCl3) l 15.3, 17.1, 17.9,
28.3, 32.0, 53.9, 59.3, 70.4, 85.9, 126.9, 127.5, 127.9,
128.3, 128.4, 131.1, 135.7, 155.1, 165.0, 170.1; [h]2D0=
+137.5 (c 0.4; CHCl3); MS (m/z): 405 (M+, 20), 362 (100),
215 (12), 191 (46), 188 (21), 104 (59), 76 (43), 57 (5), 43
(36); C24H27N3O3 (405.49); calcd: C, 71.09; H, 6.71; N,
10.36. Found: C, 71.10; H, 6.71; N, 10.33%.
4.5. (4S,5R,2%S,3%R)-1,5-Dimethyl-4-phenyl-3-[(2%-N-
benzoyl-aziridinyl-3%-isopropyl)carbonyl]-imidazolidin-2-
one 6 and (4S,5R,2%R,3%S)-1,5-dimethyl-4-phenyl-
3-[(2%-N-benzoyl-aziridinyl-3%-isopropyl)carbonyl]-imida-
zolidin-2-one 7
Benzoyl chloride (0.13 mL, 1.1 mmol) in CH2Cl2 (2 mL)
was added dropwise to a stirred solution of 4 or 5 (0.3
g, 1 mmol) and triethylamine (0.27 mL, 2 mmol) in
CH2Cl2 (5 mL) at 0°C. The mixture was stirred for 2 h
at room temperature and then rinsed twice with water.
The organic layer, dried over anhydrous Na2SO4, was
concentrated under reduced pressure. Aziridine 6 or 7
was purified by flash chromatography on silica gel
(AcOEt:cyclohexane, 7:3).
(4R,5S,4%S,5%R)-10 (0.190 g, 95%): IR (film) w 2933, 1732,
1686, 1640, 1393 cm−1; 1H NMR (CDCl3) l 0.82 (d, 3H,
J=6.6 Hz); 0.95 (d, 3H, J=6.7 Hz); 0.98 (d, 3H, J=6.7
Hz); 1.98–2.10 (m, 1H); 2.88 (s, 3H); 3.99 (dq, 1H, J=6.6
Hz, 8.2 Hz); 4.65 (ddꢀt, 1H, J=6.9 Hz); 5.31 (d, 1H,
J=8.2 Hz); 6.19 (d, 1H, J=6.9 Hz); 7.08–7.18 (m, 2H);
7.20–7.48 (m, 6H); 7.87–7.98 (m, 2H); 13C NMR (CDCl3)
l 14.9, 17.3, 17.8, 28.2, 32.1, 53.8, 59.8, 69.5, 87.4, 126.8,
128.0, 128.1, 128.5, 131.3, 136.5, 155.3, 165.7, 170.6;
[h]2D0=−4.8 (c 1.3; CHCl3); MS (m/z): 405 (M+, 20), 362
(100), 215 (12), 191 (46), 188 (21), 104 (59), 76 (43), 57
(5), 43 (36); C24H27N3O3 (405.49); calcd: C, 71.09; H,
6.71; N, 10.36. Found: C, 71.06; H, 6.74; N, 10.36%.
(4S,5R,2%S,3%R)-6 (0.35 g, 86%): IR (film) w 2959, 1787,
1
1731, 1689, 1375, 1214 cm−1; H NMR (CDCl3) l 0.73
(d, 3H, J=6.6 Hz); 1.08 (d, 3H, J=6.7 Hz); 1.10 (d, 3H,
J=6.7 Hz); 1.80–1.92 (m, 1H); 2.69 (dd, 1H, J=2.7 Hz,
6.6 Hz); 2.85 (s, 3H); 3.73 (dq, 1H, J=6.6 Hz, 8.4 Hz);
4.98 (d, 1H, J=8.4 Hz); 4.99 (d, 1H, J=2.7 Hz);
6.97–7.08 (m, 2H); 7.21–7.52 (m, 6H); 7.93–8.01 (m, 2H);
13C NMR (CDCl3) l 14.6, 18.6, 19.7, 28.0, 29.8, 41.2,
49.7, 53.9, 59.1, 126.5, 128.0, 128.2, 128.4, 131.8, 134.3,
135.7, 155.3, 166.3, 176.2; [h]2D0=+178.0 (c 1.5; CHCl3);
MS (m/z) 405 (M+, 2), 362 (11), 300 (9), 191 (17), 105
(83), 91 (32), 77 (100); C24H27N3O3 (405.49); calcd: C,
71.09; H, 6.71; N, 10.36. Found: C, 71.11; H, 6.69; N,
10.35%.
4.7. (4S,5R)-Methyl 5-isopropyl-2-phenyl-4,5-dihydro-
oxazole-4-carboxylate 9
A solution of 8 (0.1 g, 0.25 mmol) and triethylamine (0.2
mL, 1.5 mmol) in MeOH (5 mL) was stirred under reflux

568
G. Cardillo et al. / Tetrahedron: Asymmetry 12 (2001) 563–569
for 2 h. After removing the solvent under reduced
pressure, the residue was dissolved in EtOAc and
washed twice with water. The organic layer was dried
over Na2SO4 and the solvent was removed. Purification
by flash chromatography allowed recovery of the chiral
imidazolidinone (47 mg, 99%) and isolation of oxazo-
line 9 in 94% yield (58 mg).
J=6.8 Hz); 1.58–1.80 (m, 1H); 1.67 (s, 3H); 2.59 (dd,
1H, J=2.6 Hz, 7.0 Hz); 2.88 (s, 3H); 3.94 (dq, 1H,
J=6.6 Hz, 8.8 Hz); 4.66 (d, 1H, J=2.6 Hz); 5.30 (d,
1H, J=8.8 Hz); 7.14–7.21 (m, 2H); 7.24–7.40 (m, 3H);
13C NMR (CDCl3) l 15.1, 19.1, 19.7, 24.0, 28.3, 30.2,
39.7, 50.8, 54.1, 59.5, 126.9, 128.2, 128.4, 135.9, 155.2,
167.2, 177.4; [h]2D0=+143.6 (c=1.4; CHCl3); MS (m/z)
343 (M+, 2), 330 (9), 300 (12), 191 (100), 102 (43), 43
(90); C19H25N3O3 (343.42); calcd: C, 66.45; H, 7.34; N,
12.24. Found: C, 66.44; H, 7.36; N, 12.21%.
1
(4S,5R)-9: IR (film) w 1743, 1645, 1451, 1262 cm−1; H
NMR (CDCl3) l 1.01 (d, 3H, J=6.7 Hz); 1.04 (d, 3H,
J=6.7 Hz); 1.91–2.02 (m, 1H); 3.82 (s, 3H); 4.58 (d,
1H, J=6.6 Hz); 4.69 (ddꢀt, 1H, J=6.6 Hz); 7.39–7.53
(m, 3H); 7.96–8.02 (m, 2H); 13C NMR (CDCl3) l 17.3,
17.4, 32.4, 52.7, 71.2, 87.2, 128.2, 128.5, 131.7, 165.8,
171.9; [h]2D0=+102.5 (c 0.4; CHCl3); MS (m/z) 247 (M+,
4), 188 (41), 175 (14), 105 (80), 77 (100), 43 (74);
C14H17NO3 (247.29); calcd: C, 68.00; H, 6.93; N, 5.66.
Found: C, 68.02; H, 6.96; N, 5.67%.
4.10. (4S,5R,4%S,5%R)-4,5-Dihydro-2-methyl-4-[(1%,5%-
dimethyl-4%-phenylimidazolidin-2%-on-3%-yl)carbonyl]-5-
isopropyl-oxazole 13
To a solution of 12 (0.20 g, 0.58 mmol) in CH2Cl2 (7
mL), BF3·Et2O (73 mL, 0.58 mmol) was added at rt.
After 1 h the reaction was quenched with sat. NaHCO3
(4 mL), extracted three times with CH2Cl2 and dried
over Na2SO4. The solvent was evaporated under
reduced pressure and 13 was obtained pure after flash
chromatography (EtOAc:cyclohexane, 1:1).
4.8. (4R,5S)-5-Isopropyl-2-phenyl-4,5-dihydrooxazole-4-
carboxylic acid 11
To a mixture of 10 (0.1 g, 0.25 mmol) in THF (4 mL)
and water (1 mL), H2O2 (0.1 mL, 30% p/v, 1 mmol)
and LiOH (12 mg, 0.5 mmol) were added at 0°C. The
mixture was stirred at rt for 1 h. The reaction was
quenched with sat. Na2SO3 (2 mL), and the mixture
was extracted with EtOAc. The organic layer was dried
over Na2SO4 and the solvent was removed under
reduced pressure to recover the chiral imidazolidinone
(42 mg, 90%). The aqueous layer was acidified to pH 2,
and extracted twice with EtOAc, then the solvent was
removed under reduced pressure giving 11 (55 mg,
95%).
(4S,5R,4%S,5%R)-13 (0.19 g, 95%): IR (film) w 1734, 1719,
1654, 1388 cm−1; 1H NMR (CDCl3) l 0.82 (d, 3H,
J=6.6 Hz); 0.90 (d, 3H, J=6.6 Hz); 0.94 (d, 3H, J=6.7
Hz); 1.85–1.92 (m, 1H); 1.96 (s, 3H); 2.87 (s, 3H); 3.95
(dq, 1H, J=6.6 Hz, 8.8 Hz); 4.70 (ddꢀt, 1H, J=6.2
Hz); 5.35 (d, 1H, J=8.8 Hz); 5.79 (bd, 1H, J=6.2 Hz);
7.20–7.40 (m, 5H); 13C NMR (CDCl3) l 13.9, 15.3,
17.1, 17.8, 28.3, 31.9, 53.9, 59.4, 70.2, 85.9, 127.0, 128.0,
128.4, 135.8, 155.0, 166.4, 170.2; [h]2D0=+275.6 (c=0.9;
CHCl3); MS (m/z): 343 (M+, 4), 300 (13), 289 (45), 191
(100), 188 (6), 76 (31), 58 (76), 43 (37); C19H25N3O3
(343.42); calcd: C, 66.45; H, 7.34; N, 12.24. Found: C,
66.42; H, 7.35; N, 12.24%.
(4R,5S)-11: IR (film) w 3423, 2924, 1733, 1652, 1264
cm−1; 1H NMR (CDCl3) l 1.03 (d, 3H, J=6.0 Hz); 1.04
(d, 3H, J=6.0 Hz); 1.95–2.09 (m, 1H); 4.61–4.75 (bm,
1H); 4.81–4.92 (bm, 1H); 6.60–7.2 (bs, 1H); 7.40–7.60
(m, 3H); 7.95–8.08 (m, 2H); 13C NMR (CDCl3) l 17.0
(2C), 29.7, 75.6, 80.0, 128.4, 128.7, 129.1, 133.4, 160.2,
173.0; [h]2D0=−45 (c=1.2; CHCl3); MS (m/z) 233 (M+,
1), 188 (42), 175 (11), 146 (36), 105 (83), 77 (100);
C13H15NO3 (233.26); calcd: C, 66.94; H, 6.48; N, 6.00.
Found: C, 66.96; H, 6.48; N, 6.02%.
4.11. (4S,5R)-Methyl 5-isopropyl-2-methyl-4,5-dihydro-
oxazole-4-carboxylate 14 and (2S,3R)-N-acetyl-
hydroxyleucine methyl ester 15
A solution of 13 (0.1 g, 0.29 mmol) and triethylamine
(0.24 mL, 1.75 mmol) in MeOH (5 mL) was refluxed
for 2 h. After removing the solvent under reduced
pressure, the residue was dissolved in EtOAc and rinsed
twice with water. The organic layer was dried over
Na2SO4 and the solvent was removed to give oxazoline
14 and the chiral imidazolidinone in the crude reaction
mixture. Purification by flash chromatography fur-
nished exclusively 15 in 90% yield (0.053 g).
4.9. (4S,5R,2%S,3%R)-1,5-Dimethyl-4-phenyl-3-[(2%-N-acet-
yl-aziridinyl-3%-isopropyl)carbonyl]-imidazolidin-2-one 12
Acetyl chloride (78 mL, 1.1 mmol) in CH2Cl2 (2 mL)
was added dropwise to a stirred solution of 4 (0.3 g, 1
mmol) and triethylamine (0.27 mL, 2 mmol) in CH2Cl2
(5 mL) at 0°C. The mixture was stirred for 2 h at room
temperature and then washed twice with water. The
organic layer, dried over anhydrous Na2SO4, was con-
centrated under reduced pressure. Aziridine 12 was
purified by flash chromatography on silica gel
(AcEtO:cyclohexane, 7:3).
1
(4S,5R)-14: H NMR (CDCl3) l 0.89 (d, 3H, J=7.2
Hz); 0.92 (d, 3H, J=7.2 Hz); 1.75–1.86 (m, 1H); 1.99 (s,
3H); 3.74 (s, 3H); 4.29 (d, 1H, J=6.9 Hz); 4.43 (ddꢀt,
1H, J=6.9 Hz).
(2S,3R)-15: IR (film) w 3421, 1732, 1686, 1640, 1391
cm−1; 1H NMR (CDCl3) l 0.95 (d, 3H, J=6.6 Hz); 1.02
(d, 3H, J=6.6 Hz); 1.62–1.75 (m, 1H); 2.08 (s, 3H);
3.73 (bdd, J=9.3 Hz, 2.0 Hz); 3.77 (s, 3H), 4.84 (dd,
1H, J=2.0 Hz, 9.5 Hz); 6.23 (d, 1H, J=9.5 Hz); 13C
NMR (CDCl3) l 18.9 (2C), 23.2, 30.9, 52.6, 54.0, 77.2,
170.3, 172.2; [h]2D0=+16.9 (c 0.4; CHCl3); MS (m/z):
(4S,5R,2%S,3%R)-12 (0.29 g, 84%): IR (film) w 2920, 1780,
1
1733, 1682, 1221 cm−1; H NMR (CDCl3) l 0.83 (d,
3H, J=6.6 Hz); 1.01 (d, 3H, J=6.8 Hz); 1.05 (d, 3H,

G. Cardillo et al. / Tetrahedron: Asymmetry 12 (2001) 563–569
569
144 (8), 131 (36), 99 (74), 59 (25), 43 (18); C9H17NO4
(203.24); calcd: C, 53.19; H, 8.43; N, 6.89. Found: C,
53.16; H, 8.44; N, 6.91%.
McCormick, T. J.; Unger, S. E. J. Org. Chem. 1989, 54,
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8. Armaroli, S.; Cardillo, G.; Gentilucci, L.; Gianotti, M.;
Tolomelli, A. Org. Lett. 2000, 2, 1105–1107.
9. (a) Nagamitsu, T.; Sunatura, T.; Tanaka, H.; Omura, S.;
Sprengeler, P. A.; Smith, III, A. B. J. Am. Chem. Soc.
1996, 118, 3584–3590; (b) Corey, E. J.; Choi, S. Tetra-
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C. E. Angew. Chem., Int. Ed. 1999, 38, 1093–1095.
10. (a) Perlmutter, P. Conjugate Addition Reactions in
Organic Synthesis; Pergamon Press: Oxford, 1992. For
recent examples of conjugate addition of nitrogen nucle-
ophile, see: (b) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse,
C. P. J. Am. Chem. Soc. 1998, 120, 6615–6616; (c)
Falborg, L.; Jørgensen, K. A. J. Chem. Soc., Perkin
Trans. 1 1996, 2823–2826; (d) Bunnage, M. E.; Davies, S.
G.; Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1993,
1375–1376.
11. (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am.
Chem. Soc. 1988, 110, 1238–1256; (b) Snider, B. B.;
Zhang, Q. J. Org. Chem. 1991, 56, 4908; (c) Castellino,
S.; Dwight, W. J. J. Am. Chem. Soc. 1993, 115, 2986–
2987.
12. The structure of boron–imidate complexes is currently
under investigation. For some examples on boron com-
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hedron Lett. 1984, 25, 729–732; (b) Hunsken, J.;
Goddard, R.; Reetz, M. T. J. Am. Chem. Soc. 1998, 120,
6617–6618.
13. The trans relationship was established on the basis of the
1H NMR coupling constants that are in agreement with
the data reported in the literature. The regiochemistry
was assigned on the basis of H4 and H5 chemical shifts,
by comparison with the data reported in the literature for
the same class of compounds, and was confirmed by the
structure determination of the protected hydroxyamino
acid (see Refs. 6d–6f).
14. Davies, S. G.; Dixon, D. J. Synlett 1998, 963–964.
15. Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 83–91.
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Leslie, C. P.; Morgan, I. T.; Peukert, S.; Sarkar, A. K. J.
Chem. Soc., Perkin Trans. 1 1996, 1171–1196; (b) Fad-
naris, N. W.; Sharfuddin, N.; Vadivel, S. K.; Bhalerao,
U. T. J. Chem. Soc., Perkin Trans. 1 1997, 11, 3577–3578.
Acknowledgements
Financial support from MURST (Cofin 2000 and 60%)
and from the University of Bologna (funds for selected
topics ‘Sintesi e Caratterizzazione di Biomolecole per la
Salute Umana’).
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