Synthesis of substituted oxazoles from N-acyl-β-hydroxyamino acid derivatives

Article abstract of DOI:10.1002/ejoc.200800602

Several N-acyl-β-hydroxyamino acids were prepared and treated with di-tert-butyl dicarbonate in the presence of 4-(dimethylamino)pyridine, followed by treatment with N,N,N′,N′-tetramethylguanidine to give the corresponding N-acyldehydroamino acids in good

Full text of DOI:10.1002/ejoc.200800602

FULL PAPER
DOI: 10.1002/ejoc.200800602
Synthesis of Substituted Oxazoles from N-Acyl-β-hydroxyamino Acid
Derivatives
Paula M. T. Ferreira,*[a] Luís S. Monteiro,*[a] and Goreti Pereira[a]
Keywords: Amino acids / Dehydroamino acids / Iodine / Cyclization / Oxygen heterocycles / Nitrogen heterocyles
Several N-acyl-β-hydroxyamino acids were prepared and
treated with di-tert-butyl dicarbonate in the presence of 4-
(dimethylamino)pyridine, followed by treatment with
N,N,NЈ,NЈ-tetramethylguanidine to give the corresponding
N-acyldehydroamino acids in good to high yields. These
were then treated with I2/K2CO3 followed by 1,8-diazabicy-
clo[5.4.0]undec-7-ene. The methyl esters of N-acyldehyd-
roaminobutyric acid gave the corresponding substituted ox-
azoles in good to high yields. The N-acyldehydrophenylalan-
ines gave 5-phenyloxazole derivatives in low to moderate
yields together with β-iododehydrophenylalanines.
tion was carried out in the absence of DBU, it was possible
to isolate the β,β-diiododehydroalanine derivatives. Al-
though the reason for the different reactivities of the N-acyl-
dehydroamino acids is not completely clear to us, cyclic vol-
tammetry studies showed that the less-reactive derivatives
have higher reduction potentials. This suggests that the
double bonds in dehydroaminobutyric acid derivatives are
more susceptible to electrophilic attack by iodine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Under the same conditions, N-acyldehydroalanines failed to
give the corresponding oxazoles. However, when the reac-
In our group, we developed an efficient synthesis of N-
acyldehydroamino acid derivatives.[10] The high reaction
yields and the simple workup procedures allowed the prepa-
ration of large quantities of these compounds, which were
used as substrates in several types of reactions, giving a
wide range of nonproteinogenic amino acids.[11] Here we
report the synthesis of substituted oxazoles from N-acyl-β-
hydroxyamino acids by a sequence involving a dehydration
reaction followed by an intramolecular cyclization pro-
moted by iodine.
Introduction
Oxazoles are important structural motifs of a wide range
of biologically active molecules. Natural products contain-
ing the oxazole ring have been isolated from marine inverte-
brates and microorganisms.[1] This heterocyclic ring system
is biosynthesized from serine, threonine and cysteine pre-
cursors by enzyme-catalysed cyclodehydration and redox
reactions.[2] There have been many synthetic efforts to de-
velop efficient and mild methodologies for the preparation
of oxazoles. These include, among others, the Cornforth
protocol,[3] catalytic decomposition of α-diazocarbonyl
compounds,[4] photolysis and pyrolysis of N-acylisoxazo-
lones[5] and modified Robinson–Gabriel reactions.[6] Wipf
and co-workers[7] reported the synthesis of oxazoles by
treatment of serine derivatives with diethylaminosulfur tri-
fluoride (DAST) followed by bromotrichloromethane and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Morwick et al.
prepared 2,4-disubstituted oxazoles from N-acylamino ac-
ids by cyclodehydration of the intermediate α-acylamino al-
dehydes.[8] Recently, Buchwald et al.[9] described the synthe-
sis of oxazoles by a sequential copper-catalysed amidation
of vinyl halides, followed by iodine-promoted cyclization.
Results and Discussion
Several N-acyldehydroaminobutyric acid derivatives were
prepared by treating the corresponding threonine deriva-
tives with one equivalent of di-tert-butyl dicarbonate
(Boc2O) and 4-(dimethylamino)pyridine (DMAP), followed
by treatment with N,N,NЈ,NЈ-tetramethylguanidine (TMG)
(Scheme 1, conditions i; Table 1).[10b] The stereochemistry
of the dehydroaminobutyric acid derivatives was deter-
mined by NOE difference experiments, through irradiation
of the α-NH proton and observation of a NOE enhance-
ment on the γ-methyl protons. These N-acyldehydroamino-
butyric acids were then treated with iodine in the presence
of K2CO3 followed by DBU to give the corresponding 2-
substituted methyl 5-methyloxazole-4-carboxylates (3a–f;
Scheme 1, conditions ii; Table 1) in good to high yields.
[a] Department of Chemistry, University of Minho,
Gualtar, 4710-057 Braga, Portugal
Fax: +351-253604382
E-mail: pmf@quimica.uminho.pt
monteiro@quimica.uminho.pt
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Substituted Oxazoles from N-Acyl-β-hydroxyamino Acid Derivatives
Table 1. Synthesis of N-acylthreonine, N-acyldehydroaminobutyric acid and methyl oxazole-4-carboxylate derivatives.
tuted methyl oxazole 4-carboxylates, and the starting mate-
rials were the only products isolated. When N-benzoyldehy-
drophenylalanine (7a) was used as a substrate, it was pos-
sible to obtain the corresponding 2,5-diphenyloxazole in
moderate yield (8a; Scheme 2, conditions ii), together with
the Z isomer of the β-iododehydrophenylalanine derivative
(9a). In the cases of compounds 7b and 7e the oxazoles were
detectable in the 1H NMR spectra of the reaction mixtures,
together with the starting materials and the corresponding
β-iododehydrophenylalanine derivatives. Treatment of com-
pounds 6a, 6c–e, 7a, 7b and 7e with I2/K2CO3 in THF, with-
out addition of DBU, afforded the corresponding β,β-di-
iododehydroalanines (10a, 10c–e) or β-iododehydrophenyl-
alanines (9a, 9b, 9e) in good yields (Scheme 2, conditions iii;
Table 2). These reaction conditions were also applied to
compound 2a, giving the Z isomer of the methyl ester of
N-benzoyl-β-iododehydroaminobutyric acid (11).
Scheme 1.
The cyclization reaction was tested with the methyl ester
of tert-(butoxycarbonyl)dehydroaminobutyric acid as sub-
strate. However, the only product isolated was the Z isomer
of the corresponding β-iodo derivative, in 87% yield. Re-
cently, Licini et al. described the iodocyclization of allylala-
nine derivatives to γ-lactones and oxazolinones in good
yields.[12] According to the authors, the efficiencies of I2 and
N-iodosuccinimide (NIS) as I+ sources appear to be com-
parable in terms of reactivity. However, when compound 2a
was treated with NIS, the Z isomer of the methyl ester of N-
benzoyl-β-iododehydroaminobutyric acid was obtained in
81% yield.
The stereochemistries of compounds 9 and 11 were de-
termined by irradiation of the methyl ester protons and ob-
servation of NOE enhancements on the C6H5 or β-CH3
protons, respectively.
The reason for the good yields obtained in the synthesis
of 5-methyloxazoles, relative to those for 5-phenyloxazoles,
and the impossibility of obtaining 5-unsubstituted oxazoles
from dehydroalanine derivatives is not clear to us. However,
cyclic voltammetry studies of compounds 2a, 2c, 6a, 6c, 7a
and 7c (Table 3) show that the N-acyldehydroaminobutyric
The dehydration/cyclization protocol was also applied to
serine and β-hydroxyphenylalanine derivatives. The methyl
esters of N-acyl dehydroalanines and dehydrophenylala-
nines were prepared in good yields (Scheme 2, Table 2). As
expected in the case of dehydrophenylalanine derivatives the
dehydration reaction was stereoselective for the Z iso-
mers.[10b] These compounds were then treated with acid derivatives have lower reduction peak potentials. This
I2/K2CO3 followed by DBU. The N-acyldehydroalanine de- might suggest that in this case the double bond can undergo
rivatives (6a, 6c–e) failed to give the corresponding 2-substi- electrophilic attack by iodine more easily.
Eur. J. Org. Chem. 2008, 4676–4683
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P. M. T. Ferreira, L. S. Monteiro, G. Pereira
FULL PAPER
Scheme 2.
Table 2. Synthesis of N-acyldehydroamino acid and N-acyl-β-iododehydroamino acid derivatives.
N-Acyldehydroamino acids
% Yield
N-Acyl-β-iododehydroamino acids
% Yield
Bz-∆Ala-OMe (6a)[13]
71
50
72
67
90
87
91
83
Bz-∆Ala(β,β-I)-OMe (10a)
40
42
47
53
87
85
83
81
Bz(4-OMe)-∆Ala-OMe (6c)
1-Naph-∆Ala-OMe (6d)
2-Fur-∆Ala-OMe (6e)
Bz(4-OMe)-∆Ala(β,β-I)-OMe (10c)
1-Naph-∆Ala(β,β-I)-OMe (10d)
2-Fur-∆Ala(β,β-I)-OMe (10e)
Bz-Z-∆Phe(β-I)-OMe (9a)[a]
Bz(4-NO2)-Z-∆Phe(β-I)-OMe (9b)[a]
2-Fur-Z-∆Phe(β-I)-OMe (9e)
Bz-Z-∆Abu(β-I)-OMe (11)
Bz-Z-∆Phe-OMe (7a)
Bz(4-NO2)-Z-∆Phe-OMe (7b)
2-Fur-Z-∆Phe-OMe (7e)
Bz-Z-∆Abu-OMe (2a)
[a] The reaction was carried out under conditions ii (Scheme 2) at room temperature.
Table 3. Peak potentials obtained by cyclic voltammetry of N-acyl-
The higher reactivities of dehydroaminobutyric acid de-
rivatives towards iodocyclization seem to be related to the
more strongly electrophilic characters of the double bonds
in these dehydroamino acid derivatives relative to those in
dehydroalanine and dehydrophenylalanine derivatives.
dehydroamino acid derivatives.[a]
Compound
–Ep [V] (vs. SCE[b]
)
Bz-∆Ala-OMe (6a)
Bz-Z-∆Abu-OMe (2a)
Bz-Z-∆Phe-OMe (7a)
Bz(OMe)-∆Ala-OMe (6c)
Bz(OMe)-Z-∆Abu-OMe (2c)
Bz(OMe)-Z-∆Phe-OMe (7c)
1.91[13]
2.21[13]
1.87[13]
2.03
2.39
1.74
Experimental Section
General Methods: Melting points were determined with a Gallen-
kamp apparatus and are uncorrected. 1H and 13C NMR spectra
were recorded with a Varian Unity Plus instrument at 300 and
75.4 MHz, respectively, or with a Bruker Avance II+ instrument at
[a] Cathode: vitreous carbon. Solvent: DMF. Supporting electro-
lyte: Bu4NBF4 0.1 . Substrate conc. = 0.005 . [b] SCE: standard
calomel electrode.
1
400 and 100.6 MHz, respectively. H–1H spin-spin decoupling and
DEPT θ 45° were used. MS and HRMS data were recorded by the
mass spectrometry service of the University of Vigo, Spain; elemen-
tal analysis was performed with a LECO CHNS 932 elemental ana-
lyser. The reactions were monitored by thin-layer chromatography
(TLC). Column chromatography was performed on Macherey–Na-
gel silica gel 230–400 mesh. Petroleum ether refers to the boiling
range 40–60 °C. When solvent gradients were used, the increase in
polarity was made from neat petroleum ether to mixtures of diethyl
ether/petroleum ether, with diethyl ether being increased by 10%
each time until the isolation of the product. Cyclic voltammetry
experiments were carried out with a Hi-Tek potentiostat type
DT 2101 and a Hi-Tek wave generator type PPRl, connected to a
Philips recorder type PM 8043 and to a three-electrode, home-built
glass cell.
Conclusions
The reactivities of several N-acyldehydroamino acid de-
rivatives – namely, dehydroalanine, dehydroaminobutyric
acid and dehydrophenylalanine – towards iodine-induced
cyclization were studied, with the goal of obtaining ox-
azole-4-carboxylate derivatives. With dehydroaminobutyric
acid derivatives good to high yields of methyl 5-methylox-
azole-4-carboxylate derivatives were obtained, whereas with
dehydrophenylalanine derivatives the yields ranged from
poor to moderate. With dehydroalanine derivatives no cycli-
zation occurred. A modification of the reaction conditions
allowed the preparation of β,β-diiododehydroalanines in
moderate yields and of (Z)-β-iododehydroaminobutyric
acid and dehydrophenylalanine derivatives in high yields.
General Procedure for the Synthesis of N-Acylamino Acid Methyl
Esters: Triethylamine (2.2 equiv.) was added to a solution of a β-
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Substituted Oxazoles from N-Acyl-β-hydroxyamino Acid Derivatives
hydroxyamino acid methyl ester hydrochloride (5 mmol) in dichlo-
romethane (0.1 ), and the corresponding acyl chloride (1.1 equiv.)
was then slowly added with vigorous stirring and cooling in an ice
bath. After stirring at 0 °C for 30 min the solution was stirred at
room temperature for 3 h. The reaction mixture was then concen-
trated and partitioned between ethyl acetate (200 mL) and KHSO4
(1 , 100 mL) and washed with KHSO4 (1 ), NaHCO3 (1 ) and
brine (3ϫ50 mL). After drying over MgSO4 the extract was taken
to dryness at reduced pressure to afford the corresponding N-acyla-
mino acid methyl ester.
(287.31): calcd. C 66.89, H 5.96, N 4.88; found C 66.88, H 5.79, N
5.03.
2-Fur-L-Thr-OMe (1e): The general procedure described above was
followed with HCl·H--Thr-OMe and 2-furanoyl chloride to give
compound 1e (0.65 g, 57%) as a colourless oil. 1H NMR (CDCl3):
δ = 1.23 (d, J = 6.0 Hz, 3 H, γCH3), 3.73 (s, 3 H, CH3 CO2Me),
4.38–4.45 (m, 1 H, βCH), 4.70–4.74 (m, 1 H, αCH), 6.46–6.48 (m,
1 H, ArH), 7.11–7.12 (m, 1 H, ArH), 7.20 (br. d, J = 8.7 Hz, 1 H,
NH), 7.43–7.44 (m, 1 H, ArH) ppm. 13C NMR (CDCl3): δ = 19.89
(γCH3), 52.48 (OCH3), 57.00 (αC), 67.79 (βC), 112.09 (CH), 114.96
(CH), 144.36 (CH), 147.12 (C), 158.68 (C=O), 171.18 (C=O) ppm.
C10H13NO5 (227.21): calcd. C 52.86, H 5.77, N 6.16; found C
52.56, H 5.66, N 5.92.
Bz-
L-Ser-OMe (4a) and Boc-L-Thr-OMe: The synthesis of these
compounds has been described elsewhere.[10a]
Bz- -Thr-OMe (1a): The general procedure described above was
L
2-Qnx-L-Thr-OMe (1f): The general procedure described above was
followed with HCl·H--Thr-OMe and benzoyl chloride to give
compound 1a (0.913 g, 77%) as a white solid. M.p. 94.0–95.5 °C
(ethyl acetate/diethyl ether). 1H NMR (CDCl3): δ = 1.31 (d, J =
6.6 Hz, 3 H, γCH3), 2.30 (br. s, 1 H, OH), 3.81 (s, 3 H, CH3
CO2Me), 4.47 (dd, J = 2.4 Hz, J = 6.6 Hz, 1 H, βCH), 4.83 (dd, J
= 2.4 Hz, J = 8.7 Hz, 1 H, αCH), 6.96 (br. s, 1 H, αNH), 7.53–7.59
(m, 3 H, ArH), 7.85–7.87 (m, 2 H, ArH) ppm. 13C NMR (CDCl3):
δ = 19.96 (γCH3), 52.57 (OCH3), 57.73 (αC), 68.01 (βC), 127.16
(CH), 128.52 (CH), 131.86 (CH), 133.51 (C), 168.05 (C=O), 171.55
(C=O) ppm. C12H15NO4 (237.26): calcd. C 60.75, H 6.37, N 5.90;
found C 60.82, H 6.46, N 5.99.
followed with HCl·H--Thr-OMe and 2-quinoloyl chloride to give
compound 1f (1.10 g, 78%) as a light yellow solid. M.p. 130.0–
1
131.0 °C (ethyl acetate/n-hexane). H NMR (CDCl3): δ = 1.34 (d,
J = 6.3 Hz, 3 H, γCH3), 3.83 (s, 3 H, CH3 CO2Me), 4.53–4.61 (m,
1 H, βCH), 4.89 (dd, J = 6.9, J = 9.3 Hz, 1 H, αCH), 7.82–7.91
(m, 2 H, ArH), 8.15–8.20 (m, 2 H, ArH), 8.67 (d, J = 9.0 Hz, 1 H,
NH), 9.66 (s, 1 H, ArH) ppm. 13C NMR (CDCl3): δ = 20.03
(γCH3), 52.76 (OCH3), 57.37 (αC), 68.09 (βC), 129.39 (CH), 129.86
(CH), 130.87 (CH), 131.80 (CH), 140.30 (C), 142.79 (C), 143.75
(CH), 143.94 (C), 163.85 (C=O), 171.12 (C=O) ppm. C14H15N3O4
(289.29): calcd. C 58.13, H 5.23, N 14.53; found C 58.30, H 5.25,
N 14.19.
Bz(4-NO2)-L-Thr-OMe (1b): The general procedure described
above was followed with HCl·H--Thr-OMe and 4-nitrobenzoyl
chloride to give compound 1b (0.428 g, 30%) as a white solid. M.p.
122.0–123.0 °C (ethyl acetate/n-hexane). 1H NMR (CDCl3): δ =
1.33 (d, J = 6.6 Hz, 3 H, γCH3), 3.84 (s, 3 H, CH3 CO2Me), 4.50–
4.53 (m, 1 H, βCH), 4.83 (dd, J = 2.1 Hz, J = 8.6 Hz, 1 H, αCH),
6.97 (d, J = 8.1 Hz, 1 H, NH), 8.03 (d, J = 8.7 Hz, 2 H, ArH), 8.33
(d, J = 8.7 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3): δ = 20.18
(γCH3), 52.86 (OCH3), 57.74 (αCH), 68.05 (βCH2), 123.82 (CH),
128.44 (CH), 139.20 (C), 149.81 (C), 165.90 (C=O), 171.26
(C=O) ppm. C12H14N2O6 (282.25): calcd. C 51.07, H 5.00, N 9.93;
found C 51.06, H 5.03, N 9.85.
Bz(4-OMe)-L-Ser-OMe (4c): The general procedure described
above was followed with HCl·H--Ser-OMe and 4-methoxybenzoyl
chloride to give compound 4c (1.222 g, 97%) as a white solid. M.p.
1
41.5–43.0 °C (methanol/diethyl ether). H NMR (CDCl3): δ = 3.84
(s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.07 (d, J = 3.6 Hz, 2 H,
βCH2), 4.85–4.90 (m, 1 H, αCH), 6.95 (d, J = 9.0 Hz, 2 H, ArH),
7.20 (br. d, J = 6.6 Hz, 1 H, NH), 7.80 (d, J = 9.0 Hz, 2 H,
ArH) ppm. 13C NMR (CDCl3): δ = 52.63 (COOCH3), 55.06 (αC),
55.30 (OCH3), 63.03 (βC), 113.65 (CH), 125.53 (C), 129.02 (CH),
162.43 (C), 167.30 (C=O), 171.20 (C=O) ppm.
1-Naph-L-Ser-OMe (4d): The general procedure described above
Bz(4-OMe)-L-Thr-OMe (1c): The general procedure described
was followed with HCl·H--Ser-OMe and 1-naphthaloyl chloride
to give compound 4d (1.243 g, 91%) as a white solid. M.p. 82.5–
83.0 °C (ethyl acetate/petroleum ether). 1H NMR (CDCl3): δ = 3.84
(s, 3 H, CH3 CO2Me), 4.06–4.17 (m, 2 H, βCH2), 4.94–4.99 (m, 1
H, αCH), 7.00 (br. d, J = 9.0 Hz, 1 H, NH), 7.43–7.59 (m, 3 H,
ArH), 7.59–7.71 (m, 1 H, ArH), 7.86–7.95 (m, 2 H, ArH), 8.35–
8.38 (m, 1 H, ArH) ppm. 13C NMR (CDCl3): δ = 52.76 (OCH3),
55.01 (αC), 63.13 (βC), 124.58 (CH), 125.20 (CH), 125.45 (CH),
126.42 (CH), 127.23 (CH), 128.27 (CH), 130.01 (C), 131.02 (CH),
133.23 (C), 133.57 (C), 169.83 (C=O), 170.84 (C=O) ppm.
C15H15NO4 (273.29): calcd. C 65.93, H 5.53, N 5.13; found C
66.00, H 5.55, N 5.27.
above was followed with HCl·H--Thr-OMe and 4-methoxyben-
zoyl chloride to give compound 1c (1.072 g, 81%) as a white solid.
M.p. 108.0–109.0 °C (ethyl acetate/diethyl ether). 1H NMR
(CDCl3): δ = 1.25 (d, J = 6.3 Hz, 3 H, γCH3), 2.92 (br. s, 1 H,
OH), 3.75 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 4.38–4.45 (m, 1 H,
βCH), 4.76–4.80 (m, 1 H, αCH), 6.88 (d, J = 9.0 Hz, 2 H, ArH),
7.07 (d, J = 9.0 Hz, 1 H, NH), 7.80 (d, J = 9.0 Hz, 2 H, ArH) ppm.
13C NMR (CDCl3): δ = 19.95 (CH3), 52.53 (OCH3), 55.33 (OCH3),
57.72 (CH), 68.12 (CH), 113.69 (CH), 125.76 (C), 129.07 (CH),
162.43 (C), 167.53 (C=O), 171.75 (C=O) ppm. C13H17NO5
(267.28): calcd. C 58.42, H 6.41, N 5.24; found C 58.57, H 6.47, N
5.23.
2-Fur-L-Ser-OMe (4e): The general procedure described above was
1-Naph-L-Thr-OMe (1d): The general procedure described above
followed with HCl·H--Ser-OMe and 2-furanoyl chloride to give
compound 4e (0.49 g, 46%) as a light yellow oil. 1H NMR
(CDCl3): δ = 3.76 (s, 3 H, CH3 CO2Me), 3.92–4.07 (m, 2 H, βCH2),
4.76–4.81 (m, 1 H, αCH), 6.45–6.47 (m, 1 H, ArH), 7.10–7.12 (m,
1 H, ArH), 7.39 (br. d, J = 7.5 Hz, 1 H, NH), 7.43–7.44 (m, 1 H,
ArH) ppm. 13C NMR (CDCl3): δ = 52.68 (OCH3), 54.33 (αC),
62.84 (βC), 112.10 (CH), 115.03 (CH), 144.49 (CH), 147.01 (C),
158.46 (C=O), 170.76 (C=O) ppm.
was followed with HCl·H--Thr-OMe and 1-naphthaloyl chloride
to give compound 1d (1.26 g, 88%) as a white solid. M.p. 110.0–
1
111.0 °C (ethyl acetate/n-hexane). H NMR (CDCl3): δ = 1.37 (d,
J = 6.6 Hz, 3 H, γCH3), 3.85 (s, 3 H, CH3 CO2Me), 4.48–4.55 (m,
1 H, βCH), 4.93 (dd, J = 2.4 Hz, J = 9.0 Hz, 1 H, αCH), 6.80 (br.
d, J = 8.7 Hz, 1 H, NH), 7.45–7.60 (m, 3 H, ArH), 7.60–7.74 (m,
1 H, ArH), 7.87–7.96 (m, 2 H, ArH), 8.36–8.39 (m, 1 H, ArH) ppm.
13C NMR (CDCl3): δ = 20.06 (γCH3), 52.59 (OCH3), 57.68 (αC),
67.85 (βC), 124.56 (CH), 125.26 (CH), 125.27 (CH), 126.39 (CH), Bz-D
127.17 (CH), 128.23 (CH), 130.02 (C), 130.90 (CH), 133.51 (C), above was followed with HCl·H-,-Phe(β-OH)-OMe and benzoyl
133.55 (C), 170.05 (C=O), 171.36 (C=O) ppm. C16H17NO4 chloride to give compound 5a (1.332 g, 89%) as a white solid. M.p.
,L-Phe(β-OH)-OMe (5a): The general procedure described
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P. M. T. Ferreira, L. S. Monteiro, G. Pereira
FULL PAPER
124.0–125.0 °C (ethyl acetate/diethyl ether). 1H NMR (CDCl3): δ
= 3.78 (s, 3 H, CH3 CO2Me), 5.07 (dd, J = 3.0, J = 8.7 Hz, 1 H,
Bz(4-NO2)-Z-∆Abu-OMe (2b): The general procedure described
above was followed with compound 1b as substrate to give 2b
αCH), 5.40 (d, J = 3.0 Hz, 1 H, βCH), 6.92 (d, J = 8.7 Hz, 1 H, (0.375 g, 71%) as a white solid. M.p. 122.5–123.0 °C (ethyl acetate/
αNH), 7.27–7.72 (m, 10 H, ArH) ppm. 13C NMR (CDCl3): δ =
52.63 (OCH3), 58.53 (αC), 73.53 (βC), 125.69 (CH), 127.04 (CH),
n-hexane). 1H NMR (CDCl3): δ = 1.88 (d, J = 7.2 Hz, 3 H, γCH3),
3.82 (s, 3 H, CH3 CO2Me), 6.97 (q, J = 7.2 Hz, 1 H, βCH), 7.62
128.00 (CH), 128.35 (CH), 128.44 (CH), 131.72 (C), 133.51 (C), (br. s, 1 H, NH), 8.04 (d, J = 9.0 Hz, 2 H, ArH), 8.34 (d, J =
139.66 (C), 167.71 (C=O), 170.95 (C=O) ppm. C17H17NO4
(299.30): calcd. C 68.22, H 5.72, N 4.68; found C 68.22, H 5.73, N
4.73.
9.0 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3): δ = 15.04 (γCH3),
52.59 (OCH3), 123.84 (CH), 125.60 (αC), 128.61 (CH), 134.85
(βCH), 139.38 (C), 149.80 (C), 163.45 (C=O), 164.86 (C=O) ppm.
C12H12N2O5 (264.24): calcd. C 54.55, H 4.58, N 10.60; found C
54.52, H 4.43, N 10.57.
Bz(4-NO2)-D,L-Phe(β-OH)-OMe (5b): The general procedure de-
scribed above was followed with HCl·H-,-Phe(β-OH)-OMe and
4-nitrobenzoyl chloride to give compound 5b (0.671 g, 39%) as a
white solid. M.p. 153.0–155.0 °C (ethyl acetate/diethyl ether). 1H
NMR (DMSO): δ = 3.60 (s, 3 H, CH3 CO2Me), 4.85 (br. s, 1 H,
αCH), 5.22 (br. s, 1 H, βCH), 5.94 (d, J = 6.0 Hz, 1 H, OH), 7.18–
7.42 [m, 5 H, ArH Phe(β-OH)], 7.96 [d, J = 8.7 Hz, 2 H, ArH
Bz(NO2)], 8.27 [d, J = 8.7 Hz, 2 H, ArH Bz(NO2)], 8.95 (d, J =
8.7 Hz, 1 H, NH) ppm. 13C NMR (CDCl3): δ = 52.96 (OCH3),
58.43 (αC), 73.45 (βC), 123.80 (CH), 125.55 (CH), 128.24 (CH),
128.43 (CH), 128.61 (C), 139.26 (C), 149.68 (C), 165.51 (C=O),
170.53 (C=O) ppm. C17H16N2O6 (344.33): calcd. C 59.30, H 4.68,
N 8.14; found C 59.04, H 4.80, N 8.03.
Bz(4-OMe)-Z-∆Abu-OMe (2c): The general procedure described
above was followed with compound 1c (3 mmol, 0.804 g) as sub-
strate to give 2c (0.409 g, 82%) as a white solid. M.p. 112.0–
113.0 °C (diethyl ether/petroleum ether). 1H NMR (400 MHz,
CDCl3): δ = 1.82 (d, J = 5.4 Hz, 3 H, γCH3), 3.77 (s, 3 H, CH3),
3.85 (s, 3 H, CH3), 6.85 (q, J = 5.4 Hz, 1 H, βCH), 6.93 (d, J =
6.6 Hz, 2 H, ArH), 7.58 (br. s, 1 H, NH), 7.83 (d, J = 6.6 Hz, 2 H,
ArH) ppm. 13C NMR (CDCl3): δ = 14.87 (γCH3), 52.32 (OCH3),
55.36 (OCH3), 113.77 (CH), 126.07 (C), 126.20 (C), 129.27 (CH),
133.40 (CH), 162.51 (CO), 164.96 (C), 165.22 (CO) ppm.
C13H15NO4 (249.26): calcd. C 62.64, H 6.07, N 5.62; found C
62.05, H 6.00, N 5.63.
2-Fur-D,L-Phe(β-OH)-OMe (5e): The general procedure described
1-Naph-Z-∆Abu-OMe (2d): The general procedure described above
was followed with compound 1d as substrate to give 2d (0.473 g,
88%) as a white solid. M.p. 139.5–140.5 °C (ethyl acetate/n-hex-
ane). 1H NMR (CDCl3): δ = 1.97 (d, J = 6.9 Hz, 3 H, γCH3), 3.83
(s, 3 H, CH3 CO2Me), 6.98 (q, J = 6.9 Hz, 1 H, βCH), 7.40 (br. s,
1 H, NH), 7.47–7.62 (m, 4 H, ArH), 7.79 (d, J = 6.9 Hz, 1 H, ArH),
7.88–7.98 (m, 2 H, ArH), 8.44 (d, J = 7.8 Hz, 1 H, ArH) ppm. 13C
NMR (CDCl3): δ = 15.11 (γCH3), 52.44 (OCH3), 124.62 (CH),
125.36 (CH), 125.62 (CH), 126.01 (βCH), 126.51 (CH), 127.35
(CH), 128.34 (CH), 130.22 (C), 131.25 (CH), 133.50 (C), 133.72
(C), 134.40 (αC), 165.02 (C=O), 167.30 (C=O) ppm. C16H15NO3
(269.30): calcd. C 71.36, H 5.61, N 5.20; found C 71.13, H 5.44, N
5.33.
above was followed with HCl·H-,-Phe(β-OH)-OMe and 2-fu-
ranoyl chloride to give compound 5e (1.24 g, 86%) as a white solid.
M.p. 126.0–127.0 °C (ethyl acetate/n-hexane). 1H NMR (CDCl3): δ
= 3.33 (br. s, 1 H, OH), 3.73 (s, 3 H, CH3 CO2Me), 4.98 (dd, J =
9.0, 3.0 Hz, 1 H, αCH), 5.34 (d, J = 3.0 Hz, 1 H, βCH), 6.43–6.45
(m, 1 H, ArH), 7.00 (d, J = 3.6 Hz, 1 H, ArH), 7.18 (d, J = 9.0 Hz,
1 H, NH), 7.24–7.42 (m, 6 H, ArH) ppm. 13C NMR (CDCl3): δ =
52.62 (OCH3), 57.82 (βCH), 73.43 (αCH), 112.06 (CH), 115.00
(CH), 125.74 (CH), 128.02 (CH), 128.35 (CH), 139.60 (C), 144.33
(CH), 147.00 (C), 158.38 (C=O), 170.72 (C=O) ppm. C15H15NO5
(289.28): calcd. C 62.28, H 5.23, N 4.84; found C 62.23, H 5.25, N
4.90.
General Procedure for the Synthesis of N-Acyldehydroamino Acid
Methyl Esters: DMAP (0.1 equiv.) was added to a solution of the
N-acylamino acid methyl ester (2 mmol) in dry acetonitrile (1 ),
followed by di-tert-butyl dicarbonate (1.0 equiv.) with rapid stirring
at room temperature. The reaction was monitored by TLC (diethyl
ether/n-hexane, 1:1) until all the reactant had been consumed.
TMG (2% in volume) was then added, stirring was continued, and
the reaction was followed by TLC. When all the reactant had been
consumed, evaporation at reduced pressure gave a residue that was
partitioned between diethyl ether (100 mL) and KHSO4 (1 ,
30 mL). The organic phase was thoroughly washed with KHSO4
(1 ), NaHCO3 (1 ) and saturated brine (2ϫ30 mL) and dried
with MgSO4. Removal of the solvent afforded the corresponding
N-acyldehydroamino acid methyl ester.
2-Fur-Z-∆Abu-OMe (2e): The general procedure described above
was followed with compound 1e as substrate to give 2e (0.37 g,
88%) as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 1.84 (d,
J = 7.2 Hz, 3 H, γCH3), 3.78 (s, 3 H, CH3), 6.51–6.53 (m, 1 H,
ArH), 6.90 (q, J = 7.2 Hz, 1 H, βCH), 7.18–7.19 (m, 1 H, ArH),
7.49–7.50 (m, 1 H, ArH), 7.76 (br. s, 1 H, NH) ppm. 13C NMR
(CDCl3): δ = 14.93 (γCH3), 52.39 (OCH3), 112.33 (CH), 115.43
(CH), 125.10 (C), 134.67 (CH), 144.44 (CH), 156.00 (C=O), 164.86
(C=O) ppm.
2-Qnx-Z-∆Abu-OMe (2f): The general procedure described above
was followed with compound 1f as substrate to give 2f (0.455 g,
84%) as a light yellow solid. M.p. 106.0–107.5 °C (ethyl acetate/n-
1
hexane). H NMR (CDCl3): δ = 1.93 (d, J = 7.2 Hz, 3 H, γCH3),
3.83 (s, 3 H, CH3), 7.00 (q, J = 7.2 Hz, 1 H, βCH), 7.84–7.92 (m,
3 H, ArH), 8.15–8.22 (m, 1 H, ArH), 9.37 (br. s, 1 H, NH) 9.69 (s,
1 H, ArH) ppm. 13C NMR (CDCl3): δ = 15.04 (γCH3), 52.46
(OCH3), 125.58 (αC), 129.34 (CH), 129.76 (CH), 130.92 (CH),
131.84 (CH), 134.89 (βCH), 140.17 (C), 142.87 (C), 143.83 (CH),
143.98 (C), 161.17 (C=O), 164.75 (C=O) ppm. C14H13N3O3
(271.27): calcd. C 61.99, H 4.83, N 15.49; found C 62.17, H 4.90,
N 14.88.
Bz-∆Ala-OMe (6a) and Boc-Z-∆Abu-OMe: The synthesis of these
compounds has been described elsewhere.[10a,13]
Bz-Z-∆Abu-OMe (2a): The general procedure described above was
followed with compound 1a as substrate to give 2a (0.34 g, 83%)
as a white solid. M.p. 78.0–79.0 °C (diethyl ether/petroleum ether).
1H NMR (CDCl3): δ = 2.76 (d, J = 7.5 Hz, 3 H, γCH3), 3.77 (s, 3
H, CO2CH3), 6.88 (q, J = 7.5 Hz, 1 H, βCH), 7.41–7.55 (m, 3 H,
ArH), 7.69 (br. s, 1 H, NH), 7.85–7.88 (m, 2 H, ArH) ppm. 13C
NMR (CDCl3): δ = 14.86 (γCH3), 52.32 (OCH3), 126.07 (C),
127.35 (CH), 128.56 (CH), 131.90 (CH), 133.80 (CH), 133.83 (C),
165.06 (C=O), 165.41 (C=O) ppm. C12H13NO3 (219.24): calcd. C
65.74, H 5.98, N 6.39; found C 65.30, H 5.93, N 6.48.
Bz(4-OMe)-∆Ala-OMe (6c): The general procedure described
above was followed with compound 4c as substrate to give 6c
(0.235 g, 50%) as a white solid. M.p. 39.5–41.0 °C (ethyl acetate/n-
1
hexane). H NMR (CDCl3): δ = 3.86 (s, 3 H, CH3), 3.89 (s, 3 H,
CH3), 5.63 (d, J = 1.8 Hz, 1 H, βCH), 6.77 (s, 1 H, βCH), 6.96 (d,
4680
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4676–4683

Substituted Oxazoles from N-Acyl-β-hydroxyamino Acid Derivatives
J = 9.0 Hz, 2 H, ArH), 7.81 (d, J = 9.0 Hz, 2 H, ArH), 8.46 (br. s,
(0.44 mmol), K2CO3 (2 equiv.) and THF (2 mL). A solution of I2
1 H, NH) ppm. 13C NMR (CDCl3): δ = 53.02 (OCH3), 55.40 (1.2 equiv.) in THF (1 mL) was added at 0 °C. The tube was sealed,
(OCH3), 108.38 (βCH2), 113.94 (CH), 126.46 (C), 128.82 (CH), and the reaction mixture was stirred at 80 °C for ≈3 h. After the
131.05 (C), 162.61 (C), 164.87 (C=O), 165.24 (C=O) ppm.
C12H13NO4 (235.24): calcd. C 61.27, H 5.57, N 5.95; found C
61.31, H 5.44, N 6.07.
system had cooled to room temperature, DBU (2 equiv.) was added
and the tube was heated for ≈3 h at 80 °C. The reaction mixture
was quenched with a saturated solution of Na2S2O3 (2 mL). The
organic phase was separated and dried with MgSO4, and the sol-
vent was evaporated. The residue was subjected to column
chromatography.
Oxazole 3a:[14] The general procedure described above was used
with 2a (97.0 mg, 0.44 mmol) to give compound 3a (87.0 mg, 91%)
as a white solid after column chromatography in diethyl ether/pe-
troleum ether (1:1) . M.p. 88.0–89.0 °C (diethyl ether/petroleum
ether). 1H NMR (CDCl3): δ = 2.70 (s, 3 H, CH3), 3.94 (s, 3 H,
CH3 CO2Me), 7.42–7.45 (m, 3 H, ArH), 8.04–8.07 (m, 2 H,
ArH) ppm. 13C NMR (CDCl3): δ = 12.04 (CH3), 51.93 (OCH3),
126.45 (CH), 128.43 (C), 128.64 (CH), 130.68 (CH), 156.31 (C),
159.58 (C), 162.77 (C=O) ppm. C12H11NO3 (217.22): calcd. C
66.35, H 5.10, N 6.45; found C 66.54, H 5.12, N 6.46.
1-Naph-∆Ala-OMe (6d): The general procedure described above
was followed with compound 4d as substrate to give 6d (0.365 g,
72%) as a colourless oil that solidified on standing. M.p. 58.0–
1
59.0 °C. H NMR (CDCl3): δ = 3.89 (s, 3 H, CH3 CO2Me), 6.08
(d, J = 1.5 Hz, 1 H, βCH), 6.92 (s, 1 H, βCH), 7.49–7.62 (m, 4 H,
ArH), 7.70–7.73 (m, 1 H, ArH), 7.89–8.00 (m, 2 H, ArH), 8.32 (br.
s, 1 H, NH), 8.35–8.38 (m, 1 H, ArH) ppm. 13C NMR (CDCl3): δ
= 53.08 (OCH3), 109.35 (βC), 124.69 (CH), 125.18 (CH), 125.27
(CH), 126.60 (CH), 127.45 (CH), 128.43 (CH), 130.04 (C), 131.28
(αC), 131.38 (CH), 133.74 (C), 134.78 (C), 164.56 (C=O), 167.90
(C=O) ppm. C15H13NO3 (255.27): calcd. C 70.58, H 5.13, N 5.49;
found C 70.65, H 5.29, N 5.61.
2-Fur-∆Ala-OMe (6e): The general procedure described above was
followed with compound 4e as substrate to give 6e (0.260 g, 67%)
as a white solid. M.p. 55.0–56.0 °C (diethyl ether/n-hexane). 1H
NMR (CDCl3): δ = 3.89 (s, 3 H, OCH3), 5.96 (d, J = 1.5 Hz, 1 H,
βCH), 6.52–6.45 (m, 1 H, ArH), 6.72 (s, 1 H, βCH), 7.19–7.21 (m,
1 H, ArH), 7.50–7.51 (m, 1 H, ArH), 8.68 (br. s, 1 H, NH) ppm.
13C NMR (CDCl3): δ = 53.04 (OCH3), 109.14 (βCH2), 112.50
(CH), 115.41 (CH), 130.56 (C), 144.50 (CH), 146.87 (C), 147.30
(C=O), 164.34 (C=O) ppm.
Oxazole 3b: The general procedure described above was used with
2b (116 mg, 0.44 mmol) to give compound 3b (82.0 mg, 71%) as a
white solid after column chromatography in diethyl ether/petro-
leum ether (1:1). M.p. 169.0–170.0 °C (diethyl ether/petroleum
ether). 1H NMR (CDCl3): δ = 2.77 (s, 3 H, CH3), 3.98 (s, 3 H,
CH3 CO2Me), 8.26 (d, J = 9.0 Hz, 2 H, ArH), 8.34 (d, J = 9.0 Hz, 2
H, ArH) ppm. 13C NMR (CDCl3): δ = 12.21 (CH3), 52.10 (OCH3),
124.11 (CH), 127.26 (CH), 129.37 (C), 131.88 (C), 148.86 (C),
157.48 (C), 157.68 (C), 162.31 (C=O) ppm. HRMS (EI): calcd. for
C12H10N2O5 262.0590; found 262.0591.
Bz-Z-∆Phe-OMe (7a): The general procedure described above was
followed with compound 5a as substrate to give 7a (0.51 g, 90%)
as a white solid. M.p. 126.0–127.0 °C (diethyl ether/petroleum
ether). 1H NMR (CDCl3): δ = 3.88 (s, 3 H, CO2CH3), 7.28–7.35
(m, 3 H, ArH), 7.42–7.57 (m, 6 H, ArH, βCH), 7.86–7.90 (m, 2 H,
ArH), 8.03 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3): δ = 52.66
(OCH3), 124.30 (C), 127.45 (CH), 128.53 (CH), 128.63 (CH),
129.39 (CH), 129.62 (CH), 132.06 (CH), 133.40 (C), 133.70 (C),
165.83 (C=O) ppm.
Oxazole 3c: The general procedure described above was used with
2c (110 mg, 0.44 mmol) to give compound 3c (79.4 mg, 73%) as a
white solid after column chromatography in diethyl ether/petro-
leum ether (1:1). M.p. 105.0–106.0 °C (diethyl ether/petroleum
ether). 1H NMR (CDCl3): δ = 2.70 (s, 3 H, CH3), 3.87 (s, 3 H,
OCH3), 3.95 (s, 3 H, OCH3), 6.97 (d, J = 9.0 Hz, 2 H, ArH), 8.02
(d, J = 9.0 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3): δ = 12.01
(CH3), 51.90 (OCH3), 55.30 (OCH3), 114.07 (CH), 119.20 (C),
128.19 (CH), 155.82 (C), 159.70 (C), 161.58 (C), 162.93
(C=O) ppm. HRMS (EI): calcd. for C13H13NO4 247.0845; found
247.0840.
Bz(4-NO2)-Z-∆Phe-OMe (7b): The general procedure described
above was followed with compound 5b as substrate to give 7b
(0.568 g, 87%) as a light yellow solid. M.p. 186.5–187.5 °C (ethyl
acetate/n-hexane). 1H NMR (CDCl3): δ = 3.89 (s, 3 H, CH3
CO2Me), 7.34–7.36 (m, 3 H, ArH), 7.47–7.50 (m, 2 H, ArH), 7.55
(s, 1 H, βCH), 8.00 (br. s, 1 H, NH), 8.02 [d, J = 8.4 Hz, 2 H, ArH
Bz(NO2)], 8.31 [d, J = 8.4 Hz, 2 H, ArH Bz(NO2)] ppm. 13C NMR
(CDCl3): δ = 52.95 (OCH3), 123.84 (CH), 123.44 (αC), 123.97
(CH), 128.64 (CH), 128.72 (CH), 129.58 (CH), 129.83 (CH), 132.92
(C), 133.54 (αC), 138.98 (C), 149.95 (C), 163.75 (C=O), 165.49
(C=O) ppm. C17H14N2O5 (326.31): calcd. C 62.58, H 4.32, N 8.59;
found C 62.43, H 4.13, N 8.64.
Oxazole 3d: The general procedure described above was used with
2d (118 mg, 0.44 mmol) to give compound 3d (100 mg, 85%) as a
white solid after column chromatography in diethyl ether/petro-
leum ether (1:1). M.p. 78.0–79.0 °C (diethyl ether/petroleum ether).
1H NMR (CDCl3): δ = 2.78 (s, 3 H, CH3), 3.99 (s, 3 H, CH3
CO2Me), 7.52–7.70 (m, 3 H, ArH), 7.91 (d, J = 8.1 Hz, 1 H, ArH),
7.98 (d, J = 8.1 Hz, 1 H, ArH), 8.20 (dd, J = 7.2, 1.2 Hz, 1 H,
ArH), 9.20 (d, J = 7.2 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3): δ =
12.14 (CH3), 51.95 (OCH3), 123.09 (C), 124.76 (CH), 126.03 (CH),
126.36 (CH), 127.77 (CH), 128.12 (CH), 128.49 (CH), 128.56 (C),
130.04 (C), 131.60 (CH), 133.80 (C), 156.15 (C), 159.54 (C), 162.97
(C=O) ppm. HRMS (EI): calcd. for C16H13NO3 267.0895; found
267.0899.
2-Fur-Z-∆Phe-OMe (7e): The general procedure described above
was followed with compound 5e as substrate to give 7e (0.493 g,
91%) as a white solid. M.p. 122.0–123.0 °C (diethyl ether/n-hex-
ane). 1H NMR (CDCl3): δ = 3.86 (s, 3 H, CH3 OMe), 6.53–6.55
(m, 1 H, ArH), 7.19–7.21 (m, 1 H, ArH), 7.33–7.40 (m, 3 H, ArH),
7.47 (s, 1 H, βCH), 7.50–7.53 (m, 3 H, ArH), 7.94 (br. s, 1 H,
NH) ppm. 13C NMR (CDCl3): δ = 52.69 (OCH3), 112.42 (CH),
115.81 (CH), 123.25 (C), 128.56 (CH), 129.46 (CH), 129.66 (CH),
132.32 (CH), 133.61 (C), 144.60 (CH), 147.20 (C), 156.24 (C),
165.50 (CH) ppm. C15H13NO4 (271.27): calcd. C 66.42, H 4.83, N
5.16; found C 66.41, H 4.94, N 5.19.
Oxazole 3e: The general procedure described above was followed
with 2e as substrate to give compound 3e (82.0 mg, 90%) as a white
solid. M.p. 110.0–111.0 °C (diethyl ether/petroleum ether). 1H
NMR (CDCl3): δ = 2.71 (s, 3 H, CH3), 3.95 (s, 3 H, CO2CH3),
6.54–6.56 (m, 1 H, ArH), 7.11–7.12 (m, 1 H, ArH), 7.56–7.57 (m, 1
H, ArH) ppm. 13C NMR (CDCl3): δ = 11.92 (CH3), 51.96 (OCH3),
111.89 (CH), 112.25 (CH), 128.22 (C), 141.97 (C), 144.64 (CH),
152.28 (C), 155.81 (C), 162.55 (C=O) ppm. C10H9NO4 (207.18):
calcd. C 57.97, H 4.38, N 6.76; found C 57.69, H 4.42, N 6.65.
General Procedure for the Synthesis of Oxazole Derivatives: A dried
Schlenk tube was charged with the dehydroamino acid derivative
Eur. J. Org. Chem. 2008, 4676–4683
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4681

P. M. T. Ferreira, L. S. Monteiro, G. Pereira
FULL PAPER
Oxazole 3f: The general procedure described above was used with
troleum ether (1:1). M.p. 165.0–166.0 °C (ethyl acetate/n-hexane).
2f (119 mg, 0.44 mmol) to give compound 3f (45 mg, 38%) as a 1H NMR (CDCl3): δ = 4.00 (s, 3 H, CH3 OMe), 7.51–7.64 (m, 5
white solid after column chromatography in diethyl ether/petro-
leum ether (1:1). M.p. 176.0–177.0 °C (diethyl ether/petroleum
H, ArH, NH), 7.81 (d, J = 7.2 Hz, 1 H, ArH), 7.90–7.93 (m, 1 H,
ArH), 8.03 (d, J = 8.1 Hz, 1 H, ArH), 8.42 (d, J = 8.1 Hz, 1 H,
ether). 1H NMR (CDCl3): δ = 2.86 (s, 3 H, CH3), 4.01 (s, 3 H, ArH) ppm. 13C NMR (CDCl3): δ = 8.40 (C), 53.20 (OCH3), 124.61
CH3 CO2Me), 7.84–7.90 (m, 2 H, ArH), 8.18–8.28 (m, 2 H, ArH), (CH), 125.20 (CH), 126.03 (CH), 126.87 (CH), 127.83 (CH), 128.48
9.75 (s, 1 H, ArH) ppm. 13C NMR (CDCl3): δ = 12.46 (CH3), 52.28
(CH), 130.18 (C), 130.95 (C), 132.33 (CH), 133.76 (C), 139.54 (C),
(OCH3), 129.46 (CH), 129.80 (CH), 131.02 (CH), 131.29 (CH), 165.05 (C=O), 163.35 (C=O) ppm. HRMS (ESI): calcd. for
139.97 (C), 141.49 (C), 142.71 (C), 143.66 (CH), 156.84 (C), 158.79 C15H12NO3I2 507.8901; found 507.8828.
(C), 162.26 (C=O) ppm. C14H11N3O3 (269.26): calcd. C 62.45, H
4.12, N 15.61; found C 62.66, H 4.18, N 15.24.
2-Fur-∆Ala(β,β-I)-OMe (10e): The general procedure described
above was followed with 6e (86.0 mg, 0.44 mmol) as substrate, but
Oxazole 8a: The general procedure described above was used with
7a (124 mg, 0.44 mmol) to give compound 8a (53.0 mg, 43%) as a
white solid after column chromatography in diethyl ether/petro-
leum ether (1:1). M.p. 74.0–75.0 °C (diethyl ether/petroleum ether).
without addition of DBU, to give compound 10e (104 mg, 53%) as
a white solid after column chromatography in diethyl ether/petro-
leum ether (1:1). M.p. 135.0–136.0 °C (diethyl ether/petroleum
1
ether). H NMR (CDCl3): δ = 3.94 (s, 3 H, CH3 OMe), 6.58–6.59
1H NMR (400 MHz, CDCl3): δ = 3.99 (s, 3 H, CH3 CO2Me), 7.49– (m, 1 H, ArH), 7.25–7.27 (m, 1 H, ArH), 7.56–7.58 (m, 1 H, ArH),
7.52 (m, 6 H, ArH), 8.15–8.18 (m, 4 H, ArH) ppm. 13C NMR
8.06 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3): δ = 6.12 (C), 53.13
(100.6 MHz, CDCl3): δ = 52.38 (OCH3), 126.30 (C), 126.83 (CH), (OCH3), 112.96 (CH), 117.20 (CH), 138.73 (C), 145.38 (CH),
126.97 (C), 127.91 (C), 128.43 (CH), 128.45 (CH), 128.82 (CH), 145.60 (C), 153.78 (C=O), 162.54 (C=O) ppm.
130.36 (CH), 131.11 (CH), 130.74 (C), 155.20 (C), 159.79 (C),
162.69 (C=O) ppm. HRMS (EI): calcd. for C17H13NO3 279.0895;
found 279.0895. Bz-Z-∆Phe(β-I)-OMe (9a) was also isolated in
32% yield.
Bz(4-NO2)-Z-∆Phe(β-I)-OMe (9b): The general procedure de-
scribed above was followed with 7b (144 mg, 0.44 mmol) as sub-
strate, but without addition of DBU, to give compound 9b (169 mg,
85%) as a white solid after column chromatography in diethyl
Bz-Z-∆Phe(β-I)-OMe (9a): The same procedure as described above
but at room temperature afforded 9a as a white solid (156 mg,
87%). M.p. 136.0–137.0 °C (diethyl ether/petroleum ether). 1H
NMR (400 MHz, CDCl3): δ = 3.56 (s, 3 H, CH3 CO2Me), 7.30–
ether/petroleum ether (1:2). M.p. 157.0–158.0 °C (ethyl acetate/n-
hexane). 1H NMR (CDCl3): δ = 3.55 (s, 3 H, OCH3), 7.35 (br. s, 5
H, ArH), 7.94 (br. s, 1 H, NH), 8.09 (d, J = 8.7 Hz, 2 H, ArH),
8.37 (d, J = 8.7 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3): δ = 52.76
7.39 (s, 5 H, ArH), 7.50–7.63 (s, 3 H, ArH), 7.88 (br. s, 1 H, NH), (OCH3), 98.88 (C), 124.12 (CH), 128.33 (CH), 128.44 (CH), 128.67
7.92–7.94 (m, 2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ (CH), 129.33 (CH), 132.94 (C), 137.70 (C), 139.95 (C), 150.20 (C),
= 52.61 (OCH3), 95.69 (C), 127.45 (CH), 128.24 (CH), 128.85 161.89 (C=O), 162.93 (C=O) ppm. HRMS (ESI): calcd. for
(CH), 128.93 (CH), 129.03 (CH), 132.24 (C), 132.73 (CH), 133.65
(C), 140.17 (C), 162.11 (C=O), 164.78 (C=O) ppm. C17H14INO3
(407.20): calcd. C 50.14, H 3.47, N 3.44; found C 50.55, H 3.52, N
3.80. Compound 9a was also obtained from compound 3a in 86%
yield by treatment with NIS (2.5 equiv.) in dichloromethane fol-
lowed by triethylamine (1.5 equiv.).
C17H14N2O5I 452.9942; found 452.9869.
2-Fur-Z-∆Phe(β-I)-OMe (9e): The general procedure described
above was followed with 7e (119 mg, 0.44 mmol) as substrate, but
without addition of DBU, to give compound 9e (145 mg, 83%) as
a white solid after column chromatography in diethyl ether/petro-
1
leum ether (1:2). M.p. 130.0–131.0 °C (ethyl acetate/n-hexane). H
Bz-∆Ala(β,β-I)-OMe (10a): The general procedure described above
was followed with 6a (90.3 mg, 0.44 mmol) as substrate, but with-
out addition of DBU, to give compound 10a (80.4 mg, 40%) as a
white solid after column chromatography in diethyl ether/petro-
leum ether (1:1). M.p. 138.0–139.0 °C (diethyl ether/petroleum
NMR (CDCl3): δ = 3.54 (s, 3 H, OCH3), 6.58–6.60 (m, 1 H, ArH),
7.26–7.37 (m, 6 H, ArH), 7.58–7.59 (m, 1 H, ArH), 8.06 (br. s, 1
H, NH) ppm. 13C NMR (CDCl3): δ = 52.60 (OCH3), 95.51 (C),
112.82 (CH), 116.68 (CH), 128.23 (CH), 128.85 (CH) 129.02 (CH),
132.87 (C), 140.22 (C), 145.17 (CH), 146.31 (C), 155.41 (C=O),
ether). 1H NMR (400 MHz, CDCl3): δ = 3.95 (s, 3 H, CH3 162.02 (C=O) ppm.
CO2Me), 7.51–7.61 (m, 3 H, ArH), 7.85–7.87 (m, 3 H, ArH) ppm.
Bz-Z-∆Abu(β-I)-OMe (11): The general procedure described above
13C NMR (CDCl3): δ = 6.01 (C), 53.16 (OCH3), 127.45 (CH),
128.52 (C), 129.08 (CH), 131.68 (C), 132.97 (CH), 139.53 (C),
162.62 (C=O), 163.24 (C) ppm.
was followed with 2a (96.5 mg, 0.44 mmol) as substrate, but with-
out addition of DBU, to give compound 11 (123 mg, 81%) as a
white solid after column chromatography in diethyl ether/petro-
1
Bz(4-OMe)-∆Ala(β,β-I)-OMe (10c): The general procedure de-
scribed above was followed with 6c (104 mg, 0.44 mmol) as sub-
strate, but without addition of DBU, to give compound 10c
(90.0 mg, 42%) as a white solid after column chromatography in
diethyl ether/petroleum ether (1:1). M.p. 151.0–152.0 °C (diethyl
leum ether (1:2). M.p. 155.0–156.0 °C (diethyl ether/n-hexane). H
NMR (CDCl3): δ = 2.82 (s, 3 H, γCH3), 3.86 (s, 3 H, CH3 CO2Me),
7.46–7.60 (m, 3 H, ArH), 7.64 (s, 1 H, NH), 7.85–7.89 (m, 2 H,
ArH) ppm. 13C NMR (CDCl3): δ = 28.88 (γCH3), 52.72 (OCH3),
101.82 (C), 127.33 (CH), 128.82 (CH), 131.58 (C), 132.46 (CH),
1
ether/petroleum ether). H NMR (400 MHz, CDCl3): δ = 3.87 (s,
132.55
(C),
161.47
(C=O),
164.98
(C=O) ppm.
3 H, CH3 OMe), 3.94 (s, 3 H, CH3 OMe), 6.97 (d, J = 8.7 Hz, 2
C12H12NO3I(345.13): calcd. C 41.76, H 3.50, N 4.07; found C
H, ArH), 7.82 (d, J = 8.7 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3): 41.89, H 3.56, N 4.42. Compound 11 was also obtained from com-
δ = 5.32 (C), 53.11 (OCH3), 55.52 (OCH3), 114.24 (CH), 123.70 pound 2a in a 87% yield by treatment with NIS (2.5 equiv.) in
(C), 128.61 (C), 129.48 (CH), 139.71 (C), 162.70 (C=O), 163.35 dichloromethane followed by triethylamine (1.5 equiv.).
(C=O) ppm. HRMS (EI): calcd. for C12H11NO4I2 486.8777; found
486.8771.
Boc-Z-∆Abu(β-I)-OMe: The general procedure described above was
followed with Boc-∆Abu-OMe (94.7 mg, 0.44 mmol) as substrate,
1-Naph-∆Ala(β,β-I)-OMe (10d): The general procedure described
but without addition of DBU, to give Boc-Z-∆Abu(β-I)-OMe
above was followed with 6d (112 mg, 0.44 mmol) as substrate, but (131 mg, 87%) as a white solid after column chromatography in
without addition of DBU, to give compound 10d (105 mg, 47%)
as a white solid after column chromatography in diethyl ether/pe-
diethyl ether/petroleum ether (1:2). M.p. 67.0–68.0 °C (diethyl
ether/n-hexane). 1H NMR (300 MHz, CDCl3): δ = 1.47 (s, 9 H,
4682
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4676–4683

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CH3 Boc), 2.73 (s, 3 H, γCH3), 3.83 (s, 3 H, OCH3), 6.15 (s, 1 H,
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52.44 (OCH3), 81.51 [(CH3)3C], 98.62 (C), 131.69 (C), 152.48
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the Univ. of Minho and through project POCI/QUI/59407/2004.
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Received: June 20, 2008
Published Online: August 15, 2008
Eur. J. Org. Chem. 2008, 4676–4683
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4683