Efficient synthesis of β-halogeno protected L-alanines and their β-phosphonium derivatives

Article abstract of DOI:10.1016/S0957-4166(03)00484-1

Ring opening of oxazolines, prepared from L-serinates, with trimethylsilyl halides (TMSX) led to β-halogeno-N-benzoyl-α-amino esters in good to excellent yields. Quaternization of triphenylphosphine by the β-bromo or -iodo amino esters gave the corresponding β-phosphonium salts in overall yields of up to 93% and with e.e. >96%. Hydrolysis of the ester function afforded the phosphonium salt bearing an N-benzoyl-α-amino acid substituent, with partial racemization. However, the reaction of the TMSX with the carboxylic salt, prepared by saponification of the starting oxazoline ester, furnished the corresponding β-halogeno-N-benzoyl-α-amino acids in 70-95% yields. Quaternization of triphenylphosphine by the bromo or iodo derivatives led to the phosphonium salts bearing a free acid function in 95% yield, without racemization. The efficiency of this synthesis was demonstrated by the preparation of these phosphonium salts in excellent overall yields, by a one-pot procedure starting from the oxazoline.

Full text of DOI:10.1016/S0957-4166(03)00484-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2229–2238
Efficient synthesis of b-halogeno protected
L
-alanines and their
b-phosphonium derivatives
Franck Meyer,a Abdelhamid Laaziri,a Anna Maria Papini,b Jacques Uziela and Sylvain Juge´c,*
aUniversite´ de Cergy Pontoise, 5 mail Gay Lussac, 95031 Cergy Pontoise, France
bDipartimento di Chimica Organica, Universita` degli Studi di Firenze, via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
cUniversite´ de Bourgogne, LSEO associe´ CNRS, 6 boulevard Gabriel, 21000 Dijon, France
Received 8 May 2003; accepted 16 June 2003
Abstract—Ring opening of oxazolines, prepared from -serinates, with trimethylsilyl halides (TMSX) led to b-halogeno-N-ben-
L
zoyl-a-amino esters in good to excellent yields. Quaternization of triphenylphosphine by the b-bromo or -iodo amino esters gave
the corresponding b-phosphonium salts in overall yields of up to 93% and with e.e. >96%. Hydrolysis of the ester function
afforded the phosphonium salt bearing an N-benzoyl-a-amino acid substituent, with partial racemization. However, the reaction
of the TMSX with the carboxylic salt, prepared by saponification of the starting oxazoline ester, furnished the corresponding
b-halogeno-N-benzoyl-a-amino acids in 70–95% yields. Quaternization of triphenylphosphine by the bromo or iodo derivatives led
to the phosphonium salts bearing a free acid function in 95% yield, without racemization. The efficiency of this synthesis was
demonstrated by the preparation of these phosphonium salts in excellent overall yields, by a one-pot procedure starting from the
oxazoline.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
In order to achieve the synthesis of phosphonium salts
derived from -alanine, which are useful for the
L
Serine is a naturally occurring amino acid available in
both its enantiomeric forms and useful for the hemisyn-
thesis of non classical derivatives by b-homologation of
its side-chain.1 Modifications of amino acid side chains
can influence their steric hindrance, polarity or confor-
mation. This is particularly important for the develop-
ment of back-bone modified peptides given their
structure–activity relationships and the stabilization of
their bioactivity against enzymatic degradation.2
hemisynthesis of unusual amino acids by CꢀC bond
formation, we turned our attention to the synthesis of
b-bromo or -iodo alanine precursors. It should be
noted that very few examples of phosphonium salts
bearing a chiral amino acid substituent have been
described to date.6,7 The stereoselective synthesis of the
b-chloro amino acids derived from serine,9,10 cystine11
or aspartic acid,12 is well-documented, however only a
few methods lead directly to the bromo or iodo
analogues.7,13
The principle of the hemisynthesis starting from serine,
lies in its transformation into a b-cation, -anion or
-radical equivalent of alanine.1b,c This is illustrated by
protected b-bromo and b-iodo alanine which can be
used as electrophilic blocks,3 radical precursors4 and for
the preparation of organozinc reagents5 or phospho-
nium salts.6,7 In addition, I-labelled b-iodo alanine has
been proposed as a localizing agent for the site of
infection.8
We previously described the synthesis of N,N-dipro-
tected b-halogeno-a-amino esters by the reaction of the
oxazolines 2 derived from
L
-serine 1 with chlorofor-
mates in the presence of the corresponding sodium
salt,10 and preliminary results showed the ring opening
of the oxazoline
(TMSX).7,10 We decided to investigate further this reac-
-alanine
2
with trimethylsilyl halides
tion for the synthesis of b-heterosubstituted
L
derivatives. Herein we report an efficient stereospecific
synthesis of b-halogeno (-iodo or -bromo) protected
L
-alanines, and their triphenyl phosphonium salt
* Corresponding
author.
Fax:
+33-(0)3-8039-6098;
e-mail:
sylvain.juge@u-bourgogne.fr
derivatives.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00484-1

2230
F. Meyer et al. / Tetrahedron: Asymmetry 14 (2003) 2229–2238
Scheme 1.
2. Results and discussion
Treatment of the oxazolines 2a–d with TMSI (or
TMSBr) in chloroform for 15 h at room temperature
furnished the corresponding b-halogeno amino esters
3a–g, which were obtained quantitatively as solids
(Scheme 1 and Table 1, entries 1–7). Chiral HPLC
analysis of these compounds by comparison with a
racemic sample showed, in each case, a single enan-
tiomer,14 confirming the stereospecificity of the reac-
tion. In the case of TMSCl, the oxazoline 2a must be
heated at reflux in THF to afford the chloro derivative
3h (entry 8). The ring opening of the oxazolines 2 by
TMSX can be explained by the formation of an oxa-
zolinium salt 5, which undergoes attack by the halide
ion at the C(5) position leading to the C(5)ꢁO(1) bond
cleavage (Scheme 1). Cleavage of the TMSꢁnitrogen
bond of the intermediate 6 using traces of acid (HX), or
by hydrolysis during the work up, finally resulted in the
product 3.
The oxazolines 2a–d were prepared in high yields
according to the classical condensation of phenyl imino
ether, with the appropriate L-serine ester hydrochloride
1, using triethylamine as a base (Scheme 1). In addition,
saponification of 2a with NaOH led to the oxazoline
sodium salt 2%. Surprisingly, the pure enantiomer (S)-
oxazoline 2a, which is known to be a viscous product,
gave crystals allowing us to establish its X-ray structure
(Fig. 1).
When the oxazoline sodium salt 2% was used in place of
the ester 2, the reaction with TMSI (or TMSBr) in
chloroform at room temperature took place only after
the addition of water (1 equiv.) and gave the N-benzoyl
b-halogeno a-amino acids 3i or 3j in high yields
(Scheme 2 and Table 2, entries 1 and 2). The use of
TMSCl required heating of the salt 2% at reflux in
chloroform to provide the chloro compound 3k (entry
3). Since water is necessary for the reaction of 2%, we
assumed that this reaction resulted mainly from HX,
which is generated in situ by hydrolysis of TMSX to
give the oxazolinium intermediate 7, which upon ring
opening, afforded the product 3 (Scheme 2).
Figure 1. Crystal structure of the oxazoline 2a. Selected bond
,
lengths (A) angles (°), dihedral angles (°): O(1)ꢁC(2) 1.345(4),
The b-iodo and b-bromo amino acid derivatives 3a–g
C(5)ꢁO(1) 1.435(4), C(3)ꢁO(3) 1.445(5), N(3)ꢁC(4) 1.473(4),
N(3)ꢁC(2) 1.268(4), C(4)ꢁC(5) 1.525(5); O(1)ꢁC(2)ꢁN(3)
118.5(3), C(4)ꢁC(5)ꢁO(1) 103.5(3), C(5)ꢁC(4)ꢁN(3) 105.2(3),
were used for the preparation of their corresponding
phosphonium
salts
by
quaternization
with
triphenylphosphine. This was achieved by heating 3
with PPh3 in refluxing chloroform for 48 h, to afford
the phosphonium salts 4a–g in 68–98% isolated yields
C(1)ꢁC(4)ꢁN(3)
N(3)ꢁC(2)ꢁC(6)ꢁC(7) 176.67, N(3)ꢁC(4)ꢁC(1)ꢁO(2) 82.29.
108.6(3);
N(3)ꢁC(2)ꢁO(1)ꢁC(5)
0.03,
1
(Scheme 1 and Table 3, entries 1–7). The H and 31P
NMR analysis of the phosphonium salt 4a in the
presence of the chiral hexacoordinated phosphate anion
BINPHAT15 showed the presence of only one enan-
tiomer indicating no significant racemization for this
reaction. Interestingly, the phosphonium salts 4 could
also be obtained on a preparative scale according to a
one-pot procedure from the oxazolines 2. Thus, when
the oxazoline 3b was stirred with TMSI (1.5 equiv.) in
chloroform at room temperature for 48 h, and the
The structure of compound 2a shows the oxazoline and
phenyl rings in a plane with a dihedral angle of 13°,
and a C(5)ꢁO(1) bond length close to those of the
,
acyclic bond length C(3)ꢁO(3) (1.435 versus 1.445 A)
(Fig. 1). It should be noted that such values cannot
account for the ring opening by C(5)ꢁO(1) bond cleav-
age when the oxazoline reacts with an electrophilic
agent (vide infra).

F. Meyer et al. / Tetrahedron: Asymmetry 14 (2003) 2229–2238
Table 1. Preparation of N-benzoyl b-halogeno a-amino esters 3
2231
Entry
Oxazoline
TMSX
equiv.
b-Halogeno a-amino estera
Yieldb (%)
R
2
X
3
1
2
3
4
5
6
7
8
Me
i-Pr
All
Bn
i-Pr
All
Bn
2a
2b
2c
2d
2b
2c
2d
2d
I
I
I
I
Br
Br
Br
Cl
1.5
1.5
1.5
1.5
3
1.5
1.5
4
3a
3b
3c
3d
3e
3f
96
99
98
99
99
98
99
99
3g
3h
Bn
a The enantiomeric purity was checked by liquid chromatography for 3a–g.
b Isolated yield.
Scheme 2.
More interestingly, the enantiomerically pure phospho-
nium salts 4i and 4j were obtained in 95% yield, by
quaternization of triphenylphosphine with the bromo 3i
or iodo amino acid 3j (Table 3, entries 8 and 9).
Table 2. Preparation of N-benzoyl b-halogeno a-amino
acids 3i–k from oxazoline salt 2%
Entry
TMSX/H2O
b-Halogeno a-amino acidsb
X
equiva
3
Yieldd (%)
Unfortunately preliminary results of the Wittig reaction
between the phosphonium salt 4j and benzaldehyde led
to the optically inactive a-benzamido unsaturated acid
8 in 30% yield (Scheme 4). If this moderate reactivity is
comparable to those obtained with similar reagents,6
the racemization of 8 was attributed to the excess of
n-BuLi used to promote the Wittig reagent. Further
investigations on the hemisynthesis of unsaturated
amino acids via this strategy, are currently under study
in our laboratory.
1
2
3
I
Br
Cl
3
3
4
3ib
3jb
3kc
90
85
75
a With respect to 2%.
b The enantiomeric purity was checked by 31P NMR of the corre-
sponding phosphonium salt derivatives 4i, 4j.7,15
c The enantiomeric purity was determined after reaction with dia-
zomethane.16
d Isolated yield.
mixture refluxed with PPh3 (2.5 equiv.) for an addi-
tional 48 h, the phosphonium salt 4b was obtained
quantitatively. Since the presence of a free carboxylic
acid group on the phosphonium salt 4 is crucial in
preventing elimination or racemization under the condi-
tions required for the Wittig reaction,6,7 we investigated
the preparation of such derivatives by deprotection of
the ester function. Unfortunately, deprotection of the
allyl or benzyl esters 4c, 4f or 4d was unsuccessful
under the usual conditions, using PhSiH3 or by
hydrogenolysis in the presence of various transition
metal catalysts. However, a partial debenzylation of 4d
was observed under the conditions described by Tsuji,17
using a mixture of anisole and AlCl3. Hydrolysis of the
isopropyl derivatives 4b or 4e led to 4i or 4j after
heating with a 1 M solution of HX for 24 h (Scheme 3).
Unfortunately, the enantiomeric purity of 4i or 4j deter-
mined by 31P NMR in the presence of a cinchona
alkaloid revealed a partial racemization with 80 and
85% e.e., respectively.
Scheme 3.
Scheme 4.

2232
F. Meyer et al. / Tetrahedron: Asymmetry 14 (2003) 2229–2238
Table 3. Preparation of phosphonium salts 4 from the b-halogeno a-amino acid derivatives 3
Entry
b-Halogeno a-amino acid derivatives
Phosphonium salt
X
4
R
Yielda (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3i
3j
4ab
4b
4c
4d
4e
4f
4g
4ib
4j
Me
i-Pr
Allyl
Bn
i-Pr
Allyl
Bn
I
I
I
I
Br
Br
Br
I
84
90
93
95
98
68
90
95
95
H
H
Br
a Isolated yield.
b The enantiomeric purity was checked by NMR with chiral derivatives.7,15
3. Conclusion
prepared by addition of acetyl chloride to a solution of
-serine in the corresponding alcohol for 1a,b,19b or by
bubbling HCl gas for 1c.18
L
Herein, we described an improved stereospecific synthe-
sis of b-halogeno and b-phosphonium amino acid
derivatives. The key step of this synthesis is the ring
opening of an oxazoline ester derived from
with trimethylsilyl halide, giving b-iodo or b-bromo
-alanine derivatives without racemization. These com-
HPLC analyses were performed on Gilson and Shi-
madzu chromatographs equipped with a UV detector
(flow rate 1 mL min−1; u=254 nm). Thin-layer chro-
matography was performed on silica chromagel (60
L-serine
L
pounds were easily quaternized with triphenylphos-
phine to give the corresponding phosphonium salts in
F254) and visualized by UV, iodine or permanganate
treatment. Flash chromatography was performed on
silica gel (60ACC, 6–35 microns and 35–70 microns).
NMR spectra were obtained on Bruker DPX 250 and
Avance 300–500 spectrometers, using TMS as the inter-
nal reference for 1H and 13C NMR and 85% phosphoric
acid as the external reference for 31P NMR. Melting
points were measured on a Bu¨chi 530 melting point
apparatus and are uncorrected. Optical rotation values
were determined at 22°C on a Perkin–Elmer 241 polar-
imeter. Infrared spectra were recorded on a Bruker
Equinox 55 and a Vector 22. Mass spectral analyses
were performed on NERMAG R10-10C, JEOL MS
700 and KRATOS Concept S, at the ENSCP (Paris),
ENS (Paris) and Burgundy University (Dijon), respec-
tively. The major peak m/z is reported with the inten-
sity as a percentage of the base peak in brackets.
Elemental analyses were measured with a precision
>0.3% at the Microanalysis Laboratories of P. & M.
Curie (Paris) and Burgundy Universities (Dijon). The
X-ray structures were determined on a CAD4 Enraf-
Nonius diffractometer at the P. & M. Curie University
(Paris).
overall yields up to 85% from
L-serine. In addition,
even though the hydrolysis of the i-propyl ester gave
the corresponding phosphonium salts bearing a free
acid function with a partial racemization, these com-
pounds can be obtained in high yields by the reaction
of the oxazoline sodium salts (prepared by saponifica-
tion of the ester) with TMSX, and subsequent quater-
nization of triphenylphosphine. The efficiency of this
synthesis was demonstrated by the preparation of phos-
phonium salts in excellent overall yields, in a one-pot
procedure starting from the corresponding oxazoline.
4. Experimental
4.1. General
All reactions were carried out under an argon atmo-
sphere in dried glassware. Solvents were dried and
freshly distilled under a nitrogen atmosphere. In partic-
ular, THF, diethyl ether, toluene and benzene, were
distilled over sodium/benzophenone, CH2Cl2 over P2O5,
hexane over calcium hydride and methanol, ethanol
and isopropanol over sodium alcoholate. The reactions
were carried out with chloroform stabilized with
amylene. Chromatographic grade hexane and iso-
propanol were used without further purification for
HPLC. Commercially available allyl and benzyl alco-
4.2. Typical procedure for oxazolines 2
A round-bottomed flask equipped with a magnetic stir-
rer and a reflux condenser was charged with L-serinate
hydrochloride 1a–d (10 mmol), chloroform (50 mL) and
triethylamine (11 mmol). The mixture was stirred at
room temperature until dissolution. Phenyl imino ethyl
ether hydrochloride (10 mmol) was then added and the
mixture refluxed for 24 h. The solvent was evaporated
and triethylamine hydrochloride precipitated in ether
and filtered. After removal of the solvent, the residue
was purified by chromatography on silica gel with
c-Hex/AcOEt (3:1) as the eluent. The enantiomeric
hols were distilled before use, whereas
-serine benzyl ester hydrochloride 1d were used with-
L-serine and
L
out further purification. Trimethylsilyl bromide and
iodide were used without purification if colorless. The
phenyl imino ethyl ether hydrochloride18 was prepared
by bubbling HCl gas into a solution of benzonitrile
with ethanol. The
L-serine ester hydrochlorides were

F. Meyer et al. / Tetrahedron: Asymmetry 14 (2003) 2229–2238
2233
purity was checked by HPLC analysis on a Chiralcel
OK Daicel column, (flow rate 1 mL min−1; u=254 nm),
by comparison with a racemic sample.
131.7 (C arom.), 131.4 (CHꢀCH2), 128.4, 128.2 (C
arom.), 118.8 (CHꢀCH2), 69.4 (CH2O), 68.5 (CH), 66.1
(CO2CH2); Anal. calcd for C13H13NO3: C, 67.52; H,
5.66; N, 6.06; found: C, 67.54; H, 5.72; N, 6.00; HRMS
(DCI, CH4) anal. calcd for C13H14NO3 [M+H+]:
232.0974; found: 232.0971. HPLC (eluent: hexane/i-
PrOH 9:1): (S)-2c tR=40 min; (R)-enantiomer tR=50
min.
4.2.1. (S)-(+)-2-Phenyl-4-methoxycarbonyl-2-oxazoline
2a18,19. Colorless solid; 80% yield; mp <40°C; Rf: 0.35
(c-Hex/AcOEt 1:1); IR (KBr, cm−1): 2953, 1742, 1642,
1
1210; H NMR (250 MHz, CDCl3) l 7.99 (2H, d, J=8,
H arom.), 7.43–7.33 (3H, m, H arom.), 4.88 (1H, dd,
J=8, J=11, CHN), 4.65 (1H, t, J=9, CHH), 4.52 (2H,
dd, J=9, J=11, CHH), 3.76 (3H, s, CH3); 13C NMR
(62.5 MHz, CDCl3) l 171.5 (CO2Me), 166.1 (CꢀN),
131.8, 128.5, 128.3, 127.0 (C arom.), 69.5 (CH2), 68.6
(CHN), 52.5 (CH3). HPLC (eluent: hexane/i-PrOH
9:1): (S)-2a tR=57 min; (R)-enantiomer tR=64 min.
4.2.4. (S)-(+)-2-Phenyl-4-benzyloxycarbonyl-2-oxazoline
2d22. Colorless solid; 96% yield; mp <40°C; Rf: 0.5
(c-Hex/AcOEt 3:1); [h]2D0=+94.7 (c 1, CHCl3); IR (KBr,
cm−1): 2923, 1723, 1639, 1194; 1H NMR (250 MHz,
CDCl3) l 8.00 (2H, d, J=8, H arom.), 7.53–7.31 (8H,
m, H arom.), 5.28 (1H, d, J=12, CH2Ph), 5.22 (1H, d,
J=12, CH2Ph), 4.96 (1H, dd, J=8, J=11, CH), 4.60
(2H, m, CH2); 13C NMR (62.5 MHz, CDCl3) l 170.8
(CO2Bn), 166.3 (CꢀN), 135.2, 131.7, 128.4, 127.3, 126.7
(C arom.), 69.2 (CH2Ph), 68.2 (CH), 66.8 (CH2); Anal.
calcd for C17H15NO3: C, 72.58; H, 5.37; N, 4.98; found:
C, 72.42; H, 5.35; N, 4.99.
Crystal data:20 Orthorhombic; a (A)=7.409(5); b (A)=
,
,
,
7.432(3); c (A)=19.268(1); h (°)=90; i (°)=90; k (°)=
3
,
90; V (A )=1063 (1); Z=4; space group: P212121;
crystal shape: parallelepiped; crystal colour: colourless;
linear absorption coefficient v (cm−1): 0.94; density z (g
cm3): 1.285; diffractometer: CAD4 Enraf-Nonius: radi-
ation Mo Ka (u=0.71069 A); scan type ꢀ/2q; scan
4.3. Preparation of the oxazoline sodium salt 2%23
,
range (°): 0.8+0.345 tgq; q limits (°) 1–30; temperature
of measurement: room temperature; octants collected:
0, 10; 0, 10; 0, 27; number of data collected: 1818;
number of unique data used for refinement: 934 (Fo)2
>3|(Fo)2: decay of standards reflections (%) <1; R=
Oxazoline 2a (8.15 g, 39 mmol) was stirred at rt in a 2
M solution of NaOH (19.5 mL) for 3 h. Water (3 mL)
was then added and the mixture poured into acetone
(200 mL) to precipitate the salt. After filtration and
2 1/2
1
ꢀꢁꢁFoꢁ−ꢁFcꢁꢁ/ꢀꢁFoꢁ 0.0434; Rw*=[ꢀw(ꢁꢁFoꢁ−ꢁFcꢁꢁ)2/ꢀwFo ]
drying, 8.3 g of the salt was recovered (yield 99%). H
0.0466; absorption correction: none; secondary extinc-
NMR (250 MHz, D2O) l 7.77 (2H, d, J=7, H arom.),
7.53–7.36 (3H, m, H arom.), 4.57 (2H, m, CH2), 4.37
(1H, t, J=8, CH); 13C NMR (62.5 MHz, D2O) l 176.7
(CO2Na), 166.1 (CꢀN), 133.6, 132.5, 129.1, 127.5 (C
arom.), 62.4 (CH2), 58.1 (CH).
tion coefficient 212.58; goodness-of-fit 1.117; number of
−3
−3
,
,
variables 137; Dzmin (e A ) −0.167; Dzmax (e A )
0.158.
* Weighting scheme of form w=w%{1−[(ꢁꢁFoꢁ−ꢁFcꢁꢁ)/
6|(Fo)]2}2 with w%=1/ꢀrArTr(X) with coefficients 16.9,
−20.4, 17.0, −7.43 and 2.52 for the Chebyshev series for
which X=Fc/Fc(max).
4.4. Typical procedure for b-iodo or -bromo a-amino
esters
Oxazoline (4.9 mmol) and TMSX (7.3 mmol) were
stirred in chloroform24 (15 mL) at room temperature
for 48 h. The solvent was then evaporated and the
residue recrystallized in hexane/benzene. The enan-
tiomeric purity was checked by HPLC analysis on a
Chiralcel OK Daicel column, (flow rate 1 mL min−1;
u=254 nm), by comparison with a racemic sample.
4.2.2. (S)-(+)-2-Phenyl-4-isopropyloxycarbonyl-2-oxazo-
line 2b21. Colorless solid; 90% yield; mp <40°C; Rf: 0.5
(c-Hex/AcOEt 2:1); [h]2D2=+130 (c 2, CHCl3); IR (KBr,
cm−1): 2953, 1730, 1630, 1205, 1090, 695; 1H NMR (250
MHz, CDCl3) l 7.96 (2H, m, H arom.), 7.46–7.34 (3H,
m, H arom.), 5.08 (1H, spt, J=6, CH(CH3)2), 4.86 (1H,
dd, J=8, J=11, CHCH2), 4.57 (2H, t, J=9, CHCH2),
1.29 (3H, d, J=6, CH3), 1.25 (3H, d, J=6, CH3); 13C
NMR (62.5 MHz, CDCl3) l 170.4 (CO2iPr), 165.8
(CꢀN), 131.4, 128.3, 128.0, 126.7 (C arom.), 69.3
(CH2), 68.9 (CH(CH3)2), 68.6 (CHN), 21.4 (CH3).
HPLC (eluent: hexane/i-PrOH 95:5): (S)-2b tR=30
min; (R)-enantiomer tR=35 min.
4.4.1. (R)-(+)-Methyl-2-benzamido-3-iodopropanoate 3a.
White solid; mp=134°C; [h]2D0=+59 (c 1, CHCl3); IR
(KBr, cm−1): 3294, 1735, 1643, 1528, 698; 1H NMR
(250 MHz, CDCl3) l 7.84 (2H, dd, J=2, J=7, H
arom.), 7.56–7.45 (3H, m, H arom.), 6.95 (1H, d, J=7,
NH), 5.00 (1H, td, J=4, J=7, CH), 3.86 (3H, s, CH3),
3.73 (2H, 2dd, J=4, J=10, CH2I); 13C NMR (62.5
MHz, CDCl3) l 169.7(COPh), 167.1 (CO2Me), 133.3,
132.6, 128.7, 127.0 (C arom.), 53.2 (CH3), 52.6 (CH),
7.4 (CH2I); Anal. calcd for C11H12INO3: C, 39.66; H,
3.63; N, 4.20; found: C, 39.72; H, 3.66; N, 4.14. HPLC
(eluent: hexane/i-PrOH 9:1): (R)-3a tR=57 min; (S)-
enantiomer tR=62 min.
4.2.3. (S)-(+)-2-Phenyl-4-allyloxycarbonyl-2-oxazoline
2c. Colorless solid; 94% yield; mp <40°C; Rf: 0.4 (c-
Hex/AcOEt 3:1); [h]D20=+124 (c 1, CHCl3); IR (KBr,
cm−1): 3140, 1733, 1652, 1635, 692; 1H NMR (250
MHz, CDCl3) l 7.97 (2H, m, H arom.), 7.50–7.35 (3H,
m, H arom.), 5.93 (1H, m, CHꢀCH2), 5.33 (1H, ddd,
J=1, J=3, J=17, CHꢀCHH), 5.23 (1H, ddd, J=1,
J=2, J=10, CHꢀCHH), 4.99 (1H, dd, J=9, J=11,
CHCH2), 4.72 (4H, m, CH2O, CO2CH2); 13C NMR
(62.5 MHz, CDCl3) l 170.7 (CO2Allyl), 166.2 (CꢀN),
4.4.2. (R)-(+)-Isopropyl-2-benzamido-3-iodopropanoate
3b. White solid; mp=110–111°C; [h]2D0=+35.6 (c 1,
CHCl3); IR (KBr, cm−1): 3294, 1751, 1652, 1521, 750;

2234
F. Meyer et al. / Tetrahedron: Asymmetry 14 (2003) 2229–2238
1H NMR (250 MHz, CDCl3) l 7.80 (2H, m, H arom.),
7.52–7.37 (3H, m, H arom.), 7.05 (1H, d, J=7, NH),
5.09 (1H, spt, J=6, CH(CH3)2), 4.86 (1H, td, J=3,
J=7, CH2CH), 3.68 (2H, 2dd, J=4, J=10, CH2I), 1.30
(3H, d, J=7, CH3), 1.24 (3H, d, J=7, CH3); 13C NMR
(62.5 MHz, CDCl3) l 168.7 (COPh), 166.6 (CO2iPr),
133.3, 131.8, 128.4, 127.0 (C arom.), 70.3 (CH(CH3)2),
52.4 (CH), 21.6 (CH3), 21.5 (CH3), 7.7 (CH2I); Anal.
calcd for C13H16INO3: C, 43.23; H, 4.46; N, 3.88;
found: C, 43.35; H, 4.64; N, 3.71; HRMS (DCI, CH4)
anal. calcd for C13H17INO3 [M+H+]: 362.0253; found:
362.0255. HPLC (eluent: hexane/i-PrOH 95:5): (R)-3b
tR=31 min; (S)-enantiomer tR=35 min.
4.4.6. (R)-(+)-Allyl-2-benzamido-3-bromopropanoate 3f.
White solid; mp=94°C; [h]2D0=+50.7 (c 1, CHCl3); IR
(KBr, cm−1): 3320, 3140, 1733, 1652, 1539, 698; 1H
NMR (250 MHz, CDCl3) l 7.81 (2H, m, H arom.),
7.51–7.39 (3H, m, H arom.), 7.09 (1H, d, J=7, NH),
5.91 (1H, m, CHꢀCH2), 5.36 (1H, dd, J=1, J=17,
CHꢀCHH), 5.27 (1H, d, J=10, CHꢀCHH), 5.21 (1H,
td, J=3, J=7, CH2CH), 4.70 (2H, m, CH2), 3.90 (2H,
d, J=3.5, CH2Br); 13C NMR (62.5 MHz, CDCl3) l
168.7 (COPh), 166.9 (CO2Allyl), 133.3, 132.0 (C
arom.), 131.0 (CHꢀCH2), 128.6, 127.1 (C arom.), 119.3
(CHꢀCH2), 66.8 (CH2), 52.9 (CH), 33.6 (CH2Br);
Anal. calcd for C13H14BrNO3: C, 50.02; H, 4.52; N,
4.49; found: C, 50.13; H, 4.65; N, 4.41; HRMS (DCI,
CH4) anal. calcd for C13H15BrNO3 [M+H+]: 312.0235;
found: 312.0232. HPLC (eluent: hexane/i-PrOH 9:1):
(R)-3f tR=40 min; (S)-enantiomer tR=42 min.
4.4.3. (R)-(+)-Allyl-2-benzamido-3-iodopropanoate 3c.
White solid; mp=104°C; [h]2D0=+31.9 (c 1, CHCl3); IR
(KBr, cm−1): 3338, 3230, 1733, 1652, 1539, 698; 1H
NMR (250 MHz, CDCl3) l 7.83 (2H, dd, J=2, J=7, H
arom.), 7.54–7.43 (3H, m, H arom.), 7.00 (1H, d, J=6,
NH), 5.95 (1H, m, CHꢀCH2), 5.39 (1H, dd, J=1,
J=17, CHꢀCHH), 5.30 (1H, dd, J=1, J=10,
CHꢀCHH), 4.98 (1H, td, J=4, J=7, CH), 4.73 (2H,
m, CH2CH), 3.73 (2H, 2dd, J=4, J=8, CH2I); 13C
NMR (62.5 MHz, CDCl3) l 170.7 (COPh), 166.2
(CO2Allyl), 133.2, 132.0 (C arom.), 131.0 (CHꢀCH2),
128.6, 127.1 (C arom.), 119.5 (CHꢀCH2), 66.9 (CH2),
52.6 (CH), 7.4 (CH2I); Anal. calcd for C13H14INO3: C,
43.47; H, 3.93; N, 3.90; found: C, 43.42; H, 4.05; N,
3.73; HRMS (DCI, CH4) anal. calcd for C13H15INO3
[M+H+]: 360.0097; found: 360.0098. HPLC (eluent:
hexane/i-PrOH 9:1): (R)-3c tR=44 min; (S)-enantiomer
tR=48 min.
4.4.7. (R)-(+)-Benzyl-2-benzamido-3-bromopropanoate
3g. White solid; mp=98°C; [h]2D0=+34.8 (c 1, CHCl3);
1
IR (KBr, cm−1): 3307, 1744, 1638, 1524, 697; H NMR
(250 MHz, CDCl3) l 7.71 (2H, d, J=7, H arom.),
7.42–7.24 (8H, m, H arom.), 7.04 (1H, d, J=7, NH),
5.30 (1H, d, J=12, CHHPh), 5.25 (1H, d, J=12,
CHHPh), 5.25 (1H, m, CH), 3.93 (2H, 2dd, J=3,
J=11, CH2Br); 13C NMR (62.5 MHz, CDCl3) l 168.8
(COPh), 166.8 (CO2Bn), 134.6, 133.2, 131.8, 128.5,
127.0 (C arom.), 67.9 (CH2Ph), 53.0 (CH), 33.4
(CH2Br); Anal. calcd for C17H16BrNO3: C, 56.37; H,
4.45; N, 3.87; found: C, 56.39; H, 4.39; N, 3.81; HRMS
(DCI, CH4) anal. calcd for C17H17BrNO3 [M+H+]:
362.0391; found: 362.0381.
4.4.4. (R)-(+)-Benzyl-2-benzamido-3-iodopropanoate 3d.
White solid; mp=97°C; Rf: 0.55 (c-Hex/AcOEt 3:1);
[h]2D0=+19.7 (c 1, CHCl3); IR (KBr, cm−1): 3309, 1752,
4.5. (R)-(+)-Benzyl-2-benzamido-3-chloropropanoate 3h
Under an inert atmosphere, oxazoline benzyl ester (1
mmol) and TMSCl (4 mmol) were stirred in refluxing
THF (15 mL) for 15 h. The solvent was then evapo-
rated and the residue recrystallized in hexane/benzene.
White solid; mp=108°C; [h]2D0=+52.1 (c 1, CHCl3); IR
(KBr, cm−1): 3286, 1748, 1639, 1524, 693; 1H NMR
(250 MHz, CDCl3) l 7.83 (2H, d, J=7, H arom.),
7.58–7.38 (8H, m, H arom.), 7.07 (1H, d, J=6, NH),
5.29 (2H, s, CH2Ph), 5.25 (1H, td, J=3, J=7, CH),
4.07 (2H, 2dd, J=3, J=11, CH2Cl); 13C NMR (62.5
MHz, CDCl3) l 168.8 (COPh), 167.0 (CO2Bn), 134.7,
133.3, 132.0, 128.6, 127.1 (C arom.), 68.0 (CH2Ph), 53.5
(CH) 45.1 (CH2Cl); Anal. calcd for C17H16ClNO3: C,
64.26; H, 5.07; N, 4.41; found: C, 64.17; H, 5.08; N,
4.46; HRMS (EI) anal. calcd for C17H16ClNO3 [M+]:
317.0818; found: 317.0822.
1
1642, 1523, 697; H NMR (250 MHz, CDCl3) l 7.82
(2H, dd, J=7, H arom.), 7.51–7.34 (8H, m, H arom.),
7.02 (1H, d, J=7, NH), 5.27 (1H, d, J=12, CHHPh),
5.22 (1H, d, J=12, CHHPh), 5.00 (1H, td, J=4, J=7,
CH), 3.70 (2H, 2dd, J=4, J=10, CH2I); 13C NMR
(62.5 MHz, CDCl3) l 169.3 (COPh), 166.7 (CO2Bn),
134.6, 133.3, 131.9, 128.6, 127.1 (C arom.), 68.1
(CH2Ph), 52.6 (CH), 7.3 (CH2I); Anal. calcd for
C17H16INO3: C, 49.90; H, 3.94; N, 3.42; found: C,
50.07; H, 3.96; N, 3.33; HRMS (EI) anal. calcd for
C17H16INO3 [M+]: 409.0174; found: 409.0177.
4.4.5. (R)-(+)-Isopropyl-2-benzamido-3-bromopropanoate
3e. White solid; mp=97°C; [h]2D0=+57.6 (c 1, CHCl3);
1
IR (KBr, cm−1): 3307, 1751, 1652, 1521, 750; H NMR
(250 MHz, CDCl3) l 7.80 (2H, m, H arom.), 7.48–7.36
(3H, m, H arom.), 7.10 (1H, d, J=7, NH), 5.10 (2H, m,
CH(CH3)2, CH2CH), 3.93 (2H, d, J=13, CH2Br), 1.28
(3H, d, J=6, CH3), 1.24 (3H, d, J=6, CH3); 13C NMR
(62.5 MHz, CDCl3) l 168.0 (COPh), 166.6 (CO2iPr),
133.0, 131.4, 128.1, 126.8 (C arom.), 69.8 (CH(CH3)2),
52.8 (CH2CH) 33.3 (CH2Br), 21.3 (CH(CH3)2); Anal.
calcd for C13H16BrNO3: C, 49.70; H, 5.13; N, 4.46;
found: C, 49.61; H, 5.11; N, 4.30; HRMS (DCI, CH4)
anal. calcd for C13H17BrNO3 [M+H+]: 314.0391; found:
314.0389. HPLC (eluent: hexane/i-PrOH 95:5): (R)-3e
tR=29 min; (S)-enantiomer tR=31 min.
4.6. Typical procedure for the b-halogeno-a-amino
acid25
Water (510 mL, 28.2 mmol) and halogenotrimethylsi-
lane (28.2 mmol) were added to a suspension of oxazo-
line sodium salt 2% (2 g, 9.4 mmol) in CHCl3 (30 mL).23
In the case of TMSBr or TMSI, the mixture was stirred
at room temperature for 48 h. For TMSCl, the mixture
was heated for 20 h. The solvent was then removed
under vacuum and the residue triturated with acetone.
After removal of the sodium salt by filtration, acetone

F. Meyer et al. / Tetrahedron: Asymmetry 14 (2003) 2229–2238
2235
was evaporated. The b-halogeno-a-amino acid was
obtained as a mixture with a small quantity of sodium
salt (<10%), but it was used without further
purification.
31P NMR (101 MHz, CDCl3) l +22.2; Anal. calcd for
C29H27INO3P: C, 58.50; H, 4.57; N, 2.35; found: C,
57.56; H, 4.86; N, 2.22; HRMS (FAB, MB) anal. calcd
for C29H27NO3P [M+−I]: 468.1728; found: 468.1739.
4.6.1. (R)-2-Benzamido-3-iodopropanoic acid 3i. White
solid; mp=127°C; IR (KBr, cm−1): 3366, 1714, 1631,
1198, 712; H NMR (250 MHz, acetone-d6) l 8.00 (3H,
The enantiomeric purity of this phosphonium salt was
checked by NMR using BINPHAT anion as the chiral
reagent.15
1
m, NH, H arom.), 7.64–7.42 (3H, m, H arom.), 4.95
(1H, td, J=5, J=7, CH), 3.85 (2H, 2dd, J=5, J=11,
CH2I); 13C NMR (62.5 MHz, acetone-d6) l 171.2
(COPh), 168.1 (CO2H), 135.4, 133.2, 130.0, 128.9 (C
arom.), 55.6 (CH), 6.6 (CH2I); HRMS (FAB, MB)
anal. calcd for C10H11INO3 [M+H+]: 319.9783; found:
319.9771.
4.7.2.
(R)-(−)-(2-Benzamido-2-isopropyloxycarbonyl)
ethyltriphenylphosphonium iodide 4b. White solid; mp=
160°C; [h]2D0=−23.9 (c 1, CHCl3); IR (KBr, cm−1): 3412,
1733, 1652, 1103, 724; H NMR (250 MHz, CDCl3) l
1
8.90 (1H, d, J=9, NH), 7.89–7.32 (20H, m, H arom.),
5.33 (1H, dd, J=3, J=10, CHHP), 5.15 (1H, ddd,
J=10.5, J=15, J=20, CHHP), 4.99 (1H, spt, J=6,
CH(CH3)2), 3.94 (1H, ddd, J=2, J=13, J=16, CH),
1.23 (3H, d, J=6, CH(CH3)2), 1.15 (3H, d, J=6,
CH(CH3)2); 13C NMR (62.5 MHz, CDCl3) l 169.4 (d,
J=15, CO2iPr), 167.2 (COPh), 134.8, 133.8, 133.7,
131.8, 131.7, 130.2, 130.0, 127.9, 127.8, 118.3, 116.9 (C
arom.), 70.9 (CH(CH3)2), 47.4 (CH), 25.0 (d, J=50,
CH2P), 21.5 (CH3), 21.4 (CH3); 31P NMR (101 MHz,
CDCl3) l +22.8; Anal. calcd for C31H31INO3P: C,
59.72; H, 5.01; N, 2.25; found: C, 59.88; H, 4.83; N,
2.18; HRMS (FAB, MB) anal. calcd for C31H31NO3P
[M+−I]: 496.2041; found: 496.2054.
4.6.2. (R)-2-Benzamido-3-bromopropanoic acid 3j. White
solid; mp=106°C; IR (KBr, cm−1): 3378, 3285, 1717,
1
1635, 719; H NMR (250 MHz, acetone-d6) l 7.97 (2H,
dd, J=3, J=5, H arom.), 7.53 (3H, m, H arom.), 5.11
(1H, t, J=5, CH), 4.02 (2H, d, J=4, CH2Br); 13C
NMR (62.5 MHz, acetone-d6) l 171.1 (COPh), 168.5
(CO2H), 135.0, 133.2, 130.2, 129.0 (C arom.), 55.2
(CH), 33.8 (CH2Br); HRMS (FAB, MB) anal. calcd for
C10H11BrNO3 [M+H+]: 271.9922; found: 271.9916.
4.6.3. (R)-2-Benzamido-3-chloropropanoic acid 3k.
White solid; mp=113°C; IR (KBr, cm−1): 3378, 3285,
1717, 1635, 719; 1H NMR (250 MHz, acetone-d6) l
7.97 (2H, d, H arom.), 7.58–7.46 (3H, m, H arom.),
5.12 (1H, t, J=5, CH), 4.16 (2H, d, J=5, CH2Cl); 13C
NMR (62.5 MHz, acetone-d6) l 171.1 (COPh), 168.4
(CO2H), 135.3, 133.3, 130.0, 128.9 (C arom.), 55.5
(CH), 45.8 (CH2Cl); HRMS (FAB, MB) anal. calcd for
C10H11BrNO3 [M+H+]: 228.0427; found: 228.0425.
4.7.3.
(R)-(−)-(2-Allyloxycarbonyl-2-benzamido)ethyl
triphenylphosphonium iodide 4c. White solid; mp=
137°C; [h]2D0=−26.2 (c 1, CHCl3); IR (KBr, cm−1): 3305,
1
1751, 1652, 1436, 688; H NMR (250 MHz, CDCl3) l
8.9 (1H, d, J=9, NH), 7.89–7.34 (20H, m, H arom.),
5.83 (1H, m, CHꢀCH2), 5.40 (1H, dd, J=2, J=11,
CHHP), 5.27 (1H, m, CHHP), 5.23 (1H, ddd, J=1,
J=3, J=17, CHꢀCHH), 5.13 (1H, dd, J=1, J=11,
CHꢀCHH), 4.60 (2H, ddd, J=1, J=2, J=5, CH2),
3.96 (1H, ddd, J=2, J=13, J=16, CH); 13C NMR
(62.5 MHz, CDCl3) l 169.3 (d, J=16, CO2Allyl), 167.0
(COPh), 134.8, 133.3, 133.4, 131.6, 131.4, (C arom.),
130.8 (CHꢀCH2), 130.1, 129.9, 127.9, 127.7, 117.7,
116.4 (C arom.), 118.5 (CHꢀCH2), 66.8 (CH2), 46.9
(CH), 24.7 (d, J=54, CH2P); 31P NMR (101 MHz,
CDCl3) l +22.9; Anal. calcd for C31H29INO3P: C,
59.91; H, 4.70; N, 2.25; found: C, 59.43; H, 4.79; N,
2.00; HRMS (FAB, MB) anal. calcd for C31H29NO3P
[M+−I]: 494.1885; found: 494.1880.
The enantiomeric purity of 3k was determined from its
methyl ester derivative prepared by reaction with
CH2N2: [h]2D0=−13.5 (c 1, EtOH); lit.16a [h]2D0=−14
(EtOH), lit.16b [h]2D0=−12.9 (EtOH).
4.7. Typical procedure for the preparation of amino
ester phosphonium salts
Under an inert atmosphere, b-halogeno amino ester
(4.26 mmol) and triphenylphosphine (10.1 mmol) were
stirred in refluxing chloroform24 (50 mL) for 48 h. The
solvent was then evaporated and the residue triturated
in ether (100 mL) to precipitate the phosphonium salt,
which was recovered by filtration.
4.7.4. (R)-(−)-(2-Benzamido-2-benzyloxycarbonyl)ethyl
triphenylphosphonium iodide 4d. White solid; mp=165–
167°C; [h]2D0=−13 (c 1, CHCl3); IR (KBr, cm−1): 3250,
1
1738, 1651, 1438, 688; H NMR (250 MHz, CDCl3) l
4.7.1.
(R)-(−)-(2-Benzamido-2-methoxycarbonyl)ethyl
8.94 (1H, d, J=9, NH), 7.88–7.23 (25H, m, H arom.),
5.42 (1H, dd, J=3, J=10, CHHP), 5.27 (1H, dd,
J=11, J=15, CHHP), 5.15 (2H, s, CH2Ph), 3.99 (1H,
ddd, J=3, J=13, J=16, CH); 13C NMR (62.5 MHz,
CDCl3) l 169.6 (d, J=15, CO2Bn), 167.2 (COPh),
134.9, 134.8, 134.7, 133.7, 133.6, 131.9, 131.7, 131.6,
130.2, 130.0, 128.2, 128.0, 127.9, 118.0, 116.6 (C arom.),
68.2 (CH2Ph), 47.3 (CH), 24.9 (d, J=55, CH2P); 31P
NMR (101 MHz, CDCl3) l +22.6; Anal. calcd for
C35H31INO3P: C, 62.60; H, 4.66; N, 2.09; found: C,
62.69; H, 4.77; N, 2.00; HRMS (FAB, MB) anal. calcd
for C35H31NO3P [M+−I]: 544.2041; found: 544.2026.
triphenylphosphonium iodide 4a. White solid; mp=
178°C; [h]2D0=−33.3 (c 1, CHCl3); IR (KBr, cm−1): 3412,
1740, 1654, 1109, 724; H NMR (250 MHz, CDCl3) l
1
8.90 (1H, d, J=9, NH), 7.90–7.34 (20H, m, H arom.),
5.33 (1H, ddd, J=3, J=11, J=11, CHHP), 5.07 (1H,
ddd, J=11, J=16, J=22 CHHP), 3.90 (1H, ddd, J=3,
J=13, J=16, CH), 3.60 (3H, s, CH3); 13C NMR (62.5
MHz, CDCl3) l 169.9 (d, J=16, CO2Me), 166.7
(COPh), 134.7, 133.4, 133.2, 131.7, 131.6, 131.5, 131.4,
131.2, 130.0, 129.8, 128.2, 128.0, 127.7, 117.5, 116.1 (C
arom.), 53.1 (CH3), 46.5 (CH), 24.7 (d, J=55, CH2P);

2236
F. Meyer et al. / Tetrahedron: Asymmetry 14 (2003) 2229–2238
4.7.5.
(R)-(−)-(2-Benzamido-2-isopropyloxycarbonyl)
4.9. Preparation of the amino acid phosphonium salts
ethyltriphenylphosphonium bromide 4e. White solid;
mp=187°C; [h]D20=−28 (c 1, CHCl3); IR (KBr, cm−1):
3412, 1747, 1652, 1109, 724; 1H NMR (250 MHz,
CDCl3) l 9.44 (1H, d, J=7, NH), 7.90–7.32 (20H, m,
H arom.), 5.35 (2H, m, CH2P), 4.98 (1H, spt, J=6,
CH(CH3)2), 3.88 (1H, m, CH), 1.24 (3H, d, J=6,
CH(CH3)2), 1.15 (3H, d, J=6, CH(CH3)2); 13C NMR
(62.5 MHz, CDCl3) l 169.7 (d, J=16, CO2iPr), 167.2
(COPh), 134.8, 134.0, 133.8, 132.1, 131.6, 130.2, 130.0,
128, 127.9, 118.4, 117.0 (C arom.), 70.9 (CH(CH3)2),
47.4 (CH), 24.7 (d, J=55, CH2P), 21.6 (CH3), 21.5
(CH3); 31P NMR (101 MHz, CDCl3) l +22.9; Anal.
calcd for C31H31BrNO3P: C, 64.59; H, 5.42; N, 2.43;
found: C, 64.13; H, 5.51; N, 2.17; HRMS (FAB, MB)
anal. calcd for C31H31NO3P [M+−Br]: 496.2041; found:
496.2045.
4.9.1. By quaternization of triphenylphosphine with a
b-halogeno amino acid. Triphenylphosphine (1.05 g, 4
mmol) was added to either b-iodo (1.6 mmol) or b-
bromo amino acid (1.6 mmol) in CHCl3 (35 mL).24 The
mixture was heated under reflux for 48 h. with some of
the phosphonium salt being recovered by filtration. The
filtrate was then evaporated and the residue stirred in
ether in order to precipitate the phosphonium salt and
to extract the phosphine excess. The combined precipi-
tates gave a white powder in 95% yield.
4.9.1.1.
(R)-(−)-(2-Benzamido-2-carboxyl)ethyltri-
phenyl phosphonium iodide 4i. White solid; mp=195°C;
[h]2D0=−42 (c 1, MeOH); IR (KBr, cm−1): 3413, 2925,
1
1741, 1624, 1439, 746; H NMR (250 MHz, CD3OD) l
4.7.6.
(R)-(−)-(2-Allyloxycarbonyl-2-benzamido)ethyl
7.84–7.30 (20H, m, H arom.), 5.02 (1H, ddd, J=3,
J=11, J=13, CH), 4.22 (1H, ddd, J=3, J=14, J=17,
CHHP), 3.97 (1H, ddd, J=11, J=16, J=22, CHHP);
13C NMR (62.5 MHz, CD3OD) l 172.1 (d, J=15,
CO2H), 169.7 (COPh), 136.4, 136.3, 135.0, 134.9, 133.8,
133.3, 131.6, 131.4, 129.3, 128.4, 119.9, 118.5 (C arom.),
48.4 (CH), 25.6 (d, J=55, CH2P); 31P NMR (101 MHz,
CD3OD) l +22.3; Anal. calcd for C28H25INO3P: C,
57.85; H, 4.33; N, 2.41; found: C, 57.99; H, 4.36; N,
2.29; HRMS (FAB, MB) anal. calcd for C28H25NO3P
[M+−I]: 454.1572; found: 454.1582.
triphenylphosphonium bromide 4f. White solid; mp=
151°C; [h]2D0=−23.9 (c 1, CHCl3); IR (KBr, cm−1): 3305,
1750, 1652, 1436, 689; H NMR (250 MHz, CDCl3) l
1
8.53 (1H, d, J=9, NH), 7.92–7.28 (20H, m, H arom.),
5.80 (1H, m, CHꢀCH2), 5.54–5.32 (2H, m, CH2P), 5.24
(1H, ddd, J=1, J=3, J=17, CHꢀCHH), 5.14 (1H,
ddd, J=1, J=3, J=11, CHꢀCHH), 4.60 (2H, ddd,
J=1, J=3, J=6, CH2), 3.88 (1H, ddd, J=2, J=13,
J=15, CH); 13C NMR (62.5 MHz, CDCl3) l 169.8 (d,
J=16, CO2Allyl), 167.1 (COPh), 134.8, 133.8, 133.6,
131.8, 131.6 (C arom.), 131.0 (CHꢀCH2), 130.2, 130.0,
127.9, 127.8, 118.0, 116.6 (C arom.), 118.5 (CHꢀCH2),
66.9 (CH2), 47.1 (CH), 24.4 (d, J=55, CH2P); 31P
NMR (101 MHz, CDCl3) l +22.8; Anal. calcd for
C31H29BrNO3P: C, 64.82; H, 5.09; N, 2.44; found: C,
64.80; H, 5.29; N, 2.34; HRMS (FAB, MB) anal. calcd
for C31H29NO3P [M+−Br]: 494.1885; found: 494.1874.
The enantiomeric purity of this phosphonium salt was
checked by NMR using cinchonidine,7 or BINPHAT
anion as the chiral reagent.15
4.9.1.2.
(R)-(−)-(2-Benzamido-2-carboxyl)ethyltri-
phenyl phosphonium bromide 4j. White solid; mp=
135°C; [h]2D0=−37.4 (c 1, MeOH); IR (KBr, cm−1):
3413, 2904, 1741, 1623, 747; 1H NMR (250 MHz,
CD3OD) l 7.93–7.42 (20H, m, H arom.), 5.10 (1H,
ddd, J=3, J=10, J=13, CH), 4.32 (1H, ddd, J=3,
J=14, J=17, CHHP), 4.09 (1H, ddd, J=11, J=16,
J=22, CHHP); 13C NMR (62.5 MHz, CD3OD) l 172.9
(d, J=16, CO2H), 170.3 (COPh), 137.1, 135.8, 135.7,
135.3, 134.5, 134.1, 132.4, 132.2, 130.1, 129.3, 120.7,
119.3 (C arom.), 48.8 (CH), 26.31 (d, J=55, CH2P);
31P NMR (101 MHz, CD3OD) l +22.3; HRMS (FAB,
MB) anal. calcd for C28H25NO3P [M+−Br]: 454.1572;
found: 454.1560.
4.7.7. (R)-(−)-(2-Benzamido-2-benzyloxycarbonyl)ethyl
triphenylphosphonium bromide 4g. White solid; mp=
165°C; [h]2D0=−18.5 (c 1, CHCl3); IR (KBr, cm−1): 3420,
1
1741, 1652, 1438, 688; H NMR (250 MHz, CDCl3) l
9.48 (1H, d, J=8, NH), 7.85–7.18 (25H, m, H arom.),
5.38 (2H, m, CH2P), 5.10 (2H, s, CH2Ph), 3.84 (1H,
ddd, J=2, J=13, J=15, CH); 13C NMR (62.5 MHz,
CDCl3) l 169.8 (d, J=16, CO2Bn), 167.1 (COPh),
134.8, 134.2, 134.0, 133.8, 133.6, 131.8, 131.5, 130.2,
130.0, 128.7, 128.0, 127.9, 127.8, 118.0, 116.6 (C arom.),
68.0 (CH2Ph), 47.2 (CH), 24.5 (d, J=55, CH2P); 31P
NMR (101 MHz, CDCl3) l +22.9; Anal. calcd for
C35H31BrNO3P: C, 67.31; H, 5.00; N, 2.24; found: C,
66.41; H, 5.02; N, 2.12; HRMS (FAB, MB) anal. calcd
for C35H31NO3P [M+−Br]: 544.2041; found: 544.2032.
The enantiomeric purity of this phosphonium salt was
checked by 31P NMR using cinchonine as the chiral
reagent.7
4.8. Preparation of the amino ester phosphonium salt
4b by a one pot procedure from the oxazoline 2b
4.9.2. By hydrolysis of the (R)-(−)-(2-benzamido-2-iso-
propyloxycarbonyl)ethyltriphenylphosphonium salts. In
an aqueous solution of either HI or HBr (50 mL),
phosphonium salt 4b or 4e (1.6 mmol) was heated
under reflux for 24 h. After cooling, the phosphonium
salt 4i or 4j was precipitated and extracted with CHCl3.
After drying, the solvent was evaporated and the
residue stirred in ether in order to precipitate the phos-
phonium salt.
TMSI (1.5 equiv.) was added to a 0.3 M solution of
oxazoline 2 in CHCl3.24 The mixture was stirred at
room temperature for 48 h. A 0.3 M solution of
triphenylphosphine (2.5 equiv.) in CHCl3 was added
and the mixture was heated under reflux for 48 h. The
phosphonium salt 4b was recovered quantitatively using
a similar work-up as described in Section 4.7.

F. Meyer et al. / Tetrahedron: Asymmetry 14 (2003) 2229–2238
2237
The enantiomeric purity of the phosphonium salts was
determined by 31P NMR using cinchona alkaloid as the
chiral reagent:7 4i and 4j were obtained in 80 and 85%
e.e., respectively.
Duthaler, R. O. Tetrahedron 1994, 50, 1539–1650; (c)
Kulkarni, Y. S. Aldrichim. Acta 1999, 32, 18–27.
2. (a) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1244–1267; (b) Gante, J. Angew. Chem.,
Int. Ed. Engl. 1994, 32, 1699–1720; (c) Hannesian, S.;
McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W.
D. Tetrahedron 1997, 53, 12789–12854; (d) Gibson, S.
E.; Guillo, N.; Tozer, M. J. Tetrahedron 1999, 55, 585–
615.
3. (a) Bajgrowicz, J. A.; El Hallaoui, A.; Jacquier, R.;
Pigie`re, C.; Viallefont, P. Tetrahedron 1985, 41, 1833–
1843; (b) El Marini, A.; Roumestant, M. L.; Pap-
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4.10. Preparation of the amino acid phosphonium salts
by a one pot procedure from the oxazoline salt 2%
Water (3 equiv.) and TMSBr (or TMSI; 3 equiv.) were
added to a 0.4 M suspension of oxazoline sodium salt 2%
(1 equiv.) in CHCl3.24 The mixture was stirred at room
temperature for 48 h. A 0.2 M solution of triphenylphos-
phine (2.5 equiv.) in CHCl3 was then added and the
mixture was heated under reflux for 48 h. The phospho-
nium salts were recovered with a yield up to 80%, using
a similar work up as described in Section 4.9.1.
4.11. Preparation of 2-benzamido-4-phenyl-3-butenoic
acid 8 by a Wittig reaction using the amino acid phos-
phonium salt 4j
Phosphonium salt 4j (0.629 g, 1.18 mmol) was dissolved
in a THF/HMPA mixture (4 mL, 1:1) and the solution
was cooled to −70°C. An n-BuLi reagent (1.83 mL, 2.56
mmol) was added under stirring, and the mixture warmed
to room temperature for 1 h. Benzaldehyde (0.14 mL,
1.42 mmol) was then added and the mixture left for 15
h while stirring. After heating at reflux for one additional
hour, the mixture was then hydrolyzed with a 1 M HCl
solution (15 mL), and extracted 3 times with ether. The
combined extracts were washed with an HCl solution
then extracted 3 times with 10% NaHCO3. The aqueous
phase was acidified to pH 1, and extracted 3 times with
ether. The organic extracts were successively washed with
water and finally dried on MgSO4. The solvent was
removed under vacuum and the residue triturated with
chloroform to give 100 mg of the 2-benzamido-4-phenyl-
3-butenoic acid 8 ([h]D20=0 (c 1, 1 M NaOH); 30% yield).
White solid; mp=210°C (lit.26 mp=210–212°C); IR
(KBr, cm−1): 3284, 3057 1724, 1623, 1427; 1H NMR (250
MHz, DMSO) l 12.89 (1H, l, CO2H), 9.01 (1H, d J=7,
NH), 7.95 (2H, d, J=7, H arom), 7.60–7.26 (3H, m, H
arom), 6.76 (1H, d, J=16, CHꢀCHPh), 6.49 (1H, dd,
J=7, J=16, CHꢀCHPh), 5.18 (1H, t, J=4, CH); 13C
NMR (62.5 MHz, DMSO) l 171.8 (CO2H), 166.1
(COPh), 136.0, 133.7, 132.4, 131.0, 128.3, 126.4, 124.5
(CHꢀCHPh), 55.2(CH).
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Acknowledgements
14. Under the liquid chromatography conditions, the for-
mation of the oxazoline 2 from 3 was observed.
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We thank S. Hallut and P. Herson for the X-ray
crystallographic analyses. This work was supported by
the French Ministry of Research, the Burgundy Country
Council and the CNRS.
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24. The chloroform used was stabilized with amylene rather
than EtOH in order to avoid transesterification or the
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Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 209373. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:
44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
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