Synthesis of the enantiomers and N-protected derivatives of 3-amino-3-(4-cyanophenyl)propanoic acid

Article abstract of DOI:10.1016/j.tetasy.2004.05.012

Racemic ethyl 3-amino-3-(4-cyanophenyl)propanoate was synthesized and the enantiomers separated through enantioselective N-acylation by Candida antarctica lipase A (CAL-A) in neat butyl butanoate. The free amino acid enantiomers were transformed to the Boc and Fmoc-protected derivatives.

Full text of DOI:10.1016/j.tetasy.2004.05.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1893–1897
Synthesis of the enantiomers and N-protected derivatives
of 3-amino-3-(4-cyanophenyl)propanoic acid
a
Magdolna Solymar, Liisa T. Kanerva and Ferenc Fulop
b
a,
*
ꢀ
€ €
aInstitute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, PO Box 121, Hungary
bLaboratory of Synthetic Drug Chemistry and Department of Chemistry, University of Turku,
Lemmink€aisenkatu 2, FIN-20520 Turku, Finland
Received 24 March 2004; accepted 11 May 2004
Abstract—Racemic ethyl 3-amino-3-(4-cyanophenyl)propanoate was synthesized and the enantiomers separated through enantio-
selective N-acylation by Candida antarctica lipase A (CAL-A) in neat butyl butanoate. The free amino acid enantiomers were
transformed to the Boc and Fmoc-protected derivatives.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The design and synthesis of peptide oligomers contain-
ing nonnatural amino acids,1–4 and of other biologically
active amino acid derivatives,5;6 is a challenge in current
drug design and peptide secondary structure analysis (b-
peptides and foldamers).7
The lipase-catalysed enantioselective acylation strategy
has acquired a valued position for the preparation of
highly enantiopure compounds, with the advantage that
both enantiomers can be obtained. Relying on this
strategy, the racemic amino acid 1 was prepared by the
modified Rodionov method13 and transformed to its
ethyl ester ( )-4 in EtOH in the presence of SOCl2. The
optimization of the N-acylation conditions for ( )-4
with lipase A from Candida antarctica (CAL-A) (Table
1) was started by testing the gram-scale conditions of the
previously examined kinetic resolutions of phenyl, thi-
enyl and furyl-substituted 3-aminocarboxylates.14;15 The
reaction of ( )-4 exhibited almost no selectivity in ethyl
butanoate, which was the solvent (and the acyl donor) of
choice for the gram-scale resolution of the heteroaryl-
substituted analogues (Table 1, entry 5).14 N-Acylation
of ( )-4 with 2,2,2-trifluoroethyl butanoate revealed
solvent dependence with the reactivity decreasing in the
sequence i-Pr2O, Et2O, MeCN, THF, with low to
moderate enantioselectivities (entries 1–4). The highest
enantioselectivity was observed for the reaction in neat
butyl butanoate, although the reactivity was then
moderate as compared with that observed for acylation
with 2,2,2-trifluoroethyl butanoate in solvents other
than THF (entry 6). An elevated substrate concentration
in butyl butanoate resulted in a decreased enantio-
selectivity and reactivity (entry 7). It is interesting that,
taking the same conditions into consideration, the
For peptide structural studies, it is useful to incorporate
amino acid scaffolds which possess easy-to-detect func-
tional groups as internal local environment markers.
One good possibility is to introduce a small, intermedi-
ately polar nitrile group, which has a characteristic
vibrational stretching band in the IR spectrum, and
which is sensitive to the environment. For this purpose,
the use of cyano derivatives of enantiomerically pure
alanine and phenylalanine has been reported recently.8;9
Racemic p-cyanophenylalanine is applied in the syn-
thesis of aromatase inhibitors,6 TNFa inhibitors,10 and
antifungal11 and antiepileptogenic12 agents. Enantio-
merically pure b-amino acid derivatives of p-cyanophen-
ylalanine have not yet been described in the literature.
Our aim was to find an appropriate method for prepa-
ration of the enantiomers of 3-amino-3-(4-cyanophe-
nyl)propanoic acid.
* Corresponding author. Tel.: +36-62-545564; fax: +36-62-545705;
e-mail: fulop@pharma.szote.u-szeged.hu
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.012

1894
M. Solymꢀar et al. / Tetrahedron: Asymmetry 15 (2004) 1893–1897
Table 1. N-Acylation of ( )-4 (0.05 M) by CAL-A (15 mg/mL) at room temperature
Entry
Acyl donor
Solvent
Time (h)
c (%)a
Ees (%)
Eep (%)
Eb
28
1
2
3
4
5
6
7
PrCO2CH2CF3
PrCO2CH2CF3
PrCO2CH2CF3
PrCO2CH2CF3
THF
Et2O
16
1
16
52
51
53
18
50
47
17
97
94
99
4
92
90
91
86
19
95
93
83
80
68
2
i-Pr2O
MeCN
0.33
1.5
1
PrCO2Et
PrCO2Bu
PrCO2Buc
9
12.5
94
83
143
70
a c ¼ ees/(ees + eep).
b E ¼ ln[(1 ) ees)/(1 ) ees/eep)]/ ln[(1 ) ees)/(1 + ees/eep)].17
c 0.1 M substrate concentration.
enzyme systematically displayed a lower enantioselec-
tivity for ( )-4 than for the heteroaryl-substituted ana-
logues (for instance, E ¼ 580 and 220 were observed for
the reactions of ethyl 3-amino-3-(2-thienyl)propanoate
and 3-amino-3-(2-furyl)propanoate, respectively, in neat
butyl butanoate).14 On the other hand, the enantio-
selectivity was higher than that for the more hydro-
phobic 3-phenyl-substituted analogue under the same
conditions (E ¼ 75, in the case of 2,2,2-trifluoroethyl
butanoate as acyl donor in diisopropyl ether).15 Amino
ester ( )-4 was finally subjected to enzymatic N-acyl-
ation on a gram scale under optimized conditions in
neat butyl butanoate at 0.05 M substrate concentration
and at 15 mg/mL of the 20% (w/w) CAL-A preparation
on Celite.16
amide stage could also be detected. The resulting amino
acid hydrochlorides were desalted either by ion-
exchange chromatography or by propylene oxide to give
7 and 10 and recrystallized (Scheme 1). The use of ion-
exchange resin catalysis for deacylation18 resulted in
hydrolysed product 10 in low yields, too.
For peptide synthetic purposes, we transformed
enantiomers 7 and 10 to Boc (8 and 11) and Fmoc-
protected (9 and 12) derivatives. The racemic counter-
parts of the protected amino acids, 2 and 3, were also
synthesized in parallel.
For all the products reported here, appropriate NMR
and IR spectra were taken and mass spectra were
recorded by means of CI-MS, except for 1, 7 and 10, the
mass spectra of which were recorded by means of EI-
MS. Physical data on the isolated enantiomerically pure
compounds are included in Table 2.
After the gram-scale resolution was stopped by filtering
off the enzyme, the substrate was isolated as the
hydrochloride salt 5, and the product as the butanamide
derivative 6. The isolated enantiomeric compounds were
subjected to acid hydrolysis. The ester group of 5 could
be easily hydrolysed with 12% HCl at room tempera-
ture, while the amide bond of 6 was cleaved with 18%
HCl under reflux conditions. Due to the forced condi-
tions of hydrolysis of 6, cyano group hydrolysis to the
The absolute configurations of the products were
established on the basis of the (S)-selectivity of CAL-A
for the previously resolved aromatic and heteroaromatic
3-amino ester analogues.14;15 Comparison of their
chromatographic behaviour confirmed this conclusion.
COOEt
COOEt
COOEt
iii, iv
.
+
NH2 HCl
NHCOPr
NH2
NC
NC
NC
( )-4
5
6
0.05 M
vi, vii
v, vii
i, ii
COOH
NHR
COOH
NHR
COOH
NHR
NC
NC
NC
1 R = H
7 R = H
10 R = H
viii
viii
viii
ix
ix
ix
2 R = Boc
8 R = Boc
11 R = Boc
3 R = Fmoc
9 R = Fmoc
12 R = Fmoc
Scheme 1. Reagents and conditions: (i) SOCl2, abs EtOH, )10 ꢁC, 3 h rt, 1 h reflux; (ii) Et3N, CH2Cl2, column chromatography: CH2Cl2/
MeOH ¼ 95:5; (iii) PrCO2Bu, 15 mg/mL CAL-A 20% on Celite; (iv) dry HCl bubbling; (v) 12% aq HCl, 20 h, rt; (vi) 18% aq HCl, 3 h reflux; (vii) ion-
exchange chromatography on Varion KS resin or propylene oxide; (viii) K2CO3, Boc2O, dioxane/H2O ¼ 2:1, 5 h, rt; (ix) NaHCO3, Fmoc-OSu,
acetone/H2O ¼ 1:1, 2 h, 0 ꢁC, then rt.

M. Solymꢀar et al. / Tetrahedron: Asymmetry 15 (2004) 1893–1897
Table 2. Physical data on the isolated compounds
1895
25
D
Compound
Yield (%)a
Mp (ꢁC)
Ee (%)b;c
½aꢂ
5
52
74
66
83
80
15
98
44
196–199
Oil
97
90
)7 (c 0.5, MeOH)
)66 (c 1, MeOH)
+4 (c 0.15, H2O)
+50 (c 0.53, MeOH)
+30 (c 0.69, MeOH)
)4 (c 0.16, H2O)
6
7
240–242
120–123
170–172
229–231
127–130
165–170
96
98
8
9
>99
99
10
11
12
99
99
)50 (c 0.46, MeOH)
)30 (c 0.09, MeOH)
a Referring to crude product.
b Determined by GC on an
L-valine column; 7, 10: after derivatization with CH2N2, and then acetic anhydride and 1% DMAP/pyridine; 8, 11: after
derivatization with CH2N2; 9, 12: after deprotection with 5% piperidine, and then similarly as for 7 and 10.
c After column chromatography and recrystallization; the ee values increased during recrystallization.
3. Experimental
2978, 2627, 2224, 1710, 1530, 1391, 1366. MS (m=z, CI)
(rel abund.) 291 (100, [M + H]þ), 263 (10), 245 (4), 235
(20), 217 (20), 191 (24), 174 (12), 130 (32).
Melting points were determined with a Kofler apparatus
1
at a heating rate of 4 ꢁC/min. H NMR spectra were
recorded in DMSO-d6 at ambient temperature on a
Bruker DRX400 spectrometer. Chemical shifts are given
in d (ppm) relative to TMS as internal standard; multi-
plicities were recorded as s (singlet), d (doublet), t
(triplet) or m (multiplet). IR spectra were measured in
KBr disks on a Perkin Elmer Paragon 1000PC FT-IR
spectrometer. MS spectra were recorded on a Finnigan
MAT 95 S instrument. Elemental analyses were per-
formed with a Perkin–Elmer CHNS-2400 Ser II Ele-
mental Analyzer. Optical rotations were measured with
a Perkin–Elmer 341 polarimeter.
3.1.3. ( )-3-(9-Fluorophenylmethoxycarbonylamino)-3-
(4-cyanophenyl)propanoic acid 3. Amino acid 1 (40 mg,
0.2 mmol) was dissolved in 1.33 mL of an acetone/
water ¼ 1:1 mixture and cooled to 0 ꢁC. NaHCO3
(104 mg, 1.2 mmol) and Fmoc-OSu (83 mg, 0.25 mmol)
were added. The mixture was stirred for 2 h at 0 ꢁC and
at rt overnight. After removal of the acetone, the pH
was adjusted to 2 with 1 M HCl, the product was ex-
tracted with EtOAc and dried on Na2SO4, and the sol-
vent was evaporated off. White crystals (50 mg, 58%),
1
mp 179–182 ꢁC (diisopropyl ether). H NMR d 2.55–
2.80 (2H, m, CH2), 4.10–4.35 (3H, m, Fmoc CH2, CH),
4.90–5.10 (1H, m, CH), 7.20–7.95 (12H, m, aromatic),
8.06 (1H, s, NH). 13C NMR d 40.3, 46.6, 51.4, 65.3,
109.8, 118.7, 2 · 120.1, 2 · 125.0, 2 · 127.0, 2 · 127.4,
2 · 127.5, 2 · 132.3, 2 · 140.7, 143.6, 143.8, 148.4, 155.3,
171.3. IR (KBr) m (cmꢀ1) 3353, 2926, 2234, 1703, 1536,
1082. MS (m=z, CI) (rel abund.) 413 (10, [M+H]þ), 196
(64), 191 (2), 178 (100), 165 (60), 157 (4), 131 (1).
3.1. Preparation of racemic compounds
3.1.1. ( )-3-Amino-3-(4-cyanophenyl)propanoic acid 1.
Compound ( )-1 was prepared according to a known
procedure.6 Mp 243–245 ꢁC, lit. mp19 233–236 ꢁC. 1H
NMR d 2.41 (2H, d, J ¼ 6.69, CH2), 4.25–4.35 (1H, m,
CH), 7.59 (2H, d, J ¼ 8.21 Hz, aromatic), 7.85 (2H, d,
J ¼ 8.24 Hz, aromatic). 13C NMR d 41.9, 52.4, 110.4,
119.3, 2 · 128.2, 2 · 132.6, 149.2, 173.1. IR (KBr) m
(cmꢀ1) 2548 (br), 2228, 2161, 1628, 1560, 1394. MS (m=z,
EI) (rel abund.) 190 (4, [Mþ]), 172 (4), 144 (10), 131
(100), 129 (20), 104 (20), 77 (10). Anal. Calcd for
C10H10N2O2 C: 63.15%, H: 5.30%, N: 14.73%, found: C:
62.25%, H: 4.85%, N: 14.03%.
3.1.4. Ethyl ( )-3-amino-3-(4-cyanophenyl)propanoate
hydrochloride 4ꢁHCl. Absolute EtOH (8 mL) was
cooled below )10 ꢁC. SOCl2 (0.7 mL, 9.6 mmol) was
added dropwise, the temperature being kept below )10
ꢁC. Amino acid 1 (1.7 g, 8.7 mmol) was added to the
mixture, which was then stirred for 0.5 h at 0 ꢁC and 3 h
at rt, and finally refluxed for 1 h. The solvent was
evaporated off and the hydrochloride of 4 was recrys-
tallized from EtOH/diethyl ether. White crystals (1.75 g,
3.1.2. ( )-3-(tert-Butoxycarbonylamino)-3-(4-cyanophen-
yl)propanoic acid 2. Amino acid 1 (40 mg, 0.2 mmol) was
dissolved in 3 mL of a dioxane/water ¼ 1:1 mixture.
K2CO3 (276 mg, 2 mmol) and di-tert-butyl dicarboxylate
(44 mg, 0.2 mmol) were added. After stirring for 5 h, the
pH was adjusted to 2 with 1 M HCl, the product was
extracted with EtOAc and dried on Na2SO4, and the
solvent was evaporated off. White crystals (60 mg, 98%),
mp 168–171 ꢁC (diisopropyl ether). 1H NMR d 1.40 (9H,
s, t-Bu), 2.60–2.80 (2H, m, CH2), 4.90–5.05 (1H, m,
CH), 7.55 (2H, d, J ¼ 8.11, aromatic), 7.61 (1H, d,
J ¼ 8.21 Hz, NH), 7.85 (2H, d, J ¼ 7.98, aromatic). 13C
NMR d 40.5, 51.0, 78,1, 109.7, 118.7, 4 · 127.4,
3 · 132.2, 148.8, 154.7, 171.4. IR (KBr) m (cmꢀ1) 3327,
1
78%), mp 215–218 ꢁC. H NMR (400 MHz, CDCl3) d
1.08 (3H, t, J ¼ 7.09 Hz, CH3), 2.95–3.25 (2H, ddd,
J ¼ 8.75, 16.34, 69.66 Hz, CH2CO), 3.92–4.10 (2H, m,
CH2CH3), 4.71 (1H, t, J ¼ 7.18 Hz, CH), 7.76 (2H, d,
J ¼ 8.22 Hz, aromatic), 7.91 (2H, d, J ¼ 8.16 Hz, aro-
matic), 8.83 (3H, s, NHþ3 Clꢀ). 13C NMR d 13.8, 38.2,
50.5, 60.6, 111.6, 118.4, 2 · 128.9, 2 · 132.5, 142.0, 168.8.
IR (KBr) m (cmꢀ1) 3056, 2930, 2787, 2227, 2026, 1725,
1510, 1208, 845. Anal. Calcd for C12H15ClN2O2 C:
56.59%, H: 5.94%, Cl: 13.92%, N: 11.00%, found: C:
56.82%, H: 6.03%, Cl: 13.67%, N: 11.34%.

1896
M. Solymꢀar et al. / Tetrahedron: Asymmetry 15 (2004) 1893–1897
3.1.5. Ethyl ( )-3-amino-3-(4-cyanophenyl)propanoate 4.
The base was released by the addition of 3 equiv of Et3N
to the CH2Cl2 suspension of ( )-4ꢁHCl. The mixture was
stirred for 3 h and the solvent was evaporated off under
reduced pressure. The residue was purified by column
chromatography, using CH2Cl2/MeOH ¼ 95:5 as elu-
ent. A yellow oil (1.33 g, 91%). 1H NMR (400 MHz,
CDCl3) d 1.23 (3H, t, J ¼ 7.14 Hz, CH3), 2.24 (2H, s,
NH2), 2.66 (2H, d, J ¼ 6.76 Hz, CH2CO), 4.14 (2H, q,
J ¼ 7.11 Hz, CH2CH3), 4.50 (1H, t, J ¼ 6.74 Hz, CH),
7.50 (2H, d, J ¼ 8.20 Hz, aromatic), 7.63 (2H, d,
J ¼ 8.32 Hz, aromatic). IR (KBr) m (cmꢀ1) 3377, 2980,
2227, 1728, 1608, 1185. Anal. Calcd for C12H14N2O2 C:
66.04%, H: 6.47%, N: 12.83%, found: C: 65.44%, H:
6.86%, N: 13.47%.
dissolved in water and purified by ion-exchange chro-
matography (0.26 g, 66%). The light-brown solid was
recrystallized from water/acetone to give a white pow-
der. The H NMR and MS data were identical with
those of 1. IR (KBr) m (cmꢀ1) 3041, 2230, 1613, 1547,
1417, 1250, 844, 573.
1
3.3.2. (R)-3-(tert-Butoxycarbonylamino)-3-(4-cyanophen-
yl)propanoic acid 8. Prepared similarly to 2. The 1H
NMR and MS data were identical with those for 2. IR
(KBr) m (cmꢀ1) 3367, 2986, 2229, 1687, 1521, 1271, 1172.
3.3.3. (R)-3-(9-Fluorophenylmethoxycarbonylamino)-3-
(4-cyanophenyl)propanoic acid 9. Prepared similarly to
1
3. The H NMR and MS data were identical with those
for 3. IR (KBr) m (cmꢀ1) 3347, 2919, 2357, 2234, 1700,
1537, 1286, 740.
3.2. Gram-scale resolution of ( )-4
Compound ( )-4 (1.20 g, 5.50 mmol) was dissolved in
butyl butanoate (110 mL) and 1.65 g of 20% CAL-A
preparation16 was added. The reaction vessel was shaken
at room temperature. The reaction was stopped at 51%
conversion by filtering off the enzyme. The enzyme was
washed with CH2Cl2, and dry HCl was bubbled through
the solution for 2 h. The solvent was evaporated off
under vacuum and 5 was crystallized from diisopropyl
ether (0.35 g, 52%, diisopropyl ether/EtOH). The mother
liquor was evaporated down and 6 was isolated by
column chromatographic purification, using CH2Cl2/
MeOH ¼ 95:5 as eluent (0.61 g, 74%).
3.3.4. (S)-3-Amino-3-(4-cyanophenyl)propanoic acid 10.
Compound 6 (0.5 g, 1.73 mmol) was refluxed in 18%
HCl (50 mL) for 3 h. After evaporation, the residue was
dissolved in MeOH and the solution was stirred with an
excess of propylene oxide and then evaporated down.
The residue was dissolved in hot MeOH and filtered,
and the solvent was removed under reduced pressure
(50 mg, 15%). The light-brown solid was recrystallized
from water/acetone to give a white powder which con-
tained the hydrolysed amide product according to the
1
NMR. The characteristic H NMR and MS lines were
identical with those for 1; the IR data were identical
with those for 7. MS (m=z, EI) (rel abund.) 208 (16) for
the amide by-product.
3.2.1. Ethyl (R)-3-amino-3-(4-cyanophenyl)propanoate
hydrochloride 5. The H NMR data were identical with
those for ( )-4ÆHCl. IR (KBr) m (cmꢀ1) 3078, 2918, 2786,
2225, 1730, 1516. Anal. Calcd for C12H15ClN2O2 C:
56.59%, H: 5.94%, Cl: 13.92%, N: 11.00%, found: C:
55.98%, H: 5.95%, Cl: 13.38%, N: 11.14%.
1
3.3.5. (S)-3-(tert-Butoxycarbonylamino)-3-(4-cyanophen-
yl)propanoic acid 11. Prepared similarly to 2. The H
1
NMR and MS data were identical with those for 2. The
IR was identical with that for 8.
3.2.2. Ethyl (S)-3-butanoylamino-3-(4-cyanophenyl)pro-
1
panoate 6. H NMR (400 MHz, CDCl3) d 0.94 (3H, t,
J ¼ 7.37 Hz, CH3CH2CH2), 1.16 (3H, t, J ¼ 7.13 Hz,
OCH2CH3), 1.55–1.75 (2H, m, CH3CH2CH2), 2.18 (2H,
t, J ¼ 7.42 Hz, CH3CH2CH2), 2.80–2.95 (2H, m,
CH2CO), 4.05 (2H, q, J ¼ 7.12 Hz, OCH2CH3), 5.40–
5.50 (1H, m, CHCH2CO), 6.79 (1H, br d, J ¼ 7.92 Hz,
NH), 7.39 (2H, d, J ¼ 8.16 Hz, aromatic), 7.61 (2H, d,
J ¼ 8.30 Hz, aromatic). 13C NMR d 13.8, 14.1, 19.1,
38.7, 39.5, 49.2, 61.2, 111.4, 118.5, 2 · 127.1, 2 · 132.5,
146.2, 170.9, 172,4. IR (KBr) m (cmꢀ1) 3296, 2964, 2228,
1740, 1654. Anal. Calcd for C16H20N2O3 C: 66.65%, H:
6.99%, N: 9.72%, found: C: 64.56%, H: 7.09%, N:
9.53%.
3.3.6. (S)-3-(9-Fluorophenylmethoxycarbonylamino)-3-
(4-cyanophenyl)propanoic acid 12. Prepared similarly to
3. The 1H NMR and MS data were identical with
those for 3. The IR spectrum was identical with that for
9.
Acknowledgements
The authors acknowledge receipt of OTKA grants T
034901 and TS 040888.
3.3. Preparation of enantiomeric amino acids and their
N-protected derivatives
References and notes
3.3.1. (R)-3-Amino-3-(4-cyanophenyl)propanoic acid 7.
Compound 5 (0.53 g, 2.08 mmol) was stirred in 12% HCl
(21 mL) for 20 h at rt. After evaporation, the residue was
1. (a) Mousa, S. A.; Bennett, J. S. Drugs Fut. 1996, 21, 1141–
1154; (b) Scarborough, R. M. Curr. Med. Chem. 1999, 6,
971–981.

M. Solymꢀar et al. / Tetrahedron: Asymmetry 15 (2004) 1893–1897
1897
2. Cardillo, G.; Gentillucci, L.; Melchiorre, P.; Spampinato,
S. Bioorg. Med. Chem. Lett. 2000, 10, 2755–2758.
3. Webster, K. L.; Maude, A. B.; O’Donnell, M. E.;
Mehrotra, A. P.; Gani, D. J. Chem. Soc, Perkin Trans. 1
2001, 1673–1695.
4. (a) Banerji, B.; Mallesham, B.; Kumar, S. K.; Kunwar, A.
C.; Iqbal, J. Tetrahedron Lett. 2002, 43, 6479–6483; (b)
Rajamohan, R. P.; Balraju, V.; Madhavan, G. R.; Banerji,
B.; Iqbal, J. Tetrahedron Lett. 2003, 44, 353–356.
5. Prasad, J. V. N. V.; Loo, J. A.; Boyer, F. E.; Stier, M. A.;
Gogliotti, R. D.; Turner, W. J.; Harvey, P. J.; Kramer, M.
R.; Mack, D. P.; Scholten, J. D.; Gracheck, S. J.;
Domagala, J. M. Bioorg. Med. Chem. 1998, 6, 1707–1730.
6. Sonnet, P.; Dallemagne, P.; Guillon, J.; Enguehard, C.;
Stiebing, S.; Tanguy, J.; Bureau, R.; Rault, S.; Auvrey, P.;
Moslemi, S.; Sourdaine, P.; Seralini, G.-E. Bioorg. Med.
Chem. 2000, 8, 945–955.
Muller, G. W.; Corral, L. G.; Shire, M. G.; Wang, H.;
Moreira, A.; Kaplan, G.; Stirling, D. I. J. Med. Chem.
1996, 39, 3238–3240; (d) Muller, G. W. U.S. 5605914 A,
1997; Chem. Abstr. 1997, 126, 199454z; (e) Muller, G. W.
U.S. 5698579 A, 1997; Chem. Abstr. 1998, 128, 75298y.
11. Camaggi, G., Filippini, L., Gusmeroli, M., Mormile, S.,
Signorini, E., Garavaglia, C. EP 718280 A2 1996; Chem.
Abstr. 1996, 125, 168644m.
12. Weaver, D. F., Tan, C. Y. K., Kim, S. T., Kong, X., Wei,
L., Carran, J. R. WO 02/073208 A2 2002; Chem. Abstr.
2002, 137, 242191.
13. (a) Rodionov, V. M.; Malivinskaya, E. F. Ber. 1926, 59,
ꢀ ꢀ
2952–2958; (b) Lazar, L.; Martinek, T.; Bernath, G.;
Fulop, F. Synth. Commun. 1998, 28, 219–224; (c) Tan, C.
ꢀ
€ €
Y. K.; Weaver, D. F. Tetrahedron 2002, 58, 7449–7461.
€ €
ꢀ
14. Solymar, M.; Fulop, F.; Kanerva, L. T. Tetrahedron:
Asymmetry 2002, 13, 2383–2388.
€ €
7. Martinek, T. A.; Fulop, F. Eur. J. Biochem. 2003, 270,
3657–3666.
8. Getahun, Z.; Huang, C.-Y.; Wang, T.; De Leon, B.;
DeGrado, W. F.; Gai, F. J. Am. Chem. Soc. 2003, 125,
405–411.
9. Huang, C.-Y.; Wang, T.; Gai, F. Chem. Phys. Lett. 2003,
371, 731–738.
10. (a) Muller, G. W. Patent WO 95/01348 A2, 1995; Chem.
Abstr. 1995, 123, 198617f; (b) Muller, G. W. Patent U.S.
5463063 A, 1995; Chem. Abstr. 1996, 124, 176936c; (c)
ꢀ ꢀ
€ €
15. Gedey, S.; Liljeblad, A.; Lazar, L.; Fulop, F.; Kanerva,
L. T. Tetrahedron: Asymmetry 2001, 12, 105–110.
16. Kanerva, L. T.; Sundholm, O. J. Chem. Soc., Perkin
Trans. 1 1993, 2407–2410.
17. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J.
J. Am. Chem. Soc. 1982, 104, 7294–7299.
18. Bolton, P. D.; Henshall, T. J. Am. Chem. Soc. 1962, 84,
1226–1232.
19. Wagner, G.; Grasshof, C.; Kasek, K. Pharmazie 1981, 36,
607–609.