Synthesis of new oxazole-containing peptidomimetics

Article abstract of DOI:10.1016/S0957-4166(98)00109-8

Enantiospecific syntheses of optically active amino acids containing an oxazole moiety are described. Two different strategies for their insertion in a peptidomimetic chain are also discussed. The procedures presented are based on materials readily available in multigram quantities.

Full text of DOI:10.1016/S0957-4166(98)00109-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1419–1426
Synthesis of new oxazole-containing peptidomimetics
Massimo Falorni,∗ Giovanna Dettori and Giampaolo Giacomelli
Dipartimento di Chimica, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy
Received 16 February 1998; accepted 12 March 1998
Abstract
Enantiospecific syntheses of optically active amino acids containing an oxazole moiety are described. Two
different strategies for their insertion in a peptidomimetic chain are also discussed. The procedures presented are
based on materials readily available in multigram quantities. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The synthesis of optically active amino acids is an area that is currently attracting considerable interest,
mainly due to the commercial importance of biologically active peptides that incorporate synthetic
amino acids.1 In continuing our studies directed towards the preparation of unnatural amino acids,2 we
have considered oxazole-containing amino acids. Oxazoles are important compounds as precursors of
peptidomimetic structures3 and constituents of biologically active natural marine metabolites,4 therefore
some methods that effect their preparation from α-amino acids have been proposed. However, several
of these methods suffer from one or more drawbacks, such as low overall yield, use of hazardous or
expensive reagents and failure in large-scale preparation.5 Here we wish to report the synthesis of
optically active oxazole amino acids 1–4 along with two different strategies for their insertion into
peptidomimetic chains.
The preparation of compounds 1–4 has been approached through the retrosynthetic correlation of the
oxazole ring with a β-carbonyl amide that could be prepared from N-protected α-amino acid amide by
rhodium(II) catalysed N–H insertion of a diazocarbonyl compound6 (Scheme 1).
∗
Corresponding author. E-mail: fmax@ssmain.uniss.it
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00109-8

1420
M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 1419–1426
Scheme 1.
2. Results and discussion
We have prepared the diazoderivatives 5 and 6 by treatment of p-toluenesulphonyl azide (p-TsN3)7
with methyl acetoacetate and dimethylmalonate respectively in benzene/Et3N at room temperature
(Scheme 2); the crude diazocompounds 5–6 were separated from unreacted products by flash chromato-
graphy. Compounds 5 and 6 were obtained in 81–88% yield as stable liquids that could be further purified
by vacuum distillation. In our experience, no hazard was apparent during preparation and handling of
these diazocompounds; however, due to the general explosive nature of diazo and azide compounds, the
experiments were conducted behind an auxiliary safety shield in a closed fume hood.7
Scheme 2.
The amides Cbz–Phe–NH2 7, Boc–Asp(OBn)–NH2 8 and Cbz–Asp(OBn)–NH2 9 were prepared
following standard methods8 (Scheme 3). When the amide 7 was treated with diazocompounds 5 or 6 in
CHCl3 in the presence of a catalytic amount of Rh(II) acetate dimer, the reaction proceeded very smoothly
to the formation of the corresponding derivatives 10 and 11 in excellent yield. By the same procedure,
starting from amides 8 and 9, we have thus obtained the intermediates 12 and 13, respectively. During
these processes, any trace of water and alcohols should be avoided since the O–H insertion reaction was
competitive with the desired N–H insertion in the C_N2 bond: we recovered derivatives 10–13 in high
yield only when dry ethanol-free CHCl3 was used. The cyclodehydration of amides 10–13 was carried
out with PPh3 and I2 in the presence of Et3N in CH2Cl2: after removal of any volatile product and
purification of the crude products we obtained the oxazoles 1–4 in satisfactory yields.
Scheme 3.
Oxazole-containing amino acids 2 and 3 were inserted into a peptidic frame following two different
strategies. As a first approach, we prepared the peptoid 14 starting from 2 and carrying out the methylester
cleavage with 2 N NaOH/MeOH followed by amide coupling with H–Val–OMe (Scheme 4) using the
mixed anhydride protocol. The hydrogenolysis of product 14 in the presence of 10% Pd/C provided the

M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 1419–1426
1421
removal of Cbz group; a successive amide coupling with Cbz–Ala–OH afforded compound 15 in good
yield. In this manner the complete incorporation of compound 2 in a peptidomimetic chain was realised.
Scheme 4.
The incorporation of compound 3 in a peptoid chain (Scheme 5) was also realised in a different
way. The sequence adopted started with the removal of the β-benzyl ester group from oxazole 3. The
subsequent amide coupling with H–Phe–OMe afforded product 16. The cleavage of the Boc group in the
structure 16 was carried out with HCl/EtOAc and the next amide coupling with Cbz–Phe–OH afforded
compound 17 in which the oxazole structure is in a side branch of the main peptoid chain.
Scheme 5.
Compounds 15 and 17 are currently under investigation as to their biological activity while oxazole
amino acids 3 and 4 are being checked as possible substrates for the preparation of new peptide
dendrimers.9
3. Experimental section
Boiling points are uncorrected. Elemental analyses were performed on a Perkin–Elmer 420 B analyser.
Optical rotations were measured with a Perkin–Elmer 241 automatic polarimeter in a 1 dm tube. The 1H
NMR (300 MHz) and 13C NMR (75.4 MHz) spectra were obtained with a Varian VXR-300 spectrometer
from CDCl3 solutions. All reactions involving air sensitive materials were carried out under an N2
atmosphere; all reagents and solvents employed were reagent grade materials purified by standard
methods and distilled before use. The CHCl3 was washed with H2O seven times, dried over CaCl2
overnight, filtered and stored over molecular sieves at 5°C. As chiral starting material, (S)-aspartic acid,
(S)-phenylalanine, (S)-valine and (S)-alanine of ‘BioChemika’ grade (chemical and enantiomeric purity
>99%) purchased from Fluka Chemie AG were used.

1422
M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 1419–1426
3.1. General procedure for diazocompounds 5 and 6
A solution of p-TsN3 (20 g, 101 mmol), Et3N (16 mL, 114 mmol) and dimethylmalonate (14.1 g, 107
mmol) or methylacetoacetate (12.4 g, 107 mmol) in dry benzene (90 mL) was allowed to stand at rt for 2
h, at which time a solid precipitated. After standing for 48 h at rt, the solvent was removed under reduced
pressure and the residue was separated from by-products by flash chromatography on silica and further
purified by vacuum distillation.
3.1.1. 2-Diazodimethylmalonate, 5
TLC: EtOAc:petroleum ether (3:7); 88% yield; bp 40–45°C/0.05 mbar. Calculated for C5H6N2O4: C,
37.98; H, 3.82; N, 17.72. Found: C, 37.89; H, 3.87; N, 17.77.
3.1.2. 2-Diazomethylacetoacetate, 6
TLC: EtOAc:petroleum ether (1.5:8.5); 81% yield; bp 38–40°C/0.05 mbar. Calculated for C5H6N2O3:
C, 42.26; H, 4.26; N, 19.71. Found: C, 42.27; H, 4.30; N, 19.65.
3.2. General procedure for 7–9
Ethyl chloroformate (1.05 mL, 11 mmol) in CH2Cl2 (20 mL) at −15°C, was added slowly and
under vigorous stirring to 4-methylmorpholine (1.21 mL, 11 mmol) and carboxylic acid [Z–Phe–OH,
Boc–Asp(OBn)–OH or Cbz–Asp(OBn)–OH] (10 mmol) in CH2Cl2 (80 mL). The mixture was stirred at
−15°C for 20 min, then saturated with NH3(g). The mixture was allowed to warm to rt. After 12 h stirring
at rt, the solvent was eliminated in vacuo; to the residue H2O (50 mL) and EtOAc (100 mL) were added
and the aqueous layer was separated. The organic solution was washed with 10% aq. KHSO4, sat. aq.
NaCl, 10% aq. NaHCO3, sat. aq. NaCl (20 mL of each), in that order, and dried (Na2SO4). The solvent
was removed under reduced pressure affording pure amides.
3.2.1. (S)-N-Benzyloxycarbonyl phenylalanylamide, 7
TLC: EtOAc:petroleum ether:Et3N (7:3:0.1); 87% yield, 1H NMR δ: 7.40–7.13 (m, 10H, Ar), 5.81 (bs,
1H, NH), 5.59 (bs, 1H, NH), 5.43 (d-like, 1H, NH), 5.07 (s, 2H, OCH2Ph), 4.44 (m, 1H, CHCH2Ph),
3.15–2.99 (m, 2H, CHCH2Ph). Calculated for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.39;
H, 6.04; N, 9.44.
3.2.2. (S)-β-Benzylester-N-tert-butoxycarbonyl aspartylamide, 8
TLC: EtOAc:petroleum ether:Et3N (7:3:0.1); 99% yield. 1H NMR δ: 7.40–7.30 (m, 5H, Ph), 6.46 (bs,
1H, NH), 5.70 (d-like, 1H, NH), 5.44 (bs, 1H, NH), 5.14 (AB system, 2H, OCH2Ph), 4.60–4.50 (m, 1H,
CH), 3.08 (dd, 1H, J1=4.3, J2=17, CHCH2COO), 2.72 (dd, 1H, J1=6, J2=17, CHCH2COO), 1.44 (s, 9H,
t-Bu). Calculated for: C16H22N2O5: C, 59.61; H, 6.88; N, 8.69. Found: C, 59.55; H, 6.91; N, 8.72.
3.2.3. (S)-β-Benzylester-N-benzyloxycarbonyl aspartylamide, 9
TLC: EtOAc:petroleum ether (6:4), 69% yield. 1H NMR δ: 7.45–7.29 (m, 10H, Ar), 6.50 (bs, 1H, NH),
6.07 (d-like, 1H, NH), 5.87 (bs, 1H, NH), 5.21–5.08 (m, 4H, OCH2Ph), 4.70–4.56 (m, 1H, CHCH2COO),
3.07 (dd, 1H, J1=4.5, J2=17, CHCH2COO). Calculated for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86.
Found: C, 64.12; H, 5.61; N, 7.82.

M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 1419–1426
1423
3.3. General procedure for 10–13
A solution of the diazocompound 5 or 6 (7 mmol) in dry chloroform (35 mL) was added dropwise over
3 h to a refluxing solution of the suitable amide 7–9 (5 mmol) and Rh2(OAc)4 (44 mg, 0.1 mmol) in dry
chloroform (130 mL). The mixture was refluxed for a further 24 h, allowed to cool, evaporated in vacuo
and the crude product purified by flash chromatography on silica.
3.3.1. (RS)-N-[(S)-N-Benzyloxycarbonylphenylalanyl]-2-amino dimethylmalonate, 10
TLC: EtOAc:petroleum ether (5:7); 80% yield, 1H NMR δ: 7.40–7.15 (m, 11H, Ar+NH), 6.80 (bs, 1H,
NH), 5.30–5.20 (m, 1H, CHCOO), 5.14–5.06 (m, 2H, OCH2Ph), 4.60–4.47 (m, 1H, CHCH2Ph), 3.79 (s,
6H, OCH3), 3.11 (d-like, 2H, CH2Ph). Calculated for C22H24N2O7: C, 61.67; H, 5.65; N, 6.54. Found:
C, 61.61; H, 5.61; N, 6.61.
3.3.2. (RS)-N-[(S)-N-Benzyloxycarbonylphenylalanyl]-2-amino methylacetoacetate, 11
1
TLC: EtOAc:petroleum ether (5:7); 92% yield, H NMR δ: 7.40–7.15 (m, 10H, Ar), 7.02–6.85 (m,
1H, NH), 5.41–5.02 (m, 3H, CHCOOCH3+OCH2Ph+NH), 4.67–4.42 (m, 1H, NH), 3.90–3.82 (m, 1H,
CHCH2Ph) 3.78 (s, 3H, OCH3) 3.10 (d-like, 2H, CHCH2Ph), 2.31 (s, 3H, COCH3). Calculated for
C22H24N2O6: C, 64.07; H, 5.87; N, 6.79. Found: C, 64.13; H, 5.88; N, 6.71.
3.3.3. (RS)-N-[(S)-β-Benzylester-N-tert-butoxycarbonylaspartyl]-2-amino dimethylmalonate, 12
TLC: EtOAc:petroleum ether (1:1); 74% yield, 1H NMR δ: 7.55 (d-like, 1H, NH), 7.31–7.15 (m, 5H,
Ph), 5.8 (d-like, 1H, NH), 5.10–4.98 (m, 3H, CHCOO+OCH2Ph), 4.65–4.49 (m, 1H, CHCH2COO), 3.67
(s, 6H, COOCH3), 2.79 (AB part of an ABX system, 2H, CHCH2COO), 1.36 (s, 9H, t-Bu). Calculated
for C21H28N2O9: C, 55.75; H, 6.24; N, 6.19. Found: C, 55.81; H, 6.22; N, 6.23.
3.3.4. (RS)-N-[(S)-β-Benzylester-N-benzyloxycarbonylaspartyl]-2-amino methylacetoacetate, 13
1
TLC: EtOAc:petroleum ether (1:1); 79% yield, H NMR δ: 7.57 (bs, 1H, NH), 7.40–7.25 (m, 10H,
Ar), 5.95 (d-like, 1H, NH), 5.21–5.05 (m, 5H, OCH2Ph+CHCOCH3), 4.77–4.61 (m, 1H, CHCH2COO),
3.79 (s, 3H, COOCH3), 3.16–3.00 (m, 1H, CHCH2COO), 2.85–2.69 (m, 1H, CHCH2COO), 2.35 (s, 3H,
COCH3). Calculated for C24H26N2O8: C, 61.27; H, 5.57; N, 5.95. Found: C, 61.31; H, 5.60; N, 5.90.
3.4. General procedure for 1–4
To a stirred solution of PPh3 (1.6 g, 6 mmol) and I2 (1.5 g, 6 mmol) in dry dichloromethane (40 mL)
at rt, Et3N (1.7 mL, 12 mmol) and the ketoamide 10–13 (3 mmol), in dry dichloromethane (10 mL)
were added sequentially. The mixture was stirred overnight, evaporated in vacuo, and the crude product
purified by flash chromatography on silica.
3.4.1. (S)-1-N-Benzyloxycarbonylamino-1-(400 -carboxymethyl-500 -methoxy-200-oxazolyl)-2-
phenylethane, 1
TLC: EtOAc:petroleum ether (8:2); 34% yield, [α]D −18.7 (c 0.5, CH2Cl2); 1H NMR δ: 7.39–7.12
20
(m, 10H, Ar), 7.03 (bs, 1H, NH), 5.46–4.87 (m, 3H, CH+OCH2Ph), 3.91 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3), 3.30–3.18 (m, 2H, CHCH2Ph). 13C NMR δ: 163.2, 160.7, 156.3, 155.5, 140.1, 136.1, 135.6,
128.6, 128.2, 128.0, 127.9, 127.4, 126.3, 66.0, 52.4, 51.2, 39.1, 26.8. Calculated for C22H22N2O6: C,
64.38; H, 5.40; N, 6.83. Found: C, 64.45; H, 5.39; N, 6.79.

1424
M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 1419–1426
3.4.2. (S)-1-N-Benzyloxycarbonylamino-1-(400 -carboxymethyl-500 -methyl-200-oxazolyl)-2-
phenylethane, 2
TLC: EtOAc:petroleum ether (8:2); 84% yield, [α]D −29.9 (c 1.4, CH2Cl2); 1H NMR δ: 7.42–7.13
19
(m, 10H, Ar), 7.05 (bs, 1H, NH), 5.51–4.95 (m, 3H, CH+OCH2Ph), 3.90 (s, 3H, OCH3), 3.33–3.10
(m, 2H, CHCH2Ph), 2.56 (s, 3H, oxazole-CH3). 13C NMR δ: 162.4, 161.2, 156.7, 155.7, 136.0, 135.4,
129.1, 128.5, 128.3, 128.0, 127.9, 127.3, 126.9, 66.9, 51.9, 50.3, 40.0, 11.8. Calculated for C22H22N2O5:
C, 66.99; H, 5.62; N, 7.10. Found: C, 67.04; H, 5.59; N, 7.12.
3.4.3. (S)-1-N-tert-Butoxycarbonylamino-1-(40 -carboxymethyl-50-methoxy-20-oxazolyl)benzyl
propionate, 3
TLC: EtOAc:petroleum ether (1:1), 35% yield, [α]D −17.3 (c 2.15, CH2Cl2); 1H NMR δ: 7.38–7.23
19
(m, 5H, Ph), 5.61 (d-like, 1H, NH), 5.21–5.15 (m, 1H, CH), 5.05 (s, 2H, CH2Ph), 4.04 (s, 3H, OCH3),
3.81 (s, 3H, OCH3), 3.02 (AB part of an ABX system, 2H, CHCH2COO), 1.40 (s, 9H, t-Bu). 13C NMR
δ: 169.9, 165.8, 161.6, 154.7, 151.6, 135.2, 128.6, 128.2, 128.1, 73.6, 66.6, 59.6, 51.6, 45.3, 37.3, 27.8.
Calculated for C21H26N2O8: C, 58.06; H, 6.03; N, 6.45. Found: C, 57.99; H, 6.10; N, 6.40.
3.4.4. (S)-3-N-Benzyloxycarbonylamino-3-(40 -carboxymethyl-50 -methyl-20-oxazolyl)benzyl propionate,
4
18
TLC: EtOAc:petroleum ether (1:1), 45% yield, [α]D −14.4 (c 1.0, CH2Cl2); 1H NMR δ: 7.44–7.11
(m, 10H, Ar), 5.87 (d-like, 1H, NH), 5.35–5.24 (m, 1H, CH), 5.11 (s, 2H, OCH2Ph), 5.03 (s, 2H,
OCH2Ph), 3.89 (s, 3H, OCH3), 3.19 (dd, 1H, J1=5, J2=16, CH2COO), 3.04 (dd, 1H, J1=5.6, J2=16,
CH2COO), 2.55 (s, 3H, oxazole-CH3). 13C NMR δ: 170.0, 162.4, 160.3, 156.8, 155.6, 135.9, 135.2,
128.5, 128.4, 128.3, 128.2, 128.1, 127.5, 67.2, 66.8, 51.9, 45.9, 37.6, 12.0. Calculated for C24H24N2O7:
C, 63.71; H, 5.35; N, 6.19. Found: C, 63.78; H, 5.31; N, 6.21.
3.5. (S)-1-N-(Benzyloxycarbonylamino)-1-{400 -[carboxyamido-(S)-valinemethylester]-500 -methyl-200-
oxazolyl}-2-phenylethane, 14
Compound 2 (0.3 g, 0.76 mmol), was stirred in the presence of 2 N NaOH:MeOH (1:2; 2.3 mL) at 35°C
for 1 h. The MeOH was evaporated under vacuum and the remaining aqueous solution was washed with
ether (2×2 mL), cooled (0°C), and brought to pH 2 with 4 N HCl. The aqueous phase was extracted with
EtOAc (3×3 mL), the combined extracts were dried (Na2SO4), and the solvent was removed in vacuo
giving the crude product which was employed without any further purification. 1H NMR δ: 9.83 (bs, 1H,
COOH), 7.41–7.03 (m, 11H, Ar+NH), 5.27 (m, 1H, CHCH2Ph), 5.02 (AB system, 2H, OCH2Ph), 3.24
(d-like, 2H, CH2Ph), 2.49 (s, 3H, oxazole-CH3). 13C NMR δ: 164.4, 163.4, 157.1, 156.1, 136.1, 135.7,
129.1, 128.5, 128.2, 127.8, 127.7, 126.9, 66.8, 50.7, 40.4, 11.6.
Isobutyl chloroformate (0.17 mL 1.32 mmol) in CH2Cl2 (10 mL) at −15°C, was added slowly and
under vigorous stirring to the crude acid (456 mg, 1.2 mmol) and 4-methylmorpholine (0.28 mL, 2.6
mmol) in CH2Cl2 (40 mL). The mixture was stirred at −15°C for 20 min, then H–Val–OMe·HCl was
added (200 mg, 1.2 mmol). After stirring at rt for 12 h, the solvent was evaporated in vacuo; H2O (50
mL) and EtOAc (50 mL) were added to the residue and the aqueous layer was discarded. The organic
solution was washed with 10% aq. KHSO4, sat. aq. NaCl, 10% aq. NaHCO3, sat. aq. NaCl (30 mL of
each), in that order, and dried (Na2SO4). The solvent was evaporated under reduced pressure affording
16
1
pure [TLC: EtOAc:MeOH (8:1)] peptoid 14 (544 mg, 92% yield), [α]D −13.9 (c 1.43, CH2Cl2); H
NMR δ: 7.57–7.20 (m, 10H, Ar), 7.05 (bs, 1H, NH), 5.61 (d-like, 1H, NH), 5.38–5.0 (m, 2H, OCH2Ph),
4.68–4.59 (dd, 1H, J1=6, J2=13, CHCH2Ph), 3.95–3.79 (m, 1H, NHCHCO), 3.73 (s, 3H, OCH3), 3.20
(AB part of an ABX system, 2H, CH2Ph), 2.53 (s, 3H, oxazole-CH3), 2.30–2.16 [m, 1H, CH(CH3)2],

M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 1419–1426
1425
1.03–0.93 [m, 6H, CH(CH3)2]. 13C NMR δ: 172.2, 161.6, 159.9, 155.6, 153.5, 140.1, 136.2, 135.7,
129.6, 129.4, 129.2, 128.9, 128.7, 128.1, 67.1, 56.7, 52.1, 50.3, 39.8, 31.3, 19.1, 18.0, 11.6. Calculated
for C27H31N3O6: C, 65.71; H, 6.33; N, 8.51. Found: C, 65.79; H, 6.30; N, 8.55.
3.6. (S)-1-N-[N-Benzyloxycarbonyl-(S)-alanilamino]-1-{400 -[carboxyamido-(S)-valinemethylester]-
500-methyl-200-oxazolyl}-2-phenylethane, 15
To a solution of the compound 14 (0.59 g, 1.2 mmol) in MeOH (20 mL) was added 10% Pd/C catalyst
(90 mg). The mixture was kept in H2 atmosphere with vigorous stirring for 40 min. The catalyst was
removed by Celite filtration and the solvent removed in vacuo affording the crude amine (0.4 g, 92%
yield) that was employed without any further purification. Isobutyl chloroformate (0.15 mL, 1.2 mmol)
in CH2Cl2 (20 mL) at −15°C, was added slowly and under vigorous stirring to a solution of Cbz–Ala–OH
(0.25 g, 1.12 mmol) and 4-methylmorpholine (0.13 mL, 1.2 mmol) in CH2Cl2 (80 mL). The mixture was
stirred at −15°C for 20 min, then the deprotected crude amine was added (0.4 g, 1.1 mmol). After 12 h
stirring at rt, the solvent was removed in vacuo; to the residue H2O (50 mL) and EtOAc (50 mL) were
added and the aqueous layer was discarded. The organic solution was washed with 10% aq. KHSO4,
sat. aq. NaCl, 10% aq. NaHCO3, sat. aq. NaCl (50 mL), in that order, and dried (Na2SO4). The solvent
was evaporated under reduced pressure affording pure [TLC: EtOAc:petroleum ether (6:4)] peptoid 15
20
(0.59 g, 94% yield), [α]D −23.3 (c 1.58, CH2Cl2); 1H NMR δ: mixture of conformers at amide bond,
7.66–7.41 (m, 10H, Ar), 7.08–6.99 (d-like, 1H, NH), 6.6 (bs, 0.4H, NH), 5.58–5.20 (m, 1.6H, NH), 5.09
(AB system, 2H, OCH2Ph), 4.61 (dd, 1H, J1=5, J2=9, CHCH2Ph), 4.35–4.22 (m, 1H, CHCH3), 4.04
[d, 1H, CHCH(CH3)2], 3.72 (s, 3H, COOCH3), 3.17 (AB part of an ABX system, 2H, CHCH2Ph), 2.54
(s, 3H, oxazole-CH3), 2.30–2.16 [m, 1H, CH(CH3)2], 1.36 (m, 1.2H, CHCH3) 1.21 (m, 1.8H, CHCH3),
1.00–0.85 [m, 6H, CH(CH3)2]. 13C NMR δ: 172.4, 172.3, 167.9, 161.7, 159.9, 153.7, 148.8, 137.0,
136.0, 129.5, 128.8, 128.6, 128.2, 128.1, 127.1, 75.9, 67.2, 67.1, 56.9, 52.3, 39.4, 31.4, 27.7, 18.1, 17.7,
11.7. Calculated for C30H36N4O7: C, 63.82; H, 6.43; N, 9.92. Found: C, 63.91; H, 6.40; N, 9.88.
3.7. (S)-1-N-tert-Butoxycarbonylamino-1-(40 -carboxymethyl-50-methoxy-20-oxazolyl)-(S)-
phenylalaninemethylester propionamide, 16
To a solution of the compound 3 (1.2 g, 2.7 mmol) in MeOH (30 mL) was added 10% Pd/C catalyst
(0.3 g). The mixture was kept under an H2 atmosphere with vigorous stirring for 40 min. The catalyst was
removed by Celite filtration and the solvent removed in vacuo affording the crude acid (0.72 g, 77% yield)
that was employed without any further purification. To the crude acid (0.41 g, 1.2 mmol) dissolved in
dichloromethane (40 mL), at −15°C under vigorous stirring 4-methylmorpholine (0.29 mL, 2.64 mmol)
and isobutyl chloroformate (0.17 mL, 1.32 mmol) were added slowly. The mixture was stirred at −15°C
for 20 min, then the H–Phe–OMe·HCl was added (0.26 g, 1.2 mmol). After 12 h of stirring at rt, the
solvent was evaporated in vacuo; to the residue H2O (50 mL) and EtOAc (50 mL) were added and the
aqueous layer was discarded. The organic solution was washed with 10% aq. KHSO4, sat. aq. NaCl, 10%
aq. NaHCO3, sat. aq. NaCl (30 mL), in that order, and dried (Na2SO4). The solvent was evaporated under
reduced pressure affording pure [TLC: EtOAc:MeOH (8:1)] peptoid 16 (0.52 g, 85% yield), [α]D19 +36.9
(c 1.5, CH2Cl2); 1H NMR δ: mixture of conformers at amide bond, 7.35–7.11 (m, 5H, Ph), 7.0 (d-like,
1H, NH), 6.23 (d-like, 0.6H, NH), 5.46 (d-like, 0.4H, NH), 4.80 (m, 1H, CH), 4.61 (m, 1H, CH), 3.78 (s,
3H, OCH3), 3.68 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 3.19–2.77 (m, 4H, CHCH2CO+CHCH2Ph), 1.43
(s, 9H, t-Bu). 13C NMR δ: 171.8, 171.4, 169.1, 165.6, 161.3, 161.2, 155.7, 135.6, 128.8, 127.9, 126.4,
70.4, 59.9, 54.4, 52.8, 51.7, 51.0, 37.4, 27.8, 18.5. Calculated for C24H31N3O9: C, 57.02; H, 6.18; N,
8.31. Found: C, 57.12; H, 6.12; N, 8.25.

1426
M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 1419–1426
3.8. (S)-1-N-[N-Benzyloxycarbonyl-(S)-phenylalanilamino]-1-(40 -carboxymethyl-50 -methoxy-20-
oxazolyl)-(S)-phenylalaninemethylester propionamide, 17
The protected product 16 (0.28 g, 0.5 mmol) was treated at rt with 3 N HCl in EtOAc (4 mL). After 30
min, the solvent was removed under reduced pressure, affording pure (TLC) crude amine hydrochloride
(0.22 g, 90% yield) that was employed without any further purification.
To a solution of Cbz–Phe–OH (0.14 g, 0.5 mmol) in dichloromethane (20 mL) at −15°C, were added
slowly and under vigorous stirring 4-methylmorpholine (0.17 mL, 1.5 mmol) and isobutyl chloroformate
(0.1 mL, 0.55 mmol). The mixture was stirred at −15°C for 20 min, then the crude amine hydrochloride
was added (0.22 g, 0.45 mmol). After 12 h of stirring at rt, the solvent was evaporated in vacuo; to the
residue H2O (20 mL) and EtOAc (20 mL) were added and the aqueous layer was discarded. The organic
solution was washed with 10% aq. KHSO4, sat. aq. NaCl, 10% aq. NaHCO3, sat. aq. NaCl (15 mL), in
that order, and dried (Na2SO4). The solvent was evaporated under reduced pressure and the crude peptoid
17 was purified by flash cromatography on silica [EtOAc:petroleum ether (2:7)] affording pure product
19
1
17 (0.2 g, 48% yield), [α]D +25.0 (c 0.2, CH2Cl2); H NMR δ: 7.45–7.1 (m, 17H, Ar+NH), 7.03
(m, 1H, NH) 5.26–4.92 (m, 3H, OCH2Ph+CH), 4.73–4.62 (m, 1H, CH), 4.59–4.50 (m, 1H, CH), 3.92
(s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.23–3.01 (m, 6H, CH2CONH+CH2Ph). 13C
NMR δ: 172.1, 171.8, 171.4, 169.1, 165.6, 161.3, 156.2, 155.2, 135.6, 135.7, 129.5, 129.0, 128.8, 128.7,
128.4, 128.2, 127.8, 127.1, 126.7, 71.3, 61.6, 54.7, 52.3, 45.5, 38.3, 29.7, 27.9, 27.5, 14.1. Calculated for
C36H38N4O10: C, 62.96; H, 5.58; N, 8.16. Found: C, 62.91; H, 5.57; N, 8.14.
Acknowledgements
This work was financially supported by MURST, Roma in the project 40%, Es. Fin. 96, Sostanze
Organiche Naturali and by CNR, Roma with the grant no. 97.02804.CT03.
References
1. Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis: Construction of Chiral Molecules Using Amino Acids, Wiley, New
York, 1987. O’Donnell, M. J., Ed. Tetrahedron Symposia in Print, 1988, 44, 5253. Williams, R. M. Organic Chemistry
Series Volume 7: Synthesis of Optically Active α-Amino Acids, Baldwin, J. E., Magnus, P. D., Eds., Pergamon Press,
Oxford, 1989. Duthaler, R. O. Tetrahedron, 1994, 50, 1539.
2. Falorni, M.; Giacomelli, G. Synlett, 1996, 143–144. D’Aniello, F.; Falorni, M.; Mann, A.; Taddei, M. Tetrahedron:
Asymmetry, 1996, 7, 1217–1226. Falorni, M.; Porcheddu, A.; Giacomelli, G. Tetrahedron: Asymmetry, 1996, 7,
1999–2005. Falorni, M.; Porcheddu, A.; Giacomelli, G. Tetrahedron: Asymmetry, 1997, 8, 1633–1639.
3. Gordon, T. D.; Singh, J.; Hansen, P. E.; Morgan, B. A. Tetrahedron Lett., 1993, 34, 1901–1904. Gordon, T.; Hansen, P. E.;
Morgan, B.; Singh, J.; Balzman, E.; Ward, S. Bioorg. Med. Chem. Lett., 1993, 3, 915–920.
4. For a review on the argument: Wipf, P. Chem. Rev. 1995, 95, 2115–2134. See for recent examples: Yoo S.-K. Tetrahedron
Lett., 1992, 33, 2159–2162. Wipf, P.; Miller, C. P. J. Org. Chem., 1993, 58, 3604–3606. Chattopadhyay, S. K.; Pattenden,
G. Synlett, 1997, 1342–1344. Pihko, P. M.; Koskinen, A. M. P. J. Org. Chem., 1998, 63, 92–98.
5. Shapiro, R. J. Org. Chem., 1993, 58, 5759–5764.
6. Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J.; Slawin, A. M. Z. Synlett, 1996, 825–826. Moody, C. J.; Bagley, M.
C. Synlett, 1996, 1171–1172.
7. The same results are obtained using 4-acetamidobenzensulfonazide instead of p-TsN3. Tullis, J. S.; Helquist, P. Organic
Syntheses, 1996, 74, 229–240.
8. Falorni, M.; Chelucci, G.; Conti, S.; Giacomelli, G. Synthesis, 1992, 972–976.
9. Tam, J. P. In Peptides, Gutte, B., Ed., Academic Press, London, 1995, pp. 455–500.