Crystallization-induced asymmetric transformations (CIAT): Stereoconvergent acid-catalyzed lactonization of substituted 2-amino-4-aryl-4-hydroxybutanoic acids

Article abstract of DOI:10.1016/j.tetasy.2005.04.024

Acid-catalyzed lactonization in dilute hydrochloric acid of N-substituted 2-amino-4-aryl-4-hydroxybutanoic acids with electron donating aryl substituents is stereoconvergent. The stereochemical outcome is controlled by the precipitation of little soluble

Full text of DOI:10.1016/j.tetasy.2005.04.024

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1927–1934
Crystallization-induced asymmetric transformations (CIAT):
stereoconvergent acid-catalyzed lactonization of substituted
2-amino-4-aryl-4-hydroxybutanoic acids
a
Dusan Berkes, Andrej Kolarovic, Robert Manduch,
b
ˇ
ˇ a,*
Peter Baran and Frantisek Povazˇanec
ˇ
c
a
ˇ
a
´
Department of Organic Chemistry, Slovak University of Technology, Radlinskeho 9, SK-812 37 Bratislava, Slovak Republic
bZentiva a.s., Nitrianska cesta 100, SK-920 27 Hlohovec, Slovak Republic
cDepartment of Chemistry, Juniata College, Huntingdon, PA 16652, USA
Received 28 January 2005; revised 22 April 2005; accepted 25 April 2005
Abstract—Acid-catalyzed lactonization in dilute hydrochloric acid of N-substituted 2-amino-4-aryl-4-hydroxybutanoic acids with
electron donating aryl substituents is stereoconvergent. The stereochemical outcome is controlled by the precipitation of little sol-
uble cis-lactones, starting from both syn-2-amino-4-aryl-4-hydroxybutanoic acids and anti-2-amino-4-aryl-4-hydroxybutanoic acids
or their mixtures. A highly diastereoselective two-step sequence (acid-catalyzed lactonization with CIAT process followed by alka-
line hydrolysis) for the transformation of syn-3b–d to the corresponding anti-3b–d is reported.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
This has been used for the synthesis of ACE inhibi-
tors13,14 as well as the synthesis of enantiomerically pure
homophenylalanines.15 The application of 1-phenyleth-
ylamine in such a transformation is especially favorable
as both the enantiomers of phenylethylamine are
readily available, with both antipodes of the final
compounds attainable. Recent applications of aza-
Michael-based CIAT processes have been elaborated
in our laboratory.16–19
The c-hydroxy-a-amino acid unit plays an important
role in biologically active substances. Among them the
c-aryl-c-hydroxy-a-amino acids and the related 4-aryl-
substituted 2-aminobutanolides form part of the anti-
fungal agents such as nikkomycines,1 echinocandins2–4
or immunosuppressive cymbimycins5 and have been
used as unnatural acids in peptidomimetics and in the
site-directed mutagenesis studies.6
The reduction of c-oxo-a-amino acids or their esters was
realized with different types of reducing agents. In the
case of c-arylsubstituted c-oxo-a-aminobutanoic acids
or esters, the best diastereoselectivity in favor of the
anti-isomer was achieved using Et3SiH under acidic con-
ditions (54:7 or 90:10).20,21
The preparation of such hydroxy substituted amino
acids remains a significant synthetic challenge. The key
intermediates for their synthesis are enantiomerically
pure aroylalanines. Such alanines are readily available
via a chiral pool approach using aspartic acid7,8 and
serine9 as the source of chirality or alternatively via
enantioselective alkylation of 2-imino esters.10–12 This
efficient synthetic method represents a sequence consist-
ing of an aza-Michael addition coupled to the crystalli-
zation-induced asymmetric transformation (CIAT).
We have developed the highly diastereoselective cata-
lytic reduction of N-alkyl substituted aroylalanines 2
leading to the corresponding syn-c-aryl-c-hydroxy-a-
amino acids.22 The stereoselectivity of the reduction
can be interpreted in terms of chelate formation with a
manganese(II) salt, followed by an axial attack of the
hydride on the half-chair transition state, which favors
the formation of a chair conformation (Fig. 1).
*
Corresponding author. Tel.: +421 2 52968560; fax: +421 33
7361951; e-mail: dusan.berkes@stuba.sk
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.04.024

ˇ
D. Berkes et al. / Tetrahedron: Asymmetry 16 (2005) 1927–1934
1928
H-
tone hydrochlorides proceeds more easily. In the case
H
H
H
of 4-methoxysubstituted 3c and d, simple stirring of
the reaction mixture in 4 M HCl at 20–25 ꢁC for several
hours was sufficient. The tolyl substituted derivative 3b
requires prolonged reaction time and elevated tempera-
ture (50 ꢁC). Attempted lactonization of the phenyl
derivative 3a under the above mentioned conditions (c
0.05 M in 4 M HCl; 50 ꢁC) gives a mixture of the start-
ing material as well as both cis- and anti-lactones
together with the growing amount of b,c-unsaturated
(E)-4-phenyl-2-(1phenylethylamino)but-3-enoic acids.23
The solid butanolide trans-4a was obtained in reason-
able yield (68%) by increasing both the concentration
of 3a and hydrochloric acid (0.14 M in 8 M HCl;
20 ꢁC) (Scheme 1). Prepared butanolides 4a–d, unlike
starting syn-hydroxyamino acids 3a–d, are easy to han-
dle and can be further purified by crystallization.
Cl
Cl
R
NH
O
HOOC
HOOC
Ar
Mn
O
Mn
Cl
Cl
Ar
NH
R
Figure 1.
The chelation increases the solubility of the starting
oxoamino acids in reaction media and also augments
the reactivity of the carbonyl group. The catalytic
amount of MnCl2 was sufficient for the control of stereo-
selectivity in all the cases studied. Unfortunately, the
enantiomerically pure syn-c-hydroxy-a-amino acids
3a–d exhibited a high gelation ability, making their puri-
fication a tedious and time consuming operation. Herein,
we report their transformation to more convenient
derivatives.
The diastereomeric ratio of the precipitated products
was high in all cases. However, only with phenyl deriv-
ative 3a was the expected trans-4a obtained. In all other
examples, an inversion of the configuration on C-4 of
the starting 3b–d took place and cis-butanolides 4b–d
were isolated in high yield (70–91%) and excellent dia-
stereoselectivity (d.r. >95:5 in the reaction mixture and
up to 99:1 in filtered solid product). The inversion of
the configuration on C-4 was unambiguously confirmed
by the alkaline hydrolysis of the 4b–d to the correspond-
ing anti-3b–d (Scheme 1) as well as confrontation of the
HPLC records with those of the starting syn-3b–d.
2. Results and discussion
The acid-catalyzed lactonization of syn-3a–d in dilute
HCl was selected. The conditions of the high yield pre-
cipitation of the only slightly soluble hydrochlorides of
the corresponding lactones 4a–d (Scheme 1) were opti-
mized. As an aryl substituent becomes progressively
more electron donating, the precipitation of solid lac-
Ar
CO2H
In order to establish that no loss of stereochemical integ-
rity at C-2 had occurred during the lactonization pro-
cess, a sample of lactone 4c was subjected to catalytic
hydrogenation to give 4-methoxyhomophenylalanine
5c (Scheme 2), which was enantiomerically pure as con-
firmed by comparison of the specific rotation data with
those in the literature15 as well as with the sample pre-
pared by direct hydrogenolysis of compound 2c.
O
1a-d
1.1 eq.
CIAT H2N
MeOH
Ph
lit.15
Ar
NaBH4
CO2H
MeOH
Ar
CO2H
Ph
O
HN
cat.MnCl2
d.r.>97:3
HO HN
Ph
. HCl
HN
2a-d
syn-3a-d
Ar
COOH
NH2
H2 / Pd/C
81 %
Ph
Ar
O
O
CIAT
cis-4c
5c
4 M HCl
Scheme 2.
HN
HN
.HCl
Ph
.HCl
The 2,4-relationship of lactones 4a–d was further con-
firmed by the NOE experiments depicted in Figure 2.
The butyrolactones are known to exist in the envelope
conformation and in the solution an equilibrium of
two conformers should be considered.24 In analogous
3,5-dihydro-2(3H)-furanones,20,25 the cis-isomers were
found to be conformationally stable with the substitu-
ents taking up pseudo-equatorial positions, causing a
very distinct NOE between the H-2 and H-5 protons.
In the case of the more conformationally labile trans-
4a, the decoupling at the signals of H-2- and H-5,
respectively, led to NOE effect between the H-4a and
H-4b only (Fig. 2).
Ph
Ph
O
trans-4a
O
Ar
O
O
cis-4b-d
1. 1 M NaOH
MeOH
comp.
1-4
Ar
2. HCl
Ar
CO2H
a
b
c
d
C6H5
4-CH3C6H4
HO HN
4-CH3OC6H4
4-CH3O-3-CH3C6H3
Ph
anti-3b-d
Scheme 1.

ˇ
D. Berkes et al. / Tetrahedron: Asymmetry 16 (2005) 1927–1934
1929
1.68 %
1.68 %
0.36 %
0.36 %
H
H
NH-R*
H
NH-R*
Ph
%
%
NH-R*
7
6
5
8
.
H
.
%
1
1
4
H
H
6
O
H
.
O
H
0
O
O
O
H
Ar
O
%
H
H
7
7
.
1
%
H
8
4
.
1
Ph
%
5
6
.
1
trans-4a
trans-4a
cis-4d
Figure 2. A result of NOE experiments on cis-4d and trans-4a, respectively (free base in CDCl3 solution).
The configuration on the newly formed stereogenic cen-
ters in relation to the 1-phenylethylamino moiety has
been validated by X-ray analysis of 4c (Fig. 3).26
Figure 3. ORTEP drawing of cis-butanolide hydrochloride 4c with
thermal ellipsoids drawn at the 50% probability level.ꢀ
In order to gain a deeper understanding of the lactoniza-
tion process, we carried out a series of HPLC-monitored
experiments of the cyclization of the hydroxyamino
acids 3a–c.
In the case of phenyl derivative 3a, the cyclization was
straightforward with the formation of trans-4a, with
small epimerization on C-4 only. HPLC study of lacton-
ization of 3b was more illustrative. It has demonstrated
the rapid formation of trans-butanolide trans-4b, which
reached the maximum concentration when the precipita-
tion of little soluble cis-butanolide cis-4b started (Graph
1a). From this point on, the stereoselectivity was fully
controlled by the slow precipitation of cis-4b, which
after the relevant time was filtered off in high diastereo-
and enantiomeric purity. Surprisingly, the same result
was obtained from the mixture of the hydroxyamino
acids (syn-3b:anti-3b = 1:1). The precipitation of the so-
lid was more rapid and the predominance of cis-4b was
unequivocal after the first 20 min of the reaction time
(Graph 1b).
Graph 1. The distribution of hydroxyamino acids 3b and their lactones
4b in the reaction mixture (a) starting from the syn-3b; (b) from the
mixture of syn-3b:anti-3b (1:1).
In the case of the 4-methoxysubstituted derivative 3c,
the lactonization was even more rapid. The precipitation
of the cis-4c started within 3–4 min of the reaction, and
within one hour the conversion was practically com-
plete. The result is independent of the stereochemistry
of the starting hydroxyamino acid. Both syn-3c and
anti-3c produce the same cis-4c in high diastereomeric
purity (Fig. 4).
ꢀ CCDC 260109 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033; or deposit@ccdc.cam.ac.uk).
It has herein been demonstrated that the level of the ob-
served stereoselectivity is ultimately determined by the

ˇ
D. Berkes et al. / Tetrahedron: Asymmetry 16 (2005) 1927–1934
1930
consideration of all the other possible equilibria in the
reaction (Scheme 3), the stereoselectivity is fully con-
trolled by the precipitation of the less soluble cis-isomer.
Furthermore, the final cis-4b–d:trans-4b–d ratio in the
solution does not depend on the syn-/anti-ratio of
the starting hydroxyamino acids 3b–d. It follows that
the lactonization is stereoconvergent for all syn- and
anti-hydroxyamino acids 3b–d with aryl substituents
capable or stabilizing the putative benzylic cation and
providing less soluble crystalline cis-butanolides 4b–d.
The stereochemical outcome of the lactonization is
controlled by crystallization and represents an efficient
example of the crystallization-induced asymmetric
transformation. This CIAT approach could also explain
some discrepancies in the earlier experiments on lacton-
ization of racemic c-aryl-c-hydroxy-a-amino butanoic
acid derivatives.29
The efficiency of the CIAT approach is shown in Scheme
4. Regardless of the low selectivity of catalytic hydroge-
nation of 2c, which provides a 7:3 mixture of both syn-
and anti-2-amino-4-hydroxy-4-(4-methoxyphenyl)buta-
noic acids, the following one-pot stereoconvergent lact-
onization with CIAT allows isolation of butanolide 6c,30
which precipitated from the reaction mixture in good
yield and high diastereo- and enantiomeric purity.
Figure 4. A typical HPLC chromatogram of a reaction mixture of 3c
lactonization (c 0.02 M in 4 M HCl; 20 ꢁC). Red line—starting from
the syn-3c (d.r. 97:3), blue line—starting from the anti-3c (d.r. 99:1).
(A) Within the first 3 min of the reaction—clear solution; (B) After
15 min—a suspension. Mobile phase 1.5% (v/v) solution of triethyl-
amine in a mixture of acetonitrile–water (1:2) adjusted to pH 2.9,
0.9 ml/min, other conditions as in the experimental part.
2c
1eq.HBr / MeOH-H2O
1.1 bar H2 / Pd-C
r.t., 24 h
electronic nature of the aryl substituents. The electronic
nature of the aryl substituents has previously been
shown to effect the stereoselectivity of benzylic substitu-
tion reactions with the stereoselectivity being attributed
to variations of the cationic nature, and SN1 versus SN2
character of the reaction pathway.27,28
NH2
O
.HCl
4M HCl
Ar
COOH
OH NH2
CIAT
Ar
O
d.r. 7:3
6c (d.r.>95:5)
The acid catalyzed lactonization of the hydroxyamino
acids 3b–d provides selective formation of cis-butano-
lides 4b–d and can be rationalized by the presence of a
rapid equilibrium between the diastereomers in the solu-
tion, realized via a stabilized benzylic cation. Without
Scheme 4.
3. Conclusion
We have reported herein a direct and inexpensive
preparation of the N-substituted cis-3-amino-5-aryl-
dihydrofuran-2(3H)-ones and anti-2-amino-4-aryl-4-
. HCl
HN
Ar
COOH
Ph
H+
Ph
OH HN
hydroxybutanoic acids, with
a
high degree of
Ar
O
O
diastereomeric purity. The high diastereoselectivity
of this lactonization is independent of the bulkiness
of the substituents on the nitrogen atom and initial
d.r. of the hydroxyamino acids. Approximately equal
d.r.s were obtained in both lactonizations 4b–d and 6c.
Conversely, the p-donor ability of the aryl substituents
had a vital influence on the selectivity.
syn-3b-d
trans-4b-d
Ar
COOH
Ph
H+
HN
. HCl
HN
Ar
COOH
Ph
H+
4. Experimental
OH HN
Ph
Ar
O
O
Melting points were obtained using a Kofler hot plate
and are uncorrected. Optical rotations were measured
with a Perkin–Elmer 241 polarimeter and a POLAR
L-lP polarimeter (IBZ Messtechnik) with a water-jack-
anti-3b-d
cis-4b-d
Scheme 3. Proposed mechanism for the tandem lactonization followed
by CIAT.

ˇ
D. Berkes et al. / Tetrahedron: Asymmetry 16 (2005) 1927–1934
1931
eted 10.000 cm cell at the wavelength of sodium line
D (k = 589 nm). Specific rotations are given in units of
10ꢀ1 deg cm2 gꢀ1 and concentrations are given in
g/100 ml. Elemental analyses were performed by the
Microanalytical Service of Slovak University of Tech-
3H, J = 6.9, H-20). 13C NMR (D2O/DCl): d 201.4 (s,
C-4), 173.7 (s, C-1), 65.2 (C-2), 56.6 (C-10), 41.5 (C-3),
21.9 (C-20), CAr 137.9 (s), 137.5 (s), 137.8 (d), 133.0
(d), 132.5 (d), 131.9 (d), 131.2 (d), 130.9 (d). Anal. Calcd
for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.44; H, 6.49; N, 4.44.
1
nology. H NMR spectra were recorded on a Varian
VXR-300 (299.94 MHz) spectrometer. Chemical shifts
(d) are quoted in ppm and are either referenced to
4.1.2. (2R)-4-(4-Methylphenyl)-4-oxo-2-{[(1R)-1-phenyl-
ethyl]amino}butanoic acid 2b. Yield 6.1 g (78%; d.r.
tetramethylsilane (TMS) as internal standard (dMe
=
20
0.00 ppm for 299.94 MHz) or the residual protic solvent
(CH3OH, dH = 3.34 ppm for 299.94 MHz) was used
as the internal reference. Coupling constants (J) are
recorded in hertz. The following abbreviations were
used to characterize signal multiplicities: s (singlet), d
(doublet), t (triplet), m (multiplet), b (broad). The
COSY and transition-NOESY techniques were used in
the assignment of proton–proton relationships and
the determination of the relative configuration. 13C
NMR spectra were recorded on a Varian VXR-300
(75.43 MHz) spectrometer. The multiplicities of carbons
were assigned from a broadband decoupled analysis
used in conjunction with either APT or DEPT pro-
grams. Chemical shifts are quoted in ppm and are either
referenced to the tetramethylsilane (TMS) as internal
standard (d = 0.00 ppm for 75.43 MHz) or the central
resonance of CD3OD (d = 49.0 ppm for 75.43 MHz)
was used as the internal reference.
97:3); mp 199–200 ꢁC (CH3CN/H2O); ½aꢁ ¼ ꢀ52.5 (c 0.5,
D
MeOH/1 M H2SO4 = 3:1); 1H NMR (CD3OD/DCl):
d 7.88 (d, 2H, J = 8.1 Hz, H-200, H-600), 7.42–7.62
(m, 5H, Ph), 7.35 (d, 2H, J = 8.0 Hz, H-300, H-500), 4.73
(q, 1H, J = 6.9 Hz, H-10), 4.11 (m, 1H, H-2), 3.59–3.83
(m, 2H, H-3), 2.42 (s, 3H, CH3), 1.78 (d, 3H, J =
6.3 Hz, H-20). 13C NMR (CD3OD/DCl): d 196.6 (C-4),
170.8 (C-1), 60.4 (C-2), 54.7 (C-10), 39.8 (C-3), 21.7
(CH3), 20.3 (C-20), 146.6 (s), 136.7 (s), 134.0 (s), 131.0
(d), 130.7 (d), 130.5 (d), 129.5 (d), 129.1 (d). Anal. Calcd
for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C,
73.01; H, 6.99; N, 4.14.
4.1.3. (2R)-4-(4-Methoxyphenyl)-4-oxo-2-{[(1R)-1-phenyl-
ethyl]amino}butanoic acid 2c. Yield 5.8 g (71%;
20
d.r. 98:2); mp 191–192 ꢁC (CH3CN/H2O); ½aꢁ
¼
D
ꢀ64.0 (c 0.5, MeOH/1 M H2SO4 = 3:1); 1H NMR
(CD3OD/DCl): d 7.98 (d, 2H, J = 8.8 Hz, H-200, H-600),
7.45–7.60 (m, 5H, Ph), 7.05 (d, 2H, J = 8.7 Hz, H-300,
H-500), 4.75 (q, 1H, J = 6.9 Hz, H-10), 4.11 (dd, 1H,
J = 6.1 Hz, J = 4.0 Hz, H-2), 3.90 (s, 3H, OCH3), 3.62–
3.82 (m, 2H, H-3), 1.79 (d, 3H, J = 6.3 Hz, H-20). 13C
NMR (CD3OD/DCl): d 195.4 (C-4), 170.8 (C-1), 60.4
(C-2), 56.3 (OCH3), 54.8 (C-10), 39.5 (C-3), 20.4 (C-20),
165.9 (C-400), 136.7 (s), 131.9 (s), 131.0 (d), 130.7 (d),
129.5 (d), 129.2 (d), 115.1 (d). Anal. Calcd for
C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C,
69.47; H, 6.33; N, 4.29.
HPLC experiments were carried out using a chromato-
graphy system Pye Unicam with PU4225 UV detector.
Detection was carried out at 210 nm. The HPLC column
used was Spherisorb 5 ODS-2, 250 · 4.6 mm (Varian).
The mobile phase was a 1.5% (v/v) solution of triethyl-
amine in a mixture of acetonitrile and water (from 1:2
to 1:4) adjusted to pH 2.9 with o-phosphoric acid, which
was pumped through the system at 0.5–1.5 ml/min at
room temperature. The amount injected was 20 ll. All
data were collected and analyzed using CSW 1.7 soft-
ware (DATAAPEX). (R)-Phenylethylamine (99+%,
99% ee) was obtained from ACROS.
4.1.4. (2R)-4-(4-Methoxy-3-methylphenyl)-4-oxo-2-{[(1R)-
1-phenylethyl]amino}butanoic acid 2d. Yield 6.3 g
20
(74%; d.r. 98:2); mp 188–192 ꢁC (CH3CN/H2O); ½aꢁ
¼
D
4.1. (2R)-4-Aryl-4-oxo-2-{[(1R)-1-phenylethyl]amino}-
butanoic acids 2a–d
ꢀ63.3 (c 0.5, MeOH/1 M H2SO4 = 3:1); 1H NMR
(CD3OD/DCl): d 7.89 (dd, 1H, J = 8.7 Hz, J = 2.4 Hz,
H-600), 7.8 (d, 1H, J = 2.4 Hz, H-200), 7.45–7.55 (m, 5H,
Ph), 7.05 (d, 1H, J = 8.7 Hz, H-500), 4.73 (q, 1H,
J = 6.9 Hz, H-10), 4.10 (dd, 1H, J = 6.4 Hz, J = 4.2 Hz,
H-2), 3.94 (s, 3H, OCH3), 3.54–3.80 (ABx, 2H,
J = 6.4 Hz, J = 4.2 Hz, H-3), 2.25 (s, 3H, CH3), 1.79
(d, 3H, J = 6.9 Hz, H-20). 13C NMR (NaOD/D2O): d
195.7 (C-4), 170.9 (C-1), 164.2 (C-400), 136.7 (C-Ph),
129.0, 128.2 (q), 131.7, 131.1, 130.1, 110.8 (CH), 130.7,
129.1 (CH), 60.3 (C-2), 56.4 (C-10), 54.9 (OCH3), 39.4
(C-3), 20.3 (C-20), 16.3 (CH3). Anal. Calcd for
C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C,
70.39; H, 6.54; N, 3.97.
To the solution of aroylacrylic acids 1a–d (25 mmol) in
methanol (100 ml), (R)-1-phenylethylamine (3.33 g,
27.5 mmol) was added under stirring. The mixture was
stirred at 45 ꢁC for 20–40 h in the dark. The course of
the CIAT process was monitored by HPLC. The precip-
itate was filtered off, washed with methanol (10 ml) and
ether (2 · 10 ml), and dried under reduced pressure to
give the corresponding adduct as a white powder with
d.r. >96:4. Small quantity of diastereommerically pure
crystals has been obtained by crystallization from the
acetonitrile–water mixture.
4.1.1. (2R)-4-Oxo-4-phenyl-2-{[(1R)-1-phenylethyl]amino}-
butanoic acid 2a. Yield 5.3 g (71%; d.r. 97:3); mp 194–
4.2. syn-(2R,4S)-4-Aryl-4-hydroxy-2-{[(1R)-1-phenyl-
ethyl]amino}butanoic acid syn-3a-syn-3d
20
196 ꢁC (CH3CN/H2O); ½aꢁ ¼ ꢀ36.5 (c 0.5; MeOH/1 M
D
H2SO4 = 3:1); 1H NMR (D2O/DCl): d 7.90 (d, 2H,
J = 7.2 Hz, H-200, H-600), 7.70 (m, 1H, H-400), 7.45–7.60
(m, 7H, Ph, H-300, H-500), 4.70 (q, 1H, J = 6.9, H-10),
4.28 (m, 1H, H-2), 3.63–3.91 (m, 2H, H-3), 1.76 (d,
To a presonicated (1 min) stirred suspension of 2a–d
(8 mmol) and MnCl2Æ4H2O (320 mg, 1.6 mmol) in
MeOH (120 ml) at 15 ꢁC, NaBH4 (2 · 296 mg,
2 · 8 mmol) was added slowly (20 min). The reaction

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D. Berkes et al. / Tetrahedron: Asymmetry 16 (2005) 1927–1934
1932
mixture was stirred for an additional 30 min, after which
water (40 ml) followed by 5 ml of 10% solution of potas-
sium carbonate was added. Methanol was removed
under reduced pressure and the remaining volume adjusted
to 100 ml with water. The precipitated MnCO3 was
filtered off and the pH of the remaining solution adjusted
to 6.0 with 1 M HCl. The precipitateꢁ was filtered off,
washed with EtOH, ether, and dried under reduced pres-
sure (50 Pa, 50 ꢁC) to afford crude syn-2a–d as white
powders (syn-2a–d:anti-2a–d >97:3).
HAr), 4.61 (ꢂtꢃ, 1H, J ffi 6.8, H-4), 3.83 (s, 3H, CH3O),
3.63 (q, 1H, J 6.6, H-10), 2.69 (ꢂtꢃ, 1H, J ffi 6.9, H-2),
2.15 (s, 3H, CH3), 1.90 (ꢂtꢃ, 2H, J ffi 7.1, H-3), 1.38 (d,
3H, J 6.6, H-20). 13C NMR (NaOD/D2O): d 184.9 (s,
C-1), 75.0 (d, C-4), 62.5 (d, C-2), 59.4 (d, C-10), 58.5
(CH3O), 44.0 (t, C-3), 26.0 (q, C-20), 18.3 (CH3), 146.6
(s, Cipso of Ph), 130.3 (d, C-400 of Ph), 159.4, 137.8,
129.4 (s, CAr), 131.6, 131.7, 130.2, 128.0, 113.9 (d,
CHAr). Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34;
N, 4.08. Found: C, 70.2; H, 7.44; N, 4.16.
4.2.1. syn-(2R,4S)-4-Hydroxy-4-phenyl-2-{[(1R)-1-phenyl-
ethyl]amino}butanoic acid syn-3a. Yield 1.72 g (72%);
4.3. trans-(3R,5R)-5-Phenyl-3-{[(1R)-1-phenyl-
ethyl]amino}dihydrofuran-2(3H)-one hydrochloride 4a
20
D
mp 194–195 ꢁC (70% EtOH; d.r. 98:2); ½aꢁ ¼ ꢀ14.0 (c
1
1, 0.1 M NaOH); H NMR (NaOD/D2O): d 7.32–7.50
(m, 8H, HAr), 7.18–7.25 (m, 2H, HAr), 4.69 (ꢂtꢃ, 1H,
J ffi 6.9, H-4), 4.70 (q, 1H, J 6.6, H-10), 2.82 (ꢂtꢃ, 1H,
J ffi 6.9, H-2), 1.93 (ꢂtꢃ, 2H, J ffi 6.9, H-3), 1.42 (d, 3H,
J ffi 6.6, H-20). 13C NMR (NaOD/D2O): d 184.7 (s, C-
1), 75.6 (d, C-4), 62.7 (d, C-2), 59.5 (d, C-10), 44.3 (t,
C-3), 26.0 (q, C-20), 146.6, 146.7 (s, Cipso of Ph), 130.7,
130.4 (d, C-400 of Ph), 131.6, 131.5, 130.3, 129.1 (d, CH
of Ph). Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07;
N, 4.68. Found: C, 70.48; H, 7.27; N, 4.48.
To the well-homogenized (ultrasound) suspension of
syn-hydroxy acid 3a (1 g, 3.34 mmol) in water (8 ml),
concd hydrochloric acid (16 ml) was added in one por-
tion. Starting material was dissolved and small precipi-
tation of the product started under vigorous stirring at
25 ꢁC. The mixture was stirred for 4 h at 25 ꢁC. The pre-
cipitated product was filtered off, washed with 2 · 5 ml
1 M HCl, and dried under the diminished pressure at
60 ꢁC. Raw product (0.88 g, d.r. >96:4) was crystallized
from the acetonitrile–ether mixture. Yield : 0.72 g (68%;
20
D
d.r. 98:2); mp: 160–162 ꢁC (CH3CN/Et2O); ½aꢁ
¼
1
4.2.2. syn-(2R,4S)-4-Hydroxy-4-(4-methylphenyl)-2-{[(1R)-
1-phenylethyl]amino}butanoic acid syn-3b. Yield 1.90 g
ꢀ115.2 (c 0.6, MeOH); H NMR (DMSO-d6): d 7.60–
7.68 (m, 2H, Ph), 7.30–7.50 (m, 8H, Ph), 5.9 (dd, 1H,
20
(76%); mp 196–199 ꢁC; ½aꢁ ¼ þ2.3 (c 1, 0.1 M NaOH);
1H NMR (NaOD/D2O): dD7.3–7.5 (m, 5H, Ph), 7.17 (d,
2H, J 8.1, HTol), 7.06 (d, 2H, J 8.1, HTol), 4.64 (ꢂtꢃ, 1H,
J ffi 6.9, H-4), 3.66 (q, 1H, J 6.6, H-10), 2.76 (ꢂtꢃ, 1H,
J ffi 6.9, H-2), 2.31 (s, 3H, CH3), 1.90 (ꢂtꢃ, 2H, J ffi 6.6,
H-3), 1.40 (d, 3H, J 6.6, H-20). 13C NMR (NaOD/
D2O): d 184.8 (s, C-1), 75.4 (d, C-4), 62.7 (d, C-2),
59.5 (d, C-10), 44.3 (t, C-3), 26.0 (q, C-20), 23.0 (CH3),
146.6 (s, Cipso of Ph), 130.4 (d, C-400 of Ph), 142.6, 140.
8 (s, CTol), 132.0, 131.6, 130.3, 129.2 (d, CHAr). Anal.
Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47.ꢁ
J = 7.8 Hz, J = 5.8 Hz, H-4), 4.66 (q, 1H, J = 6.9 Hz,
H-10), 4.05 (dd, 1H, J = 9 Hz, J = 6.6 Hz, H-2), 2.80–
2.96 (m, 1H, H-3), 2.37–2.50 (m, 1H, H-3), 1.63 (d,
3H, J = 6.9 Hz). 13C NMR (NaOD/D2O): d 171.5 (C-
1), 138.5, 136.6 (C-Ar,q), 129.2, 128.7 (1 · CHAr),
129.0, 128.8, 128.3, 126.1 (2 · CHAr), 79.3 (C-4), 56.3
(C-10), 51.5 (C-2), 32.9 (C-3), 19.7 (C-200). Anal. Calcd
for C18H20 ClNO2: C, 68.03; H, 6.34; N, 4.41. Found:
C, 68.24; H, 6.48; N, 4.52.
4.4. cis-(3R,5R)-5-(4-Methylphenyl)-3-{[(1R)-1-phenyl-
ethyl]amino}dihydrofuran-2(3H)-one hydrochloride 4b
4.2.3. syn-(2R,4S)-4-Hydroxy-4-(4-methoxyphenyl)-2-
{[(1R)-1-phenylethyl]amino}butanoic acid syn-3c. Yield
To the well-homogenized presonicated suspension of hy-
droxy acid 3b (1.25 g, 4 mmol) in water (40 ml), 5 M
HCl (160 ml) was added dropwise under vigorous stir-
ring. The reaction mixture was stirred at 50 ꢁC for
30 h. Fine crystalline raw product (d.r. >95:5) was fil-
20
D
1.66 g (63%); mp 192–195 ꢁC; ½aꢁ ¼ ꢀ4.6 (c 1, 0.1 M
1
NaOH); H NMR (NaOD/D2O): d 7.28–7.46 (m, 5H,
Ph), 7.13 (d, 2H, J 8.7, HAn), 6.90 (d, 2H, J 8.7, HAn),
4.64 (ꢂtꢃ, 1H, J ffi 6.9, H-4), 3.82 (s, 3H, CH3O), 3.64 (q,
1H, J 6.9, H-10), 2.71 (ꢂtꢃ, 1H, J ffi 6.5, H-2), 1.90 (ꢂtꢃ,
2H, J ffi 6.8, H-3), 1.38 (d, 3H, J 6.6, H-20). 13C NMR
(NaOD/D2O): d 184.8 (s, C-1), 75.0 (d, C-4), 62.6 (d, C-
2), 59.4 (d, C-10), 58.2 (CH3O), 44.0 (t, C-3), 26.0 (q, C-
20), 146.6 (s, Cipso of Ph), 130.4 (d, C-400 of Ph), 161.1,
138.1 (s, CAn), 131.6, 130.6, 130.3, 116.8 (d, CHAr). Anal.
Calcd for C19H23NO4: C, 69.28; H, 7.04; N, 4.25.ꢁ
tered off and recrystallized. Yield: 0.93 g (70%); m.p.:
20
217–220 ꢁC (CH3CN/EtOH; d.r. >99:1); ½aꢁ ¼ þ2.8
D
(c 0.6, MeOH); 1H NMR (DMSO-d6): d 10.7 (br s,
2H, NH2+), 7.65 (br d, 2H, J = 6 Hz, H-2, H-6 Ph),
7.38–7.48 (m, 3H, Ph), 7.36 (d, 2H, J = 8.1 Hz, H-2,
H-6 Tol.), 7.21 (d, 2H, J = 8.1 Hz, H-3, H-5 Tol.),
5.41 (dd, 1H, J = 5.4 Hz, J = 10.6 Hz, H-4), 4.83 (bq,
1H, J = 6.6 Hz, H-10), 4.29 (dd, 1H, J = 8.4 Hz,
J = 11.0 Hz, H-2), 2.74 (ddd, 1H, J = 12.3 Hz,
J = 8.4 Hz, J = 5.7 Hz, H-3eq.), 2.54 (bdd, 1H, J =
12.3 Hz, J = 10.6 Hz, H-3ax.), 2.29 (s, 3H, CH3),
1.64 (d, 3H, J = 6.9 Hz, H-20). 13C NMR (NaOD/
D2O): d 171.5 (C-1), 138.6 (C- qAr), 136.7 (C- qAr),
134.8 (C- qAr), 129.2 (CHAr), 129.1 (CHPh), 129.0
(CHAr), 128.3, 126.9 (CHAr), 79.0 (C-4), 55.8, 52.8 (C-
10, C-2), 34.8 (C-3) 20.8 (C-20), 19.4 (CH3). Anal. Calcd
for C19H22ClNO2: C, 68.77; H, 6.68; N, 4.22. Found: C,
68.92; H, 6.72; N, 4.42.
4.2.4.
syn-(2R,4S)-4-Hydroxy-4-(4-methoxy-3-methyl-
phenyl)-2-{[(1R)-1-phenylethyl]amino}butanoic acid (syn-
3d). Yield 2.30 g (84%); mp 192–193 ꢁC (70% EtOH;
20
1
d.r. 98:2); ½aꢁ ¼ ꢀ4.7 (c 1, 0.1 M NaOH); H NMR
D
(NaOD/D2O): d 7.22–7.48 (m, 5H, Ph), 7.00 (br s, 1H,
H-200Ar), 6.99 (d, 1H, J 8.1, HAr), 6.89 (d, 1H, J 8.1,
ꢁ In the case of syn-3b and c and anti-3c voluminous gel, no satisfactory
elemental analysis was obtained.

ˇ
D. Berkes et al. / Tetrahedron: Asymmetry 16 (2005) 1927–1934
1933
4.5. One-pot preparation of butanolides 4c and d
room temperature. The reaction mixture was stirred
for 30 min and treated with 20 ml of water. Methanol
was evaporated under reduced pressure. The pH of the
residue was adjusted to 5.5–6.0 with 1 M HCl. Precipi-
tated crude product was filtered off, washed with water
(2 · 5 ml) and ether (10 ml), and dried at 50 ꢁC under
diminished pressure for 2 h.
To a homogenized suspension (ultrasound) of oxoamino
acids 2c and d (4 mmol) in methanol (60 ml), MnCl2Æ
4H2O (0.16 g; 0.8 mmol) was added in one portion.
Sodium borohydride (0.222 g, 6 mmol) was added to a
well-stirred reaction mixture at 15 ꢁC in small portions
over a period of 20 min. When the reduction was com-
plete (monitored by HPLC), water (60 ml) was added
and the methanol evaporated under reduced pressure.
The remaining water solution (50 ml) of hydroxyamino
acids 3c and d was treated with concentrated HCl
(25 ml) and the reaction mixture stirred at room temper-
ature for an additional 5–10 h. The course of CIAT pro-
cess was monitored by HPLC. The crystalline solid was
filtered, washed with cold 1% HCl solution and ether,
and thereafter dried in vacuo to give raw product
(d.r. >95:5). Recrystallization from appropriate solvent
gave the desired cis-butanolide hydrochloride 4c (84%)
and 4d (91%), respectively.
4.6.1. anti-(2R,4R)-4-Hydroxy-4-(4-methylphenyl)-2-{[(1R)-
1-phenylethyl]amino}butanoic acid anti-3b. Yield 0.51 g
20
D
(81%; d.r. 98:2); mp 180–190 ꢁC; ½aꢁ ¼ þ29.6 (c 1,
1
0.1 M NaOH); H NMR (NaOD/D2O): d 7.2–7.5 (m,
5H, Ph), 7.23 (d, 2H, J 7.8, HTol), 7.04 (d, 2H, J 7.8,
HTol), 4.69 (ꢂtꢃ, 1H, J ffi 6.6, H-4), 3.63 (q, 1H, J 6.6,
H-10), 2.72 (ꢂtꢃ, 1H, J ffi 6.6, H-2), 2.29 (s, 3H, CH3),
1.95 (ꢂtꢃ, 2H, J ffi 6.6, H-3), 1.34 (d, 3H, J 6.6, H-20).
13C NMR (NaOD/D2O): d 184.4 (s, C-1), 74.7 (d, C-
4), 61.6 (d, C-2), 59.3 (d, C-10), 43.8 (t, C-3), 25.9 (q,
C-20), 23.0 (CH3), 146.7 (s, Cipso of Ph), 143.1, 139.8
(s, CTol), 131.6, 131.2, 129.9, 128.7 (d, CHAr). Anal.
Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47.
Found: C, 72.62; H, 7.52; N, 4.29.
4.5.1. cis-(3R,5R)-5-(4-Methoxyphenyl)-3-{[(1R)-1-phenyl-
ethyl]amino}dihydrofuran-2(3H)-one hydrochloride 4c.
Yield: 1.17 g (84%; d.r. = 99:1); mp 220–224 ꢁC
4.6.2. anti-(2R,4R)-4-Hydroxy-4-(4-methoxyphenyl)-2-{[(1R)-
1-phenylethyl]amino}butanoic acid anti-3c. Yield 0.38
20
(CH3CN/EtOH; d.r. >99:1); ½aꢁ ¼ ꢀ5.2 (c 1, MeOH);
D
20
1H NMR (CD3OD/DCl): d 7.2–7.5 (m, 5H, Ph), 7.19
(d, 2H, J = 8.7 Hz, H-20, H-60), 6.86 (d, 2H,
J = 8.7 Hz, H-30, H-50), 5.08 (dd, 1H, J = 11.4 Hz,
J = 5.1 Hz, H-4), 4.2 (m, 1H, H-5), 3.79 (s, 3H, H-7),
3.59 (dd, 1H, J = 12 Hz, J = 7.8 Hz, H-2), 2.25 (m, 1H,
H-3), 1.80 (m, 1H, H-3), 1.44 (d, 3H, J = 6.6 Hz, H-6).
13C NMR (NaOD/D2O): d 176.9 (C-1), 160.0, 144.3,
129.9 (C-q), 129.6, 127.6, 127.2, 114.1 (CAr), 78.6 (C-
4), 58.5, 57.5 (C-2, C-10), 55.3 (OCH3), 40.4 (C-3), 24.5
(C-6). Anal. Calcd for C19H22ClNO3: C, 65.61; H,
6.38; N, 4.03. Found: C, 65.47; H, 6.48; N, 4.08.
g (57%; d.r. 97:3); mp 182–185 ꢁC; ½aꢁ ¼ þ18.8 (c 1,
D
0.1 M NaOH); 1H NMR (NaOD/D2O): d 7.18–7.40
(m, 5H, Ph), 7.08 (d, 2H, J 8.7, HAn), 6.84 (d, 2H, J
8.7, HAn), 4.65 (ꢂtꢃ, 1H, J ffi 6.6, H-4), 3.77 (s, 3H,
CH3O), 3.61 (q, 1H, J 6.6, H-10), 2.66 (ꢂtꢃ, 1H, J ffi 6.6,
H-2), 1.93 (m, 2H, H-3), 1.31 (d, 3H, J 6.6, H-20). 13C
NMR (NaOD/D2O): d 184.7 (s, C-1), 74.3 (d, C-4),
61.4 (d, C-2), 59.3 (d, C-10), 58.1 (CH3O), 44.0 (t, C-
3), 26.0 (q, C-20), 146.6 (s, Cipso of Ph), 130.2 (d, C-400
of Ph), 160.9, 138.4 (s, CAn), 131.5, 130.4, 130.1, 116.7
(d, CHAr). Anal. Calcd for C19H23NO4: C, 69.28; H,
7.04; N, 4.25.ꢁ
4.5.2. cis-(3R,5R)-5-(4-Methoxy-3-methylphenyl)-3-{[(1R)-
1-phenylethyl]amino}dihydrofuran-2(3H)-one hydrochlo-
ride 4d. Yield: 1.32 g (91%; d.r. 99:1); mp 212–
4.6.3. anti-(2R,4R)-4-Hydroxy-4-(4-methoxy-3-methyl-
phenyl)-2-{[(1R)-1-phenylethyl]amino}butanoic acid anti-
20
213ꢁC (CH2Cl2/MeOH/Et2O; d.r. >99:1); ½aꢁ ¼ ꢀ8.7
3d. Yield 0.55 g (80%; d.r. 99:1); mp 179–181 ꢁC;
D
20
1
(c 0.6, MeOH); H NMR (DMSO-d6): d 7.62–7.68 (m,
2H, Ph), 7.36–7.50 (m, 3H, Ph), 7.28 (d, 1H, J =
9.3 Hz, H-600), 7.28 (br s, 1H, H-200), 6.95 (d, 1H,
J = 9.3 Hz, H-500), 5.39 (dd, 1H, J = 5.4 Hz,
J = 10.8 Hz, H-4), 4.81 (bq, 1H, J = 6.9 Hz, H-10), 4.35
(dd, 1H, J = 8.7 Hz, J = 11.7 Hz, H-2), 3.79 (s, 3H,
OCH3), 2.65–2.77 (m, 1H, H-3), 2.40–2.56 (m, 1H, H-
3), 2.15 (s, 3H, CH3), 1.65 (d, 3H, J = 6.6 Hz, H-20)
13C NMR (NaOD/D2O): d 171.5 (C-1, C-2), 158.0,
129.0, 126.0 (C- q), 136.8 (C-100), 129.1, 128.3, 128.2,
110.3 (CHPh) 126.2 (C-400), 79.2 (C-4), 56.0, 55.5, 53.1
(C-2, 5.8), 34.7 (C-3), 19.3 (CH3), 16.1 (C-20). Anal.
Calcd for C20H24ClNO3: C, 66.38; H, 6.69; N, 3.87. C,
66.08; H, 6.87; N, 3.92.
½aꢁ ¼ þ12.6 (c 1, 0.1 M NaOH); 1H NMR (NaOD/
D
D2O): d 7.15–7.40 (m, 5H, Ph), 6.99 (br s, 1H, H-
200Ar), 6.96 (d, 1H, J 8.4, HAr), 6.83 (d, 1H, J 8.4,
HAr), 4.62 (ꢂtꢃ, 1H, J ffi 6.3, H-4), 3.79 (s, 3H, CH3O),
3.61 (q, 1H, J 6.6, H-10), 2.66 (ꢂtꢃ, 1H, J ffi 6.5, H-2),
2.11 (s, 3H, CH3), 1.93 (m, 2H, H-3), 1.30 (d, 3H, J
6.6, H-20). 13C NMR (NaOD/D2O): d 184.7 (s, C-1),
74.4 (d, C-4), 61.5 (d, C-2), 59.3 (d, C-10), 58.5
(CH3O), 44.0 (t, C-3), 26.1 (q, C-20), 18.3 (CH3), 146.6
(s, Cipso of Ph), 130.2 (d, C-400 of Ph), 159.3, 138.1,
129.3 (s, CAr), 131.4, 131.3, 130.0, 127.9, 113.8 (d,
CHAr). Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34;
N, 4.08. Found: C, 70.06; H, 7.55; N, 3.96.
4.7. Hydrogenation of cis-(3R,5R)-5-(4-methoxyphenyl)-
3-{[(1R)-1-phenylethyl]amino}dihydrofuran-2(3H)-one
hydrochloride 4c
4.6. anti-(2R,4R,10R)-4-(4-Aryl)-4-hydroxy-2-(10-phenyl-
ethylamino)butanoic acids anti-3b-anti-3d; General
procedure
Palladium on charcoal (10%) (0.4 g) was added to a sus-
pension of the lactone 4c (2 g; 5.7 mmol) in ethanol
(30 ml)—0.5 M H2SO4 (90 ml). The resulting mixture
was stirred under hydrogen at 1.1 bar for 68 h, after
To a solution of the corresponding butanolides 4b–d
(2 mmol) in methanol (20 ml), 1 M NaOH solution
(4 ml; 4 mmol) was added under vigorous stirring at

ˇ
D. Berkes et al. / Tetrahedron: Asymmetry 16 (2005) 1927–1934
1934
4. Kurokawa, N.; Ohfune, Y. J. Am. Chem. Soc. 1986, 108,
6041–6043.
which HPLC analysis showed that no starting material
remained. The reaction mixture was then filtered
through a Celite pad and ethanol evaporated under re-
duced pressure. The pH of the remaining water solution
was adjusted to 5.5–6.0 at which point, raw product was
filtered off and recrystallized from 70% ethanol to give
(R)-2-amino-4-(4-methoxyphenyl)butanoic acid 5c (0.97 g,
81%); mp 261–263 ꢁC; ee 99% (HPLC column
CROWNPAK CR(+), 150 · 4 mm, mob. phase aque-
5. Fehr, T.; Quesniaux, V. F. J.; Sanglier, J. J.; Oberer, L.;
Gschwind, L.; Ponelle, M.; Schilling, W.; Wehrli, S.; Enz,
A.; Zenke, G.; Schuler, W. J. Antibiot. 1997, 50, 893–899.
6. Cornish, V. W.; Mendel, D.; Schultz, P. G. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 621–633.
7. Golubev, A. S.; Sewald, N.; Burger, K. Tetrahedron 1996,
52, 14757–14776.
8. Lin, W.-Q.; He, Z.; Zhang, H.; Zhang, X.; Mi, A.-Q.;
Jiang, Y. Synthesis 2001, 1007–1009.
9. Jackson, R. F. W.; Fraser, J. L.; Wishart, N.; Porter, B.;
Wythes, M. J. J. Chem. Soc., Perkin Trans. 1 1998, 1903–
1912.
10. Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am.
Chem. Soc. 1998, 120, 4548–4549.
11. Ferraris, D.; Young, B.; Dudding, T.; Drury, W. J., Jr.;
Lectka, T. Tetrahedron 1999, 55, 8869–8882.
12. Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc.
1998, 120, 2474–2475.
13. Urbach, H.; Henning, R. Tetrahedron Lett. 1984, 25,
1143–1146.
14. Fischer, J.; Fodor, T.; Dobay, L. Monatsh. Chem. 1988,
119, 645–647.
15. Yamada, M.; Nagashima, N.; Hasegawa, J.; Takahashi, S.
Tetrahedron Lett. 1998, 39, 9019–9022.
16. Kolarovic, A.; Berkes, D.; Baran, P.; Povazanec, F.
Tetrahedron Lett. 2001, 42, 2579–2582.
17. Berkes, D.; Lopuch, J.; Proksa, B.; Povazanec, F. Chem.
Papers 2003, 57, 350–354.
18. Jakubec, P.; Berkes, D.; Povazanec, F. Tetrahedron Lett.
2004, 45, 4755–4758.
19. Kolarovic, A.; Berkes, D.; Baran, P.; Povazanec, F.
Tetrahedron Lett. 2005, 46, 975–978.
20. Jackson, R. F. W.; Rettie, A. B.; Wood, A.; Wythes, M. J.
J. Chem. Soc., Perkin Trans. 1 1994, 1719–1726.
21. Yato, M.; Homma, K.; Ishida, A. Heterocycles 1995, 41,
17–20.
22. Berkes, D.; Kolarovic, A.; Povazanec, F. Tetrahedron
Lett. 2000, 41, 5257–5260.
ous solution of HClO4 pH = 1.0, 1.2 ml/min, tR(S)-
20
D
5c = 53 min, tR(R)-5c = 115 min); ½aꢁ ¼ ꢀ50 (c 0.4,
20
THF/1 M HCl = 4:1){lit.15 for (S)-5c ½aꢁ ¼ þ42 (c
D
0.1, 5M HCl)}.
4.8. cis-(3S,5S)-3-Amino-5-(4-methoxyphenyl)dihydro-
furan-2(3H)-one hydrochloride 6c
To a suspension of oxoamino acid 2c (2 mmol) in a mix-
ture of methanol/water (150 ml/30 ml), 46% HBr (0.352 g,
2 mmol) was added. The resulting solution was hydro-
genated (1.1 bar H2) over 10% Pd/C (200 mg) at room
temperature. The course of the reduction was monitored
by HPLC. After consumption of the starting material
(3.5–4 h), the catalyst was filtered off. The pH of the
solution was adjusted to about 7.0 with 1 M NaOH.
Methanol was evaporated in vacuo. The precipitated
mixture of hydroxyamino acids (3:7, HPLC) (540 mg)
was filtered off, treated with 4 M HCl (8 ml) and vigor-
ously stirred for 4 h at 25 ꢁC. Thereafter, the solid prod-
uct was isolated by filtration, washed with Et2O,
and dried. Yield 0.40 g (82%; d.r. 95:5); mp 215–
20
D
216 ꢁC dec. (EtOH/Et2O; d.r. = 98:2); ½aꢁ ¼ ꢀ9 (c 0.6,
20
D
DMSO) {lit.30 mp 202–203 ꢁC dec.; ½aꢁ ¼ ꢀ3.1
1
(c 1, H2O)}. H NMR (DMSO-d6): 7.44 (d, 2H, J =
8.7, H-Ar), 6.99 (d, 2H, J = 8.7, H-Ar), 5.50 (dd, 1H,
J4A,5 = 5.3, J4B,5 = 10.4, H-5), 4.53 (ꢂtꢃ, 1H, J3,4A = 8.7,
J3,4B = 10.8, H-3), 2.92–2.82 (m, 1H, H-4A); H-4B over-
lapped with solvent. 13C NMR (DMSO-d6): 172.5 (C-2);
159.9, 129.5, 128.6, 114.1 (C-Ar); 79.0 (C-5); 55.3, 49.4
(C-3, CH3); 35.0 (C-4). Anal. Calcd for C19H22ClNO3:
C, 54.22; H, 5.79; N, 5.75. Found: C, 54.17; H, 5.93;
N, 5.71.
23. Haufe, G.; Laue, K. W.; Triller, M. U.; Takeuchi, Y.;
Shibata, N. Tetrahedron 1998, 54, 5929–5938.
24. Fischer, J.; Fodor, P.; Dobay, L.; Kiss, B.; Toth, G.;
Snatzke, G.; Otvos, L. Liebigs Ann. Chem. 1989, 1093–
1097.
25. Madau, A.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry
1996, 7, 825–830.
26. Crystal data for 4c: C19H22ClNO3, M = 347.83, 0.320 0.280
0.12 mm3, monoclinic, space group C2 (No. 5), a =
Acknowledgments
˚
29.681(8), b = 7.004(2), c = 9.338(3) A, b = 105.595(4)ꢁ,
V = 1869.9(9) A , Z = 4, Dc 1.236 g cmꢀ3, l(MoKa) =
3
˚
Financial support by the Slovak Grant Agency No. 1/
9250/02 is gratefully acknowledged. Dr. Raphael G.
Raptis (UPR) is gratefully acknowledged for providing
access to the X-ray diffractometer.
2.20 cmꢀ1, T = 298 K, 2hmax = 46.68ꢁ, 4111 reflections
collected, 2279 unique (Rint = 0.0216). The refinement
(220 variables, 1 restriction) based on F2 converged with
R = 0.0282, Rw = 0.0767, and GOF = 1.058 using 2179
unique reflections with I > 2r(I).
References
27. Hutton, C. A. Tetrahedron Lett. 1997, 38, 5899–5902.
27. Hutton, C. A. Tetrahedron Lett. 1997, 38, 5899–5902.
28. Nagumo, S.; Ono, M.; Kakimoto, Y.; Furukawa, T.;
Hisano, T.; Mizukami, M.; Kawahara, N.; Akita, H. J.
Org. Chem. 2002, 67, 6618–6622.
1. Konig, W. A.; Hahn, H.; Rathmann, R.; Hass, W.;
Keckeisen, A.; Hagenmeier, H.; Bormann, C.; Dehler, W.;
Kurth, R.; Zahner, H. Liebigs Ann. Chem. 1986, 407–421.
´
2. Keller-Juslen, C.; Kuhn, M.; Loosli, H. R.; Petcher, T. J.;
Weber, H. P.; Von Wartburg, A. Tetrahedron Lett. 1976,
¨
¨
29. Jager, V.; Grund, H.; Buß, V.; Schwab, W.; Muller, I.;
Schone, R.; Franz, R.; Ehler, R. Bull. Soc. Chim. Belg.
1983, 92, 1039–1054.
30. Hegedus, L. S.; Schmeck, C. J. Am. Chem. Soc. 1994, 116,
9927–9934.
4147–4150.
3. Traber, R.; Keller-Juslen, C.; Loosli, H. R.; Kuhn, M.;
´
Von Wartburg, A. Helv. Chim. Acta 1979, 62, 1252–1267.