Application of 4-alkoxy-1,1,1-trifluoro[chloro]alk-3-en-2-ones as selective protecting groups of amino acids

Article abstract of DOI:10.1055/s-2002-35218

A convenient selective protection of the α-amino carboxyl group of amino acids bearing reactive side chain groups such as arginine, asparagine, glutamine, cysteine, histidine, serine and lysine, using 4-alkoxy-1,1,1-trifluoro[chloro]alk-3-en-2-ones is reported. The reactions were performed without esterification of the carboxyl group and N-deprotection was carried out using a six molar solution of hydrochloric acid.

Full text of DOI:10.1055/s-2002-35218

PAPER
2409
Application of 4-Alkoxy-1,1,1-trifluoro[chloro]alk-3-en-2-ones as Selective
Protecting Groups of Amino Acids
A
lkoxy-1,1,1-triflu
i
oro[ch
l
loro]alk
o
-3-en-2-ones as Pr
Z
otecting
G
roup
a
s
of
A
mino
n
A
cids atta,* Adriana M. C. Squizani, Leonardo Fantinel, Fabiane M. Nachtigall, Helio G. Bonacorso,
Marcos A. P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.
105-900, Santa Maria, RS, Brazil
Fax +55(55)2208031 ; E-mail: zanatta@base.ufsm.br
Received 8 November 2001; revised 23 August 2002
On the course of our research concerning the application
of -alkoxy , -unsaturated trihalomethyl ketones to ob-
tain trihalomethylated containing compounds,6 we dis-
covered that ketones 2–4 selectively react on the -amino
Abstract: A convenient selective protection of the -amino carbox-
yl group of amino acids bearing reactive side chain groups such as
arginine, asparagine, glutamine, cysteine, histidine, serine and
lysine, using 4-alkoxy-1,1,1-trifluoro[chloro]alk-3-en-2-ones is re-
ported. The reactions were performed without esterification of the carboxyl group of amino acids bearing reactive groups on
carboxyl group and N-deprotection was carried out using a six mo-
lar solution of hydrochloric acid.
the side chain residue. Therefore, considering the impor-
tance of amino acid protecting groups for the synthesis of
Key words: ketones, fluorine, halogens, amino acids, protecting
groups
proteins prompted us to report a new aspect of the appli-
cation of 4-alkoxy-1,1,1-trifluoro[chloro]alk-3-ene-2-
ones 2–4 as selective protecting groups for amino acids
bearing reactive groups on the side chain, such as argin-
Protecting groups play a very important role in protein ine, asparagine, glutamine, cysteine, histidine, serine and
synthesis. Over the last decades many new protecting lysine, according to the Scheme 1.
groups for amino acids have been developed which are re-
The reaction of ketones 2–4 with L-amino acids in the free
sponsible for a great improvement in protein synthesis.1
form and L-lysine hydrochloride were carried out in the
An important development in this field was the applica-
presence of a one molar solution of sodium hydroxide. Af-
ter the addition of the reactants the reactions were stirred
for 15 minutes at room temperature and the isolation of
tion of 4-alkoxy-1,1,1-trifluorobut-3-ene-2-one 2 as an -
amino carboxyl protecting group.2,3 Ketone 2, however,
has been applied only to protect the -amino carboxyl
the products was done as described in the experimental
group of amino acids bearing hydrocarbons on the side
part. Under these conditions the amino acids bearing reac-
chain residue. Ketones 2 and 3 have also been used in re-
tive groups on the side chain reacted selectively on the -
amino carboxyl group. The amino acid phenylalanine in
actions with amino acids bearing hydrocarbons on the side
chain, with the objective to obtain useful precursors of
the free acid and the methyl ester forms was used as the
fluorine-containing pyrroles and related heterocycles.4,5
reaction control. The results showed that the reaction pro-
Scheme 1
Synthesis 2002, No. 16, Print: 14 11 2002.
Art Id.1437-210X,E;2002,0,16,2409,2415,ftx,en;M05402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2410
N. Zanatta et al.
PAPER
ceeds for the amino acids on the free acid form as well as were used in a molar ratio of 1:1, the reaction occurred on
on the ester form. In addition, ketones 3 and 4 were used both nitrogens of lysine, sequentially, furnishing a 1:1
for the first time for the protection of amino acids. It was mixture of amino acids protected in the -amino group or
observed that the ketone 3 and 4 showed the same selec- in the -amino group. Simultaneous reaction on both N-
tivity as the ketone 2, but the ketone 3 allowed the isola- and N- of the lysine was not observed when a molar ratio
tion of products 5g–i and the ketone 4 gave better yields of 1:1 of ketones and lysine were used. However, when a
and the products were obtained in higher purity than the molar ratio of 2:1 of the ketone 3 and lysine, respectively,
analogous fluorinated ketones 2 and 3. Compounds 5g–i, was used the dimer 8 was obtained (see Scheme 2). Yields
and 7h,i could not be recovered from the reaction mixture.
and selected physical and spectroscopic data of com-
pounds 5a–f, 6a–i, and 7a–g are reported in Table 1. The
data of compound 8 are reported in the experimental part.
The only observed exception to this trend was the reaction
of ketones 2–4 with lysine. When the ketones and lysine
Scheme 2
Table 1 Yields, Melting Points, and Infrared Data of 5–7
Compound Yield (%)a
Mp (ºC)b
IR (cm–1)c
5–7
5
6
7
5
6
7
5
6
7
a
90
90
89
94–95
65–66
82–83
3264, 1742,
1648, 1568
3345, 2960,
1743, 1620,
1591
3264, 2956,
1731, 1647,
1579
b
c
84
61
66
86
54
67
91
81
79
156–157 157–158 189–191
230–231 220–221 199–200
149–150 144–145 152–153
2936, 1737,
1647, 1550
2935, 1734,
1620, 1560
2947, 1730,
1650, 1548
3359, 1739,
1645, 1545
3366, 1654,
1628, 1541
3359, 1753,
1641, 1547
d
3494, 3222,
1721, 1653,
1553
3383, 3102,
1718, 1682,
1589
3380, 2992,
1744, 1634,
1548
e
fd
g
h
i
68
70
–
71
74
60
66
61
77
70
79
–
121–122 154–155 110–111
3347, 3235,
1739, 1630,
1549
3406, 3215,
1708, 1647,
1583
3369, 2938,
1718, 1647,
1563
oil
–
oil
oil
3221, 1717,
1648, 1569
3434, 3063,
1681, 1539
3390, 2948,
1733, 1644,
1576
238–239 173–175
–
–
–
3110, 2858,
1622, 1542
3252, 3097,
1740, 1635,
1545
–
–
128–129
167–168
-
-
3315, 2922,
1693, 1621,
1521
–
–
–
3300, 2883,
1734, 1658,
1566
a Yield of isolated compounds.
b Melting points are uncorrected.
c Solid compounds were registered in KBr pellets and oils in film (neat).
d Data is from the mixture of isomers.
Synthesis 2002, No. 16, 2409–2415 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Alkoxy-1,1,1-trifluoro[chloro]alk-3-en-2-ones as Protecting Groups of Amino Acids
2411
Figure 1 Possible configurations and conformations assumed by the 4,4,4-trihalo-3-oxobuten-1-yl protected amino acids in DMSO
Many products such as 5c–f and 7a,c–e,g were poorly sol- boxyl group of amino acids bearing reactive groups on the
uble in chloroform and then 1H and 13C NMR spectra were side chain residue. Furthermore, this work used for the
registered in DMSO-d6. According with previous studies first time the trichloromethylated -alkoxyvinyl ketone 4
done by Andrew and Mellor 5 and Wojcik et al.7 in DMSO which showed to be superior protecting group for amino
each compound exhibits three stable forms in the NMR acids than the trifluorinated analogs since better yields
time scale as indicated in Figure 1. Both 1H and 13C NMR and more pure compounds were obtained.
spectra of 5 and 7 registered in DMSO-d6 showed three
sets of signals for each compound. One set of signals cor-
Unless otherwise indicated all common reagents and solvents were
responds to structure I (Z, s-trans), the second set belongs
to the structure IIa (E, s-trans), and the third set of signals
belongs to the structure IIb (E, s-cis) which is a conformer
of IIa.
used as obtained from commercial suppliers without further purifi-
cation. The 4-alkoxy-1,1,1-trifluoro[chloro]alk-3-en-2-ones 2–4
were prepared according to the literature procedure.9 The esterifica-
tion of phenylalanine was done according to the literature proce-
dure.10 The removal of the protecting groups, 4,4,4-trihalo-3-oxo-1-
butenyl, was done according to the literature procedure.2 Mps were
determined on a Reichert Thermovar apparatus and are uncorrected.
A detailed NMR study based on 1D and 2D experiments8
allowed the absolute assignment of all hydrogen and car-
bon nuclei on the mixture of isomers of each compound. 1H and 13C NMR spectra and 2D NMR experiments were acquired
on a Bruker DPX 400 spectrometer (1H at 400.13 MHz and 13C at
Compounds 6a,b,d–f were soluble in chloroform and the
100.62 MHz) or on a Bruker DPX 200 spectrometer (1H at 200.13
NMR spectra of these compounds showed only one set of
MHz and 13C at 50.32 MHz) in DMSO-d6 or CDCl3 using TMS as
the internal reference. IR spectra were recorded on a Bruker IFS 28
FT-IR spectrometer in film for the oils and KBr pellets for the solid
signals, as expected. Compounds 6c,g–i, however, were
registered in DMSO-d6, but surprisingly they also showed
a single set of signals. It seems that the 4-methyl group on
ketone 3 helps to stabilize the Z form in both chloroform
and DMSO. For compounds 6, the major evidence of the
Z-isomer is from the chemical shift of the NH-5. The
NH–5 of Z-isomers of 5 and 7 are more deshielded (10.1 to
10.4 and 9.7 to 10.3 ppm, respectively) than the E-isomers
(8.0 to 9.3 and 8.5 to 9.0 ppm, respectively). The NH–5 of
compounds 6a–i are in a range of 11.1 to 11.4 ppm which
is a solid indication of the Z-form.1H and 13C NMR data
together with the elemental analysis of compounds 5–7
are reported in the experimental part. Figure 2 shows the
atom numbering used for the NMR assignment of 4,4,4-
trihalo-3-oxobuten-1-yl protected amino acids.
compounds. Elemental analysis was performed on a Vario EL Ele-
mentar Analysensysteme. The mass spectrum of 8 was registered in
a HP 5973 MSD connected to a HP 6890 GC and interfaced by a
pentium PC. The GC was equipped with a split-splitless injector,
autosampler, cross-linked HP-5 capillary column (30 m, 0.32 mm
of internal diameter), and helium was used as the carrier gas. Com-
pound 8 was treated with diazomethane solution and analyzed on
the GC/MS in the methyl ester form.
4,4,4-Trihalo-3-oxo-buten-1-yl Protected Amino Acids 5a–f,
6a–i, 7a–g; General Procedure
To a solution of L-amino acids (1b–e,g–i), L-lysine hydrochloride
(1f), or L-phenylalanine methyl ester (1a) (10 mmol) and sodium
hydroxide (10 mmol, 0.4 g) in H2O (10 mL) the ketones 2–4 (10
mmol) were added under vigorous stirring at r.t.. The stirring was
continued for 15 min at r.t.. Compounds 5a–c, 6a–c, and 7a,c pre-
cipitated in the reaction medium and were isolated by filtration,
washed with distilled H2O and dried in a desiccator with phospho-
rous pentoxide under vacuum. The isolation of compounds 5d,e,
6d,e,g–i, and 7d,e,g was done by acidification of the reaction mix-
ture with hydrochloric acid (6 M) to pH less than 3 when they pre-
cipitated and were isolated as the former ones. Compounds 5f, 6f,
and 7b,f did not precipitate upon acidification and were isolated by
extraction with EtOAc (3 15 mL). The organic layers were com-
bined, dried (MgSO4), and the solvent removed by rotary evapora-
tor. Yields, melting points, and infrared data of compounds 5a–f,
6a–i, and 7a–g are presented in Table 1. 1H and 13C NMR data and
elemental analysis are reported in the experimental part.
Figure 2 Atom numbering used for the NMR assignment of 4,4,4-
trihalo-3-oxo-buten-1-yl protected amino acids
Compounds 5–7 were deprotected using a 6 molar solu-
tion of hydrochloric acid in methanol for 20 hours at 70 ºC
and the amino acids were recovered in 57–92% yield (see
experimental). According to previous studies, under this
condition racemization of the amino acids were not ob- Methyl 3-Phenyl-2-[(Z)-4,4,4-trifluoro-3-oxo-1-butenylami-
served.2
no]propanoate (5a)
3
1H NMR (200 MHz, CDCl3): = 3.01 (dd, 1 H, JH7H6 = 8.8 Hz,
In conclusion, this work presented a simple and conve-
nient, procedure to selectively protect the -amino car-
2JH7H7 = 14.0 Hz, H-7), 3.25 (dd, 1 H, 3JH7H6 = 4.8 Hz, 2JH7H7 = 14.0
Hz, H-7), 3.74 (s, 3 H, OCH3), 4.13–4.24 (m, 1 H, H-6), 5.26 (d, 1
3
3
H, JH3H4 = 7.2 Hz, H-3), 6.76 (dd, 1 H, JH4H3 = 7.4 Hz,
Synthesis 2002, No. 16, 2409–2415 ISSN 0039-7881 © Thieme Stuttgart · New York

2412
N. Zanatta et al.
PAPER
3JH4H5 = 13.4 Hz, H-4), 7.11–7.34 (m, 5 H, Ph), 10.24–10.35 (m, 1
H, H-5).
Anal. Calcd for C8H9F3N2O4 (254,16): C, 37.81; H, 3.57; N, 11.02.
Found: C, 37.89; H, 3.60; N,10.86.
13C NMR (50 MHz, CDCl3): = 39.6 (C7), 52.5 (OCH3), 63.1 (C6),
87.7 (C3), 117.0 (1JCF = 289.0 Hz, C1), 127.3, 128.7, 129.2, 134.8
(Ph), 156.5 (C4), 169.9 (CO2Me), 178.2 (2JCF = 33.4 Hz, C2).
4-Carbamoyl-2-[(Z,E)-4,4,4-trifluoro-3-oxo-1-butenylami-
no]butanoic Acid (5e)
5e (Z, s-trans)
1H NMR (200 MHz, DMSO-d6): = 1.81–2.20 (m, 4 H, H-7, H-8),
4.21–4.34 (m, 1 H, H-6), 5.41 (d, 1 H, 3JH3H4 = 6.0 Hz, H-3), 6.90
(br s, 2 H, NH2), 7.84–8.01 (m, 1 H, H-4), 10.30 (dd, 1 H,
3JH5H4 = 14.0 Hz, 3JH5H6 = 8.0 Hz, H-5).
Anal. Calcd for C14H14F3NO3 (301.26): C, 55.82; H, 4.68; N, 4.65.
Found: C, 55.75; H, 4.55; N, 4.72.
3-Phenyl-2-[(Z)-4,4,4-trifluoro-3-oxo-1-butenylamino]pro-
panoic Acid (5b)
13C NMR (50 MHz, DMSO-d6): = 28.5 (C7), 30.6 (C8), 60.3
(C6), 86.7 (C3), 117.3 (1JCF = 290.0 Hz, C1), 159.0 (C4), 171.8
(CO2H), 173.5 [C(=O)NH2], 176.0 (2JCF = 31.4 Hz, C2).
3
1H NMR (200 MHz, CDCl3): = 3.00 (dd, 1 H, JH7H6 = 9.0 Hz,
2JH7H7 = 14.0 Hz, H-7), 3.32 (dd, 1 H, 3JH7H6 = 4.2 Hz, 2JH7H7 = 14.0
Hz, H-7), 4.08–4.19 (m, 1 H, H-6), 5.2 (d, 1 H, 3JH3H4 = 7.2 Hz, H-
3), 6.7 (dd, 1 H, 3JH4H3 = 7.2 Hz, 3JH4H5 = 13.4 Hz, H-4), 7.15–7.35
(m, 5 H, Ph), 9.78 (s, 1 H, OH), 10.25–10.35 (m, 1 H, H-5).
5e (E, s-trans/s-cis)
1H NMR: = 1.81–2.20 (m, 8 H, H-7, H-8), 4.21–4.34 (m, 2 H, H-
6), 5.45 (d, 1 H, 3JH3H4 = 12.0 Hz, H-3), 5.60 (d, 1 H, 3JH3H4 = 12.0
Hz, H-3), 7.45–7.61 (m, 6 H, H-4, NH2), 8.94 (br s, 1 H, H-5), 9.17–
9.28 (m, 1 H, H-5).
13C NMR (50 MHz, CDCl3): = 39.3 (C7), 62.8 (C6), 87.1 (C3),
116.7 (1JCF = 289.0 Hz, C1), 127.0, 128.2, 129.0, 135.1 (Ph), 156.4
(C4), 171.1 (CO2H), 177.6 (2JCF = 33.4 Hz, C2).
13C NMR: = 26.8, 27.9 (C7), 30.5, 30.9 (C8), 55.9, 60.0 (C6),
86.7, 88.5 (C3), 117.7, 118.0 (1JCF = 292.0/292.0 Hz, C1), 154.0,
158.4 (C4), 172.1, 172.6 (CO2H), 173.3, 173.5 [C(=O)NH2], 175.7,
176.0 (2JCF = 32.0/32.0 Hz, C2).
Anal. Calcd for C13H12F3NO3 (287.23): C, 54.36; H, 4.21; N, 4.88.
Found: C, 54.20; H, 4.10; N, 4.91.
5-[Amino(iminomethyl)]amino-2-[(E,Z)-4,4,4-trifluoro-3-oxo-
1-butenylamino]pentanoic Acid (5c)
Anal. Calcd for C9H11F3 N2O4 (268.19): C, 40.31; H, 4.13; N, 10.45.
Found: C, 40.43; H, 4.03; N, 10.43.
5c (Z, s-trans)
1H NMR (200 MHz, DMSO-d6): = 1.41 (m, 2 H, H-8), 1.69 (m, 2
H, H-7), 3.02 (m, 2 H, H-9), 3.74 (m, 1 H, H-6), 5.20 (d, 1 H,
3JH3H4 = 8.0 Hz, H-3), 7.37–7.77 [m, 5 H, H-4, NHC(= NH)NH2],
10.44 (dd, 1 H, 3JH5H4 = 14.0 Hz, 3JH5H6 = 8.0 Hz, H-5).
6-Amino-2-[(Z,E)-4,4,4-trifluoro-3-oxo-1-butenylamino]hex-
anoic Acid (5f)
5f (N- -Isomer in the Z and E Forms)
13C NMR (50 MHz, DMSO-d6): = 24.5 (C8), 31.1 (C7), 38.2
(C9), 62.3 (C6), 85.2 (C3), 117.2 (1JCF = 290.3 Hz, C1), 157.0 (C4),
157.3 [C( = NH)NH2], 173.0 (CO2H), 174.2 (2JCF = 31.2 Hz, C2).
1H NMR (200 MHz, DMSO-d6): = 1.57–1.96 (m, 18 H, H-7, H-8,
H-9), 3.14–3.50 (m, 6 H, H-10), 4.00–4.23 (m, 3 H, H-6), 5.22–5.62
(m, 9 H, H-3, NH2), 7.85–7.98 (m, 3 H, H-4), 8.72–9.13 (m, 2 H, H-
5), 10.14–10.39 (m, 1 H, NH-5).
5c (E, s-trans/s-cis)
13C NMR (50 MHz, DMSO-d6): = 22.4, 22.5, 22.7, 26.7, 26.8,
27.1, 30.5, 31.6, 31.7 (C7, C8, C9), 32.2, 32.3, 32.4 (C10), 60.7,
60.8, 61.1 (C6), 85.6, 85.7, 88.4 (C3), 118.0, 118.0, 118.1
(1JCF = 292.0/292.0/292.0 Hz, C1), 154.0, 154.4, 158.3 (C4), 172.0,
172.3, 172.8 (CO2H), 175.0, 175.2, 175.4 (2JCF = 31.1/31.2/31.3
Hz, C2).
1H NMR: = 1.41 (m, 4 H, H-8), 1.69 (m, 4 H, H-7), 3.02 (m, 4 H,
H-9), 3.74 (m, 2 H, H-6), 5.23 (d, 1 H, 3JH3H4 = 12.0 Hz, H-3), 5.51
3
(d, 1 H, JH3H4 = 12.0 Hz, H-3), 7.37–7.77 [m, 10 H, H-4,
NHC(=NH)NH2], 8.72 (br s, 2 H, H-5).
13C NMR: = 24.6, 24.7 (C8), 28.3, 30.4 (C7), 40.1, 40.7 (C9),
58.0, 63.0 (C6), 78.8, 87.6 (C3), 117.7, 118.7 (1JCF = 292.0/292.0
Hz, C1), 153.0, 156.7 (C4), 157.3 [C(=NH)NH2], 172.5, 173.3
(CO2H), 174.3 (2JCF = 33.0 Hz, C2).
Anal. Calcd for C10H15F3 N2O3 (268.23): C, 44.78; H, 5.64; N,
10.44. Found: C, 44.36; H, 5.41; N, 10.19.
Anal. Calcd for C10H15F3N4O3 (296,24): C, 40.54; H, 5.10; N,
18.91. Found: C, 40.22; H, 4.95; N, 18.76.
2-Amino-6-[(Z,E)-4,4,4-trifluoro-3-oxo-1-butenylamino]hex-
anoic Acid (5f )
5f (N- -isomer in the Z and E forms)
1H NMR (200 MHz, DMSO-d6): = 1.02–1.35 (m, 18 H, H-7, H-8,
H-9), 3.14–3.50 (m, 6 H, H-6), 4.00–4.23 (m, 3 H, H-10), 5.22–5.62
(m, 3 H, H-3), 7.41–7.59 (m, 3 H, H-4), 8.72–9.13 (m, 2 H, H-5),
10.14–10.39 (m, 1 H, H-5).
3-Carbamoyl-2-[(Z,E)-4,4,4-trifluoro-3-oxo-1-butenylami-
no]propanoic Acid (5d)
5d (Z, s-trans)
1H NMR (200 MHz, DMSO-d6): = 2.52–2.92 (m, 2 H, H-7), 4.49–
4.53 (m, 1 H, H-6), 5.34 (d, 1 H, 3JH3H4 = 6.0 Hz, H-3), 7.07 (br s, 2
H, NH2), 7.43–7.54 (m, 1 H, H-4), 10.42 (dd, 1 H, 3JH5H4 = 14.0 Hz,
3JH5H6 = 8.0 Hz, H-5).
13C NMR (50 MHz, DMSO-d6): = 21.5, 21.7, 22.0, 22.1, 22.2,
22.3, 29.6, 29.7, 29.8 (C7, C8, C9), 43.2, 48.7, 48.8 (C6), 56.2, 56.3,
56.4 (C10), 86.5, 86.6, 87.3 (C3), 117.3, 117.5, 117.7 (1JCF = 290.0/
290.0/290.0 Hz, C1), 158.5, 158.7, 159.5 (C4), 172.1, 172.2, 172.4
(CO2H), 175.7, 175.8, 176.0 (2JCF = 31.7/31.8/ 32.0 Hz, C2).
13C NMR (50 MHz, DMSO-d6): = 38.2 (C7), 58.2 (C6), 86.2
(C3), 117.4 (1JCF = 290.0 Hz, C1), 159.5 (C4), 171.4 (CO2H), 171.8
[C(=O)NH2], 175.6 (2JCF = 31.4 Hz, C2).
Methyl 3-Phenyl-2-[(Z)-4,4,4-trifluoro-1-methyl-3-oxo-1-bute-
nylamino]propanoate (6a)
5d (E, s-trans/s-cis)
1H NMR: = 2.52–2.92 (m, 4 H, H-7), 4.49 4.53 (m, 2 H, H-6), 5.50
(d, 1 H, 3JH3H4 = 12.0 Hz, H-3), 5.60 (d, 1 H, 3JH3H4 = 12.0 Hz, H-3),
7.43–7.54 (br s, 4 H, NH2), 7.80–7.97 (m, 2 H, H-4), 8.83 (br s, 1 H,
H-5), 9.13 (dd, 1 H, 3JH5H4 = 14.0 Hz, 3JH5H6 = 10.0 Hz, H-5).
1H NMR (400 MHz, CDCl3): = 1.70 (s, 3 H, CH3), 3.01 (dd, 1 H,
3JH7H6 = 8.8 Hz, 2JH7H7 = 13.6 Hz, H-7), 3.26 (dd, 1 H, 3JH7H6 = 4.4
Hz, 2JH7H7 = 13.6 Hz, H-7), 3.74 (s, 3 H, OCH3), 4.41–4.47 (m, 1 H,
H-6), 5.25 (s, 1 H, H-3), 7.17–7.32 (m, 5 H, Ph), 11.3 (d, 1 H,
3JH6H5 = 8.8 Hz, H-5).
13C NMR: = 36.1, 37.4 (C7), 52.8, 58.0 (C6), 86.1, 88.4 (C3),
117.8, 118.0 (1JCF = 292.0/292.0 Hz, C1), 154.0, 158.7 (C4), 170.8,
171.0 (CO2H), 171.3, 172.2 [C(=O)NH2], 175.0, 176.0 (2JCF = 32.0/
32.0 Hz, C2).
13C NMR (100 MHz, CDCl3): = 18.8 (CH3), 39.5 (C7), 52.5
(OCH3), 58.3 (C6), 89.9 (C3), 117.3 (1JCF = 289.0 Hz, C1), 127.3,
Synthesis 2002, No. 16, 2409–2415 ISSN 0039-7881 © Thieme Stuttgart · New York

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Alkoxy-1,1,1-trifluoro[chloro]alk-3-en-2-ones as Protecting Groups of Amino Acids
2413
128.7, 129.1, 135.1 (Ph), 168.4 (C4), 170.0 (CO2Me), 176.0
2-Amino-6-[(E)-4,4,4-trifluoro-1-methyl-3-oxo-1-butenylami-
no]hexanoic Acid (6f )
(2JCF = 32.8 Hz, C2).
6f (N- -isomer)
Anal. Calcd for C15H16F3NO3 (315.29): C, 57.14; H, 5.11; N, 4.44.
Found: C, 56.70; H, 4.99; N, 4.86.
1H NMR (400 MHz, CDCl3): = 1.26–1.68 (m, 8 H, H-7, H-8, H-
9, NH2), 2.06 (s, 3 H, CH3), 3.38 (br s, 2 H, H-6), 3.98 (br s, 1 H, H-
10), 5.35 (s, 1 H, H-3), 11.2 (br s, 1 H, H-5).
3-Phenyl-2-[(Z)-4,4,4-trifluoro-1-methyl-3-oxo-1-butenylami-
no]propanoic Acid (6b)
13C NMR (100 MHz, CDCl3): = 19.2 (CH3), 22.3 (C8), 29.7 (C9),
32.5 (C7), 43.5 (C6), 56.4 (C10), 90.4 (C3), 117.6 (1JCF = 288.0 Hz,
C1), 169.4 (C4), 171.1 (CO2H), 175.7 (2JCF = 33.6 Hz, C2).
1H NMR (400 MHz, CDCl3): = 1.82 (s, 3 H, CH3), 3.05 (dd, 1 H,
3JH7H6 = 8.4 Hz, 2JH7H7 = 13.6 Hz, H-7), 3.26 (dd, 1 H, 3JH7H6 = 4.4
Hz, 2JH7H7 = 13.6 Hz, H-7), 4.54–4.59 (m, 1 H, H-6), 5.24 (s, 1 H,
H-3), 7.19–7.31 (m, 5 H, Ph), 11.2 (d, 1 H, 3JH5H6 = 9.2 Hz, H-5).
Observation: signals between 6f and 6f may be interconverted.
13C NMR (100 MHz, CDCl3): = 18.8 (CH3), 36.6 (C7), 57.6 (C6),
89.1 (C3), 117.2 (1JCF = 289.0 Hz, C1), 126.9, 128.3, 129.1, 134.9
(Ph), 168.9 (C4), 171.0 (CO2H), 174.4 (2JCF = 32.0 Hz, C2).
3-(1H-Imidazol-5-yl)-2-[(E)-4,4,4-trifluoro-1-methyl-3-oxo-1-
butenylamino]propanoic Acid (6g)
1H NMR (200 MHz, DMSO-d6): = 2.06 (s, 3 H, CH3), 3.12–3.33
(m, 2 H, H-7), 4.66–4.76 (m, 1 H, H-6), 5.37 (s, 1 H, H-3), 7.12 (s,
1 H, H-9), 7.78 (br s, 1 H, NH), 8.17 (s, 1 H, H-11), 11.2 (d, 1 H,
3JH5H6 = 8.8 Hz, H-5).
Anal. Calcd for C14H14F3NO3 (301.26): C, 55.82; H, 4.68; N, 4.65.
Found: C, 55.59; H, 4.60; N, 4.60.
5-[Amino(iminomethyl)]amino-2-[(Z)-4,4,4-trifluoro-1-methyl-
3-oxo-1-butenylamino]pentanoic Acid (6c)
13C NMR (50 MHz, DMSO-d6): = 19.1 (CH3), 29.8 (C7), 56.8
(C6), 88.7 (C3), 117.1 (C9), 117.7 (1JCF = 289.6 Hz, C1), 131.1
(C8), 134.7 (C11), 170.0 (C4), 171.7 (CO2H), 173.0 (2JCF = 31.2
Hz, C2).
1H NMR (200 MHz, DMSO-d6): = 1.52 (m, 2 H H-8), 1.76 (m, 2
H H-7), 2.10 (s, 3 H, CH3), 3.11 (m, 2 H, H-9), 4.06 (m, 1 H, H-6),
5.28 (s, 1 H, H-3), 7.79 [br s, 3 H, NC(=NH)NH2], 8.82 [br s, 1 H,
NHC(=N)], 11.33 (d, 1 H, 3JH5H6 = 8.0 Hz, H-5).
Anal. Calcd for C11H11F3N3O3 (290.22): C, 45.52; H, 3.82; N,
14.48. Found: C, 45.19; H, 3.96; N, 14.17.
13C NMR (50 MHz, DMSO-d6): = 18.7 (CH3), 24.5 (C8), 30.1
(C7), 57.7 (C9), 78.7 (C6), 87.7 (C3), 117.4 (1JCF = 289.6 Hz, C1),
157.0 (C4), 168.2 [NC(=NH)NH2], 171.6 (2JCF = 31.0 Hz, C2),
173.0 (CO2H).
3-Hydroxy-2-[(Z)-4,4,4-trifluoro-1-methyl-3-oxo-1-butenyl-
amino]propanoic Acid (6h)
1H NMR (200 MHz, DMSO-d6): = 2.11 (s, 3 H, CH3), 3.74 (dd, 1
3
2
H, JH7H6 = 3.4 Hz, JH7H7 = 11.2 Hz, H-7), 3.86 (dd, 1 H,
Anal. Calcd for C11H17F3N4O3 (310.27): C, 42.58; H, 5.52; N,
18.06. Found: C, 42.11; H, 5.31; N, 17.95.
3JH7H6 = 4.0 Hz, JH7H7 = 11.0 Hz, H-7), 4.48–4.56 (m, 1 H, H-6),
2
5.38 (s, 1 H, H-3), 6.52 (br s, 1 H, OH), 11.26 (d, 1 H, 3JH5H6 = 8.6
Hz, H-5).
3-Carbamoyl-2-[(Z)-4,4,4-trifluoro-1-methyl-3-oxo-1-butenyl-
amino]propanoic Acid (6d)
13C NMR (50 MHz, DMSO-d6): = 19.3 (CH3), 58.4 (C6), 62.0
(C7), 88.8 (C3), 117.7 (1JCF = 289.6 Hz, C1), 170.1 (C4), 170.4
(CO2H), 173.1 (2JCF = 31.3 Hz, C2).
1H NMR (200 MHz, CDCl3): = 2.15 (s, 3 H, CH3), 2.68–2.91 (m,
2 H, H-7), 4.63–4.73 (m, 1 H, H-6), 5.31 (s, 1 H, H-3), 6.93, 7.53
(br s, 2 H, NH2), 11.21 (d, 1 H, 3JH5H6 = 8.0 Hz, H-5).
Anal. Calcd for C8H10F3NO4 (241.16): C, 39.84; H, 4.18; N, 5.81.
Found: C, 39.53; H, 4.35; N, 5.96.
13C NMR (50 MHz, CDCl3): = 19.2 (CH3), 37.4 (C7), 52.9 (C6),
88.8 (C3), 117.5 (1JCF = 289.0 Hz, C1), 169.6 (C4), 170.9 (CO2H),
171.4 [C(=O)NH2], 173.7 (2JCF = 31.6 Hz, C2).
3-Sulfanyl-2-[(Z)-4,4,4-trifluoro-1-methyl-3-oxo-1-butenylami-
no]propanoic Acid (6i)
Anal. Calcd for C9H11F3N2O4 (268.19): C, 40.31; H, 4.13; N, 10.45.
Found: C, 40.03; H, 4.29; N, 10.09.
1H NMR (200 MHz, DMSO-d6): = 2.23 (s, 3 H, CH3), 3.03–3.12
(m, 2 H, H-7), 4.85–4.94 (m, 1 H, H-6), 5.50 (s, 1 H, H-3), 7.53 (br
s, 1 H, SH), 11.3 (d, 1 H, 3JH5H6 = 9.0 Hz, H-5).
4-Carbamoyl-2-[(Z)-4,4,4-trifluoro-1-methyl-3-oxo-1-butenyl-
amino]butanoic Acid (6e)
13C NMR (50 MHz, DMSO-d6): = 19.5 (CH3), 41.1 (C7), 55.4
(C6), 89.4 (C3), 117.6 (1JCF = 289.0 Hz, C1), 170.4 (C4), 170.6
(CO2H), 173.7 (2JCF = 32.0 Hz, C2).
1H NMR (200 MHz, CDCl3): = 1.98–2.29 (m, 4 H, H-7, H-8),
2.14 (s, 3 H, CH3), 4.48–4.55 (m, 1 H, H-6), 5.37 (s, 1 H, H-3), 6.66,
7.37 (br s, 2 H, NH2), 11.22 (d, 1 H, 3JH5H6 = 8.0 Hz, H-5).
Anal. Calcd for C8H10F3NO3S (257.22): C, 37.36, H; 3.92; N, 5.45.
Found: C, 37.00; H, 3.95; N, 5.48.
13C NMR (50 MHz, CDCl3): = 19.1 (CH3), 28.4 (C7), 30.2 (C8),
55.6 (C6), 89.2 (C3), 117.7 (1JCF = 289.3 Hz, C1), 170.5 (C4), 171.8
(CO2H), 173.2 [C(=O)NH2], 173.5 (2JCF = 31.4 Hz, C2).
Methyl 3-Phenyl-2-[(Z,E)-4,4,4-trichloro-3-oxo-1-butenylami-
no]propanoate (7a)
Anal. Calcd for C10H13F3N2O4 (282.21): C, 42.56; H, 4.64; N, 9.93.
Found: C, 42.36; H, 4.77; N, 10.33.
7a (Z, s-trans)
1H NMR (400 MHz, DMSO-d6): = 3.12–3.24 (m, 2 H, H-7), 3.66
(s, 3 H, OCH3), 4.62–4.70 (m, 1 H, H-6), 5.54 (d, 1 H, 3JH3H4 = 7.6
Hz, H-3), 7.17–7.37 (m, 1 H, H-4), 7.17–7.37 (m, 5 H, Ph), 8.67 (t,
1 H, 3JH4H5H6 = 7.6 Hz, H-5).
6-Amino-2-[(Z)-4,4,4-trifluoro-1-methyl-3-oxo-1-butenylami-
no]hexanoic Acid (6f)
6f (N- -isomer)
1H NMR (400 MHz, CDCl3): = 1.26–1.68 (m, 8 H, H-7, H-8, H-
9, NH2), 2.07 (s, 3 H, CH3), 2.90 (br s, 2 H, H-10), 4.36 (br s, 1 H,
H-6), 5.32 (s, 1 H, H-3), 11.4 (d, 1 H, 3JH5H6 = 8.8 Hz, H-5).
13C NMR (100 MHz, DMSO-d6): = 36.4 (C7), 52.2 (OCH3), 61.4
(C6), 84.0 (C3), 96.7 (C1), 126.7, 128.3, 129.1, 135.8 (Ph), 157.9
(C4), 170.6 (CO2Me), 179.0 (C2).
13C NMR (100 MHz, CDCl3): = 19.3 (CH3), 22.2 (C8), 28.8 (C9),
32.6 (C7), 38.7 (C10), 56.9 (C6), 89.8 (C3), 117.8 (1JCF = 288.0 Hz,
C1), 170.4 (C4), 172.6 (CO2H), 177.4 (2JCF = 32.7 Hz, C2).
7a (E, s-trans/s-cis)
1H NMR (400 MHz, DMSO-d6): = 2.94 (dd, 1 H, 3JH7H6 = 9.6 Hz,
2JH7H7 = 14 Hz, H-7), 3.04 (dd, 1 H, 3JH7H6 = 8.0 Hz, 2JH7H7 = 14 Hz,
H-7), 3.12–3.24 (m, 2 H, H-7), 3.68 (s, 3 H, OCH3), 3.71 (s, 3 H,
OCH3), 4.48–4.54 (m, 1 H, H-6), 4.62–4.70 (m, 1 H, H-6), 5.64 (d,
Synthesis 2002, No. 16, 2409–2415 ISSN 0039-7881 © Thieme Stuttgart · New York

2414
N. Zanatta et al.
PAPER
3
3
3
1 H, JH3H4 = 12.0 Hz, H-3), 5.85 (d, 1 H, JH3H4 = 12.0 Hz, H-3),
7.17–7.37 (m, 5 H, Ph), 7.66–7.72 (m, 2 H, H-4), 9.00 (dd, 1 H,
3JH5H4 = 13.7 Hz, 3JH5H6 = 8.9 Hz, H-5), 9.7 (dd, 1 H, 3JH5H4 = 13.6
Hz, 3JH5H6 = 8.7 Hz, H-5).
2 H, H-4), 8.56 (t, 1 H, JH4H5H6 = 7.8 Hz, H-5), 8.84 (dd, 1 H,
3JH5H4 = 14.0 Hz, 3JH5H6 = 8.6 Hz, H-5).
13C NMR: = 36.1, 37.5 (C7), 52.7, 57.5 (C6), 84.0, 85.9 (C3),
98.1, 98.4 (C1), 154.0, 158.7 (C4), 170.6, 170.7 (CO2H), 171.3,
172.1 [C(=O)NH2], 179.0, 179.6 (C2).
13C NMR: = 37.9, 38.2 (C7), 52.3, 52.4 (OCH3), 57.3, 61.8 (C6),
84.8, 86.2 (C3), 97.9, 98.2 (C1), 126.8, 126.9, 128.3, 128.4, 129.2,
129.3, 135.9, 136.3 (Ph), 153.6, 158.3 (C4), 170.7, 171.2 (CO2Me),
179.6, 180.2 (C2).
Anal. Calcd for C8H9Cl3N2O4 (303,52): C, 31.66; H, 2.99; N, 9.23.
Found: C, 31.10; H, 3.26; N, 9.47.
Anal. Calcd for C14H14Cl3NO3 (350.62): C, 47.96; H, 4.02; N, 3.99.
Found: C, 47.17; H, 4.02; N, 3.91.
4-Carbamoyl-2-[(Z,E)-4,4,4-trichloro-3-oxo-1-butenylami-
no]butanoic Acid (7e)
7e (Z, s-trans)
3-Phenyl-2-[(Z)-4,4,4-trichloro-3-oxo-1-butenylamino]pro-
1H NMR (400 MHz, DMSO-d6): = 1.60–2.17 (m, 4 H, H-7, H-8),
panoic Acid (7b)
4.16–4.27 (m, 1 H, H-6), 5.60 (d, 3JH3H4 = 7.4 Hz, H-3), 6.78 (br s,
3
3
3
1H NMR (200 MHz, CDCl3): = 2.96 (dd, 1 H, JH7H6 = 9.5 Hz,
2 H, NH2), 7.47 (dd, 1 H, JH4H3 = 7.6 Hz, JH4H5 = 13.8 Hz, H-4),
9.73 (dd, 1 H, 3JH5H4 = 13.8 Hz, 3JH5H6 = 8.3 Hz, H-5).
2JH7H7 = 13.6 Hz, H-7), 3.34 (dd, 1 H, 3JH7H6 = 3.6 Hz, 2JH7H7 = 13.6
Hz, H-7), 4.06–4.20 (m, 1 H, H-6), 5.53 (d, 1 H, 3JH3H4 = 7.5 Hz, H-
3), 6.60 (dd, 1 H, 3JH4H3 = 7.5 Hz, 3JH4H5 = 13.5 Hz, H-4), 7.14–7.30
(m, 5 H, Ph), 8.78 (br s, 1 H, OH), 9.85–9.96 (m, 1 H, H-5).
13C NMR (100 MHz, DMSO-d6): = 27.8 (C7), 30.5 (C8), 59.8
(C6), 84.0 (C3), 98.1 (C1), 158.2 (C4), 172.2 (CO2H), 173.3
[C(=O)NH2], 179.7 (C2).
13C NMR (50 MHz, CDCl3): = 40.0, 40.2 (C7), 63.3, 63.4 (C6),
85.5, 85.9 (C3), 96.4, 96.5(C1), 127.4, 127.5, 128.8, 129.0, 129.3,
129.4, 135.0, 135.3 (Ph), 155.8, 156.4 (C4), 173.8, 173.9 (CO2H),
182.2, 182.3 (C2).
7e (E, s-trans/s-cis)
1H NMR: = 1.60–2.17 (m, 8 H, H-7, H-8), 4.06 (q, 1 H,
3JH6H5H7 = 7.5 Hz, H-6), 4.16–4.27 (m, 1 H, H-6), 5.62 (d, 1 H,
3JH3H4 = 12.8 Hz, H-3), 5.86 (d, 1 H, 3JH3H4 = 12.0 Hz, H-3), 7.34 (br
s, 2 H, NH2), 7.71 (dd, 1 H, 3JH4H3 = 13.4 Hz, 3JH4H5 = 7.7 Hz, H-4),
5-[Amino(iminomethyl)]amino-2-[(Z,E)-4,4,4-trichloro-3-oxo-
1-butenylamino]pentanoic Acid (7c)
3
3
7.76 (t, 1 H, JH4H3H5 = 13.4 Hz, H-4), 8.62 (t, 1 H, JH4H5H6 = 7.6
7c (Z, s-trans)
Hz, H-5), 8.90 (dd, 1 H, 3JH5H4 = 13.9 Hz, 3JH5H6 = 7.6 Hz, H-5).
1H NMR (400 MHz, DMSO-d6): = 1.72 (m, 2 H, H-8), 1.98 (m, 2
H, H-7), 3.34 (m, 2 H, H-9), 4.07–4.12 (m, 1 H, H-6), 5.54 (d, 1 H,
3JH3H4 = 7.2 Hz, H-3), 7.74 (dd, 1 H, 3JH4H3 = 7.3 Hz, 3JH4H5 = 14.0
Hz, H-4), 7.88 [br s, 3 H, NC(=NH)NH2], 9.00 (br s, 1 H, NH),
10.29 (dd, 1 H, 3JH5H4 = 14.4 Hz, 3JH5H6 = 7.6 Hz, H-5).
13C NMR: = 26.7, 28.4 (C7), 30.5, 30.9 (C8), 55.7, 60.3 (C6),
84.3, 86.0 (C3), 96.9, 98.4 (C1), 154.2, 158.6 (C4), 172.0, 172.7
(CO2H), 173.1, 173.3 [C(=O)NH2], 179.1, 180.2 (C2).
Anal. Calcd for C9H11Cl3N2O4 (317.55): C, 34.04; H, 3.49; N, 8.82.
Found: C, 33.56; H, 3.43; N, 8.84.
13C NMR (100 MHz, DMSO-d6): = 24.8 (C8), 31.3 (C7), 40.2
(C9), 61.8 (C6), 82.6 (C3), 97.2 (C1), 157.0 (C4), 157.1
[NC(=NH)NH2], 173.6 (CO2H), 179.2 (C2).
6-Amino-2-[(Z)-4,4,4-trichloro-3-oxo-1-butenylamino]hexano-
ic Acid (7f)
7f (N- -isomer)
7c (E, s-trans/s-cis)
1H NMR (400 MHz, CDCl3): = 1.25–1.88 (m, 8 H, H-7, H-8, H-
9, NH2), 3.09 (br s, 2 H, H-10). 4.12–4.16 (m, 1 H, H-6), 5.65–5.73
(m, 1 H, H-3), 7.80–7.90 (m, 1 H, H-4), 10.02 (br s, 1 H, H-5).
1H NMR (400 MHz, DMSO-d6): = 1.72 (m, 4 H, H-8), 1.98 (m, 4
H, H-7), 3.34 (m, 4 H, H-9), 3.76–4.00 (m, 1 H, H-6), 4.00–4.12 (m,
3
1 H, H-6), 5.82 (d, 1 H, JH3H4 = 12.4 Hz, H-3), 6.12 (d, 1 H,
13C NMR (100 MHz, CDCl3): = 21.9 (C8), 29.5 (C9), 33.1 (C7),
40.0 (C10), 61.5 (C6), 85.7 (C3), 97.9 (C1), 158.2 (C4), 174.6
(CO2H), 182.1 (C2).
3JH3H4 = 12.0 Hz, H-3), 7.88 [br s, 6 H, NC(=NH)NH2], 7.96–8.02
(m, 2 H, H-4), 8.76 (t, 1 H, 3JH4H5H6 = 7.6 Hz, H-5), 8.91 (dd, 1 H,
3JH5H4 = 14.4 Hz, 3JH5H6 = 8.4 Hz, H-5), 9.00 (br s, 2 H, NH).
13C NMR: = 25.0, 25.2 (C8), 28.5, 30.4 (C7), 40.1, 40.3 (C9),
57.7, 62.6 (C6), 82.9, 84.9 (C3), 98.4, 98.7 (C1), 153.8, 157.2 (C4),
157.4, 158.1 [NC(=NH)NH2], 173.4, 174.3 (CO2H), 178.5, 179.2
(C2).
2-Amino-6-[(Z)-4,4,4-trichloro-3-oxo-1-butenylamino]hexano-
ic Acid (7f )
7f (N- -isomer)
1H NMR (400 MHz, CDCl3): = 1.25–1.88 (m, 8 H, H-7, H-8, H-
9, NH2), 3.34 (br s, 2 H, H-6), 4.05–4.10 (m, 1 H, H-10), 5.65–5.73
(m, 1 H, H-3), 7.11–7.27 (m, 1 H, H-4), 9.78 (br s, 1 H, H-5).
Anal. Calcd for C10H15Cl3N4O3 (345.61): C, 34.75; H, 4.37; N,
16.21. Found: C, 34.66; H, 4.27; N, 16.00.
13C NMR (100 MHz, CDCl3): = 22.2 (C8), 28.8 (C9), 32.6 (C7),
49.1 (C6), 58.3 (C10), 84.7 (C3), 97.7 (C1), 156.6 (C4), 174.4
(CO2H), 181.9 (C2).
3-Carbamoyl-2-[(Z,E)-4,4,4-trichloro-3-oxo-1-butenylami-
no]propanoic Acid (7d)
7d (Z, s-trans)
1H NMR (400 MHz, DMSO-d6): = 2.55–2.85 (m, 2 H, H-7), 4.44–
4.49 (m, 1 H, H-6), 5.57 (d, 1 H, 3JH3H4 = 7.4 Hz, H-3), 7.02 (br s, 2
H, NH2), 7.42–7.50 (m, 1 H, H-4), 9.93 (dd, 1 H, 3JH5H4 = 14.0 Hz,
3JH5H6 = 8.9 Hz, H-5).
3-(1H-Imidazol-5-yl)-2-[(Z,E)-4,4,4-trichloro-3-oxo-1-butenyl-
amino]propanoic Acid (7g)
7g (Z, s-trans)
1H NMR (400 MHz, DMSO-d6): = 2.80–3.12 (m, 2 H, H-7), 4.17–
4.33 (m, 1 H, H-6), 5.39 (d, 1 H, 3JH3H4 = 7.4 Hz, H-3), 6.92 (s, 1 H,
H-9), 7.19 (dd, 1 H, 3JH4H3 = 7.6 Hz, 3JH4H5 = 14.0 Hz, H-4), 7.57 (br
s, 2 H, H-4, -NH), 9.80 (dd, 1 H, 3JH5H4 = 13.9 Hz, 3JH5H6 = 8.06 Hz,
H-5).
13C NMR (100 MHz, DMSO-d6): = 37.4 (C7), 57.7 (C6), 83.4
(C3), 97.0 (C1), 158.6 (C4), 171.1 (CO2H), 171.8 [C(=O)NH2],
179.8 (C2).
7d (E, s-trans/s-cis)
13C NMR (100 MHz, DMSO-d6): = 30.2 (C7), 60.9 (C6), 83.3
(C3), 97.0 (C1), 116.8 (C9), 131.7 (C8), 134.4 (C11), 157.7 (C4),
172.2 (-CO2H), 179.7 (C2).
1H NMR (400 MHz, DMSO-d6): = 2.5–2.85 (m, 4 H, H-7), 4.37–
4.51 (m, 2 H, H-6), 5.71 (d, 1 H, 3JH3H4 = 12.7 Hz, H-3), 5.88 (d, 1
H, 3JH3H4 = 12.0 Hz, H-3), 7.42–7.50 (br s, 4 H, NH2), 7.71–7.80 (m,
Synthesis 2002, No. 16, 2409–2415 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Alkoxy-1,1,1-trifluoro[chloro]alk-3-en-2-ones as Protecting Groups of Amino Acids
2415
7g (E, s-trans/s-cis)
7e
1H NMR: = 2.80–3.12 (m, 4 H, H-7), 4.17–4.33 (m, 2 H, H-6),
5.45 (d, 1 H, 3JH3H4 = 12.8 Hz, H-3), 5.73 (d, 1 H, 3JH3H4 = 12.0 Hz,
H-3), 6.90, 6.96 (s, 2 H, H-9), 7.57 (br s, 4 H, H-4, NH), 8.03, 8.17
(s, 2 H, H-11), 8.51 (t, 1 H, 3JH4H5H6 = 7.6 Hz, H-5), 8.88 (dd, 1 H,
3JH5H4 = 13.7 Hz, 3JH5H6 = 8.7 Hz, H-5).
Yield: 85%; mp 184–185 °C (Lit.11 185–186 °C).
Acknowledgment
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq), PADCT-III/CNPQ 62.0228/97-0
– QEQ, and Fundação de Apoio a Pesquisa do Estado do Rio Gran-
de do Sul (FAPERGS) for financial support. Fellobships from
CAPES (A. M. C. S.) and FAPERGS (L. F.), are also acknowled-
ged.
13C NMR: = 28.2, 29.3 (C7), 56.8, 61.3 (C6), 83.7, 85.7 (C3),
98.2, 98.4 (C1), 117.0, 117.1 (C9), 131.2, 131.5 (C8), 134.7, 134.8
(C11), 154.1, 158.3 (C4), 171.7 (CO2H), 178.8, 179.5 (C2).
Anal. Calcd for C10H9Cl3N3O3 (325.55): C, 36.89; H, 2.79; N,
12.91. Found: C, 36.41; H, 2.68; N, 12.74.
2,6-Bis-(4,4,4-trifluoro-1-methyl-3-oxo-but-1-enylamino)hex-
anoic Acid (8)
References
To a solution of L-lysine hydrochloride (1f) (10 mmol) and sodium
hydroxide (20 mmol, 0.8 g) in H2O (20 mL) the ketones 3 (20
mmol) were added under vigorous stirring at r.t.. The stirring was
continued for 15 min. at r.t.. The isolation of compound 8 was done
by acidification of the reaction mixture with hydrochloric acid (6
M) until pH less than 3 followed by extraction with EtOAc (3 15
mL). The organic layers were combined, dried (MgSO4), and the
solvent removed by rotary evaporator.
(1) Bodanszky, M. In Principles of Peptide Synthesis, 2nd ed.;
Trost, B., Ed.; Springer: New York, 1993.
(2) Gorbunova, M. G.; Gerus, I. I.; Galushko, S. V.; Kukhar, V.
P. Synthesis 1991, 207.
(3) Gerus, I. I.; Gorbunova, M. G.; Kukhar, V. P. J. Fluorine
Chem. 1994, 69, 195.
(4) Okada, E.; Masuda, R.; Hojo, M.; Inoue, R. Synthesis 1992,
533.
(5) Andrew, R. J.; Mellor, J. M. Tetrahedron 2000, 56, 7267.
(6) (a) Martins, M. A. P.; Zoch, A. N.; Flores, A. F. C.; Clar, G.;
Zanatta, N.; Bonacorso, H. G. J. Heterocycl. Chem. 1995,
32, 739. (b) Martins, M. A. P.; Siqueira, G.; Bastos, G. P.;
Zanatta, N. J. Heterocycl. Chem. 1996, 33, 1223.
(c) Martins, M. A. P.; Freitag, R.; Flores, A. F. C.; Zanatta,
N. J. Heterocycl. Chem. 1996, 33, 1619. (d) Martins, M. A.
P.; Flores, A. F. C.; Bastos, G. P.; Sinhorin, A.; Bonacorso,
H. G.; Zanatta, N. Tetrahedron Lett. 2000, 41, 293.
(e) Martins, M. A. P.; Freitag, R.; Flores, A. F. C.; Zanatta,
N. J. Heterocycl. Chem. 1995, 32, 1491. (f) Bonacorso, H.
G.; Oliveira, M. R.; Wentz, A. P.; Oliveira, A. B.; Hörner,
M.; Zanatta, N.; Martins, M. A. P. Tetrahedron 1999, 55,
345. (g) Pacholski, I. L.; Blanco, I.; Zanatta, N.; Martins, M.
A. P. J. Braz. Chem. Soc. 1992, 2, 118. (h) Zanatta, N.;
Madruga, C. C.; Marisco, P. C.; Flores, D. C.; Bonacorso, H.
G.; Martins, M. A. P. J. Heterocycl. Chem. 2000, 37, 1213.
(i) Zanatta, N.; Madruga, C. C.; Clerice, E.; Martins, M. A.
P. J. Heterocycl. Chem. 1995, 32, 735. (j) Zanatta, N.;
Cortelini, M. F.; Carpes, M. J. S.; Bonacorso, H. G.; Martins,
M. A. P. J. Heterocycl. Chem. 1997, 34, 509. (k) Zanatta,
N.; Fagundes, M. B.; Hellensohn, R.; Martins, M. A. P.;
Bonacorso, H. G. J. Heterocycl. Chem. 1998, 35, 451.
(l) Bonacorso, H. G.; Bittencourt, S. R. T.; Wastobski, A. D.;
Wentz, A. P.; Zanatta, N.; Martins, M. A. P. Tetrahedron
Lett. 1996, 37, 9155. (m) Bonacorso, H. G.; Bittencourt, S.
R. T.; Wastobski, A. D.; Wentz, A. P.; Zanatta, N.; Martins,
M. A. P. J. Heterocycl. Chem. 1999, 36, 45. (n) Zanatta, N.;
Barichello, R.; Bonacorso, H. G.; Martins, M. A. P.
Synthesis 1999, 765. (o) Zanatta, N.; Rosa, L. S.; Loro, E.;
Bonacorso, H. G.; Martins, M. A. P. J. Fluorine Chem. 2001,
107, 149.
Yield: 79% from the lysine; yellow oil.
IR (film): 3220, 3020, 1720, 1680 cm–1.
1H NMR (400 MHz, CDCl3): = 1.43–1.70 (m, 6 H, H-7, H-8, H-
9), 2.06, 2.07 (s, 6 H, 2 CH3), 3.36–3.40 (m, 2 H, H-10), 4.30–4.35
(m, 1 H, H-6), 5.32, 5.35 (s, 2 H, H-3, H-3 ), 11.19 (d, 1 H,
3JH5H6 = 5.6 Hz, H-5), 11.45 (t, 1 H, 3JH11H5 = 9.0 Hz, H-5 ).
13C NMR (50 MHz, CDCl3): = 19.1, 19.3 (CH3), 22.2 (C8), 28.8
(C9) 32.6 (C7), 56.9 (C6), 43.5 (C10), 89.7, 90.2 (C3, C3 ), 117.7,
117.8 (q, 1JCF = 288/288 Hz, C1, C1 ), 169.6, 170.5 (C4, C4 ), 173.2
(CO2H), 174.1, 175.1 (q, 2JCF = 32.6/32.6 Hz, C2, C2 ).
MS EI (70 ev) methyl ester derivative of 8: m/z (%) = 432 (M, 12),
363 (17), 278 (12), 220 (100), 182 (17), 154 (18).
Deprotection of 4,4,4-Trihalo-3-oxo-buten-1-ylamino Acids
5b–e and 7b–e; General Procedure
Compounds 5b–e and 7b–e (1 mmol) were dissolved in hydrochlo-
ric acid (6 M) in MeOH (10 mL). The solution was stirred for 20 h
at 70 °C. The reaction mixture was extracted with CH2Cl2 (3 15
mL) and the organic phase was discarded. The H2O layer was evap-
orated and the resulting solid dried in a desiccator with phosphorus
pentoxide.
5b
Yield: 57%; mp 280–281 °C (Lit.11 283–284 °C).
5c
Yield: 82%; mp 241–242 °C (Lit.11 244 °C).
5d
Yield: 72%; mp 234–235 °C (Lit.11 236 °C)
(7) Wojcik, J.; Domalebski, W.; Kamienska-Trela, K.;
Stefaniak, L.; Vdovenko, S. I.; Gerus, I. I.; Gorbunova, M.
G. Mag. Res. Chem. 1993, 31, 808.
5e
Yield: 92%; mp 182–183 °C (Lit.11 185–186 °C)
(8) Sanders, J. K. M.; Hunter, B. K. Modern NMR Spectroscopy
a Guide for Chemists, 2nd ed.; Oxford: New York, 1994,
97–153.
7b
Yield: 89%; mp 282–283 °C (Lit.11 283–284 °C).
(9) Colla, A.; Clar, G.; Martins, M. A. P.; Krimmer, S.; Fischer,
P. Synthesis 1991, 483.
(10) Brenner, M.; Huber, W. Helv. Chim. Acta 1953, 36, 1109.
(11) Handbook of Fine Chemicals and Laboratory Equipment,
Aldrich, 2001-2002.
7c
Yield: 83%; mp 242–243 °C (Lit.11 244 °C).
7d
Yield: 70%; mp 233–234 °C (Lit.11 236 °C).
Synthesis 2002, No. 16, 2409–2415 ISSN 0039-7881 © Thieme Stuttgart · New York