Synthesis of new N-ethyl dehydroamino acid derivatives: N-ethyl β,β-dibromo, N-ethyl β-bromo β-substituted, and N-ethyl β,β-disubstituted N-protected dehydroamino acid methyl esters

Article abstract of DOI:10.1002/ejoc.201100907

Recently, we reported the use of a sequence of alkylation and dehydration methodologies to obtain new non-proteinogenic amino acids (N-ethyl α,β-dehydroamino acids) from the methyl esters of N-(4-nitrophenylsulfonyl) β-hydroxy amino acids. Thus, it was possible to obtain for the first time, non-natural amino acids that incorporate both N-ethyl and α,β-dehydro moieties. Herein, we report the application of this N-alkylation procedure to several methyl esters of β,β-dibromo and β-bromo β-substituted dehydroamino acids protected with standard amine protecting groups such as tert-butyloxycarbonyl, benzyloxycarbonyl, and (4-nitrobenzyl)oxycarbonyl, as well as acyl and sulfonyl groups. The procedure allows the synthesis of the methyl esters of N-protected N-ethyl β,β-dibromo and N-ethyl β-bromo β-substituted dehydroamino acids in fair to high yields. Some of these N-ethylated dehydroamino acid derivatives were used as substrates in cross-coupling reactions to give β,β-disubstituted N-ethyldehydroalanine derivatives. N-Ethylation of the methyl esters of β,β-dibromo and β-bromo, β-substituted dehydroamino acids protected with standard amine protecting groups is reported. The procedure allows the corresponding N-ethyl derivatives to be obtained in fair to high yields. These substrates can be applied in cross-coupling reactions, and constitute valuable synthons for the synthesis of N-ethyl derivatives. Copyright

Full text of DOI:10.1002/ejoc.201100907

FULL PAPER
DOI: 10.1002/ejoc.201100907
Synthesis of New N-Ethyl Dehydroamino Acid Derivatives:
N-Ethyl β,β-Dibromo, N-Ethyl β-Bromo β-Substituted, and
N-Ethyl β,β-Disubstituted N-Protected Dehydroamino Acid Methyl Esters
Luís S. Monteiro,*[a] Juliana J. Andrade,[a] and Ana C. Suárez[a]
Keywords: Amino acids / Nonnatural amino acids / Alkylation / Cross-coupling / Protecting groups
Recently, we reported the use of a sequence of alkylation and
dehydration methodologies to obtain new non-proteinogenic
amino acids (N-ethyl α,β-dehydroamino acids) from the
methyl esters of N-(4-nitrophenylsulfonyl) β-hydroxy amino
acids. Thus, it was possible to obtain for the first time, non-
natural amino acids that incorporate both N-ethyl and α,β-
dehydro moieties. Herein, we report the application of this
N-alkylation procedure to several methyl esters of β,β-di-
tected with standard amine protecting groups such as tert-
butyloxycarbonyl, benzyloxycarbonyl, and (4-nitrobenzyl)-
oxycarbonyl, as well as acyl and sulfonyl groups. The pro-
cedure allows the synthesis of the methyl esters of N-pro-
tected N-ethyl β,β-dibromo and N-ethyl β-bromo β-substi-
tuted dehydroamino acids in fair to high yields. Some of
these N-ethylated dehydroamino acid derivatives were used
as substrates in cross-coupling reactions to give β,β-disubsti-
bromo and β-bromo β-substituted dehydroamino acids pro- tuted N-ethyldehydroalanine derivatives.
ated amino acids and their derivatives are available in the
Introduction
literature.[5] Chen and Benoiton prepared N-ethyl amino ac-
ids by reaction of N-acetyl amino acids with trimethylox-
onium tetrafluoroborate (Meerwein’s reagent) in a two-step
procedure.[6] Initially, an imino ether fluoroborate is formed
and then reduced by treatment with sodium borohydride.
McDermott and Benoiton were able to carry out complete
N-methylations of N-(benzyloxycarbonyl)amino acids using
methyl iodide and sodium hydride[7] but N-ethylations with
ethyl iodide were far from complete.[6] More recently,
Stodulski and Mlynarski tried the same strategy to obtain
N-benzyloxycarbonyl-N-ethylalanine by substituting lith-
ium bis(trimethylsilyl)amide or cesium carbonate for so-
dium hydride, but were also unsuccessful.[8] However, by
carrying out the original protocol (ethyl iodide and NaH in
tetrahydrofuran) at elevated temperatures they were able to
obtain N-benzyloxycarbonyl N-ethyl amino acids in moder-
ate to high yields. Papaioannou and co-workers described
a Mitsunobu-type N-ethylation of tosylamino esters with
excess ethanol.[9] Difficulties found in the chemical detosyl-
ation step could be overcome by reductive electrochemical
cleavage of the protecting group.[10] The stronger electron-
withdrawing effect of nitroarylsulfonamides further en-
hances the acidity of the α-amide hydrogen, making these
groups unique for the preparation of N-alkyl peptides.[11]
Recently, Liguori et al. proposed the ethylation of several
4-nitrophenylsulfonyl (Nosyl) protected amino acids using
triethyloxonium tetrafluoroborate (Et3OBF4) as alkylating
agent and N,N-diisopropylethylamine (DIPEA) as base to
give N-ethyl amino acid derivatives in high yields.[12] These
authors demonstrated the compatibility of the procedure
with standard Fmoc chemistry.[12]
Non-proteinogenic amino acids are an important class of
organic compounds that can have intrinsic biological ac-
tivity or can be found in peptides with antiviral, antitumor,
anti-inflammatory, or immunosuppressive activities.
Among the non-proteinogenic amino acids are N-alkyl
amino acids and dehydroamino acids, both of which can be
found in many biologically important peptides.[1]
N-Alkyl amino acids are constituents of various impor-
tant naturally occurring peptides and proteins.[1] They have
been isolated from plant strains, microorganisms, and ma-
rine species. N-Alkylation of the peptide bond causes
changes in volume and conformation of peptides, resulting
in reduced flexibility, increase of permeability for the mem-
brane (increased lipophilicity), and prevention of cleavage
by proteolytic enzymes.[2] Several N-alkylated peptides show
antibiotic, anticancer, or antiviral activity.[3] The incorpora-
tion of N-alkyl amino acids in peptides has been used in
medicinal chemistry to change conformation and restrict
flexibility, thus increasing receptor selectivity, and also im-
proving oral activity and duration of action.[4]
Many methods for the synthesis of N-alkyl amino acids
have been developed, mostly involving N-methylation reac-
tions.[2] Many of these approaches require treatment of the
amino acids with strong bases to form anionic nucleophiles
that are then reacted with alkyl halides, which can result in
racemization. Fewer methods for the synthesis of N-ethyl-
[a] Chemistry Centre, University of Minho,
Gualtar, 4710-057 Braga, Portugal
Fax: +351-253604382
E-mail: monteiro@quimica.uminho.pt
6764
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of New N-Ethyl Dehydroamino Acid Derivatives
Dehydroamino acids have been found in naturally occur- attempts at alkylating dehydroamino acids with amine pro-
ring peptides of fungal and microbial origin[13] and from tecting groups other than the 4-nitrophenylsulfonyl group
marine organisms,[14] in which they play a catalytic role in were carried out. Thus, the methyl esters of N-(tert-bu-
the active sites of some enzymes. They are also found in a tyloxycarbonyl)dehydroalanine (Boc-ΔAla-OMe) and of N-
variety of peptide antibiotics of bacterial origin that include (4-nitrobenzyloxycarbonyl)dehydroalanine [Z(NO2)-ΔAla-
the lantibiotics (nisin, epidermin, subtilin, gallidermin).[15] OMe] were subjected to N-ethylation with triethyloxonium
Because they affect both chemical reactivity and conforma- tetrafluoroborate. However, after several hours of reaction
tion, dehydroamino acids have been introduced into pept- and addition of a large excess of alkylating agent, no N-
ides for structure–function relationship studies, and can ethylated dehydroalanine derivative could be detected. The
also be used as precursors to obtain new non-proteinogenic 1H NMR chemical shift of the NH proton of Boc-ΔAla-
amino acids.[16] In our laboratories, an efficient method for OMe and Z(NO2)-ΔAla-OMe in dimethyl sulfoxide
the synthesis of N,N-diacyl α,β-dehydroamino acid deriva- (DMSO) solutions were determined (δNH = 8.35 and
tives from N-acyl β-hydroxy amino acid derivatives was de- 9.13 ppm, respectively) and compared with a dehydroamino
veloped by treatment with two equivalents of tert-butyl pyr- acid derivative in which alkylation under the same condi-
ocarbonate and 4-(dimethylamino)pyridine as catalyst in tions was complete, such as the methyl ester of N-(4-ni-
anhydrous acetonitrile.[17] To allow the synthesis of N-acyl trophenylsulfonyl)dehydroaminobutyric acid (Nosyl-ΔAbu-
α,β-dehydroamino acid derivatives, a modification of this OMe, δNH = 9.66 ppm). Thus, the strong electron-with-
method was subsequently reported.[18]
drawing effect of the nitroarylsulfonamide group was con-
Recently, we reported the use of a combination of the firmed to be essential for N-ethylation even of the more
alkylation procedure reported by Liguori et al.[12] and our conjugated dehydroalanine derivatives.
dehydration methodologies[17,18] to obtain new non-pro-
In the case of N-alkylation of dehydroamino acids, an
teinogenic amino acids, namely, N-(4-nitrophenylsulfonyl) alternative to the electron-withdrawing effect of the amine
N-ethyl α,β-dehydroamino acids.[19] Thus, it was possible to protecting group could be the presence of electron-with-
obtain for the first time, new non-natural amino acids that drawing substituents on the β-carbon atom. In our
incorporate both the N-ethyl and the α,β-dehydro moieties. laboratories, we have been synthesizing β-halogenated dehy-
Herein, we report the application of this N-alkylation pro- droamino acid derivatives and using them as substrates in
cedure to several methyl esters of β,β-dibromo and β-bromo Suzuki–Miyaura cross-coupling reactions with aryl and het-
β-substituted dehydroamino acids protected with standard eroarylboronic acids to obtain new dehydroamino acid de-
amine protecting groups such as tert-butyloxycarbonyl rivatives.[20] Thus, we decided to study how the presence of
(Boc), benzyloxycarbonyl (Z), and (4-nitrobenzyl)oxycarb- bromine substituents on the β-C atom of dehydroalanine
onyl [Z(NO2)], as well as acyl and sulfonylamine protect- derivatives affects N-ethylation.
ing groups. The procedure allows the synthesis of N-pro-
The methyl esters of dehydroalanine that are N-protected
tected, N-ethyl β,β-dibromo and N-ethyl β-bromo β-substi- with the (4-nitrobenzyl)oxycarbonyl, benzyloxycarbonyl,
tuted dehydroamino acid methyl esters. Some of these N- tert-butyloxycarbonyl, 2-furanoyl (2-Fur), or 4-meth-
ethylated dehydroamino acid derivatives are used as sub- oxybenzoyl [Bz(4-OMe)] groups (compounds 1a–e,
strates in cross-coupling reactions to give the methyl esters Scheme 1) were prepared from the corresponding N-pro-
of N-protected, β,β-disubstituted N-ethyldehydroalanines. tected serine methyl ester, according to the dehydration pro-
Thus, this methodology opens the possibility of obtaining cedure previously developed by us.[18] The N-protected de-
a large range of new β,β-disubstituted N-ethyldehydroalan- hydroalanine derivatives were treated with 2.2 equiv. of N-
ines.
bromosuccinimide (NBS) followed by treatment with trieth-
ylamine to give the corresponding N-protected β,β-dibromo-
dehydroalanine derivatives (4a–e; Scheme 1).[18] These
compounds were subjected to N-ethylation using the pre-
Results and Discussion
To expand the scope of the procedure for N-ethylation viously established conditions[12] [2.5 equiv. of triethyl-
of dehydroamino acid derivatives previously reported,[19] oxonium tetrafluoroborate, 3.5 equiv. of N,N-diisopropyl-
Scheme 1. Synthesis of the methyl esters of N-acyl-N-ethyl-β,β-dibromodehydroalanines and of N-acyl N-ethyl β-bromo β-substituted
dehydroamino acids.
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Table 1. Results obtained in the N-ethylation of the methyl esters of N-acyl-β,β-dibromodehydroalanines and of N-acyl β-bromo β-
substituted dehydroamino acids.
Reactant
1H NMR δNH [ppm][a]
Product
Ratio prod./reac.[b]
Yield [%]
Z(NO2)-ΔAla(β,β-Br)-OMe
Z-ΔAla(β,β-Br)-OMe
Boc-ΔAla(β,β-Br)-OMe
2-Fur-ΔAla-(β,β-Br)-OMe
4a
4b
4c
4d
9.85
9.69
9.20
10.16
10.07
9.58
9.42
9.26
9.01
10.24
9.69
9.82
9.65
9.15
10.66
Z(NO2)-N(Et)-ΔAla(β,β-Br)-OMe
Z-N(Et)-ΔAla(β,β-Br)-OMe
Boc-N(Et)-ΔAla(β,β-Br)-OMe
2-Fur-N(Et)-ΔAla(β,β-Br)-OMe
7a
7b
7c
7d
100:0
100:0
48:52
82:18
64:36
80:20
37:63
43:57
0:100
100:0
100:0
45:55
38:62
15:85
100:0
100:0
85
82
44
80
47
75
33
40
–
93
78
30
36
–
Bz(4-OMe)-ΔAla(β,β-Br)-OMe 4e
Bz(4-OMe)-N(Et)-ΔAla(β,β-Br)-OMe 7e
Z(NO2)-E-ΔAbu(β-Br)-OMe
Z(NO2)-Z-ΔAbu(β-Br)-OMe
Z-(Z)-ΔAbu(β-Br)-OMe
Boc-Z-ΔAbu(β-Br)-OMe
Nosyl-Z-ΔAbu(β-Br)-OMe
Tos-Z-ΔAbu(β-Br)-OMe
Z(NO2)-Z-ΔPhe(β-Br)-OMe
Z-(Z)-ΔPhe(β-Br)-OMe
Boc-Z-ΔPhe(β-Br)-OMe
Nosyl-Z-ΔPhe(β-Br)-OMe
Tos-Z-ΔPhe(β-Br)-OMe
E-5a
Z(NO2)-N(Et)-E-ΔAbu(β-Br)-OMe
Z(NO2)-N(Et)-Z-ΔAbu(β-Br)-OMe
Z-N(Et)-Z-ΔAbu(β-Br)-OMe
Boc-N(Et)-Z-ΔAbu(β-Br)-OMe
Nosyl-N(Et)-Z-ΔAbu(β-Br)-OMe
Tos-N(Et)-Z-ΔAbu(β-Br)-OMe
Z(NO2)-N(Et)-Z-ΔPhe(β-Br)-OMe
Z-N(Et)-Z-ΔPhe(β-Br)-OMe
E-8a
Z-5a
Z-5b
Z-5c
Z-5f
Z-5g
Z-6a
Z-6b
Z-6c
Z-6f
Z-8a
Z-8b
Z-8c
Z-8f
Z-8g
Z-9a
Z-9b
Z-9c
Z-9f
Z-9g
Boc-N(Et)-Z-ΔPhe(β-Br)-OMe
Nosyl-N(Et)-Z-ΔPhe(β-Br)-OMe
Tos-N(Et)-Z-ΔPhe(β-Br)-OMe
90
89
Z-6g 10.08
1
1
[a] H NMR shift of the amide hydrogen measured in DMSO. [b] Ratio of product to reactant determined by H NMR spectroscopic
analysis.
ethylamine (DIPEA) in anhydrous dichloromethane] to give ylserine methyl esters protected with Z(NO2), Z, and Boc,
the corresponding N-protected N-ethyl-β,β-dibromodehy- and also with the strong electron-withdrawing sufonyl de-
droalanine derivative (7a–e; Scheme 1, Table 1).
rivatives Nosyl and 4-toluenesulfonyl (Tos) were prepared.
The reactions were complete with the urethane protect- With the exception of the Nosyl derivatives, these com-
ing groups Z(NO2) and Z, giving the corresponding N-acyl- pounds were subject to dehydration with 1 equiv. of tert-
and N-ethyl-β,β-dibromodehydroalanine derivatives in 85 butyl pyrocarbonate,[18] to give the corresponding N-pro-
and 82% yields, respectively (compounds 7a and 7b). With tected derivatives of dehydroaminobutyric acid and of dehy-
Boc as protecting group, the reaction could not be taken to drophenylalanine (2a–c, 2g, 3a–c, and 3g; Scheme 1). For
completion, giving an approximately 1:1 mixture of product the Nosyl derivatives, dehydration had to be carried out
and starting material. The product 7c could be isolated by using 2 equiv. of tert-butyl pyrocarbonate to give the corre-
column chromatography. Thus, the β,β-dibromodehydroal- sponding N-Boc and N-Nosyl dehydroamino acid deriva-
anine derivatives protected with the more electron-with- tives, followed by treatment with a 4% solution of trifluoro-
drawing groups Z(NO2) and Z, gave complete reactions acetic acid in dichloromethane to give compounds 2f and
with good yields of the N-ethylated product, whereas the 3f.[19] The dehydroamino acid derivatives were treated with
reaction could not be taken to completion with the dehy- 1.2 equiv. NBS followed by triethylamine to give N-pro-
droalanine derivative containing the less electron-with- tected β-bromodehydroaminobutyric acid and dehydro-
1
drawing Boc group. The H NMR shifts of the NH proton phenylalanine derivatives (5a–c, 5f, 5g, 6a–c, 6f, and 6g;
of compounds 4a–c in DMSO solutions were measured Scheme 1). The β-bromo β-substituted dehydroamino acid
(Table 1). Compounds 4a and 4b showed higher chemical derivatives were subject to N-ethylation under identical con-
shifts than compound 4c. Thus, a correlation could be ob- ditions to those described previously for the β,β-dibromo-
served between the chemical shift of the nitrogen protons dehydroalanine derivatives.
and reaction yields.
N-Ethylation of dehydroaminobutyric acid derivatives
With the acyl-protected derivatives 4d and 4e, the N-eth- protected with Z(NO2) and Z (E-5a, Z-5a, and Z-5b) could
ylation reactions were also incomplete, but the desired not be taken to completion, in contrast to the reaction with
products 7d and 7e could be isolated after column β,β-dibromodehydroalanine derivatives protected with the
chromatography. For the reaction with 4d, a ratio of ap- same groups (4a and 4b). However, the N-ethylated product
proximately 8:2 of product to reactant was obtained, could be isolated after column chromatography. The 1H
whereas for 4e this ratio was approximately 6:4. These ratios NMR chemical shifts of the NH proton of compounds E-
could be correlated with the 1H NMR chemical shift of the 5a, Z-5a, and Z-5b in DMSO solutions were measured
nitrogen protons (δNH = 10.16 and 10.07 ppm for 4d and (Table 1). It was observed that the substitution of a β-
4e, respectively).
methyl group of the dehydroamino acids for a bromine
1
The results obtained in the N-alkylation of β,β-dibromo- atom reduces the H NMR chemical shift. Comparison of
dehydroalanine derivatives led us to attempt to expand the the chemical shift of the NH proton of both diastereomers
scope of this methodology to other dehydroamino acid de- of compounds 5a shows that the E isomer exhibits a higher
rivatives, namely β-bromo β-substituted dehydroamino ac- chemical shift than the Z isomer. For compound E-5a, a
ids. Because β,β-dibromodehydroalanine derivatives that ratio of 8:2 product to reactant was obtained, whereas for
were N-protected with urethane-type protecting groups Z-5a a ratio was of approximately 4:6 was found. For the
gave the best results in N-alkylation, threonine and phen- Boc-protected dehydroaminobutyric acid derivative Z-5c,
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Synthesis of New N-Ethyl Dehydroamino Acid Derivatives
Table 2. Results obtained in the Suzuki cross-coupling reactions of N-ethyl β,β-dibromo and N-ethyl β-bromo β-substituted dehydroamino
acid derivatives with phenylboronic acid.
Reactant
Product
Yield [%]
Z(NO2)-N(Et)-ΔAla(β,β-Br)-OMe
Z-N(Et)-Z-ΔAbu(β-Br)-OMe
Z(NO2)-N(Et)-Z-ΔPhe(β-Br)-OMe
Nosyl-N(Et)-Z-ΔPhe(β-Br)-OMe
7a
Z(NO2)-N(Et)-ΔPhe(β-C6H5)-OMe
Z-N(Et)-Z-ΔAbu(β-C6H5)-OMe
Z(NO2)-N(Et)-ΔPhe(β-C6H5)-OMe
Nosyl-N(Et)-ΔPhe(β-C6H5)-OMe
10a
81
50
63
95
Z-8b
Z-9a
Z-9f
Z-10b
10a
10f
no N-ethylation was observed. The 1H NMR chemical shift ethylated dehydroamino acids, compounds 7a, Z-8b, Z-9a,
of the NH proton was again significantly lower than for the and Z-9f were reacted with phenylboronic acid under Su-
Z(NO2) and Z-protected dehydroaminobutyric acid deriva- zuki–Miyaura cross-couplings conditions (Scheme 2).
tives, and was also lower than for the N-Boc-β,β-dibromo-
The corresponding N-ethyl β-phenyl β-substituted dehy-
dehydroalanine derivative.
droamino acid derivatives were obtained in moderate to
Both N-sulfonamide derivatives of dehydroaminobutyric high yields (10a, Z-10b, and 10f; Scheme 2, Table 2).
1
acid Z-5f and Z-5g gave rise to higher H NMR chemical
shifts for their respective NH proton, and the N-ethylation
reactions were complete, giving the N-ethylated products Z-
Conclusions
8f and Z-8g in yields of 93 and 78%, respectively.
The triethyloxonium tetrafluoroborate/N,N-diisopropyl-
N-Ethylation of dehydrophenylalanine derivatives pro-
ethylamine alkylation procedure was applied in the N-ethyl-
tected with Z(NO2) and Z (compounds Z-6a and Z-6b)
ation of several derivatives of β,β-dibromodehydroalanine,
could not be taken to completion. Again, the N-ethylated
β-bromodehydroaminobutyric acid, and β-bromodehydro-
product could be isolated after column chromatography.
phenylalanine, N-protected with urethane, acyl, and sufonyl
The ratio of N-ethylated dehydrophenylalanine derivative to
groups. Depending on the nature of the halogenated dehy-
starting material was comparable to those obtained from
droamino acid and of the protecting group, variable ratios
the corresponding β-bromodehydroaminobutyric acid de-
rivatives. However, the 1H NMR chemical shifts for the NH
proton of compounds Z-6a and Z-6b were higher than
those of the corresponding dehydroaminobutyric acid de-
rivatives, as would be expected from the electron-with-
drawing effect of the β-phenyl ring compared to the elec-
tron-donating effect of the β-methyl group. Thus, it is pos-
sible that the more extended conjugation of the dehydroph-
enylalanine derivatives counteracts the higher acidity of the
NH proton in this ethylation reaction. For the N-Boc deriv-
ative Z-6a, a 15:85 ratio of product to reactant was ob-
tained, however the product could not be isolated by
chromatography.
N-Ethylation of the N-sulfonamide derivatives of dehy-
drophenylalanine (Z-6f and Z-6g) were complete, giving Z-
9f and Z-9g in yields of 90 and 89%, respectively.
To demonstrate the applicability of these N-ethyl β,β-di-
bromo and N-ethyl β-bromo β-substituted dehydroamino
acid derivatives as substrates for the synthesis of new N-
of product to reactant were obtained. These varied from
total conversion into product [β,β-dibromodehydroalanine
derivatives protected with Z(NO2) and Z, β-bromodehyd-
roaminobutyric acid and dehydrophenylalanine derivatives
protected with Nosyl and Tos] to complete absence of reac-
tion (β-bromodehydroaminobutyric acid protected with
1
Boc). A correlation between the H NMR chemical shift of
the NH proton and the extent of the N-ethylation reaction
can be established within the same type of dehydroamino
acid with protecting groups also of the same type. With the
exception of the N-ethyl-β-bromodehydroaminobutyric acid
and dehydrophenylalanine derivatives protected with the
Boc group, all other N-ethyl β-bromo dehydroamino acid
derivatives could be obtained in yields ranging from 30 to
93%. Some of these new non-proteinogenic amino acids
were used successfully as substrates in Suzuki–Miyaura
cross-coupling reactions. Thus, in addition to their intrinsic
potential interest, these compounds also constitute impor-
tant substrates for the synthesis of new β,β-disubstituted N-
ethyldehydroalanine derivatives.
Experimental Section
General: Melting points were determined with a Gallenkamp appa-
ratus and are uncorrected. 1H and 13C NMR spectra were recorded
with a Varian Unity Plus spectrometer operating at 300 and
75.4 MHz, respectively, or with a Bruker Avance II+ operating at
400 and 100.6 MHz, respectively. 1H–1H spin–spin decoupling,
DEPT (θ 45°), HMQC, and HMBC were used to attribute some
signals. Chemical shifts are given in ppm and coupling constants
(J) in Hz. HRMS data were obtained by the mass spectrometry
service of the University of Vigo, Spain. Elemental analysis was
Scheme 2. Suzuki cross-coupling reactions of N-ethyl β,β-dibromo
and N-ethyl β-bromo β-substituted dehydroamino acid derivatives
with phenylboronic acid.
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L. S. Monteiro et al.
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performed with a LECO CHNS 932 elemental analyzer. The reac-
tions were monitored by thin layer chromatography (TLC). Col-
umn chromatography was performed with Macherey–Nagel silica
gel 230–400 mesh. Petroleum ether refers to fractions with the boil-
ing range 40–60 °C. When solvent gradients were used, the increase
of polarity was made from neat petroleum ether to mixtures of
diethyl ether/petroleum ether, increasing 10% of diethyl ether each
time until isolation of the product was complete. Solvents were
used without purification except for acetonitrile and dichlorometh-
ane, which were dried according to standard procedures.
(1 moldm–3, 3ϫ 30 mL), and brine (3ϫ30 mL), and dried with
MgSO4. Removal of the solvent afforded the corresponding methyl
ester of the N-protected α,β-dehydroamino acid.
Z(NO2)-Z-ΔPhe-OMe (3a): The general procedure described above
was followed using Z(NO2)-d,l-Phe(β-OH)-OMe (1.608 g,
4.300 mmol) as reactant to afford 3a (1.166 g, 76%) as an orange
1
oil; m.p. 108.0–109.0 °C (ethyl acetate/petroleum ether). H NMR
(300 MHz, CDCl3): δ = 3.86 (s, 3 H, CH3 OMe), 5.20 [s, 2 H, CH2
Z(NO2)], 6.40 (br. s, 1 H NH), 7.27–7.41 (m, 6 H, ArH, βH), 7.55
(d, J = 8.4 Hz, 2 H, ArH), 8.23 (d, J = 8.7 Hz, 2 H, ArH) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 52.77 (OCH3), 65.92 [CH2
Z(NO2)], 123.67 (CH), 126.95 (C), 128.23 (CH), 128.47 (CH),
128.66 (CH), 129.67 (CH), 132.52 (CH), 133.46 (C), 143.21 (C),
147.63 (C), 153.45 (C=O), 165.56 (C=O) ppm. C18H16N2O6
(356.33): calcd. C 60.67, H 4.53, N 7.86; found C 60.36, H 4.69, N
8.09.
Methyl Esters of N-Protected β-Hydroxy Amino Acids: Z(NO2)-l-
Ser-OMe,[17] Z-l-Ser-OMe,[17] Boc-l-Ser-OMe,[17] 2-Fur-l-Ser-
OMe,[21] Bz(4-OMe)-l-Ser-OMe,[21] Z(NO2)-l-Thr-OMe,[17] Z-l-
Thr-OMe,[17] Boc-l-Thr-OMe,[17] Nosyl-l-Thr-OMe,[19] Tos-l-Thr-
OMe,[17] Z(NO2)-d,l-Phe(β-OH)-OMe,[17] Boc-d,l-Phe(β-OH)-
OMe,[22]
Nosyl-d,l-Phe(β-OH)-OMe,[19]
Tos-d,l-Phe(β-OH)-
OMe;[18] the synthesis of these compounds has been described pre-
viously.
Z-Z-ΔPhe-OMe (3b): The general procedure described above was
followed using Z-d,l-Phe(β-OH)-OMe (1.028 g, 3.120 mmol) as re-
actant to afford 3b (0.795 g, 82%) as a yellowish oil that failed to
crystallize. 1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H, CH3
OMe), 5.13 (s, 2 H, CH2 Z), 6.39 (br. s, 1 H NH), 7.33–7.37 (m, 9
Z-D,L-Phe(β-OH)-OMe: HCl,H-d,l-Phe(β-OH)-OMe (1.158 g,
5.000 mmol) was dissolved in dichloromethane (0.2 moldm–3) and
triethylamine (2.2 equiv.) was added. Benzyl chloroformate
(1.1 equiv.) was 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
evaporated and partitioned between of ethyl acetate (200 mL) and
KHSO4 (1 moldm–3, 100 mL) and washed with KHSO4
(1 moldm–3, 3ϫ50 mL), NaHCO3 (1 moldm–3, 3ϫ50 mL), and
brine (3ϫ50 mL). After drying over MgSO4, the extract was taken
to dryness at reduced pressure to afford Z-d,l-Phe(β-OH)-OMe
(1.548 g, 94%) as a white solid; m.p. 87.0–88.0 °C (ethyl acetate/n-
H, ArH, βH), 7.51–7.52 (m,
2
H, ArH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 52.63 (OCH3), 67.50 (CH2), 128.17 (CH),
128.22 (CH), 128.33 (C), 128.47 (CH), 128.59 (CH), 129.45 (CH),
129.70 (CH), 131.71 (CH), 133.57 (C), 135.89 (C), 153.80 (C=O),
165.71 (C=O) ppm. HRMS (ESI): calcd. for C18H17NNaO4
334.10553; found 334.10553.
Methyl Esters of N-Protected β-Bromo Dehydroamino Acids:
Z(NO2)-ΔAla(β,β-Br)-OMe (4a),[18] Z-ΔAla(β,β-Br)-OMe (4b),[18]
Boc-ΔAla(β,β-Br)-OMe (4c),[20a] 2-Fur-ΔAla(β,β-Br)-OMe (4d),[23]
Bz(4-OMe)-ΔAla(β,β-Br)-OMe (4e),[23] Z(NO2)-E-ΔAbu(β-Br)-
OMe (E-5a),[18] Z(NO2)-Z-ΔAbu(β-Br)-OMe (Z-5a),[18] Z-Z-ΔAbu-
(β-Br)OMe (Z-5b),[18] Boc-Z-ΔAbu(β-Br)-OMe (Z-5c),[24] Tos-Z-
ΔAbu(β-Br)-OMe (Z-5g),[18] Boc-Z-ΔPhe(β-Br)-Ome (Z-6c),[20b]
Tos-Z-ΔPhe(β-Br)-OMe (Z-6g);[18] the syntheses of these com-
pounds have been described previously.
1
hexane). H NMR (400 MHz, CDCl3): δ = 2.60 (br. s, 1 H, OH),
3.76 (s, 3 H, CH3 OMe), 4.61–4.63 (m, 1 H, αCH), 5.00 (s, 2 H,
CH2 Z), 5.28 (d, J = 2.0 Hz, 1 H, βCH), 5.66 (br. d, J = 8.8 Hz, 1
H, NH), 7.31–7.35 (m, 10 H, ArH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 52.63 (OCH3), 59.80 (αCH), 66.97 (CH2 Z), 73.57
(βCH), 125.85 (CH), 127.88 (CH), 128.05 (CH), 128.11 (CH),
128.41 (2CH), 136.13 (C), 139.52 (C), 156.24 (C=O), 171.11
(C=O) ppm. C18H19NO5 (329.35): calcd. C 65.64, H 5.81, N 4.25;
found C 65.49, H 5.89, N 4.41.
General Procedure: The methyl ester of the N-protected α,β-dehy-
droamino acid was dissolved in dichloromethane (0.1 moldm–3)
and N-bromosuccinimide (1.2 equiv.) was added with vigorous stir-
ring. After reacting for 16 h, triethylamine (1.5 equiv.) was added
and stirring was continued for 1 h. Additional dichloromethane
(100 mL) was added and the organic phase was washed with
KHSO4 (1 moldm–3, 3ϫ30 mL), NaHCO3 (1 moldm–3,
3ϫ30 mL), and brine (3ϫ30 mL). After drying over MgSO4, the
extract was taken to dryness under reduced pressure. When neces-
sary, the diastereomers were separated by column chromatography
(petroleum ether to diethyl ether/petroleum ether, 40%) to afford
the corresponding methyl ester of the N-protected β-bromo α,β-
dehydroamino acid.
Methyl Esters of N-(tert-Butoxycarbonyl) N-(4-Nitrophenylsulfonyl)
α,β-Dehydroamino Acids: The synthesis of Nosyl-Z-ΔAbu(N-Boc)-
OMe[19] and Nosyl-Z-ΔPhe(N-Boc)-OMe[19] have been described
previously.
Methyl Esters of N-Protected Dehydroamino Acids: Z(NO2)-ΔAla-
OMe (1a),[18] Z-ΔAla-OMe (1b),[18] Boc-ΔAla-OMe (1c),[17] 2-Fur-
ΔAla-OMe (1d),[21] Bz(4-OMe)-ΔAla-OMe (1e),[21] Z(NO2)-Z-
ΔAbu-OMe (2a),[17] Z-Z-ΔAbu-OMe (2b),[17] Boc-Z-ΔAbu-OMe
(2c),[17] Nosyl-Z-ΔAbu-OMe (2f),[19] Tos-Z-ΔAbu-OMe (2g),[18]
Boc-Z-ΔPhe-OMe (3c),[22] Nosyl-Z-ΔPhe-OMe (3f),[19] Tos-Z-
ΔPhe-OMe (3g);[18] the synthesis of these compounds has been de-
scribed previously.
Nosyl-Z-ΔAbu(β-Br)-OMe (Z-5f): The general procedure described
above was followed using Nosyl-Z-ΔAbu-OMe (2f; 0.660 g,
2.200 mmol) as reactant to afford Z-5f (0.746 g, 89%) as a light-
yellow solid; m.p. 116.0–117.0 °C (ethyl acetate/n-hexane). 1H
NMR (300 MHz, CDCl3): δ = 2.60 (s, 3 H, γCH3), 3.80 (s, 3 H,
CH3 OMe), 6.46 (s, 1 H, NH), 8.07 (d, J = 8.7 Hz, 2 H, ArH), 8.38
(d, J = 8.7 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 25.75 (γCH3), 52.96 (OCH3), 124.22 (CH), 125.78 (C), 128.64
(CH), 133.37 (C), 144.96 (C), 150.38 (C), 162.72 (C=O) ppm.
C11H11BrN2O6S (379.18): calcd. C 34.84, H 2.92, N 7.39, S 8.46;
found C 34.82, H 3.02, N 7.33, S 8.22.
General Procedure: The methyl ester of the N-protected β-hydroxy
amino acid was dissolved in anhydrous acetonitrile (0.5 moldm–3),
and DMAP (0.1 equiv.) was added followed by tert-butyl pyrocarb-
onate (1.0 equiv.) under rapid stirring at room temperature. The
reaction was monitored by TLC (diethyl ether/n-hexane, 1:1) until
all the reactant had been consumed. Then, N,N,NЈ,NЈ-tetrameth-
ylguanidine (2% by volume) was added, and stirring was continued
for an additional 6 h. Evaporation under reduced pressure gave a
residue that was partitioned between diethyl ether (100 mL) and
KHSO4 (1 moldm–3, 30 mL). The organic phase was thoroughly
washed with KHSO4 (1 moldm–3, 3ϫ30 mL), NaHCO3
Z(NO2)-Z-ΔPhe(β-Br)-OMe (Z-6a): The general procedure de-
scribed above was followed using Z(NO2)-Z-ΔPhe-OMe (3a;
6768
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6764–6772

Synthesis of New N-Ethyl Dehydroamino Acid Derivatives
1.003 g, 2.816 mmol) as reactant to afford Z-6a (1.137 g, 93%) as a
white solid; m.p. 151.0–152.0 °C (ethyl acetate/n-hexane). 1H NMR
(300 MHz, CDCl3): δ = 3.51 (br. s, 3 H, CH3 OMe), 5.29 [s, 2 H,
CH2 Z(NO2)], 6.80 (br. s, 1 H NH), 7.35 (s, 5 H, ArH), 7.55 (d, J
= 8.4 Hz, 2 H, ArH), 8.25 (d, J = 8.4 Hz, 2 H, ArH) ppm. 13C
NMR (75.4 MHz, CDCl3): δ = 52.64 (OCH3), 66.40 [CH2 Z(NO2)],
117.09 (C), 123.85 (CH), 128.34 (CH), 128.45 (CH), 128.48 (C),
128.83 (CH), 129.50 (CH), 137.03 (C), 142.53 (C), 147.85 (C),
152.50 (C=O), 163.12 (C=O) ppm. C18H15BrN2O6 (435.23): calcd.
C 49.67, H 3.47, N 6.44; found C 50.07, H 3.69, N 6.34. HRMS
(ESI): calcd. for C18H15N2NaO6Br 457.00112; found 457.00224.
C 36.08, H 3.03, N 6.01; found C 36.02, H 3.12, N 6.01. HRMS
(ESI): calcd. for C14H14N2NaO6Br2 486.91163; found 486.91108.
Z-N(Et)-ΔAla(β,β-Br)-OMe (7b): The general procedure described
above was followed using Z-ΔAla(β,β-Br)-OMe (4b; 0.158 g,
0.400 mmol) as reactant to afford 7b (0.138 g, 82%) as a colorless
oil that failed to crystallize. 1H NMR (400 MHz, CDCl3): δ = 1.22
(t, J = 7.2 Hz, 3 H, CH2CH3), 3.57 (q, J = 7.2 Hz, 2 H, CH2CH3),
3.62 (s, 3 H, CH3 OMe), 5.16 (s, 2 H, CH2 Z), 7.31–7.38 (m, 5 H,
ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 12.96 (CH3), 43.91
(CH2), 52.61 (OCH3), 66.69 (CH2 Z), 107.25 (C), 127.91 (CH),
128.08 (CH), 128.42 (CH), 134.62 (C), 136.08 (C), 153.79 (C=O),
162.92 (C=O) ppm. HRMS (ESI): calcd. for C14H15NNaO4Br2
441.92655; found 441.92600.
Z-Z-ΔPhe(β-Br)-OMe (Z-6b): The general procedure described
above was followed using Z-Z-ΔPhe-OMe (3b; 0.970 g,
3.119 mmol) as reactant to afford Z-6b (1.045 g, 86%) as a white
solid; m.p. 87.0–88.0 °C (diethyl ether/n-hexane). 1H NMR
(400 MHz, CDCl3): δ = 3.53 (br. s, 3 H, CH3 OMe), 5.19 (s, 2 H,
CH2 Z), 6.76 (br. s, 1 H, NH), 7.33–7.39 (m, 10 H, ArH) ppm. 13C
NMR (400 MHz, CDCl3): δ = 52.55 (OCH3), 68.14 (CH2 Z),
115.61 (C), 128.27 (CH), 128.46 (CH), 128.58 (CH), 128.63 (CH),
128.86 (C), 128.91 (CH), 129.30 (CH), 135.18 (C), 137.17 (C),
152.86 (C=O), 163.24 (C=O) ppm. C18H16BrNO4 (390.23): calcd.
C 55.40, H 4.13, N 3.59; found C 55.60, H 4.15, N 3.62.
Boc-N(Et)-ΔAla(β,β-Br)-OMe (7c): The general procedure de-
scribed above was followed using Boc-ΔAla(β,β-Br)-OMe (4c;
0.180 g, 0.500 mmol) as reactant to afford a colorless oil (0.176 g)
consisting of a mixture of product and reactant in a 48:52 ratio.
Purification by column chromatography (diethyl ether/petroleum
ether) afforded 7c (0.084 g, 44%) as a colorless oil that failed to
crystallize. 1H NMR (400 MHz, CDCl3): δ = 1.18 (t, J = 7.2 Hz, 3
H, CH2CH3), 1.42 (s, 9 H, CH3 Boc), 3.50 (q, J = 7.2 Hz, 2 H,
CH2CH3), 3.80 (s, 3 H, CH3 OMe) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 13.05 (CH3), 28.11 [C(CH3)3], 42.96 (CH2), 52.56
(OCH3), 81.25 [OC(CH3)3], 105.08 (C), 135.40 (C), 152.71 (C=O),
Nosyl-Z-ΔPhe(β-Br)-OMe (Z-6f): The general procedure described
above was followed using Nosyl-Z-ΔPhe-OMe (3f; 1.011 g,
2.794 mmol) as reactant to afford Z-6f (1.027 g, 83%) as a yellow 163.35 (C=O) ppm. HRMS (ESI): calcd. for C11H17NNaO4Br2
solid; m.p. 187.0–188.0 °C (ethyl acetate/n-hexane). 1H NMR
(400 MHz, CDCl3): δ = 3.58 (s, 3 H, CH3 OMe), 6.74 (s, 1 H, NH),
7.24–7.26 (m, 2 H, ArH), 7.33–7.38 (m, 3 H, ArH), 8.16 (d, J =
8.7 Hz, 2 H, ArH Nosyl), 8.43 (d, J = 8.7 Hz, 2 H, ArH No-
syl) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 53.03 (OCH3),
124.30 (CH), 125.41 (C), 127.50 (C), 128.45 (CH), 128.49 (CH),
128.77 (CH), 130.07 (CH), 136.64 (C), 144.67 (C), 150.55 (C),
162.99 (C=O) ppm. C16H13BrN2O6S (441.25): calcd. C 43.55, H
2.97, N 6.35, S 7.27; found C 43.54, H 3.02, N 6.31, S 7.16.
407.94220; found 407.94198.
2-Fur-N(Et)-ΔAla(β,β-Br)-OMe (7d): The general procedure de-
scribed above was followed using 2-Fur-ΔAla(β,β-Br)-OMe (4d;
0.177 g, 0.500 mmol) as reactant to afford a yellow oil (0.185 g)
consisting of a mixture of product and reactant in a 82:18 ratio.
Purification by column chromatography (diethyl ether/petroleum
ether) afforded 7d (0.152 g, 80%) as a colorless oil; m.p. 74.0–
75.0 °C (diethyl ether/petroleum ether). 1H NMR (400 MHz,
CDCl3): δ = 1.26 (t, J = 7.2 Hz, 3 H, CH2CH3), 3.69 (br. q, 2 H,
CH2CH3), 3.78 (s, 3 H, CH3 OMe), 6.45 (dd, J = 1.8, J = 3.3 Hz,
1 H, ArH), 7.06 (d, J = 3.3 Hz, 1 H, ArH), 7.46 (s, 1 H, ArH) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 12.64 (CH3), 43.71 (CH2),
52.97 (OCH3), 108.75 (C), 111.48 (CH), 116.80 (CH), 135.73 (C),
144.95 (CH), 147.25 (C), 158.37 (C=O), 162.91 (C=O) ppm.
C11H11Br2NO4 (381.02): calcd. C 34.67, H 2.91, N 3.68; found C
34.73, H 2.94, N 3.72.
Methyl Esters of N-Protected N-Ethyl-β,β-dibromodehydroalanines
and N-Protected N-Ethyl β-Substituted β-Bromo Dehydroamino
Acids
General Procedure: The methyl ester of the N-protected β-bromo
dehydroamino acid was dissolved in anhydrous dichloromethane
(0.05 moldm–3) followed by addition of N,N-diisopropylethylamine
(3.5 equiv.) and triethyloxonium tetrafluoroborate (2.5 equiv.) un-
der an inert atmosphere. The reaction mixture was stirred at room
temperature for 30 min. In cases where TLC indicated some start-
ing material remained, N,N-diisopropylethylamine (1 equiv.) and
triethyloxonium tetrafluoroborate (1 equiv.) were added and stir-
ring was continued for 1 h. Dichloromethane (50 mL) was added
and the organic phase was washed with KHSO4 (1 moldm–3,
3ϫ30 mL), NaHCO3 (1 moldm–3, 3ϫ30 mL), and brine
Bz(4-OMe)-N(Et)-ΔAla(β,β-Br)-OMe (7e): The general procedure
described above was followed using Bz(4-OMe)-ΔAla(β,β-Br)-OMe
(4e; 0.118 g, 0.300 mmol) as reactant to afford a colorless oil
(0.093 g) consisting of a mixture of product and reactant in a 64:36
ratio. Purification by column chromatography (diethyl ether/petro-
leum ether) afforded 7e (0.060 g, 47%) as a colorless oil; m.p. 68.0–
70.0 °C (diethyl ether/n-hexane). 1H NMR (400 MHz, CDCl3): δ =
(3ϫ30 mL), and dried with MgSO4. Removal of the solvent gen- 1.27 (t, J = 7.2 Hz, 3 H, CH2CH3), 3.59 (br. s, 2 H, CH2CH3), 3.78
erally afforded an oil, which was either subjected to column
chromatography (diethyl ether/petroleum ether) or crystallized.
(s, 3 H, CH3 OMe), 3.83 (s, 3 H, CH3 OMe), 6.86 (d, J = 8.8 Hz,
2 H, ArH), 7.56 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 12.83 (CH3), 43.49 (CH2), 52.98 (OCH3),
55.27 (OCH3), 105.52 (C), 113.34 (CH), 127.73 (C), 129.63 (CH),
137.33 (C), 161.54 (C), 163.33 (C=O), 169.98 (C=O) ppm.
C14H15Br2NO4 (421.08): calcd. C 39.93, H 3.59, N 3.33; found C
40.38, H 3.86, N 3.33.
Z(NO2)-N(Et)-ΔAla(β,β-Br)-OMe (7a): The general procedure de-
scribed above was followed using Z(NO2)-ΔAla(β,β-Br)-OMe (4a;
0.764 g, 1.745 mmol) as reactant to afford 7a (0.687 g, 85%) as a
1
yellowish oil; m.p. 58.0–59.0 °C (diethyl ether/n-hexane). H NMR
(400 MHz, CDCl3): δ = 1.23 (t, J = 7.2 Hz, 3 H, CH2CH3), 3.57
(q, J = 7.2 Hz, 2 H, CH2CH3), 3.75 (s, 3 H, CH3 OMe), 5.25 [s, 2
H, CH2 Z(NO2)], 7.48 (d, J = 8.8 Hz, 2 H, ArH), 8.23 (d, J =
Z(NO2)-N(Et)-E-ΔAbu(β-Br)-OMe (E-8a): The general procedure
described above was followed using Z(NO2)-E-ΔAbu(β-Br)-OMe
8.8 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 12.89 (E-5a; 0.118 g, 0.315 mmol) as reactant to afford a colorless oil
(CH3), 44.11 (CH2), 52.86 (OCH3), 66.23 [CH2 Z(NO2)], 108.16 (0.119 g) consisting of a mixture of product and reactant in a 80:20
(C), 123.73 (CH), 127.98 (CH), 134.32 (C), 143.42 (C), 147.62 (C),
ratio. Purification by column chromatography (diethyl ether/petro-
153.29 (C=O), 162.83 (C=O) ppm. C14H14Br2N2O6 (466.08): calcd. leum ether) afforded E-8a (0.095 g, 75%) as a white solid; m.p.
Eur. J. Org. Chem. 2011, 6764–6772
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6769

L. S. Monteiro et al.
FULL PAPER
59.0–60.0 °C (diethyl ether/n-hexane). 1H NMR (300 MHz,
CDCl3): δ = 1.19 (t, J = 7.2 Hz, 3 H, CH2CH3), 2.42 (s, 3 H, γCH3),
143.30 (C), 146.02 (C), 164.12 (C=O) ppm. C14H18BrNO4S
(376.27): calcd. C 44.69, H 4.82, N 3.72, S 8.52; found C 45.02, H
3.49 (q, J = 7.2 Hz, 2 H, CH2CH3), 3.73 (s, 3 H, CH3 OMe), 5.23 4.89, N 3.87, S 8.32.
[br. s, 2 H, CH2 Z(NO2)], 7.46 (d, J = 8.7 Hz, 2 H, ArH), 8.22 (d,
Z(NO2)-N(Et)-Z-ΔPhe(β-Br)-OMe (Z-9a): The general procedure
J = 8.7 Hz, 2 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ =
12.84 (CH3), 27.00 (γCH3), 44.43 (CH2), 52.32 (OCH3), 66.03 [CH2
Z(NO2)], 123.73 (CH), 127.88 (CH), 129.45 (C), 132.95 (C), 143.61
(C), 147.57 (C), 154.22 (C=O), 164.00 (C=O) ppm. C15H17BrN2O6
(401.21): calcd. C 44.90, H 4.27, N 6.98; found C 45.23, H 4.40, N
7.07.
described above was followed using Z(NO2)-Z-ΔPhe(β-Br)-OMe
(Z-6a; 0.109 g, 0.250 mmol) as reactant to afford a colorless oil
(0.076 g) consisting of a mixture of product and reactant in a 45:55
ratio. Purification by column chromatography (diethyl ether/petro-
leum ether) afforded Z-9a (0.034 g, 30%) as a yellowish solid; m.p.
117.0–118.0 °C (from ethyl acetate/n-hexane). 1H NMR (400 MHz,
CDCl3): δ = 1.33 (t, J = 7.6 Hz, 3 H, CH2CH3), 3.42 (s, 3 H, CH3
OMe), 3.71 (br. m, 2 H, CH2CH3), 5.28 [s, 2 H, CH2 Z(NO2)],
7.30–7.40 (m, 5 H, ArH), 7.50 (d, J = 8.4 Hz, 2 H, ArH), 8.21 (d,
J = 8.4 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
13.13 (CH2CH3), 43.85 (CH2), 52.26 (OCH3), 66.20 [CH2 Z(NO2)],
123.67 (CH), 127.90 (CH), 128.16 (CH), 128.31 (CH), 129.90 (CH),
131.28 (C), 138.32 (C), 138.60 (C), 143.71 (C), 147.56 (C), 153.89
(C=O), 164.19 (C=O) ppm. C20H19BrN2O6 (463.28): calcd. C
51.85, H 4.13, N 6.05; found C 51.91, H 4.15, N 6.12.
Z(NO2)-N(Et)-Z-ΔAbu(β-Br)-OMe (Z-8a): The general procedure
described above was followed using Z(NO2)-Z-ΔAbu(β-Br)-OMe
(Z-5a; 0.187 g, 0.500 mmol) as reactant to afford a yellowish oil
(0.178 g) consisting of a mixture of product and reactant in a 37:63
product/reactant ratio. Purification by column chromatography (di-
ethyl ether/petroleum ether) afforded Z-8a (0.066 g, 33%) as a col-
orless oil; m.p. 73.0–73.5 °C (diethyl ether/n-hexane). 1H NMR
(300 MHz, CDCl3): δ = 1.20 (t, J = 7.2 Hz, 3 H, CH2CH3), 2.85
(s, 3 H, γCH3), 3.55 (q, J = 7.2 Hz, 2 H, CH2CH3), 3.71 (s, 3 H,
CH3 OMe), 5.21 [s, 2 H, CH2 Z(NO2)], 7.45 (d, J = 8.7 Hz, 2 H,
ArH), 8.19 (d, J = 8.7 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 12.83 (CH3), 26.83 (γCH3), 44.17 (CH2), 52.36
(OCH3), 65.78 [CH2 Z(NO2)], 123.61 (CH), 127.81 (CH), 130.02
(C), 142.90 (C), 143.99 (C), 147.47 (C), 154.00 (C=O), 163.64
(C=O) ppm. C15H17BrN2O6 (401.21): calcd. C 44.90, H 4.27, N
6.98; found C 44.89, H 4.40, N 7.03.
Z-N(Et)-Z-ΔPhe(β-Br)-OMe (Z-9b): The general procedure de-
scribed above was followed using Z-Z-ΔPhe(β-Br)-OMe (Z-6b;
0.133 g, 0.341 mmol) as reactant to afford a colorless oil (0.135 g)
consisting of a mixture of product and reactant in a 38:62 ratio.
Purification by column chromatography (diethyl ether/petroleum
ether) afforded Z-9b (0.051 g, 36%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 1.32 (t, J = 7.5 Hz, 3 H, CH2CH3), 3.33
(s, 3 H, CH3 OMe), 3.72 (q, J = 7.5 Hz, 2 H, CH2CH3), 5.19 (s, 2
H, CH2 Z), 7.30–7.37 (m, 10 H, ArH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 14.08 (CH2CH3), 43.54 (CH2), 52.06 (OCH3), 67.66
(CH2 Z), 127.85 (CH), 127.94 (CH), 128.15 (CH), 128.20 (CH),
128.32 (CH), 129.57 (CH), 131.64 (C), 136.22 (C), 137.43 (C),
138.87 (C), 154.39 (C=O), 164.17 (C=O) ppm. HRMS (ESI): calcd.
for C20H20NNaO4Br 440.04734; found 440.04658.
Z-N(Et)-Z-ΔAbu(β-Br)-OMe (Z-8b): The general procedure de-
scribed above was followed using Z-Z-ΔAbu(β-Br)-OMe (Z-5b;
0.318 g, 0.970 mmol) as reactant to afford a colorless oil (0.322 g)
consisting of a mixture of product and reactant in a 43:57 ratio.
Purification by column chromatography (diethyl ether/petroleum
ether) afforded Z-8b (0.138 g, 40%) as a colorless oil that failed to
crystallize. 1H NMR (300 MHz, CDCl3): δ = 1.19 (t, J = 7.2 Hz, 3
H, CH2CH3), 2.84 (s, 3 H, γCH3), 3.52 (q, J = 7.2 Hz, 2 H,
CH2CH3), 3.59 (s, 3 H, CH3 OMe), 5.22 (s, 2 H, CH2 Z), 7.28–
7.39 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 12.91
(CH3), 26.74 (γCH3), 43.95 (CH2), 52.12 (OCH3), 67.19 (CH2 Z),
127.72 (CH), 127.84 (CH), 128.31 (CH), 130.30 (C), 136.50 (C),
142.11 (C), 154.53 (C=O), 163.82 (C=O) ppm. HRMS (ESI): calcd.
for C15H18NNaO4Br 378.03169; found 378.03114.
Attempted Synthesis of Boc-N(Et)-Z-ΔPhe(β-Br)-OMe (Z-9c): The
general procedure described above was followed using Boc-Z-
ΔPhe(β-Br)-OMe (Z-6c; 0.178 g, 0.500 mmol) as reactant to afford
a colorless oil (0.175 g) consisting of a mixture of product and reac-
tant in a 15:85 ratio that could not be separated.
Nosyl-N(Et)-Z-ΔPhe(β-Br)-OMe (Z-9f): The general procedure de-
scribed above was followed using Nosyl-Z-ΔPhe(β-Br)-OMe (Z-6f;
0.309 g, 0.700 mmol) as reactant to afford Z-9f (0.294 g, 90%) as
a colorless oil; m.p. 118.0–119.0 °C (ethyl acetate/n-hexane). 1H
NMR (300 MHz, CDCl3): δ = 1.37 (t, J = 7.2 Hz, 3 H, CH2CH3),
3.41 (s, 3 H, CH3 OMe), 3.66 (br. m, 2 H, CH2CH3), 7.31–7.41 (m,
5 H, ArH), 8.14 (d, J = 8.7 Hz, 2 H, ArH Nosyl), 8.39 (d, J =
8.7 Hz, 2 H, ArH Nosyl) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
14.06 (CH2CH3), 44.74 (CH2), 52.39 (OCH3), 124.02 (CH), 128.13
(CH), 128.34 (CH), 129.13 (CH), 129.19 (C), 130.20 (CH), 138.47
(C), 142.26 (C), 145.35 (C), 150.17 (C), 164.58 (C=O) ppm.
C18H17BrN2O6S (469.31): calcd. C 46.07, H 3.65, N 5.97, S 6.83;
found C 45.98, H 3.72, N 5.98, S 6.85.
Nosyl-N(Et)-Z-ΔAbu(β-Br)-OMe (Z-8f): The general procedure de-
scribed above was followed using Nosyl-Z-ΔAbu(β-Br)-OMe (Z-5f;
0.081 g, 0.214 mmol) as reactant to afford Z-8f (0.081 g, 93%) as
a light-yellow solid; m.p. 108.0–109.0 °C (diethyl ether/n-hexane).
1H NMR (300 MHz, CDCl3): δ = 1.23 (t, J = 7.2 Hz, 3 H,
CH2CH3), 2.85 (s, 3 H, γCH3), 3.58 (br. m, 2 H, CH2CH3), 3.67
(s, 3 H, CH3 OMe), 8.04 (d, J = 8.7 Hz, 2 H, ArH), 8.35 (d, J =
8.7 Hz, 2 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 13.82
(CH2CH3), 27.64 (γCH3), 45.20 (CH2), 52.43 (OCH3), 123.91
(CH), 128.11 (C), 128.96 (CH), 145.74 (C), 147.09 (C), 149.99 (C),
163.72 (C=O) ppm. C13H15BrN2O6S (407.24): calcd. C 38.34, H
3.71, N 6.88, S 7.87; found C 38.76, H 3.85, N 6.92, S 7.85.
Tos-N(Et)-Z-ΔPhe(β-Br)-OMe (Z-9g): The general procedure de-
scribed above was followed using Tos-Z-ΔPhe(β-Br)-OMe (Z-6g;
0.205 g, 0.500 mmol) as reactant to afford Z-9g (0.194 g, 89%) as a
colorless oil; m.p. 99.0–100.0 °C (diethyl ether/n-hexane). 1H NMR
(300 MHz, CDCl3): δ = 1.33 (t, J = 7.2 Hz, 3 H, CH2CH3), 2.45
Tos-N(Et)-Z-ΔAbu(β-Br)-OMe (Z-8g): The general procedure de-
scribed above was followed using Tos-Z-ΔAbu(β-Br)-OMe (Z-5g;
0.085 g, 0.244 mmol) as reactant to afford Z-8g (0.072 g, 78%) as
a colorless oil; m.p. 93.0–94.0 °C (diethyl ether/n-hexane). 1H NMR
(400 MHz, CDCl3): δ = 1.19 (t, J = 7.2 Hz, 3 H, CH2CH3), 2.43 (s, 3 H, CH3 Tos), 3.39 (s, 3 H, CH3 OMe), 3.62 (br. q, J = 7.2 Hz,
(s, 3 H, CH3 Tos), 2.82 (s, 3 H, γCH3), 3.46 (br. m, 2 H, CH2CH3), 2 H, CH2CH3), 7.31–7.38 (m, 7 H, ArH), 7.83 (d, J = 8.4 Hz, 2 H,
3.60 (s, 3 H, CH3 OMe), 7.29 (d, J = 8.8 Hz, 2 H, ArH), 7.73 (d, ArH Tos) ppm. 13C NMR (75.4 MHz, CDCl3):
δ
=
14.00
J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
(CH2CH3), 21.57 (Tos CH3), 44.11 (CH2), 52.16 (OCH3), 127.88
13.79 (CH2CH3), 21.51 (Tos CH3), 27.45 (γCH3), 44.63 (CH2), (CH), 128.17 (CH), 128.21 (CH), 129.36 (CH), 129.82 (CH), 129.90
52.10 (OCH3), 127.76 (CH), 128.51 (C), 129.23 (CH), 137.23 (C), (C), 136.80 (C), 138.86 (C), 140.48 (C), 143.63 (C), 164.89
6770
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6764–6772

Synthesis of New N-Ethyl Dehydroamino Acid Derivatives
(C=O) ppm. C19H20BrNO4S (438.34): calcd. C 52.06, H 4.60, N
3.20, S 7.32; found C 51.97, H 4.53, N 3.25, S 7.35.
Acknowledgments
The Portuguese Foundation for Science and Technology (FCT) and
the Fundo Europeu de Desenvolvimento Regional (FEDER) are
thanked for financial support to the Chemistry Centre of Univer-
sity of Minho. The Bruker Avance II+ 400 NMR spectrometer is
part of the National NMR Network and was purchased in the
framework of the National Program for Scientific Re-equipment,
REDE/1517/RMN/2005, with funds from POCI 2010, FEDER
and FCT.
Suzuki Cross-Coupling of the Methyl Esters of N-Protected N-Ethyl
β-Bromo α,β-Dehydroamino Acids with Phenylboronic Acid
General Procedure: To a solution of the methyl ester of N-protected
N-ethyl β-bromo α,β-dehydroamino acid in THF/H2O (1:1,
0.05 moldm–3), phenylboronic acid (1.5 equiv.), [PdCl2dppf]·
CH2Cl2 (1:1, 10 mol-%), and Cs2CO3 (1.4 equiv.) were added. The
reaction mixture was heated at 90 °C and the reaction was moni-
tored by TLC until all the N-ethyl β-brominated dehydroamino
acid derivative was consumed (1–3 h). The solvent was removed
under reduced pressure, and the residue was dissolved in ethyl acet-
ate (100 mL). The organic layer was washed with water (2ϫ30 mL)
and brine (2ϫ30 mL), dried with MgSO4, and the solvent was re-
moved. The residue was purified by column chromatography (di-
ethyl ether/petroleum ether).
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Z(NO2)-N(Et)-ΔPhe(β-C6H5)-OMe (10a): The general procedure
described above was followed using Z(NO2)-N(Et)-ΔAla(β,β-Br)-
OMe (7a; 0.093 g, 0.200 mmol) and phenylboronic acid (3.0 equiv.)
as reactant to afford 10a (0.075 g, 81%) as a colorless oil; m.p.
92.0–93.0 °C (diethyl ether/n-hexane). 1H NMR (300 MHz,
DMSO): δ = 1.00 (t, J = 7.2 Hz, 3 H, CH2CH3), 3.02 (br. m, 2 H,
CH2CH3), 3.32 (s, 3 H, CH3 OMe), 5.26 [s, 2 H, CH2 Z(NO2)],
7.06–7.11 (m, 4 H, ArH), 7.34–7.37 (m, 6 H, ArH), 7.58 (d, J =
8.7 Hz, 2 H, ArH), 8.22 (d, J = 8.7 Hz, 2 H, ArH) ppm. 13C NMR
(100.6 MHz, DMSO): δ = 12.79 (CH3), 43.37 (CH2), 51.58 (OCH3),
65.87 [CH2 Z(NO2)], 123.53 (CH), 127.94 (CH), 128.06 (CH),
128.18 (CH), 128.51 (CH), 128.67 (CH), 128.83 (CH), 129.01 (CH),
139.19 (C), 139.84 (C), 143.94 (C), 144.39 (C), 145.84 (C), 147.12
(C), 154.29 (C=O), 166.89 (C=O) ppm. C26H24N2O6 (460.48):
calcd. C 67.82, H 5.25, N 6.08; found C 67.74, H 5.27, N 6.13.
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Z-N(Et)-ΔAbu(β-C6H5)-OMe (Z-10b): The general procedure de-
scribed above was followed using Z-N(Et)-Z-ΔAbu(β-Br)-OMe (Z-
8b; 0.122 g, 0.344 mmol) as reactant to afford Z-10b (0.060 g, 50%)
as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 0.85 (t, J =
7.2 Hz, 3 H, CH2CH3), 2.46 (s, 3 H, γCH3), 3.50 (br. s, 2 H,
CH2CH3), 3.53 (s, 3 H, CH3 OMe), 5.18 (s, 2 H, CH2 Z), 7.28–
7.39 (m, 10 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
12.53 (CH3), 21.66 (γCH3), 44.53 (CH2), 51.59 (OCH3), 67.18 (CH2
Z), 126.83 (CH), 127.68 (CH), 127.84 (CH), 128.03 (CH), 128.35
(CH), 128.44 (CH), 136.67 (C), 141.18 (C), 148.07 (C), 155.65 (C),
156.31 (C=O), 166.43 (C=O) ppm. HRMS (ESI): calcd. for
C21H23NNaO4 376.15248; found 376.15193.
Z(NO2)-N(Et)-ΔPhe(β-C6H5)-OMe (10a): The general procedure
described above was followed using Z(NO2)-N(Et)-Z-ΔPhe(β-Br)-
OMe (Z-9a; 0.093 g, 0.200 mmol) as reactant to afford 10a
(0.058 g, 63%).
Nosyl-N(Et)-ΔPhe(β-C6H5)-OMe (10f): The general procedure de-
scribed above was followed using Nosyl-N(Et)-ΔPhe(β-Br)-OMe
(Z-9f; 0.215 g, 0.458 mmol) as reactant to afford 10f (0.203 g, 95%)
as a white solid; m.p. 155.0–156.0 °C (ethyl acetate/n-hexane). 1H
NMR (300 MHz, CDCl3): δ = 1.03 (t, J = 7.2 Hz, 3 H, CH2CH3),
3.00 (br. m, 2 H, CH2CH3), 3.40 (s, 3 H, CH3 OMe), 7.12–7.16 (m,
2 H, ArH), 7.30–7.37 (m, 8 H, ArH), 8.05 (d, J = 9.0 Hz, 2 H,
ArH Nosyl), 8.34 (d, J = 9.0 Hz, 2 H, ArH Nosyl) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 13.08 (CH2CH3), 43.27 (CH2), 51.96
(OCH3), 123.89 (CH), 124.76 (C), 128.22 (CH), 128.36 (CH),
128.82 (CH), 129.03 (CH), 129.23 (CH), 123.47 (CH), 129.59 (CH),
138.65 (C), 140.46 (C), 144.81 (C), 150.10 (C), 150.73 (C), 167.77
(C=O) ppm. C24H22N2O6S (466.51): calcd. C 61.79, H 4.75, N 6.00,
S 6.87; found C 61.67, H 4.90, N 6.00, S 6.70.
Eur. J. Org. Chem. 2011, 6764–6772
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6771

L. S. Monteiro et al.
FULL PAPER
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Received: June 21, 2011
Published Online: September 19, 2011
6772
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6764–6772