Stereoselective synthesis of functional dehydrophenylalanine derivatives from novel β-chloroamino esters

Article abstract of DOI:10.1002/hc.20756

New functional dehydrophenylalanines 3 were prepared from β-amino alcohols 1 in a two-step reaction sequence. The synthesis involved chlorination of the starting amino alcohols 1 to afford the intermediate erythro β-chloroamines 2. Treatment of the latter with an appropriate base led to a highly stereoselective elimination reaction, giving the corresponding (E)-dehydrophenylalanine derivatives 3 in high yields.

Full text of DOI:10.1002/hc.20756

Heteroatom Chemistry
Volume 23, Number 1, 2012
Stereoselective Synthesis of Functional
Dehydrophenylalanine Derivatives from
Novel β-Chloroamino Esters
Brahim Ould Elemine, Mohamed Rached Ennigrou,
and Rafaˆa Besbes
Laboratory of Organic Synthesis, Organometallique, Department of Chemistry, Faculty of Sciences
of Tunis, Campus Universities, 2092 El Manar, Tunis, Tunisia
Received 8 February 2011; revised 30 June 2011
of the Cα Cβ double bond [4]. This has become
a useful tool to study a structure–function rela-
tionship and to provide new bioactive peptide se-
quences of enhanced activity. In this field, dehy-
drophenylalanine is of potential use in designing
peptides with preferred secondary structures and
commonly serves as a pharmacophore [5]. For ex-
ample, Latajka et al. have recently reported on
ABSTRACT: New functional dehydrophenylalanines
3 were prepared from β-amino alcohols 1 in a two-
step reaction sequence. The synthesis involved chlo-
rination of the starting amino alcohols 1 to afford
the intermediate erythro β-chloroamines 2. Treatment
of the latter with an appropriate base led to a highly
stereoselective elimination reaction, giving the corre-
sponding (E)-dehydrophenylalanine derivatives 3 in
the synthesis and evaluation of peptides containing
ꢀ
C
high yields.
2011 Wiley Periodicals, Inc. Heteroatom
either (E)-dehydrophenylalanines in place of (Z)-
dehydrophenylalanines [6] or both of them [7] as
inhibitors and substrates of cathepsin C.
Chem 23:91–98, 2012; View this article online at wileyon-
linelibrary.com. DOI 10.1002/hc.20756
Several methods have been developed for the
synthesis of dehydroamino acid derivatives. The
most widely used approach is the dehydration of β-
hydroxy amino acid derivatives, which involves acti-
vation of the hydroxy group, followed by elimination
[8–14]. The reaction can be performed in a one-pot
procedure, and even tertiary alcohols are stereose-
lectively transformed into α, β-dehydroamino esters
[15]. Most of the procedures [16,17] involved the
synthesis of dehydroalanine and dehydroaminobu-
tyric acid derivatives from serine and threonine, re-
spectively, but they are of low to moderate yields,
and the active intermediates are quite reactive.
Ferreira et al. [14a] have reported a mild and
high yielding procedure for the direct elimination
of serine and threonine derivatives using Boc2O
and 4-dimethylaminopyridine to corresponding de-
hydroamino acid derivatives. Recently, an antise-
lective β-elimination of serine and threonine to the
INTRODUCTION
Dehydroamino acids are gaining substantial inter-
est because they are important constituents of many
fungal metabolites with antibiotic or phytotoxic pro-
prieties, such as nisin and subtilin [1,2]. In addition,
dehydroamino acids are versatile precursors for the
asymmetric synthesis of amino acids and peptides
[3].
Introduction of dehydroamino acid residues into
peptide chains has been found to influence the
three-dimensional structure of both main chains
and side chains dramatically due to the presence
Correspondence to: Rafaˆa Besbes; e-mail: rafaa.besbes@
gmail.com.
c
ꢀ
2011 Wiley Periodicals, Inc.
91

92 Ould Elemine, Ennigrou, and Besbes
TABLE 1 Synthesis of β-Chloroamine Diesters 2a–f
corresponding α, β-dehydroamino acids has been re-
ported using K2CO3 in dimethylformamide (DMF)
[18]. More recently, a nucleophilic addition to ni-
troacrylates has been applied to the synthesis of 2,3-
dehydroamino acids [19]. Ramesh et al. have also
reported an improved procedure for the synthesis
of dehydroamino acids and dehydropeptides from
the carbonate derivatives of serine and threonine us-
ing tetrabutylammonium fluoride [20]. In addition,
a valuable method for the synthesis of the E-isomer
of β-substituted dehydroalanines by controlled po-
tential electrolysis of the corresponding β-halo-β-
substituted derivatives has been reported [21].
In continuation of our previous study on the re-
activity of N-benzyl-β-amino alcohols 1 [22a] as key
intermediates, we report herein on the stereoselec-
tive synthesis of new dehydrophenylalanines 3 from
the chlorination of the same amino alcohol interme-
diates 1 with mesyl chloride, followed by treatment
with sodium ethoxide in ethanol.
Entry
R
Product 2a
Time (h)
Yield (%)b
1
2
3
4
5
6
H
CH3
C2H5
iPr
nPr
Ph
2a
2b
2c
2d
2e
2f
6
12
12
12
12
12
95
96
86
90
91
92
a2b–f were (1:1) mixtures of two diastereomers (α + β) derived from
the 1:1 mixture of 1.
bYields refer to chromatographically isolated pure compounds.
C22
C16
C15
C21
C20
C17
C23
C14
CL1
C24
C12
C19
C18
C13
O2
C7
C11
N1
O1
O4
C3
RESULTS AND DISCUSSION
C8
C2
C9
C10
C1
C5
C4
In a more recent study [22b], we reported the synthe-
sis of trans-aziridine-2-carboxylates via the forma-
tion of a mesylate intermediate, obtained after treat-
ment of amino alcohols [22a] with mesyl chloride.
This intermediate is not very stable in the reaction
medium, which gives a second type of aziridinium
intermediate. The latter is easily deprotonated by the
base added initially to provide aziridines. Following
this study, we thought that it would be possible to
obtain β-chloro amines 2 from N-benzyl amino al-
cohols 1 using the same strategy as for aziridines.
Therefore, the treatment of a series of racemic
N-benzyl amino alcohols 1 with mesyl chloride in
the presence of diisopropylethylamine afforded the
corresponding racemic diastereomeric (1:1) mixture
of β-chloro amines 2 (Scheme 1). These were derived
from the diastereomeric (1:1) mixture of 1 [22a].
The choice of N-benzyl amino alcohols 1 for
this reaction is justified by the fact that the aziri-
dinium ion formed from these compounds does not
contain a hydrogen on the nitrogen atom and thus
O3
C6
FIGURE 1 ORTEP drawing of compound 2c (α) showing
thermal ellipsoids at 50% probability. Hydrogen atoms were
omitted for clarity.
would undergo a nucleophilic attack by the chloride
ion regenerated in the reaction medium, leading to
its opening and the formation of β-chloro amines 2
(Table 1).
Importantly, the structure of diastereoisomer 2c
(α) was determined by X-ray analysis, and it showed
an erythro configuration for this product (Fig. 1).
This suggested, as expected, that the chlorination re-
action passed through an aziridinium intermediate,
which was confirmed by the rearrangement observed
(change in position of the phenyl group from C7 to
Ph
Cl
EtOOC
Ph
OH
MsCl, (iPr)2NEt
R
R
CH2Cl2, –78°C
EtOOC
N
COOEt
N
COOEt
Bn
Bn
2
1
SCHEME 1 Synthesis of β-chloroamine diesters 2.
Heteroatom Chemistry DOI 10.1002/hc

Stereoselective Synthesis of Functional Dehydrophenylalanine Derivatives from Novel β-Chloroamino Esters 93
sodium ethoxide in ethanol at 0◦C (Table 2, entry
6) and potassium hexamethyldisilazane (KHMDS)
in anhydrous THF at −78◦C (Table 2, entry 7) sig-
nificantly increased the yield (90% and 85%, respec-
tively) and improved the stereoselectivity, giving (E)-
3a as the major isomer (see Table 2).
The above reaction was then generalized us-
ing a series of β-chloro amines 2b–f. The results
showed that the use of sodium ethoxide in ethanol
gave good yields and high stereoselectivity. However,
when KHMDS was used, dehydrophenylalanines 3a
and 3b were obtained in 85% and 87% yields, respec-
tively, and no elimination reaction was observed for
β-chloro amines 2c–f. This could be interpreted in
terms of steric hindrance caused by both KHMDS
and the R group in β-chloro amines 2c–f. The use
of sodium ethoxide in ethanol (as in Table 2, en-
try 6) was thus selected as the best reaction con-
dition (Scheme 2). Various dehydrophenylalanines
were prepared in this way, and the different results
are presented in Table 3.
As shown in Table 3, the reaction provides two
diastereoisomers, (Z) and (E), when R = H or CH3
(Scheme 1), whereas the presence of bulkier groups
(R = C2H5, iPr, nPr, or Ph) leads to a high stere-
oselectivity, with only the E-diastereoisomer being
obtained. We also noted that it was necessary to op-
erate at a temperature above 0◦C when R was differ-
ent from H.
The stereochemistry of products 3a–f was con-
firmed by two-dimensional nuclear overhauser en-
hancement spectroscopy–nuclear magnetic reso-
nance (2D NOESY–NMR) experiments. For exam-
ple, the 2D NOESY experiments for 3c in CDCl3
show positive cross-peaks between the vinylic pro-
ton and benzyl protons, which confirmed the E con-
figuration of this product (Fig. 2). Furthermore, the
chemical shifts for the vinylic proton of (E)-3a,b
are in the δ-range 5.50–5.74 ppm, whereas the same
signals for the (Z)-3a,b appear in the range 6.54–
6.91 ppm. Z-isomers thus show a downfield shift
(∼1 ppm) with respect to their E-isomers. This is in
good agreement with the results obtained for related
systems [24].
TABLE 2 Various Conditions for the Synthesis of 3a
Yield
Entry
Conditions
E/Za (%)b
1
2
3
4
5
6
7
(Et)3N, (CH3CN or CH2Cl2), reflux
(iPr)2NEt, (CH3CN or CH2Cl2), reflux
DABCO, (CH3CN or CH2Cl2), reflux
K2CO3, DMF, reflux, 24 (h)
–
–
–
–
–
–
70
73
90
85
51/49
60/40
63/37
NaH, anhydrous THF, 25◦C, 3 h
EtO−Na+/EtOH, 0◦C, 0.5 h
KHMDS, anhydrous THF, −78◦C, 1 h 70/30
aThe isomer ratio was determined by 1H NMR.
bOverall yields.
C11). Such a nucleophilic attack of the chloride ion
occurring exclusively at the benzylic position with a
high regio- and stereoselectivity is well established
in the literature [23].
The synthesis of dehydrophenylalanines 3 from
β-chloro amines 2 was first attempted on β-chloro
amine 2a (R = H). Whatever operating conditions
were used, in all instances, the reaction lead to a mix-
ture of two diastereoisomers, (Z) and (E) (Table 2).
To maximize the yield of this reaction and improve
the stereoselectivity, various tests were performed
using different bases, solvents, and temperatures
(Table 2). We started this investigation using ter-
tiary amines as bases in different solvents, but the
reaction did not provide the expected dehydropheny-
lalanine 3a, and the starting material was totally
recovered in all cases. The use of potassium car-
bonate in DMF at reflux resulted in the formation
of dehydrophenylalanine 3a in a 70% yield. How-
ever, the reaction was slow and gave a mixture of
two diastereoisomers with similar proportions. We
thought then that using a stronger base and operat-
ing at a lower temperature could improve the effi-
ciency of this reaction and possibly its diastereose-
lectivity. Therefore, when sodium hydride was used
in anhydrous tetrahydrofuran (THF) at room tem-
perature, dehydrophenylalanine 3a was obtained
with a 73% yield, with the E-diastereoisomer be-
ing the major product. Finally, we found that both
Ph
Ph
Ph
Cl
R
R
R
EtO–Na+
EtOH
+
EtO C
2
N
CO Et
2
EtO C
N
CO Et
2
EtO C
2
N
CO Et
2
2
Bn
Bn
Bn
(Z)-3
2
(E)-3
SCHEME 2 Formation of dehydrophenylalanines 3.
Heteroatom Chemistry DOI 10.1002/hc

94 Ould Elemine, Ennigrou, and Besbes
TABLE 3 Synthesis of Dehydrophenylalanines 3a–f
Entry
R
Producta
Temperature (◦C)
Time (h)
Yield b(%)
E/Z
1
2
3
4
5
6
H
CH3
C2H5
iPr
nPr
Ph
3a
3b
3c
3d
3e
3f
0
25
80
80
80
80
0,5
1
1
3
3
90
86
84
91
90
95
63/37
93/7
100/0
100/0
100/0
100/0
3
aElimination was carried out on a 1:1 mixture of diastereomers (α + β) for 3b–f.
bYields refer to products isolated after column chromatography.
Preparation of β-Chloro Amine Diesters 2a–f
Ph
H
N
NOESY
General Procedure. To a solution of 1 [19a]
(2.5 mmol) and (iPr)2NEt (3 mmol) in CH2Cl2 (5 mL)
cooled at −78◦C, MsCl (3 mmol) was added slowly
in CH2Cl2 (5 mL). After the addition, the reaction
was allowed to warm to room temperature, the mix-
ture was filtered, and the solvent was evaporated in
vacuo. The residue was chromatographed on silica
gel with ether/petroleum ether (1/9) as the eluent to
give 2a and 2c–f (α) as white solids and 2b and 2c–f
(β) as colorless oils.
EtOOC
Ph
COOEt
FIGURE 2 E configuration of 3c as shown by the NOESY
experiment.
Ethyl 2 - [N - Benzyl - N - (ethoxycarbonylmethyl)
CONCLUSION
amino]-3-chloro-3-phenylpropionate
(2a). White
solid, mp 59–60◦C. IR (CHCl3, ν cm−1): 1728. MS
m/z (%): 332 (M+(37Cl) – (2CH3CH2O), 5), 330
(M+(35Cl) – (2CH3CH2O), 16), 294 (4), 278 (100), 222
The chlorination of β-amino alcohols 1 proceeded
with high stereo- and regioselectivity, providing ac-
cess to erythro β-chloro amines 2 in high yields.
The latter were easily converted to the new dehy-
drophenylalanine derivatives 3 by a highly stereose-
lective elimination reaction. Unfortunately, the use
of these compounds is limited by the fact that they
can only be in the N-terminal position of a peptide
chain. However, the scope and the synthetic utility of
these dehydrophenylalanines using other substrates
having substituted aromatic rings are underway in
our laboratory.
1
(3), 130 (10), 91 (88). H NMR (300 MHz, CDCl3)
δ = 7.34–6.73 (m, 10H), 5.18 (d, 1H, J = 10.7 Hz),
4.31, 4.04 (2q, 4H, J = 7.1 Hz), 3.96 (d, 1H, J =
10.7 Hz), 3.92 and 3.68 (AB, 2H, J = 13.6 Hz),
3.35 and 3.28 (AB, 2H, J = 18.1 Hz), 1.38, 1.18 (2t,
6H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3) δ =
170.8, 169.9 (2CO2), 138.3, 137.5 (2Carom), 128.7,
128.6, 128.3, 128.2, 127.4 (10CHarom), 69.0 (CHN),
61.1 (CHCl), 60.0, 59.9 (2CH2 O), 56.0 (CH2Ph), 50.1
(CH2 N), 14.3, 14.2 (2CH3CH2 O). HRMS (m/z): calcd
for C22H26ClNO4: 403.1550, found: 403.1520.
EXPERIMENTAL
All reagents were purchased from Acros (Germany).
Reaction progress was monitored by thin-layer chro-
matography on silica-gel plates (Fluka Kieselgel 60
F254 [Switzerland]). For column chromatography,
Fluka Kieselgel (70–230 mesh) was used. The in-
frared (IR) spectra were determined on a Perkin–
Elmer Paragon 1000 PC. 1H and 13C NMR spec-
tra were recorded on a Bruker AC 300 spec-
trometer with CDCl3 as the solvent and tetra-
methylsilane as the internal standard. Mass spectra
(GC-MS and GC-HRMS) were measured on a HP
5890 A mass spectrometer at 70 eV.
Ethyl 2-[N-Benzyl-N-[(ethoxycarbonyl-1-methyl)
methyl]amino]-3-chloro-3-phenylpropionate
(2b).
IR and MS spectra were identical for α- and β-
isomers. IR (CHCl3, ν cm−1): 1728. MS m/z (%):
347 (M+(37Cl) – (2CH3CH2O), 7), 345 (M+(35Cl) –
(2CH3CH2O), 23), 292 (100), 236 (4), 144 (8), 103
(5), 91 (95).
1
α-Isomer. A colorless oil. H NMR (300 MHz,
CDCl3) δ = 7.16–6.98 (m, 10H), 5.10 (d, 1H, J =
10.5 Hz), 4.32 (q, 2H, J = 7.1 Hz), 4.06 (s, 2H), 3.99
(d, 1H, J = 10.5 Hz), 3.90–3.85 (m, 2H), 3.72 (q, 1H,
J = 7.0 Hz), 1.21 (d, 3H, J = 7.0 Hz), 1.39, 1.13
Heteroatom Chemistry DOI 10.1002/hc

Stereoselective Synthesis of Functional Dehydrophenylalanine Derivatives from Novel β-Chloroamino Esters 95
IR and MS spectra were identical for α- and β-
(2t, 6H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3)
isomers. IR (CHCl3, ν cm−1): 1731. MS m/z (%):
374 (M+(37Cl) – (2CH3CH2O), 9), 372 (M+(35Cl) –
(2CH3CH2O), 27), 320 (100), 292 (4), 264 (4), 172
(6), 130 (6), 103 (5), 91(80).
δ = 173.0, 170.9 (2CO2), 138.1, 138.0 (2Carom),
129.5, 128.4, 128.3, 128.1, 127.1 (10CHarom), 66.6
(CHN), 61.0 (CHCl), 60.9, 59.9 (2CH2 O), 55.8
(CHCH3) 52.1 (CH2Ph), 17.5 (CH3CH), 14.3, 13.5
(2CH3CH2 O). HRMS (m/z): calcd for C23H28ClNO4:
417.1707, found: 417.1717.
α-Isomer. A white solid, mp 109–110◦C. 1H NMR
(300 MHz, CDCl3) δ = 7.34–7.25 (m, 10H), 4.81 (d,
1H, J = 11.0 Hz), 4.47 (d, 1H, J = 11.0 Hz), 4.26
and 3.86 (AB, 2H, J = 14.1 Hz), 4.25, 4.06, 3.70,
3.46 (4qd, 4H, J = 7.2 and = 10.9 Hz), 3.10 (d,
1H, J = 9.8 Hz), 2.08–2.03 (m, 1H), 1.24, 1.06 (2t,
6H, J = 7.2 Hz), 0.98, 0.84 (2d, 6H, J = 6.6 Hz).
13C NMR (75 MHz, CDCl3) δ = 172.5, 168.5 (2CO2),
139.0, 134.0 (2Carom), 130.0, 129.7, 128.3, 128.0,
127.8, 127.3 (10CHarom), 66.0 (CHN), 65.0 (CHCH),
62.0 (CHCl), 60.2, 60.0 (2CH2 O), 52.2 (CH2Ph),
29.0 (CH(CH3)2), 20.6, 19.8 (2CH3CH), 13.9, 13.7
(2CH3CH2 O). HRMS (m/z): calcd for C25H32ClNO4:
445.2020, found: 445.2016.
1
β-Isomer. A colorless oil. H NMR (300 MHz,
CDCl3) δ = 7.22–7.03 (m, 10H), 5.16 (d, 1H, J =
10.5 Hz), 4.27 (q, 2H, J = 7.1 Hz), 4.15–4.05 (m,
2H), 3.96 (d, 1H, J = 10.5 Hz), 3.91 and 3.72 (AB,
2H, J = 12.8 Hz), 3.68 (q, 1H, J = 7.0 Hz), 1.38,
1.26 (2t, 6H, J = 7.1 Hz), 1.12 (d, 3H, J = 7.0
Hz). 13C NMR (75 MHz, CDCl3)δ = 173.8, 170.1
(2CO2), 138.4, 138.1 (2Carom), 129.1, 128.4, 128.2,
128.0, 126.9 (10CHarom), 66.4 (CHN), 60.8 (CHCl),
60.4, 60.0 (2CH2 O), 54.3 (CHCH3) 51.5 (CH2Ph), 17.4
(CH3CH), 14.3, 13.5 (2CH3CH2 O).
1
β-Isomer. A colorless oil. H NMR (300 MHz,
Ethyl 2 - [N - Benzyl - N - [(ethoxycarbonyl-1-ethyl)
methyl]amino]-3-chloro-3-phenyl propionate (2c).
IR and MS spectra were identical for α- and β-
isomers. IR (CHCl3, ν cm−1): 1726. MS m/z (%):
358 (M+(37Cl) – (2CH3CH2O), 22), 356 (M+(35Cl) –
(2CH3CH2O), 7), 306 (100), 250 (4), 160 (7), 103 (5),
91 (91).
CDCl3) δ = 7.31–7.03 (m, 10H), 5.23 (d, 1H, J =
10.5 Hz), 4.30–4.14 (m, 4H), 4.04 (d, 1H, J =
10.5 Hz), 4.22 and 4.04 (AB, 2H, J = 14.3 Hz),
2.97 (d, 1H, J = 9.5 Hz), 1.93–1.86 (m, 1H), 1.40,
1.32 (2t, 6H, J = 7.2 Hz), 0.78, 0.40 (2d, 6H,
J = 6.6 Hz). 13C NMR (75 MHz, CDCl3) δ = 173.0,
170.4 (2CO2), 138.3, 137.8 (2Carom), 129.9, 128.7,
128.6, 128.4, 128.1, 127.3 (10CHarom), 65.7 (CHN),
65.2 (CHCH), 60.8 (CHCl), 60.3, 60.2 (2CH2 O), 51.9
(CH2Ph), 28.9 (CH(CH3)2), 19.8, 19.7 (2CH3CH), 14.4,
14.3 (2CH3CH2 O).
1
α-Isomer. A white solid, mp 53–54◦C. H NMR
(300 MHz, CDCl3) δ = 7.20–6.09 (m, 10H), 5.08
(d, 1H, J = 10.9 Hz), 4.31 (q, 2H, J = 7.1 Hz),
4.00 (d, 1H, J = 10.9 Hz), 4.06–3.92 (m, 2H),
4.13 and 3.77 (AB, 2H, J = 14.1 Hz), 3.51 (dd,
1H, J = 9.6 and = 4.4 Hz), 1.77–1.48 (2m, 2H),
1.39, 1.16 (2t, 6H, J = 7.1 Hz), 0.83 (t, 3H,
Ethyl 2 - [N - Benzyl - N - [(ethoxycarbonyl - 1 - n-
propyl)methyl]amino]-3-chloro-3-phenylpropionate
(2e). IR and MS spectra were identical for α- and
β-isomers. IR (CHCl3, ν cm−1): 1732. MS m/z (%):
374 (M+(37Cl) – (2CH3CH2O), 9), 372 (M+(35Cl) –
(2CH3CH2O), 29), 336 (4), 320 (100), 264 (4), 170
(5), 91 (75).
J
= 7.4 Hz).13C NMR (75 MHz, CDCl3) δ =
172.4, 170.8 (2CO2), 138.3, 138.2 (2Carom), 129.4,
128.5, 128.3, 128.1, 128.0, 127.1 (10CHarom), 67.1
(CHN), 63.1 (CHCH2CH3), 61.0 (CHCl), 60.3, 60.2
(2CH2 O), 51.31 (CH2Ph), 21.7 (CH2CH3), 14.3, 14.1
(2CH3CH2 O), 11.2 (CH3CH2CH). HRMS (m/z): calcd
for C24H30ClNO4: 431.1863, found: 431.1862.
1
α-Isomer. A white solid, mp 95–96◦C. H NMR
1
β-Isomer. A colorless oil. H NMR (300 MHz,
(300 MHz, CDCl3) δ = 7.22–6.92 (m, 10H), 5.19 (d,
1H, J = 10.9 Hz), 4.29, 4.11 (2q, 4H, J = 7.1 Hz),
4.09 (S, 2H), 3.96 (d, 1H, J = 10.9 Hz), 3.38 (t, 1H,
J = 7.2 Hz), 1.65–1.55 (m, 2H), 1.39, 1.28 (2t, 6H,
J = 7.1 Hz), 0.97–0.88 (m, 2H), 0.71 (t, 3H, J =
7.1 Hz). 13C NMR (75 MHz, CDCl3) δ = 173.7, 170.2
(2CO2), 138.4, 138.0 (2Carom), 129.6, 128.6, 128.5,
128.3, 128.1, 127.1 (10CHarom), 65.8 (CHN), 60.5
(CHCl), 60.1, 60.0 (2CH2 O), 59.1 (CHCH2CH2), 51.7
(CH2Ph), 33.6 (CH2CH2CH3), 19.4 (CH2CH3), 14.3,
14.2 (2CH3CH2 O), 14.0 (CH3CH2CH2). HRMS (m/z):
calcd for C25H32ClNO4: 445.2020, found: 445.2005.
β-Isomer. A colorless oil.1H NMR (300 MHz,
CDCl3) δ = 7.12–6.81 (m, 10H), 5.00 (d, 1H,
J = 10.9 Hz), 4.27–4.21 (m, 4H), 3.93 (d, 1H,
CDCl3) δ = 7.49–6.09 (m, 10H), 5.08 (d, 1H, J =
10.9 Hz), 4.32 (q, 2H, J = 7.2 Hz), 3.99 (d, 1H, J =
10.9 Hz), 4.08–3.91 (m, 2H), 4.09 and 3.78 (AB, 2H,
J = 14.1 Hz) 3.51 (dd, 1H, J = 10.1 and J = 4.5 Hz),
1.79–1.50 (2m, 2H), 1.39, 1.17 (2t, 6H, J = 7.2 Hz),
0.81 (t, 3H, J = 7.4 Hz). 13C NMR (75 MHz, CDCl3) δ
= 172.4, 171.0 (2CO2), 138.3, 138.2 (2Carom), 129.4,
128.5, 128.3, 128.1, 128.0, 127.0 (10CHarom), 67.1
(CHN), 63.1 (CHCH2CH3), 61.0 (CHCl), 60.3, 60.2
(2CH2 O), 51.3 (CH2Ph), 21.7 (CH2CH3), 14.3, 14.1
(2CH3CH2 O), 11.2 (CH3CH2CH).
Ethyl 2-[N-Benzyl-N-[(ethoxycarbonyl-1-i-propyl)
methyl]amino]-3-chloro-3-phenylpropionate
(2d).
Heteroatom Chemistry DOI 10.1002/hc

96 Ould Elemine, Ennigrou, and Besbes
J
= 10.9 Hz), 3.85 and 3.70 (AB, 2H,
J
J
=
=
Ethyl 2 - [N - Benzyl - N - (ethoxycarbonylmethyl)
amino]-3-phenylprop-2-enoate (3a). IR and MS
spectra were identical for E- and Z-isomers. IR
(CHCl3, ν m−1): 1731. MS m/z (%): 367 (M+, 21), 338
(2), 294 (29), 280 (11), 220 (7), 206 (10), 202 (21),
181 (7), 130 (11), 116 (8), 101 (9), 91 (100).
14.3 Hz), 3.49 (dd, 1H,
J
= 10.1 and
4.3 Hz), 1.75–1.50 (2m, 2H), 1.12, 1.06 (2t, 6H,
J = 7.2 Hz), 0.90–0.78 (m, 2H), 0.63 (t, 3H,
J = 7.2 Hz). 13C NMR (75 MHz, CDCl3) δ = 171.4,
169.7 (2CO2), 137.3, 136.8 (2Carom), 127.5, 127.2,
127.1, 127.0, 126.1 (10CHarom), 67.1 (CHN), 61.3
(CHCl), 60.1, 60.0 (2CH2 O), 59.1 (CHCH2CH2), 50.6
(CH2Ph), 32.6 (CH2CH2CH3), 18.9 (CH2CH3), 13.3,
13.0 (2CH3CH2 O), 12.9 (CH3CH2CH2).
1
E-Isomer. Yield 57%; a colorless oil. H NMR
(300 MHz, CDCl3) δ = 7.35–7.08 (m, 10H), 5.73 (s,
1H), 4.37 (s, 2H), 4.18, 4.08 (2q, 4H, J = 7.1 Hz),
3.72 (s, 2H), 1.25, 1.03 (2t, 6H, J = 7.1 Hz).13C NMR
(75 MHz, CDCl3) δ = 170.0, 167.0 (2CO2), 141.7,
137.1 (2Carom), 128.4, 128.2, 128.1, 128.0, 127.6,
127.5 (10CHarom), 125.7 (N C ), 107.5 (Ph C ),
61.4, 60.8 (2CH2 O), 54.8 (CH2–N), 50.6 (CH2Ph),
14.3, 13.5 (2CH3CH2 O). HRMS (m/z): calcd for
C22H25NO4: 367.1784, found: 367.1768.
Ethyl 2-[N-Benzyl-N-[(ethoxycarbonyl-1-phenyl)
methyl]amino]-3-chloro-3-phenylpropionate
(2f).
IR and MS spectra were identical for α- and β-
isomers. IR (CHCl3, ν cm−1): 1731. MS m/z (%):
408 (M+(37Cl) – (2CH3CH2O), 5), 406 (M+(35Cl) –
(2CH3CH2O), 17), 370 (6), 354 (100), 280 (4), 206
(10), 163 (18), 135 (9), 107 (7), 91 (65).
1
Z-Isomer. Yield 33%; a colorless oil. H NMR
(300 MHz, CDCl3) δ = 7.37–7.19 (m, 10H), 6.92 (s,
1H), 4.21, 4.14 (2q, 4H, J = 7.1 Hz), 4.12 (s. 2H),
3.75 (s, 2H), 1.31, 1.24 (2t, 6H, J = 7.1 Hz).13C NMR
(75 MHz, CDCl3) δ = 171.2, 166.6 (2CO2), 137.7,
135.0 (2Carom), 130.3, 129.1, 128.4, 128.2, 127.3,
(10CHarom), 125.8 (N C ), 110.8 (Ph C ), 61.0,
60.6 (2CH2 O), 57.6 (CH2 − N), 53.6 (CH2Ph), 14.3,
14.2 (2CH3CH2 O).
α-Isomer. A white solid, mp 103–104◦C. 1H
NMR (300 MHz, CDCl3) δ = 7.25–6.85 (m, 15H),
5.05 (d, 1H, J = 10.4 Hz), 4.74 (s, 1H), 4.20 (d,
1H, J = 10.4 Hz), 4.31–4.00 (m, 4H), 4.10 and
3.78 (AB, 2H, J = 14.8 Hz), 1.31, 1.18 (2t, 6H,
J = 7.1 Hz). 13C NMR (75 MHz, CDCl3) δ =
171.6, 169.8 (2CO2), 139.0, 138.3, 136.2 (3Carom),
129.5, 129.4, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9,
127.0 (15CHarom), 69.6 (CHPh), 68.6 (CHN), 60.8
(CHCl), 60.7, 60.6 (2CH2 O), 51.1 (CH2Ph), 14.2, 14.0
(2CH3CH2 O). HRMS (m/z): calcd for C28H30ClNO4:
479.1863, found: 479.1852.
Ethyl 2 - [N - Benzyl - N - [(1 - ethoxycarbonyl - 1-
methyl)methyl]amino]-3-phenylprop-2-enoate (3b).
IR and MS spectra were identical for E- and Z-
isomers. 1732. MS m/z (%): 381 (M+, 15), 308 (100),
290 (9), 280 (21), 234 (17), 204 (12), 200 (9), 144 (7),
119 (9), 91 (74), 101 (9), 91 (100).
1
β-Isomer. A colorless oil. H NMR (300 MHz,
CDCl3) δ = 7.21–6.65 (m, 15H), 5.35 (d, 1H, J =
10.9 Hz), 4.61 (s, 1H), 4.45–4.15 (m, 4H), 4.04 (d, 1H,
J = 10.9 Hz), 4.11 and 3.94 (AB, 2H, J = 14.3 Hz),
1.44, 1.19 (2t, 6H, J = 7.1 Hz). 13C NMR (75 MHz,
CDCl3) δ = 172.0, 170.3 (2CO2), 138.0, 137.4, 136.2
(3Carom), 129.6, 129.2, 128.8, 128.7, 128.5, 128.2,
128.0, 127.9, 127.6, 127.2, (15CHarom), 63.9 (CHPh),
63.6 (CHN), 60.9 (CHCl), 60.4, 60.1 (2CH2 O), 51.2
(CH2Ph), 14.3, 14.2 (2CH3CH2 O).
E-Isomer. Yield 80%; a colorless oil. IR (CHCl3,
1
ν m−1): H NMR (300 MHz, CDCl3) δ = 7.75–6.98
(m, 10H), 5.67 (s, 1H), 4.38 (s. 2H), 4.22, 4.01
(m, 5H), 1.48 (d, 3H, J = 7.1 Hz), 1.29, 1.03 (2t,
6H, J = 7.1 Hz).13C NMR (75 MHz, CDCl3) δ =
172.7, 167.4 (2CO2), 140.1, 138.1 (2Carom), 130.8,
129.3, 128.3, 128.0, 127.8, 127.1 (10CHarom), 125.7
(N C ), 110.7 (Ph C ), 61.3, 61.0 (2CH2 O), 58.2
(CH–CH3), 53.8 (CH2Ph), 15.8 (CH3–CH), 14.3, 13.5
(2CH3CH2 O). HRMS (m/z): calcd for C23H27NO4:
381.1940, found: 381.1940.
Preparation of Dehydrophenylalanines 3a–f
General Procedure. A solution of β-chloro
amine 2 (5.45 mmol) in ethanol (3 mL) was added
to a solution of sodium ethoxide (Na (6 mmol) in
dry ethanol (5 mL)) and cooled at 0◦C under a nitro-
gen atmosphere. The reaction mixture was allowed
to warm to room temperature and was stirred for
a fixed time and at the temperature indicated in
Table 3. The solvent was evaporated in vacuo, and
the residue was purified by flash chromatography
using petroleum ether to give 3a–f as colorless oils
(for the separation of Z- and E-isomers, we used
ether/petroleum ether (9/1) as the eluent).
Z-Isomer. Yield 6%; a colorless oil. 1H NMR (300
MHz, CDCl3) δ = 7.74–7.02 (m, 10H), 6.52 (s, 1H),
4.34 (q, 1H, J = 7.1 Hz), 4.22, 4.15 (m, 4H), 4.02
(q, 2H, J = 7.1 Hz), 1.37 (d, 3H, J = 7.1 Hz), 1.28,
1.26 (2t, 6H, J = 7.1 Hz).13C NMR (75 MHz, CDCl3)
δ = 174.0, 166.8 (2CO2), 138.2, 135.7 (2Carom),
130.8, 129.3, 128.4, 128.0, 127.9, 127.5 (10CHarom),
125.9 (N C ), 110.7 (Ph C ), 60.8, 60.7 (2CH2 O),
60.5 (CH–CH3), 53.7 (CH2Ph), 16.5 (CH3–CH), 14.3,
14.2 (2CH3CH2 O).
Heteroatom Chemistry DOI 10.1002/hc

Stereoselective Synthesis of Functional Dehydrophenylalanine Derivatives from Novel β-Chloroamino Esters 97
(E) - Ethyl 2 - [N - Benzyl - N - [(1 - ethoxycarbonyl-
443 (M+, 5), 370 (87), 352 (9), 296 (13), 267 (25),
206 (38), 193 (32), 178 (12), 91 (100).1H NMR (300
MHz, CDCl3) δ = 7.28–6.95 (m, 10H), 5.80 (s, 1H),
5.18 (s, 1H), 4.24 (q, 2H, J = 7.10 Hz), 4,47 and 4.14
(AB, 2H, J = 16.0 Hz), 4.07–4.03 (m, 2H), 1.27, 1.03
(2t, 6H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3) δ =
171.0, 167.5 (2CO2), 139.2, 137,7, 136.9 (3Carom),
128.8, 128.6, 128,4, 128.1, 127.9, 127.5, 127.3, 126,7
(15CHarom), 125.9 (N C ), 115.3 (Ph C ), 66.6
(CHPh), 61.3, 61.1 (2CH2 O), 50.4 (CH2Ph), 14.3,13.6
(2CH3CH2 O). HRMS (m/z): calcd for C28H29NO4:
443.2097, found: 443.2088.
1-ethyl)methyl]amino]-3-phenylprop-2-enoate (3c).
Colorless oil. IR (CHCl3, ν m−1): 1724. MS m/z (%):
395 (M+, 4), 266 (21), 235 (15), 234 (99), 206 (5),
1
105 (4), 91 (100). H NMR (300 MHz, CDCl3) δ =
7.39–6.97 (m, 10H), 5.71 (s, 1H), 4.40 (s, 2H), 4.16,
4,07 (2q, 4H, J = 7.1 Hz), 3.38 (dd, 1H, J = 6.7
and = 8.2 Hz), 1.99–1.84 (m, 2H), 1.26, 1.05 (2t, 6H,
J = 7.1 Hz), 1.02 (t, 3H, J = 7.1 Hz).13C NMR
(75 MHz, CDCl3) δ = 172.1, 167.4 (2CO2), 140.3,
138.0 (2Carom), 128.0, 127.9, 127.7, 127.4, 127.3,
126.8 (10CHarom), 125.7 (N C ), 111.8 (Ph C ),
61.2, 60.8 (2CH2 O), 50.00 (CH2Ph), 23.1 (CH2CH3),
14.3, 13.6 (2CH3CH2 O).11.10 (CH3CH2). HRMS
(m/z): calcd for C24H29NO4: 395.2097, found:
395.2099.
SUPPLEMENTARY MATERIAL
CCDC 752143 (3c (α)) contains the supple-
mentary crystallographic data for this article.
These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data request/cif.
(E)-Ethyl 2-[N-Benzyl-N-[(1-ethoxycarbonyl-1-i-
propyl)methyl]amino]-3-phenylprop-2-enoate (3d).
Colorless oil. IR (CHCl3, ν m−1): 1730. MS m/z (%):
409 (MH+, 43), 362 (57), 334 (13), 316 (27), 302 (43),
1
273 (26), 227 (10), 105 (21), 91 (100). H NMR (300
MHz, CDCl3) δ = 7.64–6.94 (m, 10H), 5.75 (s, 1H),),
4.49 and 4.38 (AB, 2H, J = 12.8 Hz), 4.24–4.01
(m, 4H), 3.43 (d, 1H, J = 10.6 Hz), 2.38–2.32 (m,
1H), 1.26, 1.01 (2t, 6H, J = 7.2 Hz), 1.10, 0.91
(2d, 6H, J = 7.0 Hz).13C NMR (75 MHz, CDCl3)
δ = 171.1, 167.2 (2CO2), 140.2, 137.7 (2Carom),
128.4, 128.2, 128.0, 127.8, 127.8, 127.3 (10CHarom),
125.7 (N C ), 113.2 (Ph C ), 70.0 (CHCH), 61.1,
60.5 (2CH2 O), 48.9 (CH2Ph), 28.2 (CH(CH3)2),
19.9, 19.3 (2(CH3)2CH2), 14.3, 13.6 (2CH3CH2 O).
HRMS (m/z): calcd for C25H31NO4: 409.2253, found:
409.2251.
ACKNOWLEDGMENTS
The authors wish to thank Dr. M. A. Sanhoury,
MRSC of the Department of Chemistry, Faculty
of Sciences of Tunis, Tunisia, for his helpful
discussion.
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Colorless oil. IR (CHCl3, ν m−1): 1730. MS m/z (%):
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