Synthesis and electrochemical behaviour of β-halodehydroamino acid derivatives

Article abstract of DOI:10.1007/s00726-009-0466-x

Several new β,β-dihalo and β-halo-β-substituted dehydroalanines and dehydrodipeptides were synthesized by reacting the corresponding dehydroamino acid derivative with a N-halosuccinimide or in the case of β,β-di-iododehydroalanines with iodine. The results obtained confirmed that the stereochemical outcome of the halogenation reaction with β-substituted dehydroamino acids depends on the substrate. Thus, an increase Z-stereoselectivity was found when the β-phenyldehydroalanines were used as substrates and when these compounds were N-protected with 4-tolylsulfonyl or with carbamates. From this study, it is also possible to conclude that when N-iodosuccinimide was used as reagent a much higher Z-stereoselectivity is found. The electrochemical behaviour of the halogenated dehydroamino acids was studied by cyclic voltammetry. The results show a shift in the reduction peak to higher potentials of the β-halogenated dehydroamino acids when compared with the corresponding non-halogenated derivatives. As expected, the β,β-dihalodehydroalanines exhibit higher peak potentials than β-halo-β-substituted dehydroalanines and the bromo derivatives have lower peak potentials when compared with the corresponding iododehydroamino acids. Controlled potential electrolysis of several β-halo-β-substituted dehydroamino acids afforded the corresponding dehalogenated dehydroamino acids as mixtures of their E and Z-isomers. In all cases, the major isomer isolated results from dehalogenation without isomerization. These new results show that electrochemical reduction constitutes a valuable method for the synthesis of the E-isomer of β-substituted dehydroalanines. Springer-Verlag 2010.

Full text of DOI:10.1007/s00726-009-0466-x

Amino Acids (2010) 39:499–513
DOI 10.1007/s00726-009-0466-x
ORIGINAL ARTICLE
Synthesis and electrochemical behaviour of b-halodehydroamino
acid derivatives
•
Paula M. T. Ferreira L. S. Monteiro
•
G. Pereira
Received: 5 November 2009 / Accepted: 24 December 2009 / Published online: 2 March 2010
Ó Springer-Verlag 2010
Abstract Several new b,b-dihalo and b-halo-b-substi-
tuted dehydroalanines and dehydrodipeptides were syn-
thesized by reacting the corresponding dehydroamino acid
derivative with a N-halosuccinimide or in the case of b,b-
di-iododehydroalanines with iodine. The results obtained
confirmed that the stereochemical outcome of the haloge-
nation reaction with b-substituted dehydroamino acids
depends on the substrate. Thus, an increase Z-stereoselec-
tivity was found when the b-phenyldehydroalanines were
used as substrates and when these compounds were
N-protected with 4-tolylsulfonyl or with carbamates. From
this study, it is also possible to conclude that when
N-iodosuccinimide was used as reagent a much higher
Z-stereoselectivity is found. The electrochemical behaviour
of the halogenated dehydroamino acids was studied by
cyclic voltammetry. The results show a shift in the
reduction peak to higher potentials of the b-halogenated
dehydroamino acids when compared with the correspond-
ing non-halogenated derivatives. As expected, the b,b-di-
halodehydroalanines exhibit higher peak potentials than
b-halo-b-substituted dehydroalanines and the bromo
derivatives have lower peak potentials when compared
with the corresponding iododehydroamino acids. Con-
trolled potential electrolysis of several b-halo-b-substituted
dehydroamino acids afforded the corresponding dehalo-
genated dehydroamino acids as mixtures of their E and
Z-isomers. In all cases, the major isomer isolated results
from dehalogenation without isomerization. These new
results show that electrochemical reduction constitutes
a valuable method for the synthesis of the E-isomer of
b-substituted dehydroalanines.
Keywords Dehydroamino acid Á N-halosuccinimides Á
Iodine Á Cyclic voltammetry Á Electrolysis
Introduction
b-Halogenated dehydroamino acid derivatives constitute
valuable building blocks in peptide chemistry for the
synthesis of new amino acids. In the literature, there are
several reports describing the halogenation of dehydroa-
mino acids (Danion-Bougot et al. 1990; Coleman and
Carpenter 1993; Yamada et al. 1996; Hoerner et al. 1998;
Silva et al. 2002, 2003; Abreu et al. 2003a, b, 2004; Roff
et al. 2004; Ferreira and Monteiro 2006; Ferreira et al. 2007,
2008a b). Danion-Bougot et al. (1990) reacted a N-acetyl
dehydrophenylalanine with N-bromosuccinimide (NBS) to
give the corresponding brominated imine, which was con-
verted into the b-bromodehydrophenylalanine by treatment
with triethylamine (NEt3). Coleman and Carpenter (1993)
examined the characteristics of dehydroamino acids that
affect the stereoselectivity of bromination. These authors
not only proved the proposed mechanism for the bromina-
tion reaction of this type of compounds with NBS, but also
reported an enhanced Z-stereoselectivity as the size of the
b-alkyl group increased and when an amide was used as
N-protecting group instead of a carbamate. Yamada et al.
(1996) studied the bromination of N-formyldehydroamino
acids and found that substrates with bulky substituents like
isopropyl or 1-ethylpropyl at the b-position showed a pro-
pensity to undergo highly Z-selective bromination. In con-
trast, non-selective bromination occurred with substrates
P. M. T. Ferreira (&) Á L. S. Monteiro (&) Á G. Pereira
Department of Chemistry, University of Minho, Gualtar,
4710-057 Braga, Portugal
e-mail: pmf@quimica.uminho.pt
L. S. Monteiro
e-mail: monteiro@quimica.uminho.pt
123

500
P. M. T. Ferreira et al.
with less bulky substituents such as methyl or ethyl. The
size of the ester groups also affected the selectivity of
bromination and it was found that as the size of the ester
group increased a significantly higher Z-selectivity was
observed. Hoerner et al. (1998) prepared a N-acetyl-b-
bromodehydroaminobutyric acid derivative by treating the
corresponding dehydroamino acid with N-bromosuccini-
mide followed by triethylamine. The brominated compound
was obtained in 83% yield as a 1/1 mixture of the E/Z-
isomers. Replacing the N-protecting group by a benzyl-
oxycarbonyl group an increased stereoselectivity towards
the Z-isomer was found (E/Z-isomers 1/6). The iodination
of the latter with N-iodosuccinimide (NIS) gave mainly the
Z-isomer (E/Z-isomers 1/15). Roff et al. (2004) reported
the synthesis of a b-iododehydroamino acid derivative as
1/1 mixture of E/Z isomers by treatment of the methyl
Z-2-(N-acetylamino)but-2-enoate with NIS followed by
NEt3. Adding to the reaction mixture 2% of TFA,
Z-selectivity was increased (E/Z-isomers 1/5).
mass spectrometry service of the University of Vigo,
Spain; elemental analysis was performed on a LECO
CHNS 932 elemental analyser.
The reactions were monitored by thin layer chroma-
tography (TLC). Column chromatography was performed
on Macherey-Nagel silica gel 230–400 mesh. Petroleum
ether refers to the boiling range 40–60°C. When solvent
gradient was 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 the
isolation of the product.
Cyclic voltammetry experiments were carried out using a
Hi-Tek potentiostat type DT 2101, and a Hi-Tek wave gen-
erator type PPRl, connected to a Philips recorder type PM
8043 and to a three electrode, home-built glass cell. For
controlled potential electrolyses the electrochemical cell was
a conventional two-compartment, three-electrode, home-built
batch cell of the type illustrated elsewhere (Grehn et al. 1988).
In our research group, we have been interested in the
synthesis of dehydroamino acid derivatives (Ferreira et al.
1998, 1999, 2007) and in their use as substrates in several
types of reactions, namely addition and substitution reac-
tions and palladium catalyzed cross-couplings. Thus, several
b,b-dibromodehydroalanine, b-bromodehydroaminobutyric
acid and b-bromodehydrophenylalanine derivatives were
prepared by treating the corresponding dehydroamino acid
with NBS followed by NEt3 (Silva et al. 2002, 2003; Abreu
et al. 2003a, b, 2004; Ferreira and Monteiro 2006; Ferreira
et al. 2007, 2008a, b). Continuing this work on the prepara-
tion of halogenated dehydroamino acids, it was decided to
expand the scope of the bromination reaction to other
dehydroamino acid derivatives and to other N-halosuccini-
mides in order to prepare new halogenated compounds. The
electrochemical behaviour of the halodehydroamino acid
derivatives was also investigated by cyclic voltammetry and
compared with that of the corresponding dehydroamino
acids. Controlled potential electrolysis of the b-halodehyd-
roamino acids were carried out giving the corresponding
dehalogenated dehydroamino acids as E/Z mixtures.
Synthesis of the methyl esters of N-acylamino acids
Synthesis of compounds 2-Fur-L-Ser-OMe (1a) (Ferreira
et al. 2008a, b), 1-Naph-L-Ser-OMe (1b) (Ferreira et al.
2008a, b), Bz(4-OMe)-L-Ser-OMe (1c) (Ferreira et al.
2008a, b), Bz-L-Ser-OMe (1d) (Fry 1950), Z-L-Ser-OMe
(1f) (Hassall et al. 1968), Boc-L-Ser-OMe (1g) (Ferreira
et al. 1999), 2-Fur-L-Thr-OMe (5a) (Ferreira et al. 2008a, b),
Bz(4-OMe)-L-Thr-OMe (5c) (Ferreira et al. 2008a, b), Bz-
L-Thr-OMe (5d) (Ferreira et al. 2008a, b), Tos-L-Thr-OMe
(5e) (Ferreira et al. 1999), Z-L-Thr-OMe (5f) (Ferreira et al.
1999), Boc-L-Thr-OMe (5g) (Ferreira et al. 1999), 2-Fur-
D,L-Phe(b-OH)-OMe (6a) (Ferreira et al. 2008a, b),
Bz-D,L-Phe(b-OH)-OMe (6d) (Ferreira et al. 2008a, b),
Tos-D,L-Phe(b-OH)-OMe (6e) (Ferreira et al. 2003a, b).
The synthesis of these compounds was described in the
references given above.
General procedure for the synthesis of the methyl esters
of N-acylamino acids
To a solution of b-hydroxyamino acid methyl ester
hydrochloride (5 mmol) in dichloromethane (0.1 mol
dm-3), 2.2 eq. of triethylamine were added, then 1.1 eq. of
the respective acyl chloride was slowly added with vigor-
ous 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 parti-
tioned between 200 cm3 of ethyl acetate and 100 cm3
of KHSO4 (1 mol dm-3) and washed with KHSO4
(1 mol dm-3), NaHCO3 (1 mol dm-3) and brine (3 times,
50 cm3 each). After drying over MgSO4, the extract was
taken to dryness at reduced pressure to afford the respec-
tive N-acylamino acid methyl ester.
Materials and methods
Melting points (°C) were determined in a Gallenkamp
apparatus and are uncorrected. H and 13C NMR spectra
1
were recorded on a Varian Unity Plus at 300 and
75.4 MHz, respectively, or on a Bruker Avance II? at 400
and 100.6 MHz, respectively. 1H–1H spin-spin decoupling,
DEPT h 45°, HMQC and HMBC were used to attribute
some signals. NOE difference experiments were also per-
formed. Chemical shifts are given in ppm and coupling
constants in Hz. MS and HRMS data were recorded by the
123

Synthesis and electrochemical behaviour of b-halodehydroamino acid derivatives
501
1
Synthesis of Bz(4-OMe)-D,L-Phe(b-OH)-OMe (6c) The
general procedure described above using HCl.H-D,L-
Phe(b-OH)-OMe (1.158 mg, 5.0 mmol) and 4-methoxy-
benzoyl chloride as substrates was followed to give 6c
(1.04 g, 63%) as a white solid. M.p. 113.0–114.0°C (from
ethyl acetate/n-hexane). 1H NMR (300 MHz, CDCl3): 7.36
(d, J = 9.0 Hz, 2H, ArH), 7.24–7.39 (m, 5H, ArH), 6.98
(d, J = 8.7 Hz, 1H, NH), 6.83 (d, J = 9.0 Hz, 2H, ArH),
5.34 (d, J = 3.3 Hz, 1H, bCH), 5.03 (dd, J = 8.7 Hz,
J = 3.3 Hz, 1H, aCH), 3.80 (s, 3H, OCH3), 3.72 (s, 3H,
OCH3), 3.42 (br s, 1H, OH) ppm. 13C NMR (75.4 MHz,
CDCl3): 171.12 (C=O), 167.26 (C=O), 162.34 (C), 139.75
(C), 128.95 (CH), 128.32 (CH), 127.96 (CH), 125.75 (CH),
113.64 (29 CH), 73.66 (aCH), 58.58 (bCH), 55.31
(OCH3), 52.57 (OCH3) ppm. Anal. Calcd for C18H19NO5
(329.35): C 65.64, H 5.81, N 4.25; found C 65.57, H 5.71,
N 4.37.
ether). H NMR (300 MHz, CDCl3): 7.20–7.27 (m, 5H,
ArH), 6.99 (d, J = 9.0 Hz, 1H, NH Thr), 5.26 (d,
J = 7.5 Hz, 1H, NH Phe), 4.59 (m, 1H, bCH Thr), 4.27–
4.30 (m, 1H, aCH Thr), 3.71 (s, 3H, OCH3), 3.45 (m, 1H,
aCH Phe), 2.97–3.17 (m, 2H, bCH2 Phe), 1.38 (s, 9H, CH3
Boc), 1.15 (d, J = 6.6 Hz, 3H, cCH3 Thr) ppm. 13C NMR
(75.4 MHz, CDCl3): 171.97 (C=O), 171.08 (C=O), 155.56
(C=O), 136.48 (C), 129.32 (CH), 128.42 (CH), 126.77
(CH), 80.21 (C), 68.13 (aCH Thr), 57.35 (bCH Thr), 55.68
(aCH Phe), 52.47 (OCH3), 38.02 (bCH2 Phe), 28.17
[C(CH3)3], 19.69 (cCH3 Thr) ppm. HRMS (EI): calcd. for
C19H28N2NaO6 403.18451; found 403.18347.
Synthesis of Boc-L-Val-L-Thr-OMe (5j) The general
procedure described above using Boc-L-Val-OH (4.34 g,
20 mmol) and HCl,H-L-Thr-OMe (3.39 g, 20 mmol) as
1
substrates gave compound 5j (6.00 g, 90%) as an oil. H
NMR (400 MHz, CDCl3): 7.03 (d, J = 7.6 Hz, 1 H, NH-
Thr), 5.28 (d, J = 8.4 Hz, 1 H, NH-Val), 4.62 (dd, J = 2.4
and 2.8 Hz, 1H, aCH-Thr), 4.32–4.38 (m, 1H, bCH-Thr),
3.93 (t, J = 7.6 Hz, 1 H, aCH-Val), 3.76 (s, 3 H, OCH3),
2.04–2.10 (m, 1 H, bCH-Val), 1.42 (s, 9 H, CH3-Boc), 1.19
(d, J = 6.4 Hz, cCH3-Thr), 0.95–0.99 (m, 6 H, cCH3-Val)
ppm. 13C NMR (100.6 MHz, CDCl3): 172.42 (C=O),
171.24 (C=O), 156.10 (C=O), 80.04 (C), 68.09 (bCH-Thr),
60.19 (aCH-Val), 57.31 (aCH-Thr), 52.45 (OCH3), 30.77
(bCH-Val), 28.24 [C(CH3)3], 19.79 (cCH3-Thr),
19.11(cCH3-Val), 18.08 (cCH3-Val) ppm. HRMS (EI):
calcd. for C15H28N2NaO6 355.18451; found 355.18351.
Synthesis of Boc-D,L-Phe(b-OH)-OMe (6g) The general
procedure described above using HCl.H-D,L-Phe(b-OH)-
OMe (1.158 mg, 5.0 mmol) and di-tert-butylpyrocarbonate
as substrates was followed to give 6g (1.34 g, 91%). M.p.
74.0–75.0°C (from diethyl ether/petroleum ether). 1H
NMR (300 MHz, CDCl3): 7.22–7.42 (m, 5H, ArH) 5.42 (d,
J = 8.4 Hz, 1H, NH), 5.21 (br s, 1H, bCH), 4.51 (br s, 1H,
aCH), 3.73 (s, 3 H, OCH3), 3.35 (sl, 1H, bOH), 1.31 (s, 9H,
CH3 Boc) ppm. 13C NMR (75.4 MHz, CDCl3): 171.40
(C=O), 155.57 (C=O), 146.65 (C), 139.80 (CH), 128.20
(CH), 127.81 (CH), 125.89 (CH), 85.14 (C), 73.62 (CH2),
59.39 (CH), 52.45 (OCH3), 27.29 [C(CH3)3] ppm. Anal.
Calcd for C15H21NO5 (295.34): C 61.00, H 7.17, N 4.74;
found C 60.78, H 7.19, N 4.79.
Synthesis of Boc-L-Phe-D,L-Phe(b-OH)-OMe (6i) The
general procedure described above using Boc-L-Phe-OH
(5.30 g, 20 mmol) and HCl,H-D,L-Phe(b-OH)-OMe
(4.63 g, 20 mmol) as substrates gave compound 6i as a
white solid (8.00 g, 91%). M.p.113.0–114.0°C (from
dichloromethane/petroleum ether). 1H NMR (400 MHz,
CDCl3): 7.18–7.28 (m, 9H, ArH), 7.13 (d, J = 6.8 Hz, 1H,
ArH), 6.96 [br s, 1 H, NH Phe(b-OH)], 5.22 and 5.26 [br s
and d, J = 3.2 Hz, 1H, bCH Phe(b-OH)], 5.01 and 5.06 (d
and br s, J = 5.4 Hz, 1H, NH Phe), 4.83–4.88 [m, 1H, aCH
Phe(b-OH)], 4.38 (d, J = 14.8 Hz, 1H, aCH Phe), 3.66 and
3.71 (s, 3H, OCH3), 2.76–3.02 (m, 2H, bCH2 Phe), 1.37 (s,
9H, CH3 Boc) ppm. 13C NMR (100.6 MHz, CDCl3):
171,57 and 171.74 (C=O), 170.49 and 170.82 (C=O),
155.37 (C=O), 139.52 and 139.60 (C), 136.31 and 136.51
(C), 129.24 (CH), 128.38 and 128.46 (CH), 128.26 (CH),
127.97 and 128.04 (CH), 126.69 and 126.72 (CH), 125.79
and 125.90 (CH), 80.09 [OC(CH3)3], 73.33 and 73.71
[bCH Phe(b-OH)], 58.20 and 58.33 [aCH Phe(b-OH)],
55.07 and 55.50 (aCH Phe), 52.47 and 52.57 (OCH3),
38.12 (bCH2 Phe), 28.15 [C(CH3)3] ppm. HRMS
(EI): calcd. for C24H30N2NaO6 465.20016; found
465.19884.
Synthesis of the methyl esters of N-acyldipeptides
Synthesis of compounds Boc-Gly-L-Thr-OMe (5h)
(Ferreira et al. 2007) and Boc-Gly-D,L-Phe(b-OH)-OMe
(6h) (Ferreira et al. 2007).
The synthesis of these compounds was described in the
references given above.
General procedure for the synthesis of the methyl esters
of N-acyldipeptides
In all cases, the N-protected amino acid was reacted with
the respective amino acid methyl ester in acetonitrile using
the standard DCC/HOBt procedure.
Synthesis of Boc-L-Phe-L-Thr-OMe (5i) The general
procedure described above using Boc-L-Phe-OH (5.30 g,
20 mmol) and HCl, H-L-Thr-OMe (2.23 g, 20 mmol) as
substrates gave compound 5i as a white solid (6.84 g,
90%). M.p. 122.0–123.0°C (from ethyl acetate/petroleum
123

502
P. M. T. Ferreira et al.
(d J = 6.6 Hz, 3H, CH3 Val) ppm. 13C NMR (75.4 MHz,
CDCl3): 170.24 (C=O), 164.70 (C=O), 155.93 (C=O),
134.45 (CH), 125.96 (C), 79.95 [C(CH3)3], 60.00 (CH),
52.19 (OCH3), 30.75 (CH), 28.21 [C(CH3)3], 17.69 (CH3),
14.45 (CH3) ppm Anal. Calcd for C15H26N2O5 (314.18): C
57.31, H 8.34, N 8.91; found C 57.34, H 8.15, N 8.86.
Synthesis of the methyl esters of N-acyldehydroamino
acids and of N-acyldehydrodipeptides
Synthesis of compounds 2-Fur-DAla-OMe (2a) (Ferreira
et al. 2008a, b), 1-Naph-DAla-OMe (2b) (Ferreira et al.
2008a, b), Bz(4-OMe)-DAla-OMe (2c) (Ferreira et al.
2008a, b), Bz-DAla-OMe (2d) (Ferreira et al. 2008a, b),
Z-DAla-OMe (2f) (Bertj et al. 1992), Boc-DAla-OMe (2g)
(Ferreira et al. 1999), 2-Fur-Z-DAbu-OMe (7a) (Ferreira
et al. 2008a, b), Bz(4-OMe)-Z-DAbu-OMe (7c) (Ferreira
et al. 2008a, b), Bz-Z-DAbu-OMe (7d) (Ferreira et al.
2008a, b), Tos-Z-DAbu-OMe (7e) (Ferreira et al. 2007),
Z-Z-DAbu-OMe (7f) (Ferreira et al. 1999), Boc-Z-DAbu-
OMe (7g) (Ferreira et al. 1999), Boc-Gly-Z-DAbu-OMe
(7h) (Ferreira et al. 2007), Boc-L-Phe-Z-DAbu-OMe (7i)
(Ferreira et al. 2008a, b), 2-Fur-Z-DPhe-OMe (8a) (Ferre-
ira et al. 2008a, b), Bz-Z-DPhe-OMe 8d) (Ferreira et al.
2008a, b), Tos-Z-DPhe-OMe (8e) (Ferreira et al. 2007),
Boc-Z-DPhe-OMe (8g) (Ferreira et al. 2001) and Boc-Gly-
Z-DPhe-OMe (8h) (Ferreira et al. 2007).
Synthesis of Bz(4-OMe)-Z-DPhe-OMe (8c) The general
procedure described above using 6c (0.659 g, 2.0 mmol) as
substrate was followed to give 8c (0.523 g, 84%). M.p.
178.0–179.0°C (from diethyl ether/n-hexane). 1H NMR
(300 MHz, CDCl3): 7.84 (d, J = 9.0 Hz, 2H, ArH), 7.74
(br s, 1H, NH), 7.48–7.51 (m, 2H, ArH), 7.43 (s, 1H, bCH),
7.30–7.35 (m, 3H ArH), 6.95 (d, J = 9.0 Hz, 2H, ArH),
3.87 (s, 3H, OCH3), 3.85 (s, 3H, OCH3) ppm. 13C NMR
(75.4 MHz, CDCl3): 165.95 (C) 165.20 (C), 162.73 (C),
133.88 (C), 131.23 (CH), 129.61 (CH), 129.42 (CH),
129.33 (CH), 128.57 (CH), 125.73 (C), 124.49 (C), 113.90
(CH), 55.42 (OCH3), 52.70 (OCH3) ppm. Anal. Calcd for
C18H17NO4 (311.34): C 69.44, H 5.50, N 4.50; found C
69.34, H 5.47, N 4.65.
The synthesis of these compounds was described in the
references given above.
Synthesis of Boc-L-Phe-Z-DPhe-OMe (8i) The general
procedure described above using 6i (4.42 g, 10 mmol) as
substrate gave compound 8i as a white solid (4.00 g, 94%).
M.p.116.0–117.0°C (from diethyl ether/petroleum ether).
1H NMR (300 MHz, CDCl3): 7.77 (br s, 1H, NH DPhe),
7.38–7.23 (m, 11H, ArH and bCH DPhe), 5.06 (d,
J = 6.9 Hz, 1H, NH Phe), 4.54 (d, J = 6.6 Hz, 1H, aCH
Phe), 3.81 (s, 3H, OCH3), 3.02–3.25 (m, 2H, bCH2 Phe),
1.40 (s, 9H, CH3 Boc) ppm. 13C NMR (75.4 MHz, CDCl3):
170.19 (C=O), 165.30 (C=O), 155.59 (C=O), 136.40 (C),
133.39 (bCH DPhe), 132.66 (C), 129.67 (CH), 129.42
(CH), 129.34 (CH), 128.63 (CH), 128.54 (CH), 126.92
(CH), 80.48 [OC(CH3)3], 55.87 (aCH Phe), 52.57 (OCH3),
37.44 (bCH2 Phe), 28.19 [C(CH3)3] ppm. Anal. Calcd for
C24H28N2O5 (424.20): C 67.91, H 6.65, N 6.60; found C
67.49, H 6.71, N 6.52.
General procedure for the synthesis of the methyl esters of
N-acyldehydroamino acids and of N-
acyldehydrodipeptides
To a solution of the methyl ester of the N-acylamino acid
or dipeptide (2 mmol) in dry acetonitrile (1 mol dm-3), 0.1
equiv. of DMAP was added followed by 1.0 equiv. of
di-tert-butyl dicarbonate under rapid stirring at room tem-
perature. The reaction was monitored by TLC (diethyl
ether/n-hexane, 1/1) until all the reactant had been con-
sumed. Then 2% in volume of TMG was added and stirring
was continued and the reaction followed by TLC. When all
reactant was consumed evaporation at reduced pressure
gave a residue that was partitioned between 100 cm3 of
diethyl ether and 30 cm3 of KHSO4 (1 mol dm-3). The
organic phase was thoroughly washed with KHSO4
(1 mol dm-3), NaHCO3 (1 mol dm-3) and saturated brine
(2 9 30 cm3 each), and dried over MgSO4. Removal of the
solvent afforded the respective N-acyldehydroamino acid
or N-acyldehydrodipeptide methyl ester.
Synthesis of the methyl esters of N-acyl-b,b-di-bromo-
dehydroamino acids
Synthesis of compounds Z-DAla(b,b-Br)-OMe (3f)
(Ferreira et al. 2007) and Boc-DAla(b,b-Br)-OMe (3g)
(Silva et al. 2003).
Synthesis of Boc-L-Val-Z-DAbu-OMe (7j) The general
procedure described above using 5j (3.32 g, 10 mmol) as
substrate gave compound 7j (2.39 g, 76%). M.p. 107.5–
108.0°C (from diethyl ether/n-hexane). 1H NMR
(300 MHz, CDCl3): 7.61 (brs, 1H, NH), 6.80 (q
J = 7.2 Hz, 1H, CH DAbu), 5.18 (d J = 8.4 Hz, 1H, NH),
4.05–4.12 (m, 1H, CH Val), 3.73 (s, 3H, OCH3), 2.13–2.25
(m, 1H, CH Val), 1.75 (d J = 7.2 Hz, 3H, CH3 DAbu), 1.43
(s, 9H, CH3 Boc), 1.02 (d J = 6.6 Hz, 3H, CH3 Val), 0.97
The synthesis of these compounds was described in the
references given above.
General procedure for the synthesis of the methyl esters
of N-acyl-b,b-di-bromo-dehydroamino acids
The dehydroamino acid derivative (2 mmol) was dissolved
in dichloromethane (0.1 mol dm-3) and 2.5 equiv. of
123

Synthesis and electrochemical behaviour of b-halodehydroamino acid derivatives
503
N-bromosuccinimide were added with vigorous stirring.
After reacting for 16 h, triethylamine (1.5 equiv.) was added
and stirring continued for an additional hour. The solvent
was then evaporated at reduced pressure and the residue
partitioned between 100 cm3 of dichloromethane and
50 cm3 of KHSO4 (1 mol dm-3). The organic phase was
quenched with a saturated solution of Na2S2O3 (2 cm3).
The organic phase was separated, dried with MgSO4 and
the solvent evaporated. The residue was submitted to col-
umn chromatography.
Synthesis of Boc-DAla(b,b-I)-OMe (4g) The general
procedure described above using 2g (88.5 mg, 0.44 mmol)
as substrate gave compound 4g (110.0 mg, 55%). M.p.
72.0–73.0°C (from diethyl ether/n-hexane). 1H NMR
(400 MHz, CDCl3): 6.40 (brs, 1H, NH), 3.86 (s, 3H,
OCH3), 1.46 (s, 9H, CH3 Boc) ppm. 13C NMR
(100.6 MHz, CDCl3): 162.72 (C=O), 150.54 (C=O),
139.77 (C), 82.69 [(CH3)3CO], 52.94 (OCH3), 28.00
[(CH3)3C] ppm. Anal. Calcd for C9H13NO4I2 (453.01): C
23.86, H 2,89, N 3,09; found C 23.96, H 3.07, N 3.46.
washed with KHSO4 (1 mol dm-3), NaHCO3 (1 mol dm-3
)
and brine (3 9 30 cm3 each). After drying over MgSO4 the
extract was taken to dryness at reduced pressure.
Synthesis of 2-Fur-DAla(b,b-Br)-OMe (3a) The general
procedure described above using 2a (0.394 g, 2.0 mmol) as
substrate was followed to give 3a (0.600 g, 85%). M.p.
115.0–116.0°C (from diethyl ether/petroleum ether). 1H
NMR (400 MHz, CDCl3): 7.80 (brs, 1H, NH), 7.54–7.55
(m, 1H, HetArH), 7.24–7.27 (m, 1H, HetArH), 6.57–6.58
(m, 1H, HetArH), 3.92 (s, 3H, OCH3) ppm. 13C NMR
(100.6 MHz, CDCl3): 162.22 (C=O), 154.27 (C=O),
145.79 (C), 145.29 (CH), 131.67 (C), 117.13 (CH), 112.92
(CH), 85.48 (C), 53.20 (OCH3) ppm. HRMS (EI): calcd.
for C9H7Br2NNaO4 373.86340; found 373.86327.
Synthesis of the methyl esters of N-acyl-b-halo-
dehydroamino acids and N-acyl-b-halo-
dehydrodipeptides
Synthesis of compounds Z-DAbu(b-Br)-OMe (9f) (Ferreira
et al. 2007), Boc-DAbu(b-Br)-OMe (9g) (Silva et al. 2002),
Boc-Gly-DAbu(b-Br)-OMe (9h) (Ferreira et al. 2007),
Boc-L-Phe-DAbu(b-Br)-OMe (9i) (Ferreira et al. 2008a,
b), Tos-DPhe(b-Br)-OMe (10e) (Ferreira et al. 2007),
Boc-DPhe(b-Br)-OMe (10g) (Abreu et al. 2004), Boc-Gly-
DPhe(b-Br)-OMe (10h) (Ferreira et al. 2007), Bz-DAbu
(b-I)-OMe (11d) (Ferreira et al. 2008a, b), 2-Fur-DPhe
(b-I)-OMe (12a) (Ferreira et al. 2008a, b), Bz-DPhe(b-I)-
OMe (12d) (Ferreira et al. 2008a, b) and Boc-DPhe(b-I)-
OMe (12g) (Queiroz et al. 2008).
Synthesis of Bz(4-OMe)-DAla(b,b-Br)-OMe (3c) The
general procedure described above using 2c (0.470 g,
2.0 mmol) as substrate was followed to give 3c (0.582 g,
74%). M.p. 126.0–127.0°C (from diethyl ether/n-hexane).
1H NMR (400 MHz, CDCl3): 7.80 (d J = 8.8 Hz, 2H,
ArH), 7.75 (brs, 1H, NH), 6.96 (d J = 8.8 Hz, 2H, ArH),
3.93 (OCH3), 3.87 (OCH3) ppm. 13C NMR (100.6 MHz,
CDCl3): 163.34 (C=O), 162.52 (C=O), 132.75 (C), 129.47
(CH), 123.93 (C), 114.19 (CH), 84.74 (C), 55.51
(OCH3), 53.16 (OCH3) ppm. HRMS (EI): calcd. for
C12H11Br2NNaO4 413.89470; found 413.89425.
The synthesis of these compounds was described in the
references given above.
Synthesis of the methyl esters of N-acyl-b,b-di-iodo-
dehydroamino acids
General procedure for the synthesis of the methyl esters of
N-acyl-b-halo-dehydroamino acids and N-acyl-b-halo-
dehydrodipeptides
Synthesis of compounds 2-Fur-DAla(b,b-I)-OMe (4a)
(Ferreira et al. 2008a, b), 1-Naph-DAla(b,b-I)-OMe (4b)
(Ferreira et al. 2008a, b), Bz(4-OMe)-DAla(b,b-I)-OMe
(4c) (Ferreira et al. 2008a, b) and Bz-DAla(b,b-I)-OMe
(4d) (Ferreira et al. 2008a, b).
The dehydroamino acid or dehydrodipeptide derivative
(2 mmol) was dissolved in dichloromethane (0.1 mol
dm-3) and 1.5 equiv. of N-halosuccinimide were added
with vigorous stirring. After reacting for 16 h, triethyl-
amine (1.5 equiv.) was added and stirring continued for an
additional hour. The solvent was then evaporated at
reduced pressure and the residue partitioned between
100 cm3 of dichloromethane and 50 cm3 of KHSO4
(1 mol dm-3). The organic phase was washed with KHSO4
The synthesis of these compounds was described in the
references given above.
General procedure for the synthesis of N-acyl-b,b-di-iodo-
dehydroamino acid methyl esters
(1 mol dm-3), NaHCO3 (1 mol dm-3
)
and brine
A dried Schlenk tube was charged with the dehydroamino
acid derivative (0.44 mmol), K2CO3 (2 equiv.) and THF
(2 cm3). A solution of I2 (1.2 eq.) in THF (1 cm3) was
added at 0°C. The tube was sealed and the reaction mixture
stirred at 80°C for &3 h. The reaction mixture was
(3 9 30 cm3 each). After drying over MgSO4 the extract
was taken to dryness at reduced pressure.
Synthesis of 2-Fur-DAbu(b-Br)-OMe (9a) The general
procedure described above using 7a (0.418 mg, 2.0 mmol)
123

504
P. M. T. Ferreira et al.
as substrate and NBS was followed to give 9a as a 1/1 E/Z
mixture (0.539 g, 93%). The diastereomers were separated
by column chromatography using diethyl ether/n-hexane
1/2 as eluent to give:
(0.578 g, 97%). The diastereomers were separated by col-
umn chromatography using diethyl ether/petroleum ether
7/3 as eluent to give:
E-9d. M.p. 153.0–154.0°C (from diethyl ether/n-hex-
ane). H NMR (300 MHz, CDCl3): 8.04 (brs, 1H, NH),
1
E-9a. M.p. 147.0–148.0°C (from ethyl acetate/n-
hexane). 1H NMR (300 MHz, CDCl3): 7.62 (br s, 1H, NH),
7.52–7.51 (m, 1H, ArH), 7.23–7.22 (m, 1H, ArH), 6.57–
6.55 (m, 1H, ArH), 3.85 (s, 3H, OCH3), 2.48 (s, 3H, bCH3)
ppm. 13C NMR (75.4 MHz, CDCl3): 163.94 (C=O), 155.67
(C=O), 146.63 (C), 144.72 (CH), 124.77 (C), 116.21 (C),
116.12 (CH), 112.60 (CH), 52.53 (OCH3), 26.36 (cCH3)
ppm. Anal. Calcd for C10H10NO4Br (288.10): C 41.69, H
3.50, N 4.86; found C 41.83, H 3.53, N 5.09.
7.80 (d J = 8.4 Hz, 2H, ArH), 7.38–7.54 (m, 3H, ArH),
3.85 (s, 3H, OCH3), 2.44 (s, 3H, bCH3).ppm. 13C NMR
(75.4 MHz, CDCl3): 165.44 (C=O), 164.79 (C=O), 132.56
(C), 132.27 (CH), 128.66 (CH), 127.36 (CH), 125.96 (C),
124.33 (C), 52.53 (OCH3), 26.17 (CH3) ppm. HMRS (EI
TOF) [M?]: Calcd. for C12H12BrNO3 297.0001; found
297.0002.
Z-9d. M.p. 145.0–146.0°C (from diethyl ethet/petro-
leum ether). 1H NMR (300 MHz, CDCl3): 7.86 (d
J = 8.4 Hz, 2H, ArH), 7.74 (brs, 1H, NH), 7.45–7.60 (m,
3H, ArH), 3.85 (s, 3H, OCH3), 2.61 (s, 3H, bCH3) ppm.
13C NMR (75.4 MHz, CDCl3): 165.02 (C=O), 162.88
(C=O), 132.60 (C), 132.43 (CH), 128.78 (CH), 127.35
(CH), 123.56 (C), 52.71 (OCH3), 24.56 (CH3) ppm. Anal.
Calcd for C12H12BrNO3 (298.13): C 48.34, H 4.06, N 4.70;
found C 48.57, H 4.05, N 4.83.
Z-9a. M.p. 108.0–108.5°C (from diethyl ether/n-
hexane). 1H NMR (300 MHz, CDCl3): 7.89 (br s, 1H, NH),
7.54–7.53 (m, 1H, ArH), 7.22–7.21 (m, 1H, ArH), 6.57–
6.55 (m, 1H, ArH), 3.86 (s, 3H, OCH3), 2.61 (s, 3H, cCH3)
ppm. 13C NMR (75.4 MHz, CDCl3): 162.79 (C=O), 155.53
(C=O), 146.56 (C), 144.86 (CH), 126.43 (C), 123.64 (C),
116.21 (CH), 112.63 (CH), 52.77 (OCH3), 24.61 (cCH3)
ppm. Anal. Calcd for C10H10NO4Br (288.10): C 41.69, H
3.50, N 4.86; found C 41.70, H 3.67, N 5.08.
Synthesis of Boc-L-Val-DAbu(b-Br)-OMe (9j) The gen-
eral procedure described above using 7j (628.8 mg,
2.0 mmol) as substrate and NBS gave a 1/1 mixture of E/Z
isomers (755.1 mg, 96%) The diastereomers were sepa-
rated by column chromatography using diethyl ether/
petroleum ether 1/4 as eluent to give:
Synthesis of Bz(4-OMe)-DAbu(b-Br)-OMe (9c) The gen-
eral procedure described above using 7c (0.498 mg,
2.0 mmol) as substrate and NBS was followed to give 9c as
a 1/1 E/Z mixture (0.591 g, 90%). The diastereomers were
separated by column chromatography using diethyl ether/
petroleum ether 1/1 as eluent to give:
E-9j. M.p. 158.5–159.0°C (from diethyl ether/n-
hexane). H NMR (300 MHz, CDCl3): 8.25 (s, 1H, NH),
1
E-9c. M.p. 133.5–134.0°C (from ethyl acetate/n-hex-
ane). H NMR (300 MHz, CDCl3): 7.79 (d, J = 8.7 Hz,
1
5.28 (d J = 8.4 Hz, 1H, NH), 3.99–4.04 (m, 1H, CH Val),
3.78 (s, 3H, OCH3), 2.35 (s, 3H, CH3 DAbu), 2.08–2.19
(m, 1H, CH Val), 1.42 (s, 9H, CH3 Boc), 0.99 (d
J = 6.6 Hz, 3H, CH3 Val), 0.95 (d J = 6.6 Hz, 3H, CH3
Val) ppm. 13C NMR (75.4 MHz, CDCl3): 170.49 (C=O),
164.01 (C=O), 156.21 (C=O), 125.97 (C), 122.92 (C),
80.36 [C(CH3)3], 59.70 (CH), 52.22 (OCH3), 30.49 (CH),
28.21 [C(CH3)3], 25.63 (CH3), 19.10 (CH3), 17.95 (CH3)
ppm Anal. Calcd for C15H25BrN2O5 (393.27): C 45.81, H
6.41, N 7.12; found C 45.75, H 6.38, N 7.28.
2H, ArH), 7.61 (br s, 1H, NH), 6.93 (d, J = 8.7 Hz, 2H,
ArH), 3.86 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 2.45 (s, 3H,
cCH3) ppm. 13C NMR (75.4 MHz, CDCl3): 165.08 (C=O),
164.91 (C), 162.77 (C=O), 129.34 (CH), 126,24 (C),
124.70 (C), 123.37 (C), 113.83 (CH), 55.42 (OCH3), 52.54
(OCH3), 26.02 (cCH3) ppm. Anal. Calcd for C13H14NO4Br
(328.16): C 47.58, H 4.30, N 4.27; found C 47.39, H 4.24,
N 4.52.
Z-9c. M.p. 152.5–153.5°C (from ethyl acetate/n-
hexane). 1H NMR (300 MHz, CDCl3): 7.82 (d, J = 8.7 Hz,
2H, ArH), 7.64 (br s, 1H, NH), 6.97 (d, J = 8.7 Hz, 2H,
ArH), 3.88 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 2.60 (s, 3H,
cCH3) ppm. 13C NMR (75.4 MHz, CDCl3): 164.49 (C=O),
163.04 (C), 162.98 (C=O), 129.34 (CH), 127,51 (C),
124.79 (C), 122.12 (C), 114.03 (CH), 55.48 (OCH3), 52.75
(OCH3), 24.46 (cCH3) ppm. Anal. Calcd for C13H14NO4Br
(328.16): C 47.58, H 4.30, N 4.27; found C 47.35, H 4.23,
N 4.52.
Z-9j. M.p. 137.5–138.0°C (from diethyl ether/n-
hexane). H NMR (300 MHz, CDCl3): 8.25 (s, 1H, NH),
1
5.28 (d J = 8.4 Hz, 1H, NH), 3.99–4.04 (m, 1H, CH Val),
3.78 (s, 3H, OCH3), 2.35 (s, 3H, CH3 DAbu), 2.08–2.19
(m, 1H, CH Val), 1.42 (s, 9H, CH3 Boc), 0.99 (d
J = 6.6 Hz, 3H, CH3 Val), 0.95 (d J = 6.6 Hz, 3H, CH3
Val) ppm. Anal. Calcd for C15H25BrN2O5 (393.27): C
45.81, H 6.41, N 7.12; found C 45.80, H 6.32, N 7.27.
Synthesis of 2-Fur-DPhe(b-Br)-OMe (10a) The general
procedure described above using 8a (0.543 mg, 2.0 mmol)
as substrate and NBS was followed to give 10a as a 1/1 E/Z
mixture (0.637 g, 91%). The diastereomers were separated
Synthesis of Bz-DAbu(b-Br)-OMe (9d) The general pro-
cedure described above using 7d (0.438 g, 2.0 mmol) as
substrate and NBS gave a 1/1 mixture of E/Z isomers
123

Synthesis and electrochemical behaviour of b-halodehydroamino acid derivatives
505
by column chromatography using diethyl ether/petroleum
ether 1/1 as eluent to give:
mixture (0.650 g, 90%). The diastereomers were separated
by column chromatography using diethyl ether/n-hexane 1/
2 as eluent to give:
E-10a. M.p. 119.0–120.0°C (from ethyl acetate/n-
hexane). 1H NMR (300 MHz, CDCl3): 7.72 (br s, 1H, NH),
7.50–7.37 (m, 6H, ArH), 7.18–7.17 (m, 1H, ArH 2-Fur),
6.51–6.49 (m, 1H, ArH 2-Fur), 3.97 (s, 3H, OCH3) ppm.
13C NMR (75.4 MHz, CDCl3): 164.23 (C=O), 154.68
(C=O), 145.96 (C), 144.95 (CH), 136.14 (C), 129.85 (CH),
129.12 (CH), 128.94 (CH), 127.47 (C), 116.52 (CH),
113.65 (C), 112.64 (CH), 52.83 (OCH3) ppm. Anal. Calcd
for C15H12NO4Br (350.17): C 51.45, H 3.45, N 4.00; found
C 51.21, H 3.58, N 4.07.
E-10d. M.p. 139.5–140.0°C (from diethyl ether/n-
hexane). H NMR (300 MHz, CDCl3): 7.62–7.59 (m, 2H,
1
ArH), 7.52–7.37 (m, 9H, ArH ? NH), 3.98 (s, 3H, OCH3)
ppm. 13C NMR (75.4 MHz, CDCl3): 164.50 (C=O), 164.16
(C=O), 136.38 (C), 132.45 (CH), 132.01 (C), 129.88 (CH),
129.14 (CH), 128.92 (CH), 128.77 (CH), 128.37 (C),
127.19 (CH), 114.32 (C), 52.82 (OCH3) ppm. HRMS (EI):
calcd. for C17H14BrNNaO3 382.00493; found 382.00442.
Z-10d. M.p. 138.5–139.0°C (from diethyl ether/n-
hexane). 1H NMR (300 MHz, CDCl3): 8.00 (br s, 1H, NH),
7.93–7.90 (m, 2H, ArH), 7.63–7.50 (m, 3H, ArH), 7.43–
7.36 (m, 5H, ArH), 3.60 (s, 3H, OCH3) ppm. 13C NMR
(75.4 MHz, CDCl3): 164.74 (C=O), 163.29 (C=O), 136.94
(C), 132.71 (C), 132.31 (C), 129.45 (CH), 129.10 (CH),
128.98 (CH), 128.90 (CH), 128.30 (CH), 127.47 (CH),
117.52 (C), 52.61 (OCH3) ppm. Anal. Calcd for
C17H14NO3Br (360.21): C 56.69, H 3.92, N 3.89; found C
56.78, H 3.79, N 3.93.
Z-10a. M.p. 98.5–99.0°C (from ethyl acetate/n-hexane).
1H NMR (300 MHz, CDCl3): 8.19 (br s, 1H, NH), 7.58–
7.57 (m, 1H, ArH 2-Fur), 7.43–7.35 (m, 5H, ArH), 7.27–
7.26 (m, 1H, ArH 2-Fur), 6.60–6.58 (m, 1H, ArH 2-Fur),
3.59 (s, 3H, OCH3) ppm. 13C NMR (75.4 MHz, CDCl3):
163.20 (C=O), 155.28 (C=O), 146.30 (CH), 145.12 (CH),
136.91 (C), 129.46 (CH), 128.95 (CH), 128.30 (CH),
128.19 (C), 117.50 (C), 116.72 (C), 112.81 (CH), 52.69
(OCH3) ppm. Anal. Calcd for C15H12NO4Br (350.17): C
51.45, H 3.45, N 4.00; found C 51.16, H 3.69, N 4.03.
Synthesis of Boc-L-Phe-DPhe(b-Br)-OMe (10i) The
general procedure described above using 8i (2.02 g,
4.8 mmol) as substrate and NBS was followed to give 10i
as a 1/2 E/Z mixture (1.87 g, 78%). The diastereomers
were separated by column chromatography using diethyl
ether/petroleum ether 1/1 as eluent to give:
Synthesis of Bz(4-OMe)-DPhe(b-Br)-OMe (10c) The
general procedure described above using 8c (0.543 mg,
2.0 mmol) as substrate and NBS was followed to give 10c
as a 1/1 E/Z mixture (0.487 g, 62%). The diastereomers
were separated by column chromatography using diethyl
ether/petroleum ether 1/2 as eluent to give:
E-10i. M.p. 153.0–154.0°C (from ethyl acetate/petro-
leum ether). H NMR (300 MHz, CDCl3): 7.51 (br s, 1H,
1
E-10c. M.p. 113.0–114.5°C (from ethyl acetate/n-
hexane). 1H NMR (300 MHz, CDCl3): 7.92 (br s, 1H, NH),
7.56 (d, J = 8.7 Hz, 2H, ArH), 7.51–7.39 (m, 5H, ArH),
6.87 (d, J = 8.7 Hz, 2H, ArH), 3.97 (s, 3H, OCH3), 3.83 (s,
3H, OCH3) ppm. 13C NMR (75.4 MHz, CDCl3): 164.61
(C=O), 163.66 (C), 162.96 (C=O), 136.43 (C), 129.80
(CH), 129.21 (C), 129.13 (CH), 128.97 (CH), 128.64 (CH),
124.17 (C), 114.01 (C), 114.21 (CH), 55.42 (OCH3), 52.76
(OCH3) ppm. Anal. Calcd for C18H16NO4Br (390.23): C
55.40, H 4.13, N 3.59; found C 56.00, H 4.52, N 3.59.
Z-10c. M.p. 144.0–144.5°C (from ethyl acetate/n-
hexane). 1H NMR (300 MHz, CDCl3): 7.92 (br s, 1H, NH),
7.88 (d, J = 9.0 Hz, 2H, ArH), 7.42–7.35 (m, 5H, ArH),
7.00 (d, J = 9.0 Hz, 2H, ArH), 3.89 (s, 3H, OCH3), 3.60 (s,
3H, OCH3) ppm. 13C NMR (75.4 MHz, CDCl3): 164.23
(C=O), 163.44 (C), 163.19 (C=O), 137.01 (C), 129.48
(CH), 129.37 (C), 129.30 (CH), 129.00 (CH), 128.28 (CH),
124.48 (C), 116.64 (C), 114.13 (CH), 55.49 (OCH3), 52.64
(OCH3) ppm. Anal. Calcd for C18H16NO4Br (390.23): C
55.40, H 4.13, N 3.59; found C 55.25, H 3.93, N 3.72.
NH DPhe), 7.34–7.14 (m, 10H, ArH), 4.80 (br s, 1H, NH
Phe), 4.28–4.21 (m, 1H, aCH Phe), 3.93 (s, 3H, OCH3),
3.02 (d, J = 6.6 Hz, 2H, bCH2 Phe), 1.32 (s, 9H, CH3 Boc)
ppm. 13C NMR (75.4 MHz, CDCl3): 168.60 (C=O), 164.15
(C=O), 155.27 (C=O), 135.92 (C), 129.65 (CH), 129.28
(CH), 128.97 (CH), 128.75 (CH), 128.58 (C), 127.50 (CH),
127.01 (CH), 126.97 (C), 113.89 (C), 80.55 [OC(CH3)3],
55.35 (aCH Phe), 52.67 (OCH3), 37.50 (bCH2 Phe), 28.11
[C(CH3)3] ppm. HRMS (EI): calcd. for C24H27BrN2NaO5
525.09956; found 525.09895.
Z-10i. M.p. 181.0–182.0°C (from ethyl acetate/petro-
leum ether). H NMR (300 MHz, CDCl3): 8.15 (br s, 1H,
1
NH DPhe), 7.34–7.25 (m, 10H, ArH), 5.06 (d, J = 7.5 Hz,
1H, NH Phe), 4.58 (br s, 1H, aCH Phe), 3.54 (s, 3H,
OCH3), 3.24–3.08 (m, 2H, bCH2 Phe), 1.44 (s, 9H, CH3
Boc) ppm. 13C NMR (75.4 MHz, CDCl3): 169.75 (C=O),
163.15 (C=O), 155.55 (C=O), 137.02 (C), 136.08 (C),
129.33 (CH), 128.93 (C), 128.82 (CH), 128.77 (CH),
128.40 (C), 128.20 (CH), 127.09 (CH), 118.07 (CH), 80.74
[OC(CH3)3], 55.35 (aCH Phe), 52.47 (OCH3), 37.35
(bCH2 Phe), 28.22 [C(CH3)3] ppm. Anal. Calcd for
C24H27N2O5Br (503.39): C 57.26, H 5.41, N 5.56; found C
57.41, H 5.55, N 5.88.
Synthesis of Bz-DPhe(b-Br)-OMe (10d) The general
procedure described above using 8d (0.562 mg, 2.0 mmol)
as substrate and NBS was followed to give 10d as a 1/1 E/Z
123

506
P. M. T. Ferreira et al.
Synthesis of 2-Fur-Z-DAbu(b-I)-OMe (11a) The general
procedure described above using 7a (0.418 mg, 2.0 mmol)
as substrate and NIS was followed to give 11a (0.522 g,
78%) as 1:4 mixture of the E and Z-isomers. Z-11a: M.p.
163.5–164.5°C (from diethyl ether/n-hexane). 1H NMR
(300 MHz, CDCl3): 7.80 (br s, 1H, NH), 7.56–7.55 (m, 1H,
ArH), 7.23–7.22 (m, 1H, ArH), 6.58–6.56 (m, 1H, ArH),
3.85 (s, 3H, OCH3), 2.81 (s, 3H, cCH3) ppm. 13C NMR
(75.4 MHz, CDCl3): 161.41 (C=O), 155.63 (C=O), 146.50
(C), 144.94 (CH), 144.71 (C), 130.76 (C), 116.25 (CH),
112.66 (CH), 52.77 (OCH3), 28.96 (cCH3) ppm. Anal.
Calcd for C10H10NO4I (235.10): C 35.84, H 3.01, N 4.18;
found C 36.18, H 3.25, N 4.45.
(s, 3H, OCH3), 2.77 (s, 3H, cCH3 DAbu), 1.46 (s, 9H, CH3
Boc) ppm. 13C NMR (75.4 MHz, CDCl3): 168.01 (C=O),
161.43 (C=O), 156.07 (C=O), 130.87 (C), 103.46 (C),
80.59 [OC(CH3)3], 52.61 (OCH3), 44.36 (CH2 Gly), 29.13
(cCH3 DAbu), 28.31 [C(CH3)3] ppm. Anal. Calcd for
C12H19N2O5I (398.03): C 36.20, H 4.81, N 7.04; found C
36.36, H 4.87, N 7.26.
Synthesis of Boc-L-Phe-Z-DAbu(b-I)-OMe (11i) The
general procedure described above using 7i (0.725 g,
2 mmol) and NIS as substrates gave compound 11i
(0.898 g, 92%). M.p. 125.5–126.5°C (from diethyl ether/n-
hexane). 1H NMR (300 MHz, CDCl3): 7.68 (br s, 1H, NH)
7.34–7.22 (m, 5H, ArH), 5.00–4.47 (d, J = 8.4 Hz, 1H,
NH), 4.51 (m, 1H, CH Phe), 3.79 (s, 3H, OCH3), 3.20–3.04
(m, 2H, CH2 Phe), 2.75 (s, 3H, CH3), 1.41 (s, 9H, CH3
Boc) ppm. 13C NMR (75.4 MHz, CDCl3): 169.71 (C=O),
161.30 (C=O), 155.41 (C=O), 136.12 (C), 130.94 (C),
129.33 (CH), 129.26 (CH), 128.69 (CH), 127.01 (CH),
102.40 (C), 80.56 [(CH3)3CO], 55.18 (CH), 52.50 (OCH3),
37.39 (CH2), 29.00 (CH3), 28.24 [(CH3)3C] ppm. Anal.
Calcd for C19H25N2O5I (488.08): C 46.73, H 5.16, N 5.74;
found C 46.66, H 5.15, N 6.14.
Synthesis of Bz(4-OMe)-Z-DAbu(b-I)-OMe (11c) The
general procedure described above using 7c (0.498 mg,
2.0 mmol) as substrate and NIS was followed to give 11c
(0.619 g, 83%) as 1:4 mixture of the E and Z-isomers.
Z-11c: M.p. 148.5–149.5°C (from ethyl acetate/n-hexane).
1H NMR (300 MHz, CDCl3): 7.84 (d, J = 8.7 Hz, 2H,
ArH), 7.55 (br s, 1H, NH), 6.98 (d, J = 8.7 Hz, 2H, ArH),
3.88 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 2.80 (s, 3H, cCH3)
ppm. 13C NMR (75.4 MHz, CDCl3): 64.49 (C=O), 162.96
(C=O), 161.61 (C), 129.30 (CH), 128,55 (C), 127.15 (C),
124.66 (C), 114.01 (CH), 55.45 (OCH3), 52.71 (OCH3),
28.75 (cCH3) ppm. Anal. Calcd for C13H14NO4I (375.16):
C 41.62, H 3.76, N 3.73; found C 41.37, H 3.84, N 4.15.
Synthesis of Bz(4-OMe)-Z-DPhe(b-I)-OMe (12c) The
general procedure described above using 8c (0.622 mg,
2.0 mmol) as substrate and NIS was followed to give 12c
(0.717 g, 82%). M.p. 173.0–174.0°C (from diethyl ether/
1
Synthesis of Boc-DAbu(b-I)-OMe (11g) The general
procedure described above using 7g (0.43 g, 2 mmol) and
NIS as substrates gave compound 11g as a 1/4 mixture of E
and Z-isomers (0.60 g, 88%). The diastereomers were
separated by column chromatography using diethyl ether/
petroleum ether 1/1 as eluent to give:
petroleum ether). H NMR (300 MHz, CDCl3): 7.90–7.83
(m, 2H, ArH), 7.80 (br s, 1H, NH), 7.51–7.29 (m, 5H,
ArH), 7.01–6.95 (m, 2H, ArH), 3.89 (s, 3H, OCH3), 3.87 (s,
3H, OCH3) ppm. 13C NMR (75.4 MHz, CDCl3): 164.27
(C), 163.21 (C), 162.24 (C), 133.94 (C), 131.15 (C), 129.47
(CH), 128.91 (CH), 128.60 (CH), 128.22 (CH), 125.82 (C),
124.43 (C), 114.16 (CH), 55.49 (OCH3), 52.57 (OCH3)
ppm. HRMS (EI): calcd. for C18H16INNaO4 460.00162;
found 460.00107.
E-11g. M.p. 150.5–151.0°C (from diethyl ether/petro-
leum ether). H NMR (300 MHz, CDCl3): 6.10 (br s, 1H,
1
MH), 3.82 (s, 3H, OCH3), 2.61 (s, 3H, cCH3 DAbu), 1.46
(s, 9H, CH3 Boc) ppm. 13C NMR (75.4 MHz, CDCl3):
164.88 (C=O), 152.28 (C=O), 130.15 (C), 93.92 (C), 81.44
[OC(CH3)3], 52.28 (OCH3), 30.27 (CH3 DAbu), 28.08
[C(CH3)3] ppm. Anal. Calcd for C10H16NO4I (341.01): C
35.21, H 4.73, N 74.11; found C 35.56, H 4.81, N 4.26.
Z-11g. This compound was already described (Ferreira
et al. 2008a, b).
Synthesis of Boc-L-Phe-Z-DPhe(b-I)-OMe (12i) The
general procedure described above using 8i (0.849 g,
2.0 mmol) and NIS as substrates gave 12i. M.p. (1.02 g,
93%). 173.0–174.0°C (from diethyl ether/n-hexane). 1H
NMR (400 MHz, CDCl3): 7.91 (brs, 1H, NH), 7.26–7.36
(m, 10H, ArH), 5.00 (d J = 7.2 Hz, 1H, NH), 4.57 (brs,
1H, aCH Phe), 3.50 (s, 3H, OCH3), 3.15–3.23 (m, 2H,
bCH2 Phe), 1.44 (s, 9H, CH3 Boc) ppm. 13C NMR
(75.4 MHz, CDCl3): 169.81 (C=O), 161.98 (C=O), 155.51
(C=O), 140.32 (C), 136.08 (C), 133.08 (C), 129.38 (CH),
128.94 (CH), 128.84 (CH), 128.70 (CH), 128.16 (CH),
127.17 (CH), 96.03 (C), 80.75 [C(CH3)3], 55.30 (CH),
52.44 (OCH3), 37.43 (CH2), 20.32 [C(CH3)3] ppm. Anal.
Calcd for C24H27IN2O5 (550.38): C 52.37, H 4.94, N 5.09;
found C 52.09, H 4.97, N 5.56.
Synthesis of Boc-Gly-Z-DAbu(b-I)-OMe (11h) The gen-
eral procedure described above using 7h (0.54 g, 2 mmol)
and NIS as substrates gave after column chromatography
using diethyl ether/petroleum ether (1/1) compound 11h
(0.609 g, 76%) as a white solid. M.p. 102.0–103.0°C (from
diethyl ether/petroleum ether). 1H NMR (300 MHz,
CDCl3): 7.80 (br s, 1H, NH DAbu), 5.31 (t, J = 5.7 Hz,
1H, MH Gly), 3.87 (d, J = 5.7 Hz, 1H, CH2 Gly), 3.79
123

Synthesis and electrochemical behaviour of b-halodehydroamino acid derivatives
507
Controlled potential electrolysis
Controlled potential electrolysis of Boc-Z-DAbu(b-Br)-
OMe (Z-9g) The general procedure described above
using Z-9g (0.170 g, 0.58 mmol) as substrate was followed
to give 7g as a 4/1 E/Z mixture (0.973 g, 78%). The
diastereomers were separated by column chromatogra-
phy using diethyl ether/petroleum ether 1/5 as eluent to
give:
E-7g. 1H NMR (400 MHz, CDCl3): 6.79 (br q, 1H,
bCH), 6.56 (br s, 1H, NH), 3.83 (s, 3H, OCH3), 2.64 (d,
J = 7.5 Hz, 3H, cCH3), 1.47 (s, 9H, CH3 Boc) ppm. 13C
NMR (75.4 MHz, CDCl3): 164.87 (C=O), 153.41 (C=O),
125.71 (2C), 80.26 [C(CH3)3], 52.08 (OCH3), 28.27
[C(CH3)3], 14.14 (cCH3) ppm.
of b-halodehydroamino acid derivatives
General procedure for the controlled potential electrolysis
of b-halodehydroamino acids
A solution of Et4NCl (0.1 mol dm-3; supporting electro-
lyte) and Et3NHCl (0.04 mol dm-3; proton donor) in ace-
tonitrile was added to a three-electrode cell. To its cathodic
compartment the b-halogenated dehydroamino acid deriv-
ative was added and a cyclic voltammogram recorded. The
potential was adjusted to a value 50 mV more negative
than that corresponding to the CV peak and the electrolysis
started, the reaction being monitored by HPLC. When all
starting material had disappeared, the content of the
cathodic compartment was concentrated at reduced pres-
sure and the residue partitioned between 100 cm3 of ethyl
acetate and 50 cm3 of KHSO4 (1 mol dm-3). The organic
phase was washed with KHSO4 (1 mol dm-3), NaHCO3
(1 mol dm-3) and brine (3 9 30 cm3 each). After drying
over MgSO4 the extract was taken to dryness at reduced
pressure.
Z-7g. This compound was described elsewhere (Ferreira
et al. 1999).
Controlled potential electrolysis of Boc-E-DAbu(b-Br)-
OMe (E-9g) The general procedure described above
using E-9g (0.147 g, 0.50 mmol) as substrate was followed
to give 7g as a 1/4 E/Z mixture (0.029 g, 27%). Com-
pounds E-7g and Z-7g were separated by column chro-
matography using diethyl ether/petroleum ether 1/5 as
eluent.
Controlled potential electrolysis of Bz-Z-DPhe(b-Br)-OMe
(Z-10d) The general procedure described above using
Z-10d (0.160 g, 0.44 mmol) as substrate was followed to
give 8d as a 4/1 E/Z mixture (0.041 g, 33%). The diaste-
reomers were separated by column chromatography using
diethyl ether/petroleum ether 1/5 as eluent to give:
E-8d. 1H NMR (400 MHz, CDCl3): 8.32 (br s, 1H, NH),
8.19 (br s, 1H, bCH), 7.89–7.86 (m, 1H, ArH), 7.59–7.32
(m, 9H, ArH), 3.69 (s, 3H, OCH3) ppm. 13C NMR
(100.6 MHz, CDCl3): 165.77 (C=O), 165.40 (C=O),
135.35 (C), 134.22 (C), 128.80 (CH), 128.40 (CH), 127.83
(CH), 127.63 (CH), 127.02 (CH), 126.46 (CH), 125.87
(CH), 114.08 (C), 52.38 (OCH3) ppm.
Controlled potential electrolysis of Boc-Z-DAbu(b-I)-OMe
(Z-11g) The general procedure described above using
Z-11g (0.171 g, 0.50 mmol) as substrate was followed to
give 7g as a 4/1 E/Z mixture (0.071 g, 66%). Compounds
E-7g and Z-7g were separated by column chromatography
using diethyl ether/petroleum ether 1/5 as eluent.
Controlled potential electrolysis of Boc-E-DAbu(b-I)-OMe
(E-11g) The general procedure described above using
E-11g (0.171 g, 0.50 mmol) as substrate was followed to
give 7g as a 1/4 E/Z mixture (0.066 g, 61%). Compounds
E-7g and Z-7g were separated by column chromatography
using diethyl ether/petroleum ether 1/5 as eluent.
Z-8d. This compound was described elsewhere (Ferreira
et al. 2008a, b).
Controlled potential electrolysis of Boc-Z-DPhe(b-Br)-
OMe (Z-10g) The general procedure described above
using Z-10g (0.270 g, 0.76 mmol) as substrate was fol-
lowed to give 8g as a 4/1 E/Z mixture (0.194 g, 92%). The
diastereomers were separated by column chromatography
using diethyl ether/petroleum ether 1/5 as eluent to give:
E-8g. 1H NMR (400 MHz, CDCl3): 7.51 (br s, 1H, NH),
7.34–7.21 (m, 5H, ArH), 6.72 (br s, 1H, bCH), 3.64 (s, 3H,
OCH3), 1.51 (s, 9H, CH3 Boc) ppm. 13C NMR (75.4 MHz,
CDCl3): 165.24 (C=O), 152.79 (C=O), 135.60 (C), 128.63
(CH), 127.79 (CH), 127.29 (CH), 126.20 (C), 123.38 (CH),
80.96 [C(CH3)3], 52.16 (OCH3), 28.25 [C(CH3)3] ppm.
Z-8g. This compound was described elsewhere (Ferreira
et al. 1999).
Controlled potential electrolysis of Bz-E-DPhe(b-Br)-OMe
(E-10d) The general procedure described above using
E-10d (0.182 g, 0.50 mmol) as substrate was followed to
give 8d as a 1/4 E/Z mixture (0.110 g, 78%). Compounds
E-8d and Z-8d were separated by column chromatography
using diethyl ether/petroleum ether 1/5 as eluent.
Controlled potential electrolysis of Bz-Z-DPhe(b-I)-OMe
(Z-12d) The general procedure described above using
Z-12d (0.205 g, 0.50 mmol) as substrate was followed to
give 8d as a 4/1 E/Z mixture (0.118 g, 84%). Compounds
E-8d and Z-8d were separated by column chromatography
using diethyl ether/petroleum ether 1/5 as eluent.
123

508
P. M. T. Ferreira et al.
Controlled potential electrolysis of Boc-E-DPhe(b-Br)-
OMe (E-10g) The general procedure described above
using E-10g (0.178 g, 0.50 mmol) as substrate was followed
to give 8g as a 1/4 E/Z mixture (0.133 g, 96%). Compounds
E-8g and Z-8g were separated by column chromatography
using diethyl ether/petroleum ether 1/5 as eluent.
reduction potentials of the protecting groups (Maia et al.
1993). As already reported by us (Ferreira et al. 2003a, b)
when the protecting group is conjugated with a double bond
there is shift of the reduction potentials to less negative
values. Since the Boc group is stable to electrochemical
reduction, the peak potential observed for Boc-DAla-OMe
(-2.12 V vs. ECS) corresponds to the reduction of the
a,b-double bond. The b,b-dihalodehydroalanines show
activation potentials less negative than those observed for
the corresponding dehydroalanines. It is possible to observe
a 310 mV and a 680 mV shift to less negatives values of the
peak potentials of compounds 3a and 4a when compared
with that of 2-Fur-DAla-OMe. This was also found when
peak potentials of compounds 3g and 4g were compared
with that of Boc-DAla-OMe (320 mV and 790 mV shift to
less negative values) (Table 1).
Controlled potential electrolysis of Boc-Z-DPhe(b-I)-OMe
(Z-12g) The general procedure described above using
Z-12g (0.201 g, 0.76 mmol) as substrate was followed to
give 8g as a 4/1 E/Z mixture (0.101 g, 73%). Compounds
E-8g and Z-8g were separated by column chromatography
using diethyl ether/petroleum ether 1/5 as eluent.
Results and discussion
The halogenation of b-substituted dehydroamino acids
was carried out using N-halosuccinimides followed by
treatment with NEt3 (Scheme 2). The stereochemistry of
the products was determined by NOE difference experi-
ments by irradiating the OCH3 protons and observing in the
case of the Z-isomers an NOE enhancement on the signals
of the b-CH3 or b-C6H5 protons. The b-bromodehyd-
roaminobutyric acid derivatives (9a, 9c, 9d, 9f-j) were
obtained as 1:1 mixtures of the E and Z isomers. The
same was observed with the N-acyl-b-bromodehy-
drophenylalanines (10a, 10c and 10d). However an
increase Z-stereoselectivity was found in the bromination
of N-carbamate dehydrophenylalanines (compound 10g
was obtained a 1:2 mixture of the E and Z isomers) or when
the N-protecting group was 4-tolylsulfonyl (compound 10e
The synthesis of several b-halodehydroamino acids was
carried out from b-hydroxyamino acids using a sequential
dehydration followed by a halogenation reaction. The b,b-
dibromodehydroalanines were prepared in good to high
yields by reacting the corresponding dehydroalanines with
2.5 equivalents of NBS (Silva et al. 2003). The same reaction
with NIS gave complex mixtures impossible to separate,
thus in order to synthesize b,b-di-iododehydroalanines the
corresponding dehydroamino acids were reacted with iodine
at 80°C (Ferreira et al. 2008a, b) (Scheme 1).
The activation potentials of these compounds and of the
corresponding serine and dehydroalanine derivatives were
determined by cyclic voltammetry (Table 1). The peak
potentials observed for serine derivatives correspond to the
H
N
CO2CH3
Br
P
Br
1. NBS (2.5 equiv.)
2. NEt3
3a (85%), 3c (74%),
3f (86%), 3g (52%).
H
H
N
CO2CH3
N
CO2CH3
1. Boc2O / DMAP
2. TMG
P
P
OH
H
N
CO2CH3
2a-d, 2f, 2g
I2 (80 ºC)
1a-d, 1f, 1g
P
4a (53%), 4b (47%),
4c (42%), 4d (40%),
4g (55 %).
I
I
P =
O
O
O
O
O
O
O
H3CO
O
O
(2-Fur), a;
(1-Naph), b;
[Bz(4-OMe)], c;
(Bz), d;
(Z), f;
(Boc), g.
Scheme 1 Synthesis of b,b-dihalodehydroalanines
123

Synthesis and electrochemical behaviour of b-halodehydroamino acid derivatives
509
Table 1 Peak potentials obtained by cyclic voltammetry of serine, dehydroalanine and b,b-dihalodehydroalanine derivatives
Compound
-Ep (V vs. ECS) Compound
-Ep (V vs. ECS) Compound
-Ep (V vs. ECS)
2-Fur-Ser-OMe, 1a
2.32
2-Fur-DAla-OMe, 2a
1.88
2-Fur-DAla(b,b-Br)-OMe, 3a
1.57
1.20
1.77
1.58
2-Fur-DAla(b,b-I)-OMe, 4a
1-Naph-DAla(b,b-I)-OMe, 4b
1-Naph-Ser-OMe, 1b
2.05
2.51
1-Naph-DAla-OMe, 2b
1.86
2.03a
Bz(4-OMe)-Ser-OMe,
1c
Bz(4-OMe)-DAla-OMe,
2c
Bz(4-OMe)-DAla(b,b-Br)-OMe,
3c
Bz(4-OMe)-DAla(b,b-I)-OMe, 4c 1.99
Bz-Ser-OMe, 1d
Z-Ser-OMe, 1f
2.41b
2.86b
Bz-DAla-OMe, 2d
Z-DAla-OMe, 2f
Boc-DAla-OMe, 2g
1.91
Bz-DAla(b,b-I)-OMe, 4d
Z-DAla(b,b-Br)-OMe, 3f
Boc-DAla(b,b-Br)-OMe, 3g
Boc-DAla(b,b-I)-OMe, 4g
1.85
1.72
1.80
1.33
2.29b
2.12b
c
–
Boc-Ser-OMe, 1g
Cathode vitreous carbon, solvent dimethylformamide, supporting electrolyte Bu4NBF4 0.1 mol dm-3, substrate conc. &0.005 mol dm-3
a
Ferreira et al. 2008a, b
b
Ferreira et al. 2003a, b
c
No reduction peak was detected
R=CH3, 9a (93%), 9c (90%,),
9d (97%), 9f (89%), 9g (92%),
9h (90%), 9i (90%), 9j (96%),.
R=Ph, 10a (91%), 10c (62%),
10d (90%), 10e (78%), 10g
(97%), 10h (87%), 10i (78%).
H
N
CO2CH3
Br
P
1. NBS
R
2. NEt3
2. NEt3
H
N
H
N
CO2CH3
CO2CH3
OH
P
1. Boc2O/DMAP
2. TMG
P
R
R
1. NIS
H
N
R=CH3,11a (78%), 11c (83%),
11d (87%), 11g (88%), 11h
(76%), 11i (92%).
R=Ph, 12a (83%), 12c (82%),
12d (87%), 12g (87%), 12i
(93%).
CO2CH3
I
P
R=CH3, 7a, 7c-j;
R=C6H5, 8a, 8c-e, 8g-i.
R=CH3, 5a, 5c-j;
R=C6H5, 6a, 6c-e, 6g-i.
R
O
O
S
O
O
O
O
P =
O
H3CO
O
(Tos), e;
(Z), f;
(2-Fur), a;
[Bz(4-OMe)], c;
(Bz), d;
O
O
O
O
O
O
N
O
N
O
N
H
H
H
O
O
O
(Boc-Val), j.
(Boc-Gly), h;
(Boc), g;
(Boc-Phe), i;
Scheme 2 Synthesis of b-halo,b-substituted dehydroamino acids
was obtained stereoselectively as the Z-isomer). Also
observed was an increased stereoselectivity towards the
Z-isomer in the reactions with NIS when compared with
those with NBS (dehydroaminobutyric acids 11a, 11c and
11d were obtained as 1:4 mixtures of the E and Z-isomer
and in the case of dehydrophenylalanines 12a, 12c, 12d
and 12g the only isomer isolated was the Z-isomer). These
results are in agreement with those reported by Hoerner
et al. (Hoerner et al. 1998) and were also found in the
halogenation of dehydrodipeptides.
123

510
P. M. T. Ferreira et al.
Table 2 Peak potentials obtained by cyclic voltammetry of b-halo-b-dehydroamino acid derivatives
Compound
-Ep
(V vs. ECS)
Compound
-Ep
(V vs. ECS)
Compound
-Ep (V vs.
ECS)
2-Fur-Thr-OMe, 5a
2.58
2.46
2-Fur-Z-DAbu-OMe, 7a
2.21
2-Fur-E-DAbu(b-Br)-OMe, E-9a 1.95
2-Fur-Z-DAbu(b-Br)-OMe, Z-9a 1.94
Bz(4-OMe)-Thr-OMe, 5c
Bz(4-OMe)-Z-DAbu-OMe, 7c 2.39a
Bz(4-OMe)-E-DAbu(b-Br)-OMe, 1.97
E-9c
Bz(4-OMe)-Z-DAbu(b-Br)-OMe, 1.88
Z-9c
Bz(4-OMe)-Z-DAbu(b-I)-OMe,
Z-11c
1.62
Bz-Thr-OMe, 5d
2.36b
Bz-Z-DAbu-OMe, 7d
2.21b
Bz-E-DAbu(b-Br)-OMe, E-9d
Bz-Z-DAbu(b-Br)-OMe, Z-9d
Bz-Z-DAbu(b-I)-OMe, Z-11d
1.93
1.78
1.69
Tos-Thr-OMe, 5e
Z-Thr-OMe, 5f
2.50b
2.82b
Tos-Z-DAbu-OMe, 7e
Z-Z-DAbu-OMe, 7f
2.18b
2.34b
Z-E-DAbu(b-Br)-OMe, E-9f
Z-Z-DAbu(b-Br)-OMe, Z-9f
Boc-E-DAbu(b-Br)-OMe, E-9g
Boc-Z-DAbu(b-Br)-OMe, Z-9g
Boc-Z-DAbu(b-I)-OMe, Z-11g
2.08
2.06
2.22
2.12
1.81
b,c
Boc-Thr-OMe, 5g
–
Boc-Z-DAbu-OMe, 7g
2-Fur-Z-DPhe-OMe, 8a
2.46b
2-Fur-Phe(b-OH)-OMe, 6a
2.48
1.70
2-Fur-E-DPhe (b-Br)-OMe, E-10a 1.42
2-Fur-Z-DPhe(b-Br)-OMe, Z-10a 1.44
2-Fur-Z-DPhe(b-I)-OMe, Z-12a
1.34
1.47
Bz(4-OMe)-Phe(b-OH)-OMe, 6c 2.47
Bz(4-OMe)-Z-DPhe-OMe, 8c 1.74a
Bz(4-OMe)-Z-DPhe(b-Br)-OMe,
Z-10c
Bz(4-OMe)-Z-DPhe(b-I)-OMe,
Z-12c
1.41
Bz- Phe(b-OH)-OMe, 6d
2.38b
2.53b
Bz-Z-DPhe-OMe, 8d
1.87b
Bz-E-DPhe(b-Br)-OMe, E-10d
Bz-Z-DPhe(b-Br)-OMe, Z-10d
Bz-Z-DPhe(b-I)-OMe, Z-12d
Tos-Z-DPhe(b-Br)-OMe, Z-10e
Boc-E-DPhe(b-Br)-OMe, E-10g
Boc-Z-DPhe(b-Br)-OMe, Z-10g
Boc-Z-DPhe(b-I)-OMe, Z-12g
1.52
1.51
1.39
1.62
1.72
1.62
1.67
Tos- Phe(b-OH)-OMe, 6e
Boc- Phe(b-OH)-OMe, 6g
Tos-Z-DPhe-OMe, 8e
Boc-Z-DPhe-OMe, 8g
1.65b
1.84b
b,c
–
Cathode vitreous carbon, solvent dimethylformamide, supporting electrolyte Bu4NBF4 0.1 mol dm-3, substrate conc. &0.005 mol dm-3
a
Ferreira et al. 2008a, b
b
Ferreira et al. 2003a, b
c
No reduction peak was detected
Previous work on the electrochemical behaviour of de-
hydroamino acid derivatives enabled the synthesis of dia-
mino dicarboxylic acids by reduction at controlled
potential (Ferreira et al. 2003a, b). Studies on the reduction
of vinyl halides have demonstrated that these compounds
are first reduced to the dehalogenated olefin and only at
lower potentials is the double bond hydrogenated (Miller
and Riekena 1969; Fry and Mitnick 1969; Ji and Peters
2001). Thus, the electrochemical properties of b-halode-
hydroamino acids were studied by cyclic voltammetry and
controlled potential electrolysis. In Tables 2 and 3 we
present the peak potentials obtained by cyclic voltammetry
of b-halo-b-dehydroamino acid derivatives and those of the
corresponding dehydroamino acids and b-hydroxyamino
acids.
From these results it is possible to observe higher
reduction potentials for dehydrophenylalanines relatively to
the corresponding dehydroaminobutyric acids and for N-acyl
dehydroamino acids when compared to their urethane
counterparts. This is due to the more extended p system,
which corresponds to a lower energy for the p antibonding
orbital into which an electron will be transferred. It is also
possible to observe in Tables 2 and 3 higher reduction peak
potentials for b-iododehydroamino acids when compared
with those of the corresponding b-bromo derivatives. The
first reduction peak of all b-halodehydroamino acids studied
123

Synthesis and electrochemical behaviour of b-halodehydroamino acid derivatives
511
Table 3 Peak potentials obtained by cyclic voltammetry of dehydropeptide and b-halodehydropeptide derivatives
Compound
-Ep
(V vs. ECS)
Compound
-Ep
(V vs. ECS)
Compound
-Ep
(V vs. ECS)
Boc-Gly-Z-DAbu-OMe, 7h 2.26
Boc-Gly-E-DAbu(b-Br)-OMe,
E-9h
2.07
1.97
Boc-Gly-Z-DAbu(b-Br)-OMe,
Z-9h
2.09
Boc-Gly-Z-DAbu(b-I)-OMe,
Z-11h
1.76
1.91
Boc-L-Phe-Z-DAbu-OMe, 7i 2.21
Boc-L-Val-Z-DAbu-OMe, 7j 2.38
Boc-L-Phe-E-DAbu(b-Br)-
OMe,
E-9i
Boc-L-Phe-Z-DAbu(b-Br)-OMe,
Z-9i
Boc-L-Phe-Z-DAbu(b-I)-OMe, Z-11i 1.71
Boc-L-Val-E-DAbu(b-Br)-
OMe,
E-9j
1.97
1.78
Boc-L-Val-Z-DAbu(b-Br)-OMe,
Z-9j
1.97
Boc-Gly-Z-DPhe-OMe, 8h
1.84
Boc-Gly-E-DPhe(b-Br)-OMe,,
E-10h
Boc-Gly-Z-DPhe(b-Br)-OMe,
Z-10h
1.70
1.49
1.47
Boc-L-Phe-Z-DPhe-OMe, 8i 1.86
Boc-L-Phe-E-DPhe(b-Br)-OMe, 1.47
E-10i
Boc-L-Phe-Z-DPhe(b-Br)-OMe,
Z-10i
Boc-L-Phe-Z-DPhe(b-I)-OMe,
Z-12i
Cathode vitreous carbon, solvent dimethylformamide, supporting electrolyte Bu4NBF4 0.1 mol dm-3, substrate conc. &0.005 mol dm-3
Table 4 Results obtained in the
controlled potential electrolysis
Substrate
Product
Yield/%
E/Z ratio
of b-halodehydroamino acids
Bz-Z-DPhe(b-Br)-OMe, Z-10d
Bz-E-DPhe(b-Br)-OMe, E-10d
Bz-Z-DPhe(b-I)-OMe, Z-12d
Boc-Z-DAbu(b-Br)-OMe, Z-9g
Boc-E-DAbu(b-Br)-OMe, E-9g
Boc-Z-DAbu(b-I)-OMe, Z-11g
Boc-E-DAbu(b-I)-OMe, E-11g
Boc-Z-DPhe(b-Br)-OMe, Z-10g
Boc-E-DPhe(b-Br)-OMe, E-10g
Boc-Z-DPhe(b-I)-OMe, Z-12g
Bz-E,Z-DPhe-OMe, 8d
Bz-E,Z-DPhe-OMe, 8d
Bz-E,Z-DPhe-OMe, 8d
Boc-E,Z-DAbu-OMe, 7g
Boc-E,Z-DAbu-OMe, 7g
Boc-E,Z-DAbu-OMe, 7g
Boc-E,Z-DAbu-OMe, 7g
Boc-E,Z-DPhe-OMe, 8g
Boc-E,Z-DPhe-OMe, 8g
Boc-E,Z-DPhe-OMe, 8g
33
78
84
78
27
66
61
92
96
73
82/18
15/85
83/17
85/15
21/79
87/13
16/84
77/23
22/78
83/17
occurs at higher potentials when compared with the corre-
sponding non-halogenated derivatives. In order to establish
that the first reduction peak corresponds to the dehalogen-
ation process and not to reduction of the double bond, con-
trolled potential electrolysis were carried out using as
substrates the pure stereoisomers of compounds 9g, 10d,
10g, 11g, 12d and 12g at the peak potentials indicated in
Table 4 (Scheme 3, Table 2). The major product isolated
corresponds to a mixture of E and Z-isomers of the de-
halogenated dehydroamino acid. The stereochemistry of the
products was determined by NOE difference experiments by
irradiating the OCH3 protons and observing in the case of the
Z-isomers an NOE enhancement on the signals of the b-CH3
or b-C6H5 protons. In all cases the ratio of stereoisomers is
approximately 4:1 being the predominant isomer that
resulting from dehalogenation without isomerization. Thus,
this constitutes a valuable method for the synthesis of the
less thermodynamically stable E-isomer of dehydroamin-
obutyric acid and dehydrophenylalanine derivatives.
R
R
X
e-
P
N
H
P=Bz, R=Ph, 8d;
P=Boc, R=CH3, 7g;
P=Boc, R=Ph, 8g.
P
CO2H
N
H
CO2H
P=Bz, R=Ph, X=Br, 10d;
P=Bz, R=Ph, X=I, 12d;
P=Boc, R=CH3, X=Br, 9g;
P=Boc, R=CH3, X=I, 11g;
P=Boc, R=Ph, X=Br, 10g;
P=Boc, R=Ph, X=I, 12g.
Scheme 3 Controlled potential electrolysis of b-halo-b-substituted
dehydroamino acids
In the case of electrolysis of N-benzoyl-b-halodehy-
drophenylalanines it was possible to isolate in 10–20%
yield the methyl 2,5-diphenyloxazole-4-carboxylate. This
compound was previously prepared from the methyl ester
of N-benzoyldehydrophenylalanine by an intramolecular
cyclization promoted by iodine (Ferreira et al. 2008a, b).
123

512
P. M. T. Ferreira et al.
Abreu AS, Ferreira PMT, Monteiro LS, Queiroz MJRP, Ferreira
ICFR, Calhelha RC, Estevinho LM (2004) Synthesis of pure
stereoisomers of benzo[b]thienyl dehydrophenylalanines by
Suzuki cross-coupling. Preliminary studies of antimicrobial
activity. Tetrahedron 60:11821–11828
Bertj F, Ebert L, Gardossi L (1992) One-step stereospecific synthesis
of a, b-dehydroamino acids and dehydropeptides. Tetrahedron
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reactivity of protected b-bromo a-iminoacids: a convenient
route to structurally diversified amino acids. Tetrahedron Lett
31:3739–3742
Conclusions
Several new b-halodehydroamino acids were prepared by
reacting the corresponding b-hydroxyamino acid with
Boc2O/DMAP and TMG followed by treatment with
N-halosuccinimides (NBS or NIS) or in the case of b,b-di-
iododehydroalanines with iodine. The stereochemistry of
these reactions was evaluated and an increase Z-stereose-
lectivity was found in the reactions with NIS when com-
pared with those with NBS. This selectivity towards the
Z-isomer was also found for dehydrophenylalanines when
compared with the corresponding dehydroaminobutyric
acid derivatives.
Ferreira PMT, Monteiro LS (2006) Synthesis and reactivity of
b-bromo-b-substituted dehydroalanines. Eur J Org Chem 2006:
3226–3234
Ferreira PMT, Maia HLS, Monteiro LS (1998) Efficient synthesis
of dehydroamino acid derivatives. Tetrahedron Lett 39:9575–
9578
In the case of dehydrophenylalanine derivatives an
additional increase in Z-stereoselectivity was obtained
when the N-protecting group was a carbamate or the
4-toluenesulfonyl group.
Ferreira PMT, Maia HLS, Monteiro LS, Sacramento J (1999) High
yielding synthesis of dehydroamino acid and dehydropeptide
derivatives. J Chem Soc Perkin Trans 1:3697–3703
Ferreira PMT, Maia HLS, Monteiro LS, Sacramento J (2001) Michael
addition of thiols, carbon nucleophiles and amines to dehydro-
amino acid and dehydropeptide derivatives. J Chem Soc Perkin
Trans 1:3167–3173
Ferreira PMT, Maia HLS, Monteiro LS (2003a) Electrochemical
synthesis of diaminodicarboxylic acid derivatives. Tetrahedron
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natural amino acids from N-(4-toluenesulfonyl)-a,b-didehydro-
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Ferreira PMT, Monteiro LS, Pereira G, Ribeiro L, Sacramento J, Silva
L (2007) Reactivity of dehydroamino acids towards N-bromo-
succinimide: synthesis of b-bromo and b,b-dibromodehydroa-
mino acid derivatives and of 4-imidazolidinones. Eur J Org
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Ferreira PMT, Monteiro LS, Pereira G (2008) Synthesis of substituted
oxazoles from N-acyl-b-hydroxyamino acid derivatives. Eur J
Org Chem 2008:4676–4683
Ferreira PMT, Abreu AS, Castanheira EMS, Monteiro LS, Pereira G,
Queiroz MJRP (2008) Pyrenylamino acids: synthesis, photophy-
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Electrochemical data of the b-halodehydroamino acids
was obtained by cyclic voltammetry and controlled
potential electrolysis. The reduction peak potentials of
these compounds were compared with those of the corre-
sponding dehydroamino acids and of the b-hydroxyamino
acid derivatives. It was found that the former compounds
showed higher reduction peak potentials than the latter.
Generally, the b-halo, b-substituted dehydroamino acids
have lower reduction potentials when compared with the
corresponding b,b-di-halodehydroalanines. The b-iodode-
hydroamino acids show higher reduction peak potentials
when compared with their bromo analogues. Controlled
potential electrolysis showed that the first peak in the cyclic
voltammograms of the b-halodehydroamino acids corre-
sponds to dehalogenation, since the major products isolated
in these reactions were the corresponding dehydroamino
acids as 4:1 mixtures of stereoisomers. The predominant
isomer is that resulting from dehalogenation without
isomerization. These new results show that electrochemical
reduction constitutes a valuable method for the synthesis of
the E-isomer of b-substituted dehydroalanines.
Acknowledgments Foundation for the Science and Technology
(FCT)–Portugal and FEDER (Fundo Europeu de Desenvolvimento
´
Regional) for financial support to Centro de Quımica (CQ-UM) The
NMR spectrometer Bruker Avance II 400 is part of the National NMR
Network and was acquired with funds from FCT and FEDER. G.P.
acknowledges FCT for a PhD grant SFRH/BD/38766/2007.
Hoerner RS, Askin D, Volante RP, Reider PJ (1998) A highly
enantioselective asymmetric hydrogenation route to b-(2R, 3S)-
methyltryptophan. Tetrahedron Lett 39:3455–3458
Ji C, Peters DG (2001) Electrochemical reduction of benzyl iodide,
benzal bromide and benzal chlorobromide at carbon cathodes in
the presence of nitric oxide in acetonitrile. J Electroanal Chem
516:39–49
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123