Crystallisation induced asymmetric transformation (CIAT) in the synthesis of furoylalanines and furylcarbinols

Article abstract of DOI:10.1016/j.tetasy.2006.04.024

A new synthesis of enantiomerically highly enriched N-substituted furoylalanines has been developed. This process involves the combination of crystallisation induced asymmetric transformation (CIAT) and a conjugate addition of N-nucleophiles to furoylacrylic acids. Further transformations to furoylalanines and substituted furylcarbinols are also described.

Full text of DOI:10.1016/j.tetasy.2006.04.024

Tetrahedron: Asymmetry 17 (2006) 1629–1637
Crystallisation induced asymmetric transformation (CIAT) in
the synthesis of furoylalanines and furylcarbinols
*
ˇ
´
´
ˇ
Pavol Jakubec, Dusˇan Berkesˇ, Richard Sisˇka, Maria Gardianova and Frantisek Povazˇanec
Department of Organic Chemistry, Slovak University of Technology, Radlinske´ho 9, SK-812 37 Bratislava, Slovakia
Received 2 March 2006; accepted 24 April 2006
Available online 30 June 2006
Abstract—A new synthesis of enantiomerically highly enriched N-substituted furoylalanines has been developed. This process involves
the combination of crystallisation induced asymmetric transformation (CIAT) and a conjugate addition of N-nucleophiles to furoyl-
acrylic acids. Further transformations to furoylalanines and substituted furylcarbinols are also described.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Kynurenine 6 is a key intermediate in a trypthophane
methabolic pathway7 (Scheme 1).
c-Hydroxy- and c-oxo-a-aminoacids represent two classes
of compounds with frequent occurrence in nature. Many
of them are isolated from different sources, for example,
c-hydroxynorvaline 1 was found in the seeds of Lathyrus
odoratus and in the fungi Boletus satanus.1 Leaves of
Calliandra pittieri and Strophantus scandeus2 contain
4-hydroxypipecolic acid 2, the compound representing
a basic building block of antibiotic virginiamycin S2.3
4-Hydroxyornithine 3 is a structural unit of biphenomycine
A, B.4 c-Oxo-norleucine 4 was isolated from Citrobacter
In 1973, Hanabusha isolated a new member of c-oxo-a-
aminoacids family, namely L-2-(20-furoyl)alanine 7a from
Fagopyrum esculentum,8 (Scheme 1). There have also been
two reports claiming its occurrence in the roots of Rumex
obtusifolius9 and in the seeds of Fagus silvatica.10 In addi-
tion, this natural product is considered to be an important
degradation product, as revealed by the structure elucida-
tion of ascorbalamic acid.11 Since the discovery of 7a, only
two of its syntheses have appeared and both represent a
similar chiral-pool approach starting from enantiomeri-
cally pure aspartic acid.12,13
freundii,5 5-hydroxy-c-oxo-norvaline
5
from both
Streptomyces H-8997 and Streptomyces akiyoshiensis.6
Over the last decade, we14 and others15 have discovered a
unique stereoselective approach to the synthesis of c-oxo-
derivatives of L-homophenylalanine (L-Hpa) featuring a
OH
OH NH2
COOH
OH NH2
COOH
crystallisation
induced
asymmetric
transformation
(CIAT).16 Thus, we are able to prepare highly enantiome-
rically enriched derivatives of L-Hpa using inexpensive
and readily available aroylacrylic acids and a-methylbenz-
ylamine. The notable advantage of CIAT over previous
synthetic methods is the high stereoselectivity, mild reac-
tion conditions (ranging from rt to 40 ꢁC), the use of inex-
pensive solvents and a simple work-up.
H2N
O
N
H
COOH
1
2
3
O
NH2
O
NH2
O
NH2
COOH
R
COOH
COOH
4 R=H
6
7a
NH2
5 R=OH
Herein we report a new and highly stereoselective synthesis
of furoylalanines 7a–c using CIAT in the conjugate addi-
tion of (R)-phenylglycinol and/or (S)-phenylethylamine to
a,b-unsaturated furoylacrylic acids 10a–c. The highly
enantiomerically enriched, N-substituted furoylalanines
Scheme 1. Some c-hydroxy- and c-oxo-a-aminoacids occurring in nature.
*
Corresponding author. Tel.: +421 2 5932 5746; fax: +421 2 5296 8560;
e-mail: pavol.jakubec@zoznam.sk
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.024

1630
P. Jakubec et al. / Tetrahedron: Asymmetry 17 (2006) 1629–1637
obtained 11a–c, 12a–c, which were further transformed to
the furylcarbinols 13a–c and 14a–c. The latter represent
suitable substrates for many useful transformations of
the furan ring and are expedient starting materials for the
synthesis of natural products using the Achmatowicz
reaction.17
CIAT highly diastereoselective conjugate addition of (R)-
2-amino-2-phenylethanol and/or (S)-1-phenylethylamine
to the unsaturated acids 10a–c (Scheme 3).
The reaction conditions are mild (40 ꢁC, 24–48 h) and the
respective adducts 11a–c and/or 12a–c can be obtained in
moderate to good yields (51–80%) and in excellent de’s
(92–98%). The reaction medium used plays a crucial role
in the success or failure of such CIAT processes. Small
alteration of the solvent from more polar MeOH to slightly
more lipophilic EtOH was vital to the precipitation of the
desired adducts in the case of 10b and c (Table 1).
2. Synthesis
Due to their gastric anti-secretory, anti-ulcer and cytopro-
tective properties, furoylacrylic acids 10a–c represent a class
of biologically active compounds.18 There are two methods
in the literature describing the preparation of acids 10a and
b. However, we found the results reported by Ichihara et al.8
(KOH, MeOH) as experimentally irreproducible and only
complex reaction mixtures were obtained. On the other
hand, Bianchi’s acid-catalysed condensation18 (AcOH,
concd HCl) worked well for 9a–c, although, the subsequent
elimination failed in our hands. Thus, we have screened dif-
ferent dehydrating agents in order to arrive at the desired
products 10a–c. The best results were obtained using
KHSO4 in boiling toluene19 (Scheme 2).
Table 1. CIAT in the conjugate addition of N-nucleophiles to 10a–c
Adduct
R1
Conditions
dra (%)
Yielda (%)
12a
12b
12b
12c
12c
11a
11b
11b
11c
11c
H
MeOH, 24 h
MeOH, 24 h
EtOH, 48 h
MeOH, 24h
EtOH, 48 h
MeOH, 24 h
MeOH, 24 h
EtOH, 48 h
MeOH, 48 h
EtOH, 48 h
>99:1
—
99:1
—
>99:1
99:1
—
>99:1
—
74
0
56
0
55
80
0
71
0
Me
Me
Et
Et
H
Me
Me
Et
Et
96:4
51
O
O
OH
COOH
a Data for solid product isolated by filtration.
i
O
O
R1
R1
In order to establish the expected stereochemical develop-
ment of (S)-1-phenylethylamine addition to 10a, we moni-
tored the reaction by HPLC (Biospher SGX C18 5 lm,
4.6 · 250 mm). As can be gleaned from Figure 1, the ratio
of both diastereomeric products 120a/12a formed in the
reaction mixture was approximately equal at the initial
stages (conversion > 90%, dr = 44:56 after 30 min). How-
ever, as the CIAT progressed in time, 12a clearly became
a major adduct of the transformation with the concomitant
decline of the content of its (2R,10S)-configured diastereo-
isomer 120a. Thus, after 24 h of stirring and subsequent fil-
tration of the heterogenous reaction mixture, we obtained
12a in 74% yield and with 98% de (Fig. 1).
8a-c
9a-c
ii
O
O
COOH
R1
10a-c
Scheme 2. Reagents and conditions: (i) glyoxylic acid, 95 ꢁC, 12 h; (ii)
KHSO4, toluene, reflux, 2–3 h; crystallisation R1 = H, Me, Et 22–39% in
two steps.
An analogous stereochemical course was also observed for
additions of (S)-1-phenylethylamine to 10b and c as well as
for CIAT process using (R)-phenylglycinol and 10a–c.
The key step in our synthesis of substituted furoylalanines
is represented by the regiospecific and, in tandem with
Ph
Ph
OH
OH
O
O
HN
O
HN
O
O
O
O
i
+
R1
R1
COOH
COOH
11a-c
major
11´a-c
minor
Ph
Ph
10a-c
O
HN
HN
ii
R1
R1
COOH
COOH
+
12a-c
major
12´a-c
minor
Scheme 3. Reagents and conditions: (i) (R)-2-amino-2-phenylethanol, 40 ꢁC; (ii) (S)-phenylethylamine, 40 ꢁC, other conditions are in Table 1.

P. Jakubec et al. / Tetrahedron: Asymmetry 17 (2006) 1629–1637
Table 2. Reduction of 11a–c and 12a–c
1631
100
80
60
40
20
0
Product
R1
R2
syn:anti
Yieldb (%)
a
b
13a
13b
13c
14a
14b
14c
H
H
H
H
OH
OH
OH
95:5
96:4
96:4
95:5
96:4
96:4
98:2
97:3
97:3
98:2
97:3
99:1
90
72
82
70
70
77
Me
Et
H
Me
Et
0.5
1
2
3
4
6
7
8
10 12 24
Time [h]
Figure 1. Stereochemical development of (S)-1-phenylethylamine addition
to 10a; ( ) (2R,10S)-diastereomer 120a, ( ) (2S,10S)-diastereomer 12a.
a Data for crude reaction mixture.
b Data for isolated solid product.
The final stage of the furoylalanines 7a–c synthesis required
the removal of benzyl substituents on nitrogen. The at-
tempts to deprotect 11a–c and/or 12a–c under acidic
hydrogenolytic conditions (H2/Pd, cat. HCl, MeOH)
failed. Gratifyingly, the neutral oxidative conditions20 ap-
plied to 11a–c furnished the desired free amino acids 7a–c
in poor to acceptable yields (20–69%). This was mainly
due to the high solubility and instability of the products
in aqueous solvent that considerably complicate the
work-up and subsequent purification of targets 7a–c. We
assume that N-dealkylation proceeeds via the mechanism
analogous to the oxidative cleavage of 1,2-diols with
NaIO4. This hypothesis is strongly supported by the fact
that we have isolated benzaldehyde from the reaction mix-
ture. Finally, the oxidative N-dealkylation proceeds with-
out any observable racemisation (Scheme 4).
this highly diastereoselective reduction, due to the com-
plexation with 2-amino-4-oxo moiety forming a six-mem-
bered chelate ring.
2.1. Elucidation of the relative configuration
The determination of the relative configurations of furyl-
carbinols 13a–c and 14a–c were based on the results ob-
tained from NOE experiments, which were performed on
cyclic derivatives 15a and 150a. Acidic lactonisation of
13a under various conditions (HCl or PTSA or SOCl2)
led, however, to complex reaction mixtures only. Gratify-
ingly, the employment of DCC allowed us to prepare the
desired lactone 15a under mild conditions (Scheme 6).
Ph
Ph
O
OH
OH
HN
O
O
NH2
COOH
O
HN
i
4
i
O
O
O
O
COOH
2
4
2
R1
COOH
11a-c
R1
Ph
HN
13a
15a
7a-c
Scheme 6. Reagents and conditions: (i) DCC, CH2Cl2, 24 h, rt, 51%.
Scheme 4. Reagents and conditions: (i) NaIO4, H2O, Et3N, rt, pH = 7,
30 min; R1 = H 69% (7a), R1 = Me 36% (7b), R1 = Et 35% (7c) after
crystallisation.
As expected, there were no NOE’s observed between pro-
tons at C-2 and C-4 suggesting the relative 2,4-anti-config-
uration of 15a. This, in turn, would indicate the 2,4-syn-
configuration of 13a. On the other hand, the reduction of
12a with the exclusion of MnCl2 produced a diastereomeric
mixture of 2,4-syn-13a and 2,4-anti-130a furylcarbinols in a
66:34 ratio. Subsequent lactonisation of this mixture fur-
nished the corresponding lactones 15a and 150a in a diaste-
reomeric ratio of 66:34 suggesting that no epimerisation
occurred during the cyclisation. The desired 150a was iso-
lated from the mixture by means of FLC and its NOE data
clearly showed the expected 2,4-cis relative configuration
(Scheme 7).
Next, we have turned our attention to the synthesis of
substituted furylcarbinols 13a–c and 14a–c. In our previous
paper,21 we have described the highly diastereoselective
reduction of N-substituted 2-amino-4-aryl-4-oxobutanoic
acids to the corresponding N-substituted syn-a-amino-c-
hydroxybutanoic acids. In the cases of 11a–c and 12a–c,
the application of NaBH4/MnCl2Æ4H2O reductive system
led to the formation of the desired syn-c-hydroxyamino
acids 13a–c and 14a–c in good yields (70–90%) and excel-
lent syn:anti selectivities (de 94–98%) (Scheme 5 and Table
2). Manganese(II) chloride is an indispensable reagent in
Ph
Furthermore, the basic hydrolysis of 2,4-cis lactone 150a
furnished its parent 2,4-anti-hydroxyacid 130a, thus con-
firming its stereochemistry. Finally, the hydroxyacid 130a
is a minor product obtained by stereoselective reduction
of 12a in the NaBH4–MnCl2 system (Scheme 5). This nat-
urally implies that the major product of the reduction has
to be 2,4-syn-hydroxyacid 13a. The relative configurations
of all other furylcarbinols 13b–c and 14a–c were tentatively
assigned on the basis of these results.
Ph
R2
R2
O
HN
OH
HN
i
O
O
COOH
R1
R1
COOH
11a-c,12a-c
13a-c,14a-c
Scheme 5. Reagents and conditions: (i) NaBH4, MnCl2Æ4H2O, MeOH, 0–
5 ꢁC, 30 min.

1632
P. Jakubec et al. / Tetrahedron: Asymmetry 17 (2006) 1629–1637
absolute (S)-configuration. In order to establish the abso-
Ph
Ph
lute configuration of the newly created stereogenic centre
at C-2 of 12a, we transformed 12a into a known compound
(Scheme 9). As expected, the NaIO4/RuCl3 mediated oxi-
dation of the furan ring22 afforded the N-substituted diacid
16. Its final transformation to (S)-aspartic acid 17 was
accomplished by catalytic reduction. Finally, the absolute
configuration of 17 was determined by HPLC on a chiral
stationary phase.
O
HN
OH
HN
i
O
O
COOH
COOH
4
2
12a
13a/13'a
(66:34)
ii, iii
O
O
O
O
H
Ph
N
O
3. Conclusion
4
O
H4 5.4%
3.4%
15a
H2
2
We have successfully broadened the scope of CIAT in the
conjugate addition of N-nucleophiles to furoylacrylic acids
10. We have subsequently utilised this stereoselective pro-
cess in the novel synthesis of highly diastereo- and/or enan-
tiomerically enriched furoylalanines 7, 11, 12. The main
advantage of our synthetic approach over the previous
methods lies in the simple experimental setup including
work-up and purification. The furoylalanines prepared
were employed as suitable substrates for the synthesis of
furylcarbinols 13 and 14. These compounds represent an
appropriate starting material for many synthetically useful
transformations of furan rings. The determination of the
relative and/or absolute configurations was carried out by
comparison of the known literature data with results ob-
tained from polarimetric and NOE experiments, as well
as those of chiral HPLC analyses.
Ph
HN
15'a
15'a
Scheme 7. Reagents and conditions: (i) NaBH4, MeOH, rt, 30 min, 79%,
dr 66:34; (ii) DCC, rt, CH2Cl2, 24 h; (iii) FLC; 15a 36%, 150a 19%.
2.2. Elucidation of the absolute configuration
At first, we have prepared racemic mixtures of 7a–c by the
conjugate addition of aqueous ammonia to furoylacrylic
acids 10a–c (Scheme 8).
O
O
NH2
COOH
i
O
O
R1
R1
COOH
2
10a-c
7a-c
Rac
4. Experimental
4.1. General
Scheme 8. Reagents and conditions: (i) 26% aq NH3, 1 h, R1 = H 40%,
R1 = Me 43%, R1 = Et 43%, yields refer to the pure material after
crystallisation.
All reagents were used as received without further purifica-
tion unless otherwise specified. (S)-Phenylethylamine
(99+%, 99% ee) was obtained from ACROS and (R)-2-
amino-2-phenylethanol was prepared from (R)-phenylgly-
cine.23 Melting points were obtained using a Kofler hot
plate and are uncorrected. Optical rotations were measured
with POLAR L-lP polarimeter (IBZ Messtechnik) with a
water-jacked 10.000 cm cell at a wavelength of sodium line
D (k = 589 nm). Specific rotations are given in units of
10ꢁ1 deg cm2 gꢁ1 and concentrations are given in g/
100 ml. 1H NMR spectra were recorded on a Varian
VXR-300 (299.94 MHz) spectrometer. Chemical shifts (d)
are quoted in parts per million and are referenced to the
tetramethylsilane (TMS) as internal standard (dMe = 0.00
for 299.94 MHz). Coupling constants (J) are recorded in
hertz. The following abbreviations were used throughout
to characterise signal multiplicities: s (singlet), d (doublet),
t (triplet), m (multiplet), b (broad). Abbreviations with
quotation marks mean that the appearance of the signal
is different from that theoretically predicted. 13C NMR
spectra were recorded on a Varian VXR-300 (75.43 MHz)
spectrometer. The multiplicities of the carbons were
assigned from a broadband decoupled analysis used in a
conjunction with either APT or DEPT programmes.
Chemical shifts are quoted in parts per million and are
referenced to the tetramethylsilane (TMS) as internal
standard (d = 0.00 ppm for 75.43 MHz).
This material was used next as HPLC standard for the
determination of enantiomeric excesses. On the basis of
the claim that (S)-a-amino acids always elute first under
the respective analytical conditions (CROWNPAK CR
(+), Daicel, Japan, eluent HClO4, pH = 2.0), we were able
to tentatively assign the absolute configuration of the newly
created stereogenic centre at C-2 of 7a–c. In addition, the
comparison of the measured value of specific rotation of
20
7a {½aꢀD ¼ þ43:2 (c 0.5, 1 M HCl)/with known literature
20
data for 7a/½aꢀD ¼ þ43:0 (c 1, 2 M HCl)}12 confirmed the
Ph
Ph
HN
. HCl
O
HN
i, ii
HOOC
O
COOH
COOH
12a
16
iii
NH2
COOH
17
HOOC
Scheme 9. Reagents and conditions: (i) RuCl3, NaIO4, H2O, CCl4,
CH3CN, rt, 30 min; (ii) HCl, 25% after two steps; (iii) H2, Pd/C, ꢂ100%.

P. Jakubec et al. / Tetrahedron: Asymmetry 17 (2006) 1629–1637
1633
HPLC experiments were performed on PYE UNICAM
4.3. General procedure for the conjugate addition of
N-nucleophiles to unsaturated acids (10a–c)
chromatographic system (PU 4015 pump working in izo-
cratic mode). Multichannel detector PU 4021 was per-
formed in SUM ABS mode at wavelengths ranging from
210 to 310 nm. The following columns and eluents were
used for HPLC experiments: Biospher SGX C18 5 lm,
4.6 · 250 mm; Nova-Pak C18 5 lm; 4.6 · 250 mm,
CROWNPAK CR (+); HClO4, pH = 2.0, water/CH3CN
6:1, 1.5% of Et3N; water/CH3CN 2:3, 1.5% of Et3N. Injec-
tion volume was 20 ll.
Acid 10a (12.0 mmol, 2.0 g) was dissolved in methanol
(30 ml). (S)-1-Phenylethylamine (1.1 equiv, 13.2 mmol,
1.69 ml) was then added and the resulting solution vigor-
ously stirred at 40 ꢁC for 24 h. The suspension was cooled
to rt, at which point the solid was filtered off, washed with
Et2O (20 ml) and dried to obtain amino acid 12a (2.551 g,
74%, dr 99:1) as a white solid.
4.2. Synthesis
4.3.1. (2S,10S)-4-(Furan-2-yl)-4-oxo-2-[(10-phenylethyl)amino]-
butanoic acid 12a. After recrystallisation from H2O: dr
25
4.2.1. (2E)-4-(Furan-2-yl)-4-oxobut-2-enoic acid 10a.
A
>99:1. Mp = 172–173 ꢁC (decomposition); ½aꢀD ¼ þ37:2
mixture of ketone 8a (181.6 mmol, 20 g) and glyoxylic acid
monohydrate (1.5 equiv, 272.5 mmol, 25.069 g) was stirred
for 12 h at 95 ꢁC. Toluene (500 ml) and KHSO4 (2 equiv,
363.2 mmol, 49.453 g) were added and the resulting suspen-
sion vigorously stirred at reflux for 2.5 h. Activated char-
coal was added and insoluble material was removed by
filtration. The crystalline compound obtained by filtrate
cooling was filtered off, washed with heptane and dried to
furnish an acid 10a (11.891 g, 39%) as a yellow solid.
Mp = 160–162 ꢁC (H2O), lit.18 mp = 158–160 ꢁC (pro-
pane-2-ol); 1H NMR (d6-DMSO): 8.12 (d, 1H, J = 1.5,
H–Ar); 7.82 (d, 1H, J = 3.7, H–Ar); 7.70 (d, 1H,
J = 15.4, H-3); 6.80 (dd, 1H, J = 3.7, J = 1.5, H–Ar);
6.74 (d, 1H, J = 15.4, H-2); 13C NMR (d6-DMSO): 175.8
(C-4); 166.1 (C-1); 152.0, 149.5, 135.4, 132.4, 121.4, 113.2
(C–Ar, C-2, C-3).
(c 0.9, MeOH/1 M HCl 3:1); 1H NMR (CD3OD/DCl):
7.86 (d, 1H, J = 1.5, H–Ar); 7.51–7.56 (m, 5H, H–Ph);
7.45 (d, 1H, J = 3.5, H–Ar); 6.71 (dd, 1H, J = 3.5,
J = 1.5, H–Ar); 4.73 (q, 1H, J = 6.9, H-10); 4.15 (dd, 1H,
J = 4.5, J = 5.9, H-2); 3.61 (dd, 1H, J = 18.8, J = 5.9, H-
3B); 3.54 (dd, 1H, J = 18.8, J = 4.5, H-3A); 1.78 (d, 3H,
J = 6.9, H-20); 13C NMR (CD3O/DCl): 185.0 (C-4); 170.4
(C-1); 152.5, 149.5, 136.6, 131.1, 130.7, 129.2, 120.6,
114.0 (C–Ar); 60.3, 54.1 (C-10, C-2); 39.3 (C-3); 20.4 (C-
20). Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88.
Found: C, 67.06; H, 6.01; N, 4.85.
4.3.2. (2S,10S)-4-(5-Methylfuran-2-yl)-4-oxo-2-[(10-phenyl-
ethyl)amino]-butanoic acid 12b. According to the gen-
eral procedure (for 3.0 g of 10b used 2.33 ml of
(S)-phenylethylamine, 90 ml of EtOH at 40 ꢁC, 48 h),
12b (2.83 g, 56%, dr 99:1) was obtained as a white solid.
4.2.2. (2E)-4-(5-Methylfuran-2-yl)-4-oxobut-2-enoic acid
(10b). According to the procedure above (for 3.0 g of 8b
used 3.336 g of glyoxylic acid, 6.591 g of KHSO4, 50 ml
of toluene) 10b (1.250 g, 29%) was obtained as a yellow
solid. Mp = 164–166 ꢁC (H2O), lit.18 mp = 159–162 ꢁC
After recrystallisation from EtOH: dr 99:1. Mp = 172–
25
173 ꢁC (decomposition), ½aꢀD ¼ þ50:3 (c 1.0, MeOH/1 M
HCl 3:1); 1H NMR (CD3OD/DCl): 7.49–7.58 (m, 5H,
H–Ph); 7.37 (d, 1H, J = 3.5, H–Ar); 6.35 (d, 1H, J = 3.5,
H–Ar); 4.73 (q, 1H, J = 6.9, H-10); 4.10 (‘t’, 1H, J = 4.5,
J = 5.4, H-2); 3.58 (dd, 1H, J = 18.8, J = 5.4, H-3B); 3.50
(dd, 1H, J = 18.8, J = 4.5, H-3A); 2.40 (s, 3H, CH3);
1.79 (d, 3H, J = 6.9, H-20); 13C NMR (CD3OD/DCl):
184.2 (C-4); 170.4 (C-1); 160.8, 151.2, 136.7, 131.0,
130.6, 129.2, 122.6, 110.8 (C–Ar), 60.2 (C-2); 54.3 (C-10);
38.9 (C-3); 20.4 (C-20); 13.9 (CH3). Calcd for C17H19NO4:
C, 67.76; H, 6.36; N, 4.65. Found C, 67.69; H, 6.33; N,
4.64.
1
(AcOEt); H NMR (CDCl3): 7.80 (d, 1H, J = 15.4, H-3);
7.34 (d, 1H, J = 3.4, H–Ar); 6.97 (d, J = 15.4, H-2); 6.28
(d, 1H, J = 3.4, H–Ar); 2.46 (s, 3H, CH3); 13C NMR
(CDCl3): 175.1 (C-4); 170.2 (C-1); 160.2, 151.6, 137.7,
130.5, 122.2, 110.1 (C–Ar, C-2, C-3); 14.2 (CH3).
4.2.3. (2E)-4-(5-Ethylfuran-2-yl)-4-oxobut-2-enoic acid
(10c). A mixture of ketone 8c (112.5 mmol, 15.5 g) and
glyoxylic acid monohydrate (1.5 equiv, 168.8 mmol,
15.535 g) was stirred for 12 h at 95 ꢁC. The viscous liquid
was partitioned to six equal parts in toluene (6 · 40 ml),
KHSO4 (6 · 5.11 g, overall 225 mmol) was added and
resulting mixtures were vigorusly stirred at reflux for 3 h.
Activated charcoal was added and the insoluble solid re-
moved by filtration. The combined filtrates were cooled
to ꢁ20 ꢁC and left to stand for 24 h. The crystalline mate-
rial was filtered, washed with heptane and dried to obtain
acid 10c (4.832 g, 22%) as a yellow solid. Mp = 112–
4.3.3. (2S,10S)-4-(5-Ethylfuran-2-yl)-4-oxo-2-[(10-phenylethyl)-
amino]-butanoic acid 12c. According to the general
procedure (for 3.0 g of 10c used 2.16 ml of (S)-phenylethyl-
amine, 90 ml of EtOH at 40 ꢁC, 48 h), 12c (2.66 g, 55%,
dr >99:1) was obtained as a white solid. After recrystallisa-
tion from H2O: dr >99:1. Mp = 173–175 ꢁC (decompo-
25
sition), ½aꢀD ¼ þ50:7 (c 0.3, MeOH/1 M HCl 3:1);
1H NMR (CD3OD/DCl): 7.50–7.57 (m, 5H, H–Ph); 7.38
(d, 1H, J = 3.5, H–Ar); 6.37 (d, 1H, J = 3.5, H–Ar); 4.73
(q, 1H, J = 6.9, H-10); 4.12 (dd, 1H, J = 5.0, J = 6.4,
H-2); 3.56 (dd, 1H, J = 18.6, J = 6.4, H-3B); 3.49 (d, 1H,
J = 18.6, J = 5.0, H-3A); 2.77 (q, 2H, J = 7.4, CH2CH3);
1.78 (d, 3H, J = 6.9, H-20); 1.30 (t, 3H, J = 7.4, CH2CH3);
13C NMR (CD3OD/DCl): 184.2 (C-2); 170.4 (C-1);
165.9, 151.2, 136.7, 131.0, 130.7, 129.1, 122.3, 109.3
(C–Ar); 60.3 (C-2); 54.4 (C-10); 38.9 (C-3); 22.6 (CH2CH3);
20.2 (C-20); 12.2 (CH2CH3). Calcd for C18H21NO4:
1
113 ꢁC (H2O); H NMR (CDCl3): 7.81 (d, 1H, J = 15.8,
H-3); 7.37 (d, 1H, J = 3.4, H–Ar); 6.98 (d, 1H, J = 15.8,
H-2); 6.29 (d, 1H, J = 3.4, H–Ar); 2.80 (q, 2H, J = 7.3,
CH2CH3); 1.32 (t, 3H, J = 7.3, CH2CH3); 13C NMR
(CDCl3): 175.2 (C-4); 170.4 (C-1); 165.6, 151.4, 137.7,
130.5, 122.2, 108.5 (C–Ar, C-2, C-3); 21.9 (CH2CH3);
11.6 (CH2CH3). Calcd for C10H10O4: C, 61.85; H, 5.19.
Found C, 61.62; H, 5.17.

1634
P. Jakubec et al. / Tetrahedron: Asymmetry 17 (2006) 1629–1637
C, 68.55; H, 6.71; N, 4.44. Found: C, 68.25; H, 6.73; N,
4.42.
4.4. General procedure for the preparation of hydroxyacids
13 and 14
4.3.4. (2S,10R)-4-(Furan-2-yl)-2-[(20-hydroxy-10-phenylethyl)-
amino]-4-oxobutanoic acid 11a. According to the general
procedure (for 6.6 mmol, 1.1 g of 10a used 1.1 equiv,
7.3 mmol, 0.999 g of (R)-2-amino-2-phenylethanol, 20 ml
of MeOH at 40 ꢁC, 24 h), 11a (1.16 g, 80%, dr 99:1) was ob-
Acid 12a (10.4 mmol, 3.0 g) was suspended in MeOH
(90 ml) and MnCl2Æ4H2O (0.2 equiv, 2.1 mmol, 0.41 g),
was dissolved in the mixture. The resulting suspension
was cooled to 0–5 ꢁC, NaBH4 (2 equiv, 20.9 mmol,
0.773 g) was then added over 10 min and the reaction mix-
ture stirred for 30 min. The solvent was evaporated in vacuo
and 5% aq soln of NaHCO3 (150 ml) was added to the
residue and the mixture stirred at rt for 15 min. The brown
solid was filtered off and the pH of the filtrate adjusted to
6.0–6.5. The precipitated solid was filtered, washed with
H2O (100 ml), Et2O (50 ml) and dried to obtain the hydroxy-
acid 13a (2.70 g, 90%, dr 98:2) as a white solid.
tained as a white solid. After recrystallisation from EtOH:
25
dr >99:1. Mp = 165–167 ꢁC (decomposition), ½aꢀD ¼ þ23:2
(c 0.5, MeOH/1 M HCl 3:1); 1H NMR (CD3OD/DCl):
7.86 (d, 1H, J = 1.5, H–Ar); 7.52–7.60 (m, 5H, H–Ph);
7.48 (d, 1H, J = 3.5, H–Ar); 6.71 (dd, 1H, J = 3.5,
J = 1.5, H–Ar); 4.75 (dd, 1H, J = 5.0, J = 8.9, H-10); 4.26
(dd, 1H, J = 4.5, J = 6.4, H-2); 4.07 (dd, 1H, J = 11.9,
J = 8.9, H-20B); 3.98 (dd, 1H, J = 11.9, J = 5.0, H-20A);
3.69 (dd, 1H, J = 18.8, J = 6.4, H-3B); 3.58 (dd, 1H,
J = 18.8, J = 4.5, H-3A); 13C NMR (d6-acetone/DCl):
186.0 (C-4); 170.5 (C-1); 153.1, 149.2, 133.2, 131.6, 131.3,
131.0, 120.9, 114.4 (C–Ar); 67.0 (C-20); 64.3, 54.3 (C-10,
C-2); 40.0 (C-3). Calcd for C16H17NO5: C, 63.36; H, 5.65;
N, 4.62. Found: C, 63.09; H, 5.66; N, 4.64.
4.4.1. (2S,4R,10S)-4-(Furan-2-yl)-4-hydroxy-2-[(10-phenyl-
ethyl)amino]-butanoic acid 13a. After recrystallisation
from EtOH: dr >99:1. Mp = 216–217 ꢁC (decomposition);
25
1
½aꢀD ¼ ꢁ37:2 (c 1.0, 0.1 M NaOH); H NMR (CD3OD/
DCl): 7.45–7.60 (m, 6H, H–Ar); 6.35–6.39 (m, 1H, H–
Ar); 6.29 (d, 1H, J = 3.0, H–Ar); 4.83 (dd, 1H, J = 4.0,
J = 9.4, H-4); 4.61 (q, 1H, J = 6.9, H-10); 3.78 (t, 1H,
J = 6.4, H-2); 2.27–2.44 (m, 2H, H-3); 1.79 (d, 3H,
J = 6.9, H-20); 13C NMR (d6-DMSO/DCl): 169.3 (C-1);
156.2, 142.1, 136.1, 129.2, 129.1, 128.1, 110.2, 105.9 (C–
Ar); 62.0 (C-4); 56.7, 54.2 (C-2, C-10), 35.5 (C-3); 20.1
(C-20). Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84.
Found: C, 66.64; H, 6.44; N, 4.80.
4.3.5. (2S,10R)-2-[(20-Hydroxy-10-phenylethyl)amino]-4-(5-
methylfuran-2-yl)-4-oxobutanoic acid 11b. According to
the general procedure (for 1.0 g of 10b used 0.840 g of
(R)-2-amino-2-phenylethanol, 25 ml of EtOH at 40 ꢁC,
48 h), 11b (1.259 g, 71%, dr >99:1) was obtained as a white
solid. After recrystallisation from EtOH–CH3CN: dr
25
>99:1. Mp = 164–165 ꢁC (decomposition), ½aꢀD ¼ þ36:7
(c 0.6, MeOH/1 M HCl 3:1). 1H NMR (CD3OD/DCl):
7.51–7.59 (m, 5H, H–Ph); 7.36 (d, 1H, J = 3.5, H–Ar);
6.35 (d, 1H, J = 3.5, H–Ar); 4.74 (dd, 1H, J = 5.0,
J = 8.9, H-10); 4.24 (dd, 1H, J = 4.0, J = 6.4, H-2); 4.05
(dd, 1H, J = 11.9, J = 8.9, H-20B); 3.98 (dd, 1H,
J = 11.9, J = 5.0, H-20A); 3.62 (dd, 1H, J = 18.8, J = 6.4,
H-3B); 3.51 (dd, 1H, J = 18.8, J = 4.0, H-3A); 2.41 (s,
3H, CH3); 13C NMR (CD3OD/DCl): 184.7 (C-4); 170.4
(C-1); 160.9, 151.3, 132.6, 131.4, 130.7, 129.9, 122.6,
110.8 (C–Ar); 66.1 (C-20); 63.6, 54.3 (C-2, C-10); 38.7 (C-
3); 13.9 (CH3). Calcd for C17H19NO5: C, 64.34; H, 6.03;
N, 4.41. Found: C, 63.91; H, 6.09; N, 4.44.
4.4.2. (2S,4R,10S)-4-Hydroxy-4-(5-methylfuran-2-yl)-2-[(10-
phenylethyl)amino]-butanoic acid 13b. According to the
general procedure (from 1.0 g of 12b), 13b (0.723 g, 72%,
dr 97:3) was obtained as a white solid. Compound 13b cre-
ates only stable gel in EtOH, analytical sample obtained
after drying of gel, dr >99:1. Mp = 182–184 ꢁC (EtOH);
25
1
½aꢀD ¼ ꢁ44:0 (c 0.1, 0.1 M NaOH); H NMR (CD3OD):
7.35–7.55 (m, 5H, H–Ph); 6.08 (d, 1H, J = 3.5, H–Ar);
5.91 (d, 1H, J = 3.5, H–Ar); 4.68 (dd, 1H, J = 8.8,
J = 3.5, H-4); 4.32 (q, 1H, J = 6.4, H-10); 3.28–3.31 (m,
1H, H-2); 2.02–2.33 (m, 5H, H-3, CH3); 1.64 (d, 3H,
J = 6.4, H-20); 13C NMR (CD3OD): 174.6 (C-1); 155.3,
152.8, 139.9, 130.3, 130.2, 128.7, 107.9, 107.0 (C–Ar);
67.9 (C-4); 61.6, 59.1 (C-10, C-2); 37.7 (C-3); 22.0 (C-20);
13.4 (CH3). Calcd for C17H21NO4: C, 67.31; H, 6.98; N,
4.62. Found: C, 66.97; H, 6.95; N, 4.65.
4.3.6. (2S,10R)-4-(5-Ethylfuran-2-yl)-2-[(20-hydroxy-10-phenyl-
ethyl)amino]-4-oxobutanoic acid 11c. According to the
general procedure (for 2.0 g of 10c used 1.549 g of (R)-2-
amino-2-phenylethanol, 40 ml of EtOH at 40 ꢁC, 48 h),
11c (1.719 g, 51%, dr 96:4) was obtained as a white solid.
4.4.3. (2S,4R,10S)-4-(5-Ethylfuran-2-yl)-4-hydroxy-2-[(10-phen-
ylethyl)amino]-butanoic acid 13c. According to the general
procedure (from 1.50 g of 12c), 13c (1.273 g, 82%, dr 97:3)
After recrystallisation from EtOH: dr 98:2. Mp = 172–
25
173 ꢁC (decomposition); ½aꢀD ¼ þ31:3 (c 0.5, MeOH/1 M
1
HCl 3:1); H NMR (CD3OD/DCl): 7.50–7.62 (m, 5H, H–
was obtained as a white solid. After recrystallisation from
25
Ph); 7.40 (d, 1H, J = 3.5, H–Ar); 6.38 (d, 1H, J = 3.5,
H–Ar); 4.73 (dd, 1H, J = 4.5, J = 8.9, H-10); 4.35–4.39
(m, 1H, H-2); 4.08 (dd, 1H, J = 11.4, J = 8.9, H-20B);
3.99 (dd, 1H, J = 11.4, J = 4.5, H-20A); 3.54–3.68 (m,
2H, H-3); 2.77 (q, 2H, J = 7.4, CH2CH3); 1.30 (t, 3H,
J = 7.4, CH2CH3); 13C NMR (CD3OD/DCl): 184.5 (C-
4); 169.6 (C-1); 166.2, 151.0, 132.5, 131.4, 130.0, 130.7,
122.7, 109.4 (C–Ar); 66.0 (C-20); 63.6, 54.4 (C-2, C-10);
38.7 (C-3); 22.6 (CH2CH3); 12.2 (CH2CH3). Calcd for
C18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C, 65.51;
H, 6.40; N, 4.24.
EtOH–CH3CN: dr 99:1. Mp = 193–195 ꢁC; ½aꢀD ¼ ꢁ35:1
1
(c 1.0, 0.1 M NaOH); H NMR (CD3OD): 7.47–7.59 (m,
5H, H–Ph); 6.15 (d, 1H, J = 2.7, H–Ar); 5.96 (d, 1H, J =
2.7, H–Ar); 4.76 (‘t’, 1H, J = 5.2, J = 8.2, H-4); 4.60 (q,
1H, J = 6.4, H-10); 2.62 (q, 2H, J = 7.7, CH2CH3); 2.23–
2.39 (m, 1H, H-3); 1.78 (d, 3H, J = 6.4, H-20); 1.22 (t, 3H,
J = 7.7, CH2CH3); 13C NMR (CD3OD): 174.5 (C-1); 158.9,
154.4, 136.7, 131.1, 130.8, 128.9, 108.2, 105.6 (C–Ar); 66.1
(C-4); 61.5, 59.5 (C-10, C-2); 36.3 (C-3); 22.2 (CH2CH3);
20.4 (C-20); 12.6 (CH2CH3). Calcd for C18H23NO4: C,
68.12; H, 7.30; N, 4.41. Found: C, 68.29; H, 7.33; N, 4.43.

P. Jakubec et al. / Tetrahedron: Asymmetry 17 (2006) 1629–1637
1635
4.4.4. (2S,4R,10R)-4-(Furan-2-yl)-4-hydroxy-2-[(20-hydroxy-
10-phenylethyl)amino]-butanoic acid 14a. According to the
general procedure (from 2.6 g of 11a), 14a (1.843 g, 70%, dr
98:2) was obtained as a white solid. After recrystallisation
from EtOH–CH3CN–H2O: dr 99:1. Mp = 169–171 ꢁC
(decomposition); ½aꢀD ¼ ꢁ43:9 (c 1.0, 0.1 M NaOH); H
NMR (d6-DMSO): 7.47 (d, 1H, J = 1.8, H–Ar); 7.20–7.32
(m, 5H, H–Ph); 6.28 (dd, 1H, J = 3.5, J = 1.8, H–Ar);
6.06 (d, 1H, J = 3.5, H–Ar); 4.70 (‘t’, 1H, J = 6.4,
J = 7.0, H-4); 3.72 (dd, 1H, J = 4.1, J = 8.2, H-10); 3.33–
3.46 (m, 2H, H-20); 2.88 (dd, 1H, J = 5.2, J = 7.6, H-2);
1.82–2.04 (m, 2H, H-3); 13C NMR (d6-DMSO): 174.7 (C-
1); 156.8, 141.4, 139.8, 128.0, 127.5, 127.1, 109.8, 105.4
(C–Ar); 66.1 (C-20); 63.7, 62.8, 55.8 (C-10, C-2, C-4); 39.1
(C-3). Calcd for C16H19NO5Æ1/2H2O: C, 61.14; H, 6.41;
N, 4.46. Found: C, 61.37; H, 6.44; N, 4.40.
water (2 ml) added while refluxing. The resulting emulsion
was cooled to ꢁ20 ꢁC and kept for 1 h. After warming
to room temperature, the solid was filtered off, washed
with THF (20 ml), Et2O (20 ml) and dried to obtain the
aminoacid 7a (0.585 g, 67%, ee >98%) as a white solid.
Mp = 153–155 ꢁC (H2O), lit.8 mp = 148–149 ꢁC, lit.10
mp > 150 ꢁC (H2O) lit.12 mp = 150 ꢁC, lit.13 mp = 156 ꢁC,
25
1
25
25
½aꢀD ¼ þ43:2 (c 0.5, 1 M HCl), lit.13 ½aꢀD ¼ þ39:0 (c 1.0,
22
1 M HCl), lit.12 ½aꢀD ¼ þ43:0 (c 1.0, 2 M HCl), lit.10
22
½aꢀD ¼ þ46:5 (c 1.1, 2 M HCl); 1H NMR (D2O): 7.83
(d, 1H, J = 1.4, H–Ar); 7.53 (d, 1H, J = 3.4, H–Ar); 6.70
(dd, 1H, J = 3.4, J = 1.4, H–Ar); 4.21 (dd, 1H, J = 6.2,
J = 4.1, H-2); 3.62 (dd, 1H, J = 18.6, J = 4.1, H-3B); 3.54
(dd, 1H, J = 18.6, J = 6.2, H-3A); 13C NMR (D2O):
190.4 (C-4); 176.2 (C-1); 153.7, 152.1, 124.3, 116.0
(C–Ar); 53.2 (C-2); 40.8 (C-3). Calcd for C8H9NO4ÆH2O:
C, 47.76; H, 5.51; N, 6.96. Found: C, 47.66; H, 5.53; N,
6.95.
4.4.5. (2S,4R,10R)-4-Hydroxy-2-[(20-hydroxy-10-phenylethyl)-
amino]-4-(5-methylfuran-2-yl)-butanoic acid 14b. Accord-
ing to the general procedure (from 1.0 g of 11b), 14b
(0.72 g, 70%, dr 97:3) was obtained as a white solid. After
recrystallisation from H2O: dr >99:1. Mp = 172–173 ꢁC
4.4.8. (2S)-2-Amino-4-(5-methylfuran-2-yl)-4-oxo-butanoic
acid 7b. According to the preparation of 7a (from 1.0 g
of 11b), 7b (0.25 g, 36%, er >99:1) was obtained as a white
25
25
1
(decomposition); ½aꢀD ¼ ꢁ43:1 (c 1.0, 0.1 M NaOH); H
NMR (NaOD/D2O): 7.30–7.45 (m, 5H, H–Ph); 6.06 (d,
1H, J = 2.7, H–Ar); 5.93 (d, 1H, J = 2.7, H–Ar); 4.69 (t,
1H, J = 6.9, H-4); 3.69–3.73 (m, 3H, H-20, H-10); 2.85
(dd, 1H, J = 4.8, J = 8.9, H-2); 2.23 (s, 3H, CH3), 1.90–
2.10 (m, 2H, H-3); 13C NMR (NaOD/D2O): 184.2 (C-1);
155.6, 155.5, 141.9, 131.6, 130.0, 130.9, 110.8, 108.7
(C–Ar); 68.6 (C-20); 68.5, 65.8, 62.1 (C-2, C-10, C-4); 40.8
(C-3); 15.4 (CH3). Calcd for C17H21NO5ÆH2O: C, 60.52;
H, 6.87; N, 4.15. Found: C, 60.57; H, 6.88; N, 4.13.
solid. Mp = 153–156 ꢁC (THF–H2O); ½aꢀD ¼ þ49:1 (c 1.0,
1
1 M HCl); H NMR (D2O): 7.45 (d, 1H, J = 3.4, H–Ar);
6.35 (d, 1H, J = 3.4, H–Ar); 4.15 (dd, 1H, J = 6.2,
J = 4.8, H-2); 3.54 (dd, 1H, J = 18.6, J = 4.8, H-3B); 3.47
(dd, 1H, J = 18.6, J = 6.2, H-3A); 2.39 (s, 3H, CH3); 13C
NMR (D2O): 189.4 (C-4); 176.3 (C-1); 164.0, 152.5,
126.5, 112.9 (C–Ar); 53.5 (C-2); 40.3 (C-3); 16.1 (CH3).
Calcd for C9H11NO4ÆH2O: C, 50.23; H, 6.09; N, 6.51.
Found: C, 50.29; H, 6.06; N, 6.54.
4.4.9.
(2S)-2-Amino-4-(5-ethylfuran-2-yl)-4-oxo-butanoic
4.4.6. (2S,4R,10R)-4-(5-Ethylfuran-2-yl)-4-hydroxy-2-[(20-
hydroxy-10-phenylethyl)amino]-butanoic acid 14c. Accord-
ing to the general procedure (from 1.0 g of 12c), 14c
(0.77 g, 77%, dr 99:1) was obtained as a white solid. After
recrystallisation from EtOH: dr 99:1. Mp = 175–177 ꢁC;
½aꢀD ¼ ꢁ40:5 (c 1.0, 0.1 M NaOH); H NMR (CD3OD):
7.47–7.54 (m, 5H, H–Ph); 6.13 (d, 1H, J = 3.5, H–Ar);
5.94 (d, 1H, J = 3.5, H–Ar); 4.73 (dd, 1H, J = 4.1,
J = 8.8, H-4); 4.46 (‘t’, 1H, J = 5.3, J = 5.3, H-10); 4.03
(dd, 1H, J = 11.7, J = 4.1, H-20B); 3.94 (dd, 1H,
J = 11.7, J = 5.3, H-20A); 3.47 (dd, 1H, J = 5.3, J = 8.2,
H-2); 2.65 (q, 2H, J = 7.6, CH2CH3); 2.18–2.34 (m, 2H,
H-3); 1.22 (t, 3H, J = 7.6, CH2CH3); 13C NMR (CD3OD):
172.4 (C-1); 158.7, 155.1, 134.6, 130.7, 130.4, 129.8, 107.8,
105.6 (C–Ar); 68.8 (C-4); 64.8, 64.1, 61.2 (C-2, C-10, C-20);
36.9 (C-3); 22.2 (CH2CH3); 12.6 (CH2CH3). Calcd for
C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C, 65.19;
H, 7.01; N, 4.18.
acid 7c. According to the preparation of 7a (from 1.0 g
of 11c), 7c (0.21 g, 35%, er 96:4) was obtained as a white
25
solid. Mp = 154–155 ꢁC (THF–H2O); ½aꢀD ¼ þ40:4 (c 0.5,
1
1 M HCl); H NMR (D2O): 7.48 (d, 1H, J = 3.4, H–Ar);
6.39 (d, 1H, J = 3.4, H–Ar); 4.15 (dd, 1H, J = 6.9,
J = 4.8, H-2); 3.55 (dd, 1H, J = 17.9, J = 4.8, H-3B); 3.48
(dd, 1H, J = 17.9, J = 6.9, H-3A); 2.75 (q, 2H, J = 7.6,
CH2CH3); 1.26 (t, 3H, J = 7.6, CH2CH3); 13C NMR
(D2O): 189.4 (C-4); 176.3 (C-1); 169.2, 152.3, 126.4, 111.3
(C–Ar); 53.4 (C-2); 40.2 (C-3); 24.2 (CH2CH3); 13.8
(CH2CH3). Calcd for C10H13NO4ÆH2O: C, 52.40; H, 6.60,
N, 6.11. Found C, 52.14; H, 5.95; N, 6.15.
25
1
4.4.10.
rac-2-Amino-4-(furan-2-yl)-4-oxobutanoic
acid
7a. Acid 10a (60.2 mmol, 10.000 g) was dissolved in
ammonia (26% aq soln, 250 ml) and stirred at rt. After
1 h, the solution was evaporated to dryness (brown solid,
12.521 g). The crude product was dissolved in boiling
MeOH (280 ml), activated charcoal was added and the
mixture filtered. The filtrate was cooled to rt, precipitated
solid was filtered off, washed with MeOH and dried to ob-
tain acid rac-7a (4.391 g, 40%) as a white solid. Mp = 156–
158 ꢁC (H2O), lit.8 mp = 149–150 ꢁC.
4.4.7.
(2S)-2-Amino-4-(furan-2-yl)-4-oxobutanoic
acid
7a. The adduct 11a (4.3 mmol, 1.3 g) was suspended in
4% aq soln of NaIO4 (1.5 equiv, 6.4 mmol, 34.4 g), Et3N
(0.13 ml) was added and the resulting mixture stirred at
rt for 30 min. The solid was filtered off, the filtrate washed
with Et2O (2 · 20 ml) and the water layer evaporated to
dryness in vacuo (t < 45 ꢁC). The obtained yellow solid
was washed with MeOH (30 ml); the insoluble material
was filtered and the filtrate evaporated to dryness in vacuo.
The crude product was suspended in THF (25 ml) and
4.4.11. rac-2-Amino-4-(5-methylfuran-2-yl)-4-oxobutanoic
acid 7b. According to the preparation of rac-7a (from
2.6 g of 10b, 65 ml of 26% aq soln of ammonia) rac-7b
(1.21 g, 43%) was obtained as a white solid. Mp = 156–
158 ꢁC (MeOH).

1636
P. Jakubec et al. / Tetrahedron: Asymmetry 17 (2006) 1629–1637
4.4.12. rac-2-Amino-4-(5-ethylfuran-2-yl)-4-oxobutanoic acid
7c. According to the preparation of rac-7a (from 3.0 g of
10c, 75 ml of 26% aq soln of ammonia) rac-7c (1.403 g,
43%, crystallisation from H2O) was obtained as a white
solid, mp = 154–156 ꢁC (H2O).
was vigorously stirred at rt for 5 min, then aminoacid 12a
(13.9 mmol, 4.0 g) was added in one portion and the mix-
ture stirred at rt for 30 min. The organic solvents were
evaporated and the residue filtered. The filtrate was applied
on to the top of column of DOWEX (50 W · 8). The col-
umn was washed with water until neutral reaction
(400 ml) and with ammonia (4% aq soln, 500 ml). A frac-
tion containing aminoacid was evaporated to dryness.
The solid (2.015 g, 61%) was dissolved in H2O (8 ml), after
which activated charcoal was added and the mixture fil-
tered. The pH of the filtrate was adjusted to 3.5 with concd
HCl. The precipitated solid was filtered off, washed with
Et2O (20 ml) and dried to obtain HCl salt of acid 16
(0.951 g, 25%, dr >95:5) as a white solid. Mp = 204–
206 ꢁC lit.24 mp = 179–181 ꢁC (free aminoacid);
4.4.13. (2R,4S,100S)-4-[(100-Phenylethyl)amino]-3,4-dihydro-
2,20-bifuran-5(2H)-one 15a. Acid 13a (1.7 mmol, 0.5 g)
was suspended in CH2Cl2 (12 ml), DCC (1.05 equiv,
1.8 mmol, 0.374 g) was added and the resulting suspension
stirred at rt for 24 h. The mixture was evaporated to ca.
5 ml volume and the insoluble solids filtered off. The filtrate
was evaporated to dryness. The crude product (brown oil,
0.552 g) was purified by column chromatography (AcOEt/
heptane 1:3) to obtain trans-lactone 15a (0.239 g, 51%, dr
99:1) as a yellowish oil. Rf = 0.22 (AcOEt/heptane 1:3),
25
25
½aꢀD ¼ ꢁ46:2 (c 0.5, MeOH), lit.24 ½aꢀD ¼ ꢁ13:4 (free ami-
noacid); 1H NMR (free aminoacid, CD3OD): 7.48–7.57 (m,
5H, H–Ph); 4.72 (q, 1H, J = 7.0, H-10); 3.95 (‘t’, 1H,
J = 5.3, J = 5.9, H-2); 3.04 (dd, 1H, J = 18.2, J = 5.9, H-
3B); 2.96 (dd, 1H, J = 18.2, J = 5.3, H-3A); 1.79 (d, 3H,
J = 7.0, H-20); 13C NMR (CD3OD): 172.2, 170.0 (C-1, C-
4); 136.6, 131.0, 130.7, 129.1 (C–Ar); 60.2, 55.4 (C-2, C-
10); 35.2 (C-3); 20.2 (C-20).
25
1
½aꢀD ¼ ꢁ189:6 (c 0.5, CHCl3); H NMR (CDCl3): 7.22–
7.40 (m, 6H, H–Ar); 6.29 (dd, 1H, J = 3.5, J = 1.8, H–
Ar); 6.24 (d, 1H, J = 3.5, H–Ar); 5.40 (dd, 1H, J = 2.9,
J = 8.2, H-2); 4.10 (q, 1H, J = 6.4, CHCH3); 3.76 (dd,
1H, J = 8.2, J = 9.4, H-4); 2.05–2.23 (m, 2H, H-3); 1.41
(d, 3H, J = 6.4, CHCH3); 13C NMR (CDCl3): 177.2 (C-
5); 150.9, 144.7, 143.2, 128.4, 127.2, 126.9, 110.3, 109.0
(C–Ar); 71.8 (C-2); 58.0, 55.1 (C-4, CHCH3); 35.3 (C-3);
24.5 (CHCH3). Calcd for C16H17NO3: C, 70.83; H, 6.32;
N, 5.16. Found C, 70.68; H, 6.33; N, 5.19.
By hydrogenolysis of 16 (1.8 mmol, 0.5 g), aspartic acid 17
(0.26 g, ꢂ100%) was prepared. A sample of 17 was ana-
lysed by HPLC with chiral stationary phase (CROWN-
PAK CR (+), eluent HClO4, pH = 2.0, tR = 1.33 min, er
96:4). NMR data are in good agreement to those
published.
4.4.14. (2S,4S,100S)-4-[(1-Phenylethyl)amino]-3,4-dihydro-
2,20-bifuran-5(2H)-one 150a. Aminoacid 12a (7.0 mmol,
2.0 g) was suspended in MeOH (30 ml), NaBH4 (4 equiv,
28.0 mmol, 1.031 g) was then added in one portion and
the resulting mixture stirred at rt for 10 min. The solvent
was evaporated, and H2O (40 ml) was added and the pH
of a solution adjusted to 6.5. The precipitated solid was fil-
tered off, washed with water (20 ml), Et2O (20 ml) and
dried to obtain a mixture of acids 13a/130a (1.607 g, 79%,
dr 66:34) as a white solid. This material was suspended in
CH2Cl2 (60 ml), DCC (1.1 equiv, 6.1 mmol, 1.256 g) was
added and the resulting suspension was stirred at rt for
24 h. The insoluble solid was filtered off and a filtrate was
evaporated to dryness (brown oil, 1.71 g). The crude oil
was purified by column chromatography (AcOEt/heptane
1:6) to obtain trans-lactone 15 (0.680 g, 36%, dr 99:1,
Rf = 0.22 AcOEt/heptane 1:3) as a yellowish oil and
cis-lactone 150a (0.360 g, 19%, dr 98:2, Rf = 0.31 AcOEt/
heptane 1:3) as a white solid. Mp = 74–76 ꢁC (AcOEt/
Acknowledgements
Financial support by the Slovak Grant Agency No. 1/
2469/05 is gratefully acknowledged. We are grateful to
´
Dr. Peter Szolcsanyi for his help with the manuscript
preparation.
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